👤 Maria A Pedrosa

Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE) triggered by a shift in peripheral inflammation. A main mechanism by which peripheral alterations are transmitted to the brain is the infiltration of extracellular vesicles (EV). Hyperammonemic rats are a model of MHE that reproduces cognitive impairment. Injection of EV from plasma or peripheral blood mononuclear cells (PBMC) of hyperammonemic rats to normal rats induces neuroinflammation, alterations in neurotransmission, and cognitive impairment. PBMC contain different cell types. The aims were 1) to identify which cell type produces the pathological EV in hyperammonemic rats; 2) to identify the mechanisms by which hyperammonemia increases EV release from monocytes and induces the formation of pathological EV; and 3) to analyze the role of TNFα and PKA in these mechanisms. EV were isolated from primary cultures of CD4 In hyperammonemic rats, monocytes but not CD4 These data unveil that monocytes produce the pathological EV in hyperammonemia and the underlying mechanisms and provide the bases for new treatments to improve cognitive and motor function in hyperammonemia and MHE. Show less

Nowadays, there is an unmet need for reliable and minimally-invasive diagnosis tools capable of detecting Alzheimer's disease at early stages. Such tools could significantly reduce the reliance on confirmatory tests that are invasive and costly, such as cerebrospinal fluid (CSF) biomarkers and neuroimaging. The aim of this study is to validate previously developed diagnosis tools (multivariate models and plasma p-Tau217 levels) in three independents cohorts. For this, a cohort was obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) including some variables (age, Apolipoprotein E (ApoE) genotype, plasma p-Tau217, CSF biomarkers) (n = 113); and two cohorts from cognitive disorders units (Hospital Universitari i Politècnic La Fe (HUiPLaFe, n = 163), Hospital Doctor Peset (n = 31)), whose plasma samples were analysed to determine plasma p-Tau217, and to evaluate the previous diagnosis tools performance. For the cohort from HUiPLaFe, the multivariate model (plasma p-Tau217, age, ApoE genotype) showed a sensitivity of 94.9% and a specificity of 88.2%; for the cohort from Hospital Doctor Peset, the sensitivity was 100% and specificity 80%; for the ADNI cohort, sensitivity was 89.5% and specificity 39.5%. Regarding the plasma p-Tau217 levels, the results were satisfactory for the cognitive disorders units; while ADNI cohort showed very low specificity. In conclusion, the multivariate model was clinically validated in independent cohorts from clinical units, representing its first step for implementation. Show less

Genetic progress for fertility and reproduction traits in dairy cattle has been limited due to the low heritability of most indicator traits. Moreover, most of the quantitative trait loci (QTL) and candidate genes associated with these traits remain unknown. In this study, we used 5.6 million imputed DNA sequence variants (single nucleotide polymorphisms, SNPs) for genome-wide association studies (GWAS) of 18 fertility and reproduction traits in Holstein cattle. Aiming to identify pleiotropic variants and increase detection power, multiple-trait analyses were performed using a method to efficiently combine the estimated SNP effects of single-trait GWAS based on a chi-square statistic. There were 87, 72, and 84 significant SNPs identified for heifer, cow, and sire traits, respectively, which showed a wide and distinct distribution across the genome, suggesting that they have relatively distinct polygenic nature. The biological functions of immune response and fatty acid metabolism were significantly enriched for the 184 and 124 positional candidate genes identified for heifer and cow traits, respectively. No known biological function was significantly enriched for the 147 positional candidate genes found for sire traits. The most important chromosomes that had three or more significant QTL identified are BTA22 and BTA23 for heifer traits, BTA8 and BTA17 for cow traits, and BTA4, BTA7, BTA17, BTA22, BTA25, and BTA28 for sire traits. Several novel and biologically important positional candidate genes were strongly suggested for heifer (SOD2, WTAP, DLEC1, PFKFB4, TRIM27, HECW1, DNAH17, and ADAM3A), cow (ANXA1, PCSK5, SPESP1, and JMJD1C), and sire (ELMO1, CFAP70, SOX30, DGCR8, SEPTIN14, PAPOLB, JMJD1C, and NELL2) traits. These findings contribute to better understand the underlying biological mechanisms of fertility and reproduction traits measured in heifers, cows, and sires, which may contribute to improve genomic evaluation for these traits in dairy cattle. Show less

The rs17782313 variant of the MC4R gene plays an important role in the obesity phenotype. Studies that evaluate environmental factors and genetic variants associated with obesity may represent a great advance in understanding the development of this disease. This work seeks to assess the association of the polymorphism of MC4R rs17782313 on plasma parameters, including leptin, ghrelin, tumor necrosis factor (TNFα) and interleukin 6 (IL6), and on the eating behaviors of morbidly obese women. 70 adult women with BMI between 40 and 60 kg/m This study found that female patients with the MC4R rs17782313 polymorphism had high levels of ghrelin and reduced levels of IL6 in the postprandial period. We observed a higher prevalence of severe binge eating in more than 50% of women with at least one risk allele. Our hypothesis is that the MC4R rs17782313 polymorphism may influence the release of ghrelin, even without being associated with feelings of hunger and satiety. More than half of women with this polymorphism exhibited severe binge eating. Level III: case-control analytic study. Show less

Identifying genes or genomic regions influencing carcass-quality traits such as fatness (FTN) is essential to optimize the genetic selection processes in beef cattle. The aim of this study was to identify genomic regions associated with FTN in Nellore cattle as well as to elucidate the metabolic pathways related to the phenotypic expression. Ultrasound-based measurements of FTN were collected in 11 750 animals, with 39 903 animals in the pedigree file. Additionally, 1440 animals were genotyped using the GGP-indicus 35K SNP panel, which contained 33 623 SNPs after quality control. Twenty genes related to FTN were found on 11 chromosomes, explaining 12.96% of the total additive genetic variance. Gene ontology revealed seven genes: NR1L2, PKD2, GSK3β, EXT1, RAD51B, SORCS1 and DPH6, associated with important processes related to FTN. In addition, novel candidate genes (MAATS1, LYPD1, CDK5RAP2, RAD51B, c13H2Oorf96 and TRAPPC11) were detected and could provide further knowledge to uncover genetic regions associated to carcass fatness in beef cattle. Show less

Genome-wide association study (GWAS) is a powerful tool to identify candidate genes and genomic regions underlying key biological mechanisms associated with economically important traits. In this context, the aim of this study was to identify genomic regions and metabolic pathways associated with backfat thickness (BFT) and rump fat thickness (RFT) in Nellore cattle, raised in pasture-based systems. Ultrasound-based measurements of BFT and RFT (adjusted to 18 months of age) were collected in 11,750 animals, with 39,903 animals in the pedigree file. Additionally, 1,440 animals were genotyped using the GGP-indicus 35K SNP chip, containing 33,623 SNPs after the quality control. The single-step GWAS analyses were performed using the BLUPF90 family programs. Candidate genes were identified through the Ensembl database incorporated in the BioMart tool, while PANTHER and REVIGO were used to identify the key metabolic pathways and gene networks. A total of 18 genomic regions located on 10 different chromosomes and harbouring 23 candidate genes were identified for BFT. For RFT, 22 genomic regions were found on 14 chromosomes, with a total of 29 candidate genes identified. The results of the pathway analyses showed important genes for BFT, including TBL1XR1, AHCYL2, SLC4A7, AADAT, VPS53, IDH2 and ETS1, which are involved in lipid metabolism, synthesis of cellular amino acids, transport of solutes, transport between Golgi Complex membranes, cell differentiation and cellular development. The main genes identified for RFT were GSK3β, LRP1B, EXT1, GRB2, SORCS1 and SLMAP, which are involved in metabolic pathways such as glycogen synthesis, lipid transport and homeostasis, polysaccharide and carbohydrate metabolism. Polymorphisms located in these candidate genes can be incorporated in commercial genotyping platforms to improve the accuracy of imputation and genomic evaluations for carcass fatness. In addition to uncovering biological mechanisms associated with carcass quality, the key gene pathways identified can also be incorporated in biology-driven genomic prediction methods. Show less

Lactation persistency and milk production are among the most economically important traits in the dairy industry. In this study, we explored the association of over 6.1 million imputed whole-genome sequence variants with lactation persistency (LP), milk yield (MILK), fat yield (FAT), fat percentage (FAT%), protein yield (PROT), and protein percentage (PROT%) in North American Holstein cattle. We identified 49, 3991, 2607, 4459, 805, and 5519 SNPs significantly associated with LP, MILK, FAT, FAT%, PROT, and PROT%, respectively. Various known associations were confirmed while several novel candidate genes were also revealed, including Show less

Milking speed (MS) and temperament (MT) are 2 workability traits of great importance in dairy cattle production and breeding. This is mainly due to an increased intensification of the worldwide production systems and greater adoption of precision technologies with less human-cattle interaction. Both MS and MT are heritable traits and thus, genomic selection is a promising tool to expedite their genetic progress. However, the genetic architecture and biological mechanisms underlying the phenotypic expression of these traits remain underexplored. In this study, we investigated the association of >5.7 million imputed whole-genome sequence variants with MT and MS in 4,381 and 4,219 North American Holstein cattle, respectively. The statistical analyses were performed using a mixed linear model fitting a polygenic effect. We detected 40 and 35 significant SNPs independently associated with MT and MS, respectively, which were distributed across 26 chromosomes. Eight candidate genes (GRIN3A, KCNJ3, BOSTAUV1R417, BOSTAUV1R419, MAP2K5, KCTD3, GAP43, and LSAMP) were suggested to play an important role in MT as they are involved in biologically relevant pathways, such as glutamatergic synapse, vomeronasal receptor and oxytocin signaling. Within their coding and upstream sequences, we used an independent data set to further detect or validate significantly differentiated SNP between cattle breeds with known differences in MT. There were fewer candidate genes potentially implicated in MS, but immunity-related genes (e.g., BOLA-NC1 and LOC512672), also identified in other populations, were validated in this study. The significant SNP and novel candidate genes identified contribute to a better understanding of the biological mechanisms underlying both traits in dairy cattle. This information will also be useful for the optimization of prediction of genomic breeding values by giving greater weights to SNP located in the genomic regions identified. Show less

Hypertrophic cardiomyopathy (HC) is the most prevalent genetic cardiac disease caused by a mutation in sarcomeres, Z-disks, or calcium-handling genes and is characterized by unexplained left ventricular hypertrophy. The aim of this study was to determine the genetic profile of Brazilian patients with HC and correlate the genotype with the phenotype. We included 268 index patients from São Paulo city and 3 other cities in Brazil and extracted their DNA from whole blood. We amplified the coding sequencing of MYH7, MYBPC3, and TNNT2 genes and sequenced them with an automatic sequencer. We identified causal mutations in 131 patients (48.8%). Seventy-eight (59.5%) were in the MYH7 gene, 50 (38.2%) in the MYBPC3 gene, and 3 (2.3%) in the TNNT2 gene. We identified 69 mutations, 24 not previously described. Patients with an identified mutation were younger at diagnosis and at current age, had a higher mean heart rate and higher nonsustained ventricular tachycardia frequency compared with those without a mutation. Patients with MYH7 gene mutations had a larger left atrium and higher frequency of atrial fibrillation than did patients with MYBPC3 gene mutations. The presence of a mutation in one of the genes suggests a worse prognosis. Mutations in the MYH7 gene, rather than in the MYBPC3 gene, were also related to a worse prognosis. This is the first work characterizing HC molecular epidemiology in the Brazilian population for the 3 most important genes. Show less

Recent findings regarding Dll4 function in physiological and pathological conditions indicate that this Notch ligand may constitute an important therapeutic target. Dll4 appears to be a major anti-angiogenic agent, occupying a central role in various angiogenic pathways. The first trials of anti-Dll4 therapy in mice demonstrated a paradoxical effect, as it reduced tumor perfusion and growth despite leading to an increase in vascular density. This is seen as the result of insufficient maturation of the newly formed vasculature causing a circulatory defect and increased tumor hypoxia. As Dll4 function is known to be closely dependent on expression levels, we envisioned that the therapeutic anti-Dll4 dosage could be modulated to result in the increase of adequately functional blood vessels. This would be useful in conditions where vascular function is a limiting factor for recovery, like wound healing and tissue hypoxia, especially in diabetic patients. Our experimental results in mice confirmed this possibility, revealing that low dosage inhibition of Dll4/Notch signaling causes improved vascular function and accelerated wound healing. Show less