Explore the vast range of titles available.

The T cell repertoire is generated during thymic development in preparation for the response to antigens from pathogens. The T cell repertoire is shaped by positive selection, which requires recognition by the T cell antigen receptor (TCR) of complexes of self peptide and major histocompatibility complex proteins (self-pMHC) with low affinity, and negative selection, which eliminates T cells with TCRs that recognize self-pMHC with high affinity. This generates a repertoire with low affinity for self-pMHC but high affinity for foreign antigens. The TCR must successfully engage both of these ligands for development, homeostasis and immune responses. This review discusses mechanisms underlying the interaction of the TCR with peptide–major histocompatibility complex ligands of varying affinity and highlights signaling mechanisms that enable the TCR to generate different responses to very distinct ligands.

AimsSeveral modes of assay interference common to immunoassays affect solid-phase single-antigen bead-based immunoassays (SAB) used to detect antibodies against human leucocyte antigens (HLA). Best practice recommendations include methods to address assay interference, though the clinical impact and optimal approaches are undefined. We sought to evaluate assay interference in HLA SAB to identify an efficient approach for avoiding erroneous results.MethodsRetrospective analysis of 14 059 patient samples tested for anti-HLA antibodies was performed. This included 4685 samples tested prior to implementation of serum pretreatment with EDTA and 4982 samples tested with routine EDTA treatment using the same testing algorithm. An algorithm for efficiently identifying and processing samples with suspected interference was evaluated in a separate cohort of 4392 EDTA-treated samples.ResultsEDTA serum pretreatment reduced assay interference, but did not eliminate all modes of interference. A protocol for identification and testing of samples with suspected interference facilitated efficient detection of interference while reducing the amount of additional testing required.ConclusionsOur data indicate that a single-method approach is insufficient to address all sources of interference in HLA SAB. A multimodal approach with a proactive screening is a more effective way to minimise risk of erroneous results.

With the continued promise of immunotherapy for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Here, we study 1084 eQTLs affecting the TIME found through analysis of The Cancer Genome Atlas and literature curation. These TIME eQTLs are enriched in areas of active transcription, and associate with gene expression in specific immune cell subsets, such as macrophages and dendritic cells. Polygenic score models built with TIME eQTLs reproducibly stratify cancer risk, survival and immune checkpoint blockade (ICB) response across independent cohorts. To assess whether an eQTL-informed approach could reveal potential cancer immunotherapy targets, we inhibit CTSS , a gene implicated by cancer risk and ICB response-associated polygenic models; CTSS inhibition results in slowed tumor growth and extended survival in vivo. These results validate the potential of integrating germline variation and TIME characteristics for uncovering potential targets for immunotherapy. The contribution of genetic factors to the tumour immune microenvironment (TIME) remains to be investigated. Here, the authors suggest the role of TIME eQTLs for target genes involved in reversing immune suppressive features.

We report direct measurements of the magnetic field screening at the limits of the Meissner phase for two superconducting niobium (Nb) samples. The samples are processed with two different surface treatments that have been developed for superconducting radio-frequency (SRF) cavity applications—a “baseline” treatment and an oxygen-doping (“O-doping”) treatment. The measurements show: (1) that the screening length is significantly longer in the “O-doping” sample compared to the “baseline” sample; (2) that the screening length near the limits of the Meissner phase increases with applied field; (3) the evolution of the screening profile as the material transitions from the Meissner phase to the mixed phase; and (4) a demonstration of the absence of any screening profile for the highest applied field, indicative of the full flux entering the sample. Measurements are performed utilizing the β -detected nuclear magnetic resonance ( β -NMR) technique that allows depth resolved studies of the local magnetic field within the first 100 nm of the surface. The study takes advantage of the β -SRF beamline, a new facility at TRIUMF, Canada, where field levels up to 200 mT are available parallel to the sample surface to replicate radio frequency fields near the Meissner breakdown limits of Nb.

It is known that a subpopulation of T cells expresses two T cell receptor (TCR) clonotypes, though the extent and functional significance of this is not established. To definitively evaluate dual TCRα cells, we generated mice with green fluorescent protein and red fluorescent protein reporters linked to TCRα, revealing that ∼16% of T cells express dual TCRs, notably higher than prior estimates. Importantly, dual TCR expression has functional consequences, as dual TCR cells predominated response to lymphocytic choriomeningitis virus infection, comprising up to 60% of virus-specific CD4⁺ and CD8⁺ T cells during acute responses. Dual receptor expression selectively influenced immune memory, as postinfection memory CD4⁺ populations contained significantly increased frequencies of dual TCR cells. These data reveal a previously unappreciated contribution of dual TCR cells to the immune repertoire and highlight their potential effects on immune responses.

The β-NMR facility at ISAC is constructed specifically for experiments in condensed matter physics with radioactive ion beams. Using co-linear optical pumping, a 8Li +  ion beam having a large nuclear spin polarisation and low energy (nominally 30 keV) can be generated. When implanted into materials these ions penetrate to shallow depths comparable to length scales of interest in the physics of surfaces and interfaces between materials. Such low-energy ions can be decelerated with simple electrostatic optics to enable depth-resolved studies of near-surface phenomena over the range of about 2–200 nm. Since the β-NMR signal is extracted from the asymmetry intrinsic to beta-decay and therefore monitors the polarisation of the radioactive probe nuclear magnetic moments, this technique is fundamentally a probe of local magnetism. More generally though, any phenomena which affects the polarisation of the implanted spins by, for example, a change in resonance frequency, line width or relaxation rate can be studied. The β-NMR program at ISAC currently supports a number of experiments in magnetism and superconductivity as well as novel ultra-thin heterostructures exhibiting properties that cannot occur in bulk materials. The general purpose zero/low field and high field spectrometers are configured to perform CW and pulsed RF nuclear magnetic resonance and spin relaxation experiments over a range of temperatures (3–300 K) and magnetic fields (0–9 T).

Purpose The contribution of common genetic variants to pre-cancer progression is understudied due to long follow-up time, rarity of poor outcomes and lack of available germline DNA collection. Alternatively, DNA from diagnostic archival tissue is available, but its somatic nature, limited quantity and suboptimal quality would require an accurate cost-effective genome-wide germline genotyping methodology. Experimental design Blood and tissue DNA from 10 individuals were used to benchmark the accuracy of Single Nucleotide Polymorphisms (SNP) genotypes, Polygenic Risk Scores (PRS) or HLA haplotypes using low-coverage whole-genome sequencing (lc-WGS) and genotype imputation. Tissue-derived PRS were further evaluated for 36 breast cancer patients (11.7 years median follow-up time) diagnosed with DCIS and used to model the risk of Breast Cancer Subsequent Events (BCSE). Results Tissue-derived germline DNA profiling resulted in accurate genotypes at common SNPs (blood correlation r 2  > 0.94) and across 22 disease-related polygenic risk scores (PRS, mean correlation r = 0.93). Imputed Class I and II HLA haplotypes were 96.7% and 82.5% concordant with clinical-grade blood HLA haplotypes, respectively. In DCIS patients, tissue-derived PRS was significantly associated with BCSE (HR = 2, 95% CI 1.2–3.8). The top and bottom decile patients had an estimated 28% and 5% chance of BCSE at 10 years, respectively. Conclusions Archival tissue DNA germline profiling using lc-WGS and imputation, represents a cost and resource-effective alternative in the retrospective design of long-term disease genetic studies. Initial results in breast cancer suggest that common risk variants contribute to pre-cancer progression.

BackgroundDiscovery that ~16% of T cells naturally co-express two T-cell receptor (TCR) clonotypes prompts examining the role of dual TCR cells in immune functions.MethodsUsing TCRα-reporter transgenic mice, enabling unambiguous identification of single-TCR and dual-TCR cells, we tested the role of dual TCR cells in antitumor immune responses against immune-responsive syngeneic 6727 sarcoma and immune-resistant B16F10 melanoma.ResultsDual TCR cells were specifically increased among tumor-infiltrating lymphocytes (TILs) in both models, indicating selective advantage in antitumor responses. Phenotype and single-cell gene expression analyses identified dual TCR are predominant during the effective antitumor response, demonstrating selectively increased activation in the TIL compartment and skewing toward an effector memory phenotype. Absence of dual TCR cells impaired immune response to B16F10 but not 6727, suggesting that dual TCR cells may be more influential in responses against poorly immunogenic tumors. Dual TCR cells demonstrated an advantage in recognition of B16F10-derived neoantigens in vitro, providing a mechanistic basis for their antitumor reactivity.ConclusionsThese results discover an unrecognized role for dual TCR cells in protective immune function and identify these cells and their TCRs as a potential resource for antitumor immunotherapy.

Thymocytes must undergo positive selection to survive and differentiate. This process is regulated by the TCR-sensitive protein CHMPS by preventing Bcl2 oxidation and degradation.

Digital health coaching is an intervention for type 2 diabetes mellitus (T2DM) that has potential to improve the quality of care for patients. Previous research has established the efficacy of digital interventions for behavior change. This pilot study addresses a research gap in finding effective and accessible behavioral interventions for under-resourced individuals with T2DM. We examined the impact of Healthy at Home , a 12-week phone and SMS-based (short message service) digital health coaching program, on insulin resistance which is an upstream marker for T2DM progression. We compared this intervention to usual diabetic care in a family medicine residency clinic in a randomized controlled trial. Digital health coaching significantly improved participants' calculated Homeostatic Model Assessment for Insulin Resistance (HOMA2-IR) by −0.9 ± 0.4 compared with the control group ( p = 0.029). This significance remained after controlling for years diagnosed with T2DM, enrollment in Medicaid, access to food, baseline stage of change, and race ( p = 0.027). Increasing access to digital health coaching may lead to more effective control of diabetes for under-resourced patients. This study demonstrates the potential to implement a personalized, scalable, and effective digital health intervention to treat and manage T2DM through a lifestyle and behavioral approach to improve clinical outcomes ( http://clinicaltrials.gov , NCT04872647).