Restrictive nosebands are common in equestrian sport. This is concerning, as recent evidence suggests that very tight nosebands can cause a physiological stress response, and may compromise welfare. The objective of the current study was to investigate relationships that noseband tightness has with oral behavior and with physiological changes that indicate a stress response, such as increases in eye temperature (measured with infrared thermography) and heart rate and decreases in heart rate variability (HRV). Horses (n = 12) wearing a double bridle and crank noseband, as is common in dressage at elite levels, were randomly assigned to four treatments: unfastened noseband (UN), conventional area under noseband (CAUN) with two fingers of space available under the noseband, half conventional area under noseband (HCAUN) with one finger of space under the noseband, and no area under the noseband (NAUN). During the tightest treatment (NAUN), horse heart rate increased (P = 0.003), HRV decreased (P < 0.001), and eye temperature increased (P = 0.011) compared with baseline readings, indicating a physiological stress response. The behavioral results suggest some effects from bits alone but the chief findings are the physiological readings that reflect responses to the nosebands at their tightest. Chewing decreased during the HCAUN (P < 0.001) and NAUN (P < 0.001) treatments. Yawning rates were negligible in all treatments. Similarly, licking was eliminated by the NAUN treatment. Following the removal of the noseband and double bridle during the recovery session, yawning (P = 0.015), swallowing (P = 0.003), and licking (P < 0.001) significantly increased compared with baseline, indicating a post-inhibitory rebound response. This suggests a rise in motivation to perform these behaviors and implies that their inhibition may place horses in a state of deprivation. It is evident that a very tight noseband can cause physiological stress responses and inhibit the expression of oral behaviors.
The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing nonpioneer TFs to enter otherwise inaccessible genomic sites. PU.1 deficiency fatally arrests lymphopoiesis and myelopoiesis in mice, but human congenital PU.1 disorders have not previously been described. We studied six unrelated agammaglobulinemic patients, each harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1. Affected patients lacked circulating B cells and possessed few conventional dendritic cells. Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation. Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear localize or bind target DNA. In PU.1-haploinsufficient pro–B cell lines, euchromatin was less accessible to nonpioneer TFs critical for B cell development, and gene expression patterns associated with the pro– to pre–B cell transition were undermined. Our findings molecularly describe a novel form of agammaglobulinemia and underscore PU.1’s critical, dose-dependent role as a hematopoietic euchromatin gatekeeper.
Despite substantial evidence for the central role of hemodynamic shear stress in the functional integrity of vascular endothelial cells, hemodynamic and molecular regulation of the endocardial endothelium lining the heart chambers remains understudied. We propose that regional differences in intracardiac hemodynamics influence differential endocardial gene expression leading to phenotypic heterogeneity of this cell layer. Measurement of intracardiac hemodynamics was performed using 4-dimensional flow MRI in healthy humans (n=8) and pigs (n=5). Local wall shear stress (WSS) and oscillatory shear indices (OSI) were calculated in three distinct regions of the LV – base, mid-ventricle (midV), and apex. In both the humans and pigs, WSS values were significantly lower in the apex and midV relative to the base. Additionally, both the apex and midV had greater oscillatory shear indices (OSI) than the base. To investigate regional phenotype, endocardial endothelial cells (EEC) were isolated from an additional 8 pigs and RNA sequencing was performed. A false discovery rate of 0.10 identified 1051 differentially expressed genes between the base and apex, and 321 between base and midV. Pathway analyses revealed apical upregulation of genes associated with translation initiation. Furthermore, tissue factor pathway inhibitor (TFPI; mean 50-fold) and prostacyclin synthase (PTGIS; 5-fold), genes prominently associated with antithrombotic protection, were consistently upregulated in LV apex. These spatio-temporal WSS values in defined regions of the left ventricle link local hemodynamics to regional heterogeneity in endocardial gene expression.
The mechanisms by which FOXP3 + T follicular regulatory (Tfr) cells simultaneously steer antibody formation toward microbe or vaccine recognition and away from self-reactivity remain incompletely understood. To explore underappreciated heterogeneity in human Tfr cell development, function, and localization, we used paired TCRVA / TCRVB sequencing to distinguish tonsillar Tfr cells that are clonally related to natural regulatory T cells (nTfr) from those likely induced from T follicular helper (Tfh) cells (iTfr). The proteins iTfr and nTfr cells differentially expressed were used to pinpoint their in situ locations via multiplex microscopy and establish their divergent functional roles. In silico analyses and in vitro tonsil organoid tracking models corroborated the existence of separate T reg -to-nTfr and Tfh-to-iTfr developmental trajectories. Our results identify human iTfr cells as a distinct CD38 + , germinal center–resident, Tfh-descended subset that gains suppressive function while retaining the capacity to help B cells, whereas CD38 − nTfr cells are elite suppressors primarily localized in follicular mantles. Interventions differentially targeting specific Tfr cell subsets may provide therapeutic opportunities to boost immunity or more precisely treat autoimmune diseases.
How FOXP3+ T follicular regulatory (Tfr) cells simultaneously steer antibody formation toward microbe/vaccine recognition and away from self-reactivity remains unsettled. To explore human Tfr cell provenance, function and location heterogeneity, we used paired TCRVA/TCRVB sequencing to distinguish tonsillar Tfr cells clonally related to natural Tregs (nTfr) from those likely induced from Tfh cells (iTfr). The proteins iTfr and nTfr cells differentially expressed were utilized to pinpoint their in situ locations via multi-plex microscopy and establish divergent functional roles. In-silico and tonsil organoid tracking models corroborated the existence of separate Treg-to-nTfr and Tfh-to-iTfr developmental trajectories. In total, we have identified human iTfr cells as a distinct CD38-expressing, GC-resident, Tfh-descended subset that gains suppressive function while retaining capacities for B-cell help whereas CD38- nTfr cells are elite suppressors primarily localized to follicular mantles. Interventions differentially targeting Tfr subsets may provide therapeutic opportunities to boost immunity or more precisely treat autoimmune diseases.
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