Agency for Science, Technology and Research Singapore

Singapore, Singapore

Agency for Science, Technology and Research Singapore

Singapore, Singapore
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Chen N.,Massachusetts Institute of Technology | Chen N.,Agency for Science, Technology and Research Singapore | Sugihara H.,Massachusetts Institute of Technology | Sur M.,Massachusetts Institute of Technology
Nature Neuroscience | Year: 2015

Cholinergic modulation of cortex powerfully influences information processing and brain states, causing robust desynchronization of local field potentials and strong decorrelation of responses between neurons. We found that intracortical cholinergic inputs to mouse visual cortex specifically and differentially drive a defined cortical microcircuit: they facilitate somatostatin-expressing (SOM) inhibitory neurons that in turn inhibit parvalbumin-expressing inhibitory neurons and pyramidal neurons. Selective optogenetic inhibition of SOM responses blocked desynchronization and decorrelation, demonstrating that direct cholinergic activation of SOM neurons is necessary for this phenomenon. Optogenetic inhibition of vasoactive intestinal peptide-expressing neurons did not block desynchronization, despite these neurons being activated at high levels of cholinergic drive. Direct optogenetic SOM activation, independent of cholinergic modulation, was sufficient to induce desynchronization. Together, these findings demonstrate a mechanistic basis for temporal structure in cortical populations and the crucial role of neuromodulatory drive in specific inhibitory-excitatory circuits in actively shaping the dynamics of neuronal activity. © 2015 Nature America, Inc.


Hoe K.K.,Agency for Science, Technology and Research Singapore | Verma C.S.,Agency for Science, Technology and Research Singapore | Verma C.S.,National University of Singapore | Lane D.P.,National University of Singapore
Nature Reviews Drug Discovery | Year: 2014

The tumour suppressor p53 is the most frequently mutated gene in human cancer, with more than half of all human tumours carrying mutations in this particular gene. Intense efforts to develop drugs that could activate or restore the p53 pathway have now reached clinical trials. The first clinical results with inhibitors of MDM2, a negative regulator of p53, have shown efficacy but hint at on-target toxicities. Here, we describe the current state of the development of p53 pathway modulators and new pathway targets that have emerged. The challenge of targeting protein-protein interactions and a fragile mutant transcription factor has stimulated many exciting new approaches to drug discovery. © 2014 Macmillan Publishers Limited.


Biswas S.K.,Agency for Science, Technology and Research Singapore | Mantovani A.,Instituto Clinico Humanitas | Mantovani A.,University of Milan
Nature Immunology | Year: 2010

Plasticity is a hallmark of cells of the myelomonocytic lineage. In response to innate recognition or signals from lymphocyte subsets, mononuclear phagocytes undergo adaptive responses. Shaping of monocyte-macrophage function is an essential component of resistance to pathogens, tissue damage and repair. The orchestration of myelomonocytic cell function is a key element that links inflammation and cancer and provides a paradigm for macrophage plasticity and function. A better understanding of the molecular basis of myelomonocytic cell plasticity will open new vistas in immunopathology and therapeutic intervention.


Biswas S.K.,Agency for Science, Technology and Research Singapore | Mantovani A.,University of Milan
Cell Metabolism | Year: 2012

Metabolic adaptation is a key component of macrophage plasticity and polarization, instrumental to their function in homeostasis, immunity, and inflammation. Macrophage products also impact metabolism, as illustrated by obesity-associated pathologies. Defining the mechanisms regulating macrophage metabolic activity and orchestration of metabolism by macrophages is crucial to pathology and therapeutic intervention. © 2012 Elsevier Inc.


Javed A.,Agency for Science, Technology and Research Singapore
Nature Methods | Year: 2014

We introduce Phen-Gen, a method that combines patients' disease symptoms and sequencing data with prior domain knowledge to identify the causative genes for rare disorders. Simulations revealed that the causal variant was ranked first in 88% of cases when it was a coding variant-a 52% advantage over a genotype-only approach-and Phen-Gen outperformed other existing prediction methods by 13-58%. If disease etiology was unknown, the causal variant was assigned the top rank in 71% of simulations. Phen-Gen is available at http://phen-gen.org/.


Newell E.W.,Agency for Science, Technology and Research Singapore | Davis M.M.,Howard Hughes Medical Institute
Nature Biotechnology | Year: 2014

Adaptive immune responses often begin with the formation of a molecular complex between a T-cell receptor (TCR) and a peptide antigen bound to a major histocompatibility complex (MHC) molecule. These complexes are highly variable, however, due to the polymorphism of MHC genes, the random, inexact recombination of TCR gene segments, and the vast array of possible self and pathogen peptide antigens. As a result, it has been very difficult to comprehensively study the TCR repertoire or identify and track more than a few antigen-specific T cells in mice or humans. For mouse studies, this had led to a reliance on model antigens and TCR transgenes. The study of limited human clinical samples, in contrast, requires techniques that can simultaneously survey TCR phenotype and function, and TCR reactivity to many T-cell epitopes. Thanks to recent advances in single-cell and cytometry methodologies, as well as high-throughput sequencing of the TCR repertoire, we now have or will soon have the tools needed to comprehensively analyze T-cell responses in health and disease. © 2014 Nature America, Inc. All rights reserved.


Biswas S.K.,Agency for Science, Technology and Research Singapore
Immunity | Year: 2015

Immune cells play a key role in host defense against infection and cancer. Upon encountering danger signals, these cells undergo activation leading to a modulation in their immune functions. However, recent studies reveal that immune cells upon activation also show distinct metabolic changes that impact their immune functions. Such metabolic reprogramming and its functional effects are well known for cancer cells. Given that immune cells have emerged as crucial players in cancer progression, it is important to understand whether immune cells also undergo metabolic reprogramming in tumors and how this might affect their contribution in cancer progression. This emerging aspect of tumor-associated immune cells is reviewed here, discussing metabolic reprogramming of different immune cell types, the key pathways involved, and its impact on tumor progression. © 2015 Elsevier Inc.


Schlitzer A.,Agency for Science, Technology and Research Singapore | Ginhoux F.,Agency for Science, Technology and Research Singapore
Current Opinion in Immunology | Year: 2014

Dendritic cells (DCs) are the most potent antigen sensing and presenting cells in the body and are able to both initiate and fine-tune complex immune responses on a multitude of levels. In this review, we outline recent advances in our understanding of the organization of the DC network in mice and humans, the functional specialization of the DC subsets that compose these networks, and how this has enabled us to begin to elucidate cross-species parallels. Understanding the inter-relationships between DC populations in both man and mouse will ultimately allow us to exploit our knowledge of DC biology for effective therapeutic strategies. © 2013 The Authors.


Raida M.,Agency for Science, Technology and Research Singapore
Current Opinion in Chemical Biology | Year: 2011

Drug target deconvolution is a process where the action of a drug, a small molecule, is characterised by identifying the proteins binding the drug and initiating the biological effect. The biological relevant target has to be extracted, or deconvoluted, from a list of proteins identified in such an approach. Beside the medically desired action of the drug, the identification of other proteins binding the drug can help to identify side effects and toxicity at a very early stage of drug development. The current approach to identify the proteins binding to the drug is an affinity-enrichment based approach, where the drug molecule is immobilised to a matrix through a linker and the proteins binding to the drug are identified by proteomics. © 2011 Elsevier Ltd.


Javed A.,Agency for Science, Technology and Research Singapore
Nature methods | Year: 2014

We introduce Phen-Gen, a method that combines patients' disease symptoms and sequencing data with prior domain knowledge to identify the causative genes for rare disorders. Simulations revealed that the causal variant was ranked first in 88% of cases when it was a coding variant-a 52% advantage over a genotype-only approach-and Phen-Gen outperformed other existing prediction methods by 13-58%. If disease etiology was unknown, the causal variant was assigned the top rank in 71% of simulations. Phen-Gen is available at http://phen-gen.org/.

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