As an important antiviral target, HIV-1 integrase plays a key role in the viral life cycle, and five integrase strand transfer inhibitors (INSTIs) have been approved for the treatment of HIV-1 ...infections so far. However, similar to other clinically used antiviral drugs, resistance-causing mutations have appeared, which have impaired the efficacy of INSTIs. In the current study, to identify novel integrase inhibitors, a set of molecular docking-based virtual screenings were performed, and indole-2-carboxylic acid was developed as a potent INSTI scaffold. Indole-2-carboxylic acid derivative
was proved to effectively inhibit the strand transfer of HIV-1 integrase, and binding conformation analysis showed that the indole core and C2 carboxyl group obviously chelated the two Mg
ions within the active site of integrase. Further structural optimizations on compound
provided the derivative
, which markedly increased the integrase inhibitory effect, with an IC
value of 0.13 μM. Binding mode analysis revealed that the introduction of a long branch on C3 of the indole core improved the interaction with the hydrophobic cavity near the active site of integrase, indicating that indole-2-carboxylic acid is a promising scaffold for the development of integrase inhibitors.
IL-17-producing CD4⁺ T helper (Th17) cells have recently been defined as a unique subset of proinflammatory helper cells whose development depends on signaling initiated by IL-6 and TGF-β, autocrine ...activity of IL-21, activation of STAT3, and induction of the orphan nuclear receptor RORγt. The maintenance, expansion, and further differentiation of the committed Th17 cells depend on IL-1β and IL-23. IL-17 was originally found produced by circulating human CD45RO⁺ memory T cells. A recent study found that human Th17 memory cells selectively express high levels of CCR6. In this study, we report that human peripheral blood and lymphoid tissue contain a significant number of CD4⁺FOXP3⁺ T cells that express CCR6 and have the capacity to produce IL-17 upon activation. These cells coexpress FOXP3 and RORγt transcription factors. The CD4⁺FOXP3⁺CCR6⁺ IL-17-producing cells strongly inhibit the proliferation of CD4⁺ responder T cells. CD4⁺CD25high-derived T-cell clones express FOXP3, RORγt, and IL-17 and maintain their suppressive function via a cell-cell contact mechanism. We further show that human CD4⁺FOXP3⁺CCR6⁻ regulatory T (Treg) cells differentiate into IL-17 producer cells upon T-cell receptor stimulation in the presence of IL-1β, IL-2, IL-21, IL-23, and human serum. This, together with the finding that human thymus does not contain IL-17-producing Treg cells, suggests that the IL-17⁺FOXP3⁺ Treg cells are generated in the periphery. IL-17-producing Treg cells may play critical roles in antimicrobial defense, while controlling autoimmunity and inflammation.
Herein, we present a stable water‐soluble cobalt complex supported by a dianionic 2,2′‐(2,2′‐bipyridine‐6,6′‐diyl)bis(propan‐2‐ol) ligand scaffold, which is a rare example of a high‐oxidation ...species, as demonstrated by structural, spectroscopic and theoretical data. Electron paramagnetic resonance (EPR) spectroscopy and magnetic susceptibility measurements revealed that the CoIV center of the mononuclear complex in the solid state resides in the high spin state (sextet, S=5/2). The complex can effectively catalyze water oxidation via a single‐site water nucleophilic attack pathway with an overpotential of only 360 mV in a phosphate buffer with a pH of 6. The key intermediate toward water oxidation was speculated based on theoretical calculations and was identified by in situ spectroelectrochemical experiments. The results are important regarding the accessibility of high‐oxidation state metal species in synthetic models for achieving robust and reactive oxidation catalysis.
A stable water‐soluble cobalt(IV) complex supported by a dianionic 2,2′‐(2,2′‐bipyridine‐6,6′‐diyl)bis(propan‐2‐ol) ligand scaffold is very active in the catalysis of water oxidation at an overpotential of only 360 mV at pH=6.
The impact of the dietary potential inflammatory effect on diabetic kidney disease (DKD) has not been adequately investigated. The present study aimed to explore the association between dietary ...inflammatory index (DII) and DKD in US adults.
This is a cross-sectional study.
Data from the National Health and Nutrition Examination Survey (2007-2016) were used. DII was calculated from 24-h dietary recall interviews. DKD was defined as diabetes with albuminuria, impaired glomerular filtration rate or both. Logistic regression and restricted cubic spline models were adopted to evaluate the associations.
Data from the National Health and Nutrition Examination Survey (2007-2016) were used, which can provide the information of participants.
Four thousand two-hundred and sixty-four participants were included in this study. The adjusted OR of DKD was 1·04 (95 % CI 0·81, 1·36) for quartile 2, 1·24 (95 % CI 0·97, 1·59) for quartile 3 and 1·64 (95 % CI 1·24, 2·17) for quartile 4, respectively, compared with the quartile 1 of DII. A linear dose-response pattern was observed between DII and DKD (
= 0·73). In the stratified analyses, the OR for quartile 4 of DII were significant among adults with higher educational level (OR 1·83, 95 % CI 1·26, 2·66) and overweight or obese participants (OR 1·67, 95 % CI 1·23, 2·28), but not among the corresponding another subgroup. The interaction effects between DII and stratified factors on DKD were not statistically significant (all
values for interactions were >0·05).
Our findings suggest that a pro-inflammatory diet, shown by a higher DII score, is associated with increased odd of DKD.
A strategy for the direct functionalization strategy of inertial dialkyl phosphonates with hydroxy compounds to afford diverse mixed phosphonates with good yields and functional‐group tolerance has ...been developed. Mechanistic investigations involving both NMR studies and DFT studies suggest that an unprecedented highly reactive PV species (phosphoryl pyridin‐1‐ium salt), a key intermediate for this new synthetic transformation, is generated in situ from dialkyl phosphonate in the presence of Tf2O/pyridine.
Mild thing, you make my heart sing: The application of Tf2O to phosphorus chemistry was expanded to the generation of electrophilic P‐species. A metal‐free activation of stable dialkyl phosphonates was developed that enables the synthesis of diverse mixed phosphonates. The reaction proceeds under mild conditions and exhibits a broad substrate scope and excellent functional‐group tolerance. NMR studies and DFT calculations provide insight into the mechanism.
Exploiting noble-metal-free hydrogen evolution catalysts and light-harvesting molecular photosensitizers is of huge interest for photocatalytic H2 generation. Here we report a hybrid system ...consisting of MoS2/reduced graphene oxide (MoS2/RGO) catalyst, Zn(II)-5,10,15,20-tetrakis(4-N-methylpyridyl)porphyrin (ZnTMPyP4+) photosensitizer, and triethanolamine (TEOA) as a sacrificial electron donor for photocatalytic H2 production under visible-light irradiation. Through optimizing the component proportion of MoS2/RGO catalyst, the ZnTMPyP4+–MoS2/RGO–TEOA photocatalytic system showed the highest H2 evolution rate of 2560 μmol h–1 g–1 at pH 7 when the ratio of MoS2 to graphene is 5:1. An apparent quantum yield of 15.2% at 420 nm was observed under optimized reaction conditions. The excellent photocatalytic result can be attributed to the improved charge carrier transfer by graphene which acts as an electron transfer bridge, as demonstrated by photoluminescence quenching and photoluminescence decay studies. It is believed that these findings would open a promising strategy to develop a noble-metal-free and visible-light-responding solar-to-H2 conversion system.
Circulating tumor cells (CTCs) enter peripheral blood from primary tumors and seed metastases. The genome sequencing of CTCs could offer noninvasive prognosis or even diagnosis, but has been hampered ...by low single-cell genome coverage of scarce CTCs. Here, we report the use of the recently developed multiple annealing and looping-based amplification cycles for whole-genome amplification of single CTCs from lung cancer patients. We observed characteristic cancer-associated single-nucleotide variations and insertions/deletions in exomes of CTCs. These mutations provided information needed for individualized therapy, such as drug resistance and phenotypic transition, but were heterogeneous from cell to cell. In contrast, every CTC from an individual patient, regardless of the cancer subtypes, exhibited reproducible copy number variation (CNV) patterns, similar to those of the metastatic tumor of the same patient. Interestingly, different patients with the same lung cancer adenocarcinoma (ADC) shared similar CNV patterns in their CTCs. Even more interestingly, patients of small-cell lung cancer have CNV patterns distinctly different from those of ADC patients. Our finding suggests that CNVs at certain genomic loci are selected for the metastasis of cancer. The reproducibility of cancer-specific CNVs offers potential for CTC-based cancer diagnostics.
Bandgap-tunable black phosphorus quantum dots prepared by a liquid exfoliation method in a mixture solvent of N-methylpyrrolidone and oleic acid can act as efficient photocatalysts for the ...degradation of rhodamine B. This is the first report on solely black phosphorus capable of destroying organic pollutants under visible light irradiation.
Abstract
In subduction zones, materials on Earth’s surface can be transported to the deep crust or mantle, but the exact mechanisms and the nature of the recycled materials are not fully understood. ...Here, we report a set of migmatites from western Yangtze Block, China. These migmatites have similar bulk compositions as forearc sediments. Zircon age distributions and Hf–O isotopes indicate that the precursors of the sediments were predominantly derived from juvenile arc crust itself. Using phase equilibria modeling, we show that the sediments experienced high temperature-to-pressure ratio metamorphism and were most likely transported to deep arc crust by intracrustal thrust faults. By dating the magmatic zircon cores and overgrowth rims, we find that the entire rock cycle, from arc magmatism, to weathering at the surface, then to burial and remelting in the deep crust, took place within ~10 Myr. Our findings highlight thrust faults as an efficient recycling channel in compressional arcs and endogenic recycling as an important mechanism driving internal redistribution and differentiation of arc crust.
The strategy of bandgap regulation is important for X-ray detection, but has not been reported for 1D Pb halide perovskite materials. In this work, three such materials,
1
,
2
and
3
, with a tunable ...bandgap, were fabricated for application in X-ray detection.
3
shows high sensitivity, far superior to commercial X-ray detectors.
A series of 1D Pb halide perovskite-like materials with a tunable bandgap were fabricated and exhibit excellent X-ray detection performance.
PDF
