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Plato Grishin
Plato Grishin

Ch 301-600.pdf - Google Drive

In addition to the classic organelles that are surrounded by lipid membranes, recent evidence indicates that non-membrane-bound organelles that are driven by phase separation are also essential for controlling various cellular processes1,2,3,4,5,6,7,8. These membraneless structures behave as liquid droplets in the cytoplasm or nucleoplasm. In these structures, either multiple modular interaction domains or intrinsically disordered regions (IDRs) of proteins can mediate the inter- or intra-molecular interactions underlying their liquid-like molecular condensations9,10. In addition to maintaining specific organelle structures, phase separation enables hub proteins to assemble signalosomes which promote the speed of signaling outputs11,12. Both Wnt signaling and T cell receptor (TCR) signaling, to give two examples, have been demonstrated to rely on essential adaptor protein-mediated phase separation13,14,15,16,17. However, the roles of phase separation in the regulation of many other signaling pathways await further exploration.

ch 301-600.pdf - Google Drive

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The assembly of phase separation-mediated signalosomes relies on the polymerization of hub proteins12. Purified IRS-1 forms liquid-like droplets (Fig. 2), indicating that the self-association-mediated polymerization of IRS-1 drives its phase separation. Since both electrostatic and hydrophobic interactions contribute to IRS-1 phase separation (Fig. 2d, e), we proposed that it was primarily the self-association of IRS-1 that may mediate its phase separation. We first tested this hypothesis by examining the effects of the PTP1B D181A mutant on the IRS-1 phase separation. PTP1B is a phosphorylase of IRS-1 and the PTP1B D181A mutant has been shown to sequester its substrates38,39. This is in agreement with our finding that, compared to the PTP1B wildtype, the D181A mutant displayed enhanced interaction with IRS-1 (Supplementary Fig. S3a), which subsequently impaired the self-association of IRS-1 (Supplementary Fig. S3b). Consistent to our hypothesis, the PTP1B D181A mutant suppressed the formation of IRS-1 puncta in cells (Supplementary Fig. S3c).

Aberrant phase separation results in multiple diseases36,45,61,62,63,64. This includes the disease mutations of FUS, hnRNPA2, Tau, C9orf72 Dipeptide Repeats, and TDP-43, which drive the liquid condensates into more solid-like states65,66,67,68,69,70. It has been well recognized that IRS-1 is crucial for insulin action while the G972 substitution of IRS-1 results in metabolic disorder47,48,51,52,53. Whilst the detailed mechanism remains elusive, both in vitro cell experiments and in vivo transgenic mouse studies have demonstrated the deleterious roles of G972R mutants in insulin action and glucose homeostasis71,72,73. Here, we found that the metabolic disease-associated G972R mutation undermined the ability of IRS-1 to undergo phase separation in vitro (Fig. 6a) and in cells (Fig. 6c; Supplementary Fig. S6b). In line with these findings, G972R polymorphism impairs the self-association of IRS-1 (Fig. 6d) that is essential for mediating phase separation (Fig. 5). We thus propose that the pathological effects of the G972R mutation might be due to the impairment of IRS-1-mediated insulin/IGF signalosomes. These results thus strongly implicate aberrant IRS-1 phase separation in metabolic diseases. Recent studies have revealed the involvement of phase separation in modulating pivotal cellular metabolic events including lipid droplet formation and autophagy74,75. All such findings may provide new opportunities for therapeutic interventions in cases of metabolic disease.

This study is the first attempt to examine the causal effect of increased competitive pressures through the introduction of public reporting on the quality of hospital care in Germany. The health policy reform to release quality performance data through PR portals in 2008 serves as an intervention for a DiD design. A homogenous effect over all hospitals of competition on quality is found. This effect is mainly driven by the response of highly specialized non-profit hospitals and medium specialized private for-profit hospitals.

To estimate the causal effect of hospital competition on quality of care in Germany, we employ a DiD design with the public release of quality performance data through public reporting portals in 2008 as the intervention. The market structure determines the treatment intensity, since the release of performance data is expected to have higher effects in more competitive markets. A homogenous effect over all hospitals of competition on quality can be found that is mainly driven by the response of highly specialized non-profit hospitals and medium specialized private for-profit hospitals.

Mar 29, 2023 (The Expresswire) has conducted research titled "Filter Pressure Reducing Valve Market" for the years 2023 to 2029, which presents a detailed analysis of market dynamics and trends that will shape the future of the industry. The report offers insights into the competitive landscape, market drivers, challenges, and opportunities, along with key growth factors that will drive market expansion in the forecast period. The report has segmented the global Filter Pressure Reducing Valve market based on Type (Below 300 Psi, 301-600 Psi, Above 600 Psi) and Application (Commercial, Residential), with the Filter Pressure Reducing Valve market expected to lead during the forecast period of 2023. 041b061a72


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