The genus Coronavirus contains about 25 species of coronaviruses (CoVs), which are important pathogens causing highly prevalent diseases and often severe or fatal in humans and animals. No licensed ...specific drugs are available to prevent their infection. Different host receptors for cellular entry, poorly conserved structural proteins (antigens), and the high mutation and recombination rates of CoVs pose a significant problem in the development of wide-spectrum anti-CoV drugs and vaccines. CoV main proteases (M(pro)s), which are key enzymes in viral gene expression and replication, were revealed to share a highly conservative substrate-recognition pocket by comparison of four crystal structures and a homology model representing all three genetic clusters of the genus Coronavirus. This conclusion was further supported by enzyme activity assays. Mechanism-based irreversible inhibitors were designed, based on this conserved structural region, and a uniform inhibition mechanism was elucidated from the structures of Mpro-inhibitor complexes from severe acute respiratory syndrome-CoV and porcine transmissible gastroenteritis virus. A structure-assisted optimization program has yielded compounds with fast in vitro inactivation of multiple CoV M(pro)s, potent antiviral activity, and extremely low cellular toxicity in cell-based assays. Further modification could rapidly lead to the discovery of a single agent with clinical potential against existing and possible future emerging CoV-related diseases.
The recruitment of leukocytes to the vascular wall is a key step in hypertension development. Chemokine receptor CXCR2 mediates inflammatory cell chemotaxis in several diseases. However, the role of ...CXCR2 in hypertension development and the underlying mechanisms remain unknown.
Angiotensin II (490 ng·kg
·min
) or deoxycorticosterone acetate (DOCA) salt-induced mouse hypertensive models in genetic ablation, pharmacologic inhibition of CXCR2, and adoptive bone marrow transfer mice were used to determine the role of CXCR2 in hypertension (measured by radiotelemetry and tail-cuff system), inflammation (verified by flow cytometry and quantitative real-time polymerase chain reaction PCR analysis), vascular remodeling (studied by haematoxylin and eosin and Masson's trichrome staining), vascular dysfunction (assessed by aortic ring), and oxidative stress (indicated by nicotinamide adenine dinucleotide phosphate NADPH oxidase activity, dihydroethidium staining, and quantitative real-time PCR analysis). Moreover, the blood CXCR2
cells in normotensive controls and hypertension patients were analyzed by flow cytometry.
Angiotensin II significantly upregulated the expression of CXCR2 mRNA and protein and increased the number of CD45
CXCR2
cells in mouse aorta (n=8 per group). Selective CXCR2 knockout (CXCR2
) or pharmacological inhibition of CXCR2 markedly reduced angiotensin II- or DOCA-salt-induced blood pressure elevation, aortic thickness and collagen deposition, accumulation of proinflammatory cells into the vascular wall, and expression of cytokines (n=8 per group). CXCR2 inhibition also ameliorated angiotensin II-induced vascular dysfunction and reduced vascular superoxide formation, NADPH activity, and expression of NADPH oxidase subunits (n=6 per group). Bone marrow reconstitution of wild-type mice with CXCR2
bone marrow cells also significantly abolished angiotensin II-induced responses (n=6 per group). It is important to note that CXCR2 blockade reversed established hypertension induced by angiotensin II or DOCA-salt challenge (n=10 per group). Furthermore, we demonstrated that CXCR2
proinflammatory cells were higher in hypertensive patients (n=30) compared with normotensive individuals (n=20).
Infiltration of CXCR2
cells plays a pathogenic role in arterial hypertension and vascular dysfunction. Inhibition of CXCR2 pathway may represent a novel therapeutic approach to treat hypertension.
Both lipid-modifying therapy and antioxidant vitamins are thought to have benefit in patients with coronary disease. We studied simvastatin-niacin and antioxidant-vitamin therapy, alone and together, ...for cardiovascular protection in patients with coronary disease and low plasma levels of HDL.
In a three-year, double-blind trial, 160 patients with coronary disease, low HDL cholesterol levels and normal LDL cholesterol levels were randomly assigned to receive one of four regimens: simvastatin plus niacin, vitamins, simvastatin-niacin plus antioxidants; or placebos. The end points were arteriographic evidence of a change in coronary stenosis and the occurrence of a first cardiovascular event (death, myocardial infarction, stroke, or revascularization).
The mean levels of LDL and HDL cholesterol were unaltered in the antioxidant group and the placebo group; these levels changed substantially (by -42 percent and +26 percent, respectively) in the simvastatin-niacin group. The protective increase in HDL2 with simvastatin plus niacin was attenuated by concurrent therapy with antioxidants. The average stenosis progressed by 3.9 percent with placebos, 1.8 percent with antioxidants (P=0.16 for the comparison with the placebo group), and 0.7 percent with simvastatin-niacin plus antioxidants (P=0.004) and regressed by 0.4 percent with simvastatin-niacin alone (P<0.001). The frequency of the clinical end point was 24 percent with placebos; 3 percent with simvastatin-niacin alone; 21 percent in the antioxidant-therapy group; and 14 percent in the simvastatin-niacin-plus-antioxidants group.
Simvastatin plus niacin provides marked clinical and angiographically measurable benefits in patients with coronary disease and low HDL levels. The use of antioxidant vitamins in this setting must be questioned.
The Kuroshio current transports large amounts of heat and water vapor into the South China Sea (SCS) through the Luzon Strait and plays a key role in modulating the surrounding hydroclimate. However, ...there is no detailed high-resolution history of the Kuroshio intrusion into the SCS preceding the Holocene. Here, clay mineral assemblages and Sr–Nd isotopic values (87Sr/86Sr and εNd) of core CS11 represent the relative abundance of Taiwan and Luzon fluvial sediment contributions in the SCS deep basin, which can be further used as proxies of relative variation of the Kuroshio intrusion into the SCS over the past 40 kyr. Combined with linear sedimentation rate (LSR) and results of previous studies, we demonstrate that variations of Kuroshio currents between the SCS and the open Pacific display opposing trends within each marine isotope stage, similar to the waxing and waning of its modern configuration. The El Niño–Southern Oscillation (ENSO) has acted as the key factor driving variations of the Kuroshio currents over the past 40 kyr. During late marine isotope stage (MIS) 3, the Kuroshio intrusion into the SCS gradually decreased due to decline in intensity of El Niño-like conditions, while an El Niño-like state favored the Kuroshio intrusion into the SCS during MIS 2, in particular during the Last Glacial Maximum (LGM) when Kuroshio transport in the open Pacific weakened. The Kuroshio intrusion into the SCS was largely sluggish in the early Holocene, when a La Niña-like condition prevailed, and then the Kuroshio intrusion was enhanced during the middle to late Holocene under the influence of increased El Niño frequency.
•Kuroshio Intrusion is the key factor controlling sediments reaching deep basin of the NE SCS over the past 40 kyr.•ENSO drove distinct patterns of Kuroshio in the SCS and in open Pacific during each MIS, similar to the modern configuration.•El Niño-like conditions favored increasing Kuroshio intrusion into the SCS but decreasing the transport in the open Pacific.
Currently, the use of targeted drugs such as tyrosine kinase inhibitors (TKIs) plays an important role in clinical therapy. As the number of approved TKIs continues to increase, existing analysis ...methods will not be able to meet the growing needs, and will hamper the development of therapeutic drug monitoring (TDM) of TKIs. Based on LC-MS/MS technology, this study tends to develop and validate a multi-component analysis method for simultaneous determination of the concentrations of 39 TKIs in plasma. Spiked plasma was blended with isotope labelled internal standards, and injected into the LC-MS/MS system after protein precipitation by acetonitrile. Chromatographic separation was achieved using an ODS-4 column with gradient elution of formic acid/water (1:1000; v/v) and acetonitrile. Analytes detection was conducted in positive ionisation mode using MRM. The total run time was 8 min. The method validation was conducted by assessing the following parameters: selectivity, linearity and the lower limit of qualification, accuracy and precision, stability, matrix effect and recovery. The concentrations of 39 TKIs showed good linearity within the range of their respective standard curves in plasma, the accuracy of all quality control samples ranged from 85.9% to 114.1%, and the precision was lower than 13.3%. The extraction recovery ranged from 92.6% to 114.7%, and the matrix effect of plasma was lower than 11.3%. This new method was successfully developed, can be used for the determination of drug concentrations in multiple patients with different kinds of TKIs, and will therefore be suitable for TDM of 39 TKIs.
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•The first analysis method to quantify 39 tyrosine kinase inhibitors simultaneously.•No increase in complexity of the entire process and no prolongation in analysis time.•A promising development that will enhance the development of TDM of TKIs.
•Gender difference in toxic metals and essential metals partly explain the difference in longevity.•Toxic metals such as lead and cadmium were significantly higher in centenarians.•Essential metals ...were sufficient in centenarians and likely to be used as an index of malnutrition.•Providing reference values of metals for octogenarians, nonagenarians, centenarians.•The top four important metals in longevity were selenium, arsenic, lead and manganese.
Metals can be either toxic or essential to health, as they play different role in oxidative stress and metabolic homeostasis during the ageing process. Population-based biomonitoring have documented levels and ranges in concentrations among general population of 0–79 years of age. In people aged 80 and above, toxic metals and essential metals may have different risk profiles, and thus need to be better studied.
Our aim is to investigate concentrations of toxic metals (arsenic, cadmium, lead and mercury) and essential metals (chromium, cobalt, molybdenum, manganese, nickel and selenium) and their role in diseases, nutritional status among younger elderly, octogenarians, nonagenarians and centenarians.
A total of 932 younger elderly, 643 octogenarians, 540 nonagenarians, 386 centenarians were included from the cross-sectional Healthy Aging and Biomarkers Cohort Study in 2017–2018. Blood or urine biological substrates were collected from each participant to determine the concentrations of toxic metals and essential metals by inductively coupled plasma mass spectrometry. Random forest was constructed to rank the importance of toxic metals and essential metals in longevity. LASSO penalized regressions were performed to select the most significant metals associated with diseases and nutritional status, of which simultaneously included all metals and adjusted for the confounding factors.
Compared to women, we found higher biomarker concentrations in men for toxic metals (41.2 µg/L vs 34.4 µg/L for blood lead, 1.56 µg/L vs 1.19 µg/L for blood mercury) and lower concentration of essential metals (0.48 µg/L vs 0.58 µg/L for blood molybdenum, 10.0 µg/L vs 11.1 µg/L for blood manganese). These factors may contribute to gender difference observed in longevity, that women live longer than men. Blood lead and urine cadmium tended to increase with age (P <0.001); blood cobalt, molybdenum, manganese increased with age, blood selenium decreased with age while the prevalence of selenium deficiency was extremely low in centenarians. Among toxic metals and essential metals, LASSO penalized regression identified the most significant metals associated with chronic kidney disease was cadmium and arsenic; and it was manganese, cobalt, and selenium for diabetes; it was selenium, molybdenum, lead for anemia; it was mercury for underweight. In random forest model, the top four important metals in longevity were selenium, arsenic, lead and manganese both in men and women.
Generally, toxic metals levels were significantly higher while essential metals were relatively sufficient in Chinese centenarians. Toxic metals and essential metals played different role in diseases, nutritional status and longevity in the process of aging. Our research provided real world evidence of biomonitoring reference values to be used for the ongoing population health surveillance in longevity.
Advanced capabilities in electrical recording are essential for the treatment of heart-rhythm diseases. The most advanced technologies use flexible integrated electronics; however, the penetration of ...biological fluids into the underlying electronics and any ensuing electrochemical reactions pose significant safety risks. Here, we show that an ultrathin, leakage-free, biocompatible dielectric layer can completely seal an underlying layer of flexible electronics while allowing for electrophysiological measurements through capacitive coupling between tissue and the electronics, and thus without the need for direct metal contact. The resulting current-leakage levels and operational lifetimes are, respectively, four orders of magnitude smaller and between two and three orders of magnitude longer than those of any other flexible-electronics technology. Systematic electrophysiological studies with normal, paced and arrhythmic conditions in Langendorff hearts highlight the capabilities of the capacitive-coupling approach. Our technology provides a realistic pathway towards the broad applicability of biocompatible, flexible electronic implants.
2,4-dichlorophenol was effectively removed from water using magnetic Pd/Fe nanoparticles supported on multiwalled carbon nanotubes (MWCNTs). The adsorption kinetics, isotherms, and energy for ...2,4-dichlorophenol and its partially (4-chlorophenol, 2-chlorophenol) and completely (phenol) dechlorinated products are presented and discussed. The adsorption capacity was 2,4-dichlorophenol > 4-chlorophenol > 2-chlorophenol > phenol for MWCNTs. MWCNTs-Fe3O4–Pd/Fe nanohybrids provided rapid adsorption, gradual dechlorination, and final desorption of phenol, which is attractive as a remediation technology. Over 82.7% of the phenol was desorbed and released to the aqueous phase after 72 h due to its low adsorption capacity, leaving the majority of active sites available on the surface of MWCNTs-Fe3O4–Pd/Fe. The nanohybrids maintained high activity in five consecutive in situ experiments, and they were retrievable using magnetic separation. MWCNTs-Fe3O4–Pd/Fe nanohybrids outperform unsupported Pd/Fe nanoparticles, which were difficult to retrieve, and were easily passivated and aggregated.
In this study, GO and Fe2P were used as co-catalysts to improve the separation efficiency of photogenerated electron-hole pairs in an In2S3 photocatalyst. The metallic character of Fe2P provided a ...cheap substitute for traditional noble metal co-catalyst for H2 production in aqueous media. The GO/Fe2P/In2S3 composite demonstrated significantly enhanced photocatalytic activity compared to pure In2S3, delivering a H2 production rate of 483.35 μmol h−1 g−1 and a quantum yield was 22.68% under visible light irradiation. The design of the photocatalyst was optimized using “Design Expert” software. The analysis showed that a GO loading of 1.18 wt%, a Fe loading of 5.36 wt%, and a calcination temperature of 180 °C were optimal.
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•GO/Fe2P/In2S3 composite photocatalysts were prepared.•A H2 production rate of 485.92 μmol h−1 g−1 was achieved under a Xe lamp (400–700 nm).•Fe2P acted as the H2 evolution site, whilst GO electron transport.•The response surface method allowed optimization of photocatalyst performance.
This paper uses a randomized information intervention to shed light on whether poor understanding of social insurance, both the process of enrolling and costs and benefits, drives the relatively low ...rates of participation in urban health insurance and pension programs among China's rural-urban migrants. Among workers without a contract, the information intervention has a strong positive effect on participation in health insurance and, among younger age groups, in pension programs. Migrants are responsive to price: in cities where the premia are low relative to earnings, information induces health insurance participation, while declines are observed in cities with high relative premia.
•China's rural migrants have low rates of participation in social insurance.•Participation increases when migrants receive information about social insurance.•Participation in health insurance increases among migrants without contracts.•Enrollment in health insurance is sensitive to a city relative premium.•Enrollment in pensions only increases among migrants young enough to receive full benefits.
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