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Cambridge Institute for Medical Research

 

Research Advances

These are summaries of selected new publications from CIMR.

Read more at: A structure-based understanding of how the Integrated Stress Response is switched off

A structure-based understanding of how the Integrated Stress Response is switched off

Like many key biological pathways, the Integrated Stress Response (ISR) is carefully regulated. A known molecular trigger for the ISR is the stress-induced phosphorylation of the α-subunit of...

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Read more at: New strides made in solving protein structures

New strides made in solving protein structures

There have been some major developments in computational tools to predict the 3D structures of proteins. Nature recently published the details of AlphaFold2 , the machine-learning product of Google...

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Read more at: Somatic genetic rescue in a rare disease

Somatic genetic rescue in a rare disease

Ribosomopathies such as Shwachman-Diamond syndrome (SDS) are rare diseases caused by defects in ribosome assembly. A new international study co-led by Prof. Alan Warren (CIMR) and Prof. Patrick Revy...

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Read more at: Structural and mechanistic insights into a molecular chaperone

Structural and mechanistic insights into a molecular chaperone

BiP is a molecular chaperone of the endoplasmic reticulum (ER), playing a tightly-regulated role in protein folding and the Unfolded Protein Response. Under normal conditions, a substantial fraction...

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Read more at: Cytotoxic T cell activation and signal strength

Cytotoxic T cell activation and signal strength

Cytotoxic T lymphocytes (CTLs) of the immune system combat virally infected and cancerous cells. Killing is finely controlled according to the strength of signal generated upon T cell receptor (TCR)...

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Read more at: New vaccine targets for a neglected malaria parasite

New vaccine targets for a neglected malaria parasite

The development of effective vaccines against the Plasmodium parasites which cause malaria is a major, global research goal. There has been recent progress against P.falciparum , but another species...

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Read more at: A new phosphorylation pathway to autophagy

A new phosphorylation pathway to autophagy

Glucose starvation can activate cellular autophagy, but the exact mechanisms of this have been unclear. PhD student Cansu Karabiyik and colleagues from the Rubinsztein lab have recently uncovered a...

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Read more at: Molecular mechanisms of a rare lung disease

Molecular mechanisms of a rare lung disease

Pulmonary fibrosis (lung scarring) is a serious feature of many different lung diseases, but its precise causes are not well understood. Dr Jennifer Dickens and colleagues from Prof. Stefan Marciniak...

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Read more at: New molecular insights into alpha-1-antitrypsin-deficiency

New molecular insights into alpha-1-antitrypsin-deficiency

Alpha-1-antitrypsin (α1AT) deficiency is a rare genetic disease which can cause chronic obstructive pulmonary disease and liver cirrhosis. This condition is understood to arise from the intracellular...

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Read more at: A feedback loop links autophagy and cell growth pathways

A feedback loop links autophagy and cell growth pathways

YAP and TAZ are both transcriptional regulators with central roles in cell growth. Mariana Pavel, So Jung Park and colleagues from the Rubinsztein lab have discovered a feedback loop linking...

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Read more at: How a protein conserved in evolution links a rare dementia to autophagy

How a protein conserved in evolution links a rare dementia to autophagy

VCP/p97 is an evolutionarily-conserved ATPase with a role in cellular protein homeostasis and quality control. A human VCP mutation that decreases its activity causes dementia associated with tau...

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Read more at: Intracellular membrane trafficking and a rare neurological disorder

Intracellular membrane trafficking and a rare neurological disorder

Publishing in the Journal of Cell Biology, Dr Hirst in the Robinson lab and co-authors show that recruitment of the AP-5 complex (that includes SPG11 and SPG15) is by coincidence detection, requiring...

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Read more at: A new mechanism for a key signalling pathway

A new mechanism for a key signalling pathway

mTORC2 is a protein complex in a network which transduces extracellular signals from growth factors into cellular responses such as growth, proliferation and nutrient metabolism. The precise...

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Read more at: Dampening the Integrated Stress Response in cells

Dampening the Integrated Stress Response in cells

The Integrated Stress Response (ISR) is a protective mechanism used by cells when they detect adverse conditions. However, prolonged activation of the ISR can occur in, and contribute to some disease...

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Read more at: The discovery and molecular mechanisms of a rare multi-system syndrome.

The discovery and molecular mechanisms of a rare multi-system syndrome.

A new paper in The American Journal of Human Genetics has been published by a UK-Italian collaboration co-led by CIMR’s Dr Evan Reid and Prof. Lucy Raymond, together with Dr Marco Tartaglia (ICRCC...

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Read more at:  How a rare genetic variant protects against malaria

How a rare genetic variant protects against malaria

Over the centuries, malaria has selected for many natural human genetic variants such as sickle haemoglobin that provide protection against severe disease. One such variant, Dantu, codes for an...

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Read more at: New study links oxygen sensing to B cell development

New study links oxygen sensing to B cell development

Hypoxia-inducible factor (HIF) 1α is a key orchestrator of a wide range of responses to changes in cellular oxygen levels. Dr Natalie Burrows and colleagues from Prof. Patrick Maxwell’s lab at CIMR...

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Read more at: ‘Natural epidural’ discovered in one in a hundred women

‘Natural epidural’ discovered in one in a hundred women

A powerful example of how researching rare genetic variants can provide much wider insights was published recently in a multi-disciplinary, Cambridge-led study of childbirth pain. Together with Dr Michael Lee and colleagues at the Dept. of Anaesthetics, Prof. Geoff Woods’ CIMR team found a rare variant of the KCNG4 gene which was over-represented in a group of women who asked for no pain relief during labour.

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Read more at: A cellular dual-death inhibitor helps human cytomegalovirus infection

A cellular dual-death inhibitor helps human cytomegalovirus infection

Programmed cell death pathways can be activated as a defence mechanism in cells infected with viruses to reduce further viral spread. Final-year CIMR PhD student Alice Fletcher-Etherington in the Weekes lab, together with other colleagues have published in PNAS on how human cytomegalovirus (HCMV) can subvert host cell death pathways to enhance its cellular infectivity, revealing a potential target for anti-HCMV therapy.

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Read more at: Novel regulatory mechanism for protein tyrosine phosphatase PTPRU

Novel regulatory mechanism for protein tyrosine phosphatase PTPRU

Reversible protein tyrosine phosphorylation by kinases and phosphatases is a key component of cellular signalling. CIMR PhD student Iain Hay and colleagues from the labs of co-supervisors Janet Deane (CIMR) and Hayley Sharpe (Babraham), together with Maja Koehn (Freiburg) have published in Nature Communications on the structure and function of the receptor protein tyrosine phosphatase PTPRU.

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Read more at: mTORC1 and the regulation of autophagy

mTORC1 and the regulation of autophagy

Nutrient depletion is one of several triggers of autophagy in cells. Previous work by Sung Min Son and Rubinsztein lab colleagues showed how cells respond to levels of the essential amino acid leucine through its metabolite acetyl co-enzyme A (AcCoA) and the mTORC1 complex, a master regulator of cellular growth and metabolism, and a negative regulator of autophagy. A new paper in Nature Communications extends this sensing mechanism to autophagy regulation.

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Read more at: Signal strength in T cell activation

Signal strength in T cell activation

Millions of naïve T cells with different TCRs may interact with a peptide-MHC ligand, but very few will activate. This fine control is orchestrated using a limited set of intracellular machinery. Publishing in eLife, Dr Claire Ma from the Wellcome Clinical PhD programme and Dr Arianne Richard, a joint postdoctoral Fellow from the Griffiths and Marioni labs investigated how changes in stimulation strength alter the programme of signalling events leading to T cell activation.

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Read more at: Monocyte diversity and function revealed by proteomics

Monocyte diversity and function revealed by proteomics

The identities and functions of different white blood cell types are determined in part by their cell-surface proteins - which can also be important markers in the clinic. Clinician Dr Ben Ravenhill and colleagues in CIMR’s Weekes Lab and Proteomics Facility present in Scientific Reports the first quantitative proteomic analyses of surface proteins from these monocyte subtypes. Using selective cell surface biotinylation and MS3 mass spectrometry, this study provides new insights into the basis of monocyte diversity and function.

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Read more at: The role of optineurin in immune signalling

The role of optineurin in immune signalling

Optineurin is a multifunctional protein important in autophagy and regulation of immune signalling. Defects in optineurin gene function are linked to a number of human diseases including motor neuron disease. Dr Thomas O’Loughlin and CIMR colleagues from the Buss lab, together with collaborators from UCL have shown in the Journal of Cell Science that downstream of a signal from viral RNA, optineurin moves to distinct foci close to the Golgi complex.

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Read more at: The origins and regulation of autophagosomes

The origins and regulation of autophagosomes

With key roles in normal cellular homeostasis and a range of diseases, autophagy is mediated by autophagosomes. Using insights from a rare muscle-wasting disease, Dr Claudia Puri from the CIMR’s Rubinsztein Laboratory and colleagues present a new model for the subcellular origins of autophagosomes and their regulation.

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Read more at: Mitochondria set the pace of killing

Mitochondria set the pace of killing

Cytotoxic T lymphocytes (CTLs) recognise and destroy cells which are infected with viruses or are cancerous. This latter property puts them at the heart of new immunotherapies transforming cancer...

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