Our model achieved an accuracy of 60.94%, a specificity of 51.54%, a precision of 59.27%, and a recall of 70.48%. The AUC was 0.6506. In the heat maps for the class „hypertension”, red patchy areas were mainly distributed on or around arterial/venous bifurcations. This indicated that the model has identified these regions as being the most important for predicting hypertension. Our study suggested that the effect of hypertension on retinal microvascular morphology mainly occurred at branching of vessels. The change of the branching pattern of retinal vessels was probably the most significant in response to elevated blood pressure.α-Klotho is a type 1 transmembrane protein that exhibits aging suppression function. The large amino-terminal extracellular domain of α-klotho is shed as soluble klotho (sKlotho) and functions as a circulating cardioprotective hormone. Diacylglycerol (DAG)-activated calcium-permeable TRPC6 channel plays a critical role in stress-induced cardiac remodeling. DAG activates TRPC6 by acting directly on the channel to increase its activity and by stimulation of channel exocytosis. sKlotho protects the heart by inhibiting DAG stimulation of TRPC6 exocytosis. How DAG stimulates TRPC6 exocytosis and thereby inhibition by sKlotho are unknown. Using a compound that directly activates TRPC6 without affecting channel exocytosis, we validate that sKlotho selectively blocks DAG stimulation of channel exocytosis. We further show that DAG stimulates exocytosis of TRPC6-containing vesicles pre-docked to the plasma membrane. Mnuc13 family proteins play important roles in the proper assembly of SNARE proteins and priming the vesicle competent for fusion. We show that DAG stimulates TRPC6 exocytosis by targeting to the C1 domain of Munc13-2. The results provide fresh insights into the molecular mechanism by which DAG regulates vesicle fusion and how sKlotho protects the heart against injury.Rhabdoviruses are enveloped negative-sense RNA viruses that have numerous biotechnological applications. However, recovering plant rhabdoviruses from cDNA remains difficult due to technical difficulties such as the need for concurrent in planta expression of the viral genome together with the viral nucleoprotein (N), phosphoprotein (P) and RNA-dependent RNA polymerase (L) and viral genome instability in E. coli. Here, we developed a negative-sense minigenome cassette for Lettuce necrotic yellows virus (LNYV). We introduced introns into the unstable viral ORF and employed Agrobacterium tumefaciens to co-infiltrate Nicotiana with the genes for the N, P, and L proteins together with the minigenome cassette. The minigenome cassette included the Discosoma sp. red fluorescent protein gene (DsRed) cloned in the negative-sense between the viral trailer and leader sequences which were placed between hammerhead and hepatitis delta ribozymes. In planta DsRed expression was demonstrated by western blotting while the appropriate splicing of introduced introns was confirmed by sequencing of RT-PCR product.BACKGROUND Across North America, the opioid overdose epidemic is leading to increasing hospitalizations of people who use drugs (PWUD). However, hospitals are ill-prepared to meet the needs of PWUD. We focus on illicit drug use while admitted to hospital and how PWUD and health care providers describe, respond, and attempt to manage its use. METHODS AND FINDINGS Using varied purposive methods in Toronto and Ottawa, we recruited n = 24 PWUD (who self-reported that they were living with HIV and/or HCV infection; currently or had previously used drugs or alcohol in ways that were harmful; had a hospital admission in the past five years) and n = 26 health care providers (who were currently working in an academic hospital as a physician, nurse, social worker or other allied health professional; and 2) providing care to this patient group). All n = 50 participants completed a short, socio-demographic questionnaire and an audio-recorded semi-structured interview about receiving or providing acute care in a hospital There are increasing calls for implementation of harm reduction approaches and interventions in hospitals but uptake has been slow. Our study contributes to this emerging body of literature and highlights areas for future research, the development of interventions, and changes to policy and practice.In soil metal ecotoxicology research, dosing is usually performed with metal salts, followed by leaching to remove excess salinity. This process also removes some metals, affecting metal mixture ratios as different metals are removed by leaching at different rates. Consequently, alternative dosing methods must be considered for fixed ratio metal mixture research. In this study three different metal mixture dosing methods (nitrate, oxide and annealed metal dosing) were examined for metal concentrations and toxicity. In the nitrate metal dosing method leaching reduced total metal retention and was affected by soil pH and cation exchange capacity (CEC). Acidic soils 3.22 (pH 3.4, CEC 8 meq/100g) and WTRS (pH 4.6, CEC 16 meq/100g) lost more than 75 and 64% of their total metals to leaching respectively while Elora (6.7 pH, CEC 21 meq/100g) and KUBC (pH 5.6, CEC 28 meq/100g) with higher pH and CEC only lost 13.6% and 12.2% total metals respectively. Metal losses were highest for Ni, Zn and Co (46.0%, 63.7% and 48.4% metal loss respectively) whereas Pb and Cu (5.6% and 20.0% metal loss respectively) were mostly retained, affecting mixture ratios. Comparatively, oxide and annealed metal dosing which do not require leaching had higher total metal concentrations, closer to nominal doses and maintained better mixture ratios (percent of nominal concentrations for the oxide metal dosing were Pb = 109.9%, Cu = 84.6%, Ni = 101.9%, Zn = 82.3% and Co = 97.8% and for the annealed metal dosing were Pb = 81.7%, Cu = 80.3%, Ni = 100.5%, Zn = 89.2% and Co = 101.3%). Relative to their total metal concentrations, nitrate metal dosing (lowest metal concentrations) was the most toxic followed by metal oxides dosing while the annealed dosing method was generally non-toxic. Due to the lack of toxicity of the annealed metals and their higher dosing effort, metal oxides, are the most appropriate of the tested dosing methods, for fixed-ratio metal mixtures studies with soil invertebrates.BACKGROUND The clinical value of therapeutic drug monitoring can be increased most significantly by integrating assay results into clinical pharmacokinetic models for optimal dosing. The correct weighting in the modeling process is 1/variance, therefore, knowledge of the standard deviations (SD) of each measured concentration is important. Because bioanalytical methods are heteroscedastic, the concentration-SD relationship must be modeled using assay error equations (AEE). We describe a methodology of establishing AEE’s for liquid chromatography-tandem mass spectrometry (LC-MS/MS) drug assays using carbamazepine, fluconazole, lamotrigine and levetiracetam as model analytes. METHODS Following method validation, three independent experiments were conducted to develop AEE’s using various least squares linear or nonlinear, and median-based linear regression techniques. SD’s were determined from zero concentration to the high end of the assayed range. In each experiment, precision profiles of 6 („small” sample setce. This permits optimal dosages by providing the correct weighting factor of assay results in the development of population and individual pharmacokinetic models.Chaperones and autophagy are components of the protein quality control system that contribute to the management of proteins that are misfolded and aggregated. Here, we use yeast prions, which are self-perpetuating aggregating proteins, as a means to understand how these protein quality control systems influence aggregate loss. Chaperones, such as Hsp104, fragment prion aggregates to generate more prion seeds for propagation. While much is known about the role of chaperones, little is known about how other quality control systems contribute to prion propagation. We show that the aprotic solvent dimethyl sulfoxide (DMSO) cures a range of [PSI+] prion variants, which are related to several misfolded aggregated conformations of the Sup35 protein. Our studies show that DMSO-mediated curing is quicker and more efficient than guanidine hydrochloride, a prion curing agent that inactivates the Hsp104 chaperone. Instead, DMSO appears to induce Hsp104 expression. Using the yTRAP system, a recently developed transcriptional reporting system for tracking protein solubility, we found that DMSO also rapidly induces the accumulation of soluble Sup35 protein, suggesting a potential link between Hsp104 expression and disassembly of Sup35 from the prion aggregate. However, DMSO-mediated curing appears to also be associated with other quality control systems. While the induction of autophagy alone does not lead to curing, we found that DMSO-mediated curing is dramatically impaired in autophagy related (atg) gene mutants, suggesting that other factors influence this DMSO mechanism of curing. Our data suggest that DMSO-mediated curing is not simply dependent upon Hsp104 overexpression alone, but may further depend upon other aspects of proteostasis.OBJECTIVE Fetuin-A has been associated with the progression of metabolic syndrome, but previous studies found inconsistent results on the relationship between metabolic syndrome and the concentration of fetuin-A. The aim of this study was to perform a meta-analysis to summarize previous findings on this relationship. METHOD This study was registered with the International Prospective Register of Systematic Reviews PROSPERO (CRD42019129566). Studies examining the relationship between metabolic syndrome and the concentration of circulating fetuin-A were identified using a systematic search in the electronic databases of Embase, PubMed, Web of Science, and Cochrane Library before March 2019. A random effects model was used to summarize the effect size of the association in terms of the standardized mean difference (SMD). RESULTS Fourteen eligible studies compared fetuin-A concentrations between 4,551 metabolic syndrome patients and 8,805 controls. The circulating fetuin-A concentration was significantly higher in the metabolic syndrome patients than in the controls (SMD = 0.65, 95% confidence interval (CI) 0.48 to 0.83, Z = 7.18, p less then 0.001). Besides, circulating fetuin-A was a risk factor for metabolic syndrome (odds ratio 1.23, 95% CI 1.08 to 1.40). CONCLUSION These findings suggest that fetuin-A may be an important indicator for metabolic syndrome, in which case this may lead to new perspectives in early diagnosis, identification of novel biomarkers, and providing novel targets for pharmacological interventions.Financial scams have caused tremendous financial damage globally. In Japan, the police forewarn people by equipping them with scam-prevention techniques or providing awareness regarding examples of previous scams; however, this does not appear to effectively prevent the damage, as many scam victims do not remember these warnings when faced with actual scam encounters. Considering that scammers often use appeal to emotion techniques, peripheral processing during scam attempts might disturb people’s abilities to recall the warnings on scammers’ modus operandi, thus leading to failed counter-arguing efforts. We verified this hypothesis in an experimental setting by asking 162 participants to remember given forewarnings and resist deceptive advertisements. The results showed that participants gave the advertisers’ manipulative intent a higher rating only when they processed the advertisement through a central route, in addition to being forewarned. This means that forewarning had no effect when participants processed the advertisement through a peripheral route.