Activity

Hematopoietic progenitor kinase 1 (HPK1), also referred to as mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1), is a serine/threonine kinase that negatively regulates T-cell signaling by phosphorylating Ser376 of Src homology 2 (SH2) domain-containing leukocyte protein of 76 kDa (SLP-76), a critical mediator of T-cell receptor activation. HPK1 loss of function mouse models demonstrated enhanced immune cell activation and beneficial antitumor activity. To enable discovery and functional characterization of high-affinity small-molecule HPK1 inhibitors, we have established high-throughput biochemical, cell-based, and novel pharmacodynamic (PD) assays. Kinase activity-based time-resolved fluorescence energy transfer (TR-FRET) assays were established as the primary biochemical approach to screen for potent inhibitors and assess selectivity against members of MAP4K and other closely related kinases. A proximal target engagement (TE) assay quantifying pSLP-76 levels as a readout and a distal assay measuring IL-2 secretion as a functional response were established using human peripheral blood mononuclear cells (PBMCs) from two healthy donors. Significant correlations between biochemical and cellular assays as well as excellent correlation between the two donors for the cellular assays were observed. pSLP-76 levels were further used as a PD marker in the preclinical murine model. This effort required the development of a novel ultrasensitive single-molecule array (SiMoA) assay to monitor pSLP-76 changes in mouse spleen.Objective Despite expansion of telecommunication strategies across health services and data supporting feasibility of videoconference-based neuropsychological assessment, relatively little is known about teleneuropsychology (TeleNP) use in practice. The current COVID-19 pandemic provides an opportunity for greater use of TeleNP and understanding of neuropsychologists’ experience with this unique assessment medium.Methods During the course of a no-cost global webinar related to practical/ethical considerations of TeleNP practice, attendees were invited to engage in a 26-question survey about their TeleNP use and related COVID-19 concerns. TeleNP practices before the COVID-19 pandemic and early on during the global outbreak were queried among survey participants, along with examination of TeleNP intentions following COVID-19.Results Multiple countries were represented across five continents, with two-thirds of respondents being from the United States. Approximately one-fourth of respondents reported using TeleNP for clinical interview, feedback, and intervention prior to the onset of the COVID-19 pandemic, and approximately one-tenth of individuals used TeleNP for testadministration. Increased use of TeleNP for clinical interview, feedback, and intervention was reported within the first few weeks of the global COVID-19 outbreak, though the use of TeleNP for testing remained relatively unchanged. Most respondents indicated an intention for future use of TeleNP.Conclusions Our findings suggest the use of TeleNP is increasing, although use of remote TeleNP testing is still developing. Findings also illustrate increasing use of TeleNP in the context of the COVID-19 pandemic and encourage follow-up investigation in future studies to understand the changing practices and rates of TeleNP provision over time.ABSTRACT Pandemic SARS-CoV-2 has caused unprecedented mortalities. Vaccine is in urgent need to stop the pandemic. Despite great progresses on SARS-CoV-2 vaccine development, the efficacy of the vaccines remains to be determined. Deciphering the interactions of the viral epitopes with the elicited neutralizing antibodies in convalescent population inspires the vaccine development. In this study, we devised a peptide array composed of 20-mer overlapped peptides of spike (S), membrane (M) and envelope (E) proteins, and performed a screening with 120 COVID-19 convalescent sera and 24 non-COVID-19 sera. We identified five SARS-CoV-2-specific dominant epitopes that reacted with above 40% COVID-19 convalescent sera. Of note, two peptides non-specifically interacted with most of the non-COVID-19 sera. Neutralization assay indicated that only five sera completely blocked viral infection at the dilution of 1200. By using a peptide-compete neutralizing assay, we found that three dominant epitopes partially competed the neutralization activity of several convalescent sera, suggesting antibodies elicited by these epitopes played an important role in neutralizing viral infection. Vorapaxar The epitopes we identified in this study may serve as vaccine candidates to elicit neutralizing antibodies in most vaccinated people or specific antigens for SARS-CoV-2 diagnosis.

We evaluated long-term effects of testosterone undecanoate on glycemic control, metabolic syndrome, vascular function and morphology in obese men with functional hypogonadism (FH) and type 2 diabetes (T2D) in a 2-year prospective clinical trial.

A total of 55 participants were enrolled in this study; group P (

 = 27) received placebo during first and testosterone therapy (TTh) during second year, group T (

 = 28) received TTh both years. We pooled results after 1 year of TTh to obtain more statistical power. Results for group T after 2 years of TTh are also presented. We evaluated wide assortment of biochemical (fasting plasma glucose-FPG, glycated hemoglobin-HbA1c and lipid profile), hormonal, vascular (flow-mediated dilatation-FMD and intima-media thickness-IMT), anthropometrical and derived parameters (BMI, HOMA-IR, non-HDL cholesterol, bioavailable and calculated free testosterone). Quality of life was assessed using Aging Males’ Symptoms (AMS) questionnaire.

FPG, HbA

c, HOMA-IR and IMT decreased, FMD increased, lipid profile and AMS sexual sub-score improved, and testosterone levels fully normalized after 2 years of TTh.

Two-year of TTh resulted in normalized serum testosterone levels, improved glycemia, endothelial function, lipids and insulin sensitivity, and quelled the symptoms of hypogonadism, potentially reducing cardiovascular risk in obese men with FH and T2D.

Two-year of TTh resulted in normalized serum testosterone levels, improved glycemia, endothelial function, lipids and insulin sensitivity, and quelled the symptoms of hypogonadism, potentially reducing cardiovascular risk in obese men with FH and T2D.