SAR about the piperidine core in a series of MC4R agonists is described. A number of alkyl substituents that furnish compounds with good affinity and functional potency are reported.
SAR about the ...piperidine core in a series of MC4R agonists is described. A number of alkyl substituents that furnish compounds with good affinity and functional potency are reported.
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Herein we report identification of an imidazopyridine class of potent and selective TYK2 inhibitors, exemplified by prototype 6, through constraint of the rotatable amide bond ...connecting the pyridine and aryl rings of compound 1. Further optimization led to generation of compound 30 that potently inhibits the TYK2 enzyme and the IL-23 pathway in cells, exhibits selectivity against cellular JAK2 activity, and has good pharmacokinetic properties. In mice, compound 30 demonstrated dose-dependent reduction of IL-17 production in a PK/PD model as well as in an imiquimod-induced psoriasis model. In this efficacy model, the IL-17 decrease was accompanied by a reduction of ear thickness indicating the potential of TYK2 inhibition as a therapeutic approach for psoriasis patients.
Human cytosolic NADP-1DH （IDH1） has recently been found to be involved in tumorigenesis. Notably, the tumorderived IDH1 mutations identified so far mainly occur at Arg132, and mutation R132H is the ...most prevalent one. This mutation impairs the oxidative IDH activity of the enzyme, but renders a new reduction function of converting a-ketoglutarate （aKG） to 2-hydroxyglutarate. Here, we report the structures of the R132H mutant IDH1 with and without isocitrate OCT） bound. The structural data together with mutagenesis and biochemical data reveal a previ- ously undefined initial ICT-binding state and demonstrate that IDH activity requires a conformational change to a closed pre-transition state. Arg132 plays multiple functional roles in the catalytic reaction; in particular, the R132H mutation hinders the conformational changes from the initial ICT-binding state to the pre-transition state, leading to the impairment of the IDH activity. Our results describe for the first time that there is an intermediate conformation that corresponds to an initial ICT-binding state and that the R132H mutation can trap the enzyme in this conforma- tion, therefore shedding fight on the molecular mechanism of the ＂off switch＂ of the potentially tumor-suppressive IDH activity. Furthermore, we proved the necessity of Tyr139 for the gained aKG reduction activity and propose that Tyr139 may play a vital role by compensating the increased negative charge on the C2 atom of aKG during the trans- fer of a hydride anion from NADPH to aKG, which provides new insights into the mechanism of the ＂on switch＂ of the hypothetically oncogenic reduction activity of IDH1 by this mutation.
We observed unexpected thiazole 1B formation when 2,6‐dichlorobenzothioamide 1 and ethyl bromopyruvate were reacted under basic conditions at elevated temperatures in ethanol. Thiazole 1B, ...regio‐isomeric to that expected under conventional Hantzsch conditions, was extensively characterized and later confirmed by single crystal X‐ray structure. We carried out this transformation with several substituted benzothioamides and found that the formation of the unexpected thiazole regio‐isomer was highly dependent on the steric as well as the electronic characteristics of the ortho‐substituents on the phenyl ring. A mechanism to account for this novel transformation was proposed.
Despite high‐energy density and low cost of the lithium–sulfur (Li–S) batteries, their commercial success is greatly impeded by their severe capacity decay during long‐term cycling caused by ...polysulfide shuttling. Herein, a new phase engineering strategy is demonstrated for making MXene/1T‐2H MoS2‐C nanohybrids for boosting the performance of Li–S batteries in terms of capacity, rate ability, and stability. It is found that the plentiful positively charged S‐vacancy defects created on MXene/1T‐2H MoS2‐C, proved by high‐resolution transmission electron microscopy and electron paramagnetic resonance, can serve as strong adsorption and activation sites for polar polysulfide intermediates, accelerate redox reactions, and prevent the dissolution of polysulfides. As a consequence, the novel MXene/1T‐2H MoS2‐C‐S cathode delivers a high initial capacity of 1194.7 mAh g−1 at 0.1 C, a high level of capacity retention of 799.3 mAh g−1 after 300 cycles at 0.5 C, and reliable operation in soft‐package batteries. The present MXene/1T‐2H MoS2‐C becomes among the best cathode materials for Li–S batteries.
Phase engineered MXene/1T‐2H MoS2‐C with plentiful S‐vacancy defects is highly effective for trapping polysulfide intermediates and accelerating redox kinetics, leading to the enhanced lithium–sulfur batteries.
Zeolitic imidazolate framework ZIF-8 has shown great potential for effective separation of hydrocarbon mixtures based on its intrinsic ultramicroporous feature. In order to explore the permeation and ...diffusion properties of hydrocarbons through ZIF-8 membrane, high-quality ZIF-8 membranes with a separation factor of ~90 for propylene/propane are successfully prepared via optimizing the activation processes. Single-component permeation data for hydrocarbons (C1–C4) through the improved ZIF-8 membrane are measured and analyzed by Maxwell–Stefan (MS) model to get the transport diffusivities of these hydrocarbons. The diffusivity values of hydrocarbon compare well with those obtained by other experimental techniques. Binary mixture permeation also can be well predicted through single-component adsorption parameters.
•The quality of ZIF-8 membranes was improved by optimizing the activation process.•The separation factor for propylene/propane mixtures was improved to ~90.•Permeation of hydrocarbons can be well described by Maxwell-Stefan model.•The transport diffusivities of hydrocarbons were obtained.
Background
Head and neck squamous cell carcinoma (HNSCC), the most common head and neck cancer, is highly aggressive and heterogeneous, resulting in variable prognoses and immunotherapeutic outcomes. ...Natural killer (NK) cells play essential roles in malignancies’ development, diagnosis, and prognosis. The purpose of this study was to establish a reliable signature based on genes related to NK cells (NRGs), thus providing a new perspective for assessing immunotherapy response and prognosis of HNSCC patients.
Methods
In this study, NRGs were used to classify HNSCC from the TCGA-HNSCC and GEO cohorts. The genes were evaluated using univariate cox regression analysis based on the differential analysis of normal and tumor samples in TCGA-HNSCC conducted using the “limma” R package. Thereafter, we built prognostic gene signatures using LASSO-COX analysis. External validation was carried out in the GSE41613 cohort. Immunity analysis based on NRGs was performed
via
several methods, such as CIBERSORT, and immunotherapy response was evaluated by TIP portal website.
Results
With the TCGA-HNSCC data, we established a nomogram based on the 17-NRGs signature and a variety of clinicopathological characteristics. The low-risk group exhibited a better effect when it came to immunotherapy.
Conclusions
17-NRGs signature and nomograms demonstrate excellent predictive performance and offer new perspectives for assessing pre-immune efficacy, which will facilitate future precision immuno-oncology research.
In the current chip quality detection industry, detecting missing pins in chips is a critical task, but current methods often rely on inefficient manual screening or machine vision algorithms ...deployed in power-hungry computers that can only identify one chip at a time. To address this issue, we propose a fast and low-power multi-object detection system based on the YOLOv4-tiny algorithm and a small-size AXU2CGB platform that utilizes a low-power FPGA for hardware acceleration. By adopting loop tiling to cache feature map blocks, designing an FPGA accelerator structure with two-layer ping-pong optimization as well as multiplex parallel convolution kernels, enhancing the dataset, and optimizing network parameters, we achieve a 0.468 s per-image detection speed, 3.52 W power consumption, 89.33% mean average precision (mAP), and 100% missing pin recognition rate regardless of the number of missing pins. Our system reduces detection time by 73.27% and power consumption by 23.08% compared to a CPU, while delivering a more balanced boost in performance compared to other solutions.
Using a sample of 11,357 firm-year observations from the Chinese stock market for the period of 2001–2011, we investigate whether and how religion can mitigate earnings management. Specifically, ...based on geographic-proximity-based religion variables, we provide strong and robust evidence to show that religion is significantly negatively associated with the extent of earnings management, suggesting that religion can serve as a set of social norms to mitigate corporate unethical behavior such as earnings management. Our findings also reveal that the negative association between religion and earnings management is less pronounced for firms with closer distance to the regulatory centers than for their counterparts, implying the substitutive effects between religion and the distance to regulators (the proxy for regulatory intensity) on mitigating earnings management. The above results are robust to different measures of earnings management, various religion variables, and a variety of sensitivity tests.
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