Senescence Defines a Distinct Subset of Myofibroblasts That Orchestrates Immunosuppression in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) therapeutic resistance is largely attributed to a unique tumor microenvironment embedded with an abundance of cancer-associated fibroblasts (CAF). Distinct CAF populations were recently identified, but the phenotypic drivers and specific impact of CAF heterogeneity remain unclear. In this study, we identify a subpopulation of senescent myofibroblastic CAFs (SenCAF) in mouse and human PDAC. These SenCAFs are a phenotypically distinct subset of myofibroblastic CAFs that localize near tumor ducts and accumulate with PDAC progression. To assess the impact of endogenous SenCAFs in PDAC, we used an LSL-KRASG12D;p53flox;p48-CRE;INK-ATTAC (KPPC-IA) mouse model of spontaneous PDAC with inducible senescent cell depletion. Depletion of senescent stromal cells in genetic and pharmacologic PDAC models relieved immune suppression by macrophages, delayed tumor progression, and increased responsiveness to chemotherapy. Collectively, our findings demonstrate that SenCAFs promote PDAC progression and immune cell dysfunction. Significance: CAF heterogeneity in PDAC remains poorly understood. In this study, we identify a novel subpopulation of senescent CAFs that promotes PDAC progression and immunosuppression. Targeting CAF senescence in combination therapies could increase tumor vulnerability to chemo or immunotherapy. See related article by Ye et al., p. 1302.

Metabolic regulation of CTCF expression and chromatin association dictates starvation response in mice and flies.

Coordinated temporal control of gene expression is essential for physiological homeostasis, especially during metabolic transitions. However, the interplay between chromatin architectural proteins and metabolism in regulating transcription is less understood. Here, we demonstrate a conserved bidirectional interplay between CTCF (CCCTC-binding factor) expression/function and metabolic inputs during feed-fast cycles. Our results indicate that its loci-specific functional diversity is associated with physiological plasticity in mouse hepatocytes. CTCF differential expression and long non-coding RNA-Jpx mediated changes in chromatin occupancy, unraveled its paradoxical yet tuneable functions, which are governed by metabolic inputs. We illustrate the key role of CTCF in controlling temporal cascade of transcriptional response, with effects on hepatic mitochondrial energetics and lipidome. Underscoring the evolutionary conservation of CTCF-dependent metabolic homeostasis, CTCF knockdown in flies abrogated starvation resistance. In summary, we demonstrate the interplay between CTCF and metabolic inputs that highlights the coupled plasticity of physiological responses and chromatin function.

Disparate effects of PEG or albumin based surface modification on the uptake of nano- and micro-particles.

Surface modification of particulate systems is a commonly employed strategy to alter their interaction with proteins and cells. Past studies on nano-particles have shown that surface functionalization with polyethylene glycol (PEG) or proteins such as albumin increases circulation times by reducing their phagocytic uptake. However, studies on surface functionalized micro-particles have reported contradictory results. Here, we investigate the effects of surface functionalization using polystyrene particles with 4 different diameters ranging from 30 nm to 2.6 µm and coating them with either albumin or PEG. Our results show that with increasing particle size, surface functionalization has less to no effect on altering phagocytic uptake. The data also suggest that these differences are observed with a dense arrangement of molecules on the surface (dense brush conformation for PEG conjugation), appear to be independent of the serum proteins adsorbing on particle surfaces, and are independent of the endocytic uptake pathway. These results provide insight into the differences in the ability of surface modified nano- and micro-particles to avoid phagocytic uptake.

Assessment of energy balance against the nutritional status of women carriers in the brickfields of West Bengal.

The Indian brick industry is an unorganized sector in which large numbers of migrant women workers are employed. A survey was conducted on 62 women workers working in different brickfields of West Bengal to assess their physiological workload, nutritional profile, total energy expenditure and energy balance. Energy intake was calculated using physiological fuel values of carbohydrate, fat and protein. From the results it is seen that 13% of the sample population falls under severe (grade III) chronic energy deficiency. The average daily consumption of the workers was comparatively lower than their daily energy expenditure, considering the nature of the job which falls under heavy to extremely heavy categories. This negative energy balance is effectively observed in the nutritional anthropometry data. Thus, an immediate ergonomics intervention with better nutrition should be implemented to improve the health status of the workers so they can safely continue to work for a longer period.

Ergonomics: A bridge between fundamentals and applied research.

Ergonomics is becoming a subject of applying fundamentals on anthropocentric dimensions for holistic welfare. The so-called conflict between Basic science and Applied research finds one of its edges in Ergonomics. Be it cutting-edge technology or frontiers of scientific innovation-all start from understanding basic scientific aptitude and skill, and the best way to get familiar with the situation is practicing basic science again and again at a regular basis. Ergonomics is diversified in such paradigms that truly set an example of such harmony between two apparently never-ending straight lines. If the spirit of Science is true human welfare, be it in the form of environmental development, machine development, technological advancement, human resource development, or development of consecutive interfaces between these components, Participatory Ergonomics is one of the vivid examples of such conglomeration. Although fundamental science may appear to be of very little practical significance, it turns out that eventually it has far greater impact on human society than much of the so-called "applied research."