Multidimensional profiling of rugby league players: A systematic scoping review and expert Delphi consensus.

Player profiling can aid talent identification and development by highlighting strengths and weaknesses, and evaluating training interventions. However, there is currently no consensus in rugby league on the qualities, skills, and characteristics (i.e.

'We're All (Cauliflower) Ears': A Delphi Study Including Staff and Players to Co-Construct Sports Science and Medicine (Performance and Wellbeing) Research Priorities for Premiership Rugby.

Sports invest in research to optimise performance and enhance athlete wellbeing. Involving stakeholders allows research priorities to be determined, maximising the adoption and relevance of research findings. A three-round modified Delphi process was used to establish wellbeing and performance research priorities for Premiership Rugby (Professional men's rugby union competition in England).

The impact of high-potential status on progression and conversion within a male rugby union talent system.

The conversion rate of junior athletes to senior performance is typically used to judge efficiency in talent development. This study aimed to calculate the conversion rate of English academy rugby union players conferred with 'high-potential' 'England Academy Player' status, distinguishing them from their age-matched peers, from academy selection into the Premiership, the elite domestic league. Conversion was calculated overall and between academies, considering when players were conferred high-potential status.

Immunotherapeutic targeting of aging-associated isoDGR motif in chronic lung inflammation.

Accumulation of damaged biomolecules in body tissues is the primary cause of aging and age-related chronic diseases. Since this damage often occurs spontaneously, it has traditionally been regarded as untreatable, with typical therapeutic strategies targeting genes or enzymes being ineffective in this domain. In this report, we demonstrate that an antibody targeting the isoDGR damage motif in lung tissue can guide immune clearance of harmful damaged proteins in vivo, effectively reducing age-linked lung inflammation.

IL-21 conditions antigen-presenting human γδ T-cells to promote IL-10 expression in naïve and memory CD4 T-cells.

Direct interaction between T-cells exerts a major influence on tissue immunity and inflammation across multiple body sites including the human gut, which is highly enriched in 'unconventional' lymphocytes such as γδ T-cells. We previously reported that microbial activation of human Vγ9/Vδ2 γδ T-cells in the presence of the mucosal damage-associated cytokine IL-15 confers the ability to promote epithelial barrier defence, specifically via induction of IL-22 expression in conventional CD4 T-cells. In the current report, we assessed whether other cytokines enriched in the gut milieu also functionally influence microbe-responsive Vγ9/Vδ2 T-cells.

γδ T cells respond directly and selectively to the skin commensal yeast Malassezia for IL-17-dependent fungal control.

Stable microbial colonization of the skin depends on tight control by the host immune system. The lipid-dependent yeast Malassezia typically colonizes skin as a harmless commensal and is subject to host type 17 immunosurveillance, but this fungus has also been associated with diverse skin pathologies in both humans and animals. Using a murine model of Malassezia exposure, we show that Vγ4+ dermal γδ T cells expand rapidly and are the major source of IL-17A mediating fungal control in colonized skin.

Role of PDGFRA cells and a CD55 PDGFRA fraction in the gastric mesenchymal niche.

PDGFRA-expressing mesenchyme supports intestinal stem cells. Stomach epithelia have related niche dependencies, but their enabling mesenchymal cell populations are unknown, in part because previous studies pooled the gastric antrum and corpus. Our high-resolution imaging, transcriptional profiling, and organoid assays identify regional subpopulations and supportive capacities of purified mouse corpus and antral PDGFRA cells.

Mucosal Immunity to Gut Fungi in Health and Inflammatory Bowel Disease.

The gut microbiome is a diverse microbial community composed of bacteria, viruses, and fungi that plays a major role in human health and disease. Dysregulation of these gut organisms in a genetically susceptible host is fundamental to the pathogenesis of inflammatory bowel disease (IBD). While bacterial dysbiosis has been a predominant focus of research for many years, there is growing recognition that fungal interactions with the host immune system are an important driver of gut inflammation.

Graded BMP signaling within intestinal crypt architecture directs self-organization of the Wnt-secreting stem cell niche.

Signals from the surrounding niche drive proliferation and suppress differentiation of intestinal stem cells (ISCs) at the bottom of intestinal crypts. Among sub-epithelial support cells, deep sub-cryptal CD81 PDGFRA trophocytes capably sustain ISC functions ex vivo. Here, we show that mRNA and chromatin profiles of abundant CD81 PDGFRA mouse stromal cells resemble those of trophocytes and that both populations provide crucial canonical Wnt ligands.

Smooth muscle contributes to the development and function of a layered intestinal stem cell niche.

Wnt and Rspondin (RSPO) signaling drives proliferation, and bone morphogenetic protein inhibitors (BMPi) impede differentiation, of intestinal stem cells (ISCs). Here, we identify the mouse ISC niche as a complex, multi-layered structure that encompasses distinct mesenchymal and smooth muscle populations. In young and adult mice, diverse sub-cryptal cells provide redundant ISC-supportive factors; few of these are restricted to single cell types.

Defining the structure, signals, and cellular elements of the gastric mesenchymal niche.

PDGFRA-expressing mesenchyme provides a niche for intestinal stem cells. Corresponding compartments are unknown in the stomach, where corpus and antral glandular epithelia have similar niche dependencies but are structurally distinct from the intestine and from each other. Previous studies considered antrum and corpus as a whole and did not assess niche functions.

pSILAC-Based Determination of Cellular Protein Sorting into Extracellular Vesicles.

The protein cargo of extracellular vesicles (EVs) determines their impact on recipient cell types and the downstream effects on biological function. Environmental cues can modify EV loading with proteins derived from the plasma membrane via endocytosis, obtained from the preexisting cytosolic pool via active sorting, or packaging with newly synthesized proteins drawn from trans-golgi networks. Given the major impact these pathways exert on EV content and functional potential, it is important to study how defined stimuli influence protein sorting into these vesicles for dispersal.

Happy Birthday? Relative Age Benefits and Decrements on the Rocky Road.

(1) Background: There is abundant literature in talent development investigating the relative age effect in talent systems. There is also growing recognition of the reversal of relative age advantage, a phenomenon that sees significantly higher numbers of earlier born players leaving talent systems before the elite level. However, there has been little investigation of the mechanisms that underpin relative age, or advantage reversal.

Prebiotic fructans have greater impact on luminal microbiology and CD3+ T cells in healthy siblings than patients with Crohn's disease: A pilot study investigating the potential for primary prevention of inflammatory bowel disease.

Background & Aims: Siblings of people with Crohn's disease (CD) share aspects of the disease phenotype (raised faecal calprotectin, altered microbiota), which are markers of risk for their own development of CD. The aim was to determine whether supplementation with prebiotic oligofructose/inulin induces a prebiotic response and impacts the risk phenotype in CD patients and siblings.

Methods: Patients with inactive CD (n = 19, CD activity index <150) and 12 of their unaffected siblings (with calprotectin >50 μg/g) ingested oligofructose/inulin (15 g/day) for three weeks.

Aging-induced isoDGR-modified fibronectin activates monocytic and endothelial cells to promote atherosclerosis.

Background And Aims: Aging is the primary risk factor for cardiovascular disease (CVD), but the mechanisms underlying age-linked atherosclerosis remain unclear. We previously observed that long-lived vascular matrix proteins can acquire 'gain-of-function' isoDGR motifs that might play a role in atherosclerotic pathology.

Methods: IsoDGR-specific mAb were generated and used for ELISA-based measurement of motif levels in plasma samples from patients with coronary artery diseases (CAD) and non-CAD controls.

Microenvironmental Hypoxia Induces Dynamic Changes in Lung Cancer Synthesis and Secretion of Extracellular Vesicles.

Extracellular vesicles (EVs) mediate critical intercellular communication within healthy tissues, but are also exploited by tumour cells to promote angiogenesis, metastasis, and host immunosuppression under hypoxic stress. We hypothesize that hypoxic tumours synthesize hypoxia-sensitive proteins for packing into EVs to modulate their microenvironment for cancer progression. In the current report, we employed a heavy isotope pulse/trace quantitative proteomic approach to study hypoxia sensitive proteins in tumour-derived EVs protein.

Patients with gastrointestinal irritability after TGN1412-induced cytokine storm displayed selective expansion of gut-homing αβ and γδT cells.

Following infusion of the anti-CD28 superagonist monoclonal antibody TGN1412, three of six previously healthy, young male recipients developed gastrointestinal irritability associated with increased expression of 'gut-homing' integrin β7 on peripheral blood αβT cells. This subset of patients with intestinal symptoms also displayed a striking and persistent expansion of putative Vδ2 γδT cells in the circulation which declined over a 2-year period following drug infusion, concordant with subsiding gut symptoms. These data demonstrate that TGN1412-induced gastrointestinal symptoms were associated with dysregulation of the 'gut-homing' pool of blood αβ and γδT cells, induced directly by the antibody and/or arising from the subsequent cytokine storm.

Immune reconstitution and clinical recovery following anti-CD28 antibody (TGN1412)-induced cytokine storm.

Cytokine storm can result from cancer immunotherapy or certain infections, including COVID-19. Though short-term immune-related adverse events are routinely described, longer-term immune consequences and sequential immune monitoring are not as well defined. In 2006, six healthy volunteers received TGN1412, a CD28 superagonist antibody, in a first-in-man clinical trial and suffered from cytokine storm.

Cellular and molecular architecture of the intestinal stem cell niche.

Intestinal stem and progenitor cells replicate and differentiate in distinct compartments, influenced by Wnt, BMP, and other subepithelial cues. The cellular sources of these signals were long obscure because intestinal mesenchyme was insufficiently characterised. In this Review, we discuss how recent mRNA profiles of mouse and human intestinal submucosa, coupled with fine-resolution microscopy and gene and cell disruptions, reveal a coherent picture of an organised tissue carrying cells with distinct molecular properties and functions.

Myelopoiesis of acute inflammation: lessons from TGN1412-induced cytokine storm.

TGN1412, a superagonist monoclonal antibody targeting CD28, caused cytokine storm in six healthy volunteers in a first-in-man study in 2006. Despite clinical improvement and termination of the cytokine release syndrome within days, anemia persisted in all patients with hemoglobin reaching baseline levels as much as 6 months later. Granulocytic dysplasia continued for 20 days in association with increased expression of CD69 and IL-4, but reduced IL-10; with resolution, this profile reversed to higher IL-10 expression and counter-balanced circannual cycling of IL-4 and IL-10 thereafter over 7 months.

Pulsed SILAM Reveals In Vivo Dynamics of Murine Brain Protein Translation.

Identification of proteins that are synthesized de novo in response to specific microenvironmental cues is critical for understanding molecular mechanisms that underpin vital physiological processes and pathologies. Here, we report that a brief period of SILAM (Stable Isotope Labeling of Mammals) diet enables the determination of biological functions corresponding to actively translating proteins in the mouse brain. Our results demonstrate that the synapse, dendrite, and myelin sheath are highly active neuronal structures that display rapid protein synthesis, producing key mediators of chemical signaling as well as nutrient sensing, lipid metabolism, and amyloid precursor protein processing/stability.

Distinct Mesenchymal Cell Populations Generate the Essential Intestinal BMP Signaling Gradient.

Intestinal stem cells (ISCs) are confined to crypt bottoms and their progeny differentiate near crypt-villus junctions. Wnt and bone morphogenic protein (BMP) gradients drive this polarity, and colorectal cancer fundamentally reflects disruption of this homeostatic signaling. However, sub-epithelial sources of crucial agonists and antagonists that organize this BMP gradient remain obscure.