The obese gut microbiome across the epidemiologic transition

Abstract The obesity epidemic has emerged over the past few decades and is thought to be a result of both genetic and environmental factors. A newly identified factor, the gut microbiota, which is a bacterial ecosystem residing within the gastrointestinal tract of humans, has now been implicated in the obesity epidemic. Importantly, this bacterial community is impacted by external environmental factors through a variety of undefined mechanisms. We focus this review on how the external environment may impact the gut microbiota by considering, the host’s geographic location ‘human geography’, and behavioral factors (diet and physical activity). Moreover, we explore the relationship between the gut microbiota and obesity with these external factors. And finally, we highlight here how an epidemiologic model can be utilized to elucidate causal relationships between the gut microbiota and external environment independently and collectively, and how this will help further define this important new factor in the obesity epidemic

Minnesota's forest trees

24 pages; includes drawings. This archival publication may not reflect current scientific knowledge or recommendations. Current information available from the University of Minnesota Extension: https://www.extension.umn.edu

Dual molecular mechanisms govern escape at immunodominant HLA A2-restricted HIV epitope

Serial accumulation of mutations to fixation in the SLYNTVATL (SL9) immunodominant, HIV p17 Gag-derived, HLA A2-restricted CTL epitope produce the SLFNTIAVL triple mutant ‘ultimate’ escape variant. These mutations in solvent-exposed residues are believed to interfere with TCR recognition, although confirmation has awaited structural verification. Here, we solved a TCR co-complex structure with SL9 and the triple escape mutant to determine the mechanism of immune escape in this eminent system. We show that, in contrast to prevailing hypotheses, the main TCR contact residue is 4N and the dominant mechanism of escape is not via lack of TCR engagement. Instead, mutation of solvent exposed residues in the peptide destabilize the peptide-HLA and reduce peptide density at the cell surface. These results highlight the extraordinary lengths that HIV employs to evade detection by high-affinity TCRs with a broad peptide-binding footprint and necessitate reevaluation of this exemplar model of HIV TCR escape

Diagnostic utility of new SCAT5 neurological screen sub-tests

Background The Sports Concussion Assessment Tool (SCAT) is recommended to screen for concussion following head impact events in elite sport. The most recent 5th edition (SCAT5) included a ‘rapid neurological screen’ which introduced new subtests examining comprehension, passive neck movement, and diplopia. This study evaluated the additional diagnostic value of these new subtests. Methods A prospective cohort study was performed in the Pro14 elite Rugby Union competition between September 2018 and January 2020. The SCAT5 was administered by the team doctor to players undergoing off-field screening for concussion during a medical room assessment. Sensitivity, specificity, false negatives, and positives were examined for SCAT5 comprehension, passive neck movement, and diplopia subtests. The reference standard was a final diagnosis of concussion, established by serial standardised clinical assessments over 48 h. Results Ninety-three players undergoing off-field screening for concussion were included. Sensitivity and specificity of the comprehension, passive neck movement, and diplopia subtests were 0, 8, 5% and 0, 91, 97%, respectively (concussion prevalence 63%). No players had any abnormality in comprehension. No players had abnormal passive neck movement or diplopia in the absence of abnormalities in other SCAT5 sub-components. Conclusions The new SCAT5 neurological screen subtests are normal in the majority of players undergoing off-field concussion screening and appear to lack diagnostic utility over and above other SCAT5 subtests

T-cell libraries allow simple parallel generation of multiple peptide-specific human T-cell clones

Isolation of peptide-specific T-cell clones is highly desirable for determining the role of T-cells in human disease, as well as for the development of therapies and diagnostics. However, generation of monoclonal T-cells with the required specificity is challenging and time-consuming. Here we describe a library-based strategy for the simple parallel detection and isolation of multiple peptide-specific human T-cell clones from CD8+ or CD4+ polyclonal T-cell populations. T-cells were first amplified by CD3/CD28 microbeads in a 96U-well library format, prior to screening for desired peptide recognition. T-cells from peptide-reactive wells were then subjected to cytokine-mediated enrichment followed by single-cell cloning, with the entire process from sample to validated clone taking as little as 6 weeks. Overall, T-cell libraries represent an efficient and relatively rapid tool for the generation of peptide-specific T-cell clones, with applications shown here in infectious disease (Epstein–Barr virus, influenza A, and Ebola virus), autoimmunity (type 1 diabetes) and cancer

Visions for a walking and cycling focussed urban transport system

Walking and cycling can make a considerable contribution to sustainable transport goals, building healthier and more sustainable communities and contributing to traffic and pollution reduction. There have been many national and local initiatives to promote walking and cycling, but without a long term vision and consistent strategy it is difficult to see how a significant change may be achieved. This paper presents three alternative visions for the role of walking and cycling in urban areas for the year 2030: each vision illustrates a ‘desirable’ walking- and cycling-oriented transport system against a different ‘exogenous social background’. These visions have been developed through a process of expert discussion and review and are intended to provide a stimulus for debate on the potential for and desirability of such alternative futures. Each is based on the UK and represents a substantial change to the current situation: in particular, each of the visions presents a view of a society where walking and cycling are considerably more important than is currently the case and where these modes cater for a much higher proportion of urban transport needs than at present. The visions show pictures of urban environments where dependence on motor vehicles has been reduced, in two of the visions to very low levels. The methodological approach for devising visions is informed by work on ‘utopian thinking’: a key concept underlying this approach is one of viewing the future in social constructivist terms (i.e. the future is what ‘we’, as a society, make it) rather than considering the future as something that can be ‘scientifically’ predicted by the extrapolation of current trends

Loss of Free Fatty Acid Receptor 2 leads to impaired islet mass and beta cell survival

The regulation of pancreatic β cell mass is a critical factor to help maintain normoglycemia during insulin resistance. Nutrient-sensing G protein-coupled receptors (GPCR) contribute to aspects of β cell function, including regulation of β cell mass. Nutrients such as free fatty acids (FFAs) contribute to precise regulation of β cell mass by signaling through cognate GPCRs, and considerable evidence suggests that circulating FFAs promote β cell expansion by direct and indirect mechanisms. Free Fatty Acid Receptor 2 (FFA2) is a β cell-expressed GPCR that is activated by short chain fatty acids, particularly acetate. Recent studies of FFA2 suggest that it may act as a regulator of β cell function. Here, we set out to explore what role FFA2 may play in regulation of β cell mass. Interestingly, Ffar2(-/-) mice exhibit diminished β cell mass at birth and throughout adulthood, and increased β cell death at adolescent time points, suggesting a role for FFA2 in establishment and maintenance of β cell mass. Additionally, activation of FFA2 with Gαq/11-biased agonists substantially increased β cell proliferation in in vitro and ex vivo proliferation assays. Collectively, these data suggest that FFA2 may be a novel therapeutic target to stimulate β cell growth and proliferation

Structural mechanism underpinning cross-reactivity of a CD8(+) T-cell clone that recognizes a peptide derived from human telomerase reverse transcriptase

T-cell cross-reactivity is essential for effective immune surveillance but has also been implicated as a pathway to autoimmunity. Previous studies have demonstrated that T-cell receptors (TCRs) that focus on a minimal motif within the peptide are able to facilitate a high level of T-cell cross-reactivity. However, the structural database shows that most TCRs exhibit less focused antigen binding involving contact with more peptide residues. To further explore the structural features that allow the clonally expressed TCR to functionally engage with multiple peptide-major histocompatibility complexes (pMHCs), we examined the ILA1 CD8(+) T-cell clone that responds to a peptide sequence derived from human telomerase reverse transcriptase. The ILA1 TCR contacted its pMHC with a broad peptide binding footprint encompassing spatially distant peptide residues. Despite the lack of focused TCR-peptide binding, the ILA1 T-cell clone was still cross-reactive. Overall, the TCR-peptide contacts apparent in the structure correlated well with the level of degeneracy at different peptide positions. Thus, the ILA1 TCR was less tolerant of changes at peptide residues that were at, or adjacent to, key contact sites. This study provides new insights into the molecular mechanisms that control T-cell cross-reactivity with important implications for pathogen surveillance, autoimmunity, and transplant rejection