Ten years of the horse reference genome: insights into equine biology, domestication and population dynamics in the post-genome era.

The horse reference genome from the Thoroughbred mare Twilight has been available for a decade and, together with advances in genomics technologies, has led to unparalleled developments in equine genomics. At the core of this progress is the continuing improvement of the quality, contiguity and completeness of the reference genome, and its functional annotation. Recent achievements include the release of the next version of the reference genome (EquCab3.0) and generation of a reference sequence for the Y chromosome. Horse satellite-free centromeres provide unique models for mammalian centromere research. Despite extremely low genetic diversity of the Y chromosome, it has been possible to trace patrilines of breeds and pedigrees and show that Y variation was lost in the past approximately 2300 years owing to selective breeding. The high-quality reference genome has led to the development of three different SNP arrays and WGSs of almost 2000 modern individual horses. The collection of WGS of hundreds of ancient horses is unique and not available for any other domestic species. These tools and resources have led to global population studies dissecting the natural history of the species and genetic makeup and ancestry of modern breeds. Most importantly, the available tools and resources, together with the discovery of functional elements, are dissecting molecular causes of a growing number of Mendelian and complex traits. The improved understanding of molecular underpinnings of various traits continues to benefit the health and performance of the horse whereas also serving as a model for complex disease across species

Batti il tamburo e non avere paura.

Batti il tamburo e non aver paura è un verso di una poesia di Heinrich Heine, il maggiore poeta romantico tedesco (ebreo, contrario al pangermanesimo, morto esule a Parigi) che invita tutti al coraggio ed allo impegno, delineando un excursus tra parole chiave della filosofia della scienza e della matematica (in particolare, in Kant, Husserl e Hilbert), per ricavare i moniti alla Geomatica. Infatti questa è costituita da un insieme di discipline scientifiche e tecnologiche che possono offrire benefici al mondo ed alla società, ma causare danni gravi ed è compito dei ricercatori, tecnici, studenti ed operatori fare che scienza e tecnologia siano adoperate ai fini di pace, sviluppo e progresso, e non di guerra, abuso e dominio. Per quanto riguarda i tre studiosi, Kant è preso in considerazione, come geografo (storico e studioso della politica) e come filosofo della scienza e della morale (nelle prime due sue sintesi critiche, seppure della seconda solo brevemente). Husserl e Hilbert (nello ordine un filosofo di formazione matematica ed un matematico, attento a problemi di logica) sono presi in considerazione nelle loro ultime opere, rispettivamente sulla crisi delle scienze europee e sui fondamenti della matematica. Infatti questi due studiosi possono entrambi rappresentare insieme uno dei punti di arrivo delle possibili riletture kantiane e il segnavia per una ripartenza verso nuovi pensieri (rispettivamente la filosofia analitica della conoscenza ed il convenzionalismo critico della matematica)

Warmblood fragile foal syndrome type 1 mutation (PLOD1 c.2032G>A) is not associated with catastrophic breakdown and has a low allele frequency in the Thoroughbred breed.

BackgroundCatastrophic fractures are among the most common cause of fatalities in racehorses. Several factors, including genetics, likely contribute to increased risk for fatal injuries. A variant in the procollagen-lysine, 2-oxoglutarate 5-dioxygenase1 gene (PLOD1 c.2032G>A) was shown to cause Warmblood fragile foal syndrome type 1 (WFFS), a fatal recessive defect of the connective tissue. Screening of multiple horse breeds identified the presence of the WFFS allele in the Thoroughbred. PLOD1 is involved in cross-linking of collagen fibrils and thus could potentially increase the risk of catastrophic breakdown.ObjectivesEstimate the frequency of the WFFS allele (PLOD1 c.2032G>A) and determine if it is a risk factor for catastrophic breakdown in the Thoroughbred.Study designCase-control genetic study.MethodsGenomic DNA from hair and/or tissue samples was genotyped for the WFFS allele. Fisher's Exact tests were performed to compare allele and carrier frequencies between the case cohort (catastrophic breakdown, n = 22) and several cohorts with no record of injury (n = 138 raced/trained at same track and season and n = 185 older than 7 years and raced during same season), nonracers (n = 92), and a random sample without consideration for racing history (n = 279).ResultsThe frequency of the PLOD1 c.2032G>A variant in the Thoroughbred breed is low (1.2%). Seventeen of 716 Thoroughbreds tested were carriers (2.4%) and no WFFS homozygotes were detected. Only one catastrophic breakdown case carried the WFFS allele. No statistically significant difference in allele or carrier frequency was identified between case and control cohorts (P>0.05 in all comparisons performed).Main limitationsThis study evaluated cases from one single track.ConclusionsThis study demonstrated that the PLOD1 c.2032G>A associated with WFFS is present at very low frequency in Thoroughbreds and is not a genetic risk factor for catastrophic breakdown

Horses with equine recurrent uveitis have an activated CD4+ T-cell phenotype that can be modulated by mesenchymal stem cells in vitro.

Equine recurrent uveitis (ERU) is an immune-mediated disease causing repeated or persistent inflammatory episodes which can lead to blindness. Currently, there is no cure for horses with this disease. Mesenchymal stem cells (MSCs) are effective at reducing immune cell activation in vitro in many species, making them a potential therapeutic option for ERU. The objectives of this study were to define the lymphocyte phenotype of horses with ERU and to determine how MSCs alter T-cell phenotype in vitro. Whole blood was taken from 7 horses with ERU and 10 healthy horses and peripheral blood mononuclear cells were isolated. The markers CD21, CD3, CD4, and CD8 were used to identify lymphocyte subsets while CD25, CD62L, Foxp3, IFNγ, and IL10 were used to identify T-cell phenotype. Adipose-derived MSCs were expanded, irradiated (to control proliferation), and incubated with CD4+ T-cells from healthy horses, after which lymphocytes were collected and analyzed via flow cytometry. The percentages of T-cells and B-cells in horses with ERU were similar to normal horses. However, CD4+ T-cells from horses with ERU expressed higher amounts of IFNγ indicating a pro-inflammatory Th1 phenotype. When co-incubated with MSCs, activated CD4+ T-cells reduced expression of CD25, CD62L, Foxp3, and IFNγ. MSCs had a lesser ability to decrease activation when cell-cell contact or prostaglandin signaling was blocked. MSCs continue to show promise as a treatment for ERU as they decreased the CD4+ T-cell activation phenotype through a combination of cell-cell contact and prostaglandin signaling

Functionally Annotating Regulatory Elements in the Equine Genome Using Histone Mark ChIP-Seq.

One of the primary aims of the Functional Annotation of ANimal Genomes (FAANG) initiative is to characterize tissue-specific regulation within animal genomes. To this end, we used chromatin immunoprecipitation followed by sequencing (ChIP-Seq) to map four histone modifications (H3K4me1, H3K4me3, H3K27ac, and H3K27me3) in eight prioritized tissues collected as part of the FAANG equine biobank from two thoroughbred mares. Data were generated according to optimized experimental parameters developed during quality control testing. To ensure that we obtained sufficient ChIP and successful peak-calling, data and peak-calls were assessed using six quality metrics, replicate comparisons, and site-specific evaluations. Tissue specificity was explored by identifying binding motifs within unique active regions, and motifs were further characterized by gene ontology (GO) and protein-protein interaction analyses. The histone marks identified in this study represent some of the first resources for tissue-specific regulation within the equine genome. As such, these publicly available annotation data can be used to advance equine studies investigating health, performance, reproduction, and other traits of economic interest in the horse

Cost-effectiveness analysis of alectinib versus crizotinib in first-line treatment of anaplastic lymphoma kinase-positive advanced non-small cell lung cancer:

In the randomized, active-controlled, multicenter Phase III open-label ALEX trial, alectinib showed superior efficacy and lower toxicity compared with crizotinib in the primary treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer (ALK-positive NSCLC). The aim of this economic evaluation was to assess the cost-utility of alectinib versus crizotinib from the perspective of the Italian National Health Service (INHS). A partitioned survival model with three health states (progression-free, post-progression, and death) was used. The clinical data (progression-free survival, overall survival and time to progression) was based on the ALEX trial. Utility values were derived from EQ-5D scores evaluated in the ALEX trial and literature. Costs included drug treatments, progression-free, post-progression and supportive care. Direct medical costs and benefits (quality-adjusted life-years, QALYs) were discounted at a 3.0% annual rate. Uncertainty was assessed using deterministic and probabilistic sensitivity analyses. Treatment with alectinib versus crizotinib led to a gain of 2.82 life-years, 1.86 QALYs, and incremental costs of €58,276, resulting in an incremental cost-utility ratio of €31,353 per QALY. The deterministic analysis showed that the most critical parameters in the model were the cost of post-progression and utility scores. From the probabilistic sensitivity analysis, alectinib had a 64.5% probability of being cost-effective at a willingness-to-pay threshold of €40,000 per QALY. Compared with crizotinib, alectinib increased the length of the progression-free state and the QALYs. The incremental overall cost increase was reflective of longer treatment durations in the progression-free state. Compared with crizotinib, alectinib can be considered a valid cost-utility option in the treatment of naive patients with ALK-positive NSCLC

Breakfast skipping, weight, cardiometabolic risk, and nutrition quality in children and adolescents: A systematic review of randomized controlled and intervention longitudinal trials

Breakfast skipping increases with age, and an association with a high risk of being overweight (OW) and of obesity (OB), cardiometabolic risk, and unhealthy diet regimen has been demonstrated in observational studies with children and adults. Short-term intervention trials in adults reported conflicting results. The purpose of this systematic review was to summarize the association of breakfast skipping with body weight, metabolic features, and nutrition quality in the groups of young people that underwent randomized controlled (RCT) or intervention longitudinal trials lasting more than two months. We searched relevant databases (2000–2021) and identified 584 articles, of which 16 were suitable for inclusion. Overall, 50,066 children and adolescents were in-cluded. No studies analyzed cardiometabolic features. Interventions were efficacious in reducing breakfast skipping prevalence when multi-level approaches were used. Two longitudinal studies reported a high prevalence of OW/OB in breakfast skippers, whereas RCTs had negligible effects. Ten studies reported a lower-quality dietary intake in breakfast skippers. This review provides in-sight into the fact that breakfast skipping is a modifiable marker of the risk of OW/OB and unhealthy nutritional habits in children and adolescents. Further long-term multi-level intervention studies are needed to investigate the relationship between breakfast, nutrition quality, chronotypes, and cardiometabolic risk in youths

SAT0460 INGESTION OF LEMON JUICE MAY MODULATE BONE METABOLISM.

Background:An association between bone health and consumption of citrus fruits have been previously reported; however, the effect of lemon juice on bone metabolism have not been explored yet.Objectives:To investigate bone metabolic changes in postmenopausal women assuming lemon juice.Methods:Participants were postmenopausal osteoporotic women without history of clinical fractures who agreed to enrich their diet with lemon juice (Acti Lemon, Polenghi) over a 2-month period. The daily juice dose of 30 ml we suggested was equivalent to one Sicilian organic lemon. Surrogate markers of bone formation as procollagen type 1 N-propeptide (P1NP) and of bone resorption as C-terminal telopeptide of type I collagen (CTX), but also some regulators of bone metabolism as RANK-L, OPG, RANK-L/OPG ratio and sclerostin were assessed at baseline and then at 1 and 2 months after lemon juice administration. Controls were represented by a placebo group of age-matched osteoporotic postmenopausal women.Results:47 participants [mean age 60.2 ± 4.1 yr.] completed the study, without reporting any adverse events. Lemon juice was well tolerated. Over the observation period modifications of bone metabolism occurred: we detected a decreased RANK-L/OPG ratio and increased CTX levels at all time points vs. baseline. Particularly, change at month-1 of sclerostin (versus baseline) has been positively associated with change at month-1 and month-2 of CTX (r=0.46, p=0.01 and r=0.43, p=0.01, respectively). Change at month-1 of OPG was positively associated with change at month-1 of P1NP (r=0.49, p=0.006). Change at month-1 of RANKL/OPG has been related with variation at day 30 of P1NP (r=-0.44, p=0.013). Variation of P1NP at month-1 was related with sclerostin variation at day 30 (r=-0.56, p=0.02) and month-2 vs. baseline value (r=0.44, p=0.017) and with sclerostin variation between month-1 and month-2 (r=0.69, p<0.001). Variation of P1NP between month-1 and month-2 was associated with RANKL change at month-1 (r=-0.35, p=0.05), with sclerostin change at month-1 (r=-0.49, p=0.008) and with sclerostin change between month-1 and month-2 (r=0.41, p=0.028). At a multiple regression analysis the change of P1NP between month-1 and month-2 was independently predicted by the change of sclerostin at month-1 (ß=-1.5, SE 0.5, p=0.006), after correcting for age, BMI and change of RANKL and CTX levels at month-1. No significant modifications raised from controls.Conclusion:Drinking lemon juice may boost bone metabolic changes involving both bone resorption and bone formation.Disclosure of Interests:None declare