The outbreak of COVID-19 caused by SARS-CoV-2 has resulted in more than 50 million confirmed cases and over 1 million deaths worldwide as of November 2020. Currently, there are no effective ...antivirals approved by the Food and Drug Administration to contain this pandemic except the antiviral agent remdesivir. In addition, the trimeric spike protein on the viral surface is highly glycosylated and almost 200,000 variants with mutations at more than 1,000 positions in its 1,273 amino acid sequence were reported, posing a major challenge in the development of antibodies and vaccines. It is therefore urgently needed to have alternative and timely treatments for the disease. In this study, we used a cell-based infection assay to screen more than 3,000 agents used in humans and animals, including 2,855 small molecules and 190 traditional herbal medicines, and identified 15 active small molecules in concentrations ranging from 0.1 nM to 50 μM. Two enzymatic assays, along with molecular modeling, were then developed to confirm those targeting the virus 3CL protease and the RNA-dependent RNA polymerase. Several water extracts of herbal medicines were active in the cell-based assay and could be further developed as plant-derived anti-SARS-CoV-2 agents. Some of the active compounds identified in the screen were further tested in vivo, and it was found that mefloquine, nelfinavir, and extracts of
(RF3),
, and
were effective in a challenge study using hamsters as disease model.
In this paper, we conduct mathematical and numerical analyses for COVID-19. To predict the trend of COVID-19, we propose a time-dependent SIR model that tracks the transmission and recovering rate at ...time t. Using the data provided by China authority, we show our one-day prediction errors are almost less than 3%. The turning point and the total number of confirmed cases in China are predicted under our model. To analyze the impact of the undetectable infections on the spread of disease, we extend our model by considering two types of infected persons: detectable and undetectable infected persons. Whether there is an outbreak is characterized by the spectral radius of a 2 X 2 matrix. If R 0 > 1, then the spectral radius of that matrix is greater than 1, and there is an outbreak. We plot the phase transition diagram of an outbreak and show that there are several countries on the verge of COVID-19 outbreaks on Mar. 2, 2020. To illustrate the effectiveness of social distancing, we analyze the independent cascade model for disease propagation in a configuration random network. We show two approaches of social distancing that can lead to a reduction of the effective reproduction number R e .
Carbohydrates, which are ubiquitously distributed throughout the three domains of life, play significant roles in a variety of vital biological processes. Access to unique and homogeneous ...carbohydrate materials is important to understand their physical properties, biological functions, and disease-related features. It is difficult to isolate carbohydrates in acceptable purity and amounts from natural sources. Therefore, complex saccharides with well-defined structures are often most conviently accessed through chemical syntheses. Two major hurdles, regioselective protection and stereoselective glycosylation, are faced by carbohydrate chemists in synthesizing these highly complicated molecules. Over the past few years, there has been a radical change in tackling these problems and speeding up the synthesis of oligosaccharides. This is largely due to the development of one–pot protection, one–pot glycosylation, and one–pot protection–glycosylation protocols and streamlined approaches to orthogonally protected building blocks, including those from rare sugars, that can be used in glycan coupling. In addition, new automated strategies for oligosaccharide syntheses have been reported not only for program-controlled assembly on solid support but also by the stepwise glycosylation in solution phase. As a result, various sugar molecules with highly complex, large structures could be successfully synthesized. To summarize these recent advances, this review describes the methodologies for one-pot protection and their one-pot glycosylation into the complex glycans and the chronological developments associated with automated syntheses of oligosaccharides.
Non-ST-segment elevation acute coronary syndrome (NSTE-ACS) is the leading cause of morbidity and mortality from cardiovascular disease worldwide. Several recent studies have shown the relationship ...between the triglyceride-glucose (TyG) index and vascular disease; however, the role of the TyG index in NSTE-ACS has not been extensively assessed. Thus, we aimed to investigate the association of the TyG index with cardiovascular risk factors and outcomes in NSTE-ACS. Overall, 438 patients with NSTE-ACS were enrolled to examine the association of the TyG index with the SYNTAX score and major adverse cardiovascular events (MACEs). The TyG index was calculated as ln fasting triglyceride mg/dL×fasting glucose mg/dL/2. The severity of coronary lesions was quantified by the SYNTAX score. MACEs included cardiac death, nonfatal myocardial infarction, target vessel revascularization, congestive heart failure, and nonfatal stroke. All the patients underwent a 12-month follow-up for MACEs after admission. Multivariate regression analysis identified metabolic risk factors as independent parameters correlated with the TyG index. The prevalence of glucose metabolism disorder, metabolic syndrome, and MACEs increased with increasing TyG index. The TyG index showed a strong diagnostic performance for cardiovascular risk factors and was independently associated with the SYNTAX score (OR 6.055, 95% CI 2.915–12.579, P<0.001). The risk of MACEs (12.8% and 22.8% for the low TyG index and high TyG index groups, respectively; adjusted HR=1.791, 95% CI 1.045–3.068, P=0.034) significantly increased in the high TyG index group as compared with the low TyG index group. The multivariate Cox regression analysis further revealed that the TyG index was an independent predictor of MACEs (HR 1.878, 95% CI 1.130–3.121, P=0.015). In conclusion, the TyG index might be an independent predictor of coronary artery disease severity and cardiovascular outcomes in NSTE-ACS.
Cadmium (Cd) is a high‐risk pathogenic toxin for hepatic diseases. Excessive mitophagy is a hallmark in Cd‐induced hepatotoxicity. However, the underlying mechanism remains obscure. Mitochondrial ...calcium uniporter (MCU) is a key regulator for mitochondrial and cellular homeostasis. Here, Cd exposure upregulated MCU expression and increased mitochondrial Ca2+ uptake are found. MCU inhibition through siRNA or by Ru360 significantly attenuates Cd‐induced excessive mitophagy, thereby rescues mitochondrial dysfunction and increases hepatocyte viability. Heterozygous MCU knockout mice exhibit improved liver function, ameliorated pathological damage, less mitochondrial fragmentation, and mitophagy after Cd exposure. Mechanistically, Cd upregulates MCU expression through phosphorylation activation of cAMP‐response element binding protein at Ser133(CREBS133) and subsequent binding of MCU promoter at the TGAGGTCT, ACGTCA, and CTCCGTGATGTA regions, leading to increased MCU gene transcription. The upregulated MCU intensively interacts with voltage‐dependent anion‐selective channel protein 1 (VDAC1), enhances its dimerization and ubiquitination, resulting in excessive mitophagy. This study reveals a novel mechanism, through which Cd upregulates MCU to enhance mitophagy and hepatotoxicity.
After cadmium (Cd) exposure, the cytosolic Ca2+‐dependent increases and activation of cAMP‐response element binding protein (CREB) orchestrally upregulates mitochondrial calcium uniporter (MCU) gene transcription, and promotes its translocation into mitochondria. The upregulated MCU in mitochondria directly interacts with voltage‐dependent anion‐selective channel protein 1 (VDAC1) and further enhances the dimerization and ubiquitination of VDAC1, which then overactivates mitophagy and leads to hepatocyte death.
Carbohydrates have been shown to play important roles in biological processes. The pace of development in carbohydrate research is, however, relatively slow due to the problems associated with the ...complexity of carbohydrate structures and the lack of general synthetic methods and tools available for the study of this class of biomolecules. Recent advances in synthesis have demonstrated that many of these problems can be circumvented. In this Review, we describe the methods developed to tackle the problems of carbohydrate‐mediated biological processes, with particular focus on the issue related to the development of the automated synthesis of oligosaccharides. Further applications of carbohydrate microarrays and vaccines to human diseases are also highlighted.
Sweet dreams: Carbohydrates play important roles in biological processes. The pace of carbohydrate research is, however, relatively slow due, amongst other things, to the lack of general synthetic methods. Current developments in the automated synthesis of oligosaccharides can help overcome many of these problems and to pave the way for biomedical applications.
We propose an unbiased general-purpose potential energy surface (PES) searching method for both the structure and the pathway prediction of a complex system. The method is based on the idea of ...bias-potential-driven dynamics and Metropolis Monte Carlo. A central feature of the method is able to perturb smoothly a structural configuration toward a new configuration and simultaneously has the ability to surmount the high barrier in the path. We apply the method for locating the global minimum (GM) of short-ranged Morse clusters up to 103 atoms starting from a random structure without using extra information from the system. In addition to GM searching, the method can identify the pathways for chemical reactions with large dimensionality, as demonstrated in a nanohelix transformation containing 222 degrees of freedoms.
Stitch: A language for architecture-based self-adaptation Cheng, Shang-Wen; Garlan, David
Journal of systems and software/The Journal of systems and software,
December 2012, 2012-12-00, 20121201, Volume:
85, Issue:
12
Journal Article
Peer reviewed
Open access
Requirements for high availability in computing systems today demand that systems be self-adaptive to maintain expected qualities-of-service in the presence of system faults, variable environmental ...conditions, and changing user requirements. Autonomic computing tackles the challenge of automating tasks that humans would otherwise have to perform to achieve this goal. However, existing approaches to autonomic computing lack the ability to capture routine human repair tasks in a way that takes into account the business context humans use in selecting an appropriate form of adaptation, while dealing with timing delays and uncertainties in outcome of repair actions. In this article, we present Stitch, a language for representing repair strategies within the context of an architecture-based self-adaptation framework. Stitch supports the explicit representation of repair decision trees together with the ability to express business objectives, allowing a self-adaptive system to select a strategy that has optimal utility in a given context, even in the presence of potential timing delays and outcome uncertainty.
Fondaparinux, a synthetic pentasaccharide based on the heparin antithrombin‐binding domain, is an approved clinical anticoagulant. Although it is a better and safer alternative to pharmaceutical ...heparins in many cases, its high cost, which results from the difficult and tedious synthesis, is a deterrent for its widespread use. The chemical synthesis of fondaparinux was achieved in an efficient and concise manner from commercially available D‐glucosamine, diacetone α‐D‐glucose, and penta‐O‐acetyl‐D‐glucose. The method involves suitably functionalized building blocks that are readily accessible and employs shared intermediates and a series of one‐pot reactions that considerably reduce the synthetic effort and improve the yield.
Working against the clot: The synthetic anticoagulant fondaparinux, a pentasaccharide based on the antithrombin‐binding domain of heparin, was prepared in a concise and efficient manner in the shortest route reported to date. The application of one‐pot strategies, the use of common intermediates, and the efficient preparation of monosaccharide building blocks from commercial sources are key features of this approach.
PDF
