Abbkine Scientific: Weekly Top Scientific Research Review (10/4/2017

Gene regulatory dynamics, CRTCs and Age-Related Disease Risk, Macrophage Immunometabolism, Antibody Glycosylation, cancer immunotherapy, which topic catches your eye?

1. Imaging Translational and Post-Translational Gene Regulatory Dynamics in Living Cells with Antibody-Based Probes.

Antibody derivatives, such as antibody fragments (Fabs) and single-chain variable fragments (scFvs), are now being used to image traditionally hard-to-see protein subpopulations, including nascent polypeptides being translated and post-translationally modified proteins. This has allowed researchers to directly image and quantify, for the first time, translation initiation and elongation kinetics with single-transcript resolution and the temporal ordering and kinetics of post-translational histone and RNA polymerase II modifications. Here, Kenneth Lyon at Colorado State University in Fort Collins, USA and his colleagues review these developments and discuss the strengths and weaknesses of live-cell imaging with antibody-based probes. Further development of these probes will increase their versatility and open new avenues of research for dissecting complex gene regulatory dynamics.

Fabs and scFvs are useful live-cell imaging probes. Fabs and scFvs can bring preformed fluorescence to unfolded or modified peptides in living cells, unlike standard fluorescent protein fusion tags. Fabs need to be loaded into cells to image protein dynamics; scFvs can be genetically expressed. Fabs and scFvs have recently been used to image and quantify single-mRNA translation kinetics in living cells, yielding consistent estimates of average initiation and elongation rates. Fabs and scFvs have recently been used to image and quantify post-translation modifications to histones and RNA polymerase II in living cells, revealing their spatiotemporal co-regulation. For imaging translation, probes should outnumber targets; for imaging endogenous post-translational modifications, targets should outnumber probes.

2. Deregulation of CRTCs in Aging and Age-Related Disease Risk.

Advances in public health in the past century have seen a sharp increase in human life expectancy. With these changes have come an increased prevalence of age-related pathologies and health burdens in the elderly. Patient age is the biggest risk factor for multiple chronic conditions that often occur simultaneously within a single individual. An alternative to disease-centric therapeutic approaches is that of ‘geroscience’, which aims to define molecular mechanisms that link age to overall disease risk. One such mechanism is deregulation of CREB-regulated transcriptional coactivators (CRTCs). Initially identified for their role in modulating CREB transcription, the past 5 years has seen an expansion in knowledge of new cellular regulators and roles of CRTCs beyond CREB. CRTCs have been shown to modulate organismal aging in Caenorhabditis elegans and to impact on age-related diseases in humans. Caroline C. Escoubas at Harvard University in Boston, USA and her colleagues discuss CRTC deregulation as a new driver of aging that integrates the link between age and disease risk.

Novel cellular regulators and targets of the CRTC family have recently been identified. In C. elegans CRTCs have been shown to modulate aging. Recently CRTC dysfunction has been associated with age-related human diseases. CRTCs could provide a target for healthy human aging.

3. Macrophage Immunometabolism: Where Are We (Going)?

A growing number of findings highlight the crucial role of metabolic reprogramming in macrophage activation. Metabolic pathways are closely interconnected and recent literature demonstrates the need for glucose metabolism in anti-inflammatory as well as inflammatory macrophages. Moreover, fatty acid oxidation (FAO) not only supports anti-inflammatory responses as described formerly but also drives inflammasome activation in inflammatory macrophages. Hence, defining glycolysis as proinflammatory and FAO as anti-inflammatory may be an oversimplification. Here Jan Van den Bossche at Academic Medical Center, University of Amsterdam in Amsterdam, the Netherlands and his colleagues review how the rapid growth of the immunometabolism field has improved our understanding of macrophage activation and at the same time has led to an increase in the appearance of contradictory observations. To conclude they discuss current challenges in immunometabolism and present crucial areas for future research.

Metabolic reprogramming of macrophages plays a predominant role in regulating their phenotype but also their plasticity. Metabolic repurposing of mitochondria is key to the regulation of proinflammatory responses including the expression of pro-IL-1β and the generation of reactive oxygen species via reverse electron transport. In vivo macrophages are subject to a plethora of stimuli that often do not fully fit in the binary M1/M2 frame. Moreover, nutrient competition adds an extra layer of complexity to their functional regulation. The differences between human and mouse macrophages remain in the process of being elucidated. The inability of human macrophages to produce nitric oxide in vitro, unlike murine macrophages, introduces the possibility of differential metabolic reprogramming between the two cell types.

4. The Immunoregulatory Roles of Antibody Glycosylation.

Beyond their role in neutralization, antibodies mediate functions such as phagocytosis, cytotoxicity, and maintenance of immune homeostasis. Two modifications to the constant domain control antibody activity: theirreversible genomic selection of isotype/subclass and alterations in glycosylation. Because glycosylation alters the affinity of antibodies for Fc receptors, evidence suggests that glycosylation is a central mechanism for the immune system to tune a broad range of biological activities. While monoclonal therapeutics have exploited glycosylation to improve function, its in vivo control and whether it may be selectively harnessed to target pathogens and/or tumors isunknown. Here, Madeleine F. Jennewein at Ragon Institute of MGH, MIT and Harvard in Cambridge, USA and his colleagues review the process of antibody glycosylation, how it changes with disease, how it impacts antibody functionality, and the potential for deliberately controlling this biological activity.

Antibody glycosylation defines the functional potential of the antibody by delineating the structure of the antibody Fc region and determining which Fc receptors it can bind to in order to recruit effector cells. The effector functions that antibodies mediate, including cytotoxicity and phagocytosis, are critical for protection against and prevention of many diseases. Antibody glycosylation has been harnessed to improve the efficacy of monoclonal therapeutics. Antibody glycosylation can be modulated by vaccination, indicating that rational immunogen design could seek to elicit a specific antibody glycosylation response.

5. Connecting the Metabolic and Immune Responses to Cancer.

Separate research fields have advanced our understanding of, on the one hand, cancer immunology and, on the other hand, cachexia, the fatal tumor-induced wasting syndrome. A link between the host’s immune and metabolic responses to cancer remained unexplored. Emerging work in preclinical models of colorectal and pancreatic cancer has unveiled tumor-induced reprogramming of liver metabolism in cachexia that leads to suppression of antitumor immunity and failure of immunotherapy. As research efforts in metabolism and immunology in cancer are rapidly expanding, it is timely to discuss the metabolic and immunological determinants of the cancer-host interaction. Thomas R. Flint at School of Clinical Medicine, University of Cambridge in Cambridge, UK and his colleagues also present the hypothesis that the convergence of host metabolism and antitumor immunity may offer a platform for biomarker-driven investigations of new combination therapies.

The scope of cancer research is expanding to include the molecular circuitry of both cancer cells and non-cancer cells, as well as non-tumor tissues of the cancer host. The current generation of immune therapies target cells of the cancer host. These therapies achieve durable remissions of advanced cancers, but the majority of patient subsets remain unresponsive. Tumors affect their hosts’ metabolism, often leading to the lethal wasting syndrome, cachexia. In recent years, the biology of cachexia has become an increasingly active field of mechanistic research, but still defies a unifying explanation. Preclinical studies have now connected the host’s metabolic and immune responses to cancer. Tumors reprogram the normal metabolic response to caloric deficiency in cachexia, leading to suppression of the antitumor immune reaction.

Abbkine Scientific

2017年4月14日星期五

Weekly Top Scientific Research Review (10/4/2017 – 14/4/2017)

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