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A high-quality snow depth product is very import for cryospheric science and its related disciplines. In our previous work we proposed a novel data fusion framework based on Random Forest Regression of snow products from Advanced Microwave Scanning Radiometer for the Earth Observing System (AMSR-E), Advanced Microwave Scanning Radiometer-2 (AMSR2), Global Snow Monitoring for Climate Research (GlobSnow), the Northern Hemisphere Snow Depth (NHSD), ERA-Interim, and Modern-Era Retrospective Analysis for Research and Applications, version 2 (MERRA-2), incorporating geolocation (latitude and longitude), and topographic data (elevation), which were used as input independent variables. More than 30,000 ground observation sites were used as the dependent variable to train and validate the model in different time periods. This fusion framework resulted in a long time series of continuous daily snow depth product over the Northern Hemisphere with a spatial resolution of 0.25°. Here we compared the fused snow depth and the original gridded snow depth products with 13,272 observation sites, showing an improved precision of our product. The evaluation indices of the fused (best original) dataset yielded a coefficient of determination R2 of 0.81 (0.23), Root Mean Squared Error (RMSE) of 7.69 (15.86) cm, and Mean Absolute Error (MAE) of 2.74 (6.14) cm. Most of the bias (88.31%) between the fused snow depth and in situ observations was in the range of -5 cm to 5 cm.&nbsp, The 28th IUGG General Assembly (IUGG2023) (Berlin 2023)

Background: Nationwide nonpharmaceutical interventions (NPI) were used to combat the novel coronavirus disease (COVID-19) during 2020 in the mainland of China. These NPIs have proven effective on mitigating the spread of COVID-19, but their broad impact on other diseases remains under-investigated. In this study, we aim to assess whether such broad impact exists on notifiable diseases in China. Methods: Weekly incidence and mortality data for 31 major notifiable infectious diseases at the province level were extracted from the China Information System for Disease Control and Prevention from 2014 to 2020. We assessed the impact of NPIs by contrasting the incidences of each infectious disease in predefined COVID-19 phases during 2020 to the average incidences in the corresponding time intervals during 2014-2019. Findings: We observed decreased incidences of most diseases during the phases after the lockdown of Wuhan. In general, respiratory diseases and gastrointestinal or enteroviral diseases were more affected than sexually transmitted or bloodborne diseases and vector-borne or zoonotic diseases. Seasonal flu and rubella were the most sensitive to the NPIs, with reductions of 67-99% in incidence rates throughout the NPI-implemented phases in China (Jan 27-Dec 31, 2020). Among gastrointestinal or enteroviral diseases, the hand, foot and mouth disease (HFMD) was subject to the largest declines during Jan 27-Aug 31, 2020, with >90% reduction in incidence rate. Phases with more stringent NPIs were associated with more reductions. Non-respiratory diseases, particularly HFMD, gonorrhea and brucellosis, rebounded towards the end of the year as the NPIs were relaxed. Interpretation: NPIs are broadly effective in containing infectious diseases. Less disruptive NPIs such as wearing face masks are still effective in mitigating respiratory diseases but are not adequate for containing non-respiratory diseases. Funding Statement: This work was supported by grants from the National Natural Science Funds [91846302, 81825019], the China Mega-Project on Infectious Disease Prevention [2018ZX10713001, 2018ZX10713002, 2018ZX10201001 and 2017ZX10103004], and the US National Institutes of Health [R56 AI148284]. Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: Missing.

The neuromodulator melatonin synchronizes circadian rhythms and related physiological functions through the actions of two G-protein-coupled receptors: MT1 and MT2. Circadian release of melatonin at night from the pineal gland activates melatonin receptors in the suprachiasmatic nucleus of the hypothalamus, synchronizing the physiology and behaviour of animals to the light–dark cycle1–4. The two receptors are established drug targets for aligning circadian phase to this cycle in disorders of sleep5,6 and depression1–4,7–9. Despite their importance, few in vivo active MT1-selective ligands have been reported2,8,10–12, hampering both the understanding of circadian biology and the development of targeted therapeutics. Here we docked more than 150 million virtual molecules to an MT1 crystal structure, prioritizing structural fit and chemical novelty. Of these compounds, 38 high-ranking molecules were synthesized and tested, revealing ligands with potencies ranging from 470 picomolar to 6 micromolar. Structure-based optimization led to two selective MT1 inverse agonists—which were topologically unrelated to previously explored chemotypes—that acted as inverse agonists in a mouse model of circadian re-entrainment. Notably, we found that these MT1-selective inverse agonists advanced the phase of the mouse circadian clock by 1.3–1.5 h when given at subjective dusk, an agonist-like effect that was eliminated in MT1- but not in MT2-knockout mice. This study illustrates the opportunities for modulating melatonin receptor biology through MT1-selective ligands and for the discovery of previously undescribed, in vivo active chemotypes from structure-based screens of diverse, ultralarge libraries. © 2020, The Author(s), under exclusive licence to Springer Nature Limited.

Cashmere goats, as an important part of animal husbandry production, make outstanding contributions to animal fiber industry. In recent years, a great deal of research has been done on the molecular regulation mechanism of hair follicle cycle growth. However, there are few reports on the molecular regulation mechanisms of secondary hair follicle growth cycle in cashmere goats. In this study, we used transcriptome sequencing technique to sequence the skin of Inner Mongolia cashmere goats in different periods, Analyze the variation and difference of genes in the whole hair follicle cycle. And then, we verified the regulation mechanism of cashmere goat secondary hair follicle growth cycle by fluorescence quantitative PCR. As the result shows: The results of tissue section showed that the growth cycle of cashmere hair could be divided into three distinct periods: growth period (March-September), regression period (September-December) and resting period (December-March). The results of differential gene analysis showed that March was considered the beginning of the cycle, and the difference of gene expression was the most significant. Cluster analysis of gene expression in the whole growth cycle further supported the key nodes of the three periods of villus growth, and the differential gene expression of keratin corresponding to the villus growth cycle further supported the results of tissue slices. Quantitative fluorescence analysis showed that KAP3.1, KRTAP 8-1 and KRTAP 24-1 genes had close positive correlation with the growth cycle of cashmere, and their regulation was consistent with the growth cycle of cashmere. However, there was a sequence of expression time, indicating that the results of cycle regulation made the growth of cashmere change.

Despite intense interest in expanding chemical space, libraries containing hundreds-of-millions to billions of diverse molecules have remained inaccessible. Here we investigate structure-based docking of 170 million make-on-demand compounds from 130 well-characterized reactions. The resulting library is diverse, representing over 10.7 million scaffolds that are otherwise unavailable. For each compound in the library, docking against AmpC β-lactamase (AmpC) and the D 4 dopamine receptor were simulated. From the top-ranking molecules, 44 and 549 compounds were synthesized and tested for interactions with AmpC and the D 4 dopamine receptor, respectively. We found a phenolate inhibitor of AmpC, which revealed a group of inhibitors without known precedent. This molecule was optimized to 77 nM, which places it among the most potent non-covalent AmpC inhibitors known. Crystal structures of this and other AmpC inhibitors confirmed the docking predictions. Against the D 4 dopamine receptor, hit rates fell almost monotonically with docking score, and a hit-rate versus score curve predicted that the library contained 453,000 ligands for the D 4 dopamine receptor. Of 81 new chemotypes discovered, 30 showed submicromolar activity, including a 180-pM subtype-selective agonist of the D 4 dopamine receptor.

Kappa opioid receptor (KOR) modulation has been pursued in many conceptual frameworks for the treatment of human pain, depression, and anxiety. As such, several imaging tools have been developed to characterize the density of KORs in the human brain and its occupancy by exogenous drug-like compounds. While exploring the pharmacology of KOR tool compounds using positron emission tomography (PET), we observed discrepancies in the apparent competition binding as measured by changes in binding potential (BP ND , binding potential with respect to non-displaceable uptake). This prompted us to systematically look at the relationships between baseline BP ND maps for three common KOR PET radioligands, the antagonists [ 11 C]LY2795050 and [ 11 C]LY2459989, and the agonist [ 11 C]GR103545. We then measured changes in BP ND using kappa antagonists (naloxone, naltrexone, LY2795050, JDTic, nor-BNI), and found BP ND was affected similarly between [ 11 C]GR103545 and [ 11 C]LY2459989. Longitudinal PET studies with nor-BNI and JDTic were also examined, and we observed a persistent decrease in [ 11 C]GR103545 BP ND up to 25 days after drug administration for both nor-BNI and JDTic. Kappa agonists were also administered, and butorphan and GR89696 (racemic GR103545) impacted binding to comparable levels between the two radiotracers. Of greatest significance, kappa agonists salvinorin A and U-50488 caused dramatic reductions in [ 11 C]GR103545 BP ND but did not change [ 11 C]LY2459989 binding. This discrepancy was further examined in dose-response studies with each radiotracer as well as in vitro binding experiments.

Opioids are widely used analgesic medications with a high potential for tolerance and dependence and represent a frequent cause of death due to overdose. Opioids mediate their actions via a family of opioid G protein coupled receptors. Elucidating the biochemical mechanism(s) responsible for both the therapeutic and deleterious side effects of opioids could provide a biochemical roadmap for selectively targeting therapeutic signaling pathways. Here we provide a perspective on emerging findings, which illuminate these signaling pathways via unbiased and quantitative phosphoproteomic analysis. What emerged from these studies is the discovery that certain deleterious actions mediated by the κ opioid receptors appear due to specific activation of mTOR pathways. The findings imply that designing drugs, which bypass mTOR signaling, could yield safer and more effective analgesics.

W-18 (4-chloro-N-[1-[2-(4-nitrophenyl)ethyl]-2-piperidinylidene]-benzenesulfonamide) and W-15 (4-chloro-N-[1-(2-phenylethyl)-2-piperidinylidene]-benzenesulfonamide) represent two emerging drugs of abuse chemically related to the potent opioid agonist fentanyl (N-(1-(2-phenylethyl)-4-piperidinyl)-N-phenylpropanamide). Here, we describe the comprehensive pharmacological profiles of W-18 and W-15, as examination of their structural features predicted that they might lack opioid activity. We found W-18 and W-15 to be without detectible activity at μ, δ, κ, and nociception opioid receptors in a variety of assays. We also tested W-18 and W-15 for activity as allosteric modulators at opioid receptors and found them devoid of significant positive or negative allosteric modulatory activity. Comprehensive profiling at essentially all the druggable GPCRs in the human genome using the PRESTO-Tango platform revealed no significant activity. Weak activity at the sigma receptors and the peripheral benzodiazepine receptor was found for W-18 (Ki = 271 nM). W-18 showed no activity in either the radiant heat tail-flick or the writhing assays and also did not induce classical opioid behaviors. W-18 is extensively metabolized, but its metabolites also lack opioid activity. Thus, although W-18 and W-15 have been suggested to be potent opioid agonists, our results reveal no significant activity at these or other known targets for psychoactive drugs.

The aims was to construct a prokaryotic expression plasmid and develop a subunit vaccine for bovine rotavirus (BRV), also to investigate the efficacy of this vaccine. BRV total RNA was extracted from M-A104 cell infected by the strain GSB01 of bovine rotavirus. Total RNA as template, BRV VP7 gene was amplified with real time fluorescence quantitative PCR (qPCR), PCR product was cloned into pEASY-T3 vector. The pEASY-T3-VP7 plasmid was recombined into the prokaryotic expression vector pET32a (+) after it was digested using double enzymes. The pET32a-VP7 and VP7-LTB used for prokaryotic expression were constructed, which were converted into Escherichia coli BL21 (DE3) competent cells. After IPTG induction and SDS-PAGE analysis were performed, the fusion proteins of pEASY-T3-VP7 and VP7-LTB with molecular weights of 42.2kD and 53.2kD were acquired respectively. Such a gene engineering bacteria for expressing VP7 protein within BL21(DE3) cells was constructed successfully. The mice immunized using both fusion proteins of pEASYT3-VP7 and VP7-LTB could promote VP7 IgG antibody production (8.33 vs 17.3). The immunization protection ratio of both fusion proteins in neonatal mice was 86.4% and 91.7%, respectively. These findings laid a foundation for further developing a high-efficiency subunit vaccine of BRV VP7 gene.