Notes

Your multifaceted characteristics of sirtuins in cancer malignancy.
TERN-101 is a nonsteroidal farnesoid X-receptor agonist being developed for the treatment of nonalcoholic steatohepatitis (NASH). We assessed the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of TERN-101 capsule and tablet formulations in healthy volunteers. In a randomized, double-blind, placebo-controlled study, 38 participants were enrolled and randomized to receive placebo or 25-, 75-, or 150-mg TERN-101 capsules orally once daily for 7 days. In a separate open-label PK and formulation-bridging study, 16 participants received single doses of TERN-101 tablets (5 and 25 mg) or capsules (25 mg). TERN-101 was overall well-tolerated in this healthy volunteer population; no pruritus was reported. TERN-101 capsule administration over 7 days resulted in decreases in serum 7α-hydroxy-4-cholesten-3-one that were sustained for 24 hours after the last dose (maximum suppression 91% from baseline), indicating target engagement in the liver. TERN-101 capsules exhibited less than dose-proportional PK. Relative to capsules, TERN-101 tablets showed increased bioavailability, with 24-hour plasma exposure of the 5-mg tablet similar to that of the 25-mg capsule. There was no significant effect of food on exposure. The overall safety, PK, and PD profiles of TERN-101 support its further evaluation for the treatment of NASH.
Hypoxia within the plateau has a negative effect on skeletal muscle and may play a role in the development of sarcopenia in humans. Tibetans having lived in the Qinghai-Tibet Plateau for thousands of years, are a high-risk group for sarcopenia; however, they have a distinctive suite of genetic traits that enable them to tolerate environmental hypoxia and are genetically significantly different from Han Chinese and other lowland populations. Sarcopenia has been consistently found to be associated with single-nucleotide polymorphisms, but few studies have investigated the role of single-nucleotide polymorphisms in a range of muscle phenotypes and sarcopenia in Tibetan peoples.

Our study aimed to investigate the skeletal muscle mass and fat mass of 160Tibetans (80men and 80 women) from Lhasa (altitude of 3600meters) and analyze the association between the polymorphisms of fat mass and obesity protein (FTO) rs9939609, FTO rs9936385, activin type IIB receptor (ACVR2B) rs2276541, insulin receptor substrate 1 (IRS1) 2943656 and sarcopenia.

FTO rs9939609 and rs9936385 polymorphisms were associated with lower limb skeletal muscle mass and sarcopenia for Tibetan women, and TT homozygotes had a higher risk for sarcopenia. But ACVR2B rs2276541 and IRS1 2943656 polymorphisms were unassociated with sarcopenia in Tibetan.

In Tibetans, FTO rs9939609 and rs9936385 polymorphisms were associated with sarcopenia, and ACVR2B rs2276541 and IRS1 2943656 polymorphisms were unassociated with sarcopenia.
In Tibetans, FTO rs9939609 and rs9936385 polymorphisms were associated with sarcopenia, and ACVR2B rs2276541 and IRS1 2943656 polymorphisms were unassociated with sarcopenia.
Graph theory (GT) is a mathematical field that analyses complex networks that can be applied to neuroimaging to quantify brain's functional systems in Parkinson's disease (PD) and essential tremor (ET).

To evaluate the functional connectivity (FC) measured by the global efficiency (GE) of the motor network in PD and compare it to ET and healthy controls (HC), and correlate it to clinical parameters.

103 subjects (54PD, 18ET, 31HC) were submitted to structural and functional MRI. A network was designed with regions of interest (ROIs) involved in motor function, and GT was applied to determine its GE. Clinical parameters were analyzed as covariates to estimate the impact of disease severity and medication on GE.

GE of the motor circuit was reduced in PD in comparison with HC (p .042). Areas that most contributed to it were left supplementary motor area (SMA) and bilateral postcentral gyrus. AZD5582 Tremor scores correlated positively with GE of the motor network in PD subgroups. For ET, there was an increase inassociated with movement modulation. The ET group presented an increased connectivity of the anterior cerebellar network to the other ROIs of the motor circuit when compared to PD, which reinforces what it is known about its role in this pathology.The electronic structure of active sites is critically important for electrochemical reactions. Here, the authors report a facile approach to independently regulate the electronic structure of Fe in Ni0.75 Fe0.25 Se2 by P doping. The resulting electrode exhibits superior catalytic performance for the oxygen evolution reaction (OER) showing a low overpotential (238 mV at 100 mA cm-2 , 185 mV at 10 mA cm-2 ) and an impressive durability in an alkaline medium. Additionally, the mass activity of 328.19 A g-1 and turnover frequency (TOF) of 0.18 s-1 at an overpotential of 500 mV are obtained for P─Ni0.75 Fe0.25 Se2 which is much higher than that of Ni0.75 Fe0.25 Se2 and RuO2 . This work presents a new strategy for the rational design of efficient electrocatalysts for OER.The pharmaceutical industry faces a growing demand and recurrent shortages in many anticancer plant drugs given their extensive use in human chemotherapy. Efficient alternative strategies of supply of these natural products such as bioproduction by microorganisms are needed to ensure stable and massive manufacturing. Here, we developed and optimized yeast cell factories efficiently converting tabersonine to vindoline, a precursor of the major anticancer alkaloids vinblastine and vincristine. First, fine-tuning of heterologous gene copies restrained side metabolites synthesis towards vindoline production. Tabersonine to vindoline bioconversion was further enhanced through a rational medium optimization (pH, composition) and a sequential feeding strategy. Finally, a vindoline titre of 266 mg l-1 (88% yield) was reached in an optimized fed-batch bioreactor. This precursor-directed synthesis of vindoline thus paves the way towards future industrial bioproduction through the valorization of abundant tabersonine resources.Ordered bio-inorganic hybridization has evolved for the generation of high-performance materials in living organisms and inspires novel strategies to design artificial hybrid materials. Virus-like particles (VLPs) are attracting extensive interest as self-assembling systems and platforms in the fields of biotechnology and nanotechnology. However, as soft nanomaterials, their structural stability remains a general and fundamental problem in various applications. Here, an ultrastable VLP assembled from the major capsid protein (VP1) of simian virus 40 is reported, which contains a carbon dot (C-dot) core. Co-assembly of VP1 with C-dots led to homogeneous T = 1 VLPs with a fourfold increase in VLP yields. The resultant hybrid VLPs showed markedly enhanced structural stability and sequence plasticity. C-dots and a polyhistidine tag fused to the inner-protruding N-terminus of VP1 contributed synergistically to these enhancements, where extensive and strong noncovalent interactions on the C-dot/VP1 interfaces are responsible according to cryo-EM 3D reconstruction, molecular simulation, and affinity measurements.
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