Pre-existing chromatin accessibility and gene expression differences among naive CD4+ T cells influence effector potential

CD4+ T cells have a remarkable potential to differentiate into diverse effector lineages following activation. Here, we probe the heterogeneity present among naive CD4+ T cells before encountering their cognate antigen to ask whether their effector potential is modulated by pre-existing transcriptional and chromatin landscape differences. Single-cell RNA sequencing shows that key drivers of variability are genes involved in T cell receptor (TCR) signaling. Using CD5 expression as a readout of the strength of tonic TCR interactions with self-peptide MHC, and sorting on the ends of this self-reactivity spectrum, we find that pre-existing transcriptional differences among naive CD4+ T cells impact follicular helper T (TFH) cell versus non-TFH effector lineage choice. Moreover, our data implicate TCR signal strength during thymic development in establishing differences in naive CD4+ T cell chromatin landscapes that ultimately shape their effector potential

Minimal information for studies of extracellular vesicles 2018 (MISEV2018):a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points

West of the Red \u2014 The Role of Transportation in the Development of North Dakota

In reading this book you will undoubtedly discover that a history of North Dakota transportation is really a history of the state itself. Whereas states along the eastern seaboard had been settled for 200 years before the whistle of a steamboat or locomotive was heard, rails stretched across Dakota Territory before there was any significant white pioneer settlement. Transportation facilities were built long before there were any towns to serve. The development of agriculture was an immediate necessity if railroads were to survive. The iron horse and the traction engine were partners in the cultivation of the prairies, and although agriculture and transportation were, and are often adversaries, this close and highly interdependent relationship has continued to the present day

Understanding the Potential of Mental Health Apps to Address Mental Health Needs of the Deaf and Hard of Hearing Community: Mixed Methods Study

BackgroundMental health concerns are a significant issue among the deaf and hard of hearing (D/HH) community, but community members can face several unique challenges to accessing appropriate resources. ObjectiveThe aim of this study was to investigate the mental health needs of the D/HH community and how mental health apps may be able to support these needs. MethodsA total of 10 members of the D/HH community participated in a focus group and survey to provide their perspectives and experiences. Participants were members of the Center on Deafness Inland Empire team, which comprises people with lived experience as members of and advocates for the D/HH community. ResultsFindings identified a spectrum of needs for mental health apps, including offering American Sign Language and English support, increased education of mental health to reduce stigma around mental health, direct communication with a Deaf worker, and apps that are accessible to a range of community members in terms of culture, resources required, and location. ConclusionsThese findings can inform the development of digital mental health resources and outreach strategies that are appropriate for the D/HH community

The integrated stress response contributes to tRNA synthetase-associated peripheral neuropathy.

Dominant mutations in ubiquitously expressed transfer RNA (tRNA) synthetase genes cause axonal peripheral neuropathy, accounting for at least six forms of Charcot-Marie-Tooth (CMT) disease. Genetic evidence in mouse and Drosophila models suggests a gain-of-function mechanism. In this study, we used in vivo, cell type-specific transcriptional and translational profiling to show that mutant tRNA synthetases activate the integrated stress response (ISR) through the sensor kinase GCN2 (general control nonderepressible 2). The chronic activation of the ISR contributed to the pathophysiology, and genetic deletion or pharmacological inhibition of Gcn2 alleviated the peripheral neuropathy. The activation of GCN2 suggests that the aberrant activity of the mutant tRNA synthetases is still related to translation and that inhibiting GCN2 or the ISR may represent a therapeutic strategy in CMT