2012 report - Cambridge Institute for Medical Research

Transcription

School of Clinical Medicine
Cambridge Institute for Medical Research
Research Report 2012
Front cover illustration:
Crystal structure of the lysosomal enzyme galactocerebrosidase which, when
defective, causes widespread demyelination resulting in the fatal neurodegenerative
disorder Krabbe disease. The structure illustrates how the substrate-mimic
galactose binds in the active site. Figure modified from Deane et al. (2011)
Proc Natl Acad Sci USA.
University of Cambridge
Wellcome Trust/MRC Building
Hills Road
Cambridge CB2 0XY
www.cimr.cam.ac.uk
Photography by Media Studio, Cambridge University Hospitals NHS Foundation Trust
Print management by H2 Associates (Cambridge)
School of Clinical Medicine
Research Report 2012
Contents
4
Foreword by Paul Luzio
40 MRC Mitochondrial Biology Unit
6
CIMR Principal Investigators
7
Science in the Institute
7 Folma Buss
8 Janet Deane
9 Andres Floto
10 Bertie Göttgens
11 Tony Green
12 Fiona Gribble
13 Gillian Griffiths
14 James Huntington
15 Brian Huntly
16 Fiona Karet
17 Paul Lehner
18 David Lomas
19 Paul Luzio
20 Stefan Marciniak
21 Katrin Ottersbach
22 David Owen
23 Lucy Raymond
24 Randy Read
25 Evan Reid
26 Frank Reimann
27 Margaret Robinson
28 David Rubinsztein
29 Christopher Rudd
30 Peter St George-Hyslop
31 Matthew Seaman
32 Symeon Siniossoglou
33 Ken Smith
34 John Todd
35 The Juvenile Diabetes Research
Foundation/Wellcome Trust Diabetes
and Inflammation Laboratory
36 John Trowsdale
37 Linda Wicker
38 Geoff Woods
41 CIMR Affiliated Principal Investigators
41 Jenefer Blackwell
41 Damian Crowther
42 Sadaf Farooqi
42 Sergey Nejentsev
43 Stephen O’Rahilly
43 David Ron
44 Principal Investigators who will be moving
on from CIMR shortly
44 David Clayton
44 Andrew Peden
46 Postgraduate Opportunities in the Institute
47 CIMR Research Retreat 2011
48 Administration, IT and Technical Support
50 Funding of CIMR
52 NIHR Cambridge Biomedical Research
Centre core facilities supporting CIMR PIs
53 Other Information
57 Publications for Scientists in CIMR
since 2010
79 Regulations for CIMR
3
Foreword: Cambridge Institute for Medical Research
Paul Luzio
CIMR Director
Mark Dawson
Rhys Roberts
Wellcome-Beit Prize/
Wellcome Trust Intermediate
Clinical Fellows
4
The Cambridge Institute for Medical Research
(CIMR), which is housed in the Wellcome Trust/
MRC Building, is a cross-departmental institute
of the University of Cambridge Clinical School.
It provides a unique interface between basic
and clinical science, houses over 250 scientists
and has as its major goal, the determination and
understanding of the molecular mechanisms of
disease. Over 40% of our Principal Investigators
(PIs) are medically qualified and clinically active,
a percentage that has remained steady since
the CIMR opened in 1998. Our annual research
grant expenditure is now the third highest in the
University behind the Departments of Engineering and Physics (Cavendish Laboratory).
In the University’s financial year 2010–11 the
expenditure exceeded £21M, with about 60%
funded by the Wellcome Trust and 15% by the
MRC (see p 50).
Research in the CIMR is led by individual Principal Investigators (PIs) who determine their own
research priorities and follow their own instincts.
It is focussed on four research themes that
transcend individual research groups, namely
misfolded proteins and disease, intracellular
membrane traffic in health and disease, autoimmune disease and haematopoietic stem cells
and their disorders. In each of these themes,
there have been many recent discoveries and
advances that are referenced in this Research
Report on the pages of individual PIs. Examples
of activities that are further down the translational path to patient benefit include (i) the
introduction by Tony Green of the diagnostic
use of genetic mutations for frontline investigation of myeloproliferative disorders that are
now a central part of national and international
guidelines; (ii) Ken Smith’s identification and
use of novel transcription signatures to predict
prognosis in autoimmune disease; (iii) the
clinical safety trial of an autophagy-inducing
drug for Huntington’s disease following David
Rubinsztein’s pioneering studies of the activation of autophagy to clear mutant huntingtin in
cell and animal models of Huntington’s disease;
(iv) David Lomas’ high through-put screens to
identify small molecules to block serpin aggregation and so treat patients with serpinopathies
and (v) the interactions of Fiona Gribble and
Frank Reimann with pharmaceutical companies
to develop new therapies for type II diabetes.
Taken together our four research themes constitute a comprehensive approach to molecular
and cellular mechanisms of disease in which
there is clear ‘added value’ from the extensive
interactions between basic and clinical scientists
and across different themes.
A question that is increasingly asked about
research activities funded by major grant giving
bodies in Universities is how they fit with the
University’s overall research strategy. In a
recent submission to the Wellcome Trust, the
Heads of the Schools of Biological Sciences
and Clinical Medicine have pointed out that the
ability to attract outstanding biomedical scientists working on important problems increasingly
depends upon the establishment of ‘critical
mass’ and the provision of optimal research
infrastructure. Together, these have required
a change in strategic approach exemplified by
the establishment and development within the
University of cross-departmental, interdisciplinary institutes including the CIMR. There are
ten strategic research themes within the basic
biological and biomedical sciences that cross
the two Schools and the CIMR plays a major
role in two of these, Structural and Cell Biology
and its Application to Medicine, and Genomics
and its Application to Medicine. PIs in the CIMR
also make a significant contribution to four
other strategic themes, Infection and Immunity,
Neurosciences and Mental Health, Stem Cell
Biology and Medicine, and Systems Medicine.
The research activities in the CIMR are complementary to those in other research institutes and
departments of the University and NHS as well
as major research institutes in the Cambridge
area, with many of whom we have excellent
interactions. Through the activities and collaborations of individual PIs and often through
the placing of research students from PhD
programmes administered through the CIMR,
we have active interactions with the Wellcome
Trust Sanger Institute, the MRC-Laboratory of
Molecular Biology, the Babraham Institute, the
CRUK-Cambridge Research Institute, the MRC
Cancer Cell Biology Unit, the Wellcome Trust/
CRUK Gurdon Institute and the Wellcome Trust
Centre for Stem Cell Research. Within the
Clinical School, three of our PIs are currently
Heads of Department, namely Ken Smith
(Medicine), Tony Green (Haematology) and
John Todd (Medical Genetics). We have
recently strengthened our relationship with
the Institute of Metabolic Science through
the appointment of one of their PIs, David
Ron to our Institute Management Committee. CIMR PIs also contributed significantly
to the recent successful renewal of the
NIHR Cambridge Biomedical Research
Centre (BRC). John Todd, David Rubinsztein, Ken Smith, Tony Green and David
Lomas are all theme leads in the BRC and
Peter St George-Hyslop is the lead PI for
the new NIHR Cambridge Dementia Biomedical Research Unit.
No research strategy or focus can be
meaningful without the appointment and
nurturing of outstanding individual scientists.
A remarkably high proportion of our PIs have
part or all of their salaries funded through
very competitive fellowships awarded by
biomedical funding agencies. The CIMR
presently has the highest number of
Wellcome Trust Principal Research Fellows
(8, although David Clayton will retire in
March 2012), in any institute or department
in the country. Amongst these are David
Owen and David Rubinsztein who won their
awards in the past two years. We are also
proud of our record in training and developing young scientists including clinician
scientists. In the past two years, two young
CIMR clinician scientists, Mark Dawson and
Rhys Roberts were awarded WellcomeBeit Prize Fellowships. It was especially
pleasing that Rhys Roberts and also Mike
Weekes gained their intermediate fellowships from the Wellcome Trust following
periods funded as CIMR Next Generation
Fellows to help them back into research
from full time clinical posts. We hope that in
time all of our intermediate clinical research
fellows will do well enough to be competitive for senior fellowships, following in the
footsteps of other clinician scientists such
as Evan Reid and Stefan Marciniak who
became CIMR PIs in recent years. We also
take seriously the development and promotion of women scientists. It is a pleasure to
note that Katrin Ottersbach has taken up a
Bennett Senior Fellowship from Leukaemia
and Lymphoma Research and that Janet
Deane has been appointed as one of our
new PIs following the recent award of a
Royal Society University Research Fellow-
ship. In the CIMR we are aware that our
track record of consistently having around
30% of our PIs who are women compares
favourably with other institutes. However,
this proportion must be at least maintained
and preferably increased. Therefore, we will
fully support Fiona Karet, one of our PIs,
in her work leading the Clinical School’s
efforts to develop an application for an
Athena Swan Silver Award. We must aim
to improve our recruitment, retention and
promotion of women in the CIMR as well as
elsewhere in the Clinical School.
I have referred briefly above to the imminent
retirement of David Clayton who has contributed so much to the work of the Diabetes
and Inflammation Laboratory in the CIMR.
I thank David for his work in the institute
and wish him well in the future. There are
two other people who will reach retirement
in 2012 that I also wish to thank for their
support of the CIMR. The first is Sir John
Walker FRS, the Director of the MRC Mitochondrial Biology Unit with whom we share
our building. I hope that we are able to build
up equally good relations with his successor. The second is the Regius Professor of
Physic, Sir Patrick Sissons who has been
a stalwart supporter of the CIMR both as
Regius and in his previous role as Head of
the Department of Medicine. It has been a
great pleasure to work with Patrick who has
led the Clinical School with great wisdom
and care to a point where it is poised for
very exciting developments in the future.
In the CIMR the major challenges are both
to continue to improve our science and to
be a flagship in the UK for interdisciplinary
research at the interface between basic and
clinical science. We remain very grateful for
the Wellcome Trust Strategic Award, currently extended until late 2012. That award
greatly enhances our efforts as a translational institute and specifically supports
our core scientific facilities, funds PhD
studentships and also provides funds to
attract young clinicians back into research.
Our high proportion of clinically active PIs
allows the rapid translation of scientific
breakthroughs into clinical practice. In the
coming years such translation is likely to
include the identification of new pathways
of disease, the identification of new small
molecule and cell based therapies to
treat protein misfolding diseases and new
molecular diagnostics for haematological
malignancies. However, there is no simple
mechanical route from scientific research
to clinical practice and it behoves us all to
keep in mind the words of Marie Curie, who
in an address to Vassar College in Poughkeepsie, New York on May 14th, 1921 said,
“But we must not forget that when radium
was discovered no one knew that it would
prove useful in hospitals. The work was one
of pure science. And this is a proof that scientific work must not be considered from the
point of view of the direct usefulness of it.
It must be done for itself, for the beauty of
science, and then there is always the chance
that a scientific discovery may become like
the radium a benefit for humanity.”
Paul Luzio
January 2012
Current Membership of the CIMR
Strategy Committee:
Patrick Sissons (Chairman, Regius
Professor of Physic), Alastair Compston
(Clinical Neurosciences), John Danesh
(IPH, Faculty Board), Tony Green
(Haematology), David Lomas (Deputy
Director, CIMR), Paul Luzio (Director,
CIMR), Stephen O’Rahilly (Clinical
Biochemistry), Bruce Ponder (CRUK
CRI, Faculty Board), Geoffrey Smith
(Pathology), Ken Smith (Medicine),
John Todd (Diabetes and Inflammation
Laboratory/Medical Genetics).
Current Membership of the
International Scientific Advisory
Board:
Nick Hastie, Chairman (University of
Edinburgh), Dennis Ausiello (Harvard
University), Peter Cresswell (Yale
University), John Dick (University of
Toronto), Louise Johnson (University
of Oxford), Sandra Schmid (Scripps
Research Institute), Patrick Vallance
(GlaxoSmithKline plc)
5
CIMR Principal Investigators
6
Principal Investigator
Investigator Status
Home Department
Folma Buss
Wellcome Trust University Award
Clinical Biochemistry
Janet Deane
Royal Society University Research Fellow
Haematology
Andres Floto
Wellcome Trust Senior Research Fellow in Clinical Sciences
Medicine
Bertie Göttgens
Personal Chair
Haematology
Tony Green
University Chair
Haematology
Fiona Gribble
Gillian Griffiths
Wellcome Trust Principal Research Fellow and Personal Chair
Medicine
James Huntington
Personal Chair
Haematology
Brian Huntly
Senior Clinical Lecturer
Haematology
Fiona Karet
Personal Chair
Medical Genetics
Paul Lehner
and Personal Chair
Medicine
David Lomas
University Chair and Deputy Director CIMR
Medicine
Paul Luzio
Personal Chair and Director CIMR
Stefan Marciniak
MRC Senior Clinical Research Fellow
Medicine
Katrin Ottersbach
Leukaemia & Lymphoma Research Bennett Senior Fellow
Haematology
David Owen
Lucy Raymond
University Reader
Medical Genetics
Randy Read
Haematology
Evan Reid
Medical Genetics
Frank Reimann
Wellcome Trust Senior Research Fellow in Basic Biomedical Science
Margaret Robinson
David Rubinsztein
Medical Genetics
Christopher Rudd
Pathology
Peter St George-Hyslop
Clinical Neurosciences
Matthew Seaman
MRC Senior Research Fellow
Symeon Siniossoglou
MRC Senior Research Fellow
Ken Smith
University Chair
Medicine
John Todd
University Chair and Director DIL
Medical Genetics
John Trowsdale
University Chair
Pathology
Linda Wicker
Personal Chair and Co-Director DIL
Medical Genetics
Geoff Woods
Personal Chair
Medical Genetics
Myosin Motor Proteins in Health and Disease
We want to understand how molecular motor
proteins function in intracellular transport processes and how defects in these molecular
machines are linked to human diseases. Our
primary interests are the actin-based myosin
motors and their roles in cargo transport, cell
signalling and membrane dynamics.
The main focus of our current research is
myosin VI, which is unique because it moves in
the opposite direction along actin filaments to
all the other myosins. Myosin VI is an extremely
versatile motor that functions in membrane
trafficking pathways associated with secretion
and endocytosis and is thereby linked to cell
migration and cytokinesis. We have shown that
these diverse roles of myosin VI are mediated by
its interaction with a wide range of distinct
binding partners (adaptors) that connect it to
different cargoes.
Overexpression or mutations or the absence
of myosin VI have been linked to such diverse
pathological processes as deafness, cardiomyopathy, neurodegeneration and cancer. We
are currently unravelling the novel function(s)
of the myosins and their cargo adaptors in neurodegenerative diseases such as Alzheimer’s
and motor neuron disease. In addition we are
investigating the molecular role of myosin VI in
cardiomyocytes and heart disease.
The human genome contains 40 distinct
myosins and therefore we are expanding our
studies to investigate the complementary roles
of these different myosins in membrane trafficking pathways. For example we are currently
focusing on the role of class I myosins in endocytic membrane recycling.
Our long-term goal is to establish how the different actin- and microtubule-based motor proteins
interact together and how their actions are coordinated and regulated to maintain the health and
functions of cells.
Cargo attachment of myosin VI is mediated by binding partners
identified in Mammals (yellow) and in Drosophila (blue) (from Buss
& Kendrick-Jones (2011) PNAS 108, 5927–5928). Myosin VI and
its adaptor GIPC colocalise on early endosomes.
Folma Buss
Sue Arden
Lisa Bond
Hemma Brandstätter
David Tumbarello
Bennett Waxse
Funding:
Wellcome Trust
National Institutes
of Health (USA)
Puri, C., Chibalina, M. V., Arden,
S. D., Kruppa, A. J., KendrickJones, J. and Buss, F. (2009).
Overexpression of myosin VI in
prostate cancer cells enhances
PSA and VEGF secretion, but
has no effect on endocytosis.
Oncogene 29, 188–200.
Chibalina, M. V., Poliakov, A.,
Kendrick-Jones, J. and Buss, F.
(2010). Myosin VI and optineurin
are required for polarised EGFR
delivery and directed migration.
Traffic 11, 1290–1303.
Bond, L. M., Peden, A. A.,
Kendrick-Jones, J., Sellers, J. R.
and Buss, F. (2011). Myosin VI
and its binding partner optineurin
are novel players in secretory
vesicle fusion at the plasma
membrane. Mol Biol Cell 22,
54–66.
7
Janet Deane
Chris Hill
Funding:
The Royal Society
Schneider, M. C., Prosser, B.
E., Caesar, J. J., Kugelberg, E.,
Li, S., Zhang, Q., Quoraishi, S.,
Lovett, J. E., Deane, J. E., Sim,
R. B., Roversi, P., Johnson,
S., Tang, C. M. and Lea, S. M.
(2009). Neisseria meningitidis
recruits factor H using protein
mimicry of host carbohydrates.
Nature 458, 890–893.
Deane, J. E., Abrusci, P.
Johnson, S. and Lea, S. M.
(2010). Timing is everything: the
regulation of type III secretion.
Cell Mol Life Sci 67, 1065–
1075.
Host-pathogen Interactions During Shigella
Infection
Diseases caused by bacteria, viruses and other
parasites are major causes of death, disability,
and social and economic disruption for millions
of people. Our ability to effectively treat infectious diseases is being progressively depleted
due to increasing resistance of microbes to
antimicrobial drugs. A top priority today is the
development of new low-cost drugs that can
replace those that are becoming ineffective. An
essential part of developing new therapeutics is
a clear molecular understanding of how pathogens evade our immune defences and hijack our
cellular components.
Our research focuses on the bacterial pathogen
Shigella flexneri. This pathogen invades cells
of our digestive tract and hijacks components
of the actin polymerization pathway in order to
aid its movement within our cells and allowing
it to spread directly from cell to cell. In this
way Shigella can limit its detection by our
Deane, J. E., Graham, S. C.,
Kim, N. N., Stein, P. E., McNair,
R., Cachón-González, M. B.,
Cox, T. M. and Read, R. J.
(2011). Insights into Krabbe
disease from structures of
Galactocerebrosidase. Proc Natl
Acad Sci USA 108, 15169–
15173.
Structure of the lysosomal enzyme
galactocerebrosidase illustrating clinicallyidentified mutations which cause the fatal
neurodegenerative disorder Krabbe disease.
Figure taken from Deane et al. (2011) PNAS.
8
immune system. As an extra defence S. flexneri
produces proteins that specifically disarm the
intracellular immune response to pathogens. We
study the structure, interactions and regulation of
Shigella virulence proteins and the host proteins
they target.
In collaboration with the laboratories of Prof
Read and Prof Luzio in the CIMR and Prof Cox
in the Department of Medicine we are also
studying how clinically-identified mutations of
the enzyme galactocerebrosidase (GALC) result
in Krabbe disease, a devastating neurodegenerative disorder. Our recent structure of GALC
has provided new insight into the molecular
role of pathogenic mutations and allowed us to
identify patients that might be responsive to a
new form of therapy known as pharmacological
chaperone therapy.
Antigen Processing by Macrophages and
Dendritic Cells
We are interested in understanding how antigen
processing is controlled by macrophages and
dendritic cells and how it may be dysregulated
in autoimmune disease and subverted by pathogenic bacteria.
Our research is focused on two interrelated
areas:
1. Control of phagosomal function
Particulate antigen and bacteria are internalised into a membrane compartment known
as the phagosome that successively fuses
with early and late endosomes and finally
lysosomes. The behaviour of the phagosome
regulates cargo degradation and bacterial
killing, cytosolic export of antigen for crosspresentation and inflammasome activation.
Using a variety of live cell imaging, cellular and
biochemical techniques, we are examining how
i) signalling from Fc! receptors (Fc!Rs), Tolllike receptors (TLRs) and scavenger receptors
interact to control phagosomal function in
human macrophages and dendritic cells; ii)
how ion channels and transporters modulate
phagosomal pH and peri-phagosomal calcium
Andres Floto
levels to control cargo degradation and lysosomal fusion; and iii) how macro-autophagy
pathways interact with phagosomes to determine functional outcomes.
2. Mycobacterial infection
We are studying how M. tuberculosis and
non-tuberculous mycobacteria (NTM) interact
with macrophages and dendritic cells particularly i) defining novel host factors controlling
bacterial detection, intracellular killing and
antigen presentation (through functional
screening of genes identified from genetic
studies); ii) examining whether therapeutic
enhancement of autophagy can be used to
improve intracellular killing and how inadvertent pharmacological block of autophagy
might predispose to NTM infection; iii) identifying new genetic determinants controlling
the pathogenesis of the NTM species M.
abscessus through the combination of whole
genome sequencing (in collaboration with
Julian Parkhill, WTSI), in vitro functional phenotyping and clinical disease characteristics.
Karen Brown
Dorothy Grogono
Krisztina Hegyi
Lucy Hepburn
Tracey Pollard
Elspeth Potton
Catherine Schaffner
Mark Schiebler
Funding:
Wellcome Trust
Medical Research Council
NIHR Cambridge Biomedical
Research Centre
Papworth Hospital
Health Enterprise East SBRI
Floto, R. A., MacAry, P. A.,
Boname, J. M., Mien, T. S.,
Houben, E. N. G., Pieters, J., Day,
C., Oehlmann, W., Singh, M.,
Smith, K. G. C. and Lehner, P. J.
(2006). Dendritic cell stimulation
by mycobacterial HSP70 is
mediated through the HIV coreceptor CCR5. Science 314,
454–458.
Williams, A., Sarkar, S., Cuddon,
P., Ttofi, E. K., Saiki, S., Siddiqi,
F. H., Jahreiss, L., Fleming,
A., Pask, D., Goldsmith, P.,
O’Kane, C. J., Floto, R. A. and
Rubinsztein, D. C. (2008).
Novel targets for Huntington’s
disease in an mTOR-independent
autophagy pathway. Nat Chem
Biol 4, 295–305.
Calcium oscillations surrounding phagosomes containing IgG-coated beads (1,2) are detected in primary
macrophages using the membrane-targeted calcium
reporter Lck-GCaMP3 and are only partially mirrored
by plasma membrane calcium signalling (3).
Renna, M., Schaffner, C., Brown,
K., Shang, S., Henao Tamayo,
M., Hegyi, K., Grimsey, N. J.,
Cusens, D., Coulter, S., Cooper,
J., Bowden, A. R., Newton, S. M.,
Kampmann, B., Helm, J., Jones,
A., Haworth, C. S., Basaraba,
R. J., DeGroote, M. A., Ordway,
D. J., Rubinsztein, D. C. and
Floto, R. A. (2011). Azithromycin
blocks autophagy and may
predispose cystic fibrosis patients
to mycobacterial infection. J Clin
Invest 121, 3554–3563.
9
Bertie Göttgens
Fernando Calero-Nieto
Yi-Han Cheng
Evangelia Diamanti
Debbie Goode
Rebecca Hannah
Anagha Joshi
Sarah Kinston
Vicki Moignard
Felicia Ng
Judith Schuette
Jonathan Sive
Aileen Smith
Marloes Tijssen
Adam Wilkinson
Nicola Wilson
Transcriptional Control of Normal and Leukaemic
Blood Stem / Progenitor Cells
Haematopoiesis has long served as a model
system for studying the molecular processes
that control cell fate decisions within complex
differentiation cascades. Underpinning the molecular control of haematopoiesis are core circuits
of regulatory networks, that when unified define
the gene regulatory state of a particular cell.
These regulatory networks are composed of both
the transcription factors and the cis-regulatory
elements they are bound to. Regulatory network
reconstruction therefore requires the identification of cis-regulatory elements as well as the
upstream factors which bind them.
The long-term research goal of the Göttgens
group is to decipher the molecular hierarchy of
regulatory networks responsible for blood stem
cell and endothelial development. To this end,
the group uses complementary state-of-the-art
approaches including embryonic stem cell and
transgenic assays, bioinformatics, high throughput sequencing and mathematical modelling.
10
The importance of transcriptional control in both
normal and leukaemic cells is underlined by the
large number of transcription factor genes that
cause leukaemia when disrupted or mutated.
Future work will address how transcriptional programmes are perturbed in specific subtypes of
leukaemia and may thus open up new avenues
for the development of targeted therapies.
A Regulatory Network Model
for Blood Stem Cells. Shown
are experimentally validated
regulatory interactions for
a core set of transcriptional
regulators in blood stem/progenitor cells.
Funding:
Leukaemia & Lymphoma
Research
BBSRC
Cancer Research UK
Leukemia & Lymphoma
Foundation (USA)
EU/Marie Curie
EMBO
NIHR Cambridge
Biomedical Research
Centre
NC3Rs
Wilson, N. K. et al. (2010).
Combinatorial transcriptional
control in blood stem/progenitor
cells: Genome-wide analysis
of 10 major transcriptional
regulators. Cell Stem Cell 7,
532–544.
The cumulative output of more than 40 research
papers over the last 4 years has been the development of the most comprehensive network
model for any adult stem cell type with over
40 transcription factors and more than 100 in
vivo validated direct functional interactions. This
integrated approach has resulted in the discovery of previously unrecognised combinatorial
interactions between key regulators of blood
stem cells with important implications for the
transcriptional control of stem cell development
and differentiation.
Griffiths, D. S. et al. (2011).
LIF independent JAK signalling
to chromatin in embryonic stem
cells uncovered from an adult
stem cell disease. Nat Cell Biol
13, 13–21.
Tijssen, M. R. et al. (2011).
Genome-wide analysis of
simultaneous GATA1/2,
RUNX1, FLI1, and SCL binding
in megakaryocytes identifies
hematopoietic regulators. Dev
Cell 20, 597–609.
Haematopoietic Stem Cells and
Haematological Malignancies
The JAK/STAT pathway plays a key role in stem
cell biology and is implicated in many human
malignancies. A single acquired gain-of-function
V617F mutation in JAK2 is present in most
patients with a myeloproliferative neoplasm
(MPN), a spectrum of clonal haematological
malignancies which arise in the haematopoietic
stem cell compartment. These disorders are
experimentally tractable, permit clonal analysis
and provide a window on the earliest stages of
tumorigenesis. The Green lab is focussing on
the pathogenesis of the MPNs and particularly
on the molecular and cellular consequences of
JAK2 mutations. Recent highlights of general
relevance for stem cell and cancer biology
include unexpected insights into chromatin
biology, clonal evolution and haematopoietic
stem cell function.
non-CML MPNs.
Our subsequent results
suggest that V617F-positive ET and PV form a
phenotypic continuum and that V617F homozygosity contributes to the PV phenotype. We
made the surprising observation that leukaemic
transformation is associated with loss of the
JAK2V617F mutation and identified a cluster of
new JAK2 mutations which define a previouslyunrecognised MPN variant. In addition we have
demonstrated that inhibition of Bcl-xL deamidation represents a novel mechanism underlying
DNA damage accumulation. Most recently we
have described a novel nuclear function for
JAK2 in the phosphorylation of histone H3, have
demonstrated that JAK2V617F unexpectedly
impairs haematopoietic stem cell function and
have identified an unexpected role for STAT1
signalling in MPN pathogenesis.
Human MPNs represent a spectrum of clonal
haematological malignancies, with four main
members: polycythaemia vera (PV), essential
thrombocythaemia (ET), primary myelofibrosis
(PMF) and chronic myeloid leukaemia (CML).
A single acquired gain-of-function JAK2V617F
mutation is present in most patients with
These data are laying the foundation for new
approaches to the diagnosis, classification and
therapy of the myeloproliferative disorders –
JAK2 mutation status is already embedded in
clinical guidelines and JAK2 inhibitors are in
clinical trials.
Tony Green
Jong-Sook Ahn
Maria Ahn
Athar Aziz
Edwin Chen
Jyoti Evans
Anna Godfrey
Tina Hamilton
David Kent
Ana Leal Cervantes
Juan Li
Charlie Massie
June Park
Dean Pask
Rachel Pestridge
Yvonne Silber
Funding:
Research
Leukemia & Lymphoma
Society (USA)
Cancer Research UK
Kay Kendall Leukaemia Fund
Scott, L. M. et al. (2007). JAK2
exon 12 mutations in polycythemia
vera and idiopathic erythrocytosis.
N Engl J Med 356, 459–468.
Dawson, M. A.†, Bannister,
A. J.†, Göttgens, B., Foster,
S. D., Bartke, T., Green, A. R.*
and Kouzarides, T.* (2009).
JAK2 phosphorylates histone
H3Y41 and excludes HP1" from
chromatin. Nature 461, 819–822.
* joint senior authors; † joint first
author
Analysis of individual haematopoietic colonies revealed an unexpected role for
STAT1 signalling in the pathogenesis of distinct myeloproliferative disorders.
Colonies carrying an identical JAK2V617F mutation from patients can exhibit differential activation of the STAT1 signalling pathway which provides an explanation
for the distinct clinical phenotypes associated with these disorders (Chen et al.
Cancer Cell 2010). ET, essential thrombocythaemia; PV, polycythaemia vera.
Chen, E. et al. (2010). Distinct
clinical phenotypes associated
with JAK2V617F reflect differential
STAT1 signaling. Cancer Cell 18,
524–535.
11
Fiona Gribble
Alice Adriaenssens
Rune Kuhre
Claire Meek
Helen Parker
Paul Richards
Gwen Tolhurst
Funding:
Wellcome Trust
European Foundation for
the Study of Diabetes
Lister Institute of
Preventive Medicine
BBSRC/AstraZeneca
European Union FP7
Full4Health
Stimulus-secretion Coupling Mechanisms in
Intestinal Enteroendocrine Cells
Hormones from the gastrointestinal tract play key
roles in the control of appetite and insulin release.
Drugs based around one of these hormones,
glucagon like peptide-1 (GLP-1), have recently
proved to be highly successful for treating type
2 diabetes. This has led to the current focus on
developing strategies to enhance the release of
endogenous GLP-1 and other gut peptides, in
the hope that this may identify novel treatments
for diabetes and obesity and mimic the beneficial
physiological effects of gastric bypass surgery.
Understanding the mechanisms underlying secretion from gut endocrine cells is central to this
approach, and forms the focus of our research.
In collaboration with the group of Dr Frank
Reimann, we employ a variety of optical and
electrophysiological recording techniques to
monitor stimulus detection and vesicle release
from primary and immortalised GLP-1 secreting
L cells. As the identification of living gut endocrine cells was a previous major impediment to
Greenfield, F. R., Farooqi, I. S.,
Keogh, J., Henning, E., Habib,
A. M., Blackwood, A., Reimann,
F., Holst, J. J. and Gribble, F. M.
(2009). Oral glutamine increases
circulating GLP-1, glucagon and
insulin levels in lean, obese and
type 2 diabetic subjects. Am J
Clin Nutr 89, 106–113.
Tolhurst, G., Zheng, Y.,
Parker, H. E., Habib, A. M.,
Reimann, F. and Gribble, F.
M. (2011). Glutamine triggers
and potentiates glucagon-like
peptide-1 secretion by raising
cytosolic Ca2+ and cAMP.
Endocrinol 152, 405–413.
Parker, H. E., Wallis, K., le
Roux, C. W., Wong, K. Y.,
Reimann, F. and Gribble, F. M.
(2011). Molecular mechanisms
underlying bile acid stimulated
glucagon-like peptide-1
secretion. Br J Pharmacol (in
press).
A. Intracellular [glucose] in GLP-1 secreting
cells monitored by a FRET-based glucose
sensor, showing that blocking GLUT
transporters abolishes glucose uptake.
B. Model of L-cell glucose-sensing.
12
this field of research, we have generated transgenic mouse models in which GLP-1-expressing
cells, or other target cells of interest, are labelled
by cell-specific fluorescent markers. These are
amenable to purification by flow cytometry and
identification in primary culture for single cell
recordings. The combination of single cell recordings with transcriptional analysis of FACS-purified
cell populations has generated new models for
nutrient sensing by L cells. Detection of nutrients
in the gut lumen appears to involve electrogenic
ion-coupled transporters located on the apical L
cell membrane, generating small electrical signals
that are subsequently amplified by voltage gated
Ca2+ entry and other signalling pathways such as
cAMP elevation and stored Ca2+ release. Comparisons between different enteroendocrine cell types
suggest that the pathways identified in L cells are
likely to reflect more general stimulus detection
mechanisms employed by a wider population of
gut endocrine cells.
Control of Secretion at the Immunological
Synapse
Cells of the immune system need to communicate in order to co-ordinate an effective immune
response. The immunological synapse formed
between effector cells and their antigen-presenting cells provides a mechanism for directed
communication, either via cell surface receptors or secreted proteins. Secretion is focused
within the synapse: in the case of cytotoxic T
lymphocytes (CTL) this is essential so that only
the infected target is destroyed.
This lab studies the mechanisms that control
secretion within the immunological synapse
using a range of functional, biochemical and
imaging techniques. We have close clinical
collaborations that allow us to study CTL
from patients with genetic diseases (eg Haemophagocytic Lymphohistiocytosis) that disrupt
secretion at the immunological synapse, and
thereby identify the machinery required for
granule delivery and fusion at the synapse as
well as providing a better understanding of the
genetic disease.
We have discovered that CTL and NK cells use
a novel secretory mechanism, with the centrosome polarizing to the precise site of secretion
within the immunological synapse. This mechanism, that requires the centrosome to dock at
the plasma membrane, bears striking similarities
to cilia formation, with endocytosis and exocytosis focused at the point of centrosome docking
in both. We are currently exploring the molecular
similarities between cilia and synapse formation using genetic, morphological and functional
studies.
CTL provide an excellent model for understanding the mechanisms that control centrosome
polarization, and we have exploited genetic
models in which components of the T cell
receptor signaling pathway can be turned off.
A key aspect to all of these studies is the use
of live imaging to follow synapse formation
and secretion in real time, and dissect out the
delivery of the secretory machinery to the immunological synapse.
A cytotoxic T cell, with
the membrane labelled
with CD8 (purple), and
microtubules (green)
polarised towards a
target cell. The secretory lysosomes of the
CTL (red) move towards the microtubule
organising centre and
deliver their contents
at the immunological
synapse, leading to
the destruction of the
target. Nuclei of both
CTL and target are
stained blue.
Gillian Griffiths
Karen Angus
Yukako Asano
Maike de la Roche
Sam Grieve
Yvonne Hackmann
Jeansun Lee
Alex Ritter
Jane Stinchcombe
Roseanne Zhao
Funding:
Wellcome Trust
Griffiths, G. M., Tsun, A. and
Stinchcombe, J. C. (2010).
The immunological synapse: a
focal point for endocytosis and
exocytosis. J Cell Biol 189,
399–406.
Daniele, T., Hackmann, Y., Ritter,
A. T., Wenham, M., Booth, S.,
Bossi, G., Schintler, M., AuerGrumbach, M. and Griffiths, G.
M. (2011). A role for rab7 in the
movement of secretory granules
in cytotoxic T lymphocytes. Traffic
12, 902–911.
Tsun, A., Qureshi, I.,
Stinchcombe, J. C., Jenkins,
M. R., de la Roche, M.,
Kleczkowska, J., Zamoyska,
R. and Griffiths, G. M. (2011).
Centrosome docking at the
immunological synapse is
controlled by Lck signaling. J Cell
Biol 192, 663–674.
13
James
Huntington
Ty Adams
Daniel Johnson
Bernhard Lechtenberg
Giles Lewis
Henriet Meems
Thomas Murray-Rust
Stéphanie Polderdijk
Anja Pomowski
Timothy Sendall
Funding:
Wellcome Trust
British Heart Foundation
Molecular Recognition in Haemostasis
Haemostasis (blood coagulation) is a complex
process under tight regulatory control. Dysregulation leads to bleeding if the response is
insufficiently robust, and to thrombosis if coagulation is not limited. Understanding these regulatory
mechanisms is crucial for the prevention and
treatment of diseases such as haemophilia, deep
vein thrombosis, pulmonary embolism, heart
attack and stroke. My lab studies the structures
of individual coagulation factors and of the
multi-protein complexes they form, using the
techniques of X-ray crystallography and NMR,
in order to understand how coagulation is controlled. One project focuses on the final protease
generated by the blood coagulation cascade,
thrombin. Other projects focus on the large multiprotein complexes responsible for factor Xa
and thrombin formation, the intrinsic tenase
(factors VIIIa and IXa) and prothrombinase
(factors Va and Xa). Finally, all of the proteases
generated during the haemostatic response
must eventually be inhibited to avoid thrombosis. We have a long-standing interest in how
serpins antithrombin, heparin cofactor II, protein
C inhibitor and protease nexin-1 are regulated
by cofactors such as heparin. We have solved
several crystal structures of relevant complexes,
including all of the antithrombin-heparin-protease complexes, and now have a detailed and
complete description of how heparin regulates
serpin function. The importance of serpins is
highlighted by the association of deficiency with
disease, often caused by missense mutations
leading to the accumulation of ‘polymers’ within
the endoplasmic reticulum of secretory cells. We
recently solved two crystal structures of polymers
that showed distinct large-scale domain swaps,
and have demonstrated that the intermolecular
swapping of the 30 C-terminal residues is the
molecular basis of serpin polymerization within
living cells.
Johnson, D. J. D., Langdown, J.
and Huntington, J. A. (2010).
Molecular basis of factor IXa
recognition by heparin-activated
antithrombin revealed by a 1.7Å
structure of the ternary complex.
Proc Natl Acad Sci USA 107,
645–650.
Lechtenberg, B., Johnson, D. J.
D., Freund, S. and Huntington,
J. A. (2010). NMR resonance
assignments of thrombin reveal
the conformational and dynamic
effects of ligation. Proc Natl
14092.
Yamasaki, M., Sendall, T. J.,
Pearce, M. C., Whisstock, J. C.
and Huntington, J. A. (2011).
Molecular basis of
"1-antitrypsin deficiency
revealed by the structure of a
domain-swapped trimer. EMBO
Rep 12, 1011–1017.
Crystal structure of an "1-antitrypsin trimer formed
by the ‘swapping’ of the C-terminal portion from one
molecule into another.
14
Mechanisms of Myeloid Leukaemogenesis
and Leukaemia Stem Cell Biology
The aims of our group are broadly to study
mechanisms of leukaemogenesis. In particular
we aim to characterise leukaemia stem cells
(LSC) at the molecular and cellular level in
myeloid haematological malignancies. Leukaemias and many other cancers have recently been
demonstrated to be wholly dependent upon a
population of so-called cancer stem cells for
their continued growth and propagation. These
cells represent the most critical targets for treatment of leukaemia and a greater understanding
of their biology and its interface with normal
haematopoietic stem cell (HSC) function is fundamental to improving treatment outcomes.
We utilise a combination of functional and
genomic assays in complementary mouse
models and human primary cells to study normal
HSC biology and how this is subverted in LSC
and leukaemogenesis. An evolving paradigm
in myeloid malignancies is transcriptional dysregulation and many of the mutations involved in
myeloid leukaemogenesis involve transcriptional
and epigenetic regulators. Ongoing projects
within the group look at aberrant epigenetic regulation at chromatin via the bromodomain and
extra terminal (BET) proteins in acute myeloid
leukaemia (AML), at transcriptional dysregulation downstream of the AML-associated fusion
genes MOZ-TIF2, NUP98-HOXA9 and MLL
fusions, at the HMG-box gene SOX4, a critical
AML target gene and at functions of epigenetic regulators such as CBP in HSC and LSC
function. In addition, we are interested in the
induction and evolution of myeloid preleukaemic
disorders such as chronic myeloid leukaemia
(CML) and myeloproliferative neoplasms (MPN)
and are generating mouse models and studies in
human cells to outline disease mechanisms and
identify therapeutic targets.
Our long-term aim is to improve biological
understanding of leukaemogenesis, to identify
rational targets for therapeutic intervention and
to design novel therapeutics to improve the
outcomes in myeloid malignancies.
Brian Huntly
Shubha Anand
Polly Chan
Mark Dawson
George Giotopoulos
Emma Gudgin
Sarah Horton
Sarah Putwain
Frances Stedham
Funding:
Kay Kendall Leukaemia
Fund
Cancer Research UK
Research
Wellcome Trust
Leukemia & Lymphoma
Society (USA)
Anand, S., Stedham, F., Gudgin,
E., Cambell, P., Beer, P., Green,
A. R. and Huntly, B. J. P. (2011).
Increased basal intracellular
signaling patterns do not correlate
with JAK2 genotype in human
myeloproliferative neoplasms.
Blood 118, 1610–1621.
Kvinlaug, B. T. et al. (2011).
Common and overlapping
pathways contribute to the
evolution of acute myeloid
leukaemias. Cancer Res 71,
4117–4129.
Protein-protein interaction inhibitors of BET bromodomain
proteins (I-BET), prevent aberrant chromatin recruitment
of transcriptional complexes and switch off expression
programmes that drive LSC in MLL leukaemias.
Dawson, M. A., Prinjha, R. K.,
Dittman, A., Giotopoulos, G.,
Bantscheff, M., Chan, W. I.,
Robson, S. C., Chung, C., Hopf,
C., Savitski, M. M., Huthmacher,
C., Gudgin, E., Lugo, D., Beinke,
S., Soden, P. E., Döhner,
K., Delwel, R., Burnett, A.
K., Auger, K. R., Mirguet, O.,
Jeffrey, P., Drewes, G., Lee, K.,
Huntly, B. J. P.* and Kouzarides,
T.* (2011). Inhibition of BET
recruitment to chromatin as an
effective treatment for MLL-fusion
leukaemia. Nature 478, 529–533.
*joint senior authors
15
Fiona Karet
Molecular Physiology of Renal Tubular
Homeostasis in Health and Disease
Our aims are twofold: to characterize molecular
mechanisms governing human renal tubular
homeostasis (particularly acid-base balance) and
to dissect functions of urinary proteins.
Katy Blake-Palmer
Zoe Golder
Tannia Gracia
Liz Norgett
Caroline Robinson
Graham Smith
Ya Su
Vivian Yiu
Funding:
Wellcome Trust
NIHR Cambridge
Biomedical Research
Centre
Kidney Research UK
Intact distal nephron "-intercalated functions
(secretion of protons in to the urine coupled
to bicarbonate reclamation) are necessary for
appropriate excretion of the acid load of a normal
diet, and for generation of adequate amounts
of bicarbonate for buffering. The transporters
responsible, and their regulatory pathways, are
complex and incompletely understood. We have
used rare single-gene disorders where "-IC
function is inadequate, imparting severely detrimental effects on the kidney’s ability to maintain
normal body fluid pH. The clinical consequences
are metabolic acidosis, rickets and calcium
deposition in the kidney. Recessively inherited
syndromes present with very severe changes in
early childhood, and sensorineural hearing loss is
often associated.
Su, Y., Blake-Palmer, K. G.,
Best, A., Brown, A. C. N., Horita,
S., Fry, A. C., Zhou, A., Smith,
A. N., Toye, A. M. and Karet,
F. E. (2011). Glyceraldehyde
3-phosphate dehydrogenase
is required for band 3 (anion
exchanger 1) membrane
residency in the mammalian
kidney. Am J Physiol 300,
F157–166.
Hiemstra, T. F., Charles, P. D.,
Hester, S. S., Karet, F. E.* and
Lilley, K. S.* (2011). Uromodulin
exclusion list improves urinary
exosomal protein identification.
J Biomol Techniques (in press).
*joint authors
Smith, G. D., Robinson, C.,
Stewart, A. P., Edwards,
E., Karet, H. I., Norden, A.
G. W., Sandford, R. N. and
Karet Frankl, F. E. (2011).
Characterization of a recurrent
in-frame UMOD indel mutation
causing late-onset autosomal
dominant end-stage renal failure.
Clin J Am Soc Nephrol (in
press).
Human urinary exosomes induce lysis of E. Coli. (A)
proportion lysed; (B) lysed and (C) intact phenotypes.
16
Having described mutations in three genes:
SLC4A1 (encoding the basolateral anion
exchanger AE1), ATP6V1B1 and ATP6V0A4
(encoding kidney-specific B1 and a4 subunits
of the "-IC surface proton pump), we initially
showed that the latter two also participate in
normal inner ear function, and discovered four
novel subunit isoforms (C2, G3, d2, e2). We
have gone on to functional characterization,
and shown that essential membrane targeting motifs for AE1 reside in its C-terminal tail;
that AE1 is regulated by GAPDH and interacts
with the sodium pump. Conversely, we showed
that binding of the glycolytic enzyme PFK-1 is
essential for normal proton pump function, as is
phosphorylation by PKA.
We have catalogued the human urinary exosomal
proteome and demonstrated that these urinary
microvesicles are important innate immune effectors, maintaining urinary tract sterility. The most
abundant urinary protein, uromodulin, is mutated
in another dominant renal disease, FJHN. We
have molecularly and clinically characterized a
novel UMOD mutant, and continue with clinical
and laboratory studies of other tubulopathies.
Viral Immune Evasion
We are interested in viral evasion of the immune
system. As the ultimate intracellular parasites,
viruses target the host cellular machinery to
enable their replication and avoid elimination.
Using functional genetic and proteomic technologies we identify novel cellular receptors
manipulated by viruses, understand why these
receptors are targeted and elucidate the mechanisms used by viruses to manipulate the cellular
immunoreceptors.
Why is the study of viral evasion mechanisms
of interest? Understanding the mechanisms
used by viruses to manipulate cellular processes
provides unique insights into fundamental cell
biological pathways, teaches us about viral
pathogenesis and offers novel therapeutic
approaches, for instance by targeting the newly
identified receptor.
Viral regulation of cell surface receptors –
new approaches: Cell surface receptors are
modulated by all intracellular pathogens. Our
work on viral evasion of the MHC class I antigen
presentation pathway fuelled an interest in how
ubiquitin regulates immunoreceptor turnover.
Paul J Lehner
We identified the K3 and K5 viral ubiquitin E3
ligases which ubiquitinate and degrade cell
surface MHC I via the endolysosomal pathway.
We recently developed non-biased methods to
identify cell surface receptors up- or downregulated by viruses. Using SILAC-based proteomics
we can compare the relative abundance of >600
plasma membrane proteins, and identify those
receptors whose expression is altered by viruses.
We have identified novel amino acid transporters
regulated by HIV, and drug transporters regulated by HCMV.
Defining the mechanism of action of these
novel receptors: Using genetic, biochemical
and cell biological approaches we then determine how newly identified cell surface proteins
are compromised by intracellular pathogens. For
example, our siRNA screens identified novel E3
ligases, such as TRC8, involved in receptor regulation as well as their physiological substrates. We
use traditional biochemical as well as mutagenesis-based genetic screens to identify the critical
pathway components required for immunoreceptor regulation.
Jessica Boname
Marian Burr
Helen Bye
Florencia Cano
Lidia Duncan
Nick Matheson
Radu Rapiteanu
Suzanne Talbot
Shireen Tan
Richard Timms
Dick van den Boomen
Michael Weekes
Funding:
Wellcome Trust
Addenbrooke’s Charitable
Trust
Randow, F. and Lehner, P. J.
(2009). Viral avoidance and
exploitation of the ubiquitin
system. Nat Cell Biol 11,
527–534.
Stagg, H. R., Thomas, M., van
den Boomen, D., Wiertz, E. H.,
Drabkin, H. A., Gemmill, R. M.
and Lehner, P. J. (2009). The
TRC8 E3 Ligase ubiquitinates
MHC class I molecules before
dislocation from the ER. J Cell
Biol 186, 685–692.
Burr, M. L., Cano, F., Svobodova,
S., Boyle, L. H., Boname, J. M.
and Lehner, P. J. (2011). HRD1
and UBE2J1 target misfolded
MHC class I heavy chains for
endoplasmic reticulum-associated
degradation. Proc Natl Acad Sci
USA 108, 2034–2039.
By downregulating critical cell surface
receptors, CMV prevents infected dendritic cells
from trafficking to draining lymph nodes.
17
David Lomas
Jenny Dickens
Annelyse Duvoix
Sarah Faull
Imran Haq
James Irving
Tim Newton
Adriana Ordonez
Benoit Roussel
Lu Tan
Alison Warrington
Funding:
EPSRC
Wellcome Trust
Alzheimer’s Research Trust
Diabetes UK
GlaxoSmithKline
BBSRC
British Lung Foundation
NIHR Cambridge
Biomedical Research
Centre
Children’s Liver Disease
Foundation
Protein Misfolding, "1-Antitrypsin Deficiency
and the Serpinopathies
One in twenty-five of the Northern European
population carry the Z allele of "1-antitrypsin
(342Glu Lys). Homozygotes for this mutation
retain "1-antitrypsin within hepatocytes as inclusion bodies that are associated with neonatal
hepatitis, juvenile cirrhosis and hepatocellular
carcinoma. We have shown that Z "1-antitrypsin
is retained within hepatocytes by the formation
of ordered polymers in which the reactive centre
loop of one molecule inserts into #-sheet A of
another. Alpha-1-antitrypsin is a member of the
serine protease inhibitor or serpin superfamily of
proteins. Mutants of other serpins, antithrombin,
C1-inhibitor and "1-antichymotrypsin also form
polymers in association with plasma deficiency
that causes thrombosis, angioedema and emphysema respectively. Perhaps most striking is our
description of the same process in a neurone
specific serpin, neuroserpin in association with
an inclusion body dementia that we have called
familial encephalopathy with neuroserpin inclusion bodies (FENIB). In view of their common
Miranda, E. et al. (2010). A
novel monoclonal antibody
to characterize pathogenic
polymers in liver disease
associated with "1-antitrypsin
deficiency. Hepatol 52,
1078–1088.
Ekeowa, U. I. et al. (2010).
Defining the mechanism
of polymerization in the
serpinopathies. Proc Natl Acad
Sci USA 107, 17146–17151.
Yusa, K. et al. (2011). Targeted
gene correction of "1-antitrypsin
deficiency in induced pluripotent
stem cells. Nature 478,
391–394.
18
Immunostaining of polymeric "1-antitrypsin (green)
or all forms of "1-antitrypsin (red) in human iPS
cell–derived hepatocytes from individuals with "1antitrypsin deficiency and controls (from Rashid et al,
J Clin Invest 2010).
mechanism we have grouped these conditions
into a new class of disease that we have called
the serpinopathies. The structure and significance of the pathological loop-sheet polymers
has been defined using biochemical, biophysical,
crystallographic, and cell biology studies and
with monoclonal antibodies and animal models
of disease. We are now using this information
to undertake small molecule screens to identify
compounds that can bind to, and prevent the
polymerisation of, mutant "1-antitrypsin in vitro
and in vivo. More recently, we have used human
induced pluripotential stem cells derived from
skin fibroblasts to develop hepatocyte-like cells
that recapitulate the intracellular polymers that
characterise "1-antitrypsin deficiency. We then
used zinc finger nuclease technology to correct
the genetic defect and so produce hepatocytelike cells that secrete wild-type "1-antitrypsin.
This takes us closer to a cell based therapy for
"1-antitrypsin deficiency and the serpinopathies.
Molecular Cell Biology of Post-Golgi
Membrane Traffic Pathways
Lysosomes are small membrane bound organelles ~0.5$m diameter, which are full of
proteases and other hydrolytic enzymes as
well as internal membranes. They function late
in the endocytic pathway that takes up macromolecules from the cell surface, by fusing with
endosomes, but also play a key role in phagocytosis, autophagocytosis and probably cell
surface membrane repair, the latter by fusing
with the plasma membrane. The late endosomes
that fuse with lysosomes are observed as MVBs
(multivesicular bodies) in the electron microscope and sorting of membrane proteins into
the lumenal vesicles of these MVBs is mediated
by ESCRT (endosomal sorting complex required
for transport) proteins. Our main focus is on
how cells achieve sorting and delivery of endocytosed macromolecules to lysosomes. A key
protein in fusion events involving late endocytic
organelles is the membrane protein VAMP7.
This is targeted to the late endocytic pathway
through interactions with the clathrin adaptor
AP-3 and also by binding to the clathrin adaptor
Hrb, that ensures its retrieval from the plasma
membrane. The function of VAMP7 is regulated by interaction with Varp (Vps9 and ankyrin
repeat containing protein). We are also studying
the role of different protein machineries including the ESCRT proteins and HOPS (homotypic
fusion and vacuole protein sorting) proteins in
preparing endosomes for fusion with lysosomes.
Our structural studies are in collaboration with
David Owen and we also collaborate with Paul
Lehner on the intracellular sorting of Class I
MHC molecules following down-regulation from
the cell surface by viruses. Our group maintains
an active interest in diseases of membrane
traffic, including the work of Rhys Roberts on
Charcot-Marie-Tooth Disease.
Paul Luzio
Nicholas Bright
Sally Gray
Geoff Hesketh
Rhys Roberts
Jennifer Warren
Lena Wartosch
Funding:
Wellcome Trust
Canadian Institutes of
Health Research
EMBO
Pryor, P. R., Parker, L., Gray, S.
R., Thompson, A., Sanderson, C.
M., Evans, P. R., Owen, D. J.* and
Luzio, J. P.* (2008). Molecular
basis for sorting of the SNARE
VAMP7 into endocytic clathrincoated vesicles by the ArfGAP
Hrb. Cell 134, 817–827.
Roberts, R. C., Peden, A. A.,
Buss, F., Bright, N. A., Latouche,
M., Reilly, M. M., KendrickJones, J. and Luzio. J.P. (2010).
Mistargeting of SH3TC2 away
from the recycling endosome
causes Charcot-Marie-Tooth
Disease Type 4C. Hum Mol
Genet 19, 1009–1018.
Lawrence, S. P., Bright, N. A.,
Luzio, J. P.* and Bowers, K.*
(2010). The sodium/proton
exchanger NHE8 regulates
late endosomal morphology
and function. Mol Biol Cell 21,
3540–3551.
*equal last authors
Electron microscopic tomography of a high pressure frozen
HeLa cell showing fusion pores between late endocytic
organelles. A, a micrograph from the reconstructed volume
data set showing a plane of section containing a fusion
pore. B, the reconstructed 3D volume showing a second
fusion pore. C, a rendered surface model of the 3D data set
revealing the fusion pores ‘en face’.
19
Stefan
Marciniak
Hanna Clarke
Lucy Dalton
Jenny Dickens
Elke Malzer
Sally Thomas
Funding:
Diabetes UK
British Lung Foundation
June Hancock Mesothelioma
Research Fund
The Role of Endoplasmic Reticulum Stress
in Disease
Proteins destined for secretion or for insertion
into the cell membrane are first folded within the
endoplasmic reticulum. The process of protein
folding can become defective in many pathological states such as hypoxia, malignancy and
some forms of diabetes. When the level of misfolded proteins within the endoplasmic reticulum
increases, the cell is said to experience “endoplasmic reticulum stress”.
We wish to understand the cellular consequences
of endoplasmic reticulum stress, in particular its
effects on tissue growth and cell survival. In doing
so we hope to identify targets for the development of novel therapies. During endoplasmic
reticulum stress, protein biosynthesis is initially
inhibited by phosphorylation of the translation initiation factor eIF2" by the stress-sensing kinase
PERK. Subsequent dephosphorylation of eIF2"
by the phosphatase GADD34 restores protein
translation thereafter. We discovered that this
recovery of translation could itself contribute to
the toxic effects of endoplasmic reticulum stress.
This raises the exciting possibility that modulation of eIF2" phosphorylation may provide a
useful target for the development of novel drugs
to protect tissues from cell death.
Cellular stresses frequently impair cell cycle progression, which can impair tissue growth. Using
mammalian cell biology and Drosophila genetics
we recently described a novel G2 cell cycle
check point initiated by translation attenuation
during endoplasmic reticulum stress. This too
provides potential targets for the development of
new therapies.
Malzer, E., Daly, M. L., Moloney,
A., Sendall, T. J., Thomas, S. L.,
Ryder, E., Ryoo, H. D., Crowther,
D. C., Lomas, D. A. and Marciniak,
S. J. (2010). Impaired tissue
growth is mediated by checkpoint
kinase 1 (CHK1) in the integrated
stress response. J Cell Sci 123,
2892–2900.
Marciniak, S. J. and Ron, D.
(2010). The unfolded protein
response in lung disease. Proc Am
Thor Soc 7, 356–362.
Yusa, K.*, Rashid, S. T.*, StrickMarchand, H., Varela, I., Liu,
P.-Q., Paschon, D. E., Miranda, E.,
Ordóñez, A., Hannan, N., Rohani,
F., Alexander, A., Marciniak, S.
J., Holmes, M. C., Di Santo, J.
P., Lomas, D. A.§, Bradley, A.§
and Vallier, L.§ (2011). Targeted
gene correction of "1-antitrypsin
deficiency in induced pluripotent
stem cells. Nature 478, 391–394.
joint first* and senior§ authors
20
Drosophila eye imaginal discs expressing dPERK-KR
(upper panel) or dPERK-WT (lower) in mosaic clones
(GFP absent). PERK is stained in blue, phosphohistone H3 in red.
The Regulation of Haematopoiesis during
Development and Disease
Haematopoietic stem cells (HSCs) have been
intensely studied for many decades as a model
system for stem cell biology. Our work focuses
on the emergence and regulation of the first
haematopoietic stem and progenitor cells in
the mouse embryo in order to identify the basic
mechanisms that control their generation from
precursors and their initial expansion and dissemination to the different haematopoietic
organs. Knowledge of these early regulatory
pathways has proven to be invaluable for understanding how adult HSCs can be manipulated for
clinical purposes and how interference with these
processes may result in blood-related disorders.
We have recently obtained funding to specifically study how embryonic blood cells can be the
target for transformation in a particularly severe
type of infant leukaemia. Our research therefore
complements that of several groups within the
university which also work on various aspects of
normal and leukaemic stem cell biology.
We have recently further defined the region
where HSCs are first detected and have incorporated this information into the design of a
number of microarray experiments with the aim
of identifying novel regulators of HSC generation
in the AGM. Functional validation experiments
have revealed a role for the cell cycle regulator p57Kip2 and the growth factor Igf2 in the
generation, maintenance and/or migration of the
first pool of HSCs. The role of other cytokines
in these processes is also being investigated.
Furthermore, we have also found evidence that
the regulation of HSC generation is influenced
by the developing sympathetic nervous system,
thus providing a functional link between these
two systems in the mouse embryo. We are now
in the process of adding an additional level to our
expression studies by identifying miRNAs that
are essential for developmental haematopoiesis.
Katrin
Ottersbach
Marie-Laure Aknin
Simon Fitch
Maria Mascarenhas
Funding:
Leukaemia &
Lymphoma Research
Kay Kendall
Leukaemia Fund
British Society
for Haematology
Mascarenhas, M. I., Parker, A.,
Dzierzak, E. and Ottersbach,
K. (2009). Identification of novel
regulators of hematopoietic
stem cell development through
refinement of stem cell
localization and expression
profiling. Blood 114, 4645–
4653.
Ottersbach, K., Smith, A.,
Wood, A. and Göttgens,
B. (2010). Ontogeny of
Haematopoiesis: Recent
Advances and Open Questions.
Br J Haematol 148, 343–355.
Haematopoietic stem cells are located in the middle
region of the midgestation dorsal aorta.
Robin, C.*, Ottersbach, K.*,
Boisset, J.-C., Oziemlak, A.
and Dzierzak, E. (2011). CD41
is developmentally regulated
and differentially expressed on
mouse hematopoietic stem cells.
Blood 117, 5088–5091.
*equal contribution
21
David Owen
Stephen Graham†
Bernard Kelly
Lauren Jackson
Sharon Miller
Funding:
Wellcome Trust
Royal Commission of 1851†
Jackson, L. P., Kelly, B. T., McCoy,
A. J., Gaffry, T., James, L. C., Collins,
B. M., Höning, S., Evans, P. R. and
Owen, D. J. (2010). A large-scale
conformational change couples
membrane recruitment to cargo
binding in the AP2 clathrin adaptor
complex. Cell 141, 1220–1229.
Kelly, B. T. and Owen, D. J. (2011).
Endocytic sorting of transmembrane
protein cargo. Curr Opin Cell Biol
23, 404–412.
Structural Biology of Transport Vesicle and
Organelle Biogenesis
Transmembrane proteins are moved between
organelles in transport vesicles. Once cargo
has been sorted into a forming vesicle, the
vesicle buds from the donor membrane and is
then transported to and fuses with the target
membrane. The protein coats that surround
transport vesicle possess both a self-assembly
function, which results in polymeric lattice formation and a cargo recognition function. The latter
is mediated by the direct binding of coat components to determinants in the cytosolic portions
of trans-membrane cargo, most commonly used
being short linear motifs. In clathrin-coated
vesicles (CCVs) the most commonly used motifs
are recognised by clathrin adaptors : Yxx% and
ExxxLL recognised by AP complexes, FxNPxY
recognised by PTB containing proteins and
poly-ubiquitination modifications recognised by
epsins and GGAs. SNAREs are membraneembedded proteins, which provide specificity
and energy to transport vesicle:organelle fusion
events. Appropriate SNAREs must also be
actively sorted into transport vesicles to allow
the vesicles to fuse with their desired target
organelle and also to return SNAREs that are
required for subsequent vesicle transport events
Miller, S. E., Sahlender, D., Graham,
S. C., Hoening, S., Robinson, M.
S., Peden, A. A.* and Owen, D. J.*
(2011). The molecular basis for the
endocytosis of small R-SNAREs by
the clathrin adaptor CALM. Cell 147,
1118–1131.
* joint corresponding authors
The clathrin adaptor CALM selects endocytic SNAREs
e.g. VAMP8 for packaging into endocytic CCVs to
ensure that they can fuse with their target endosomes.
22
to their correct location. These recognition
events, which occur in parallel with standard
cargo selection, are mainly mediated by direct
and highly specific recognition of the folded
regions of SNAREs. In CCV-mediated transport
we have elucidated the molecular mechanisms
by which a variety of SNAREs (Vti1b, VAMP7,
VAMPs3&8) are transported by the clathrin
adaptors (epsinR, Hrb and CALM) respectively.
Vesicle coat components as well as proteins
that control transport vesicle:organelle and
organelle:organelle fusion through SNARE regulation and membrane tethering are recruited
to appropriate membranes through their
binding to membrane-inserted small G-proteins and membrane phospholipids as well
as by their interactions with various transmembrane proteins.
In collaboration with various groups both within
and outside the CIMR we are taking an integrated
structural/functional approach to studying such
interactions from a number of transport vesicle
and organelle biogenesis events.
Familial Intellectual Disability: From Genes
to Disease
We aim to understand how genetic abnormalities cause severe intellectual impairment. We
have recruited >1000 families with moderate
to severe intellectual disability in the iGOLD
Genetic of Learning Disability Study and have
identified many genes on the X chromosome that
cause disease using an exome sequencing and
detailed array comparative genomic hybridization
approach (aCGH). We are now taking a whole
exome approach and also testing the contribution of non-coding variants to disease.
We are continuing to quantify the genetic contribution to disease by testing whether genetic
abnormalities make a significant impact on the
poor intellectual outcome of babies born less
than 24 weeks gestation, or who are stillborn or
result in neonatal death.
Current estimates are that defects in >1500
genes are sufficient to cause severe cognitive impairment and the future challenge is to
Lucy Raymond
understand the unifying pathways and processes
that are disrupted that cause disease.
We are working on defining in detail the clinical
consequences of mutations in patients and to
understand the phenotypic effects of loss of
function mutations in neuronal cell models of
disease. In collaboration with Professor Paul
Fletcher, Wellcome Trust Senior Clinical Fellow,
we are interested in using functional MRI to
define subtle abnormalities of brain morphology and in collaboration with Dr Roger Barker,
Department of Neuroscience, we are working on
human fetal brain tissue to understand the role
of disease genes within human primary neurons.
Our ultimate aim is to be able to translate these
findings into better diagnostic tools for families
with intellectual disability and to consider unifying
cellular phenotypes that can be used in developing therapeutic agents that will ameliorate the
disease.
Elaine Baker
Kate Baker
Peng Gong
Aoife Murray
Funding:
Action Medical Research
Baily Thomas Foundation
NIHR Cambridge
Biomedical Research
Centre
Addenbrooke’s
Charitable Trust
Academy of
Medical Sciences
Tarpey, P. S. et al. (2009).
A systematic, large-scale
resequencing screen of
X-chromosome coding exons
in mental retardation.
Nat Genet 41, 535–543.
Noor, A. et al. (2010).
Disruption at the PTCHD1
Locus on Xp22.11 in Autism
spectrum disorder and
intellectual disability. Sci Transl
Med 2, 49–68.
A 6kb deletion upstream of the
CUL4B transcripts segregated
with disease and resulted in loss
of CUL4B expression in affected
individuals.
Whibley, A. C., Plagnol,
V., Tarpey, P. S., Abidi, F.,
Fullston, T., Choma, M. K.,
Boucher, C. A., Shepherd,
L., Willatt, L., Parkin, G.,
Smith, R., Futreal, P. A.,
Shaw, M., Boyle, J., Licata,
A., Skinner, C., Stevenson,
R. E., Turner, G., Field, M.,
Hackett, A., Schwartz, C. E.,
Gecz, J., Stratton, M. R. and
Raymond, F. L. (2010). Finescale survey of X chromosome
copy number variants and
indels underlying intellectual
disability. Am J Hum Genet
87, 173–88.
23
Randy Read
Gábor Bunkóczi
Wee Lee Chan
Mykhaylo Demydchuk
Airlie McCoy
Robert Oeffner
Yahui Yan
Aiwu Zhou
Funding:
Wellcome Trust
National Institutes of
Health (USA)
Zhou, A., Carrell, R. W., Murphy,
M. P., Wei, Z., Yan, Y., Stanley,
P. L. D., Stein, P. E., Broughton
Pipkin, F. and Read, R. J. (2010).
A redox switch in angiotensinogen
modulates angiotensin release.
Nature 468, 108–111.
Protein Crystallography and Pathogenesis
Research in my group is in the field of protein
crystallography. Crystallography is the primary
method for determining the three-dimensional
structure of a protein, which provides an essential framework for a detailed understanding of
its biochemistry. We work both on extending the
scope and power of the methods used in protein
crystallography, and on applying those methods
to determine new protein structures. In choosing
what to study we focus on proteins involved
in pathogenesis and disease, the structures of
which can be exploited in the development of
new therapies.
One focus of recent structural work has been
on members of the serpin family, most of
which undergo an extraordinary conformational
change on cleavage by proteases. The structures of two hormone-binding globulins show
how they harness this conformational change
to deliver thyroxine and cortisol to their sites of
action. Our work on angiotensinogen, the source
of the hormone angiotensin, has shed new light
on how blood pressure is modulated. We also
DiMaio, F., Terwilliger, T. C.,
Read, R. J., Wlodawer, A.,
Oberdorfer, G., Wagner, U.,
Valkov, E., Alon, A., Fass, D.,
Axelrod, H. L., Das, D., Vorobiev,
S. M., Iwaï, H., Pokkuluri, P. R.
and Baker, D. (2011). Improving
molecular replacement by densityand energy-guided protein
structure optimization. Nature
473, 540–543.
Deane, J. E., Graham, S. C.,
Kim, N. N., Stein, P. E., McNair,
R., Cachón-González, M. B.,
Cox, T. M. and Read, R. J.
(2011). Insights into Krabbe
disease from structures of
galactocerebrosidase. Proc Natl
15173.
Schematic illustration of the methods (including our
program Phaser) used to solve the crystal structure of
angiotensinogen, by averaging electron density over
multiple crystal forms.
24
have an interest in enzymes mutated in inherited
metabolic diseases. The structure of galactocerebrosidase is helping to understand how
mutations in this enzyme lead to Krabbe disease.
In crystallographic theory, we focus on the understanding of probability distributions relating the
structure factors that arise from the diffraction
experiment. A detailed understanding of these
probability distributions underlies new developments in maximum likelihood methods, which
we are implementing in our program Phaser. The
current version of Phaser can solve structures
by molecular replacement (i.e. using the known
structures of related proteins), by using the
information from single-wavelength anomalous
diffraction (SAD), and by a combination of the
two. In a collaboration with the developers of
the modelling program Rosetta, we have been
excited to find that the combination of molecular
replacement and advanced modelling can solve
structures that elude previous methods.
Molecular Cellular Pathology of Axonal
Degeneration
Our research is focused on the hereditary spastic
paraplegias (HSPs), genetic conditions in which
there is a distal degeneration of the longest
axons of the motor pathway in the spinal cord.
These conditions provide an excellent opportunity to understand molecular mechanisms crucial
for axonal function, potentially of relevance to
more common neurological diseases.
We want to understand the normal functions of
HSP proteins and how these functions are disrupted to cause axonopathy. Many of the disease
proteins function in membrane traffic processes,
especially at the endoplasmic reticulum and at
endosomes. Our work concentrates on understanding the functions of this membrane traffic
subgroup of HSP proteins and is based on
several related themes:
1. Understanding the functions of spastin. This
is crucial to understanding the pathogenesis of
HSP, since mutations in the spastin gene are the
most frequent cause of the disease, and since
the spastin protein is at the hub of an interacting
network of HSP proteins. Spastin is a microtubule
severing protein and our work has shown that it
is recruited to membrane traffic sites, where it
couples microtubule regulation to membrane
modelling processes. Spastin functions at the
early secretory pathway, where it is involved in
endoplasmic reticulum morphogenesis. It also
functions at endosomes. We are unravelling the
role of spastin at these locations, using a variety
of cell biological and in vivo approaches.
2. Understanding the role of HSP proteins in
BMP signalling. We are especially interested
to determine whether a group of HSP proteins
cause HSP by disrupting Bone Morphogenetic
Protein (BMP) signalling in the axon, by affecting membrane traffic of BMP receptors. If so,
targeting this pathway could open the possibility
of new therapeutic approaches for the HSPs.
Evan Reid
Rachel Allison
Virginia Clowes
James Connell
Caroline Freeman
James Gingell
Funding:
Wellcome Trust
Tsang, H. T. H., Edwards, T.
L., Wang, X., Connell, J. W.,
Davies, R. J., Durrington, H. J.,
O’Kane, C. J., Luzio, J. P. and
Reid, E. (2009). The hereditary
spastic paraplegia proteins
NIPA1, spastin and spartin are
inhibitors of mammalian BMP
signaling. Hum Mol Genet 18,
3805–3821.
Blackstone, C., O’Kane, C. J.
and Reid, E. (2011). Hereditary
Spastic Paraplegias: membrane
traffic and the motor pathway.
Nat Rev Neurosci 12, 31–42.
Montenegro, G., Rebelo, A.,
Connell, J., Allison, R., Babalini,
C., Schle, R., Ishiura, H.,
D’Aloia, M., Montieri, P., Price,
J., Strickland, A., Gonzalez, M.,
Baumbach, L., Deconinck, T.,
Huang, J., Bernardi, G., Vance,
J., Rogers, M. T., Tsuji, S., de
Jonghe, P., Pericak-Vance,
M., Schöls, L., Orlacchio, A.,
Reid, E.*, Züchner, S. (2012).
Mutations in the ER-shaping
protein Reticulon2 cause the
axonal degenerative disorder
Hereditary Spastic Paraplegia
type 12. J Clin Invest (in press).
* joint corresponding and senior
author
The microtubule severing enzyme spastin regulates
endosomal tubulation. Image shows increased
tubulation of an endosomal compartment (labelled
with SNX1) in a HeLa cell depleted of spastin by
siRNA knockdown.
25
Frank Reimann
Eleftheria
Diakogiannaki
Catherine Moss
Funding:
Wellcome Trust
European Foundation for the
Study of Diabetes
BBSRC/AstraZeneca
European Union FP7
Full4Health
Reimann, F., Cox, J. J., Belfer,
I., Diatchenko, L., Zaykin, D. V.,
McHale, D. P., Drenth, J. P. H.,
Dai, F., Wheeler, J., Sanders, F.,
Wood, L., Wu, T. X., Karppinen,
J., Nikolajsen, L., Männikkö, M.,
Mitchell, B. M., Kiselycznyk, C.,
Poddar, M., te Morsche, R. H. M.,
Smith, S., Gibson, D., Maixner,
W., Gribble, F. M. and Woods,
C. G. (2010). Pain perception
in common painful conditions
is altered by a nucleotide
polymorphism in SCN9A.
5148–5153.
Stimulus Secretion Coupling in
Enteroendocrine Cells
After a meal a range of hormones is released
from specialised intestinal cells, the enteroendocrine cells, which coordinate the body’s response
to the availability of nutrients. As enteroendocrine cells lie scattered throughout the intestinal
epithelium we have made a number of transgenic mice expressing marker proteins under
the control of specific hormone promoters to
aid their identification and manipulation. Tagging
with fluorescent markers allows the purification
of specific enteroendocrine subpopulations
for expression analysis. Surprisingly, we have
found cells expressing a number of hormones
concomitantly, challenging the traditional classification of enteroendocrine cells based on cell
morphology and limited immunohistochemical
characterisation. Fluorescent markers also allow
the identification of enteroendocrine cells in
mixed epithelial cultures, enabling the use of
single-cell techniques, like patch-clamping and
live cell fluorescent imaging, to study stimulussecretion coupling mechanisms. Whilst we have,
in collaboration with Dr Fiona Gribble’s lab,
identified electrogenic sodium-coupled glucose
uptake via SGLT-1 as a major contributor to
Friedlander, R. S., Moss, C. E.,
Mace, J., Parker, H. E., Tolhurst,
G., Habib, A. M., Wachten, S.,
Cooper, D. M., Gribble, F. M.
and Reimann, F. (2011). Role of
phosphodiesterase and adenylate
cyclase isozymes in murine
colonic glucagon like peptide 1
secreting cells. Br J Pharmacol
163, 261–271.
Rogers, G. J., Tolhurst, G.,
Ramzan, A., Habib, A. M.,
Parker, H. E., Gribble, F. M. and
Reimann, F. (2011). Electrical
activity-triggered Glucagon-Like
Peptide-1 secretion from primary
murine L-cells. J Physiol 589,
1081–1093.
L-cells expressing YFP are immuno-stained against different
gut hormones (red fluorescence) and analysed by FACS.
Overlap between cell types is shown by proportions of YFPpositive cells (dark) that are immunopositive (light).
26
carbohydrate sensing, we are less sure about
the lipid sensing machinery of enteroendocrine
cells. Ingested lipids are, however, at least as
good a stimulus as glucose for the release of
glucagon-like peptide-1 (GLP-1) and glucosedependent insulinotropic polypeptide (GIP), two
hormones which between them are believed to
account for the stimulation of >50% of insulin
released after a meal. One current focus of the
lab is thus the investigation of potential lipid
sensing mechanisms of GLP-1 and GIP releasing cells with the aim to identify potential targets
to manipulate hormone release in the treatment
of type 2 diabetes and obesity.
A second interest of our group is in the understanding of electrophysiological mechanisms
underlying pain perception. In collaboration
with the group of Professor Geoff Woods, we
characterise mutations affecting channel genes,
as exemplified by the voltage-gated sodium
channel gene SCN9A, mutations of which can
give rise to hypersensitivity or complete obliviousness to painful stimuli.
Margaret
Robinson
Coated Vesicle Adaptors
Proteins are transported between the various
organelles of the cell by vesicles, which bud
from one membrane and fuse with another. The
formation of these vesicles and the selection of
the right sort of cargo are dependent on coat
proteins. Several types of coated vesicles have
been described, the best characterised of which
are the clathrin-coated vesicles (CCVs). The
coats on CCVs consist of two major components,
clathrin and adaptor protein (AP) complexes, as
well as other less abundant proteins.
To look for novel adaptors and other components of the CCV machinery, we are using two
approaches. One is a proteomics analysis of
CCVs, both to establish the protein composition
of CCVs and to gain insights into the functional
relationships between the various components
by carrying out “CCV profiling”. The second
approach is to screen a human genome-wide
library for siRNAs that disrupt clathrin-mediated
trafficking. Top hits include several subunits of
the vacuolar ATPase, and we are investigating the
role of V-ATPase in CCV formation. We are also
making use of a novel system that we developed,
called a knocksideways, to investigate the consequences of rapidly inactivating CCV machinery
in cultured cells, and we are in the process of
generating a knocksideways mouse model.
Although for over 10 years it has been assumed
that there are four AP complexes, we recently
discovered a fifth AP complex. We are currently
characterizing the AP-5 pathway, and how
mutations affecting this pathway might lead to
hereditary spastic paraplegia. In addition, we are
investigating how the HIV-1-encoded protein
Nef hijacks adaptor-mediated trafficking to down
regulate the cell surface proteins MHC Class I
and CD4.
Georg Borner
Maja Choma
Jennifer Hirst
Nicola Hodson
Patrycja Kozik
Daniela Sahlender
Funding:
Wellcome Trust
Hirst, J., Sahlender, D. A.,
Choma, M., Sinka, R., Harbour,
M. E., Parkinson, M. and
Robinson, M. S. (2009). Spatial
and functional relationship of
GGAs and AP-1 in Drosophila
and HeLa cells. Traffic 10,
1696–1710.
Robinson, M. S.*, Sahlender,
D. A. and Foster, S. D. (2010).
Rapid inactivation of proteins
by rapamycin-induced rerouting
to mitochondria. Dev Cell 18,
324–331.
*corresponding author
Hirst, J., Francisco, G. C.,
Sahlender, D. A., Seaman, M.
N. J., Dacks, J. B. and Robinson,
M. S. (2011). The fifth adaptor
protein complex. PLoS Biol 9,
e1001170.
The “knocksideways” system reroutes much of the
AP-2 adaptor complex (red, left) to mitochondria
(green) just 6 seconds after adding a small molecule
(red, middle).
27
David
Rubinsztein
Carla Bento
Jenny Carmichael
Angeleen Fleming
Moises
Garcia-Arencibia
Zeyn Green-Thompson
Warren Hochfeld
Maike Lichtenberg
Shouqing Luo
Dunecan Massey
Fiona Menzies
Kevin Moreau
Claudia Puri
Marie Quick
Maurizio Renna
Oana Sadiq
Maria Sanchez
Farah Siddiqi
Frances Thomson
Pearl Toh
Eszter Zavodszky
Aggregate-prone Intracellular Proteins and
Disease – from Biology to Therapeutic Strategies
Intracellular protein aggregation is a feature of
many late-onset neurodegenerative diseases,
including Huntington’s disease (HD) and the
muscle disease oculopharyngeal muscular dystrophy (OPMD). Most of these mutant proteins
cause disease via toxic gain-of-function mechanisms. Therefore, the factors regulating their
clearance are crucial for understanding disease
pathogenesis and for developing rational therapeutic strategies.
The two major intracellular protein degradation
pathways are the ubiquitin-proteasome system
and (macro)autophagy.
David Rubinsztein’s laboratory studies the
relevance of autophagy in neurodegenerative disease, and the basic cell biology of this
important catabolic process. He aims to further
the understanding of the pathogenesis of Huntington’s disease and oculopharyngeal muscular
dystrophy, and to develop rational therapeutic
strategies for these conditions. He has identified
FDA-approved drugs that may have benefit in
both diseases, since he has demonstrated their
efficacies and protective mechanisms in a range
of cell and animal models.
Over the last two years, the highlights of his
work include:
1. Characterising early steps in autophagosome
biogenesis, and showing that the plasma
membrane contributes to autophagosome
precursors.
2. Showing that lysosomal positioning affects
both autophagosome biogenesis and
autophagosome-lysosome fusion, and that
this is a strategy that can influence toxicity of
aggregate prone proteins that cause diseases
like Huntington’s disease.
3. Demonstrating that mutations that cause
forms of Parkinson’s disease and the degenerative epilepsy, Lafora disease, inhibit
autophagy.
4. Showing that nitric oxide accumulation, which
occurs in many neurodegenerative diseases,
impairs autophagy, and that inhibition of nitric
oxide formation alleviates the aggregation and
toxicity of mutant huntingtin in cell culture and
in vivo.
5. Demonstrating that cystamine alleviates the
toxicity of the mutation causing OPMD in cells
and in mice.
Funding:
Wellcome Trust
Research Centre
European Union FP7
BBSRC/Lilly CASE
Studentship
Tau Consortium
Korolchuk, V. I., Saiki, S.,
Lichtenberg, M., Siddiqi, F. H.,
Roberts, E. A., Imarisio, S.,
Jahreiss, L., Sarkar, S., Futter,
M., Menzies, F. M., O’Kane, C. J.,
Deretic, V. and Rubinsztein, D.
C. (2011). Lysosomal positioning
coordinates cellular nutrient
responses. Nat Cell Biol 13,
453–460.
28
Sarkar, S., Korolchuk, V. I., Renna,
M., Imarisio, S., Fleming, A.,
Williams, A., Garcia-Arencibia, M.,
Rose, C., Luo, S., Underwood, B.
R., Kroemer, G., O’Kane, C. J. and
Rubinsztein, D. C. (2011). Complex
inhibitory effects of nitric oxide on
autophagy. Mol Cell 43, 19–32.
Moreau, K., Ravikumar, B., Renna,
M., Puri, C. and Rubinsztein, D. C.
(2011). Autophagosome precursor
maturation requires homotypic
fusion. Cell 146, 303–317.
Clathrin-coated pit labelled against
Atg16L1, a protein associated with
autophagosome precursors (15 nm gold),
and clathrin (10 nm gold). See Nat Cell
Biol (2010) 12, 747–757.
T-cell signalling and immune function
Professor Rudd’s research focuses on deciphering the signal transduction pathways in T-cells,
and their connection to immune responses and
various immune disorders. My laboratory was
the first to discover the CD4 and CD8-p56lck
(lck) complexes, initiators of the phosphorylation
and activation cascade in T-cells. We are presently interested in the identity of downstream
substrates, in particular, complexes responsible
for the ‘inside-out’ pathway for adhesion and
the movement of T-cells in lymph nodes. These
events are needed for T-cell migration to sites
of inflammation and interaction with antigen
presenting cells. Two mediators, adhesion- and
degranulation-promoting adapter protein (ADAP)
and src kinase-associated phosphoprotein 1
(SKAP1) control LFA-1 activation, while SKAP1
binding to RapL controls the ‘slowing’ of T-cells
in lymph nodes for interactions with dendritic
cells. ADAP and SKAP1 also regulate the NF&b
and ERK pathways as well as infection by the
human immunodeficiency virus (HIV-1). We are
interested in the targeting of these pathways in
Christopher
Rudd
the development of new drugs for the treatment
of infection and cancer.
We are also interested in the signalling events
responsible for the function of co-receptors
such as CD28, ICOS, CTLA-4 and PD-1. These
co-receptors qualitatively change immune
responses, and have been successfully targeted
in the treatment of auto-immune disorders
and cancer. We identified CD28 binding to the
adaptor Grb2 in the activation of the transcription factor NF&B, while the CD28 binding to PI
3K activates glycogen synthase kinase (GSK3)
for optimal cytolytic T-cell (CTL) function. We
have also proposed a new model ‘reverse stop
signal model’ to explain CTLA-4 dampening of
immune responses and protection against the
development of autoimmunity. CTLA-4 activates
T-cell motility and limits T-cell-dendritic cell
interactions. Our laboratory uses a variety of
approaches from basic biochemistry to cellular
immunology and the generation of models of
immunodeficiency and infection.
Kittiphat Chanthong
Karsten Koehler
Christian Ku
Daina Lim
Hebin Liu
Yuning Lu
Asha Recino
Pavel Riha
Helga Schneider
Xin Smith
Alison Taylor
Raj Thaker
Funding:
Wellcome Trust
Rudd, C. E. (2008). The reverse stopsignal model for CTLA4 function. Nat
Rev Immunol 8, 153–160.
Raab, M., Smith, X., Wang, H., Lu,
Y., Wu, Y., Strebhardt, K., Ladbury,
J.E. and Rudd, C.E. (2010). T cell
receptor “Inside-Out” pathway
via signaling module SKAP1RapL regulates T cell motility and
interactions in lymph nodes. Immunity
32, 541–556.
Purbhoo, M. A, Liu, H., Oddos, S.,
Owen, D. M., Neil, M. A. A., Pageon,
S., French, P. M., Rudd, C. E. and
Davis, D. M. (2010). Dynamics
of sub-synaptic vesicles and
surface microclusters at the
immunological synapse. Science
(Signal) 3, ra36.
Upper panel: T-cell receptor signalling pathway for activation of LFA-1 on T-cells.
Lower panel: motifs within the cytoplasmic tail of CD28 bind various signalling proteins.
29
Peter St
George-Hyslop
Katie Cox
Roger Dodd
Yi Li
Stephen Lu
Beth McDonald
William Meadows
Seema Qamar
Molecular Mechanisms of Neurodegeneration
My laboratory focuses on understanding the
molecular mechanisms underlying neurodegenerative diseases, using molecular genetics,
animal modelling and biophysical methods. The
presenilin complex performs the intra-membranous cleavage of the amyloid precursor protein
to generate the neurotoxic, aggregation-prone
Abeta peptide. Using a series of biophysical
tools including negative stain electromicroscopy,
mass spectrometry, FLIM-FRET and analytical
ultracentrification, we have generated a model
of the presenilin complex and demonstrated
how the binding of small molecule inhibitors and
substrates induces a conformational change
in the complex. Ongoing work now seeks
to improve the resolution of this model. In a
separate series of experiments we have also
investigated how mutations in the FUS gene
cause motor neuron disease, we have generated
a model in C.elegans. In this model, mutations
cause paralysis, the severity of which directly
mimics the severity of the human disease associated with that mutation. We have shown that
this arises because of aggregation of the mutant
FUS protein, and preliminary evidence suggests
that the disease phenotype can be reversed by
small molecule inhibitors of aggregation.
Funding:
Wellcome Trust
National Institute for Health
Research
Howard Hughes Medical
Institute
Ontario Research Fund
Naj, A. C. et al. (2011). Common
variants at MS4A4/MS4A6E,
CD2AP, CD33 and EPHA1
are associated with late-onset
Alzheimer's disease. Nat Genet
43, 436–441.
Höglinger, G. U. et al. (2011).
Identification of common variants
influencing risk of the tauopathy
progressive supranuclear palsy.
Nat Genet 43, 699–705.
Murakami, T. et al. (2011).
ALS mutations in FUS causes
neuronal dysfunction and death
in C. elegans by a dominant gainof-function mechanism. Hum Mol
Genet (epub).
View from extracellular surface of 3D reconstruction of the
presenilin complex in the absence of ligand/substrate (left) and in
the presence of ligand/substrate (right).
30
The Molecular Mechanisms of Endosome-toGolgi Retrieval
Protein localization within eukaryotic cells is
essential for normal cellular physiology. The
mechanisms that govern the localization of
membrane proteins within the post-Golgi endocytic system control diverse processes such
as; nutrient uptake, signaling receptor downregulation, synaptic transmission, the response
to infection and generation of immunity. There
is a growing awareness and appreciation of the
importance of correct endosomal protein sorting
in various neurodegenerative disorders.
In my lab we study the functioning of the
endosome-to-Golgi retrieval pathway and have
extensively characterized the role of the retromer
complex in that pathway. Retromer is a conserved
protein complex that localizes to endosomes to
sort membrane proteins into nascent tubules.
The retromer complex can be functionally dissected into two subcomplexes; a cargo-binding
complex comprising a heterotrimer of VPS35VPS29-VPS26 proteins and the sorting nexin
dimer of Snx1 or Snx2 with Snx5 and Snx6.
We have recently demonstrated the role that the
small GTPase, Rab7a, plays in regulating the
membrane association of the cargo-selective
retromer complex. In addition to Rab7a, the
TBC1D5 protein also interacts with the cargoselective retromer complex by direct binding
to VPS29. As a member of the Rab GTPase
activating protein (GAP) family, TBC1D5
operates antagonistically to Rab7a. Therefore,
Rab7a and TBC1D5 ensure that the cargoselective retromer complex mediates the sorting
of membrane proteins through a dynamic cycle
of association and dissociation of the complex
with the membrane.
Attempts to identify proteins that interact with
the retromer complex and contribute to the efficiency of endosomal protein sorting are on-going
and comprise a number of complementary techniques including; native immunprecipitation to
identify proteins associated with retromer and
functional genomics using high-throughput
siRNA screening technologies to identify candidate genes required for endosome-to-Golgi
retrieval.
As a result of these efforts, we have recently
reported the role of the retromer complex in
mediating the recruitment of the endosomal
WASH complex. One of the components of the
WASH complex is a protein called Strumpellin
that is mutated in Hereditary Spastic Paraplegia
(HSP) – a neuronal degenerative disorder. Loss
of Strumpellin function results in dysregulation
of endosomal tubules suggesting that defective
regulation of endosomal membrane dynamics
may contribute to the pathology of HSP.
Matthew
Seaman
Michael Harbour
Sophia Breusegem
Funding:
Seaman, M. N. J., Harbour, M.
E., Tattersall, D., Read, E. and
Bright, N. (2009). Membrane
recruitment of the cargoselective retromer subcomplex is
catalysed by the small GTPase
Rab7 and inhibited by the RabGAP TBC1D5. J Cell Sci 122,
2371–2382.
Kozik, P., Francis, R. W.,
Seaman, M. N. J.* and
Robinson, M. S.* (2010). A
screen for endocytic motifs.
Traffic 11, 843–855.
*co-corresponding authors
Harbour, M. E., Breusegem, S.
Y. A., Antrobus, R., Freeman,
C., Reid, E. and Seaman, M. N.
J. (2010). The cargo-selective
retromer complex is a recruiting
hub for protein complexes that
regulate endosomal tubule
dynamics. J Cell Sci 123,
3703–3717.
A. Schematic diagram of the retromer complex.
B. Cells treated with siRNA to abolish expression of the
Strumpellin protein exhibit markedly more endosomal tubules
(highlighted with arrows and arrow heads). Bar = 20$m.
31
Symeon
Siniossoglou
Hiroshi Sembongi
Funding:
Siniossoglou, S. (2009). Lipins,
lipids and nuclear envelope
structure. Traffic 10, 1181–1187.
Karanasios, E., Han, G.-S., Xu, Z.,
Carman, G. M. and Siniossoglou
S. (2010). A phosphorylationregulated amphipathic helix
controls the membrane
translocation and function of the
yeast phosphatidate phosphatase.
17539–17544.
Linking Phospholipid Metabolism to Membrane
and Organelle Function
Lipids are building blocks for membranes and
their regulated production during development
often underlies striking morphological changes
in a variety of specialized cell types. In addition,
lipids act as signals by which organelles and cells
communicate with each other and as energy
storage molecules. Defects in lipid metabolism
or signalling can lead to a large number of disorders such as metabolic syndrome or cancer.
The aim of our laboratory is to understand how
cells maintain lipid and membrane homeostasis during growth and development. Our
current studies focus on a fundamental step
in lipid metabolism, the dephosphorylation of
phosphatidic acid (PA) to diacylglycerol (DAG)
that is catalyzed by a conserved family of lipid
phosphatases, lipins. DAG generated by lipins
is used for the biosynthesis of (a) membrane
phospholipids and (b) triglyceride stored in
lipid droplets. Consistent with these essential
Choi, H. S., Su, W. M., Morgan,
J. M., Han, G.-S., Xu, Z.,
Karanasios, E., Siniossoglou,
S. and Carman G. M. (2011).
Phosphorylation of phosphatidate
phosphatase regulates its
membrane association and
physiological functions in
Saccharomyces cerevisiae. J Biol
Chem 286, 1486–1498.
Lipins catalyze the dephosphorylation of phosphatidic
acid to diacylglycerol (left panel). Loss of lipin 1
inhibits lipid accumulation in adipocytes (upper
panels, red:lipid, blue:DNA, bar: 5$m). Loss of the
lipin Pah1 causes nuclear/ER membrane expansion
in yeast (lower panel, arrows point to the expanding
nucleus in green, bar: 1$m).
32
metabolic functions, lipins are important regulators of both organelle biogenesis and fat storage
in many eukaryotic cells.
Recent work from our group led to the identification of key regulators of the yeast lipin Pah1p
and a model on how these cooperate to recruit
Pah1p onto membranes for DAG production.
We are currently expanding these studies to
both mouse and human fat cells (adipocytes)
that express lipin 1, 2 and 3 and investigate
their roles both during adipocyte differentiation
and lipogenesis. Unexpectedly, lipins also translocate into the nucleus where they regulate
gene expression. We are using a combination of genetics and gene expression profiling
approaches to identify the nuclear targets of
lipins and uncover the function of these lipid
phosphatases into the nucleus.
Immune Regulation, Autoimmune Disease
and Infection
We aim to discover how genetically determined
variation in immune regulation balances the risks
of autoimmune disease and infection. Regulation
of the B cell immune response is a major interest.
We have investigated the function of inhibitory
receptors such as FcyRIIb, which act as “brakes”
on the immune system. We have shown that
even subtle changes in expression of FcyRIIb
on B cells can prevent or induce SLE in mice.
Natural polymorphisms in FcyRIIb are associated with immune dysregulation (see Figure)
and autoimmune diseases such as systemic
lupus erythematosus (SLE) in both mouse and
man. Some reduce function and are common in
Asia and Africa, where malaria is endemic. We
have used mouse models of malaria and human
genetics (in collaboration with the KEMRI/
Wellcome Trust Unit in Kilifi, Kenya), and have
shown that FcyRIIb deficiency can protect
against severe malaria, perhaps contributing to
the evolution of predisposition to SLE in some
ethnic groups. We have recently discovered a
regulatory T cell which specifically regulates
the germinal centre and may have autoimmune
implications. Other lab members are defining
how abnormal control of plasma cell function and
migration contributes to autoimmunity, and are
studying specific micro-RNAs we have shown to
control B cell activation, lymphoid development
and oncogenesis.
We have established a programme in human
autoimmunity, working with patients with vasculitis, SLE, inflammatory bowel disease and
renal transplants (and led with Paul Lyons). By
performing detailed transcriptomic studies of
purified white blood cells we have discovered
novel biomarkers now being assessed for their
ability to guide therapy to improve efficacy and
reduce treatment toxicity. We are also using
genetics to identify novel pathways for investigation. Examples include our initiation of the
European Vasculitis Genetics Consortium which
has just completed the first genome-wide association study in ANCA-associated vasculitis, and a
novel analysis of the inflammatory bowel disease
GWAS which has identified genetic variants
associated with clinical course rather than diagnosis, and defined their functional implications in
humans using the Cambridge BioResource, and
in mouse models.
These programmes together allow us to interrogate mouse and human biology in an integrated
fashion, increasing our capacity to probe
immunity and disease and to translate basic biological findings to the clinic.
Naturally occurring
polymorphisms in
the promoter of the
inhibitory Fcgr2b
“knocked-in” to the
control C57BL6
background (KI) lead
to increased germinal
centre formation
compared to controls
(WT). Immunohistology 8
days after immunisation.
Blue: B220 (= B cell
follicle), green: CD8 (= T
cell zone), red: KI67 (=
germinal centre).
McKinney, E. F., Lyons, P. A.,
Carr, E. J., Hollis, J. L., Jayne, D.
R., Willcocks, L. C., Koukoulaki,
M., Brazma, A., Jovanovic, V.,
Kemeny, D. M. et al. (2010). A
CD8+ T cell transcription signature
predicts prognosis in autoimmune
disease. Nat Med 16, 586–591.
Ken Smith
Daniele Biasci
Susanne Bökers
Menna Clatworthy
Devina Divekar
Marion Espeli
Shaun Flint
Mariana Fonseca
Claire Hales
Alex Hatton
Lorna Jarvis
Elaine Jolly
James Lee
Michelle Linterman
Paul Lyons
Rebeccah Matthews
Eoin McKinney
James Peters
Huzefa Ratlamwala
Tim Rayner
Arianne Richard
John Sowerby
David Thomas
Liz Wallin
Tim Wilson
Matt Zilbauer
Funding:
Wellcome Trust
British Heart Foundation
Research Centre
Lister Institute of Preventive
Medicine
European Union
Lee, J. C., Lyons, P. A., McKinney,
E. F., Sowerby, J. M., Carr, E.
J., Bredin, F., Rickman, H. M.,
Ratlamwala, H., Hatton, A., Rayner,
T. F., Parkes, M., Smith, K. G. C.
(2011). Gene expression profiling
of CD8+ T cells predicts prognosis
in patients with Crohn disease and
ulcerative colitis. J Clin Invest 121,
4170–4179.
Linterman, M. A., Pierson, W.,
Lee, S. K., Kallies, A., Kawamoto,
S., Rayner, T. F., Srivastava, M.,
Divekar, D. P., Beaton, L., Hogan,
J. J. et al. (2011). Foxp3(+) follicular
regulatory T cells control the
germinal center response. Nat Med
17, 975–982.
Paul Lyons
33
John Todd
Xaquin Castro Dopico
Jason Cooper
Tony Cutler
Ricardo Ferreira
Joanna Howson
Marcin Pekalski
Corina Shtir
Austin Swafford
(Co-supervisor –
Mike Lenardo, NIH,
Bethesda, USA)
Funding:
Wellcome Trust
Juvenile Diabetes Research
Foundation International
National Institutes of
Health (USA)
Research Centre
European Union FP7
Nejentsev, S., Walker, N., Riches,
D., Egholm, M. and Todd, J. A.
(2009). Rare variants of IFIH1,
a gene implicated in antiviral
responses, protect against type 1
diabetes. Science 324, 387–389.
Dendrou, C. A., Plagnol, V.,
Fung, E., Yang, J. H. M., Downes,
K., Cooper, J. D., Nutland, S.,
Coleman, G., Himsworth, M.,
Hardy, M., Burren, O., Healy,
B., Walker, N. M., Koch, K.,
Ouwehand, W. H., Bradley, J. R.,
Wareham, N. J., Todd, J. A. and
Wicker, L. S. (2009). Cell-specific
protein phenotypes for the
autoimmune locus IL2RA using
a genotype-selectable human
bioresource. Nat Genet 41,
1011–1015.
Heinig, M. et al. (2010). A
trans-acting locus regulates an
anti-viral expression network and
type 1 diabetes risk. Nature 467,
460–464.
34
Identification of Molecular and Cellular Mechanisms
in Autoimmune Disease
Our aim is to further characterise the molecular
basis for the autoimmune inflammatory disease
type 1 diabetes. We use an integrated combination of genetics, in large collections of type
1 diabetic families and case/control, statistics,
genome informatics and data mining, and gene
expression and immunological studies. Our
major effort now is to correlate susceptibility
genotypes with biomarkers and phenotypes e.g.
we have correlated flow cytometric phenotypes
of T lymphocytes with disease-predisposing
genotypes of the IL-2RA (CD25) gene. This is
a first step towards identifying disease precursors that could be used in future therapeutic
studies to stratify patients. To achieve this we
have helped build a local biobank of volunteers and patients in whom we can study the
effects of disease-associated genotypes and
environmental factors (The Cambridge BioResource:
www.cambridgebioresource.org.uk).
Our research efforts are part of the Juvenile
Diabetes Research Foundation/Wellcome Trust
Diabetes and Inflammation Laboratory (DIL),
which includes the laboratory of Linda Wicker,
as well as collaborations with the Department of
Haematology (Willem Ouwehand), the Department of Paediatrics (David Dunger), and the
Wellcome Trust Sanger Institute.
The methylation/
demethylation of the
FOXP3 gene, which
determines T regulatory
cell number in humans,
is associated with
the genotype of the
autoimmunity, immune
signalling gene PTPN22
The Juvenile Diabetes Research
Foundation/Wellcome Trust Diabetes
and Inflammation Laboratory
The Juvenile Diabetes Research Foundation/
Wellcome Trust Diabetes and Inflammation
Laboratory (JDRF/WT DIL) has two Principal
Investigators and is composed of four integrated
research efforts: John Todd (human genetics and
immunology), Linda Wicker (mouse modelling,
human immunology), Chris Wallace (statistics)
and Frank Waldron-Lynch (clinical). In the last ten
years under programmatic funding we have discovered and defined several mouse and human
susceptibility loci for type 1 diabetes. In the last
five years we have been correlating the presence
of the identified susceptibility alleles with their
functions to determine which molecules and
pathways are underlying the pathogenesis of
type 1 diabetes. Our recent results have shown
how important the interleukin-2 pathway is in
autoimmunity and type 1 diabetes, and we are
exploring further these mechanisms and their
possible implications for new, mechanism-based
therapeutic strategies. A key approach is the collection of local healthy volunteers and patients
(The Cambridge BioResource) who are willing to
donate blood samples, with which we can study
immune cell populations and activities in relation
to genotypes associated with susceptibility and
resistance to type 1 diabetes and autoimmune
disease. The JDRF/WT DIL is centrally involved in
the activities of two major international consortia,
the National Institute of Diabetes and Digestive
and Kidney Diseases (NIDDK)-and JDRF-funded
Type 1 Diabetes Genetics Consortium (T1DGC)
and the Wellcome Trust Case Control Consortium
(WTCCC). Immunological and gene-phenotype
studies have been strengthened in the establishment of a new JDRF Centre: Diabetes Genes,
Autoimmunity and Prevention (D-GAP) which
supports collaborations with Mark Peakman, Tim
Tree, David Dunger and Polly Bingley. Investigations of therapeutic strategies in type 1 diabetes
are supported by a collaborative project funded by
the European Union’s 7th Framework Programme
(FP7), Natural immunomodulators as novel immunotherapies for type 1 diabetes (NAIMIT).
Systems Management
Vin Everett (Head)
Wojciech Giel
Sundeep Singh Nanuwa
Sample Processing
Helen Stevens (Head)
Pamela Clarke
Gillian Coleman
Sarah Dawson
Jennifer Denesha
Simon Duley
Simon Knights
Meeta Maisuria-Armer
Trupti Mistry
Interaction of a human T regulatory cell and
dendritic cell involving the type 1 diabetes
susceptibility molecule, CTLA-4. Photograph
reproduced with kind permission from Paul
MacAry and Laura Esposito.
Affiliates
Cambridge BioResource
Sarah Nutland (Co-ordinator)
Kelly Beer
Simon Hacking
Alison Hayday
Jamie Rice
Rachel Simpkins
Hannah Stark
Clinical Research
Frank Waldron-Lynch
(Head)
Louise Bell (Co-ordinator)
Pippa Tagart
Maureen Wiesner
DIL Laboratory
Management and
Administration
Judy Brown (Head)
Jennifer Newton
Anna Simpson
Niall Taylor
John Todd, Director
Linda Wicker, Co-director
Research Group (Todd)
Xaquin Castro Dopico
Jason Cooper
Tony Cutler
Ricardo Ferreira
Joanna Howson
Marcin Pekalski
Corina Shtir
Austin Swafford
(Co-supervisor –
Mike Lenardo, NIH,
Bethesda, USA)
Research Group (Wicker)
Jan Clark
Laura Esposito
Sarah Howlett
Dan Rainbow
Kara Rainbow
Research Group
(Wallace)
Chris Wallace
Hui Guo
Nikolas Pontikos
Xin Yang
Genotyping and
Sequencing
Debbie Smyth (Head)
Genome Informatics
Oliver Burren (Head)
Premanand Achuthan
Ellen Adlem
Mikkel Christensen
Richard Coulson
Sample Informatics
Matt Woodburn (Head)
James Macfarlane
Krishna Mohan
Jakub Pawlinski
Data Services
Neil Walker (Head)
Nigel Ovington
Helen Schuilenburg
Statistics
Chris Wallace (Head)
Jason Cooper
Hui Guo
Joanna Howson
Nikolas Pontikos
Corina Shtir
Xin Yang
35
John Trowsdale
Jyothi Jayaraman
Wei Jiang
Maki Ohashi
David Rhodes
James Traherne
Funding:
Wellcome Trust
Louise Boyle
Genetic and Functional Relationships between
Polymorphic Immune Receptors
We study proteins encoded in a key set of
human genes, the human Major Histocompatibility Complex (MHC). This dense cluster of
polymorphic loci influences susceptibility to a
large number of human diseases. These include
most, if not all, autoimmune conditions, many
infections and other diverse conditions, from
Narcolepsy to Schizophrenia.
The key products of the MHC are Class I and
Class II molecules. These play a pivotal role
in alerting the immune system to infection
by presentation of antigenic peptides to
receptors on T cells. A major part of our
approach concerns the regulation and functions
of these molecules. Our early work involved
discovery of antigen processing molecules
encoded in the MHC, such as the TAP peptide
transporter and immunoproteasome subunits (J
Immunol 2008 Pillars of Immunology: antigen
presentation: discovery of the peptide TAP). Following on from this, we found a novel molecule,
TAPBPR, which is related to the MHC-encoded
TAPASIN molecule. TAPBPR appears to
modulate MHC class I expression and may
have a profound affect on immune recognition.
Louise Boyle is leading a project to elucidate the
function of TAPBPR in order to understand the
role of this new player in MHC class I processing
and presentation.
Further information on the state of health of a
cell is provided by interaction of MHC class I
molecules with other receptors on Natural Killer
(NK) cells. Like some MHC genes, NK receptors form an extensive, polymorphic gene family.
We are particularly interested in understanding
the interplay between NK receptors and MHC
class I molecules, in relation to disease.
Clemens Hermann
Keith Porter
Traherne, J. A. et al. (2010).
Mechanisms of copy number
variation and hybrid gene
formation in the KIR immune gene
complex. Hum Mol Genet 19,
737–751.
Rhodes, D. A., Boyle, L. H.,
Boname, J. M., Lehner, P. J.
and Trowsdale, J. (2010).
Ubiquitination of lysine-331 by
Kaposi's sarcoma-associated
herpesvirus protein K5 targets
HFE for lysosomal degradation.
16240–16245.
Barrow, A. D. et al. (2011).
OSCAR is a collagen
receptor that costimulates
osteoclastogenesis in DAP12deficient humans and mice. J Clin
Invest 121, 3505–3516.
36
Frequencies of unique KIR haplotypes with variable gene copy number.
Inset charts: frequencies of centromeric and telomeric haplotype structures (Figure: J Traherne).
Identification of Molecular and Cellular
Mechanisms in Autoimmune Disease
Our group, as part of the Juvenile Diabetes
Research Foundation/Wellcome Trust Diabetes
and Inflammation Laboratory (DIL), is focused
on understanding the molecular and cellular
mechanisms mediating autoimmune syndromes
such as type 1 diabetes (T1D) by identifying and
characterising the function of genes that contribute to disease susceptibility in both humans
and nonobese diabetic (NOD) mice. Some
T1D-associated genes and molecular pathways
are shared by humans and mice as exemplified by the CTLA-4 and IL-2 pathways. Both
CTLA-4 and IL-2 are required for the function
of FOXP3+CD25+CD4+ regulatory T cells, a T
cell subset that dampens the immune response
and is less functional in T1D patients and NOD
mice. FOXP3+CD25+CD4+ regulatory T cells
are a therapeutic target in T1D and the subject
of intense investigation by many laboratories,
including the DIL.
To link the gene variants that cause autoimmune disease with their biological effects within
the immune system, we study the peripheral
blood of T1D patients and healthy volunteers
accessed through the Cambridge BioResource.
Genotypes at T1D-causal genes are correlated
with phenotypes ranging from protein expression of the disease-causing gene to parameters
of immune cell activation and differentiation.
One phenotype for which we have discovered a
genotype correlation is the expression of CD25
on naïve CD4+ T cells (see Figure). The variant
of the gene encoding CD25 that increases the
likelihood of developing T1D and multiple sclerosis is correlated with an increased frequency
of CD25+ naïve CD4+ T cells. In the susceptible
genotype, the frequency of CD25+ naïve CD4+ T
cells is influenced by both age and sex. We are
currently investigating this poorly characterised
subpopulation of naïve CD4+ T cells and testing
the hypothesis that CD25 expression decreases
the activation threshold thereby making it more
likely that naïve CD4+ T cells with affinity to
self antigens will differentiate into pathogenic
effector cells.
Linda Wicker
Jan Clark
Laura Esposito
Sarah Howlett
Dan Rainbow
Kara Rainbow
Funding:
Wellcome Trust
Juvenile Diabetes Research
Foundation International
National Institutes of Health
(USA)
Dendrou, C. A., Plagnol,
V., Fung, E., Yang, J. H. M.,
Downes, K., Cooper, J. D.,
Nutland, S., Coleman, G.,
Himsworth, M., Hardy, M.,
Burren, O., Healy, B., Walker,
N. M., Koch, K., Ouwehand, W.
H., Bradley, J. R., Wareham,
H. J., Todd, J. A. and Wicker, L.
S. (2009). Cell-specific protein
phenotypes for the autoimmune
locus IL2RA using a genotypeselectable human bioresource.
Nat Genet 41, 1011–1015.
Fraser, H. I., Dendrou, C.
A., Healy, B., Rainbow, D.
B., Howlett, S., Smink, L.
J., Gregory, S., Steward, C.,
Todd, J. A., Peterson, L. B. and
Wicker, L. S. (2010). NOD
congenic strain analysis of
autoimmune diabetes reveals
genetic complexity of the Idd18
locus and identifies Vav3 as a
candidate gene. J Immunol 184,
5075–5084.
Using multi-colour flow cytometry and blood
samples from Cambridge BioResource donors, we
have correlated an increased frequency of CD25+
naïve CD4+ T cells (outlined in red on the figure)
with susceptibility to type 1 diabetes and multiple
sclerosis.
Rainbow, D. B., Moule, C.,
Fraser, H. I., Clark, J., Howlett,
S. K., Burren, O., Christensen,
M., Moody, V., Steward, C. A.,
Mohammed, J. P., Fusakio,
M. E., Masteller, E. L., Finger,
E. B., Houchins, J. P., Naf, D.,
Koentgen, F., Ridgway, W. M.,
Todd, J. A., Bluestone, J. A.,
Peterson, L. B., Mattner, J. and
Wicker, L. S. (2011). Evidence
that Cd101 is an autoimmune
diabetes gene in NOD mice.
J Immunol 187, 325–336.
37
Geoff Woods
Ofelia Carvalho
Maryam Khurshid
Adeline Nicholas
Funding:
Wellcome Trust
Pfizer, UK
Birth Defects Foundation
Nicholas, A. K., Khurshid, M.,
Désir, J., Carvalho, O. P., Cox,
J. J., Thornton, G., Kausar, R.,
Ansar, M., Ahmad, W., Verloes,
A. et al. (2010). Wdr62 is
associated with the spindle
pole and is mutated in human
microcephaly. Nat Genet 42,
1010–1014.
Bakircioglu, M., Carvalho,
O. P., Khurshid, M., Cox, J. J.,
Tuysuz, B., Barak, T., Yilmaz,
S., Caglayan, O., Dincer, A.,
Nicholas, A. K. et al. (2011).
The essential role of centrosomal
NDE1 in human cerebral cortex
neurogenesis. Am J Hum Genet
88, 523–535.
Sir, J.-H., Barr, A. R., Nicholas,
A. K., Carvalho, O. P., Khurshid,
M., Sossick, A., Reichelt, S.,
D'Santos, C., Woods, C. G.*,
Gergely, F.* (2011). A primary
microcephaly protein complex
forms a ring around parental
centrioles. Nat Genet 43,
1147–1153.
38
The Study of Mendelian Disorders of
Neurogenesis and Pain
We have two main areas of research: first, to
understand early human neurogenesis by the
study of families with microcephaly; and second,
to find the genes causing Mendelian disorders
of pain perception.
humans should manifest only as a brain of
reduced size is now our “big question”. Another
strand of our work is the evolution of the human
brain and whether the MCPH genes have contributed to the recent threefold increase in size.
We have shown that “automosoal recessive
primary microcephaly” (MCPH for short) is a
disorder of neurogenic mitosis I the embryonic
and foetal developing brain. After birth the
MCPH brain is small, but architecturally normal,
and that the phenotype is mental retardation –
but not physical retardation. The MCPH proteins
are highly expressed in the neuro-epithelium
lining the interior of the brain, and from which
the majority of neurones arise in foetal life. Our
initial focus was to find the MCPH genes, now
we are trying to find what these genes do and
how perturbation of this process leads to a small
human brain. As all MCPH genes to date are
centrosomal components we are studying their
effects on mitosis, cytokinesis, cell polarity and
the centriole and centrosome cycle. We have
recently found that most of the MCPH genes
form a complex. Completely unexpectedly this
complex is involved in daughter centriole attachment and maturation on the mother centriole
– an apparently fundamental process in animal
cells. Why defects of centriole maturation in
We recently discovered that non-sense mutations in SCN9A, encoding a voltage gated
membrane sodium channel, lead to an inability to
feel any pain. Subsequently we have begun the
study of a number of Mendelian disorders where
too much or too little pain is felt, or analgesics
are ineffective. For each we have found/are
finding the causative gene and then determining
its function in normal nociception. This work has
the clear potential to generate new analgesic
targets and is part funded by Pfizer.
Using similar methodologies we study a number
of other Mendelian neurodevelopmental disorders, e.g. complete sex reversal, novel recessive
neurodevelopmental disorders. Whilst these
conditions are rare, each will yield essential
insights into normal neurodevelopment after we
identify the causative gene and determination of
its function(s).
Magnified image of
mouse E13 cerebral
cortex neuroepithelium
showing Wdr62
(red) in apical mitotic
precursors (nuclei in
blue/DAPI). Strong
Wdr62 expression
is seen in apical
neural precursor cells
undergoing mitosis with
a pair of centrosomes
(green) either side of a
metaphase plate.
Core Scientific Facilities at CIMR
Mark Bowen (Confocal/Imaging)
Matthew Gratian (Confocal/Imaging)
Kamburapola Jayawardina (Jay)
(Proteomics)
Nikol Simecek (Bioinformatics/Systems)
Anna Petrunkina Harrison (Flow Cytometry)
(Also Associate Professor, Biomedical Engineering & Reproductive Biology, University of
Veterinary Medicine, Hanover and Associate
Editor in Reproduction, Fertility, Development.)
The above are all core staff funded as part of CIMR’s Wellcome Trust Strategic Award
39
MRC Mitochondrial Biology Unit
John Walker
The MRC Mitochondrial Biology Unit evolved
from the former MRC Dunn Human Nutrition Unit.
Its formation by the MRC recognises growing
evidence for the involvement of mitochondria
and their dysfunction in an ever-increasing range
of human diseases most notably in neuromuscular and neurodegenerative diseases, and even,
perhaps, in the process of ageing.
The Unit has three major scientific aims:
s
To understand the fundamental processes
taking place in mitochondria.
s
To understand the involvement of these
processes in human diseases.
s
To exploit knowledge of these fundamental
processes for the development of new
therapies to treat human diseases.
Today, the Unit has ten independent research
groups, studying different aspects of the mitochondrion ranging from structural and functional
studies of central respiratory enzymes (John
Walker, Judy Hirst and Leo Sazanov) and transport proteins (Edmund Kunji), to studies of
mtDNA replication, mitochondrial genetics and
biogenesis of mitochondria in relation to mitochondrial disease (Ian Holt, Michal Minczuk and
Antonella Spinazzola), and to aspects of apoptosis and generation of reactive oxygen species
in relation to ageing (Michael Murphy). A bioinformatics group (Alan Robinson) has developed
modelling an in silico model of the mitochondrion.
The goal is to develop models for the dynamics
and control of the metabolic and bioenergetic
pathways, and to use them to analyse various
human pathologies. A proteomics group (John
Walker and Ian Fearnley) is using modern mass
spectrometry to characterise proteins involved
in respiration, in signalling in the mitochondrion,
in mtDNA replication and organelle biogenesis.
Their activities are focussed on understanding the fundamental biochemical and biological
processes which occur in mitochondria. Via collaborations with clinical colleagues in several
countries, the Unit is building on its fundamental
knowledge to try to understand how mitochondrial dysfunction leads to human disease. In
addition, Unit members are engaged in collaborations with pharmaceutical companies, so as to
exploit our fundamental knowledge to generate
new therapies.
Currently, the MRC Mitochondrial Biology Unit
has a staff of 105 including 49 PhD students.
Martin Montgomery prepares to carry out an X-ray diffraction
experiment on a protein crystal.
40
CIMR Affiliated Principal Investigators
Genetics, Genomics and Vaccine Studies
in Leishmaniasis
The major highlight of the research based at CIMR
during 2009–2011 has been a genome-wide
association study (GWAS) of visceral leishmaniasis undertaken as part of the Wellcome Trust
Case Control Consortium Phase Two (WTCCC2).
This involved the analysis of discovery and replication case-control samples from India, and
families from north-eastern Brazil (with Shyam
Sundar, India; Selma Jeronimo, Brazil; Mary
Wilson, USA). The HLA-DRB1-DQA1 locus was
the only region to show strong evidence of association (P=1.47x10-9 at rs9271252; 2.14x10-9
at rs9271255) in the Indian discovery dataset.
Replication occurred within India (P=5.85x10-5
at rs9271255) and Brazil (P=7.41x10-6 at
rs9271252); Pcombined=5.55x10-16 across three
studies. The protective allele at SNP rs9271252
(and at rs9271255; r2=1) tagged three DRB1
allele groups at the two digit level: *15, *16
and *01. These findings are of relevance to our
further analysis of immune responses to 12
novel vaccine candidates for leishmaniasis that
we have analysed in exposed donors (recovered
cases, skin-test positive asympotomatics) from
Brazil and India. Congenic mice bearing the
HLA DRB1 risk and protective alleles are under
construction with genOway to help us further
understand the mechanisms by which these HLA
class II molecules control disease pathogenesis
and response to vaccination.
Head, Division of Genetics and Health
Telethon Institute for Child Health Research
100 Roberts Road, Subiaco
Western Australia, 6008
(GPO Box 855, West Perth, WA 6872)
Tel: +61 (08) 9489 7910
Email: [email protected]
www.ichr.uwa.edu.au/research/divisions/gh
The Molecular Pathogenesis of Alzheimer’s and
Related Neurodegenerative Diseases
My laboratory uses Drosophila melanogaster,
Caenorhabditis elegans and prokaryotic systems
to study specific protein aggregates that have
been implicated in proteinopathies such as
Alzheimer’s disease, tauopathies, Parkinson’s
disease and Familial Encephalopathy with Neuroserpin Inclusion bodies.
We use invertebrate model organisms to link the
biophysical properties of particular proteins, and
their aggregates, with whole-organism phenotypes such as reduced longevity and locomotor
abnormalities.
One of the strengths of these systems is the
power of the genetic toolkits that are available
for studying the biological pathways that
underpin disease phenotypes. Alzheimer’s
disease appears to be initiated by the aggregation of a peptide called A#. We have created a
fly model of Alzheimer’s disease by expressing
this toxic peptide in the insects’ brains. We have
sought to modify the consequent longevity and
behavioural phenotypes by a range of genetic
manipulations and have discovered modifiers
of A# toxicity in the fly. Similarly in the worm
we can compare the network of genes that
mediate the toxicity of A# with the orthologous
network of genes implicated by human genome
wide association studies in Alzheimer’s disease.
Analogous experiments have been performed on
proteins involved in a range of neurodegenerative disorders.
Alzheimer’s Research Trust Senior Research
Fellow
Department of Genetics
Downing Street, Cambridge CB2 3EH
Tel: +44 (0) 1223 760346
www.neuroscience.cam.ac.uk/directory/profile.
php?damiancrowther
Jenefer
Blackwell
Michaela Fakiola
E Nancy Miller
Fakiola, M. et al. (2010).
Genome wide linkage study for
visceral leishmaniasis in India.
PLoS One 5, e15807.
Fakiola, M., et al. (2011).
Genetic and functional evidence
implicating DLL1 as the gene
that influences susceptibility
to visceral leishmaniasis at
chromosome 6q27. J Infect Dis
204, 467–477.
Damian
Crowther
Jahn, T. R. et al. (2011).
Detection of early locomotor
abnormalities in a Drosophila
model of Alzheimer’s disease.
J Neurosci Methods 197,
186–189.
Liu, B. et al. (2011). Iron
promotes the toxicity of amyloid
beta peptide by impeding its
ordered aggregation. J Biol
Chem 286, 4248–4256.
41
Sadaf Farooqi
Greenfield, J. R. et al. (2009).
Modulation of blood pressure
by central melanocortinergic
pathways. N Engl J Med 360,
44–52.
Bochukova, E. et al. (2010).
Large, rare chromosomal
deletions associated with severe
early-onset obesity. Nature 463,
666–670.
Sergey
Nejentsev
Nejentsev, S. et al. (2009).
Rare variants of IFIH1, a gene
implicated in antiviral responses,
protect against Type 1 Diabetes.
Science 324, 387–389.
Curtis, J. et al. (2011).
Association analysis of the
LTA4H gene polymorphisms
and pulmonary tuberculosis in
9,115 subjects. Tuberculosis 91,
22–25.
42
Genetic, Molecular and Physiological Basis of
Human Obesity
We use a number of complementary genetic
strategies including whole exome sequencing
to study a cohort of over 4000 patients with
severe early onset obesity in collaboration with
the Wellcome Trust Sanger Institute. Through
these approaches we are discovering mutations in novel obesity genes whose function is
studied using a number of molecular and cellular
approaches. As many of these proteins modulate
hypothalamic neural circuits involved in the regulation of appetite, we are developing the use of
patient specific neural cell lines derived from
inducible pluripotent stem cells (obtained from
fibroblasts), as a model system for investigating
molecular mechanisms and for drug discovery.
As part of our parallel programme of translational
research, we undertake physiological studies
in patients with monogenic obesity syndromes
to examine the role of the relevant molecules
in eating behaviour, energy expenditure and
peripheral metabolism. Our overall aim is to make
a major contribution to the design of pharmacological, nutritional and behavioural interventions
to benefit patients with severe obesity.
Wellcome Trust Senior Clinical Fellow and
Professor of Metabolism and Medicine
University of Cambridge Metabolic
Research Laboratories
Level 4, Institute of Metabolic Science
Box 289, Addenbrooke’s Hospital
Hills Road, Cambridge CB2 0QQ
www.mrl.ims.cam.ac.uk/staff/PI/Farooqi/
Genetic and Functional Mechanisms of
Susceptibility to Infection
Genetic variants in the human genome may
confer susceptibility to or resistance from infectious diseases. To discover such variants and to
understand underlying functional mechanisms
we use methods of human genetics, including
genome-wide association studies (GWAS) and
exome sequencing, cellular models of infection
as well as methods of molecular biology. We
study patients with primary immunodeficiencies
caused by Mendelian mutations that suffer from
severe and/or recurrent infections, in particular
from mycobacterial and viral infections. We also
study patients that suffer from pulmonary tuberculosis, a common infectious disease and a global
medical problem. Our objective is to understand
biological pathways involved in protection from
infection and, eventually, to find new diagnostic
approaches and novel targets for therapeutic
intervention.
Wellcome Trust Senior Research Fellow
Department of Medicine
Level 5, Addenbrooke's Hospital
Tel: +44 (0) 1223 762 605
Fax: +44 (0) 1223 336 846
http://tb.med.cam.ac.uk/
Molecular and Pathophysiological Mechanisms
in Human Obesity and Insulin Resistance
I have a long-standing interest in the aetiology
and pathophysiology of human metabolic and
endocrine disease and how such information
might be used to improve diagnosis, prognostication, therapy and prevention.
My two principle areas of research are obesity
and insulin resistance. We use a wide range of
human genetic and physiological approaches,
accompanied by studies in cellular and animal
disease models to better understand the biological causes of extreme forms of obesity, insulin
resistance and lipodystrophy and also the
mechanisms whereby more widespread genetic
variants predispose to common forms of disease.
Our long-term aim is that better understanding of
the pathways that control human energy balance,
adipocyte biology and insulin sensitivity will, ultimately, lead to clinical benefits.
Our research is supported by the MRC Centre for
Obesity and Related Metabolic Diseases (MRC
CORD), the Wellcome Trust, the NIHR Cambridge Biomedical Research Centre and the EU.
Director, University of Cambridge Metabolic
Co-Director, Institute of Metabolic Science
Scientific Director, NIHR Cambridge Biomedical
Research Centre
Box 289, Addenbrooke's Hospital
www.mrl.ims.cam.ac.uk
Bochukova, E. G. et al. (2010).
Large, rare chromosomal
deletions associated with severe
early-onset obesity. Nature 463,
666–670.
Gandotra, S. et al. (2011).
Perilpin deficiency and
autosomal dominant partial
lipodystrophy. N Eng J Med 364,
740–748.
Protein Misfolding and Metabolic Disorders
Proteins that fail to attain or maintain their
structure reduce fitness in part through toxic
gain of function mechanisms referred to as
"proteotoxicity". The latter conspicuously affects
poorly-renewable tissues of long-lived organisms
in which the threat of protein misfolding can exert
its deleterious consequences over extended
periods of time. Protein misfolding is compartment-specific and its extent is influenced by the
burden of newly-synthesized unfolded proteins
presented to a given compartment (cytosol,
endoplasmic reticulum, mitochondria) and by
the protein folding environment in that
compartment. The latter is influenced by
structural elements operating within and on the
compartment and by its metabolic state. Both
parameters are regulated by complex homeostatic pathways, constituting what has been
termed heuristically a proteostasis network, in
which compartment-specific unfolded protein
responses (UPR) are important.
Stephen
O’Rahilly
and proteotoxic features of rare mutant proteins
have revealed the importance of proteostasis
to the function of tissues such as the endocrine pancreas, liver and fat that figure heavily
in metabolic control. Less well understood, but
of potentially considerable importance, are the
emerging links between intermediary metabolism and the protein folding environment in the
various compartments of the eukaryotic cell. Our
research aims to uncover the molecular basis of
the aforementioned reciprocal links.
Wellcome Trust Principal Research Fellow
University of Cambridge Metabolic
Box 289, Addenbrooke's Hospital
Tel: +44 (0) 1223 768 940
http://ron.medschl.cam.ac.uk
David Ron
Wiseman, R. L. et al. (2010).
Flavonol activation defines an
unanticipated ligand binding site
in the kinase-rnase domain of
ire1. Mol Cell 38, 291–304.
Zito, E. et al. (2010).
Oxidative protein folding by an
endoplasmic reticulum localized
peroxiredoxin. Mol Cell 40,
787–797.
Interesting reciprocal links have been uncovered
between protein folding homeostasis and metabolism: Defects in handling unfolded protein load
43
Principal Investigators who will be moving on
from CIMR shortly
David Clayton
Wallace, C., Smyth, D. J.,
Maisuria-Armer, M., Walker,
N. M., Todd, J. A. and Clayton,
D. G. (2010). The imprinted
DLK1-MEG3 gene region on
chromosome 14q32.2 encodes
susceptibility to type 1 diabetes.
Nat Genet 42, 68–71.
Clayton, D. (2010). On inferring
presence of an individual in a
mixture: a Bayesian approach.
Biostatistics 11, 661–673.
Andrew Peden
Gordon, D. E. et al. (2010).
A targeted siRNA screen to
identify SNAREs required
for constitutive secretion in
mammalian cells. Traffic 11,
1191–1204.
Miller, S. E. et al. (2011).
The molecular basis for the
endocytosis of small R-SNAREs
by the clathrin adaptor CALM.
Cell 147, 1118–1131.
44
Biostatistical Methods in Genetics
Our aim is to develop and apply statistical
methods in genetic epidemiology and, to a lesser
extent, in other aspects of biostatistics. The main
focus of this work is provided by the Diabetes
and Inflammation Laboratory (DIL). Implementation and dissemination of analytical methods
is an important part of our work. The snpMatrix
package developed in my group became part of
the Bioconductor international project for bioinformatic software in the R language. In addition
to its uses in the analysis of genome-wide association studies, it became integral to the tools
developed for “genetic genomics”. Largely to
support and extend these uses, the package has
been further developed and has been re-badged
as “snpStats”.
The group continues to provide biostatistical support to the DIL in the rapidly changing
research environment which is evolving in
the wake of the great successes of genomewide association studies. This has involved us
addressing new problems presented by new
source of data from, for example, DNA and RNA
sequencing, expression microarrays, and flow
cytometry.
Our existing work on methods in genetic association studies has continued, in collaboration with
Matt Hurles and Jeff Barrett at the Wellcome
Trust Sanger Institute. Particular focus has been
on, respectively, copy number variation and multivariate and multinomial phenotypes.
Retiring at the end of March 2012, however
will leave the continuing research programme in
biostatistics in CIMR in the very capable hands
of Chris Wallace and other members of the
statistics team.
Elucidating the Pathways and Molecular
Machinery of Constitutive Secretion
Constitutive secretion is a fundamental, conserved process that delivers newly synthesised
proteins to the extracellular environment
and is key to many important physiological
processes such as antibody secretion. Hypersecretion of antibodies is associated with many
immune-derived diseases such as Amyloidosis,
Macroglobulinemia and Monoclonal Gammopathy of undetermined significance and may also
have a role in auto-immune diseases such as
Systemic Lupus Erythematosus. Elevated levels
of circulating antibodies can cause severe
pathology and lead to conditions such as Cryoglobulinemia and hyperviscosity syndrome. Thus,
having the ability to modulate the levels of circulating antibodies has significant therapeutic
potential. We hope that by studying the secretory pathway and determining the machinery
required for antibody secretion we will not only
provide new insights into a fundamental cellular
process, but also identify new druggable targets
for the treatment of these diseases.
My research has three main aims:
1. To understand the role of SNAREs in
constitutive secretion.
2. To identify and characterise novel machinery
required for post-Golgi trafficking and
antibody secretion.
3. To develop novel inhibitors of antibody
secretion.
Moving to the Department of Biomedical Science
at the University of Sheffield to take up the post
of Lecturer.
45
Postgraduate Opportunities in the Institute
Introduction
The CIMR offers an exciting and vibrant environment for
graduate students. Approximately 30% of the 270 scientists within the CIMR are postgraduate students carrying out
research towards a PhD. There are a variety of schemes that
we offer to allow both clinical and non-clinically qualified individuals to pursue a PhD within the Institute. Some of these are
for three years whilst others are four year programmes funded
by the Wellcome Trust and Medical Research Council (MRC).
Wellcome Trust/MRC Four Year PhD Programmes
at the CIMR
The CIMR houses 2 four year PhD programmes for non-clinical scientists. The Wellcome Trust four year PhD programme in
Infection and Immunity (Director: Professor Paul Lehner) offers
6 studentships per annum. Approximately 50% of the faculty
for this programme are members of the CIMR with other principal investigators being within the Department of Pathology,
the Veterinary School and the School of Clinical Medicine. The
CIMR also runs its own four year programme that is funded
by the Wellcome Trust and the MRC. All principal investigators and affiliated principal investigators of the CIMR serve as
faculty for this programme. The four year programmes allow
individuals to undertake 3 ten week mini projects in the first
year before deciding on the project that they wish to pursue
for their three year PhD. These programmes are advertised in
November with interviews in January/February. The successful applicants start the programme in October.
principal investigators. They are advertised separately from the
four year programmes run within the CIMR. The 3 year PhD
students have access to the same seminars, equipment and
mentoring as four year PhD students.
Clinical Research Training Fellowships
Clinical training fellowships are available as competitive
awards through the Medical Research Council, the Wellcome
Trust and the Association of Medical Charities. We also host
the University of Cambridge/Sanger Institute Wellcome Trust
PhD Programme for Clinicians that funds 7 clinical fellows per
annum for 5 years. This scheme is administered from the CIMR
although the faculty is drawn from the whole of the School of
Clinical Medicine and the wider University of Cambridge.
The Director of the four year non-clinical PhD programmes
and the Wellcome Trust clinical PhD programme is Professor
David Lomas, the Director for Graduate Studies within the
Institute is Dr Folma Buss and the Programme Administrator
is Sonia Lyne.
Prof. Sheena Radford
University of Leeds
External examiner for
CIMR 1+3 MRes/PhD
Programme 2009–11
Non-Clinical Three Year PhD Programmes
The CIMR offers standard three year PhD programmes. These
are usually awarded by the research charities to individual
Sonia Lyne
CIMR 4 Yr PhD Students, 2011 intake
46
CIMR Research Retreat 2011
21–22 March 2011
Wellcome Trust Conference Centre,
Hinxton, Cambridge
The annual CIMR Research Retreat was held on
21–22 March 2011. This year it was the turn of
the postdoctoral fellows and graduate students
to present to members of the Institute. The presentations reflected the diverse nature of ongoing
research within the building. We also had excellent presentations on antibody engineering from
Sir Greg Winter and on chromosomal instability by
Ashok Venkitaraman. We continued our tradition
of inviting a member of the MRC Mitochondrial
Biology Unit to talk at the Retreat and were
delighted to hear from Ian Holt about his work
on mitochondrial myopathies. The presentations
from members of the Institute were of a very high
standard and the judges awarded the prize for
the best presentation from a postdoctoral fellow
to Dr Janet Deane (Prof Randy Read’s group)
now a PI herself, with the runner-up being Dr
Jenny Lumb (Dr Evan Reid’s group). The prize for
the best presentation from a graduate student
went to Miss Hemma Brandstätter (Dr Folma
Buss’s group) with the runner-up being Mr David
Gordon (Dr Andrew Peden’s group). The poster
prizes were given to Dr Xin Smith (postdoctoral
fellow in Prof Chris Rudd’s group) and jointly
to Miss Sally Thomas and Miss Elke Malzer
(graduate students with Dr Stefan Marciniak).
David Lomas
Deputy Director
Janet Deane
Jenny Lumb
Hemma Brandstätter
David Gordon
Sally Thomas/Elke Malzer
Xin Smith
47
Administration, IT and Technical Support
Contacts
Administrator
Miss Sarah Smith
Tel: 01223 336457
E-Mail: [email protected]
Laboratory/Facilities Manager
Mr Dave Cheesman
Tel: 01223 762314
E-Mail: [email protected]
It is a privilege for me to introduce this section
of the Report to acknowledge the work of all the
support staff in what has been another busy and
productive year. All staff endeavour to provide a
support service to our scientists in an efficient
and effective and customer focussed manner so
that the scientific community remains satisfied
with the value of the services provided.
very happy to welcome Neil Kent to the team in
August 2011. He leads the Accounts and Purchasing Unit and replacing Susan Reeder who
retired having completed 12 years service. Neil
has joined us from Cambridge Assessment, a
department of the University, where he worked
for nine years and qualified as a CIMA Management Accountant.
As the Institute’s Administrator I have responsibility for overseeing the Administration’s individual
units and for providing advice and guidance on
a wide variety of administrative issues to the
Director, Institute committees, the scientists, and
staff. In this period of reduced funding opportunities, of particular importance is ensuring that
the grant application process is followed appropriately with particular emphasis on costings to
ensure that sufficient funds will be available to
meet the needs of the research, whilst remaining within the limits set by the grant awarding
bodies. I also have direct operational management responsibility for the Human Resources
Unit. The service includes providing advice on
all aspects of employment issues including work
permits, adhering to HR best practice, and initiating appointments/extensions/termination of
employment for employees.
The team supports scientists by undertaking
daily accounts work including the processing of
purchase orders and expense claims, dealing with
invoice queries, managing accounts receivable
and providing information and advice regarding
the financial position of grants. Training and
development is key to offering a good service
and most of the team are currently studying to
aid their professional development.
Since the last Report we have experienced the
lowest turnover of administrative staff since
the Institute was opened. However, there was
one significant managerial change. We were
Jonathan Wilson, continues to lead the IT Unit,
has responsibility for the Institute's IT facilities,
including the provision of a support service to
both the scientific and administrative staff. His
team manages the data network and audiovisual facilities within the Institute, and maintains
the Intranet and Web site. Over the next 5 years
the IT Unit will invest £300k into renewing the
Institute's internal network, data centre and
communal computing facilities. In 2010 the
IT Unit modernised the facilities in the Sackler
lecture theatre to provide state of the art digital
presentation. The generation of scientific data
within CIMR is now doubling annually and to
Building Services Supervisor
Finance Officer
Computer Officer
Mr Ray Woodstock
Mr Neil Kent
Mr Jonathan Wilson
Tel: 01223 762666
E-mail: [email protected]
Tel: 01223 762139
Tel: 01223 763194
48
meet the challenge of data storage and back-up,
the IT Unit is developing an off-site data replication system. The website presence has been
revamped but there is always more we can do to
communicate our services and facilities.
The Laboratory and Facilities team remains
under the direction of Dave Cheesman. As
with the Accounts and Purchasing Unit, various
members of the team have undertaken courses
leading to professional accreditation. This team
is responsible for the provision of building-wide
services such as cleaning, catering, security,
media preparation and glass-washing, and for
the CIMR communal laboratories. The shared
facilities provide essential equipment for use
by the Research Staff and include dark room
services, centrifugation, phosphor imaging, and
shared areas such as Tissue Culture Labs and
Containment Level 2 suites. Due to the nature of
the service provided by this unit, there is a great
deal of overlap with the Building Services Unit.
Ray Woodstock manages the Building Services
Unit which has recently expanded to include the
Custodian function. The Unit provides the dayto-day maintenance of the building, including
numerous small projects such as minor building
modifications for new equipment and redecorating of the public areas. The Unit is also involved
with major projects which have recently included
cladding and external insulation improvements,
lift refurbishment and the replacing of the building’s heating and cooling control system. Planned
projects for the next year include replacing of the
floor covering in all the public areas, and installing new cycle sheds.
Sarah Smith
CIMR Administrator
CIMR Support Organisational
Chart
CIMR Support
Organisational Chart
Director
CIMR
Deputy Director
CIMR
PA to the
Director
PhD
Administrator
Laboratory/Facilities
Manager
Building Services
Supervisor
Deputy Lab
Manager
Snr. Building
Services Tech.
2x Media
Technicians
Building Services
Tech.
Senior Level
Co-ordinator
2x
Custodians
Assistant
Level
Co-ordinator
2x Glasswash
Assistants
Other Support
Staff
Administrator
Secretary
Office
Manager
Senior
HR Clerk
Finance
Officer
4x
Receptionists
2x HR
Clerks
Accounts &
Purchasing
Supervisor
Purchasing
Clerk
(Snr. Custodian)
2x Accounts
Clerks
University Funded
Wellcome Trust Infrastructure Funded
Joint University / MRC Funded
Various Sources of Funds
Computer
Officer
Proteomics
Technician
Computing
Technician
Microscopy
Facility Manager
Bioinformatics /
Systems Support
Deputy Microscopy
Facility Manager
Head of
Flow Cytometry
Flow Cytometry
Technician
Flow Cytometry
Technician
University Funded / Cost Recovery
Level
Co-ordinator
MRC Funded / Cost Recovery
49
Funding of CIMR
Total expenditure on grants has continued to increase over the
last two years, from £20.0m in 2008/9 to £21.4m in 2010/11,
a rise of 7%.
Overall Wellcome Trust support is approximately 60%, as it has
been for the last 5 years. One-third of non-Wellcome Trust grants
are funded by the MRC.
CIMR Grant Expenditure
Total Value of Grants Held in CIMR
50
Recurrent
Costs
for the
CIMR
In respect
of building
management
and
maintenance for the
Wellcome Trust/MRC Building and the Cambridge Institute for
Medical Research annual recurrent costs remain split between
the University and MRC at a ratio directly proportional to the
space occupied in the building.
ecurrent Costs for the CIMR
Recurrent
Recurrent
Costs for Costs
CIMR
August 2009–July 2010
Recurrent Costs for the Wellcome Trust/MRC Buil
Recurrent Costs for the Wellcome Trust/MRC Build
for the Wellcome Trust/MRC
& CIMR
Recurrent Costs Building
for the Wellcome
Trust/MRC Building & CIMR
51
Centre core facilities supporting CIMR
Principal Investigators
Over the last four years the Clinical School with National Institute for Health Research (NIHR) Biomedical Research Centre
(BRC) funding has been able to establish several critical core
facilities that enable translational medical research across the
main research themes on campus (see BRC website, http://
cambridge-brc.org.uk/), including many researchers in the
Cambridge Institute for Medical Research.
1 The Cambridge BioResource (http://www.cambridgebioresource.org.uk/) allows researchers to recall volunteers for
their studies based on disease-associated genotypes and
phenotypes. This resource, with the renewal of the Cambridge Biomedical Research Centre to 2017, will now include
patients from several clinics in the hospital. Moreover, we
have just been awarded additional funding by NIHR to roll
out the BioResource nationally for patients and populations.
2 The Cell Phenotyping Hub. This is a centralised flow cytometry and microscopy facility for phenotypic and functional
analyses of human blood and tissue samples. The facility
has state of the art equipment and is closely aligned to the
Cambridge BioResource, for example in gene-to-phenotype
analyses of immune-mediated diseases, such as lupus and
type 1 diabetes.
3 The Eastern Sequence and Informatics Hub (EASIH)
provides facility and expertise in next-generation sequencing and bioinformatics. Major projects include exome and
human microbial pathogen sequencing, as well as the
translation of high throughput sequencing into the Clinical
Regional Genetics Laboratory, for example, in HLA tissue
typing. Also housed in Clinical Biochemistry are facilities for
core biomedical assays (Core Biochemical Assay Laboratory: http://www.cuh.org.uk/research/researchers/starting/
facilities/cbal/core_biochemical_assay.html) and microarray gene expression (http://cambridge-brc.org.uk/new/
infrastructure-infrastructure-laboratoryfacilities.htm).
4 The BRC BioRepository (NIHR BRC-MRC BioRepository,
F & G Block, Level 2, Addenbrooke's Hospital) has been
established with the MRC Epidemiology Unit, to provide
smart, automated sample (DNA, plasma, serum) storage
facilities of BRC- and MRC-associated samples.
52
Cambridge BRC
Other Information
Honours, Awards &
Personal Fellowships
Principal Investigators:
David Clayton: Wellcome Trust
Principal Research Fellowship, renewed
December 2010; Honorary Chair,
Department of Epidemiology and
Population Health, Medical Statistics
Unit, London School of Hygiene and
Tropical Medicine
Research Fellowship, March 2012
Fellowship Award, March 2011
Sergey Nezhentsev (Affiliated):
Wellcome Trust Senior Research
Fellowship in Basic Biomedical Science,
June 2011
Geoffrey Hesketh (Luzio): Canadian
Institute of Health Research Fellowship,
August 2011
Katrin Ottersbach: British Society for
Haematology Early Stage Investigator
Fellowship; Leukaemia & Lymphoma
Research Bennett Senior Fellowship,
September 2011
Nick Matheson (Lehner): Wellcome
Trust Clinical Research Training
Fellowship, April 2011
Janet Deane: Royal Society University
Research Fellowship, October 2011
David Owen: Wellcome Trust Principal
Research Fellowship, October 2010
Anna Petrunkina Harrison:
Extraordinary Professorship
(‘Ausserplanmaessige Professeur’).
University of Veterinary Medicine,
Hanover, 2011
Sadaf Farooqi (Affiliated):
Professorship in the University of
Cambridge, October 2011
Randy Read: William A Bridger
Lectureship in Biochemistry, University
of Alberta, Edmonton, Canada, 2010
Rhys Roberts (Luzio): Wellcome-Beit
Prize/Wellcome Trust Intermediate
Clinical Fellowship, June 2011
Andres Floto: BUPA Foundation
Researcher of the Year award 2010
David Rubinsztein: Wellcome Trust
Principal Research Fellowship, March
2012
Chris Wallace (DIL): Wellcome Trust
Career Development Fellowship,
February 2010
Bertie Göttgens: 2010 McCulloch &
Till Award by the International Society
for Hematology and Stem Cells;
Professorship in the University of
Cambridge, October 2011
Christopher Rudd: Wellcome Trust
Principal Research Fellowship, extended
December 2010
Lena Wartosch (Luzio): FEBS Longterm Fellowship, April 2010; EMBO
Fellowship, April 2011
Tony Green: Elected Distinguished
Visiting Professor Cancer Science
Institute, Singapore, 2009–10; Elected
Newton Abraham Visiting Professorship,
University of Oxford, 2011
Peter St George-Hyslop: Fellow of the
Society of Biology
Michael Weekes (Lehner): Wellcome
Trust Intermediate Clinical Fellowship,
July 2011
John Todd: David Rumbough Award for
Scientific Excellence from the JDRF
Fiona Gribble: Minkowski Prize,
EASD 2010; University of Cambridge
Readership, October 2010
Geoff Woods: Professorship in the
University of Cambridge, October 2011
Aiwu Zhou (Read): BHF Senior Basic
Science Research Fellowship, January
2011
Research Scientists:
James Huntington: ISTH 2011 WrightSchulte Memorial Lecture; Professorship
in the University of Cambridge, October
2011
Mark Dawson (Huntly): Wellcome-Beit
Prize/Wellcome Trust Intermediate
Clinical Fellowship, 2010
David Lomas: Patron, Alpha-1
Awareness; Visiting Professor, University
of Florida and Cleveland Clinic
Jyoti Evans (Green): Kay Kendall
Leukaemia Fund Junior Clinical
Research Fellowship, April 2011
Stefan Marciniak: MRC Senior Clinical
Shaun Flint (Smith): ACT Clinical
53
Editorial Boards of Journals
David Clayton: Annals of Human
Genetics
Andres Floto: PLoS ONE
Bertie Göttgens: Experimental
Hematology (Associate Editor)
Fiona Gribble: British Journal of
Pharmacology; Biochemical Journal
Gillian Griffiths: Journal of Cell Biology;
Traffic; Current Opinions in Cell Biology;
Biomed Central Biology; Centrosome
James Huntington: Journal of Biological
Chemistry; Biochemical Journal
Brian Huntly: Experimental Hematology
David Lomas: American Journal of
Respiratory Cell and Molecular Biology;
Journal of Chronic Obstructive Pulmonary
Disease (COPD); Clinical Medicine
Paul Luzio: Traffic
Stefan Marciniak: World Journal of
Diabetes
Randy Read: Acta Crystallographica
Section D
Margaret Robinson: Traffic
David Rubinsztein: Autophagy
(Associate Editor); Human Molecular
Genetics; Journal of Applied Biomedicine;
PLoS ONE (Academic Editor); Cell
Death and Differentiation
Christopher Rudd: Current Biology;
Immunology; International Journal of
Biochemistry; Proceedings National
Academy of Science (PNAS); PLoS
ONE; Frontiers in Bioscience; European
Journal of Immunology; Self/Non-Self;
Seminars in Immunopathology; Frontiers
in T Cell Biology
54
Peter St George-Hyslop:
Neurodegenerative Diseases; Molecular
Neurodegeneration; American Journal of
Alzheimer’s Disease
Staff Affiliations
Symeon Siniossoglou: Journal of
Biological Chemistry
David Clayton: MRC ASTRAL Trail
Steering Committee; SNP Steering
Group, Cancer Research UK; Council
of the International Biometrics Society;
GeneLibrary Ireland Scientific Advisory
Board
John Todd: Expert Reviews in Molecular
Medicine; Human Molecular Genetics
John Trowsdale: European Journal of
Immunology; Tissue Antigens; Human
Immunology
Linda Wicker: Journal of Experimental
Medicine (Advisory Editor)
Folma Buss: Cell Biological Committee
of the Biochemical Society
Andres Floto: European Cystic Fibrosis
Society Nontuberculous Mycobacteria
(NTM) Group (Chair); ECFS–CF
Foundation Guidelines Committee for
NTM Infection (Co-chair)
Bertie Göttgens: International Society
for Hematology and Stem Cells
(Director); BBSRC – Pool of experts/
member of core grant committees
Tony Green: Membership of National/
International Bodies: Academy of
Medical Science; American Society of
Haematology; American Association of
Physicians; Association of Physicians;
British Society for Haematology; British
Association for Cancer Research;
European Haematology Association;
European Haematology Association Scientific Program Committee; International
Society for Experimental Haematology;
1942 Club; Selected Committees/
Research Administration: Head,
University of Cambridge Department of
Haematology; Chairman: Addenbrooke’s
Hospital Haematology Senior Staff
Group; Scientific Advisers to the Kay
Kendall Leukaemia Fund (2004–);
Member: European School of Haematology Executive Committee (2002–);
NCRI Myeloproliferative Disorder Study
Group (1997–); American Society of
Hematology, Scientific Committee for
Hematopoietic Cytokines and Factors
(2008–); Scientific Advisory Board,
Hemato–Linné Stem Cell Programme;
European Haematology Association
Board (2009–); Clinical Research Fellow
Committee (2009–)
Fiona Gribble: 2010– SAB member
for OXION – Ion Channels and Disease
Initiative, Universities of Oxford,
Cambridge, London and MRC Harwell;
2011 – Aeres Visiting Committee, Dijon,
France; External SAB Roche, Basel;
EFSD/Amylin Grants Committee; WT/
NIH PhD Studentship grant panel
member
Gillian Griffiths: Wellcome Trust Sir
Henry Wellcome Postdoctoral Fellowship Committee; EMBO Membership
Committee
Brian Huntly: CRUK Discovery
Committee (2006–); LRF Medical and
Scientific Advisory Panel (2009–);
European Hematology Association,
Membership Committee, (2006–);
European Hematology Association,
Member of the Scientific Advisory Committee for the 15th Annual European
Hematology Association meeting, Barcelona 2010; Invited Faculty member,
Faculty of 1000, (2009–)
Fiona Karet: University WiSETI steering
group (2007–); Wellcome Trust Clinical
Interview Committee (2006–2011);
Academy of Medical Sciences Clinical
Research Champion (2007–); UK
Renal Association Executive and Chair
of Research Committee (2010–);
UK Kidney Research Consortium
lead: monogenics clinical study group
(2009–); Kidney Research UK Trustee
(2011–); Salt wasting alkaloses Rare
Renal Disease Group lead (2011);
Medical Education England 'Shape
of Medical Training' Steering Group
(2011–)
Paul Lehner: Wellcome Trust Expert
Review Group: ‘Immune System in
Health and Disease’ (Chair); Wellcome
Trust 4 Yr PhD Programme in Infection
and Immunity (Director); Trustee British
Society of Immunology
David Lomas: British Lung Foundation Grants Committee (Chair); MRC
Population and Systems Medicine
Board (Chair); British Lung Foundation
(Trustee); Academy of Medical Sciences
Sectional Committee; Alpha-1 Foundation (US) Grants Committee (Chair);
GSK Respiratory CEDD (Centre of
Excellence in Drug Discovery) (Board
member); Alpha-one Antitrypsin Laurell
Training Award (ALTA); Wellcome Trust
Clinical PhD Programme (Director);
Wellcome Trust/MRC 4 Yr PhD
Programme, CIMR (Director); BRC Fellowships and Capacity Building (Theme
Lead); Cambridge University Clinical
Research Society (Senior Treasurer
& Patron); External Advisory Committee, HRB PhD Scholars Programme
(Ireland); MRC PhD Studentship skills
portfolio advisory group (member)
Paul Luzio: MRC Molecular & Cellular
Medicine Board (Chair) (until March
2012); MRC Strategy Board (member)
(until March 2012)
Stefan Marciniak: Fellow of the Royal
College of Physicians; Fellow of St
Catherine’s College, Cambridge
Lucy Raymond: Action Medical
Research Grants Committee
Randy Read: wwPDB X-ray Validation
Task Force (Chair); PDB-Europe Scientific Advisory Committee (Chair); CCP4
Executive Committee (member)
Evan Reid: Scientific Advisory Board of
American Spastic Paraplegia Foundation
(member); Cell Biology Theme Panel of
Biochemical Society (member)
Margaret Robinson: Wellcome Trust
Cell and Developmental Biology Expert
Review Group (member)
David Rubinsztein: Wellcome Trust
Investigator Awards Expert Review
Group (co-Chair) (2011–); Wellcome
Trust Molecular & Cellular Neuroscience
Committee (2007–11); Parkinson’s
Disease Brain Bank Assessment Panel
(2009–); MRC Brain Banks Network
Users Group (2009–)
Christopher Rudd: Council Member,
International Union of Immunological
Societies (IUIS) (2007–); Member,
Organising Committee, 15th International Congress of Immunology (ICI)
(2009–) (Rome, August, 2013); Mentor,
Dual University Scheme, National
University of Singapore and University of
Cambridge (2009–); Member, Education Committee, International Union of
Immunological Societies (IUIS) (2010–);
Chairman and Founder, Immune
Ventures plc, Cambridge (2008–);
Consultant, AstraZeneca, UK (2009–);
Consultant, Mewburn Ellis LLP (2010–);
Scientific Advisory Board, Akanas
Therapeutics Inc., Boston, USA (2010–);
Consultant, HLBB Shaw, Epping, Essex
(2011–)
Peter St George-Hyslop: Alzheimer
Research Trust Scientific Advisory
Board, Institut du Cerveau et de la
Moelle Epiniere de France, Agence
Nationale de la Recherche, Department
of Health, Ministerial Advisory Group
on Dementia, Deutsches Zentrum Fur
Neurodegenerative Erkrankungen, Scientific Advisory Board, GlaxoSmithKline
Neuroscience
John Todd: Type 1 Diabetes Genetics
Consortium Steering Committee;
Cambridge Computational Biology
Institute Management Committee,
University of Cambridge; Wellcome Trust
Case Control Consortium Management Committee; NIHR Cambridge
Biomedical Research Centre Cambridge
BioResource Management Committee;
Institute of Metabolic Science-Metabolic
Research Laboratory Strategy Committee; Professorial Pay Committee, Clinical
School, University of Cambridge; Scientific Advisory Board of NIHR Biomedical
Research Centre Core Biochemical
Assay Lab; Juvenile Diabetes Research
Foundation UK Scientific Advisory Committee; Senior Academic Promotions
55
Committee, Clinical School, University
of Cambridge; Council of School,
Clinical School, University of Cambridge;
Board of Electors, Professorship of
Statistics in Biomedicine, University of
Cambridge; Planning Steering Group,
Clinical School, University of Cambridge;
Scientific Advisory Board of NIHR
Cambridge Biomedical Research Centre
Cambridge BioResource; Management
Committee (Chairman) of the MRC–
Centre, University of Cambridge
Eastern Sequence and Informatics Hub;
Cambridge University Hospitals NHS
Foundation Trust Biomedical Research
Centre Executive Committee; Scientific
Advisory Board of the Centre for Dermatology and Genetic Medicine, Medical
Sciences Institute, Dundee; Member
of the Advisory Committee for the
Regius Professorship of Physic; Board
of Electors, Genzyme Professorship of
Experimental Medicine, University of
Cambridge
Linda Wicker: Type 1 Diabetes
Repository Advisory Committee, National
Institutes of Health (Chair and member)
(2002–)
Fellows of the Royal
Society
Stephen O’Rahilly, Peter St GeorgeHyslop, John Todd
Fellows of the Academy
of Medical Sciences
Jenefer Blackwell, Tony Green, Gillian
Griffiths, Fiona Karet, Paul Lehner, David
Lomas, Paul Luzio, Stephen O’Rahilly,
Margaret Robinson, David Rubinsztein,
Christopher Rudd, Peter St GeorgeHyslop, Ken Smith, John Todd, John
Trowsdale
EMBO Members
Gillian Griffiths, Stephen O’Rahilly, David
Owen, Margaret Robinson, David Ron,
David Rubinsztein
56
Publications for Scientists in CIMR since 2010
Abdollahi, M. R., Morrison, E., Sirey, T.,
Molnar, Z., Hayward, B. E., Carr, I. M.,
Springell, K., Woods, C. G., Ahmed,
M., Hattingh, L. et al. (2009). Mutation
of the variant alpha-tubulin TUBA8
results in polymicrogyria with optic
nerve hypoplasia. Am J Hum Genet 85,
737–744.
Albers, C. A., Cvejic, A., Favier, R.,
Bouwmans, E. E., Alessi, M. C.,
Bertone, P., Jordan, G., Kettleborough,
R. N. W., Kiddle, G., Kostadima, M. et
al. (2011). Exome sequencing identifies
NBEAL2 as the causative gene for
gray platelet syndrome. Nat Genet 43,
735–737.
Adams, P. D., Afonine, P. V., Bunkóczi,
G., Chen, V. B., Davis, I. W., Echols, N.,
Headd, J., Hung, L.-W., Kapral, G. J.,
Grosse-Kunstleve, R. W. et al. (2010).
PHENIX: a comprehensive Pythonbased system for macromolecular
structure solution. Acta Crystallogr D Biol
Crystallogr 66, 213–221.
Anand, S., Stedham, F., Beer, P.,
Gudgin, E., Ortmann, C. A., Bench,
A., Erber, W., Green, A. R. and Huntly,
B. J. P. (2011). Effects of the JAK2
mutation on the hematopoietic stem
and progenitor compartment in human
myeloproliferative neoplasms. Blood 118,
177–181.
Adams, P. D., Afonine, P. V., Bunkóczi,
G., Chen, V. B., Echols, N., Headd, J.
J., Hung, L.-W., Jain, S., Kapral, G. J.,
Grosse-Kunstleve, R. W. et al. (2011).
The Phenix software for automated
determination of macromolecular
structures. Methods 55, 94–106.
Anand, S., Stedham, F., Gudgin, E.,
Campbell, P., Beer, P., Green, A. R.
and Huntly, B. J. P. (2011). Increased
basal intracellular signaling patterns do
not correlate with JAK2 genotype in
human myeloproliferative neoplasms.
Blood 118, 1610–1621.
Aguado, C., Sarkar, S., Korolchuk, V. I.,
Criado, O., Vernia, S., Boya, P., Sanz,
P., de Cordoba, S. R., Knecht, E. and
Rubinsztein, D. C. (2010). Laforin, the
most common protein mutated in Lafora
disease, regulates autophagy. Hum Mol
Genet 19, 2867–2876.
Andersson, A. K., Sumariwalla, P.
F., McCann, F. E., Amjadi, P., Chang,
C., McNamee, K., Tornehave, D.,
Haase, C., Agersø, H., Stennicke,
V. W. et al. (2011). Blockade of
NKG2D ameliorates disease in mice
with collagen-induced arthritis: A
potential pathogenic role in chronic
inflammatory arthritis. Arthritis Rheum 63,
2617–2629.
Agusti, A., Calverley, P. M. A., Celli,
B., Coxson, H. O., Edwards, L. D.,
Lomas, D. A., MacNee, W., Miller, B.
E., Rennard, S., Silverman, E. K. et
al. (2010). Characterisation of COPD
heterogeneity in the ECLIPSE cohort.
Respir Res 11, 122.
Ahn, H., Dib-Hajj, S. D., Cox, J. J.,
Tyrrell, L., Elmslie, F. V., Clarke, A.
A., Drenth, J. P. H., Woods, C. G. and
Waxman, S. G. (2010). A new Nav1.7
sodium channel mutation I234T in a
child with severe pain. Eur J Pain 14,
944–950.
Anichtchik, O., Diekmann, H., Fleming,
A., Roach, A., Goldsmith, P. and
Rubinsztein, D. C. (2011). Expression
of PINK1 in the brain, eye and ear of
mouse during embryonic development.
J Chem Neuroanat 42, 99–100.
Babayan, S. A., Allen, J. E., Bradley,
J. E., Geuking, M. B., Graham, A. L.,
Grencis, R. K., Kaufman, J., McCoy, K.
D., Paterson, S., Smith, K. G. C. et al.
(2011). Wild immunology: converging on
the real world. Ann N Y Acad Sci 1236,
17–29.
Bachmann, P. S., Piazza, R. G.,
Janes, M. E., Wong, N. C., Davies,
C., Mogavero, A., Bhadri, V. A.,
Szymanska, B., Geninson, G.,
Magistroni, V. et al. (2010). Epigenetic
silencing of BIM in glucocorticoid poorresponsive pediatric acute lymphoblastic
leukemia, and its reversal by histone
deacetylase inhibition. Blood 116,
3013–3022.
Bafadhel, M., McKenna, S., Terry,
S., Mistry, V., Reid, C., Haldar, P.,
Kebadze, T., Duvoix, A., Lindblad,
K., Patel, H. et al. (2011). Acute
exacerbations of COPD: identification of
biological clusters and their biomarkers.
Am J Respir Crit Care Med (epub).
Bakircioglu, M., Carvalho, O. P.,
Khurshid, M., Cox, J. J., Tuysuz, B.,
Barak, T., Yilmaz, S., Caglayan, O.,
Dincer, A., Nicholas, A. K. et al. (2011).
The essential role of centrosomal NDE1
in human cerebral cortex neurogenesis.
Am J Hum Genet 88, 523–535.
Bakke, P. S., Zhu, G., Gulsvik, A.,
Kong, X., Agusti, A. G. N., Calverley,
P. M. A., Donner, C. F., Levy, R. D.,
Make, B. J., Paré, P. D. et al. (2011).
Candidate genes for COPD in two large
data sets. Eur Respir J 37, 255–263.
Barrow, A. D., Raynal, N., Andersen,
T. L., Slatter, D. A., Bihan, D., Pugh,
N., Cella, M., Kim, T., Rho, J., NegishiKoga, T. et al. (2011). OSCAR is a
collagen receptor that costimulates
osteoclastogenesis in DAP12-deficient
humans and mice. J Clin Invest 121,
3505–3516.
Beer, P. A., Campbell, P. J. and Green,
A. R. (2010). Comparison of different
criteria for the diagnosis of primary
myelofibrosis reveals limited clinical
utility for measurement of serum lactate
dehydrogenase. Haematologica 95,
1960–1963.
57
Beer, P. A., Delhommeau, F.,
LeCouédic, J. P., Dawson, M. A., Chen,
E., Bareford, D., Kušec, R., McMullin,
M. F., Harrison, C. N., Vannucchi, A. M.
et al. (2010). Two routes to leukemic
transformation after a JAK2 mutationpositive myeloproliferative neoplasm.
Blood 115, 2891–2900.
Beer, P. A., Erber, W. N., Campbell, P.
J. and Green, A. R. (2011). Essential
thrombocythemia: seeing the wood
for the trees Response. Blood 118,
1180–1181.
Beer, P. A., Erber, W. N., Campbell, P.
J. and Green, A. R. (2011). How I treat
essential thrombocythemia. Blood 117,
1472–1482.
Beer, P. A., Ortmann, C. A., Campbell,
P. J. and Green, A. R. (2010).
Independently acquired biallelic JAK2
mutations are present in a minority of
patients with essential thrombocythemia.
Blood 116, 1013–1014.
Beer, P. A., Ortmann, C. A.,
Stegelmann, F., Guglielmelli, P.,
Reilly, J. T., Larsen, T. S., Hasselbalch,
H. C., Vannucchi, A. M., Möller, P,
Döhner, K. and Green, A. R. (2010).
Molecular mechanisms associated with
leukemic transformation of MPLmutant myeloproliferative neoplasms.
Haematologica 95, 2153–2156.
Belorgey, D., Hägglöf, P., Onda,
M. and Lomas, D. A. (2010).
pH-dependent stability of neuroserpin
is mediated by histidines 119 and 138;
implications for the control of beta-sheet
A and polymerization. Protein Sci 19,
220–228.
Belorgey, D., Irving, J. A., Ekeowa,
U. I., Freeke, J., Roussel, B. D.,
Miranda, E., Pérez, J., Robinson, C.
V., Marciniak, S. J., Crowther, D. C.,
Michel, C. H. and Lomas, D. A. (2011).
Characterisation of serpin polymers in
vitro and in vivo. Methods 53, 255–266.
Bennett, N. J., Ashiru, O., Morgan,
F. J., Pang, Y., Okecha, G., Eagle, R.
A., Trowsdale, J., Sissons, J. G. P.
and Wills, M. R. (2010). Intracellular
58
sequestration of the NKG2D ligand
ULBP3 by human cytomegalovirus.
J Immunol 185, 1093–1102.
Blackstone, C., O'Kane, C. J. and
Reid, E. (2011). Hereditary spastic
paraplegias: membrane traffic and the
motor pathway. Nat Rev Neurosci 12,
31–42.
Blyth, M., Raponi, M., Treacy, R.,
Raymond, F. L., Yates, J. R. W. and
Baralle, D. (2010). Expanding the
tuberous sclerosis phenotype: mild
disease caused by a TSC1 splicing
mutation. J Neurol Neurosur PS 81,
350–352.
Bonadies, N., Foster, S. D., Chan,
W. I., Kvinlaug, B. T., Spensberger,
D., Dawson, M. A., Spooncer, E.,
Whetton, A. D., Bannister, A. J., Huntly,
B. J. P. and Göttgens, B. (2011).
Genome-wide analysis of transcriptional
reprogramming in mouse models of
acute myeloid leukaemia. PLoS One 6,
e16330.
Boname, J. M. and Lehner, P. J.
(2011). What has the study of the K3
and K5 viral ubiquitin E3 ligases taught
us about ubiquitin-mediated receptor
regulation? Viruses-Basel 3, 118–131.
Boname, J. M., Thomas, M., Stagg,
H. R., Xu, P., Peng, J. and Lehner, P. J.
(2010). Efficient internalization of MHC
I requires lysine-11 and lysine-63 mixed
linkage polyubiquitin chains. Traffic 11,
210–220.
Bond, L. M., Brandstaetter, H., Sellers,
J. R., Kendrick-Jones, J. and Buss,
F. (2011). Myosin motor proteins are
involved in the final stages of the
secretory pathways. Biochem Soc Trans
39, 1115–1119.
Bond, L. M., Peden, A. A., KendrickJones, J., Sellers, J. R. and Buss,
F. (2011). Myosin VI and its binding
partner optineurin are involved in
secretory vesicle fusion at the plasma
membrane. Mol Biol Cell 22, 54–65.
Bowsher, D., Woods, C. G., Nicholas,
A. K., Carvalho, O. M., Haggett, C.
E., Tedman, B., Mackenzie, J. M.,
Crooks, D., Mahmood, N., Twomey,
J. A. et al. (2009). Absence of pain
with hyperhidrosis: A new syndrome
where vascular afferents may mediate
cutaneous sensation. Pain 147,
287–298.
Boyd, E. M., Bench, A. J., GodayFernández, A., Anand, S., Vaghela, K.
J., Beer, P., Scott, M. A., Bareford, D.,
Green, A. R., Huntly, B. J. P. and Erber,
W. N. (2010). Clinical utility of routine
MPL exon 10 analysis in the diagnosis
of essential thrombocythaemia and
primary myelofibrosis. Br J Haematol
149, 250–257.
Brehm, J. M., Hagiwara, K.,
Tesfaigzi, Y., Bruse, S., Mariani, T. J.,
Bhattacharya, S., Boutaoui, N., Ziniti,
J. P., Soto-Quiros, M. E., Avila, L. et
al. (2011). Identification of FGF7 as
a novel susceptibility locus for chronic
obstructive pulmonary disease. Thorax
(epub).
Brorsson, A. C., Bolognesi, B.,
Tartaglia, G. G., Shammas, S. L.,
Favrin, G., Watson, I., Lomas, D. A.,
Chiti, F., Vendruscolo, M., Dobson,
C. M., Crowther, D. C. and Luheshi,
L. M. (2010). Intrinsic determinants of
neurotoxic aggregate formation by the
amyloid beta peptide. Biophys J 98,
1677–1684.
Brorsson, A. C., Kumita, J. R.,
MacLeod, I., Bolognesi, B., Speretta,
E., Luheshi, L. M., Knowles, T. P. J.,
Lomas, D. A., Dobson, C. M. and
Crowther, D. C. (2010). Methods
and models in neurodegenerative and
systemic protein aggregation diseases.
Front Biosci 15, 373–396.
Bruni, A. C., Bernardi, L., Colao, R.,
Rubino, E., Smirne, N., Frangipane, F.,
Terni, B., Curcio, S. A. M., Mirabelli, M.,
Clodomiro, A. et al. (2010). Worldwide
distribution of PSEN1 Met146Leu
mutation: a large variability for a founder
mutation. Neurology 74, 798–806.
Bunkóczi, G. and Read, R. J. (2011).
Improvement of molecular-replacement
models with Sculptor. Acta Crystallogr D
Biol Crystallogr 67, 303–312.
Burr, M. L., Cano, F., Svobodova,
S., Boyle, L. H., Boname, J. M. and
Lehner, P. J. (2011). HRD1 and
UBE2J1 target misfolded MHC class I
heavy chains for endoplasmic reticulumassociated degradation. Proc Natl Acad
Sci USA 108, 2034–2039.
Burren, O. S., Adlem, E. C., Achuthan,
P., Christensen, M., Coulson, R. M.
and Todd, J. A. (2011). T1DBase:
update 2011, organization and
presentation of large-scale data sets for
type 1 diabetes research. Nucleic Acids
Res 39, D997–1001.
Buss, F. and Kendrick-Jones, J.
(2011). Multifunctional myosin VI has a
multitude of cargoes. Proc Natl Acad Sci
USA 108, 5927–5928.
Butler, R., Beattie, B. L., Thong, U. P.,
Dwosh, E., Guimond, C., Feldman,
H. H. et al. (2010). A novel PS1 gene
mutation in a large Aboriginal kindred.
Can J Neurol Sci 37, 359–364.
Caffarel, M. M., Zaragoza, R., Pensa,
S., Li, J., Green, A. R. and Watson, C. J.
(2011). Constitutive activation of JAK2
in mammary epithelium elevates Stat5
signalling, promotes alveologenesis and
resistance to cell death, and contributes
to tumourigenesis. Cell Death Differ
(epub).
Calero-Nieto, F. J., Wood, A. D.,
Wilson, N. K., Kinston, S., Landry,
J. R. and Göttgens, B. (2010).
Transcriptional regulation of Elf-1:
locus-wide analysis reveals four distinct
promoters, a tissue-specific enhancer,
control by PU.1 and the importance
of Elf-1 downregulation for erythroid
maturation. Nucleic Acids Res 38,
6363–6374.
Cano, F., Miranda-Saavedra, D. and
Lehner, P. J. (2010). RNA-binding E3
ubiquitin ligases: novel players in nucleic
acid regulation. Biochem Soc Trans 38,
1621–1626.
Carvalho, O. P., Thornton, G. K.,
Hertecant, J., Houlden, H., Nicholas,
A. K., Cox, J. J., Rielly, M., Al-Gazali,
L. and Woods, C. G. (2011). A novel
NGF mutation clarifies the molecular
mechanism and extends the phenotypic
spectrum of the HSAN5 neuropathy.
J Med Genet 48, 131–135.
Castaldi, P. J., Demeo, D. L., Hersh,
C. P., Lomas, D. A., Soerheim, I.
C., Gulsvik, A., Bakke, P., Rennard,
S., Pare, P., Vestbo, J., AATGM
Investigators, ICGN Investigators
and Silverman, E. K. (2011). Impact
of non-linear smoking effects on the
identification of gene-by-smoking
interactions in COPD genetics studies.
Thorax 66, 903–909.
Castanet, M., Mallya, U., Agostini,
M., Schoenmakers, E., Mitchell, C.,
Demuth, S., Raymond, F. L., Schwabe,
J., Gurnell, M. and Chatterjee, V.
K. (2010). Maternal isodisomy for
chromosome 9 causing homozygosity
for a novel FOXE1 mutation in
syndromic congenital hypothyroidism.
J Clin Endocrinol Metab 95, 4031–4036.
Castellucci, L., Jamieson, S. E., Miller,
E. N., de Almeida, L. F., Oliveira, J.,
Magalhães, A., Guimaraes, L., Lessa,
M., Lago, E., de Jesus, A., Carvalho,
E. and Blackwell, J. M. (2011). FLI1
polymorphism affects susceptibility to
cutaneous leishmaniasis in Brazil. Genes
Imm 12, 589–594.
Castellucci, L., Jamieson, S. E.,
Miller, E. N., Menezes, E., Oliveira,
J., Magalhães, A., Guimaraes, L.,
Lessa, M., Ribeiro, S., Reale, J., de
Jesus, A., Carvalho, E. and Blackwell,
J. M. (2010). CXCR1 and SLC11A1
polymorphisms affect susceptibility to
cutaneous leishmaniasis in Brazil: a
case-control and family-based study.
BMC Med Genet 11, 10.
Catapano, F., Chaudhry, A. N., Jones,
R. B., Smith, K. G. C. and Jayne, D. W.
(2010). Long-term efficacy and safety
of rituximab in refractory and relapsing
systemic lupus erythematosus. Nephrol
Dial Transplant 25, 3586–3592.
Cetica, V., Pende, D., Griffiths, G.
M. and Aricò, M. (2010). Molecular
basis of familial hemophagocytic
lymphohistiocytosis. Haematologica 95,
538–541.
Cetica, V., Santoro, A., Gilmour, K.
C., Sieni, E., Beutel, K., Pende, D.,
Marcenaro, S., Koch, F., Grieve, S.,
Wheeler, R. et al. (2010). STXBP2
mutations in children with familial
haemophagocytic lymphohistiocytosis
type 5. J Med Genet 47, 595–600.
Chacko, A. R., Arifullah, M., Sastri,
N. P., Jeyakanthan, J., Ueno, G.,
Sekar, K., Read, R. J., Dodson, E. J.,
Rao, D. C. and Suguna, K. (2011).
A novel pentameric structure of the
diarrhea-inducing region of the rotavirus
enterotoxigenic protein NSP4. J Virol 85,
12721–12732.
Chan, W. I., Hannah, R. L., Dawson,
M. A., Pridans, C., Foster, D., Joshi,
A., Göttgens, B., Van Deursen, J.
M. and Huntly, B. J. P. (2011). The
transcriptional coactivator Cbp regulates
self-renewal and differentiation in adult
hematopoietic stem cells. Mol Cell Biol
(epub).
Chen, E., Beer, P. A., Godfrey, A. L.,
Ortmann, C. A., Ahn, M., Li, J., CostaPereira, A, Ingle, C. E., Dermitzakis,
E. T. and Green, A. R. (2011). Distinct
clinical phenotypes associated with
JAK2V617F reflect differential STAT1
signalling. Exp Hematol 39, S46.
Chen, E., Beer, P. A., Godfrey, A. L.,
Ortmann, C. A., Li, J., Costa-Pereira,
A., Ingle, C. E., Dermitzakis, E. T.,
Campbell, P. J. and Green, A. R.
(2010). Distinct clinical phenotypes
associated with JAK2V617F reflect
differential STAT1 signaling. Cancer Cell
18, 524–535.
Chen, J., Morgan, A. J., StewartJones, G., Shepherd, D., Bossi, G.,
Wooldridge, L., Hutchinson, S. L.,
Sewell, A. K., Griffiths, G. M., van
der Merwe, P. A. et al. (2010). Ca2+
release from the endoplasmic reticulum
of NY-ESO-1-specific T cells is
modulated by the affinity of TCR and by
the use of the CD8 coreceptor.
J Immunol 184, 1829–1839.
59
Chibalina, M. V., Poliakov, A.,
Kendrick-Jones, J. and Buss, F.
(2010). Myosin VI and optineurin are
required for polarized EGFR delivery
and directed migration. Traffic 11,
1290–1303.
Chilvers, E. R. Lomas, D. A. (2010).
Diagnosing COPD in non-smokers:
splitting not lumping. Thorax 65,
465–466.
Chinthalapudi, K., Taft, M. H., Martin,
R., Heissler, S. M., Preller, M.,
Hartmann, F. K., Brandstaetter, H.,
Kendrick-Jones, J., Tsiavaliaris, G.,
Gutzeit, H. O. et al. (2011). Mechanism
and specificity of pentachloropseudilinmediated inhibition of myosin motor
activity. J Biol Chem 286, 29700–29708.
Cho, M. H., Boutaoui, N., Klanderman,
B. J., Sylvia, J. S., Ziniti, J. P., Hersh,
C. P., DeMeo, D. L., Hunninghake,
G. M., Litonjua, A. A., Sparrow, D. et
al. (2010). Variants in FAM13A are
associated with chronic obstructive
pulmonary disease. Nat Genet 42,
200–202.
Choi, H. S., Su, W. M., Morgan, J.
M., Han, G. S., Xu, Z., Karanasios,
E., Siniossoglou, S. and Carman,
G. M. (2011). Phosphorylation of
phosphatidate phosphatase regulates its
membrane association and physiological
functions in Saccharomyces
cerevisiae: identification of SER(602),
THR(723), AND SER(744) as the sites
phosphorylated by CDC28 (CDK1)encoded cyclin-dependent kinase. J Biol
Chem 286, 1486–1498.
Cipriani, V., Matharu, B. K., Khan, J. C.,
Shahid, H., Hayward, C., Wright, A. F.,
Armbrecht, A. M., Dhillon, B., Harding,
S. P., Bishop, P. N., Bunce, C., Clayton,
D. G., Moore, A. T. and Yates, J. R.
W. (2011). No evidence of association
between complement factor I genetic
variant rs10033900 and age-related
macular degeneration. Eur J Hum Genet
(epub).
Cipriani, V., Matharu, B. K., Khan, J. C.,
Shahid, H., Stanton, C. M., Hayward,
C., Wright A. F., Bunce, C., Clayton,
D. G., Moore, A. T. and Yates, J. R. W.
(2011). Genetic variation in complement
60
regulators and susceptibility to
age-related macular degeneration.
Immunobiol (epub).
Clark, R. D., Graham, J. M., Friez, M.
J., Hoo, J. J., Jones, K. L., McKeown,
C., Moeschler, J. B., Raymond, F. L.,
Rogers, R. C., Schwartz, C. E. et al.
(2009). FG syndrome, an X-linked
multiple congenital anomaly syndrome:
The clinical phenotype and an algorithm
for diagnostic testing. Genet Med 11,
769–775.
Clatworthy, M. R., Espeli, M., Torpey,
N. and Smith, K. G. C. (2010). The
generation and maintenance of serum
alloantibody. Curr Opin Immunol 22,
669–681.
Clayton, D. (2010). On inferring
presence of an individual in a mixture:
a Bayesian approach. Biostatistics 11,
661–673.
Cluett, C., Brayne, C., Clarke, R.,
Evans, G., Matthews, F., Rubinsztein,
D. C., Huppert, F., Llewellyn, D. J.,
Rice, N., Henley, W. et al. (2010).
Polymorphisms in LMNA and near a
SERPINA gene cluster are associated
with cognitive function in older people.
Neurobiol Aging 31, 1563–1568.
Cooper, J. D., Smyth, D. J., Walker, N.
M., Stevens, H., Burren, O. S., Wallace,
C., Greissl, C., Ramos-Lopez, E.,
Hyppönen, E., Dunger, D. B. et al.
(2011). Inherited variation in vitamin D
genes is associated with predisposition
to autoimmune disease type 1 diabetes.
Diabetes 60, 1624–1631.
Corrochano, S., Renna, M., Carter,
S., Chrobot, N., Kent, R., Stewart, M.,
Cooper, J., Brown, S. D., Rubinsztein,
D. C. and Acevedo-Arozena, A.
(2011). Alpha-synuclein levels modulate
Huntington’s disease in mice. Hum Mol
Genet (epub).
Cotsapas, C., Voight, B. F., Rossin,
E., Lage, K., Neale, B. M., Wallace,
C., Abecasis, G. R., Barrett, J. C.,
Behrens, T., Cho, J. et al. (2011).
Pervasive sharing of genetic effects in
autoimmune disease. PLoS Genet 7,
e1002254.
Cox, J. J., Sheynin, J., Shorer, Z.,
Reimann, F., Nicholas, A. K., Zubovic,
L., Baralle, M., Wraige, E., Manor, E.,
Levi, J., Woods, C. G. and Parvari, R.
(2010). Congenital insensitivity to pain:
novel SCN9A missense and in-frame
deletion mutations. Hum Mutat 31,
E1670–E1686.
Cox, J. J., Willatt, L., Homfray, T.
and Woods, C. G. (2011). A SOX9
duplication and familial 46,XX
developmental testicular disorder. N Engl
J Med 364, 91–93.
Craddock, N., Hurles, M. E., Cardin, N.,
Pearson, R. D., Plagnol, V., Robson,
S. and Wellcome Trust Case Control.
(2010). Genome-wide association
study of CNVs in 16,000 cases of eight
common diseases and 3,000 shared
controls. Nature 464, 713–720.
da Silva Xavier, G., Farhan, H., Kim,
H., Caxaria, S., Johnson, P., Hughes,
S., Bugliani, M., Marselli, L., Marchetti,
P., Birzele, F. et al. (2011). Per-arnt-sim
(PAS) domain-containing protein kinase
is downregulated in human islets in
type 2 diabetes and regulates glucagon
secretion. Diabetologia 54, 819–827.
Daniele, T., Hackmann, Y., Ritter, A.
T., Wenham, M., Booth, S., Bossi, G.,
Schintler, M., Auer-Grumbach, M. and
Griffiths, G. M. (2011). A role for Rab7
in the movement of secretory granules
in cytotoxic T lymphocytes. Traffic 12,
902–911.
Davidson, J. E., Irizarry, M. C., Bray, B.
C., Wetten, S., Galwey, N., Gibson, R.,
Borrie, M., Delisle, R., Feldman, H. H.,
Hsiung, G. et al. (2010). An exploration
of cognitive subgroups in Alzheimer's
disease. J Int Neuropsych Soc 16,
233–243.
Davies, J. E. and Rubinsztein, D.
C. (2011). Over-expression of BCL2
rescues muscle weakness in a mouse
model of oculopharyngeal muscular
dystrophy. Hum Mol Genet 20, 1154–
1163.
Davies, J. E., Rose, C., Sarkar, S. and
Rubinsztein, D. C. (2010). Cystamine
suppresses polyalanine toxicity in
a mouse model of oculopharyngeal
muscular dystrophy. Sci Transl Med 2,
34ra40.
Davison, L. J., Wallace, C., Cooper,
J. D., Cope, N. F., Wilson, N. K.,
Smyth, D. J., Howson, J. M., Saleh,
N., Al-Jeffery, A., Angus, K. L. et al.
(2011). Long-range DNA looping and
gene expression analyses identify DEXI
as an autoimmune disease candidate
gene. Hum Mol Genet (epub).
Dawson, M. A., Prinjha, R. K., Dittman,
A., Giotopoulos, G., Bantscheff, M.,
Chan, W. I., Robson, S. C., Chung,
C., Hopf, C., Savitski, M. M. et al.
(2011). Inhibition of BET recruitment
to chromatin as an effective treatment
for MLL-fusion leukaemia. Nature 478,
529–533.
Dawson, M. A., Curry, J. E., Barber,
K., Beer, P. A., Graham, B., Lyons,
J. F., Richardson, C. J., Scott, M. A.,
Smyth, T., Squires, M. S. et al. (2010).
AT9283, a potent inhibitor of the Aurora
kinases and Jak2, has therapeutic
potential in myeloproliferative disorders.
Br J Haematol 150, 46–57.
De Marinis, Y. Z., Salehi, A., Ward,
C. E., Zhang, Q. A., Abdulkader, F.,
Bengtsson, M., Braha, O., Braun, M.,
Ramracheya, R., Amisten, S. et al.
(2010). GLP-1 inhibits and adrenaline
stimulates glucagon release by
differential modulation of N- and L-type
Ca2+ channel-dependent exocytosis.
Cell Metab 11, 543–553.
Deane, J. E., Abrusci, P., Johnson,
S. and Lea, S. M. (2010). Timing
is everything: the regulation of type
III secretion. Cell Mol Life Sci 67,
1065–1075.
Deane, J. E., Graham, S. C., Kim, N.
N., Stein, P. E., McNair, R., CachónGonzález, M. B., Cox, T. M. and
Read, R. J. (2011). Insights into
Krabbe disease from structures of
galactocerebrosidase. Proc Natl Acad
Sci USA 108, 15169–15173.
Dickens, J. A. and Lomas, D. A.
(2011). Why has it been so difficult to
prove the efficacy of alpha-1-antitrypsin
replacement therapy? Insights from the
study of disease pathogenesis. Drug
Des Devel Ther 5, 391–405.
mechanism of polymerization in the
serpinopathies. Proc Natl Acad Sci USA
107, 17146–17151.
DiMaio, F., Terwilliger, T. C., Read, R. J.,
Wlodawer, A., Oberdorfer, G., Wagner,
U., Valkov, E., Alon, A., Fass, D.,
Axelrod, H. L. et al. (2011). Improved
molecular replacement by densityand energy-guided protein structure
optimization. Nature 473, 540–543.
Ekeowa, U. I., Marciniak, S. J. and
Lomas, D. A. (2011). "(1)-antitrypsin
deficiency and inflammation. Expert Rev
Clin Immunol 7, 243–252.
Downes, K., Pekalski, M., Angus, K.
L., Hardy, M., Nutland, S., Smyth, D. J.,
Walker, N. M., Wallace, C and Todd, J.
A. (2010). Reduced expression of IFIH1
is protective for type 1 diabetes. PLoS
One 5, e12646.
Duncan, L. M., Nathan, J. A. and
Lehner, P. J. (2010). Stabilization of
an E3 ligase-E2-ubiquitin complex
increases cell surface MHC class I
expression. J Immunol 184, 6978–6985.
Durrington, H. J., Upton, P. D.,
Hoer, S., Boname, J., Dunmore, B.
J., Yang, J., Crilley, T. K., Butler, L.
M., Blackbourn, D. J., Nash, G. B.,
Lehner, P. J. and Morrell, N. W. (2010).
Identification of a lysosomal pathway
regulating degradation of the bone
morphogenetic protein receptor type II.
J Biol Chem 285, 37641–37649.
Duvoix, A., Miranda, E., Perez, J.,
Sorensen, G. L., Holmskov, U.,
Trapnell, B. C., Madsen, J., Clark, H.
W., Edwards, L. D., Miller, B. E., TalSinger, R. M. and Lomas, D. A. (2011).
Evaluation of full-length, cleaved and
nitrosylated serum surfactant protein
D as biomarkers for COPD. COPD 8,
79–95.
Ehsani, S., Huo, H., Salehzadeh, A.,
Pocanschi, C. L., Watts, J. C., Wille,
H., Westaway, D., Rogaeva, E., St
George-Hyslop, P. H. and SchmittUlms, G. (2011). Family reunion-the
ZIP/prion gene family. Prog Neurobiol
93, 405–420.
Ekeowa, U. I., Freeke, J., Miranda,
E., Gooptu, B., Bush, M. F., Pérez,
J., Teckman, J., Robinson, C. V. and
Lomas, D. A. (2010). Defining the
Ellingsgaard, H., Hauselmann, I.,
Schuler, B., Habib, A. M., Baggio, L. L.,
Meier, D. T., Eppler, E., Bouzakri, K.,
Wueest, S., Muller, Y. D. et al. (2011).
Interleukin-6 enhances insulin secretion
by increasing L cell and " cell glucagonlike peptide-1 secretion. Nat Med 17,
1481–1489.
Eriguchi, M., Mizuta, H., Luo, S.,
Kuroda, Y., Hara, H. and Rubinsztein,
D. C. (2010). Alpha Pix enhances
mutant huntingtin aggregation. J Neurol
Sci 290, 80–85.
Espeli, M., Bökers, S., Giannico, G.,
Dickinson, H. A., Bardsley, V., Fogo,
A. B. and Smith, K. G. C. (2011).
Local renal autoantibody production in
lupus nephritis. J Am Soc Nephrol 22,
296–305.
Espeli, M., Niederer, H. A., Traherne,
J. A., Trowsdale, J. and Smith, K. G. C.
(2010). Genetic variation, Fc! receptors,
KIRs and infection: the evolution of
autoimmunity. Curr Opin Immunol 22,
715–722.
Fabani, M. M., Abreu-Goodger, C.,
Williams, D., Lyons, P. A., Torres, A.
G., Smith, K. G. C., Enright, A. J., Gait,
M. J. and Vigorito, E. (2010). Efficient
inhibition of miR-155 function in vivo by
peptide nucleic acids. Nucleic Acids Res
38, 4466–4475.
Fakiola, M.†, Mishra, A.†, Rai, M., Singh,
S. P., O’Leary, R., Ball, S., Francis,
R. W., Miller, E. N., Sundar, S.* and
Blackwell, J. M.* (2010). Genome wide
linkage study for visceral leishmaniasis
in India. PLoS One 5, e15807.
†
equal first authorship;
*equal contributions
61
Fakiola, M., Miller, E. N., Fadl, M.,
Mohamed, H. S., Jamieson, S. E.,
Francis, R. W., Cordell, H. J., Peacock,
C. S., Raju, M., Khalil, E. A. et al.
(2011). Genetic and functional evidence
implicating DLL1 as the gene that
influences susceptibility to visceral
leishmaniasis at chromosome 6q27.
J Infect Dis 204, 467–477.
Fitch, S., Kimber, G. M., Wilson,
N. K., Göttgens, B., Dzierzak, E.
and Ottersbach, K. (2011). A role
for GATA3 and the sympathetic
nervous system innthe emergence of
haematopoietic stem cells. Exp Hematol
39, S86.
Fleming, A. and Rubinsztein, D.
C. (2011). Zebrafish as a model to
understand autophagy and its role in
neurological disease. Biochim Biophys
Acta 1812, 520–526.
Fleming, A., Noda, T., Yoshimori,
T. and Rubinsztein, D. C. (2011).
Chemical modulators of autophagy
as biological probes and potential
therapeutics. Nat Chem Biol 7, 9–17.
Foreman, M. G., Kong, X., DeMeo, D.
L., Pillai, S. G., Hersh, C. P., Bakke,
P., Gulsvik, A., Lomas, D. A., Litonjua,
A. A., Shapiro, S. D. et al. (2011).
Polymorphisms in surfactant protein-D
are associated with chronic obstructive
pulmonary disease. Am J Respir Cell Mol
Biol 44, 316–322.
Fraser, H. I., Dendrou, C. A., Healy, B.,
Rainbow, D. B., Howlett, S., Smink, L.
J., Gregory, S., Steward, C. A., Todd,
J. A., Peterson, L. B. and Wicker, L. S.
(2010). Nonobese diabetic congenic
strain analysis of autoimmune diabetes
reveals genetic complexity of the Idd18
locus and identifies Vav3 as a candidate
gene. J Immunol 184, 5075–5084.
Friedlander, R. S., Moss, C. E., Mace,
J., Parker, H. E., Tolhurst, G., Habib,
A. M., Wachten, S., Cooper, D. M.,
Gribble, F. M.* and Reimann, F.*
(2011). Role of phosphodiesterase
and adenylate cyclase isozymes in
murine colonic glucagon-like peptide
1 secreting cells. Br J Pharmacol 163,
261–271.
62
Fung, E., Esposito, L., Todd, J. A.
and Wicker, L. S. (2010). Multiplexed
immunophenotyping of human antigenpresenting cells in whole blood by
polychromatic flow cytometry. Nat Protoc
5, 357–370.
Gabryelewicz, T., Masellis, M.,
Berdynski, M., Bilbao, J. M., Rogaeva,
E., St George-Hyslop, P., Barczak,
A., Czyzewski, K., Barcikowska, M.,
Wszolek, Z. et al. (2010). Intra-familial
clinical heterogeneity due to FTLD-U
with TDP-43 proteinopathy caused
by a novel deletion in progranulin
gene (PGRN). J Alzheimers Dis 22,
1123–1133.
Galluzzi, L., Vitale, I., Abrams, J.
M., Alnemri, E. S., Baehrecke, E.
H., Blagosklonny, M. V., Dawson,
T. M., Dawson, V. L., El-Deiry, W. S.,
Fulda, S. et al. (2011). Molecular
definitions of cell death subroutines:
recommendations of the Nomenclature
Committee on Cell Death 2012. Cell
Death Differ (epub).
García-Arencibia, M., Hochfeld, W. E.,
Toh, P. P. C. and Rubinsztein, D. C.
(2010). Autophagy, a guardian against
neurodegeneration. Semin Cell Dev Biol
21, 691–698.
Garcia-Ortega, A. M., Cañete, A.,
Quinter, C., Silberstein, L., PiquerGil, M., Alvarez-Dolado, M., Dekel,
B., Göttgens, B. and Sánchez, M.
J. (2010). Enhanced hematovascular
contribution of SCL 3' enhancer
expressing fetal liver cells uncovers their
potential to integrate in extramedullary
adult niches. Stem Cells 28, 100–112.
Garstka, M. A., Fritzsche, S., Lenart,
I., Hein, Z., Jankevicius, G., Boyle, L.
H., Elliott, T., Trowsdale, J., Antoniou,
A. N., Zacharias, M. and Springer,
S. (2011). Tapasin dependence of
major histocompatibility complex
class I molecules correlates with their
conformational flexibility. FASEB J 25,
3989–3998.
George-Hyslop, P. S. and SchmittUlms, G. (2010). Selectively tuning
!-secretase. Nature 467, 36–37.
Gerold, K. D., Zheng, P. L., Rainbow,
D. B., Zernecke, A., Wicker, L. S.
and Kissler, S. (2011). The soluble
CTLA-4 splice variant protects from
type 1 diabetes and potentiates
regulatory T-cell function. Diabetes 60,
1955–1963.
Gerrish, A., Russo, G., Richards, A.,
Moskvina, V., Ivanov, D., Harold, D.,
Sims, R., Abraham, R., Hollingworth,
P., Chapman, J. et al. (2011). The role
of variation at A#PP, PSEN1, PSEN2,
and MAPT in late onset Alzheimer’s
Disease. J Alzheimers Dis (in press).
Gibbons, D. L., Abeler-Dörner, L.,
Raine, T., Hwang, I. Y., Jandke, A.,
Wencker, M., Deban, L., Rudd, C. E.,
Irving, P. M., Kehrl, J. H. and Hayday,
A. C. (2011). Cutting edge: regulator
of g protein signaling-1 selectively
regulates gut T cell trafficking and colitic
potential. J Immunol 187, 2067–2071.
Gordon, D. E., Bond, L. M., Sahlender,
D. A. and Peden, A. A. (2010). A
targeted siRNA screen to identify
SNAREs required for constitutive
secretion in mammalian cells. Traffic 11,
1191–1204.
Göttgens, B., Ferreira, R., Sanchez, M.
J., Ishibashi, S., Li, J., Spensberger, D.,
Lefevre, P., Ottersbach, K., Chapman,
M., Kinston, S. et al. (2010). Cisregulatory remodeling of the SCL locus
during vertebrate evolution. Mol Cell Biol
30, 5741–5751.
Green, P., Wiseman, M., Crow, Y. J.,
Houlden, H., Riphagen, S., Lin, J. P.,
Raymond, F. L., Childs, A., Sheridan,
E., Edwards, S. and Josifova, D. J.
(2010). Brown-Vialetto-Van Laere
syndrome, a Ponto-Bulbar Palsy with
deafness, is caused by mutations
in C20orf54. Am J Hum Genet 86,
485–489.
Gribble, F. M. (2010). Alpha2Aadrenergic receptors and type 2
diabetes. N Engl J Med 362, 361–362.
Griffiths, D. S., Li, J., Dawson, M. A.,
Trotter, M. W., Cheng, Y. H., Smith, A.
M., Mansfield, W., Liu, P., Kouzarides,
T., Nichols, J. et al. (2011). LIF-
independent JAK signalling to chromatin
in embryonic stem cells uncovered from
an adult stem cell disease. Nat Cell Biol
13, 13–21.
Griffiths, G. M., Tsun, A. and
Stinchcombe, J. C. (2010). The
immunological synapse: a focal point for
endocytosis and exocytosis. J Cell Biol
189, 399–406.
Gudgin, E. J. and Huntly, B. J. P.
(2011). Acute myeloid leukemia:
leukemia stem cells write a prognostic
signature. Stem Cell Res Ther 2, 21.
Hackett, A., Tarpey, P. S., Licata,
A., Cox, J., Whibley, A., Boyle, J.,
Rogers, C., Grigg, J., Partington, M.
Stevenson, R. E. et al. (2010). CASK
mutations are frequent in males and
cause X-linked nystagmus and variable
XLMR phenotypes. Eur J Hum Genet
18, 544–552.
Hall, I. P. and Lomas, D. A. (2010). The
genetics of obstructive lung disease: big
is beautiful. Thorax 65, 760–761.
Halsall, S., Nicholas, A. K., Thornton,
G., Martin, H. and Woods, C. G.
(2010). Critical consequences of finding
three pathogenic mutations in an
individual with recessive disease. J Med
Genet 47, 769–770.
Hamilton-Williams, E. E., Wong, S. B.
J., Martinez, X., Rainbow, D. B., Hunter,
K. M., Wicker, L. S. and Sherman, L.
A. (2010). Idd9.2 and Idd9.3 protective
alleles function in CD4(+) T-cells and
nonlymphoid cells to prevent expansion
of pathogenic islet-specific CD8(+)
T-cells. Diabetes 59, 1478–1486.
Hannah, R., Joshi, A., Wilson, N. K.,
Kinston, S. and Göttgens, B. (2011).
A compendium of genome-wide
hematopoietic transcription factor maps
supports the identification of gene
regulatory control mechanisms. Exp
Hematol 39, 531–541.
Harbour, M. E., Breusegem, S. Y.,
Antrobus, R., Freeman, C., Reid, E.
and Seaman, M. N. J. (2010). The
cargo-selective retromer complex is a
recruiting hub for protein complexes that
regulate endosomal tubule dynamics.
J Cell Sci 123, 3703–3717.
Harrison, C. N., Bareford, D., Butt,
N., Campbell, P., Conneally, E.,
Drummond, M., Erber, W., Everington,
T., Green, A. R., Hall, G. W. et al.
(2010). Guideline for investigation and
management of adults and children
presenting with a thrombocytosis. Br J
Haematol 149, 352–375.
Harwood, D. G., Kalechstein, A.,
Barker, W. W., Strauman, S., St
George-Hyslop, P., Iglesias, C.,
Loewenstein, D. and Duara, R. (2010).
The effect of alcohol and tobacco
consumption, and apolipoprotein E
genotype, on the age of onset in
Alzheimer's disease. Int J Geriatr
Psychiatry 25, 511–518.
Heap, G. A., Yang, J. H., Downes, K.,
Healy, B. C., Hunt, K. A., Bockett, N.,
Franke, L., Dubois, P. C., Mein, C. A.,
Dobson, R. J. et al. (2010). Genomewide analysis of allelic expression
imbalance in human primary cells
by high-throughput transcriptome
resequencing. Hum Mol Genet 19,
122–134.
Heard, E., Tishkoff, S., Todd, J. A.,
Vidal, M., Wagner, G. P., Wang, J.,
Weigel, D. and Young, R. (2010). Ten
years of genetics and genomics: what
have we achieved and where are we
heading? Nat Rev Genet 11, 723–733.
Heinig, M., Petretto, E., Wallace, C.,
Bottolo, L., Rotival, M., Lu, H., Li, Y.,
Sarwar, R., Langley, S. R., Bauerfeind,
A. et al. (2010). A trans-acting locus
regulates an anti-viral expression
network and type 1 diabetes risk. Nature
467, 460–464.
Hersh, C. P., Pillai, S. G., Zhu, G. H.,
Lomas, D. A., Bakke, P., Gulsvik,
A., DeMeo, D. L., Klanderman, B.
J., Lazarus, R., Litonjua, A. A. et al.
(2010). Multistudy fine mapping of
chromosome 2q identifies XRCC5 as a
chronic obstructive pulmonary disease
susceptibility gene. Am J Respir Crit Care
Med 182, 605–613.
Hersh, C. P., Silverman, E. K., Gascon,
J., Bhattacharya, S., Klanderman,
B. J., Litonjua, A. A., Lefebvre, V.,
Sparrow, D., Reilly, J. J., Anderson,
W. H., Lomas, D. A. and Mariani, T. J.
(2011). SOX5 is a candidate gene for
chronic obstructive pulmonary disease
susceptibility and is necessary for lung
development. Am J Respir Crit Care Med
183, 1482–1489.
Heuser, M., Yun, H., Berg, T., Yung,
E., Argiropoulos, B., Kuchenbauer,
F., Park, G., Hamwi, I., Palmqvist, L.,
Lai, C. K. et al. (2011). Cell of origin
in AML: susceptibility to MN1-induced
transformation is regulated by the
MEIS1/AbdB-like HOX protein complex.
Cancer Cell 20, 39–52.
Heuser, M., Yung, E., Yun, H., Berg,
T., Argiropoulos, B., Kuchenbauer,
F., Hamwi, I., Palmqvist, L., Lai, C. K.,
Leung, M. et al. (2011). The potent
oncogenes MN1 and MEIS1 co-localize
at a large proportion of their chromatin
target sites suggestive of a higher order
leukemogenic regulatory complex. Exp
Hematol 39, S66–S67.
Hiemstra, T. F., Charles, P. D., Hester,
S. S., Karet, F. E.* and Lilley, K. S.*
(2011). Uromodulin exclusion list
improves urinary exosomal protein
identification. J Biomol Techniques (in
press).
Higgins, J., Midgley, C., Bergh, A. M.,
Bell, S. M., Askham, J. M., Roberts,
E., Binns, R. K., Sharif, S. M., Bennett,
C., Glover, D. M., Woods, C. G.,
Morrison, E. E. and Bond, J. (2010).
Human ASPM participates in spindle
organisation, spindle orientation and
cytokinesis. BMC Cell Biol 11, 85.
Hirose, K., Inukai, T., Kikuchi, J.,
Furukawa, Y., Ikawa, T., Kawamoto, H.,
Oram, S. H. Göttgens, B., Kiyokawa,
N., Miyagawa, Y. et al. (2010). Aberrant
induction of LMO2 by the E2A-HLF
chimeric transcription factor and its
implication in leukemogenesis of
B-precursor ALL with t(17;19). Blood
116, 962–970.
63
Hirst, J., Francisco, G. C., Sahlender,
D. A., Seaman, M. N. J., Dacks, J. B.
and Robinson, M. S. (2011). The fifth
adaptor protein complex. PLoS Biol 9,
e1001170.
Hisadome, K., Reimann, F., Gribble, F.
M. and Trapp, S. (2010). Leptin directly
depolarizes preproglucagon neurons in
the nucleus tractus solitarius electrical
properties of glucagon-like peptide 1
neurons. Diabetes 59, 1890–1898.
Hisadome, K., Reimann, F., Gribble,
F. M. and Trapp, S. (2011). CCK
stimulation of GLP-1 neurons involves
alpha-1-adrenoceptor-mediated
increase in glutamatergic synaptic
inputs. Diabetes 60, 2701–2709.
Höglinger, G. U., Melhem, N. M.,
Dickson, D. W., Sleiman, P. M. A.,
Wang, L., Klei, L., Rademakers, R.,
De Silva, R., Litvan, I., Riley, D. E. et
al. (2011). Identification of common
variants influencing risk of the tauopathy
progressive supranuclear palsy. Nat
Genet 43, 699–705.
Hollingworth, P., Harold, D., Sims,
R., Gerrish, A., Lambert, J. C.,
Carrasquillo, M. M., Abraham, R.,
Hamshere, M. L., Pahwa, J. S.,
Moskvina, V. et al. (2011). Common
variants at ABCA7, MS4A6A/MS4A4E,
EPHA1, CD33 and CD2AP are
associated with Alzheimer's disease. Nat
Genet 43, 429–435.
Hopkins, T. G., Maher, E. R., Reid, E.
and Marciniak, S. J. (2011). Recurrent
pneumothorax. Lancet 377, 1624.
Hov, J. R., Kosmoliaptsis, V., Traherne,
J. A., Olsson, M., Boberg, K. M.,
Bergquist, A., Schrumpf, E., Bradley, J.
A., Taylor, C. J., Lie, B. A., Trowsdale, J.
and Karlsen, T. H. (2011). Electrostatic
modifications of the human leukocyte
antigen-DR P9 peptide-binding pocket
and susceptibility to primary sclerosing
cholangitis. Hepatol 53, 1967–1976.
Howson, J. M., Rosinger, S., Smyth,
D. J., Boehm, B. O., the ADBW-END
Study Group and Todd, J. A. (2011).
Genetic analysis of adult-onset
64
autoimmune diabetes. Diabetes 60,
2645–2653.
Howson, J. M., Stevens, H., Smyth,
D. J., Walker, N. M., Chandler, K.
A., Bingley, P. J. and Todd, J. A.
(2011). Evidence that HLA Class
I and II associations with type 1
diabetes, autoantibodies to GAD and
autoantibodies to IA-2, are distinct.
Diabetes 60, 2635–2644.
Hudson, T. J., Anderson, W., Aretz,
A., Barker, A. D., Bell, C., Bernabe,
R. R. and the International Cancer
Genome Consortium. (2010).
International network of cancer genome
projects. Nature 464, 993–998.
Huntington, J. A. (2011). Serpin
structure, function and dysfunction.
J Thromb Haemost 9, 26–34.
Huntington, J. A. (2011). Thrombin
plasticity. Biochimica et Biophysica Acta
- Proteins and Proteomics (epub ahead
of print).
Huntington, J. A. and Whisstock, J. C.
(2010). Molecular contortionism - on
the physical limits of serpin 'loop-sheet'
polymers. Biol Chem 391, 973–982.
Huntington, J. A. and Yamasaki, M.
(2011). Serpin polymerization in vitro.
Methods Enzymol 501, 379–420.
Hurst, J. R., Vestbo, J., Anzueto, A.,
Locantore, N., Mullerova, H., TalSinger, R., Miller, B., Lomas, D. A.,
Agusti, A., Macnee, W. et al. (2010).
Susceptibility to exacerbation in chronic
obstructive pulmonary disease. N Engl J
Med 363, 1128–1138.
Irving, J. A., Ekeowa, U. I., Belorgey,
D., Haq, I., Gooptu, B., Miranda, E.,
Pérez, J., Roussel, B. D., Ordóñez,
A., Dalton, L. E. et al. (2011). The
serpinopathies studying serpin
polymerization in vivo. Methods Enzymol
501, 421–466.
Isachenko, V., Maettner, R.,
Petrunkina, A. M., Sterzik, K.,
Mallmann, P., Rahimi, G., Sanchez,
R., Risopatron, J., Hancke, K.,
Damjanovski, I., Kreinberg, R. and
Isachenko, E. (2011). Cryoprotectantfree vitrification of human spermatozoa
in large (up to 0.5 ml) volume: a novel
technology. Clin Lab 57, 643–650.
Jackson, L. P., Kelly, B. T., McCoy, A. J.,
Gaffry, T., James, L. C., Collins, B. M.,
Honing, S., Evans, P. R. and Owen, D.
J. (2010). A large-scale conformational
change couples membrane recruitment
to cargo binding in the AP2 clathrin
adaptor complex. Cell 141, 1220–1229.
Jahn, T. R., Kohlhoff, K. J., Scott, M.,
Tartaglia, G. G., Lomas, D. A., Dobson,
C. M., Vendruscolo, M. and Crowther,
D. C. (2011). Detection of early
locomotor abnormalities in a Drosophila
model of Alzheimer's disease. J Neurosci
Methods 197, 186–189.
Jahn, T. R., Malzer, E., Roote, J.,
Vishnivetskaya, A., Imarisio, S.,
Giannakou, M., Panser, K., Marciniak,
S. and Crowther, D. C. (2011).
Modeling serpin conformational
diseases in Drosophila melanogaster.
Methods Enzymol 499, 227–258.
Jamieson, S. E.*, Peixoto-Rangel, A.
L.*, Hargrave, A. C., de Roubaix, L. A.,
Mui, E. J., Boulter, N. R., Miller, E. N.,
Fuller, S. J., Wiley, J. S., Castellucci, L.
et al. (2010). Evidence for association
between purinergic receptor P2X7
(P2RX7) and congenital toxoplasmosis.
Genes Immun 11, 374–383.
Jayakumar, A., Castilho, T. M., Park,
E., Goldsmith-Pestana, K., Blackwell,
J. M. and McMahon-Pratt, D. (2011).
TLR1/2 activation during heterologous
prime-boost vaccination (DNA-MVA)
enhances CD8+ T cell responses
providing protection against Leishmania
(Viannia). PLoS Neg Trop Dis 5, e1204.
Jenkins, M. R. and Griffiths, G. M.
(2010). The synapse and cytolytic
machinery of cytotoxic T cells. Curr Opin
Immunol 22, 308–313.
Jimenez-Sanchez, M., Thompson, F.,
Zavodsky, E. and Rubinsztein, D. C.
(2011). Autophagy and polyglutamine
diseases. Prog Neurobiol (in press).
Jin, H., Sanjo, N., Uchihara, T., Watabe,
K., St George-Hyslop, P., Fraser, P. E.
and Mizusawa, H. (2010). Presenilin-1
holoprotein is an interacting partner of
sarco endoplasmic reticulum calciumATPase and confers resistance to
endoplasmic reticulum stress.
J Alzheimers Dis 20, 261–273.
cholesterol metabolism in the aetiology
of Alzheimer's disease. PLoS One 6.
Jing, J. A., Junutula, J. R., Wu, C.,
Burden, J., Matern, H., Peden, A.
A. and Prekeris, R. (2010). FIP1/
RCP binding to Golgin-97 regulates
retrograde transport from recycling
endosomes to the trans-Golgi network.
Mol Biol Cell 21, 3041–3053.
Jun, G., Naj, A. C., Beecham, G. W.,
Wang, L. S., Buros, J., Gallins, P.
J., Buxbaum, J. D., Ertekin-Taner,
N., Fallin, M. D., Friedland, R. et al.
(2010). Meta-analysis confirms CR1,
CLU, and PICALM as alzheimer disease
risk loci and reveals interactions with
APOE genotypes. Arch Neurol 67,
1473–1484.
Johnson, D. J., Langdown, J. and
Huntington, J. A. (2010). Molecular
basis of factor IXa recognition by
heparin-activated antithrombin revealed
by a 1.7-A structure of the ternary
complex. Proc Natl Acad Sci USA 107,
645–650.
Jones, A. V., Campbell, P. J., Beer, P.
A., Schnittger, S., Vannucchi, A. M.,
Zoi, K., Percy, M. J., McMullin, M. F.,
Scott, L. M., Tapper, W. et al. (2010).
The JAK2 46/1 haplotype predisposes
to MPL-mutated myeloproliferative
neoplasms. Blood 115, 4517–4523.
Jones, D. C., Kosmoliaptsis, V., Apps,
R., Lapaque, N., Smith, I., Kono,
A., Chang, C., Boyle, L. H., Taylor,
C. J., Trowsdale, J. and Allen, R. L.
(2011). HLA class I allelic sequence
and conformation regulate leukocyte
Ig-like receptor binding. J Immunol 186,
2990–2997.
Jones, L., Holmans, P. A., Hamshere,
M. L., Harold, D., Moskvina, V., Ivanov,
D., Pocklington, A., Abraham, R.,
Hollingworth, P., Sims, R. et al.
(2010). Genetic evidence implicates
the immune system and cholesterol
metabolism in the aetiology of
Alzheimer's disease. PLoS One 5,
e13950.
Jones, L., Holmans, P. A., Hamshere,
M. L., Harold, D., Moskvina, V., Ivanov,
D., Pocklington, A., Abraham, R.,
Hollingworth, P., Sims, R. et al.
(2011). Correction: genetic evidence
implicates the immune system and
Joshi, A. and Göttgens, B. (2011).
Maximum parsimony analysis of
gene expression profiles permits the
reconstruction of developmental cell
lineage trees. Dev Biol 353, 440–447.
Kamath, P., Huntington, J. A.
and Krishnaswamy, S. (2010).
Ligand binding shuttles thrombin
along a continuum of zymogen-and
proteinase-like states. J Biol Chem 285,
28651–28658.
Karanasios, E., Han, G. S., Xu, Z.,
Carman, G. M. and Siniossoglou, S.
(2010). A phosphorylation-regulated
amphipathic helix controls the
membrane translocation and function of
the yeast phosphatidate phosphatase.
Proc Natl Acad Sci USA 107, 17539–
17544.
Karet, F. E. (2011). Disorders of water
and acid-base homeostasis. Nephron
Physiol 118, 28–34.
Karet, F. E. (2011). The renal tubular
acidoses. In Netter's Textbook of the
Kidney (in press).
Keage, H. A., Matthews, F. E., Yip,
A., Gao, L., McCracken, C., McKeith,
I. G., Rubinsztein, D. C., Brayne, C.
and the MRC Cognitive Function
and Ageing Study. (2010). APOE and
ACE polymorphisms and dementia risk
in the older population over prolonged
follow-up: 10 years of incidence in
the MRC CFA Study. Age Ageing 39,
104–111.
Kerzendorfer, C., Whibley, A.,
Carpenter, G., Outwin, E., Chiang,
S. C., Turner, G., Schwartz, C.,
El-Khamisy, S., Raymond, F. L. and
O'Driscoll, M. (2010). Mutations
in Cullin 4B result in a human
syndrome associated with increased
camptothecin-induced topoisomerase
I-dependent DNA breaks. Hum Mol
Genet 19, 1324–1334.
Kim, S. H., Fraser, P. E., Westaway,
D., St George-Hyslop, P. H., Ehrlich,
M. E. and Gandy, S. (2010). Group
II metabotropic glutamate receptor
stimulation triggers production and
release of Alzheimer's amyloid(beta)42
from isolated intact nerve terminals.
J Neurosci 30, 3870–3875.
Klionsky, D. J., Baehrecke, E. H.,
Brumell, J. H., Chu, C. T., Codogno,
P., Cuervo, A. M., Debnath, J., Deretic,
V., Elazar, Z., Eskelinen, E. L. et al.
(2011). A comprehensive glossary
of autophagy-related molecules and
processes. Autophagy 7, 1273–1294.
Knecht, E., Aguado, C., Sarkar, S.,
Korolchuk, V. I., Criado-García,
O., Vernia, S., Boya, P., Sanz, P.,
Rodríguez de Córdoba, S. and
Rubinsztein, D. C. (2010). Impaired
autophagy in Lafora disease. Autophagy
6, 991–993.
Knezevic, K., Bee, T., Wilson, N. K.,
Janes, M. E., Kinston, S., Polderdijk,
S., Kolb-Kokocinski, A., Ottersbach,
K., Pencovich, N., Groner, Y. et al.
(2011). A Runx1-Smad6 rheostat
controls Runx1 activity during embryonic
hematopoiesis. Mol Cell Biol 31,
2817–2826.
Knobbe, C. B., Revett, T. J., Bai, Y.,
Chow, V., Jeon, A. H., Böhm, C.,
Ehsani, S., Kislinger, T., Mount, H. T.,
Mak, T. W., St George-Hyslop, P. H.
and Schmitt-Ulms, G. (2011). Choice
of biological source material supersedes
oxidative stress in its influence on DJ-1
in vivo interactions with Hsp90.
J Proteome Res 10, 4388–4404.
Kelly, B. T. and Owen, D. J. (2011).
Endocytic sorting of transmembrane
protein cargo. Curr Opin Cell Biol 23,
404–412.
65
Kohlhoff, K. J., Jahn, T. R., Lomas,
D. A., Dobson, C. M., Crowther, D.
C. and Vendruscolo, M. (2011). The
iFly tracking system for an automated
locomotor and behavioural analysis of
Drosophila melanogaster. Integr Biol
(Camb) 3, 755–760.
Kong, X. Y., Cho, M. H., Anderson, W.,
Coxson, H. O., Muller, N., Washko, G.,
Hoffman, E. A., Bakke, P., Gulsvik, A.,
Lomas, D. A. et al. (2011). Genomewide association study identifies BICD1
as a susceptibility gene for emphysema.
Am J Respir Crit Care Med 183, 43–49.
Koo, S., Huntly, B. J. P., Wang, Y.
A., Chen, J., Brumme, K., Ball, B.,
McKinney-Freeman, S. L., Yabuuchi,
A., Scholl, C., Bansal, D. et al. (2010).
Cdx4 is dispensable for murine adult
hematopoietic stem cells but promotes
MLL-AF9-mediated leukemogenesis.
Haematol-Hematol J 95, 1642–1650.
Korolchuk, V. I. and Rubinsztein, D.
C. (2011). Regulation of autophagy
by lysosomal positioning. Autophagy 7,
927–928.
Korolchuk, V. I., Menzies, F. M. and
Rubinsztein, D. C. (2010). Mechanisms
of cross-talk between the ubiquitinproteasome and autophagy-lysosome
systems. FEBS Lett 584, 1393–1398.
Korolchuk, V. I., Saiki, S., Lichtenberg,
M., Siddiqi, F. H., Roberts, E. A.,
Imarisio, S., Jahreiss, L., Sarkar, S.,
Futter, M., Menzies, F. M. et al. (2011).
Lysosomal positioning coordinates
cellular nutrient responses. Nat Cell Biol
13, 453–460.
Kozik, P., Francis, R. W., Seaman, M.
N. J.* and Robinson, M. S.* (2010). A
screen for endocytic motifs. Traffic 11,
843–855.
Kremeyer, B., Lopera, F., Cox, J. J.,
Momin, A., Rugiero, F., Marsh, S.,
Woods, C. G., Jones, N. G., Paterson,
K. J., Fricker, F. R. et al. (2010). A gainof-function mutation in TRPA1 causes
familial episodic pain syndrome. Neuron
66, 671–680.
Kvinlaug, B. T., Chan, W. I., Bullinger,
L., Ramaswami, M., Sears, C., Foster,
66
D., Lazic. S. E., Okabe, R., Benner,
A., Lee. B. H. et al. (2011). Common
and overlapping oncogenic pathways
contribute to the evolution of acute
myeloid leukemias. Cancer Res 71,
4117–4129.
D. A., Zhang, J., Basseres, D. S. et
al. (2011). RUNX1 regulates the
CD34 gene in haematopoietic stem
cells by mediating interactions with a
distal regulatory element. EMBO J 30,
4059–4070.
Kwong, T., Robinson, C., Spencer, D.,
Norden, A., Shah, N., Wiseman, O. J.,
Karet, F. E. et al. (2010). Accuracy of
urine pH testing in a regional Metabolic
stone clinic. Is the dipstick accurate
enough? J Endourol 24, A180.
Li, J., Kent, D. G., Chen, E. and
Green, A. R. (2011). Mouse models of
myeloproliferative neoplasms: JAK of all
grades. Dis Model Mech 4, 311–317.
Lawrence, S. P., Bright, N. A., Luzio,
J. P.* and Bowers, K.* (2010). The
sodium/proton exchanger NHE8
regulates late endosomal morphology
and function. Mol Biol Cell 21, 3540–
3551.
Lechtenberg, B. C., Johnson, D. J.,
Freund, S. M. and Huntington, J. A.
(2010). NMR resonance assignments of
thrombin reveal the conformational and
dynamic effects of ligation. Proc Natl
Acad Sci USA 107, 14087–14092.
Leddin, M., Perrod, C., Hoogenkamp,
M., Ghani, S., Assi, S., Heinz, S.,
Wilson, N. K., Follows, G., Schönheit,
J., Vockentanz, L. et al. (2011). Two
distinct auto-regulatory loops operate
at the PU.1 locus in B cells and myeloid
cells. Blood 117, 2827–2838.
Lee, J. H., Cheng, R., Barral, S.,
Reitz, C., Medrano, M., Lantigua, R.,
Jiménez-Velazquez, I. Z., Rogaeva, E.,
St George-Hyslop, P. H. and Mayeux,
R. (2011). Identification of novel loci
for Alzheimer disease and replication of
CLU, PICALM, and BIN1 in Caribbean
Hispanic individuals. Arch Neurol 68,
320–328.
Lee, J. C., Lyons, P. A., McKinney, E.
F., Sowerby, J. M., Carr, E. J., Bredin,
F., Rickman, H. M., Ratlamwala, H.,
Hatton, A., Rayner, T. F., Parkes, M.
and Smith, K. G. C. (2011). Gene
expression profiling of CD8+ T cells
predicts prognosis in patients with
Crohn disease and ulcerative colitis.
J Clin Invest 121, 4170–4179.
Levantini, E., Lee, S., Radomska, H.
S., Hetherington, C. J., Alberich-Jorda,
M., Amabile, G., Zhang, P., Gonzalez,
Li, J., Spensberger, D., Ahn, J. S.,
Anand, S., Beer, P. A., Ghevaert,
C., Chen, E., Forrai, A., Scott, L.
M., Ferreira, R. et al. (2010). JAK2
V617F impairs hematopoietic stem
cell function in a conditional knock-in
mouse model of JAK2 V617F-positive
essential thrombocythemia. Blood 116,
1528–1538.
Li, P., Burke, S., Wang, J., Chen, X.,
Ortiz, M., Lee, S. C., Lu, D., Campos,
L., Goulding, D., Ng, B. L. et al. (2010).
Reprogramming of T cells to natural
killer-like cells upon Bcl11b deletion.
Science 329, 85–89.
Li, W., Johnson, D. J., Adams, T.
E., Pozzi, N., De Filippis, V. and
Huntington, J. A. (2010). Thrombin
inhibition by serpins disrupts exosite II.
J Biol Chem 285, 38621–38629.
Lichtenberg, M., Mansilla, A., Zecchini,
V. R., Fleming, A. and Rubinsztein,
D. C. (2011). The Parkinson's disease
protein LRRK2 impairs proteasome
substrate clearance without affecting
proteasome catalytic activity. Cell Death
Dis 2, e196.
Linterman, M. A., Pierson, W., Lee, S.
K., Kallies, A., Kawamoto, S., Rayner,
T. F., Srivastava, M., Divekar, D. P.,
Beaton, L., Hogan, J. J. et al. (2011).
Foxp3(+) follicular regulatory T cells
control the germinal center response.
Nat Med 17, 975–982.
Lipman, P. J., Cho, M. H., Bakke, P.,
Gulsvik, A., Kong, X. Y., Lomas, D. A.,
Anderson, W., Silverman, E. K. and
Lange, C. (2011). On the follow-up
of genome-wide association studies:
an overall test for the most promising
SNPs. Genet Epidemiol 35, 303–309.
Liu, B., Moloney, A., Meehan, S.,
Morris, K., Thomas, S. E., Serpell,
L. C., Hider, R., Marciniak, S. J.,
Lomas, D. A. and Crowther, D. C.
(2011). Iron promotes the toxicity of
amyloid beta peptide by impeding its
ordered aggregation. J Biol Chem 286,
4248–4256.
Liu, H., Purbhoo, M. A., Davis, D. M.
and Rudd, C. E. (2010). SH2 domain
containing leukocyte phosphoprotein of
76-kDa (SLP-76) feedback regulation of
ZAP-70 microclustering. Proc Natl Acad
Sci USA 107, 10166–10171.
Llewellyn-Smith, I. J., Reimann, F.,
Gribble, F. M. and Trapp, S. (2011).
Preproglucagon neurons project widely
to autonomic control areas in the mouse
brain. Neurosci 180, 111–121.
Lomas, D. A. (2010). 25th anniversary
Transatlantic Airway Conference: Protein
misfolding and obstructive lung disease.
Proc Am Thorac Soc 7, 343–345.
Lugtenberg, D., Zangrande-Vieira,
L., Kirchhoff, M., Whibley, A. C.,
Oudakker, A. R., Kjaergaard, S.,
Vianna-Morgante, A. M., Kleefstra, T.,
Ruiter, M., Jehee, F. S. et al. (2010).
Recurrent deletion of ZNF630 at
Xp11.23 is not associated with mental
retardation. Am J Med Genet A 152A,
638–645.
Luheshi, L. M., Hoyer, W., de Barros,
T. P., van Dijk Härd, I., Brorsson, A. C.,
Macao, B., Persson, C., Crowther, D.
C., Lomas, D. A., Ståhl, S., Dobson,
C. M. Härd, T. (2010). Sequestration of
the Abeta peptide prevents toxicity and
promotes degradation in vivo. PLoS Biol
8, e1000334.
Lumb, J. H., Connell, J. W., Allison, R.
and Reid, E. (2011). The AAA ATPase
spastin links microtubule severing to
membrane modelling. Biochim Biophys
Acta (epub).
Luo, S. and Rubinsztein, D. C. (2010).
Apoptosis blocks Beclin 1-dependent
autophagosome synthesis: an effect
rescued by Bcl-xL. Cell Death Differ 17,
268–277.
Luzio, J. P., Gray, S. R. and Bright, N.
A. (2010). Endosome-lysosome fusion.
Biochem Soc Trans 38, 1413–1416.
Mascarenhas, M. and Ottersbach,
K. (2011). Role of cytokines in HSC
emergence. Exp Hematol 39, S85.
Lyons, P. A., McKinney, E. F., Rayner,
T. F., Hatton, A., Woffendin, H. B.,
Koukoulaki, M., Freeman, T. C., Jayne,
D. R. W., Chaudhry, A. N. and Smith,
K. G. C. (2010). Novel expression
signatures identified by transcriptional
analysis of separated leucocyte subsets
in systemic lupus erythematosus
and vasculitis. Ann Rheum Dis 69,
1208–1213.
Mason, M. J., Schaffner, C., Floto, R.
A. and Teo, Q. A. (2011). Constitutive
expression of a Mg2+ inhibited K+
current and a TRPM7-like current in
human erythroleukemia cells. Am J
Physiol Cell Physiol (epub).
Malzer, E., Daly, M. L., Moloney, A.,
Sendall, T. J., Thomas, S. E., Ryder, E.,
Ryoo, H. D., Crowther, D. C., Lomas,
D. A. and Marciniak, S. J. (2010).
Impaired tissue growth is mediated by
checkpoint kinase 1 (CHK1) in the
integrated stress response. J Cell Sci
123, 2892–2900.
Manes, T. D., Hoer, S., Muller, W.
A., Lehner, P. J. and Pober, J. S.
(2010). Kaposi's sarcoma-associated
herpesvirus K3 and K5 proteins block
distinct steps in transendothelial
migration of effector memory CD4+T
cells by targeting different endothelial
proteins. J Immunol 184, 5186–5192.
Marciniak, S. J. and Lomas, D. A.
(2010). Alpha1-antitrypsin deficiency
and autophagy. N Engl J Med 363,
1863–1864.
Marcinak, S. J. and Ron, D. (2010).
The unfolded protein response in
lung disease. Proc Am Thorac Soc 7,
356–362.
Marsh, S. G., Albert, E. D., Bodmer, W.
F., Bontrop, R. E., Dupont, B., Erlich,
H. A., Fernández-Viña, M., Geraghty,
D. E., Holdsworth, R., Hurley, C.
K. et al. (2010). An update to HLA
nomenclature, 2010. Bone Marrow
Transplant 45, 846–848.
Marsh, S. G., Albert, E. D., Bodmer, W.
F., Bontrop, R. E., Dupont, B., Erlich, H.
A., Fernández-Viña, M., Geraghty, D.
E., Holdsworth, R., Hurley, C. K. et al.
(2010). Nomenclature for factors of the
HLA system, 2010. Tissue Antigens 75,
291–455.
McCoy, A. J. and Read, R. J. (2010).
Experimental phasing: best practice and
pitfalls. Acta Crystallogr D Biol Crystallogr
66, 458–469.
McDowell, M. A., Johnson, S., Deane,
J. E., Cheung, M., Roehrich, A. D.,
Blocker, A. J., McDonnell, J. M. and
Lea, S. M. (2011). Structural and
functional studies on the N-terminal
domain of the Shigella type III secretion
protein MxiG. J Biol Chem 286,
30606–30614.
McEwan, W. A., Mallery, D. L., Rhodes,
D. A., Trowsdale, J. and James, L. C.
(2011). Intracellular antibody-mediated
immunity and the role of TRIM21.
BioEssays 33, 803–809.
McGilvray, R. W., Eagle, R. A.,
Rolland, P., Jafferji, I., Trowsdale, J.
and Durrant, L. G. (2010). ULBP2
and RAET1E NKG2D ligands are
independent predictors of poor
prognosis in ovarian cancer patients. Int
J Cancer 127, 1412–1420.
McKinney, E. F., Lyons, P. A., Carr, E.
J., Hollis, J. L., Jayne, D. R., Willcocks,
L. C., Koukoulaki, M., Brazma, A.,
Jovanovic, V., Kemeny, D. M. et al.
(2010). A CD8+ T cell transcription
signature predicts prognosis in
autoimmune disease. Nat Med 16,
586–591.
McLarren, K. W., Severson, T. M., du
Souich, C., Stockton, D. W., Kratz,
L. E., Cunningham, D., Hendson, G.,
Morin, R. D., Wu, D., Paul, J. E. et al.
(2010). Hypomorphic temperaturesensitive alleles of NSDHL cause
CK syndrome. Am J Hum Genet 87,
905–914.
67
Mduff, F. K., Hook, C. E., Tooze, R.
M., Huntly, B. J. P., Pandolfi, P. P. and
Turner, S. D. (2011). Determining the
contribution of NPM1 heterozygosity to
NPM-ALK-induced lymphomagenesis.
Lab Invest 91, 1298–1303.
Mehrotra, S., Oommen, J., Mishra, A.,
Sudharshan, M., Tiwary, P., Jamieson,
S. E., Fakiola, M., Selvi Rani, D. S.,
Thangaraj, K., Rai, M., Sundar, S. and
Blackwell. J. M. (2011). No evidence
for association between SLC11A1 and
visceral leishmaniasis in India. BMC Med
Genet 12, 71.
Menzies, F. M. and Rubinsztein, D.
C. (2010). Broadening the therapeutic
scope for rapamycin treatment.
Autophagy 6, 286–287.
Menzies, F. M., Hourez, R.,
Imarisio, S., Raspe, M., Sadiq, O.,
Chandraratna, D., O’Kane, C., Rock,
K. L., Reits, E., Goldberg, A. L. and
Rubinsztein, D. C. (2010). Puromycinsensitive aminopeptidase protects
against aggregation-prone proteins
via autophagy. Hum Mol Genet 19,
4573–4586.
Menzies, F. M., Huebener, J.,
Renna, M., Bonin, M., Riess, O. and
Rubinsztein, D. C. (2010). Autophagy
induction reduces mutant ataxin-3
levels and toxicity in a mouse model of
spinocerebellar ataxia type 3. Brain 133,
93–104.
Menzies, F. M., Moreau, K.
and Rubinsztein, D. C. (2011).
Protein misfolding disorders and
macroautophagy. Curr Opin Cell Biol 23,
190-197.
Metcalf, D. J., García-Arencibia, M.,
Hochfeld, W. E. and Rubinsztein, D.
C. (2010). Autophagy and misfolded
proteins in neurodegeneration. Exp
Neurol (epub).
Miller, S. E., Sahlender, D., Graham,
S. C., Hoening, S., Robinson, M. S.,
Peden, A. A.* and Owen, D. J.* (2011).
The molecular basis for the endocytosis
of small R-SNAREs by the clathrin
adaptor CALM. Cell 147, 1118–1131.
68
Miranda, E., Pérez, J., Ekeowa, U. I.,
Hadzic, N., Kalsheker, N., Gooptu, B.,
Portmann, B., Belorgey, D., Hill, M.,
Chambers, S. et al. (2010). A novel
monoclonal antibody to characterize
pathogenic polymers in liver disease
associated with alpha1-antitrypsin
deficiency. Hepatol 52, 1078–1088.
Miranda, K. C., Karet, F. E. and Brown,
D. (2010). An extended nomenclature
for mammalian V-ATPase subunit genes
and splice variants. PLoS One 5, e9531.
Mohammed, J. P., Fusakio, M. E.,
Rainbow, D. B., Moule, C., Fraser, H.
I., Clark, J., Todd, J. A., Peterson, L.
B., Savage, P. B., Wills-Karp, M. et al.
(2011). Identification of Cd101 as a
susceptibility gene for Novosphingobium
aromaticivorans-induced liver
autoimmunity. J Immunol 187, 337–349.
Molloy, A., Nair, S., Cooke, F. J., Wain,
J., Farrington, M., Lehner, P. J. and
Torok, M. E. (2010). First report of
Salmonella enterica serotype paratyphi
A azithromycin resistance leading to
treatment failure. J Clin Microbiol 48,
4655–4657.
Moloney, A., Sattelle, D. B., Lomas,
D. A. and Crowther, D. C. (2010).
Alzheimer's disease: insights from
Drosophila melanogaster models. Trends
Biochem Sci 35, 228–235.
Montenegro, G., Rebelo, A., Connell,
J., Allison, R., Babalini, C., Schüle,
R., Ishiura, H., D’Aloia, M., Montieri,
P., Price, J. et al. (2012). Mutations
in the ER-shaping protein Reticulon2
cause the axonal degenerative disorder
Hereditary Spastic Paraplegia type 12. J
Clin Invest (in press).
Morahan, G., Mehta, M., James, I.,
Chen, W. M., Akolkar, B., Erlich, H.
A., Hilner, J. E., Julier, C., Nerup, J.,
Nierras, C. et al. (2011). Tests for
genetic interactions in type 1 diabetes
linkage and stratification analyses of
4,422 affected sib-pairs. Diabetes 60,
1030–1040.
Moreau, K., Luo, S. and Rubinsztein,
D. C. (2010). Cytoprotective roles
for autophagy. Curr Opin Cell Biol 22,
206–211.
Moreau, K., Ravikumar, B., Renna, M.,
Puri, C. and Rubinsztein, D. C. (2011).
Autophagosome precursor maturation
requires homotypic fusion. Cell 146,
303–317.
Moritoki, Y., Tsuda, M., Tsuneyama,
K., Zhang, W., Yoshida, K., Lian, Z.,
Yang, G. X., Ridgway, W. M., Wicker,
L. S., Ansari, A. A. and Gershwin,
M. E. (2011). B cells promote hepatic
inflammation, biliary cyst formation, and
salivary gland inflammation in the NOD.
c3c4 model of autoimmune cholangitis.
Cell Immunol 268, 16–23.
Morris, H., Morgan, M. D., Wood,
A. M., Smith, S. W., Ekeowa, U. I.,
Herrmann, K., Holle, J. U., Guillevin,
L., Lomas, D. A., Perez, J. et al. (2011).
ANCA-associated vasculitis is linked to
carriage of the Z allele of "1 antitrypsin
and its polymers. Ann Rheum Dis 70,
1851–1856.
Munuswamy-Ramanujam, G., Dai, E.
B., Liu, L. Y., Shnabel, M., Sun, Y. M.,
Bartee, M., Lomas, D. A. and Lucas, A.
R. (2010). Neuroserpin, a thrombolytic
serine protease inhibitor (serpin), blocks
transplant vasculopathy with associated
modification of T-helper cell subsets.
Thromb Haemost 103, 545–555.
Murakami, T., Yang, S. P., Xie, L.,
Kawano, T., Fu, D., Mukai, A., Bohm,
C., Chen, F., Robertson, J., Suzuki, H.
et al. (2011). ALS mutations in FUS
causes neuronal dysfunction and death
in C. elegans by a dominant gain-offunction mechanism. Hum Mol Genet
(epub).
Naj, A. C., Jun, G., Beecham, G. W.,
Wang, L. S., Vardarajan, B. N., Buros,
J., Gallins, P. J., Buxbaum, J. D.,
Jarvik, G. P., Crane, P. K. et al. (2011).
Common variants at MS4A4/MS4A6E,
CD2AP, CD33 and EPHA1 are
associated with late-onset Alzheimer's
disease. Nat Genet 43, 436–441.
Narula, J., Smith, A. M., Göttgens, B.
and Igoshin, O. A. (2010). Modeling
reveals bistability and low-pass filtering
in the network module determining
blood stem cell fate. PLoS Comput Biol
6, 1–16.
Nicholas, A. K., Khurshid, M., Désir,
J., Carvalho, O. P., Cox, J. J., Thornton,
G., Kausar, R., Ansar, M., Ahmad, W.,
Verloes, A. et al. (2010). Wdr62 is
associated with the spindle pole and
is mutated in human microcephaly. Nat
Genet 42, 1010–1014.
Niederer, H. A., Clatworthy, M. R.,
Willcocks, L. C. and Smith, K. G. C.
(2010). FcgammaRIIB, FcgammaRIIIB,
and systemic lupus erythematosus. Ann
N Y Acad Sci 1183, 69–88.
Niederer, H. A., Willcocks, L. C.,
Rayner, T. F., Yang, W., Lau, Y. L.,
Williams, T. N., Scott, J. A. G., Urban,
B. C., Peshu, N., Dunstan, S. J. et
al. (2010). Copy number, linkage
disequilibrium and disease association
in the FCGR locus. Hum Mol Genet 19,
3282–3294.
Noor, A., Whibley, A., Marshall, C.
R., Gianakopoulos, P. J., Piton, A.,
Carson, A. R., Orlic-Milacic, M., Lionel,
A. C., Sato, D., Pinto, D. et al. (2010).
Disruption at the PTCHD1 locus on
Xp22.11 in autism spectrum disorder
and intellectual disability. Sci Transl Med
2, 49ra68.
Norwood, S. J., Shaw, D. J., Cowieson,
N. P., Owen, D. J., Teasdale, R. D. and
Collins, B. M. (2011). Assembly and
solution structure of the core retromer
protein complex. Traffic 12, 56–71.
Ohashi, M., Eagle, R. A. and
Trowsdale, J. (2010). Posttranslational modification of the
NKG2D ligand RAET1G leads
to cell surface expression of a
glycosylphosphatidylinositol-linked
isoform. J Biol Chem 285, 16408–
16415.
Oracki, S. A., Tsantikos, E., Quilici,
C., Light, A., Schmidt, T., Lew, A. M.,
Martin, J. E., Smith, K. G. C., Hibbs, M.
L. and Tarlinton, D. M. (2010). CTLA4Ig
alters the course of autoimmune disease
development in Lyn(-/-) mice. J Immunol
184, 757–763.
Oram, S. H., Thoms, J. A. I., Pridans,
C., Janes, M. E., Kinston, S. J.,
Anand, S., Landry, J.-R., Lock, R.
B., Jayaraman, P.-S., Huntly, B. J.
P., Pimanda, J. E. and Göttgens, B.
(2010). A previously unrecognized
promoter of LMO2 forms part of
a transcriptional regulatory circuit
mediating LMO2 expression in a subset
of T-acute lymphoblastic leukaemia
patients. Oncogene 29, 5796–5808.
Orlacchio, A., Babalini, C., Borreca,
A., Patrono, C., Massa, R., Basaran,
S., Munhoz, R. P., Rogaeva, E. A., St
George-Hyslop, P. H., Bernardi, G.
and Kawarai, T. (2010). SPATACSIN
mutations cause autosomal recessive
juvenile amyotrophic lateral sclerosis.
Brain 133, 591–598.
Ottersbach, K. and Dzierzak,
E. (2010). The placenta as a
haematopoietic organ. Int J Dev Biol 54,
1099–1106.
Ottersbach, K., Mirshekar-Syahkal, B.,
Haak, E., Kimber, G. M., van Leusden,
K., Harvey, K., O’Rourke, J., de Bruijn,
M. F., Ferguson-Smith, A. C. and
Dzierzak, E. (2011). DLK1 is a negative
regulator of emerging hematopoietic
stem cells. Exp Hematol 39, S24.
Ottersbach, K., Smith, A., Wood, A.
and Göttgens, B. (2010). Ontogeny of
haematopoiesis: Recent advances and
open questions. Br J Haematol 148,
343–355.
Owen, D. J. and Collins, B. M. (2010).
Vesicle transport: a new player in APP
trafficking. Curr Biol 20, R413–R415.
Papaemmanuil, E., Cazzola,
M., Boultwood, J., Malcovati, L.,
Vyas, P., Bowen, D., Pellagatti, A.,
Wainscoat, J. S., Hellstrom-Lindberg,
E., Gambacorti-Passerini, C. et al.
(2011). Somatic mutation of SF3B1 in
myelodysplasia with ring sideroblasts. N
Engl J Med 365, 1384–1395.
Parker, H. E., Reimann, F. and Gribble,
F. M. (2010). Molecular mechanisms
underlying nutrient-stimulated incretin
secretion. Expert Rev Mol Med 12, e1.
Parker, H. E., Wallis, K., le Roux, C. W.,
Wong, K. Y., Reimann, F. and Gribble,
F. M. (2011). Molecular mechanisms
underlying bile acid stimulated
glucagon-like peptide-1 secretion. Br J
Pharmacol (epub).
Passamonti, F., Elena, C., Schnittger,
S., Skoda, R. C., Green, A. R., Girodon,
F., Kiladjian, J. J., McMullin, M. F.,
Ruggeri, M., Besses, C. et al. (2011).
Molecular and clinical features of the
myeloproliferative neoplasm associated
with JAK2 exon 12 mutations. Blood
117, 2813–2816.
Paul, D. S., Nisbet, J. P., Yang, T. P.,
Meacham, S., Rendon, A., Hautaviita,
K., Tallila, J., White, J., Tijssen, M. R.,
Sivapalaratnam, S. et al. (2011). Maps
of open chromatin guide the functional
follow-up of genome-wide association
signals: application to hematological
traits. PLoS Genet 7, e1002139.
Pellicano, F., Cilloni, D., Helgason, G.
V., Messa, F., Panuzzo, C., Arruga, F.,
Bracco, E., Allan, E., Huntly, B. J. P.,
Holyoake, T. L. and Saglio, G. (2010).
FOXO transcription factor activity is
partially retained in quiescent CML stem
cells and induced by tyrosine kinase
inhibitors in CML progenitor cells. Blood
115, 2983.
Persengiev, S., Koeleman, B. P. C.,
Downes, K., Valdigem, G., van der
Slik, A. R., Eerligh, P., Monsuurb, A.,
Bruining, G. J., Wijmengae, C., Todd,
J. A., Roep, B. A. and Alizadeh, B. Z.
(2010). Association analysis of myosin
IXB and type 1 diabetes. Hum Immunol
71, 598–601.
Petrunkina, A. M. and Harrison, R. A.
P. (2010). Systematic misestimation of
cell subpopulations by flow cytometry:
a mathematical analysis. Theriogenology
73, 839-847.
Petrunkina, A. M. and Harrison, R.
A. P. (2011). Cytometric solutions in
veterinary andrology: Developments,
advantages, and limitations. Cytometry A
79, 338–348.
Petrunkina, A. M. and Harrison, R.
A. P. (2011). Mathematical analysis of
mis-estimation of cell subsets in flow
cytometry: viability staining revisited.
J Immunol Methods 368, 71–79.
69
Petrunkina, A. M., Waberski, D.,
Bollwein, H. and Sieme, H. (2010).
Identifying non-sperm particles
during flow cytometric physiological
assessment: a simple approach.
Theriogenology 73, 995–1000.
Pettersen, J. A., Patry, D. G., St
George-Hyslop, P. H. and Curry, B.
(2011). Variant Alzheimer disease with
spastic paraparesis: a rare presenilin-1
mutation. Can J Neurol Sci 38,
659–661.
Pillai, S. G., Kong, X. Y., Edwards, L. D.,
Cho, M. H., Anderson, W. H., Coxson,
H. O., Lomas, D. A., Silverman,
E. K. and ECLIPSE and ICGN
Investigators. (2010). Loci identified
by genome-wide association studies
influence different disease-related
phenotypes in chronic obstructive
pulmonary disease. Am J Respir Crit
Care Med 182, 1498–1505.
Pimanda, J. E. and Göttgens, B.
(2010). Gene regulatory networks
governing haematopoietic stem cell
development and identity. Int J Dev Biol
54, 1201–1211.
Pimanda, J., Thoms, J., Birger,
Y., Foster, S., Knezevic, K.,
Kirschenbaum, Y., Chandrakanthan,
V., Lock, R., MacKenzie, K., Göttgens,
B. and Izraeli, S. (2011). ERG
promotes T-acute lymphoblastic
leukemia and is transcriptionally
regulated in leukemic cells by a stem
cell enhancer. Exp Hematol 39, S108.
Piper, R. C. and Lehner, P. J. (2011).
Endosomal transport via ubiquitination.
Trends Cell Biol 21, 647–655.
Plagnol, V., Howson, J. M., Smyth, D.
J., Walker, N., Hafler, J. P., Wallace, C.,
Stevens, H., Jackson, L., Simmonds,
M. J., Type 1 Diabetes Genetics
Consortium, Bingley, P. J., Goug, S. C.
and Todd, J. A. (2011). Genome-wide
association analysis of autoantibody
positivity in type 1 diabetes cases. PLoS
Genet 7, e1002216.
Pociot, F., Akolkar, B., Concannon, P.,
Erlich, H. A., Julier, C., Morahan, G.,
Nierras, C. R., Todd, J. A., Rich, S. S.
70
and Nerup, J. (2010). Genetics of type
1 diabetes: what's next? Diabetes 59,
1561–1571.
Pollen, D. A., Baker, S., Hinerfeld, D.,
Swearer, J., Evans, B. A., Evans, J. E.,
Caselli, R., Rogaeva, E. et al. (2010).
Prevention of Alzheimer's disease
in high risk groups: statin therapy in
subjects with PSEN1 mutations or
heterozygosity for apolipoprotein E
epsilon 4. Alzheimers Res Ther 2, 31.
Proitsi, P., Hamilton, G., Tsolaki,
M., Lupton, M., Daniilidou, M.,
Hollingworth, P., Archera, N., Foya,
C., Styliosa, F., McGuinness, B. et al.
(2011). A multiple indicators multiple
causes (MIMIC) model of behavioural
and psychological symptoms in
dementia (BPSD). Neurobiol Aging 32,
434–442.
D. A. et al. (2011). Genetics of sputum
gene expression in chronic obstructive
pulmonary disease. PLoS One 6,
e24395.
Queiroz, J. W., Dias, G. D., Nobre,
M. L., De Sousa Dias, M. C., Araújo,
S. F., Barbosa, J. D., Trindade Neto,
P., Blackwell, J. M. and Jeronimo, S.
M. B. (2010). Geographic Information
Systems and Applied Spatial Statistics
are efficient tools to study Hansen’s
Disease (leprosy) and to determine
areas of greater risk of disease.
Am J Trop Med Hyg 82, 306–314.
Qutob, N., Balloux, F., Raj, T., Liu, H.,
Marion de Procé, S., Trowsdale, J.
and Manica, A. (2011). Signatures of
historical demography and pathogen
richness on MHC class I genes.
Immunogenet (epub).
Proitsi, P., Lupton, M. K., Reeves, S. J.,
Hamilton, G., Archer, N., Martin, B. M.,
Iyegbea, C., Hollingworth, P., Lawlord,
B., Gill, M. et al. (2010). Association of
serotonin and dopamine gene pathways
with behavioral subphenotypes in
dementia. Neurobiol Aging (in press).
Raab, M., Smith, X., Matthess, Y.,
Strebhardt, K. and Rudd, C. E. (2011).
SKAP1 protein pH domain determines
RapL membrane localization and Rap1
protein complex formation for T cell
receptor (TCR) activation of LFA-1. J
Biol Chem 286, 29663–29670.
Purbhoo, M. A., Liu, H. B., Oddos, S.,
Owen, D. M., Neil, M. A. A., Pageon,
S. V., French, P. M. W., Rudd, C. E.
and Davis, D. M. (2010). Dynamics
of subsynaptic vesicles and surface
microclusters at the immunological
synapse. Science Signal 3, ra36.
Raab, M., Wang, H., Lu, Y., Smith, X.,
Wu, Z., Strebhardt, K., Ladbury, J. E.
and Rudd, C. E. (2010). T cell receptor
"inside-out" pathway via signaling
module SKAP1-RapL regulates T cell
motility and interactions in lymph nodes.
Immun 32, 541–556.
Puri, C., Chibalina, M. V., Arden, S.
D., Kruppa, A. J., Kendrick-Jones, J.
and Buss, F. (2010). Overexpression
of myosin VI in prostate cancer cells
enhances PSA and VEGF secretion, but
has no effect on endocytosis. Oncogene
29, 188–200.
Rainbow, D. B., Moule, C., Fraser, H.
I., Clark, J., Howlett, S. K., Burren, O.,
Christensen, M., Moody, V., Steward,
C. A., Mohammed, J. P. et al. (2011).
Evidence that Cd101 is an autoimmune
diabetes gene in nonobese diabetic
mice. J Immunol 187, 325–336.
Qi, X., Loiseau, F., Chan, W. L., Yan,
Y., Wei, Z., Milroy, L. G., Myers, R. M.,
Ley, S. V., Read, R. J., Carrell, R. W. and
Zhou, A. (2011). Allosteric modulation
of hormone release from thyroxine and
corticosteroid-binding globulins. J Biol
Chem 286, 16163–16173.
Ramasawmy, R., Menezes, E.,
Magalhães, A., Oliveira, J., Castellucci,
L., Almeida, R., Rosa, M. E. A.,
Guimaraes, L. H., Lessa, M., Noronha,
E. et al. (2010). The -2518 A/G
promoter polymorphism in the gene
(CCL2/MCP1) encoding monocyte
chemotactic protein 1 influences
susceptibility to mucosal but not
localized cutaneous leishmaniasis in
Brazil. Infect Genet Evol 10, 607–613.
Qiu, W., Cho, M. H., Riley, J. H.,
Anderson, W. H., Singh, D., Bakke,
P., Gulsvik, A., Litonjua, A. A., Lomas,
Rashid, S. T., Corbineau, S., Hannan,
N., Marciniak, S. J., Miranda, E.,
Alexander, G., Huang-Doran, I.,
Griffin, J., Ahrlund-Richter, L, Skepper,
J. et al. (2010). Modeling inherited
metabolic disorders of the liver using
human induced pluripotent stem cells.
J Clin Invest 120, 3127–3136.
Ravikumar, B., Moreau, K. and
Rubinsztein, D. C. (2010). Plasma
membrane helps autophagosomes grow.
Autophagy 6, 1184–1186.
Ravikumar, B., Moreau, K., Jahreiss,
L., Puri, C. and Rubinsztein, D. C.
(2010). Plasma membrane contributes
to the formation of pre-autophagosomal
structures. Nat Cell Biol 12, 747–757.
Ravikumar, B., Sarkar, S., Davies, J.
E., Futter, M., Garcia-Arencibia, M.,
Green-Thompson, Z. W., JimenezSanchez, M., Korolchuk, V. I.,
Lichtenberg, M., Luo, S. et al. (2010).
Regulation of mammalian autophagy in
physiology and pathophysiology. Physiol
Rev 90, 1383–1435.
Raymond, F. L., Whittaker, J., Jenkins,
L., Lench, N. and Chitty, L. S. (2010).
Molecular prenatal diagnosis: the impact
of modern technologies. Prenat Diagn
30, 674–681.
Read, R. J. (2010). From poor resolution
to rich insight. Structure 18, 664–665.
Read, R. J., Adams, P. D., Arendall, W.
B., Brunger, A. T., Emsley, P., Joosten,
R. P., Kleywegt, G. J., Krissinel,
E. B., Lütteke, T., Otwinowski, Z.
et al. (2011). A new generation of
crystallographic validation tools for
the protein data bank. Structure 19,
1395–1412.
Read, R. J. and McCoy, A. J. (2011).
Using SAD data in Phaser. Acta
Crystallogr D Biol Crystallogr 67,
338–344.
Reimann, F. (2010). Molecular
mechanisms underlying nutrient
detection by incretin-secreting cells. Int
Dairy J 20, 236–242.
Reimann, F., Cox, J. J., Belfer, I.,
Diatchenko, L., Zaykin, D. V., McHale,
D. P., Drenth, J. P. H., Dai, F., Wheeler,
J., Sanders, F. et al. (2010). Pain
perception is altered by a nucleotide
polymorphism in SCN9A. Proc Natl Acad
Sci USA 107, 5148–5153.
Reitz, C., Cheng, R., Rogaeva, E., Lee,
J. H., Tokuhiro, S., Zou, F., Bettens,
K., Sleegers, K., Tan, E. K., Kimura,
R. et al. (2011). Meta-analysis of the
association between variants in SORL1
and Alzheimer disease. Arch Neurol 68,
99–106.
Reitz, C., Cheng, R., Schupf, N., Lee,
J. H., Mehta, P. D., Rogaeva, E., St
George-Hyslop, P. H. and Mayeux, R.
(2010). Association between variants
in IDE-KIF11-HHEX and plasma
amyloid beta levels. Neurobiol Aging 33,
199.e13–199e17.
Reitz, C., Tokuhiro, S., Clark, L. N.,
Conrad, C., Vonsattel, J. P., Hazrati,
L. N., Palotás, A., Lantigua, R.,
Medrano, M., Jiménez-Velázquez,
I. Z. et al. (2011). SORCS1 alters
amyloid precursor protein processing
and variants may increase Alzheimer's
disease risk. Ann Neurol 69, 47–64.
Renna, M., Jimenez-Sanchez, M.,
Sarkar, S. and Rubinsztein, D. C.
(2010). Chemical inducers of autophagy
that enhance the clearance of mutant
proteins in neurodegenerative diseases.
J Biol Chem 285, 11061–11067.
Renna, M., Schaffner, C., Brown, K.,
Shang, S., Tamayo, M. H., Hegyi, K.,
Grimsey, N. J., Cusens, D., Coulter, S.,
Cooper, J. et al. (2011). Azithromycin
blocks autophagy and may predispose
cystic fibrosis patients to mycobacterial
infection. J Clin Invest 121, 3554–3563.
Renna, M., Schaffner, C., Winslow, A.
R., Menzies, F. M., Peden, A. A., Floto,
R. A. and Rubinsztein, D. C. (2011).
Autophagic substrate clearance requires
activity of the syntaxin-5 SNARE
complex. J Cell Sci 124, 469–482.
Rhodes, D. A., Boyle, L. H., Boname,
J. M., Lehner, P. J. and Trowsdale, J.
(2010). Ubiquitination of lysine-331
by Kaposi’s sarcoma-associated
herpesvirus protein K5 targets HFE for
lysosomal degradation. Proc Natl Acad
Sci USA 107, 16240–16245.
Riha, P. and Rudd, C. E. (2010). CD28
co-signaling in the adaptive immune
response. Self/Nonself - Imm Recog
Signal 1, 231–240.
Roberts, R. C., Peden, A. A., Buss, F.,
Bright, N. A., Latouche, M., Reilly, M.
M., Kendrick-Jones, J. and Luzio, J. P.
(2010). Mistargeting of SH3TC2 away
from the recycling endosome causes
Charcot-Marie-Tooth disease type 4C.
Hum Mol Genet 19, 1009–1018.
Robin, C., Ottersbach, K., Boisset,
J. C., Oziemlak, A. and Dzierzak,
E. (2011). CD41 is developmentally
regulated and differentially expressed on
mouse hematopoietic stem cells. Blood
117, 5088–5091.
Robinson, M. S., Sahlender, D. A. and
Foster, S. D. (2010). Rapid inactivation
of proteins by rapamycin-induced
rerouting to mitochondria. Dev Cell 18,
324–331.
Rodriguez-Cuenca, S., Cochemé, H.
M., Logan, A., Abakumova, I., Prime, T.
A., Rose, C., Vidal-Puiga, A., Smith, A.
C., Rubinsztein, D. C., Fearnley, I. M. et
al. (2010). Consequences of long-term
oral administration of the mitochondriatargeted antioxidant MitoQ to wild-type
mice. Free Radic Biol Med 48, 161–172.
Rodriguez-Gonzalez, R., Millan,
M., Sobrino, T., Miranda, E., Brea,
D., de la Ossa, N. P., Blanco, M.,
Perez, J., Dorado, L., Castellanos, M.,
Lomas, D. A., Moro, M. A., Dávalos,
A. and Castillo, J. (2011). The natural
tissue plasminogen activator inhibitor
neuroserpin and acute ischaemic
stroke outcome. Thromb Haemost 105,
421–429.
Rodriguez-Gonzalez, R., Sobrino, T.,
Rodriguez-Yanez, M., Millan, M., Brea,
D., Miranda, E., Moldes, O., Pérez, J.,
Lomas, D. A., Leira, R., Dávalos, A. and
Castillo, J. (2011). Association between
neuroserpin and molecular markers of
brain damage in patients with acute
ischemic stroke. J Transl Med 9, 58.
71
Rogers, G. J., Tolhurst, G., Ramzan,
A., Habib, A. M., Parker, H. E., Gribble,
F. M.* and Reimann, F.* (2011).
Electrical activity-triggered glucagon-like
peptide-1 secretion from primary murine
L-cells. J Physiol 589, 1081–1093.
Rohr, J., Beutel, K., Maul-Pavicic,
A., Vraetz, T., Thiel, J., Warnatz, K.,
Bondzio, I., Gross-Wieltsch, U.,
Schündeln, M., Schütz, B. et al.
(2010). Atypical familial hemophagocytic
lymphohistiocytosis due to mutations in
UNC13D and STXBP2 overlaps with
primary immunodeficiency diseases.
Haematol-Hematol J 95, 2080–2087.
Rose, C., Menzies, F. M., Renna, M.,
Acevedo-Arozena, A., Corrochano,
S., Sadiq, O., Brown, S. D. and
Rubinsztein, D. C. (2010). Rilmenidine
attenuates toxicity of polyglutamine
expansions in a mouse model of
Huntington's disease. Hum Mol Genet
19, 2144–2153.
Roussel, B. D., Irving, J. A., Ekeowa,
U. I., Belorgey, D., Haq, I., Ordóñez, A.,
Kruppa, A. J., Duvoix, A., Rashid, S. T.,
Crowther, D. C., Marciniak, S. J. and
Lomas, D. A. (2011). Unravelling the
twists and turns of the serpinopathies.
FEBS J 278, 3859–3867.
Rubinsztein, D. C. (2010). Autophagy:
where next? EMBO Rep 11, 3.
Rubinsztein, D. C. (2010). Cdks
regulate autophagy via Vps34. Mol Cell
38, 483–484.
Rubinsztein, D. C. and Nixon, R. A.
(2010). Rapamycin induces autophagic
flux in neurons. Proc Natl Acad Sci USA
107, E181.
Rubinsztein, D. C., Mariño, G. and
Kroemer, G. (2011). Autophagy and
aging. Cell 146, 682–695.
Rudd, C. E. (2010). T-cell signaling
and immunopathologies. Semin
Immunopathol 32, 91–94.
Rudd, C. E., Trevillyan, J. M., Dasgupta,
J. D., Wong, L. L. and Schlossman,
S. F. (2010). The CD4 receptor is
complexed in detergent lysates to a
protein-tyrosine kinase (pp58) from
72
human T lymphocytes (reprinted from
Proc Nat Acad Sci 85, 5190–5194,
1988). J Immunol 185, 2645–2649.
Rujirabanjerd, S., Nelson, J., Tarpey, P.
S., Hackett, A., Edkins, S., Raymond,
F. L., Schwartz, C. E., Turner, G, Iwase,
S., Shi, Y., Futreal, P. A., Stratton, M. R.
and Gecz, J. (2010). Identification and
characterization of two novel JARID1C
mutations: suggestion of an emerging
genotype-phenotype correlation. Eur J
Hum Genet 18, 330–335.
St George-Hyslop, P. and Fraser, P.
E. (2011). Assembly of the presenilin
!-/'-secretase complex. J Neurochem
(epub).
St George-Hyslop, P. and SchmittUlms, G. (2010). Alzheimer's disease:
Selectively tuning gamma-secretase.
Nature 467, 36–37.
Saleh, N. M., Raj, S. M., Smyth, D.
J., Wallace, C., Howson, J. M., Bell,
L., Walker, N. H., Stevens, H. E. and
Todd, J. A. (2011). Genetic association
analyses of atopic illness and
proinflammatory cytokine genes with
type 1 diabetes. Diabetes Metab Res Rev
27, 838–843.
Samocha-Bonet, D., Wong, O.,
Synnott, E. L., Piyaratna, N.,
Douglas, A., Gribble, F. M., Holst, J.
J., Chisholm, D. J. and Greenfield,
J. R. (2011). Glutamine reduces
postprandial glycemia and augments
the glucagon-like peptide-1 response
in type 2 diabetes patients. J Nutr 141,
1233–1238.
Sanjo, N., Katayama, T., Hasegawa,
H., Jin, H., Duthie, M., Mount, H. T.,
Mizusawa, H., St George-Hyslop, P.
H. and Fraser, P. E. (2010). Localization
and trafficking of endogenous anterior
pharynx-defective 1, a component of
Alzheimer's disease related gammasecretase. Neurosci Lett 483, 53–56.
Sarkar, S., Korolchuk, V. I., Renna, M.,
Imarisio, S., Fleming, A., Williams, A.,
Garcia-Arencibia, M., Rose, C., Luo,
S., Underwood, B. R. et al. (2011).
Complex inhibitory effects of nitric oxide
on autophagy. Mol Cell 43, 19–32.
Saunders, A. M., Strittmatter, W. J.,
Schmechel, D., St George-Hyslop,
P. H., Pericak-Vance, M. A., Joo, S.
H., Rosi, B. L., Gusella, J. F., CrapperMacLachlan, D. R., Alberts, M. J.,
Hulette, C., Crain, B., Goldgaber, D.
and Roses, A. D. (2011). Association
of apolipoprotein E allele {varepsilon}4
with late-onset familial and sporadic
Alzheimer's disease. Neurology 77, 950.
Schiel, J. A., Park, K., Morphew, M. K.,
Reid, E., Hoenger, A. and Prekeris, R.
(2011). Endocytic membrane fusion and
buckling-induced microtubule severing
mediate cell abscission. J Cell Sci 124,
1411–1424.
Screaton, N. J., Miller, F. N., Patel, B.
D., Groves, A., Tasker, A. D., Lomas,
D. A. and Flower, C. D. (2011). The
clinical impact of high resolution
computed tomography in patients with
respiratory disease. Eur Radiol 21,
225–231.
Seaman, M. N. J. (2009). Enhanced
SnapShot: Endosome-to-Golgi retrieval.
Cell 139, 1198.
Seaman, M. N. J. and Peden, A. A.
(2010). Ricin toxin hits a retrograde
roadblock. Cell 141, 222–224.
Seki, N., Takahashi, Y., Tomiyama, H.,
Rogaeva, E., Murayama, S., Mizuno,
Y., Hattori, N., Marras, C., Lang, A. E.,
George-Hyslop, P. S. et al. (2011).
Comprehensive mutational analysis
of LRRK2 reveals variants supporting
association with autosomal dominant
Parkinson's disease. J Hum Genet 56,
671–675.
Settembre, C., Di Malta, C., Polito,
V. A., Garcia Arencibia, M., Vetrini,
F., Erdin, S., Erdin, S. U., Huynh, T.,
Medina, D., Colella, P., Sardiello,
M., Rubinsztein, D. C. and Ballabio,
A. (2011). TFEB links autophagy to
lysosomal biogenesis. Science 332,
1429–1433.
Shahid, H., Khan, J. C., Cipriani, V.,
Sepp, T., Matharu, B. K., Bunce, C.,
Harding, S. P., Clayton, D. G., Moore,
A. T., Yates, J. R. W. for the Genetic
Factors in AMD Study Group. (2011).
Age-related macular degeneration: the
importance of family history as a risk
factor. Br J Ophthalmol (epub).
Shoubridge, C., Tarpey, P. S., Abidi,
F., Ramsden, S. L., Rujirabanjerd,
S., Murphy, J. A., Boyle, J., Shaw, M.,
Gardner, A., Proos, A. et al. (2010).
Mutations in the guanine nucleotide
exchange factor gene IQSEC2 cause
nonsyndromic intellectual disability. Nat
Genet 42, 486–488.
Siedlinski, M., Cho, M. H., Bakke, P.,
Gulsvik, A., Lomas, D. A., Anderson,
W., Kong, X., Rennard, S. I., Beaty,
T. H., Hokanson, J. E., Crapo, J. D.
and Silverman, E. K. on behalf of
the COPDGene Investigators and
ECLIPSE Investigators. (2011).
Genome-wide association study of
smoking behaviours in patients with
COPD. Thorax 66, 894–902.
Sieni, E., Cetica, V., Mastrodicasa,
E., Pende, D., Moretta, L., Griffiths,
G. and. Aricò, M. (2011). Familial
hemophagocytic lymphohistiocytosis:
a model for understanding the human
machinery of cellular cytotoxicity. Cell
Mol Life Sci (epub).
Sieni, E., Cetica, V., Santoro, A.,
Beutel, K., Mastrodicasa, E., Meeths,
M., Ciambotti, B., Brugnolo, F., zur
Stadt, U., Pende, D. et al. (2011).
Genotype-phenotype study of familial
haemophagocytic lymphohistiocytosis
type 3. J Med Genet 48, 343–352.
Silverman, E. K., Vestbo, J., Agusti,
A., Anderson, W., Bakke, P. S.,
Barnes, K. C., Barr, R. G., Bleecker,
E. R., Boezen, H. M., Burkart, K.
M. et al. (2011). Opportunities and
challenges in the Genetics of COPD
2010: An international COPD Genetics
conference report. COPD: J Chron Obst
Pulmon Dis 8, 121–135.
Silverman, G. A., Whisstock, J. C.,
Bottomley, S. P., Huntington, J. A.,
Kaiserman, D., Luke, C. J., Pak, S. C.,
Reichhart, J.-M. and Bird, P. I. (2010).
Serpins flex their muscle: I. Putting
the clamps on proteolysis in diverse
biological systems. J Biol Chem 285,
24299–24305.
Sims, R., Dwyer, S., Harold, D.,
Gerrish, A., Hollingworth, P.,
Chapman, J., Jones, N., Abraham, R.,
Ivanov, D., Pahwa, J. S. et al. (2011).
No evidence that extended tracts of
homozygosity are associated with
Alzheimer's disease. Am J Med Genet B
Neuropsychiatr Genet 156, 764–771.
Sin, D. D., Miller, B. E., Duvoix, A.,
Man, S. F., Zhang, X., Silverman, E. K.,
Connett, J. E., Anthonisen, N. A., Wise,
R. A., Tashkin, D., Celli, B. R., Edwards,
L. D., Locantore, N., MacNee, W., TalSinger, R. and Lomas, D. A. on behalf
of the ECLIPSE Investigators. (2011).
Serum PARC/CCL-18 concentrations
and health outcomes in chronic
obstructive pulmonary disease. Am J
Respir Crit Care Med 183, 1187–1192.
Sir, J.-H., Barr, A. R., Nicholas, A. K.,
Carvalho, O. P., Khurshid, M., Sossick,
A., Reichelt, S., D'Santos, C., Woods,
C. G.*, Gergely, F.* (2011). A primary
microcephaly protein complex forms
a ring around parental centrioles. Nat
Genet 43, 1147–1153.
Smith, G. D., Robinson, C., Stewart,
A. P., Edwards, E., Karet, H. I., Norden,
A. G. W., Sandford, R N. and Karet
Frankl, F. E. (2011). Characterization
of a recurrent in-frame UMOD indel
mutation causing late-onset autosomal
dominant end-stage renal failure. Clin J
Am Soc Nephrol (in press).
Smith, I. A., Knezevic, B. R., Ammann,
J. U., Rhodes, D. A., Aw, D., Palmer,
D. B., Mather, I. H. and Trowsdale, J.
(2010). BTN1A1, the mammary gland
butyrophilin, and BTN2A2 are both
inhibitors of T cell activation. J Immunol
184, 3514–3525.
Smith, K. G. C. and Clatworthy,
M. R. (2010). FcgammaRIIB in
autoimmunity and infection: evolutionary
and therapeutic implications. Nat Rev
Immunol 10, 328–343.
Smith, K. G. C., Willcocks, L. C. and
Lyons, P. A. (2011). Comment on “the
inhibiting Fc receptor for IgG, Fc!RIIB, is
a modifier of autoimmune susceptibility”.
J Immunol 187, 5473.
Smyth, D. J., Cooper, J. D., Howson, J.
M., Clarke, P., Downes, K., Mistry, T.,
Stevens, H., Walker, N. M. and Todd,
J. A. (2011). FUT2 nonsecretor status
links type 1 diabetes susceptibility and
resistance to infection. Diabetes 60,
3081–3084.
Sorheim, I. C., Bakke, P., Gulsvik,
A., Pillai, S. C., Johannessen, A.,
Gaarder, P. I., Campbell, E. J., Agustí,
A., Calverley, P. M. A., Donner, C. F. et
al. (2010). alpha(1)-Antitrypsin protease
inhibitor MZ heterozygosity is associated
with airflow obstruction in two large
cohorts. Chest 138, 1125–1132.
Sorheim, I. C., DeMeo, D. L., Washko,
G., Litonjua, A., Sparrow, D., Bowler,
R., Bakke, P., Pillai, S. G., Coxson, H.
O., Lomas, D. A., Silverman, E. K. and
Hersh, C. P. (2010). Polymorphisms in
the superoxide dismutase-3 gene are
associated with emphysema in COPD.
COPD 7, 262–268.
Spruit, M. A., Polkey, M. I., Celli, B.,
Edwards, L. D., Watkins, M. L., PintoPlata, V., Vestbo, J., Calverley, P. M.,
Tal-Singer, R., Agusti, A. et al. (2011).
Predicting outcomes from 6-minute
walk distance in chronic obstructive
pulmonary disease. J Am Med Dir Assoc
(epub).
Statham, H., Ponder, M., Richards,
M., Hallowell, N. and Raymond, F. L.
(2011). A family perspective of the value
of a diagnosis for intellectual disability:
Experiences from a genetic research
study. Br J Learn Disab 39, 46–56.
Stephens, P. J., Greenman, C. D., Fu,
B., Yang, F., Bignell, G. R., Mudie, L. J.,
Pleasance, E. D., Lau, K. W., Beare, D.,
Stebbings, L. A. et al. (2011). Massive
genomic rearrangement acquired in a
single catastrophic event during cancer
development. Cell 144, 27–40.
Stinchcombe, J. C., Salio, M.,
Cerundolo, V., Pende, D., Arico, M.
and Griffiths, G. M. (2011). Centriole
polarisation to the immunological
synapse directs secretion from cytolytic
cells of both the innate and adaptive
immune systems. BMC Biol 9, 45.
73
Su, Y., Blake-Palmer, K. G., Fry, A. C.,
Best, A., Brown, A. C. N., Hiemstra,
T. F., Horita, S., Zhou, A., Toye, A. M.
and Karet, F. E. (2011). Glyceraldehyde
3-phosphate dehydrogenase is required
for band 3 (anion exchanger 1)
membrane residency in the mammalian
kidney. Am J Physiol-Renal Physiol 300,
F157-F166.
Sun, G., Tarasov, A. I., McGinty, J.,
McDonald, A., Xavier, G. D., Gorman,
T., Marley, A., French, P. M., Parker, H.,
Gribble, F. M. et al. (2010). Ablation of
AMP-activated protein kinase alpha 1
and alpha 2 from mouse pancreatic beta
cells and RIP2.Cre neurons suppresses
insulin release in vivo. Diabetologia 53,
924–936.
Swafford, A. D., Howson, J. M.,
Davison, L. J., Wallace, C., Smyth, D.
J., Schuilenburg, H., Maisuria-Armer,
M., Mistry, T., Lenardo, M. J. and Todd,
J. A. (2011). An allele of IKZF1 (Ikaros)
conferring susceptibility to childhood
acute lymphoblastic leukemia protects
against type 1 diabetes. Diabetes 60,
1041–1044.
Swarbrick, J. D., Shaw, D. J., Chhabra,
S., Ghai, R., Valkov, E., Norwood,
S. J., Seaman, M. N. J. and Collins,
B. M. (2011). VPS29 is not an active
metallo-phosphatase but is a rigid
scaffold required for retromer interaction
with accessory proteins. PLoS One 6,
e20420.
Thomas, S. E., Dalton, L. E., Daly, M. L.,
Malzer, E. and Marciniak, S. J. (2010).
Diabetes as a disease of endoplasmic
reticulum stress. Diabetes Metab Res
Rev 26, 611–621.
Thomas, S. E., Dalton, L., Malzer, E.
and Marciniak, S. J. (2011). Unravelling
the story of protein misfolding in
diabetes mellitus. World J Diabetes 2,
114–118.
Thoms, J. A., Birger, Y., Foster, S.,
Knezevic, K., Kirschenbaum, Y.,
Chandrakanthan, V., Jonquieres, G.,
Spensberger, D., Wong, J. W., Oram,
S. H. et al. (2011). ERG promotes
T-acute lymphoblastic leukemia and is
transcriptionally regulated in leukemic
cells by a stem cell enhancer. Blood 117,
7079–7089.
Tijssen, M. R., Cvejic, A., Joshi, A.,
Hannah, R. L., Ferreira, R., Forrai,
A., Bellissimo, D. C., Oram, S. H.,
Smethurst, P. A., Wilson, N. K. et
al. (2011). Genome-wide analysis of
simultaneous GATA1/2, RUNX1, FLI1,
and SCL binding in megakaryocytes
identifies hematopoietic regulators. Dev
Cell 20, 597–609.
Swayamprakasam, A. P., Stover,
E., Norgett, E., Blake-Palmer, K. G.,
Cunningham, M. J. and Karet, F. E.
(2011). Importance of early audiologic
assessment in distal renal tubular
acidosis. Int Med Case Rep J 4, 7–11.
Todd, J. A. (2010). D'oh! genes and
environment cause Crohn's disease. Cell
141, 1114–1116.
Taib, W. R. W., Smyth, D. J., Merriman,
M. E., Dalbeth, N., Gow, P. J.,
Harrison, A. A., Highton, J., Jones,
P. B. B., Stamp, L., Steer, S., Todd, J.
A. and Merriman, T. R. (2010). The
PTPN22 locus and rheumatoid arthritis:
no evidence for an effect on risk
independent of Arg620Trp. PLoS One 5,
e13544.
Todd, J. A., Knip, M. and Mathieu, C.
(2011). Strategies for the prevention
of autoimmune Type 1 diabetes. Diabet
Med 28, 1141–1143.
Tarpey, P., Thomas, S., Sarvananthan,
N., Mallya, U., Lisgo, S., Talbot, C. J.,
74
Roberts, E. O., Awan, M., Surendran,
M., McLean, R. J. et al. (2011).
Corrigendum: Mutations in FRMD7,
a newly identified member of the
FERM family, cause X-linked idiopathic
congenital nystagmus. Nat Genet 4, 720.
Todd, J. A. (2010). Etiology of type 1
diabetes. Immun 32, 457–467.
Tolhurst, G., Zheng, Y., Parker, H. E.,
Habib, A. M., Reimann, F. and Gribble,
F. M. (2011). Glutamine triggers and
potentiates glucagon-like peptide-1
secretion by raising cytosolic Ca2+ and
cAMP. Endocrinol 152, 405–413.
Traherne, J. A., Martin, M., Ward, R.,
Ohashi, M., Pellett, F., Gladman, D.,
Middleton, D., Carrington, M. and
Trowsdale, J. (2010). Mechanisms of
copy number variation and hybrid gene
formation in the KIR immune gene
complex. Hum Mol Genet 19, 737–751.
Trollet, C., Anvar, S. Y., Venema, A.,
Hargreaves, I. P., Foster, K., Vignaud,
A., Ferry, A., Negroni, E., Hourde, C.,
Baraibar, M. A. et al. (2010). Molecular
and phenotypic characterization of
a mouse model of oculopharyngeal
muscular dystrophy reveals severe
muscular atrophy restricted to fast
glycolytic fibres. Hum Mol Genet 19,
2191–2207.
Trowsdale, J. (2011). The MHC,
disease and selection. Immunol Lett 137,
1–8.
Tsun, A., Qureshi, I., Stinchcombe,
J. C., Jenkins, M. R., de la Roche, M.,
Kleczkowska, J., Zamoyska, R. and
Griffiths, G. M. (2011). Centrosome
docking at the immunological synapse
is controlled by Lck signaling. J Cell Biol
192, 663–674.
Underwood, B. R., Imarisio, S.,
Fleming, A., Rose, C., Krishna, G.,
Heard, P., Quick, M., Korolchuk, V.
I., Renna, M., Sarkar, S., GarcíaArencibia, M., O'Kane, C. J., Murphy,
M. P. and Rubinsztein, D. C. (2010).
Antioxidants can inhibit basal autophagy
and enhance neurodegeneration in
models of polyglutamine disease. Hum
Mol Genet 19, 3413–3429.
van der Weyden, L., Giotopoulos,
G., Rust, A. G., Matheson, L. S., van
Delft, F. W., Kong, J., Corcoran, A.
E, Greaves, M. F., Mullighan, C. G.,
Huntly, B. J. P. and Adams, D. J.
(2011). Modeling the evolution of ETV6RUNX1-induced B-cell precursor acute
lymphoblastic leukemia in mice. Blood
118, 1041–1051.
van Ham, T. J., Holmberg, M. A.,
van der Goot, A. T., Teuling, E.,
Garcia-Arencibia, M., Kim, H. E.,
Du, D., Thijssen, K. L., Wiersma,
M., Burggraaff, R. et al. (2010).
Identification of MOAG-4/SERF as a
regulator of age-related proteotoxicity.
Cell 142, 601–612.
Vestbo, J., Edwards, L. D., Scanlon, P.
D., Yates, J. C., Agusti, A., Bakke, P.,
Calverley, P. M. A., Celli, B., Coxson, H.
O., Crim, C., Lomas, D. A. et al. (2011).
Changes in forced expiratory volume in
1 second over time in COPD. N Engl J
Med 365, 1184–1192.
Vezzoli, A., Bonadies, N., Allen,
M. D., Freund, S. M., Santiveri, C.
M., Kvinlaug, B. T., Huntly, B. J. P.,
Göttgens, B. and Bycroft, M. (2010).
Molecular basis of histone H3K36me3
recognition by the PWWP domain of
Brpf1. Nat Struct Mol Biol 17, 617–619.
Vincent, B., Sunyach, C.,
Orzechowski, H. S., St GeorgeHyslop, P. and Checler, F. (2010).
p53-dependent transcriptional control
of cellular prion by presenilins.
J Neurochem 115, 41–42.
Virgin, H. W. and Todd, J. A. (2011).
Metagenomics and Personalized
Medicine. Cell 147, 44–56.
Waberski, D., Henning, H. and
Petrunkina, A. M. (2011). Assessment
of storage effects in liquid preserved
boar semen. Reprod Domest Anim 46,
45–48.
Waisberg, M., Tarasenko, T., Vickers,
B. K., Scott, B. L., Willcocks, L. C.,
Molina-Cruz, A., Piercea, M. A.,
Huangd, C., Torres-Veleze, F. J.,
Smith, K. G. C. et al. (2011). Genetic
susceptibility to systemic lupus
erythematosus protects against cerebral
malaria in mice. Proc Natl Acad Sci USA
108, 1122–1127.
Walker, B. A., Hunt, L. G., Sowa, A.
K., Skjodt, K., Gobel, T. W., Lehner,
P. J. and Kaufman, J. (2011). The
dominantly expressed class I molecule
of the chicken MHC is explained by
coevolution with the polymorphic peptide
transporter (TAP) genes. Proc Natl Acad
Sci USA 108, 8396–8401.
Wallace, C., Smyth, D. J., MaisuriaArmer, M., Walker, N. M., Todd, J.
A. and Clayton, D. G. (2010). The
imprinted DLK1-MEG3 gene region
on chromosome 14q32.2 alters
susceptibility to type 1 diabetes. Nat
Genet 42, 68–71.
Wan, E. S., Cho, M. H., Boutaoui,
N., Klanderman, B. J., Sylvia, J. S.,
Ziniti, J. P., Won, S., Lange, C., Pillai,
S. G., Anderson, W. H. et al. (2011).
Genome-wide association analysis
of body mass in chronic obstructive
pulmonary disease. Am J Respir Cell Mol
Biol 45, 304–310.
Wang, H., Lim, D. and Rudd, C. E.
(2010). Immunopathologies linked to
integrin signalling. Semin Immunopathol
32, 173–182.
Wang, H., Lu, Y. and Rudd, C. E.
(2010). SKAP1 is dispensable for
chemokine-induced migration of primary
T-cells. Immunol Lett 128, 148–153.
Wang, J. G., Wicker, L. S. and
Santamaria, P. (2009). IL-2 and its
high-affinity receptor: Genetic control
of immunoregulation and autoimmunity.
Semin Immunol 21, 363–371.
Wang, T. J., Zhang, F., Richards, J. B.,
Kestenbaum, B., van Meurs, J. B.,
Berry, D., Kiel, D. P., Streeten, E. A.,
Ohlsson, C., Koller, D. L. et al. (2010).
Common genetic determinants of
vitamin D insufficiency: a genome-wide
association study. Lancet 376, 180–188.
Weekes, M. P., Antrobus, R., Lill, J. R.,
Duncan, L. M., Hör, S. and Lehner,
P. J. (2010). Comparative analysis of
techniques to purify plasma membrane
proteins. J Biomol Tech 21, 108–115.
Weiss, J., Pyrski, M., Jacobi, E., Bufe,
B., Willnecker, V., Schick, B., Zizzari, P.,
Gossage, S. J., Greer, C. A., LeindersZufall, T., Woods, C. G., Wood, J. N.
and Zufall, F. (2011). Loss-of-function
mutations in sodium channel Na(v)1.7
cause anosmia. Nature 472, 186–190.
metazoan secretory pathway. EMBO J
29, 304–314.
Wenham, M., Grieve, S., Cummins,
M., Jones, M. L., Booth, S., Kilner,
R., Ancliff, P. J., Griffiths, G. M. and
Mumford, A. D. (2010). Two patients
with Hermansky Pudlak syndrome
type 2 and novel mutations in AP3B1.
Haematologica 95, 333–337.
Wheeler, D. W., Thompson, A. J.,
Corletto, F., Reckless, J., Loke, J. C.,
Lapaque, N., Grant, A. J., Mastroeni,
P., Grainger, D. J., Padgett, C. L. et
al. (2011). Anaesthetic impairment
of immune function is mediated via
GABA(A) receptors. PLoS One 6,
e17152.
Whibley, A. C., Plagnol, V., Tarpey, P.
S., Abidi, F., Fullston, T., Choma, M. K.,
Boucher, C. A., Shepherd, L., Willatt,
L., Parkin, G. et al. (2010). Finescale survey of X chromosome copy
number variants and indels underlying
intellectual disability. Am J Hum Genet
87, 173–188.
Whibley, A., Urquhart, J., Dore, J.,
Willatt, L., Parkin, G., Gaunt, L.,
Black, G., Donnai, D. and Raymond,
F. L. (2010). Deletion of MAOA and
MAOB in a male patient causes severe
developmental delay, intermittent
hypotonia and stereotypical hand
movements. Eur J Hum Genet 18,
1095–1099.
Whisstock, J. C., Silverman, G. A., Bird,
P. I., Bottomley, S. P., Kaiserman, D.,
Luke, C. J., Pak, S. C., Reichhart, J.-C.
and Huntington, J. A. (2010). Serpins
flex their muscle: II. Structural insights
into target peptidase recognition,
polymerization, and transport functions.
J Biol Chem 285, 24307–24312.
Wicker, L. S. (2010). Type 1 diabetes
susceptibility genes: Expression and
functional variations determined by
genotype. Endocr J 57, S220.
Wendler, F., Gillingham, A. K., Sinka,
R., Rosa-Ferreira, C., Gordon, D.
E., Franch-Marro, X., Peden, A. A.,
Vincent, J.-P. and Munro, S. (2010). A
genome-wide RNA interference screen
identifies two novel components of the
75
Willcocks, L. C., Carr, E. J., Niederer,
H. A., Rayner, T. F., Williams, T. N.,
Yang, W., Scott, J. A. G., Urban, B.
C., Peshub, N., Vyse, T. J., Lau, Y.
L., Lyons, P. A. and Smith, K. G. C.
(2010). A defunctioning polymorphism
in FCGR2B is associated with protection
against malaria but susceptibility to
systemic lupus erythematosus. Proc Natl
Acad Sci USA 107, 7881–7885.
Willcocks, L. C., Lyons, P. A., Rees,
A. J. and Smith, K. G. C. (2010). The
contribution of genetic variation and
infection to the pathogenesis of ANCAassociated systemic vasculitis. Arthritis
Res Ther 12, 202.
Wilson, N. K., Calero-Nieto, F.
J., Ferreira, R. and Göttgens, B.
(2011). Transcriptional regulation of
haematopoietic transcription factors.
Stem Cell Res Ther 2, 6.
Wilson, N. K., Foster, S. D., Wang, X.,
Knezevic, K., Schütte, J., Kaimakis,
P., Chilarska, P. M., Kinston, S.,
Ouwehand, W. H., Dzierzak, E. et al.
(2010). Combinatorial transcriptional
control in blood stem/progenitor cells:
genome-wide analysis of ten major
transcriptional regulators. Cell Stem Cell
7, 532–544.
Wilson, N. K., Tijssen, M. R. and
Göttgens, B. (2011). Deciphering
transcriptional control mechanisms in
hematopoiesis-The impact of highthroughput sequencing technologies.
Exp Hematol 39, 961–968.
Wilson, N. K., Timms, R. T., Kinston, S.
J., Cheng, Y. H., Oram, S. H., Landry,
J. R., Mullender, J., Ottersbach, K. and
Göttgens, B. (2010). Gfi1 expression
is controlled by five distinct regulatory
regions spread over 100 kilobases, with
Scl/Tal1, Gata2, PU.1, Erg, Meis1, and
Runx1 acting as upstream regulators in
early hematopoietic cells. Mol Cell Biol
30, 3853–3863.
Wines, B. D., Trist, H. M., Farrugia, W.,
Ngo, C., Trowsdale, J., Areschoug,
T., Lindahl, G., Fraser, J. D. and
Ramsland, P. A. (2012). A conserved
host and pathogen recognition site
76
on immunoglobulins: structural and
functional aspects. Adv Exp Med Biol
946, 87–112.
Winn, M. D., Ballard, C. C., Cowtan, K.
D., Dodson, E. J., Emsley, P., Evans,
P. R., Keegan, R. M., Krissinel, E.
B., Leslie, A. G. W., McCoy, A. et al.
(2011). Overview of the CCP4 suite and
current developments. Acta Crystallogr D
Biol Crystallogr 67, 235–242.
Winslow, A. R. and Rubinsztein, D.
C. (2011). The Parkinson disease
protein "-synuclein inhibits autophagy.
Winslow, A. R., Chen, C. W.,
Corrochano, S., Acevedo-Arozena,
A., Gordon, D. E., Peden, A. A.,
Lichtenberg, M., Menzies, F. M.,
Ravikumar, B., Imarisio, S., Brown,
S., O’Kane, C. J. and Rubinsztein,
D. C. (2010). "-Synuclein impairs
macroautophagy: implications for
Parkinson's disease. J Cell Biol 190,
1023–1037.
Woods, C. G. (2011). Pain, pain
genetics, and 'next-generation' pain
genetics. Dev Med Child Neurol 53,
874–875.
Yamanouchi, J., Puertas, M. C.,
Verdaguer, J., Lyons, P. A., Rainbow,
D. B., Chamberlain, G., Hunter, K.
M., Peterson, L. B., Wicker, L. S. and
Santamaria, P. (2010). Idd9.1 locus
controls the suppressive activity of
FoxP3(+)CD4(+)CD25(+) regulatory
T-cells. Diabetes 59, 272–281.
Yamasaki, M., Sendall, T. J., Harris,
L. E., Lewis, G. M. and Huntington, J.
A. (2010). Loop-sheet mechanism of
serpin polymerization tested by reactive
center loop mutations. J Biol Chem 285,
30752–30758.
Yamasaki, M., Sendall, T. J., Pearce, M.
C., Whisstock, J. C. and Huntington,
J. A. (2011). Molecular basis of
"1-antitrypsin deficiency revealed by the
structure of a domain-swapped trimer.
EMBO Rep 12, 1011–1017.
Yang, D. S., Stavrides, P., Mohan,
P. S., Kaushik, S., Kumar, A., Ohno,
M., Schmidt, S. D., Wesson, D. W.,
Bandyopadhyay, U., Jiang, Y. et
al. (2011). Therapeutic effects of
remediating autophagy failure in a
mouse model of Alzheimer disease
by enhancing lysosomal proteolysis.
Yang, D. S., Stavrides, P., Mohan,
P. S., Kaushik, S., Kumar, A., Ohno,
M., Schmidt, S. D., Wesson, D.,
Bandyopadhyay. U., Jiang. Y. et
al. (2011). Reversal of autophagy
dysfunction in the TgCRND8 mouse
model of Alzheimer's disease
ameliorates amyloid pathologies and
memory deficits. Brain 134, 258–277.
Yang, G., Wu, Y., Tsukamoto, H.,
Leung, P. S., Lian, Z., Rainbow, D. B.,
Hunter, K. M., Morris, G. A., Lyons,
P. A., Peterson, L. B., Wicker, L. S.,
Gershwin, E. and Ridgway, W. M.
(2011). CD8 T cells mediate direct
biliary ductule damage in nonobese
diabetic autoimmune biliary disease. J
Immunol 186, 1259–1267.
Yang, J. H., Downes, K., Howson, J. M.,
Nutland, S., Stevens, H. E., Walker, N.
M. and Todd, J. A. (2011). Evidence of
association with type 1 diabetes in the
SLC11A1 gene region. BMC Med Genet
12, 59.
Younis, R., Bingle, L. E. H., Rollauer,
S., Munera, D., Busby, S. J., Johnson,
S., Deane, J. E., Lea, S. M., Frankel,
G. and Pallen, M. J. (2010). SepL
resembles an aberrant effector in
binding to a class 1 type III secretion
chaperone and carrying an N-terminal
secretion signal. J Bacteriol 192,
6093–6098.
Yung, E., Sekulovic, S., Berg, T.,
Bilenky, M., Nielsen, C., Göttgens, B.,
Jones, S., Hirst, M. and Humphries,
K. (2011). A comprehensive genome
wide characterization of MEIS1 induced
leukemic transformation. Exp Hematol
39, S45–S46.
Yusa, K.*, Rashid, S. T.*, StrickMarchand, H., Varela, I., Liu, P.-Q.,
Paschon, D. E., Miranda, E., Ordóñez,
A., Hannan, N., Rohani, F. et al.
(2011). Targeted gene correction of
"1-antitrypsin deficiency in induced
pluripotent stem cells. Nature 478,
391–394.
Zelmer, A., Martin, M. J., Gundogdu,
O., Birchenough, G., Lever, R., Wren,
B. W., Luzio, J. P. and Taylor, P. W.
(2010). Administration of capsuleselective endosialidase E minimizes
upregulation of organ gene expression
induced by experimental systemic
infection with Escherichia coli K1.
Microbiology 156, 2205–2215.
Zheng, S., Clabough, E. B., Sarkar,
S., Futter, M., Rubinsztein, D. C.
and Zeitlin, S. O. (2010). Deletion of
the huntingtin polyglutamine stretch
enhances neuronal autophagy and
longevity in mice. PLoS Genet 6,
e1000838.
Zhou, A., Carrell, R. W., Murphy,
M. P., Wei, Z., Yan, Y., Stanley, P. L.,
Stein, P. E., Broughton Pipkin, F. and
Read, R. J. (2010). A redox switch in
angiotensinogen modulates angiotensin
release. Nature 468, 108–111.
77
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The Wellcome Trust/MRC Building which houses the Cambridge Institute for Medical Research and the MRC Mitochondrial Biology Unit.
78
Regulations for CIMR
Management
1 The Cambridge Institute for Medical
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under the general control of a Strategy
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(a) the Director (Chairman) of the Institute;
(b) the Deputy Director (Deputy Chairman)
of the Institute;
(c) the Regius Professor of Physic;
(d) the Heads of the Departments from
which staff working within the Institute are
drawn;
(e) the Director of the Diabetes and
Inflammation Laboratory;
(f) two persons appointed by the Faculty
Board of Clinical Medicine.
2 The Regius Professor of Physic shall serve
as Chairman of the Strategy Committee
and the Deputy Director (Deputy
Chairman) of the Institute shall serve as
Secretary of the Strategy Committee.
3 Subject to the powers of the Council, the
General Board, and the Faculty Board
of Clinical Medicine, the duties of the
Strategy Committee shall be as follows:
(a) to promote research in, and at the
interface of, the clinical and basic
biomedical sciences that underpin the
Institute’s major goal of determining and
understanding the molecular mechanisms
of disease;
(b) to co-operate with outside bodies
including the Wellcome Trust in the
encouragement of such research;
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relating to the administration of funds
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(d) to convene such ad hoc or standing
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of Clinical Medicine for appointment or
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4 There shall be an Institute Management
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(a) the Director (Chairman) of the Institute,
who shall be Chairman of the Committee;
(b) the Deputy Director (Deputy Chairman)
of the Institute;
(c) the Administrator of the Institute;
(d) six Principal Investigators appointed by
the Strategy Committee. The six principal
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the Strategy Committee, co-opt additional
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(a) to advise the Director (Chairman)
of the Institute on strategic issues and
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the Institute including health and safety
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(b) in consultation with the relevant Heads
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from Principal Investigators wishing to
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with commercial companies, on the part of
any Institute staff members and/or relating
to research conducted by the Institute’s
staff.
Director (Chairman) of the Institute and
Deputy Director (Deputy Chairman) of the
Institute
2 There shall be a University office of
Deputy Director (Deputy Chairman) of the
Cambridge Institute for Medical Research,
which may be held concurrently with
another University office.
3 The Director (Chairman) and Deputy
Director (Deputy Chairman) of the
shall be appointed by the Faculty Board of
Clinical Medicine on the recommendation
of the Strategy Committee. Appointments
and reappointments to the offices of
Director (Chairman) and Deputy Director
(Deputy Chairman) shall be for such
periods not exceeding five years at a time
as shall be determined by the Faculty
Board on the recommendation of the
Strategy Committee.
4 Under the general control of the Strategy
Committee, and subject to the powers of
the Management Committee, the Director
(Chairman) of the Institute shall be the
administrative Head of the Institute.
5 The Director (Chairman) or his or her
nominated deputy shall also represent
the Institute on the Wellcome Trust/MRC
Building User’s Committee.
Procedure for the appointment and reappointment of the Director (Chairman)
and Deputy Director (Deputy Chairman)
1 The Strategy Committee shall designate
one of their members to take soundings
on their behalf from amongst the Heads
of Departments from which staff of
the Institute are drawn, the Principal
Investigators based in the Institute, and
to submit a nomination or nominations to
the Strategy Committee. The Strategy
Committee shall determine the nomination
to be made to the Faculty Board of Clinical
Medicine. For the Deputy Directorship the
designated person shall be the Director
unless the Strategy Committee shall
determine otherwise.
2 This procedure shall apply also for
re-appointments.
Regulations approved by the Faculty Board of
Clinical Medicine, University of Cambridge
1 There shall be a University office of
Director (Chairman) of the Cambridge
Institute for Medical Research, which
may be held concurrently with another
University office.
(These regulations are currently under review, pending approval by the Faculty Board of Clinical Medicine)
79
Administrative, technical and other support staff
Back cover illustration:
A new “knocksideways” system, in which a coat protein, AP-2 (in red), gets rerouted
to mitochondria in cells expressing a “Mitotrap” construct (green), while clathrin (blue)
does not get rerouted. This rerouting occurs within seconds of addition of a small
molecule, and causes the rerouted protein to be unavailable for its normal role and
therefore non-functional.
(Illustration courtesy of Margaret Robinson)
www.cimr.cam.ac.uk

2012 report - Cambridge Institute for Medical Research

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