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Dose-response experiments are a mainstay of receptor biology studies and can reveal valuable insights into receptor function. Such studies of receptors that bind cell surface ligands are currently limited by the difficulty in manipulating the surface density of ligands at a cell-cell interface. Here, we describe a generic cell surface ligand system that allows precise manipulation of cell surface ligand densities over several orders of magnitude. These densities are robustly quantifiable, a major advance over previous studies. We validate the system for a range of immunoreceptors, including the T-cell receptor (TCR), and show that this generic ligand stimulates via the TCR at a similar surface density as its native ligand. We also extend our work to the activation of chimeric antigen receptors. This novel system allows the effect of varying the surface density, valency, dimensions, and affinity of the ligand to be investigated. It can be readily broadened to other receptor-cell surface ligand interactions and will facilitate investigation into the activation of, and signal integration between, cell surface receptors.

The authors report cases of familial hyperprolactinemia due to a germline, loss-of-function mutation resulting in prolactin insensitivity. It appears to be caused by a heterozygous mutation in the prolactin receptor gene, PRLR . Prolactin, a hormone that is secreted predominantly by lactotrophs in the anterior pituitary gland, is required for the induction and maintenance of lactation in the peripartum and postpartum periods. 1 However, hyperprolactinemia unrelated to pregnancy occurs in approximately 0.1 to 0.3% of the general population 2 , 3 and may result in infertility, hypogonadism, and galactorrhea. Such nonphysiologic hyperprolactinemia is caused mainly by drugs or by tumors in the anterior pituitary gland, which are usually identifiable by means of magnetic resonance imaging (MRI). Approximately 50% of cases of nonphysiologic hyperprolactinemia are due to prolactinomas 4 ; a smaller percentage is due to lesions in . . .

The T cell receptor (TCR)–peptide-MHC (pMHC) interaction is the only antigen-specific interaction during T lymphocyte activation. Recent work suggests that formation of catch bonds is characteristic of activating TCR–pMHC interactions. However, whether this binding behavior is an intrinsic feature of the molecular bond, or a consequence of more complex multimolecular or cellular responses, remains unclear. We used a laminar flow chamber to measure, first, 2D TCR–pMHC dissociation kinetics of peptides of various activating potency in a cell-free system in the force range (6 to 15 pN) previously associated with catch–slip transitions and, second, 2D TCR–pMHC association kinetics, for which the method is well suited. We did not observe catch bonds in dissociation, and the off-rate measured in the 6- to 15-pN range correlated well with activation potency, suggesting that formation of catch bonds is not an intrinsic feature of the TCR–pMHC interaction. The association kinetics were better explained by a model with a minimal encounter duration rather than a standard on-rate constant, suggesting that membrane fluidity and dynamics may strongly influence bond formation.

Dose-response experiments are a mainstay of receptor biology studies and can reveal valuable insights into receptor function. Such studies of receptors that bind cell surface ligands are currently limited by the difficulty in manipulating the surface density of ligands at a cell-cell interface. Here we describe a generic cell surface ligand system that allows precise manipulation of cell surface ligand densities over several orders of magnitude. We validate the system for a range of immunoreceptors, including the T cell receptor (TCR), and show that this generic ligand stimulates via the TCR at a similar surface density as its native ligand. This system allows the effect of surface density, valency, dimensions, and affinity of the ligand to be manipulated. It can be readily extended to other receptor-cell surface ligand interactions, and will facilitate investigation into the activation of, and signal integration between, cell surface receptors.

Tethered enzymatic reactions are ubiquitous in signalling networks but are poorly understood. Here, a novel mathematical analysis is established for tethered signalling reactions in surface plasmon resonance (SPR). Applying the method to the phosphatase SHP-1 interacting with a phosphorylated tether corresponding to an immune receptor cytoplasmic tail provides 5 biophysical/biochemical constants from a single SPR experiment: two binding rates, two catalytic rates, and a reach parameter. Tether binding increased the activity of SHP-1 by 900-fold through a binding-induced allosteric activation (20-fold) and a more significant increase in local sub- strate concentration (45-fold). The reach parameter indicates that this local substrate concentration is exquisitely sensitive to receptor clustering. We further show that truncation of the tether leads not only to a lower reach but also to lower binding and catalysis. The work establishes a new framework for studying tethered signalling processes and highlights the tether as a control parameter in clustered signalling.

Combat simulations have served as an alternative framework to study the cardiorespiratory demands of the activity in combat sports, but this setting imposes rule-restrictions that may compromise the competitiveness of the bouts. The aim of this study was to assess the cardiorespiratory responses to a full-contact taekwondo combat simulation using a safe and externally valid competitive setting. Twelve male national level taekwondo athletes visited the laboratory on two separate occasions. On the first visit, anthropometric and running cardiopulmonary exercise assessments were performed. In the following two to seven days, participants performed a full-contact combat simulation, using a specifically designed gas analyser protector. Oxygen uptake ([Formula: see text]), heart rate (HR) and capillary blood lactate measurements ([La-]) were obtained. Time-motion analysis was performed to compare activity profile. The simulation yielded broadly comparable activity profiles to those performed in competition, a mean [Formula: see text] of 36.6 ± 3.9 ml.kg-1.min-1 (73 ± 6% [Formula: see text]) and mean HR of 177 ± 10 beats.min-1 (93 ± 5% HRPEAK). A peak [Formula: see text] of 44.8 ± 5.0 ml.kg-1.min-1 (89 ± 5% [Formula: see text]), a peak heart rate of 190 ± 13 beats.min-1 (98 ± 3% HRmax) and peak [La-] of 12.3 ± 2.9 mmol.L-1 was elicited by the bouts. Regarding time-motion analysis, combat simulation presented a similar exchange time, a shorter preparation time and a longer exchange-preparation ratio. Taekwondo combats capturing the full-contact competitive elements of a bout elicit moderate to high cardiorespiratory demands on the competitors. These data are valuable to assist preparatory strategies within the sport.

During my long life in the retail business, I always have sought to offer customers a choice of fine-quality goods made both in the United States and abroad.Customers are best served when they can choose from a variety of competing brands and labels. This principle is the reason the National Retail Federation, the largest trade association representing retailers throughout the United States, supports an effort in Congress to cut a crippling tariff on materials used for making high-quality men's suits. U.S. manufacturers of high-end men's suits and formal wear are hobbled by a huge tariff -- more than 31 percent -- on the fabrics they must use.Most manufacturers of high-end suits use very fine woolens, particularly those made in Italy and England. Such fabrics are not produced in the United States.

Emergency department (ED) visits present opportunities to identify and refer suicidal youth for outpatient mental health care, although this practice is not routine. To examine whether a motivational interviewing-based intervention increases linkage of adolescents to outpatient mental health services and reduces depression symptoms and suicidal ideation in adolescents seeking emergency care for non-mental health-related concerns who screen positive for suicide risk. In this randomized clinical trial, adolescents aged 12 to 17 years who screened positive on the Ask Suicide Screening Questions (ASQ) during a nonpsychiatric ED visit at 2 academic pediatric EDs in Ohio were recruited from April 2013 to July 2015. Intention-to-treat analyses were performed from September 2018 to October 2019. The Suicidal Teens Accessing Treatment After an Emergency Department Visit (STAT-ED) intervention included motivational interviewing to target family engagement, problem solving, referral assistance, and limited case management. The enhanced usual care (EUC) intervention consisted of brief mental health care consultation and referral. Primary outcomes were mental health treatment initiation and attendance within 2 months of ED discharge and suicidal ideation (assessed by the Suicidal Ideation Questionnaire JR) and depression symptoms (assessed by the Center for Epidemiologic Studies-Depression scale) at 2 and 6 months. Exploratory outcomes included treatment initiation and attendance and suicide attempts at 6 months. A total of 168 participants were randomized and 159 included in the intention-to-treat analyses (mean [SD] age, 15.0 [1.5] years; 126 [79.2%] female; and 80 [50.3%] white). Seventy-nine participants were randomized to receive the STAT-ED intervention and 80 to receive EUC. At 2 months, youth in the STAT-ED group had similar rates of mental health treatment initiation compared with youth in the EUC group as assessed by parent report (29 [50.9%] vs 22 [34.9%]; adjusted odds ratio [OR], 2.08; 95% CI, 0.97-4.45) and administrative data from mental health care agencies (19 [29.7%] vs 11 [19.3%]; adjusted OR, 1.77; 95% CI, 0.76-4.15). At 2 months, youth in the STAT-ED group and the EUC group had similar rates of treatment attendance (1 appointment: 6 [9.7%] vs 2 [3.6%]; adjusted OR, 2.97; 95% CI, 0.56-15.73; ≥2 appointments: 10 [16.1%] vs 7 [12.7%]; adjusted OR, 1.43; 95% CI, 0.50-4.11). There were no significant group × time differences in suicidal ideation (F = 0.28; P = .72) and depression symptoms (F = 0.49; P = .60) during the 6-month follow-up period. In exploratory analyses, at 6 months, STAT-ED participants had significantly higher rates of agency-reported mental health treatment initiation (adjusted OR, 2.48; 95% CI, 1.16-5.28) and more completed appointments (t99.7 = 2.58; P = .01). This study's findings indicate that no differences were found on any primary outcome by study condition. However, STAT-ED was more efficacious than EUC at increasing mental health treatment initiation and attendance at 6 months. ClinicalTrials.gov identifier: NCT01779414.

Genome-wide association studies have identified thousands of loci for common diseases, but, for the majority of these, the mechanisms underlying disease susceptibility remain unknown. Most associated variants are not correlated with protein-coding changes, suggesting that polymorphisms in regulatory regions probably contribute to many disease phenotypes. Here we describe the Genotype-Tissue Expression (GTEx) project, which will establish a resource database and associated tissue bank for the scientific community to study the relationship between genetic variation and gene expression in human tissues.

Objectives. We investigated whether health insurance type (private vs Medicaid) influences the delivery of acute mental health care to patients with deliberate self-harm. Methods. Using National Medicaid Analytic Extract Files (2006) and MarketScan Research Databases (2005–2007), we analyzed claims focusing on emergency episodes of deliberate self-harm of Medicaid- (n = 8228) and privately (n = 2352) insured adults. We analyzed emergency department mental health assessments and outpatient mental health visits in the 30 days following the emergency visit for discharged patients. Results. Medicaid-insured patients were more likely to be discharged (62.7%), and among discharged patients they were less likely to receive a mental health assessment in the emergency department (47.8%) and more likely to receive follow-up outpatient mental health care (52.9%) than were privately insured patients (46.9%, 57.3%, and 41.2%, respectively). Conclusions. Acute emergency management of deliberate self-harm is less intensive for Medicaid- than for privately insured patients, although discharged Medicaid-insured patients are more likely to receive follow-up care. Programmatic reforms are needed to improve access to emergency mental health services, especially in hospitals that serve substantial numbers of Medicaid-insured patients.