સ્વાસ્થ્ય-સંસ્કૃતિ સહસંબંધ : એક અભ્યાસ (ડાંગી ભીલોને અનુલક્ષીને)

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Long Days Enhance Recognition Memory and Increase Insulin-like Growth Factor 2 in the Hippocampus

Light improves cognitive function in humans; however, the neurobiological mechanisms underlying positive effects of light remain unclear. One obstacle is that most rodent models have employed lighting conditions that cause cognitive deficits rather than improvements. Here we have developed a mouse model where light improves cognitive function, which provides insight into mechanisms underlying positive effects of light. To increase light exposure without eliminating daily rhythms, we exposed mice to either a standard photoperiod or a long day photoperiod. Long days enhanced long-term recognition memory, and this effect was abolished by loss of the photopigment melanopsin. Further, long days markedly altered hippocampal clock function and elevated transcription of Insulin-like Growth Factor2 (Igf2). Up-regulation of Igf2 occurred in tandem with suppression of its transcriptional repressor Wilm’s tumor1. Consistent with molecular de-repression of Igf2, IGF2 expression was increased in the hippocampus before and after memory training. Lastly, long days occluded IGF2-induced improvements in recognition memory. Collectively, these results suggest that light changes hippocampal clock function to alter memory, highlighting novel mechanisms that may contribute to the positive effects of light. Furthermore, this study provides insight into how the circadian clock can regulate hippocampus-dependent learning by controlling molecular processes required for memory consolidation

Microstructural evolution in hot compressed TiHy 600 titanium alloy

TiHy 600 alloy is a near alpha titanium alloy, widely used for gas turbine engine applications such as disc and blades for high pressure compressors. One drawback of this alloy is that it is susceptible to cold dwell fatigue, which is due to the presence of micro-textured zones. Thus, appropriate processing parameters (i.e. temperature, strain and strain rate) are required to reduce the size of the micro-textured region. In order to find out the optimized processing parameters, hot compression tests were performed up to 50% engineering strain at temperatures range of 900oC-1050oC and strain rate range of 10-3 to 101 s-1 using thermo-mechanical simulator (Gleeble 3800®). Flow behavior characteristics were studied from the data obtained during hot compression and processing map was developed at true strain of 0.6 using Dynamic Materials Modeling (DMM) approach. Microstructural examination of deformed TiHy 600 titanium alloy were carried out at a particular strain rate of 10-3 s-1 and temperatures of 900oC, 950oC, 975oC, 1000oC and 1050oC. Microstructural examination consists of orientation image mapping along compression direction using electron backscatter diffraction. Hot compression mostly resulted into new dynamic recrystallized (DRX) alpha grains at 900oC, mixture of deformed large alpha grains containing subgrain boundaries and transformed beta phase consisting of secondary alpha laths at 950oC and 975oC and alpha laths transformed from deformed beta grains at 1000oC and 1050oC

Relative performance comparison between baseline labyrinth and dual-brush compressor discharge seals in a T-700 engine test

In separate series of T-700 engine tests, direct comparisons were made between the forward-facing labyrinth and dual-brush compressor discharge seals. Compressor speeds to 43,000 rpm, surface speeds to 160 m/s (530 ft/s), pressures to 1 MPa (145 psi), and temperatures to 680 K (765 F) characterized these tests. The wear estimate for 40 hr of engine operations was less than 0.025 mm (0.001 in.) of the Haynes 25 alloy bristles running against a chromium-oxide-coated rub runner. The pressure drops were higher for the dual-brush than for the forward-facing labyrinth seal, implying better seal characteristics and engine performance for the brush seal. Modification of the secondary flow path requires that changes in cooling air and engine dynamics be accounted for

Relative performance comparison between baseline labyrinth and dual-brush compressor discharge seals in a T-700 engine test

In separate series of YT-700 engine tests, direct comparisons were made between the forward-facing labyrinth and dual brush compressor discharge seals. Compressor speeds to 43 000 rpm, surface speeds to 160 m/s (530 ft/s), pressures to 1 MPa (145 psi), and temperatures to 680 K (765 F) characterized these tests. The wear estimate for 46 hr of engine operations was less than 0.025 mm (0.001 in.) of the Haynes 25 alloy bristles running against a chromium-carbide-coated rub runner. The pressure drops were higher for the dual-brush seal than for the forward-facing labyrinth seal and leakage was lower-with the labyrinth seal leakage being 2-1/2 times greater-implying better seal characteristics, better secondary airflow distribution, and better engine performance (3 percent at high pressure to 5 percent at lower pressure) for the brush seal. (However, as brush seals wear down (after 500 to 1000 hr of engine operation), their leakage rates will increase.) Modification of the secondary flow path requires that changes in cooling air and engine dynamics be accounted for

RNA polymerase II clusters form in line with surface condensation on regulatory chromatin

It is essential for cells to control which genes are transcribed into RNA. In eukaryotes, two major control points are recruitment of RNA polymerase II (Pol II) into a paused state, and subsequent pause release toward transcription. Pol II recruitment and pause release occur in association with macromolecular clusters, which were proposed to be formed by a liquid–liquid phase separation mechanism. How such a phase separation mechanism relates to the interaction of Pol II with DNA during recruitment and transcription, however, remains poorly understood. Here, we use live and super-resolution microscopy in zebrafish embryos to reveal Pol II clusters with a large variety of shapes, which can be explained by a theoretical model in which regulatory chromatin regions provide surfaces for liquid-phase condensation at concentrations that are too low for canonical liquid–liquid phase separation. Model simulations and chemical perturbation experiments indicate that recruited Pol II contributes to the formation of these surface-associated condensates, whereas elongating Pol II is excluded from these condensates and thereby drives their unfolding

Group B Streptococcus GAPDH Is Released upon Cell Lysis, Associates with Bacterial Surface, and Induces Apoptosis in Murine Macrophages

Glyceraldehyde 3-phosphate dehydrogenases (GAPDH) are cytoplasmic glycolytic enzymes that, despite lacking identifiable secretion signals, have been detected at the surface of several prokaryotic and eukaryotic organisms where they exhibit non-glycolytic functions including adhesion to host components. Group B Streptococcus (GBS) is a human commensal bacterium that has the capacity to cause life-threatening meningitis and septicemia in newborns. Electron microscopy and fluorescence-activated cell sorter (FACS) analysis demonstrated the surface localization of GAPDH in GBS. By addressing the question of GAPDH export to the cell surface of GBS strain NEM316 and isogenic mutant derivatives of our collection, we found that impaired GAPDH presence in the surface and supernatant of GBS was associated with a lower level of bacterial lysis. We also found that following GBS lysis, GAPDH can associate to the surface of many living bacteria. Finally, we provide evidence for a novel function of the secreted GAPDH as an inducer of apoptosis of murine macrophages

Targeting tumour re-wiring by triple blockade of mTORC1, epidermal growth factor, and oestrogen receptor signalling pathways in endocrine-resistant breast cancer

Background Endocrine therapies are the mainstay of treatment for oestrogen receptor (ER)-positive (ER+) breast cancer (BC). However, resistance remains problematic largely due to enhanced cross-talk between ER and growth factor pathways, circumventing the need for steroid hormones. Previously, we reported the anti-proliferative effect of everolimus (RAD001-mTORC1 inhibitor) with endocrine therapy in resistance models; however, potential routes of escape from treatment via ERBB2/3 signalling were observed. We hypothesised that combined targeting of three cellular nodes (ER, ERBB, and mTORC1) may provide enhanced long-term clinical utility. Methods A panel of ER+ BC cell lines adapted to long-term oestrogen deprivation (LTED) and expressing ESR1wt or ESR1Y537S, modelling acquired resistance to an aromatase-inhibitor (AI), were treated in vitro with a combination of RAD001 and neratinib (pan-ERBB inhibitor) in the presence or absence of oestradiol (E2), tamoxifen (4-OHT), or fulvestrant (ICI182780). End points included proliferation, cell signalling, cell cycle, and effect on ER-mediated transactivation. An in-vivo model of AI resistance was treated with monotherapies and combinations to assess the efficacy in delaying tumour progression. RNA-seq analysis was performed to identify changes in global gene expression as a result of the indicated therapies. Results Here, we show RAD001 and neratinib (pan-ERBB inhibitor) caused a concentration-dependent decrease in proliferation, irrespective of the ESR1 mutation status. The combination of either agent with endocrine therapy further reduced proliferation but the maximum effect was observed with a triple combination of RAD001, neratinib, and endocrine therapy. In the absence of oestrogen, RAD001 caused a reduction in ER-mediated transcription in the majority of the cell lines, which associated with a decrease in recruitment of ER to an oestrogen-response element on the TFF1 promoter. Contrastingly, neratinib increased both ER-mediated transactivation and ER recruitment, an effect reduced by the addition of RAD001. In-vivo analysis of an LTED model showed the triple combination of RAD001, neratinib, and fulvestrant was most effective at reducing tumour volume. Gene set enrichment analysis revealed that the addition of neratinib negated the epidermal growth factor (EGF)/EGF receptor feedback loops associated with RAD001. Conclusions Our data support the combination of therapies targeting ERBB2/3 and mTORC1 signalling, together with fulvestrant, in patients who relapse on endocrine therapy and retain a functional ER