Niemanncoble5101

Best five hits were subjected to molecular dynamics (MD) simulations to validate their selectivity as well as stability in LdDHFR. Out of the five hits, four were found to be energetically more favorable and promising for selective binding toward LdDHFR in comparison to HsDHFR.Communicated by Ramaswamy H. Sarma.Sepsis-induced acute respiratory distress syndrome (ARDS) remains a major threat to human health without effective therapeutic drugs. Previous studies demonstrated the power of gene expression profiling to reveal pathological changes associated with sepsis-induced ARDS. However, there is still a lack of systematic data mining framework for identifying potential targets for treatment. In this study, we demonstrated the feasibility of druggable targets prediction based on gene expression data. Through the functional enrichment analysis of microarray-based expression profiles between sepsis-induced ARDS and non-sepsis ARDS samples, we revealed genes involved in anti-microbial infection immunity were significantly altered in sepsis-induced ARDS. Protein-protein interaction (PPI) network analysis highlighted TOP2A gene as the key regulator in the dysregulated gene network of sepsis-induced ARDS. We were also able to predict several therapeutic drug candidates for sepsis-induced ARDS using Connectivity Map (Cmap) database, among which doxorubicin was identified to interact with TOP2A with a high affinity similar to its endogenous ligand. Overall, our findings suggest that doxorubicin could be a potential therapeutic for sepsis-induced ARDS by targeting TOP2A, which requires further investigation and validation. The whole study relies on publicly available dataset and publicly accessible database or bioinformatic tools for data mining. Therefore, our study benchmarks a workflow for druggable target prediction which can be widely applicable in the search of targets in other pathological conditions.We report two cases from the frontotemporal lobar degeneration (FTLD) spectrum with remarkably slow progression. The first case demonstrated insidious-onset behavioral symptoms and personality changes resembling behavioral variant of frontotemporal dementia, followed a benign course over 26 years, his brain autopsy revealed the diffuse form of argyrophilic grain disease. The second case presented with slowly progressive cognitive and motor deficits, reminiscent of the corticobasal syndrome, deteriorated slowly over 22 years, his brain autopsy revealed FTLD-TDP with C9ORF72 pathology. These two cases confirm the notion of slowly progressive frontotemporal lobar degeneration caused by an underlying FTLD pathology, rather than a phenocopy.Severe Helicobacter pylori-linked gastric disorders are especially prevalent in the East Asia region. The ability of H. pylori to cause different clinical outcomes is thought to be associated with unique sets of its genetic features. However, only few genetic features have been definitively linked to specific gastrointestinal pathologies. Genome heterogeneity of clinical H. pylori strains from patients with four different gastric disorders was studied to explore the population structure and molecular genomic features and their association with pathogenicity. Population analysis showed that 92.9% of the Shanghai H. pylori isolates were clustered in the East Asia group. Among 2,866 genes detected in all genomes, 1,146 genes formed the core genome, whereas 209 unique genes were detected in individual disease groups. The unique genes of peptic ulcer and gastric cancer groups represented the inorganic ion transport and metabolism function gene clusters. Sixteen virulence genes were detected with statistically different detection rates among the four disease groups. Furthermore, 127 clustered regularly interspaced short palindromic repeats were found with significantly different rates in the four disease groups. A total of 337 putative genomic islands were identified, and three genomic islands were individually found in more than 10% of strains. The genomic islands included several metabolism-associated genes and many genes with unknown function. In total, 88 sequence types were detected among the 112 Shanghai H. pylori isolates. Our study provides an essential milestone in the mapping of specific genomic features and their functions to identify factors needed to induce specific gastric disorders in H. pylori.If Sustainable Developmental Goal 3 and Universal Health Coverage are to be achieved, functioning is a third health indicator which must be assessed and integrated into global health population-based metrics alongside mortality and morbidity. In this paper, we define functioning according to the International Classification of Functioning, Disability and Health (ICF) and present why functioning is important to measure, especially when considering the need for, and outcome of, rehabilitation and assistive technology. We discuss examples of tools that measure components of functioning through clinical assessment and self-report methodologies, and present the development of a comprehensive population level tool which aligns with the ICF and combines self-report and clinical measurement methods to measure functioning and the need for rehabilitation and AT. Throughout the paper a survivor of Coronavirus 2019 (COVID-19) is given as an example to illustrate functioning according to the ICF and how access to the interventions of rehabilitation and assistive technology might be of benefit to improve and optimise his/her functioning. We argue that the Global Health community must take action and ensure that the measurement of functioning is well established, accepted and integrated as the third health indicator following the COVID-19 pandemic.The presence of methicillin-resistant Staphylococcus aureus (MRSA) in bone infections difficults its treatment and is a sign of concern. The aim of this study was to evaluate in vitro activity of dalbavancin on pre-established adhered cells and 24 h old biofilms of MRSA strains isolated from a human bone infection. Thirty-three MRSA were isolated from osteomyelitis episodes. The antimicrobial susceptibility of these strains was assessed by the Kirby-Bauer disc diffusion method and the presence of resistance genes was screened by PCR. MRSA planktonic minimum inhibitory concentration and minimum bactericidal concentration were assessed. Minimum biofilm eradication concentration (MBEC) was performed by the microtiter biofilm formation assay. All 33 MRSA strains were classified as multidrug-resistant strains and susceptible to dalbavancin. Dalbavancin inhibited the growth of 54.6% and 52% of strains at the concentrations of 0.05 µg/mL and 1 µg/mL, respectively. The MBEC values up to 0.4 µg/mL demonstrated that dalbavancin was active against most strains in pre-established adhered cells and 24 h old biofilms. The current results show that dalbavancin is active against adhered cells and biofilms in vitro, suggesting that this antimicrobial agent may be an option for the treatment of bone infections caused by MRSA.Research on healthy life expectancy (HLE) that considers cognitive impairment has been inadequate, particularly in the context of less developed countries. Using data from the China Health and Retirement Longitudinal Study, our study fills this research gap by computing active life expectancy (ALE), cognitive-impairment-free life expectancy (CIFLE), and active and cognitive-impairment-free life expectancy (ACIFLE) for China's older population, using multistate life tables. Results show that at age 60, the three life expectancies were 19.4 years (ALE), 9.5 years (CIFLE), and 8.8 years (ACIFLE) during the period 2011-13. HLE exhibits significant differentials by sex, urban/rural residence, educational level, marital status, and health status at age 60. Among China's older people, males and those living in urban areas experience higher CIFLE, and those who live with a spouse, are more educated, and are healthy at age 60 expect more years in good health according to all three HLE measures.Supplementary material for this article is available at https//doi.org/10.1080/00324728.2021.1914854.In our previous studies, we discovered the congenital cold syndrome (CCS), which is characterized by 'qi deficiency and qi stagnation, mixed cold and heat.' And there is a type of syndrome with special incidence characteristic. However, the diagnosis of CCS still lacks an objective basis. In this study, we performed Tandem Mass Tag (TMT) based on quantitative proteomics technology to screen the significantly differentially expressed proteins (DEPs) in serum of patients with coronary heart disease (CHD) patients with CCS, patients with heart and kidney yang deficiency, and healthy people. A total of 22 DEPs (nine upregulated and 13 downregulated) were identified between patients with CCS and healthy subjects. Next, we performed GO and KEGG pathway enrichment analysis, we found the primary functions of DEPs of CCS were binding, catalytic activity, and molecular function regulator. These DEPs were mainly involved in important biological processes, such as cellular process, response to stimulus, localization, metabolic process, and biological regulation. The KEGG analysis revealed that the DEPs showed significant changes in fructose and mannose metabolism, Pentose phosphate pathway, and Arrhythmogenic right ventricular cardiomyopathy. After parallel reaction monitoring (PRM) verification, four upregulated target proteins (ALDOA, PCYOX1, Crisp3 and IGLV4-69) and three downregulated proteins (ALDOC, ADAMTSL-2 and C3) were accurately identified. These proteins were mainly related to immune response and glucose metabolism. These DEPs could be the marker proteins of coronary heart disease with CCS. This findings help to reveal the pathogenesis of CHD with CCS and provide potential therapeutic targets.Osteoporosis (OP) characterizes a decrease in bone density and bone mass which leads to brittle fractures and serious damages to individuals. In recent years, various researches have proved that miRNAs act pivotally in the onset of bone-related diseases. In our research, we probed into the impact of miR-181a-5P on viability, differentiation, as well as apoptosis of human bone marrow mesenchymal stem cells (hBMSCs). Our study reported that overexpressing miR-181a-5p considerably reduced the cell growth, whereas the miR-181a-5p inhibition showed opposite results. Furthermore, the hBMSCs apoptosis percentage was visually elevated or minimized after overexpressing or silencing miR-181a-5p, respectively. Our data also indicated that miR-181a-5p overexpression significantly inhibited ALP activity, and level of OPN, Runx2 and OCN at mRNA and protein level, whereas miR-181a-5p inhibition presented opposite results. In addition, based on luciferase reporter assay, sirtuin 1 (Sirt1) was confirmed as the target of miR-181a-5p in hBMSCs. Finally, Sirt1 overexpression significantly inhibited the impact of miR-181a-5p mimic on apoptosis and inhibited differentiation, while silencing Sirt1 eliminated the inhibitory effects of miR-181a-5p on apoptosis and promoted differentiation via PI3K/AKT pathway. In conclusion, this work revealed that miR-181a-5p could regulate hBMSCs apoptosis as well as differentiation via regulating Sirt1/PI3K/AKT signaling pathway.[Figure see text].