Notes

Personal clinical trial that compares cancer malignancy discovery employing combinations of 2nd mammography, electronic digital breasts tomosynthesis and artificial 2D photo.
Bacterial community was the main driver shaping the resistome. Nutrients also played an essential role in structuring the bacterial community and resistome in the sediments of Erhai Lake. This study sheds light on the distribution and fate of resistome under a high load of nitrogen and phosphorus in a deep lake. The pentameric γ-aminobutyric acid type A receptors (GABAARs) are the major inhibitory ligand-gated ion channels in the central nervous system. They mediate diverse physiological functions, mutations in them are associated with mental disorders and they are the target of many drugs such as general anesthetics, anxiolytics and anti-convulsants. The five subunits of synaptic GABAARs are arranged around a central pore in the order β-α-β-α-γ. In the outer third of the transmembrane domain (TMD) drugs may bind to five homologous intersubunit binding sites. Etomidate binds between the pair of β - α subunit interfaces (designated as β+/α-) and R-mTFD-MPAB binds to an α+/β- and an γ+/β- subunit interface (a β- selective ligand). Ligands that bind selectively to other homologous sites have not been characterized. We have synthesized a novel photolabel, (2,6-diisopropyl-4-(3-(trifluoromethyl)-3H-diazirin-3-yl)phenyl)methanol or pTFD-di-iPr-BnOH). It is a potent general anesthetic that positively modulates agonist and benzodiazepine binding. It enhances GABA-induced currents, shifting the GABA concentration-response curve to lower concentrations. Photolabeling-protection studies show that it has negligible affinity for the etomidate sites and high affinity for only one of the two R-mTFD-MPAB sites. Exploratory site-directed mutagenesis studies confirm the latter conclusions and hint that pTFD-di-iPr-BnOH may bind between the α+/β- and α+/γ- subunits in the TMD, making it an α+ ligand. The latter α+/γ- site has not previously been implicated in ligand binding. Thus, pTFD-di-iPr-BnOH is a promising new photolabel that may open up a new pharmacology for synaptic GABAARs. Novel anti-proliferative agents possessing pyrimidine scaffolds were designed, synthesized and evaluated for their IC50 values using MTT assay. Most compounds displayed good to excellent activity against the two tested breast cancer lines (MCF-7 and MDA-MB-231) as compared to 5-FU. The observed IC50 values for active compounds ranged from 0.27 to 10.57 µM in MCF-7 compared to the reference drug 5-FU (IC50 = 10.80 µM) and from 0.73 to 29.07 µM in MDA-MB-231 (IC50 for 5-FU = 11.40 µM). SAR analysis indicated that compounds 2c, 3b with hydrazone functionalities and compound 12 possessing pyrazolone ring exhibited superior activities. The most promising compounds were evaluated for their inhibitory activity against epidermal growth factor receptor (EGFR) and aromatase (ARO) enzymes and were further tested for caspase-9 activation, apoptosis and Annexin V/PI staining. Results of enzyme-based experiments indicated that the tested compounds 2c and 12 exert their activities through EGFR inhibition while compound 3b exhibited remarkable ARO inhibition activity. Furthermore, they remarkably induce caspase-9 activation and showed pre G1 apoptosis and cell cycle arrest at G2/M phase. In addition, docked compounds displayed good binding affinities to the target enzymes. Binding interaction details for the most promising inhibitors with the active site of the target enzymes EGFR and ARO utilizing MOE-dock method are also reported. A collection of N-substituted quinolin-2(1H)-ones were screened against a panel of clinically relevant protozoa (Leishmania, Trypanosoma and Acanthamoeba). Three quinolin-2(1H)-one compounds were identified as selective anti-Acanthamoeba agents. Further assessment revealed that these compounds were active against both trophozoite and cyst forms of A. castellanii Neff, and caused protozoa death via apoptosis. The data presented herein identify N-acyl quinolin-2(1H)-ones as a promising new class of selective anti-Acanthamoeba agents. Optimization of IG-105 (1) on the carbazole ring provided five series of new carbazole sulfonamides derivatives, 7a-e, 8a-g, 9a-g, 10a-e, and 11a-g. All of the compounds were evaluated against HepG2, MCF-7, MIA PaCa-2, and Bel-7402 cells for antiproliferative activity. Each series of compounds was 2-5 times more active against HepG2 cells (IC50 1.00-10.0 μM) than the other three tumor cell lines. Several representative compounds, selected from each series, showed aqueous solubility (13.4-176.5 µg/mL at pH 7.4 and 2.0) better than 1, with the aqueous solubility of corresponding salts > 30 mg/mL. From the results of evaluating the effects of the compounds 7b, 8c, 9c, 10c and 11c on tubulin in vitro, we speculated that their targets were different from those of 1 and CA-4P. We tested the antitumor activity of the representative compound 7b·HCl (10 mg/kg) in an in vivo study and found that its tumor growth inhibition rate was 41.1%. The tumor growth inhibition rate of 7b·HCl (20 mg/kg) was 54.6%, whereas the tumor growth inhibition rate of CA-4P (50 mg/kg) was 48.3%. And in another batch of in vivo antitumor activity testing, 9c·HCl and 11c·HCl at doses of 10 mg/kg resulted in 61.1% and 50.0% inhibition, respectively. These promising results warrant further development of the derivatives, which may use a novel mechanism and show potential potency as antitumor drug candidates. A series of structurally intriguing novel class of spiropyrrolidine tethered quinoxaline heterocyclic hybrids has been achieved in excellent yields employing ionic liquid accelerated multicomponent 1,3-dipolar cycloaddition reaction strategy. β-Nitrostyrenes were used as dipolarophiles, while the 1,3-dipole component was the azomemthine ylide, generated in situ from indenoquinoxaline and l-phenylalanine. The reaction provided three new bonds and four contiguous stereocenter with full distereomeric control. In vitro activity of these spiroheterocyclic hybrids against Mycobacterium tuberculosis H37Rv using MABA assay revealed that the compound with nitro group on the phenyl ring is the most active candidate (1.56 µg/mL) among the other analogues of the series and has an activity similar to that of the standard drug, Ethambutol. There has been an abundance of research discussing the health implications of generalised trust and happiness over the past two decades. Both attitudes have been touted as independent predictors of morbidity and mortality, with strikingly similar trajectories and biological pathways being hypothesised. To date, however, neither trust nor happiness have been considered simultaneously as predictors of mortality. This study, therefore, aims to investigate the effects of generalised trust and happiness on all-cause and cause-specific mortality. The distinction between different causes of death (i.e. cardiovascular vs. cancer-related mortality) allowed us to assess if psychosocial mechanisms could account for associations between generalised trust, happiness and mortality. The study sample was derived from US General Social Survey data from 1978 to 2010 (response rates ranged from 70 to 82 per cent), and combined with death records from the National Death Index. The analytical sample comprised 23,933 individuals with 5382 validated deaths from all-cause mortality by 2014. Analyses were performed with Cox regression models and competing-risk models. In final models, generalised trust, but not happiness, showed robust and independent associations with all-cause mortality. Regarding cause-specific mortality, trust only showed a significant relationship with cardiovascular mortality. The distinct patterns of association between generalised trust and all-cause/cause-specific mortality suggest that their relationship could be being driven by cardiovascular mortality. In turn, this supports the feasibility of psychosocial pathways as possible biological mechanisms from distrust to mortality. The modern human brain and braincase have a characteristic globular shape including parietal and cerebellar bulging. In contrast, Neanderthals, although having similar endocranial volume, displayed more elongated endocrania with flatter parietal and cerebellar regions. Based on endocranial imprints, we compare the parietal lobe morphology of modern humans and Neanderthals, as this brain region is central to several cognitive functions including tool use and visual imaging. In paleoneurology, shape analyses of endocasts are based either on anatomical landmarks that represent endocranial surface features homologous to cortical convolutions (impressions of brain gyri and sulci) or on dense meshes of semilandmarks that capture overall endocranial shape. Previous analyses using the former suggested that modern humans have relatively longer and taller parietal lobes than extinct human species, while the latter emphasized parietal bulging without a significant size difference of parietal regions. In the present studparietal cortex might affect associative and integrative functions between somatic and visual primary inputs. OBJECTIVE In the context of universal health insurance coverage, this study aimed to determine whether urban-rural inequality still exists in preventive health care (PHC) amongst children in Taiwan. STUDY DESIGN Prospective cohort study. METHODS A total of 184,117 mothers and their children born in 2009 were identified as the study cohort. The number of children born in urban, satellite and rural areas was 40,176, 57,565 and 86,805, respectively. All children were followed for 7 years, before which a total of seven times PHC were provided by Taiwan's National Health Insurance (NHI) programme. Ordinal logistic regression models were used to associate urbanisation level with the frequency of PHC utilisation. Stratified analyses were further performed in accordance with the children's birth weight and the mothers' birthplace. RESULTS Children from satellite areas had higher utilisation for the first four scheduled PHC visits. Children living in urban areas received more PHC for the fifth and sixth scheduled visits. Compared with those from rural areas, children in satellite areas exhibited a small but significant increase in odds in PHC utilisation, with a covariate-adjusted odds ratio (aOR) of 1.04 and 95% confidence interval (CI) of 1.02-1.06. By contrast, no significant difference was observed between rural and urban areas (aOR = 1.01). Further stratified analyses suggest more evident urban-rural difference in PHC utilisation amongst children with low birth weight and foreign-born mothers. CONCLUSIONS Given a universal health insurance coverage and embedded mechanisms in increasing the availability of healthcare resources in Taiwan, a slight urban-rural difference is observed in PHC utilisation amongst children. Hence, sociodemographic inequality in utilisation of PHC still exists. This issue should be addressed through policy intervention. The disposal of reverse osmosis (RO) concentrate (ROC) is a critical challenge impeding the application of RO-based wastewater reclamation. Herein, we proposed an enhanced biotreatment approach for the simultaneous removal of nitrogen, phosphorous, hardness, and methylisothiazolinone (MIT) from ROC by suspended-solid phase cultivation of Scenedesmus sp. LX1. Repeated carrier addition, guided by the developed optimal carrier addition model, efficiently enhanced algal growth and contaminant removal through dynamically controlling the suspended algal density by cell attachment. The maximum algal growth rate (212.2 mg/(L∙d)) increased by 41% compared with the control, and the time needed for reaching the maximum algal biomass (906.7 mg/L) was shortened by 1 d, attributing to the mitigation of density restriction. 91.8% of nitrogen (30.2 mg/L) was removed with 5.5 mg/(L∙d) accelerating removal rate, and phosphate (3.7 mg/L) was completely removed within 1 d. Hardness precursors calcium and inorganic carbon were also removed in large amounts, 268.
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