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The Functional Annotation of Animal Genomes (FAANG) project aims to identify genomic regulatory elements in both sexes across multiple stages of development in domesticated animals. This study represents the first stage of the FAANG project for the horse, Equus caballus. A biobank of 80 tissue samples, two cell lines and six body fluids was created from two adult Thoroughbred mares. Ante-mortem assessments included full physical examinations, lameness, ophthalmologic and neurologic evaluations. Complete blood counts and serum biochemistries were also performed. At necropsy, in addition to tissue samples, aliquots of serum, ethylenediaminetetraacetic acid (EDTA) plasma, heparinized plasma, cerebrospinal fluid, synovial fluid, urine and microbiome samples from all regions of the gastrointestinal and urogenital tracts were collected. Epidermal keratinocytes and dermal fibroblasts were cultured from skin samples. All tissues were grossly and histologically evaluated by a board-certified veterinary pathologist. The results of the clinical and pathological evaluations identified subclinical eosinophilic and lymphocytic infiltration throughout the length of the gastrointestinal tract as well as a mild clinical lameness in both animals. Each sample was cryo-preserved in multiple ways, and nuclei were extracted from selected tissues. These samples represent the first published systemically healthy equine-specific biobank with extensive clinical phenotyping ante- and post-mortem. The tissues in the biobank are intended for community-wide use in the functional annotation of the equine genome. The use of the biobank will improve the quality of the reference annotation and allow all equine researchers to elucidate unknown genomic and epigenomic causes of disease.

Objectives: Primary graft dysfunction (PGD) affects survival after lung transplant (LT). The current hypothesis was that prone positioning (PP), proposed as a rescue maneuver to treat refractory hypoxemia due to PGD, may improve LT outcomes, especially when applied early., Design: Bilateral LT recipients developing moderate-to-severe PGD within 24 hours from intensive care unit admission were enrolled. From January 2020 to November 2021, patients developing PGD after LT were turned prone between 24 and 48 hours after diagnosis, only in case of radiological or oxygenation worsening ("late PP" group). After November 2021, patients were routinely turned prone within 24 hours from PGD diagnosis ("early PP"). A propensity score-weighted analysis, adjusted for clinically relevant covariates, was applied., Setting: Intensive care unit., Participants: Bilateral LT recipients., Interventions: Early PP, late PP, or supine position., Measurements and Main Results: 130 LT patients were screened and 67 were enrolled. A total of 25 (37%) recipients were treated in the supine position, 24 (36%) in early PP, and 18 (27%) in late PP. After propensity score weighting, both supine treatment (estimated effect for 1 ventilator-free day = 8.23, standard error: 2.97, p = 0.007) and early PP treatment (estimated effect = 9.42, standard error: 2.59, p < 0.001) were associated with greater 28-day ventilator-free days than late PP treatment (reference). Compared with late PP, early PP was also associated with better oxygenation, driving pressure, and static respiratory system compliance. Compared with supine recipients, the early PP group showed better oxygenation at 72 hours after PGD diagnosis., Conclusions: Early PP in LT recipients with moderate-to-severe PGD seems to be associated with better 28-day ventilator-free days, oxygenation, and driving pressure than late PP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Mice with deficiency in tocopherol (alpha) transfer protein gene develop peripheral tocopherol deficiency and sensory neurodegeneration. Ttpa -/- mice maintained on diets with deficient α-tocopherol (α-TOH) had proprioceptive deficits by six months of age, axonal degeneration and neuronal chromatolysis within the dorsal column of the spinal cord and its projections into the medulla. Transmission electron microscopy revealed degeneration of dorsal column axons. We addressed the potential pathomechanism of α-TOH deficient neurodegeneration by global transcriptome sequencing within the spinal cord and cerebellum. RNA-sequencing of the spinal cord in Ttpa -/- mice revealed upregulation of genes associated with the innate immune response, indicating a molecular signature of microglial activation as a result of tocopherol deficiency. For the first time, low level Ttpa expression was identified in the murine spinal cord. Further, the transcription factor liver X receptor (LXR) was strongly activated by α-TOH deficiency, triggering dysregulation of cholesterol biosynthesis. The aberrant activation of transcription factor LXR suppressed the normal induction of the transcription factor retinoic-related orphan receptor-α (RORA), which is required for neural homeostasis. Thus we find that α-TOH deficiency induces LXR, which may lead to a molecular signature of microglial activation and contribute to sensory neurodegeneration., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The cause of immune-mediated myositis (IMM), characterized by recurrent, rapid-onset muscle atrophy in Quarter Horses (QH), is unknown. The histopathologic hallmark of IMM is lymphocytic infiltration of myofibers. The purpose of this study was to identify putative functional variants associated with equine IMM., Methods: A genome-wide association (GWA) study was performed on 36 IMM QHs and 54 breed matched unaffected QHs from the same environment using the Equine SNP50 and SNP70 genotyping arrays., Results: A mixed model analysis identified nine SNPs within a ~ 2.87 Mb region on chr11 that were significantly (P unadjusted  < 1.4 × 10 - 6 ) associated with the IMM phenotype. Associated haplotypes within this region encompassed 38 annotated genes, including four myosin genes (MYH1, MYH2, MYH3, and MYH13). Whole genome sequencing of four IMM and four unaffected QHs identified a single segregating nonsynonymous E321G mutation in MYH1 encoding myosin heavy chain 2X. Genotyping of additional 35 IMM and 22 unaffected QHs confirmed an association (P = 2.9 × 10 - 5 ), and the putative mutation was absent in 175 horses from 21 non-QH breeds. Lymphocytic infiltrates occurred in type 2X myofibers and the proportion of 2X fibers was decreased in the presence of inflammation. Protein modeling and contact/stability analysis identified 14 residues affected by the mutation which significantly decreased stability., Conclusions: We conclude that a mutation in MYH1 is highly associated with susceptibility to the IMM phenotype in QH-related breeds. This is the first report of a mutation in MYH1 and the first link between a skeletal muscle myosin mutation and autoimmune disease.

Objective: A pigment retinopathy has been reported in adult horses with equine motor neuron disease (EMND) arising from chronic α-tocopherol (α-TP) deficiency. A pigment retinopathy has not been identified in horses with neuroaxonal dystrophy/equine degenerative myeloencephalopathy (NAD/EDM) that affects genetically susceptible young horses with α-TP deficiency. The objective of this report is to describe, for the first time, a pigment retinopathy in a family of α-TP-deficient Warmbloods (WB) with clinically apparent NAD/EDM or EMND., Animals and Procedures: Twenty-five WB horses from one farm underwent complete neurologic and ophthalmic examinations and serum α-TP concentrations were assessed. Two of the most severely ataxic horses were euthanized and postmortem examinations performed., Results: Alpha-TP deficiency was widespread on this farm (22 of 25 horses). Eleven of 25 horses were clinically normal (age range 2-12 years), one had signs of EMND (6 years of age), 10 had signs of ataxia consistent with NAD/EDM (1-10 years), and two of these were postmortem confirmed concurrent NAD/EDM and EMND. A pigment retinopathy characterized by varying amounts of granular dark pigment in the tapetal retina was observed in four clinically apparent NAD/EDM horses (two postmortem confirmed concurrent NAD/EDM and EMND) and one horse with clinical signs of EMND., Conclusions: A pigment retinopathy can be present in young α-TP-deficient Warmblood horses with clinical signs of EMND as well as those with signs of NAD/EDM., (© 2016 American College of Veterinary Ophthalmologists.)

The aim of this study was to characterize functional parameters in the isolated and normothermic hemoperfused porcine beating heart model after pathophysiological stimuli for extended perfusion periods. Hearts were prepared and connected to a specially developed perfusion equipment, which simultaneously allowed perfusion with warm autologous blood as well as blood dialysis. Two groups were established: group A (12 hearts: no intervention) and group B (6 hearts: occlusion of the ramus circumflexus of the left coronary artery for 2 hours). Blood gas analyses and oxymetry were performed at baseline and every 30 min during a 6 hours perfusion period. Coronary perfusion pressure (CPP) and blood flow (CBF), right and left ventricular pressure, blood and dialyzate pH-values, and temperature were monitored online by a microcontroller. A steady state regarding the CPP and the CBF was achieved after 1 hour of perfusion for both groups. In group B, CPP increased during occlusion. Comparison of both groups showed no significant differences in the bicarbonate and sodium levels in blood and dialyzate. The potassium concentration in blood and dialyzate increased in both groups constantly during the experiments. No clear alteration of the oxygen consumption was observed. Lactate levels in blood and dialyzate increased during occlusion as did the aspartataminotransferase (AST) venous levels (both determined only for group B). Four concentrations of norepinephrine were injected into the stem of the coronary arteries (10, 20, 40, 80 microg). A clear inotropic effect of this hormone on right and left ventricular pressure was observed. It was concluded that longer perfusion periods and simulation of myocardial infarction for a clinically relevant period can be performed using this model. In addition, right and left ventricular function appear to be well preserved in this model, since the isolated porcine heart responded to norepinephrine stimuli.