Divergent gene expression patterns in alcohol and opioid use disorders lead to consistent alterations in functional networks within the Dorsolateral Prefrontal Cortex.

Substance Use Disorders (SUDs) manifest as persistent drug-seeking behavior despite adverse consequences, with Alcohol Use Disorder (AUD) and Opioid Use Disorder (OUD) representing prevalent forms associated with significant mortality rates and economic burdens. The co-occurrence of AUD and OUD is common, necessitating a deeper comprehension of their intricate interactions. While the causal link between these disorders remains elusive, shared genetic factors are hypothesized. Leveraging public datasets, we employed genomic and transcriptomic analyses to explore conserved and distinct molecular pathways within the dorsolateral prefrontal cortex associated with AUD and OUD. Our findings unveil modest transcriptomic overlap at the gene level between the two disorders but substantial convergence on shared biological pathways. Notably, these pathways predominantly involve inflammatory processes, synaptic plasticity, and key intracellular signaling regulators. Integration of transcriptomic data with the latest genome-wide association studies (GWAS) for problematic alcohol use (PAU) and OUD not only corroborated our transcriptomic findings but also confirmed the limited shared heritability between the disorders. Overall, our study indicates that while alcohol and opioids induce diverse transcriptional alterations at the gene level, they converge on select biological pathways, offering promising avenues for novel therapeutic targets aimed at addressing both disorders simultaneously.

Hurricane disturbance drives trophic changes in neotropical mountain stream food webs.

Food webs are complex ecological networks that reveal species interactions and energy flow in ecosystems. Prevailing ecological knowledge on forested streams suggests that their food webs are based on allochthonous carbon, driven by a constant supply of organic matter from adjacent vegetation and limited primary production due to low light conditions. Extreme climatic disturbances can disrupt these natural ecosystem dynamics by altering resource availability, which leads to changes in food web structure and functioning. Here, we quantify the response of stream food webs to two major hurricanes (Irma and María, Category 5 and 4, respectively) that struck Puerto Rico in September 2017. Within two tropical forested streams (first and second order), we collected ecosystem and food web data 6 months prior to the hurricanes and 2, 9, and 18 months afterward. We assessed the structural (e.g., canopy) and hydrological (e.g., discharge) characteristics of the ecosystem and monitored changes in basal resources (i.e., algae, biofilm, and leaf litter), consumers (e.g., aquatic invertebrates, riparian consumers), and applied Layman's community-wide metrics using the isotopic composition of 13 C and 15 N. Continuous stream discharge measurements indicated that the hurricanes did not cause an extreme hydrological event. However, the sixfold increase in canopy openness and associated changes in litter input appeared to trigger an increase in primary production. These food webs were primarily based on terrestrially derived carbon before the hurricanes, but most taxa (including Atya and Xiphocaris shrimp, the consumers with highest biomass) shifted their food source to autochthonous carbon within 2 months of the hurricanes. We also found evidence that the hurricanes dramatically altered the structure of the food web, resulting in shorter (i.e., smaller food-chain length), narrower (i.e., lower diversity of carbon sources) food webs, as well as increased trophic species packing. This study demonstrates how hurricane disturbance can alter stream food webs, changing the trophic base from allochthonous to autochthonous resources via changes in the physical environment (i.e., canopy defoliation). As hurricanes become more frequent and severe due to climate change, our findings greatly contribute to our understanding of the mechanisms that maintain forested stream trophic interactions amidst global change.

Feet and legs malformation in Nellore cattle: genetic analysis and prioritization of GWAS results.

Beef cattle affected by feet and legs malformations (FLM) cannot perform their productive and reproductive functions satisfactorily, resulting in significant economic losses. Accelerated weight gain in young animals due to increased fat deposition can lead to ligaments, tendon and joint strain and promote gene expression patterns that lead to changes in the normal architecture of the feet and legs. The possible correlated response in the FLM due to yearling weight (YW) selection suggest that this second trait could be used as an indirect selection criterion. Therefore, FLM breeding values and the genetic correlation between FLM and yearling weight (YW) were estimated for 295,031 Nellore animals by fitting a linear-threshold model in a Bayesian approach. A genome-wide association study was performed to identify genomic windows and positional candidate genes associated with FLM. The effects of single nucleotide polymorphisms (SNPs) on FLM phenotypes (affected or unaffected) were estimated using the weighted single-step genomic BLUP method, based on genotypes of 12,537 animals for 461,057 SNPs. Twelve non-overlapping windows of 20 adjacent SNPs explaining more than 1% of the additive genetic variance were selected for candidate gene annotation. Functional and gene prioritization analysis of candidate genes identified six genes (ATG7, EXT1, ITGA1, PPARD, SCUBE3, and SHOX) that may play a role in FLM expression due to their known role in skeletal muscle development, aberrant bone growth, lipid metabolism, intramuscular fat deposition and skeletogenesis. Identifying genes linked to foot and leg malformations enables selective breeding for healthier herds by reducing the occurrence of these conditions. Genetic markers can be used to develop tests that identify carriers of these mutations, assisting breeders in making informed breeding decisions to minimize the incidence of malformations in future generations, resulting in greater productivity and animal welfare.

Genomic screening of allelic and genotypic transmission ratio distortion in horse.

The phenomenon in which the expected Mendelian inheritance is altered is known as transmission ratio distortion (TRD). The TRD analysis relies on the study of the transmission of one of the two alleles from a heterozygous parent to the offspring. These distortions are due to biological mechanisms affecting gametogenesis, embryo development and/or postnatal viability, among others. In this study, TRD phenomenon was characterized in horses using SNP-by-SNP model by TRDscan v.2.0 software. A total of 1,041 Pura Raza Español breed horses were genotyped with 554,634 SNPs. Among them, 277 horses genotyped in trios (stallion-mare-offspring) were used to perform the TRD analysis. Our results revealed 140 and 42 SNPs with allelic and genotypic patterns, respectively. Among them, 63 displayed stallion-TRD and 41 exhibited mare-TRD, while 36 SNPs showed overall TRD. In addition, 42 SNPs exhibited heterosis pattern. Functional analyses revealed that the annotated genes located within the TRD regions identified were associated with biological processes and molecular functions related to spermatogenesis, oocyte division, embryonic development, and hormonal activity. A total of 10 functional candidate genes related to fertility were found. To our knowledge, this is the most extensive study performed to evaluate the presence of alleles and functional candidate genes with transmission ratio distortion affecting reproductive performance in the domestic horse.

Unravelling transmission ratio distortion across the bovine genome: identification of candidate regions for reproduction defects.

BACKGROUND: Biological mechanisms affecting gametogenesis, embryo development and postnatal viability have the potential to alter Mendelian inheritance expectations resulting in observable transmission ratio distortion (TRD). Although the discovery of TRD cases have been around for a long time, the current widespread and growing use of DNA technologies in the livestock industry provides a valuable resource of large genomic data with parent-offspring genotyped trios, enabling the implementation of TRD approach. In this research, the objective is to investigate TRD using SNP-by-SNP and sliding windows approaches on 441,802 genotyped Holstein cattle and 132,991 (or 47,910 phased) autosomal SNPs. RESULTS: The TRD was characterized using allelic and genotypic parameterizations. Across the whole genome a total of 604 chromosomal regions showed strong significant TRD. Most (85%) of the regions presented an allelic TRD pattern with an under-representation (reduced viability) of carrier (heterozygous) offspring or with the complete or quasi-complete absence (lethality) for homozygous individuals. On the other hand, the remaining regions with genotypic TRD patterns exhibited the classical recessive inheritance or either an excess or deficiency of heterozygote offspring. Among them, the number of most relevant novel regions with strong allelic and recessive TRD patterns were 10 and 5, respectively. In addition, functional analyses revealed candidate genes regulating key biological processes associated with embryonic development and survival, DNA repair and meiotic processes, among others, providing additional biological evidence of TRD findings. CONCLUSIONS: Our results revealed the importance of implementing different TRD parameterizations to capture all types of distortions and to determine the corresponding inheritance pattern. Novel candidate genomic regions containing lethal alleles and genes with functional and biological consequences on fertility and pre- and post-natal viability were also identified, providing opportunities for improving breeding success in cattle.

Transcriptome analysis of perirenal fat from Spanish Assaf suckling lamb carcasses showing different levels of kidney knob and channel fat.

Introduction: Suckling lamb meat is highly appreciated in European Mediterranean countries because of its mild flavor and soft texture. In suckling lamb carcasses, perirenal and pelvic fat depots account for a large fraction of carcass fat accumulation, and their proportions are used as an indicator of carcass quality. Material and Methods: This study aimed to characterize the genetic mechanisms that regulate fat deposition in suckling lambs by evaluating the transcriptomic differences between Spanish Assaf lambs with significantly different proportions of kidney knob and channel fat (KKCF) depots in their carcasses (4 High-KKCF lambs vs. 4 Low-KKCF lambs). Results: The analyzed fat tissue showed overall dominant expression of white adipose tissue gene markers, although due to the young age of the animals (17-36 days), the expression of some brown adipose tissue gene markers (e.g., UCP1, CIDEA) was still identified. The transcriptomic comparison between the High-KKCF and Low-KKCF groups revealed a total of 80 differentially expressed genes (DEGs). The enrichment analysis of the 49 DEGs with increased expression levels in the Low-KKCF lambs identified significant terms linked to the biosynthesis of lipids and thermogenesis, which may be related to the higher expression of the UCP1 gene in this group. In contrast, the enrichment analysis of the 31 DEGs with increased expression in the High-KKCF lambs highlighted angiogenesis as a key biological process supported by the higher expression of some genes, such as VEGF-A and THBS1, which encode a major angiogenic factor and a large adhesive extracellular matrix glycoprotein, respectively. Discussion: The increased expression of sestrins, which are negative regulators of the mTOR complex, suggests that the preadipocyte differentiation stage is being inhibited in the High-KKCF group in favor of adipose tissue expansion, in which vasculogenesis is an essential process. All of these results suggest that the fat depots of the High-KKCF animals are in a later stage of development than those of the Low-KKCF lambs. Further genomic studies based on larger sample sizes and complementary analyses, such as the identification of polymorphisms in the DEGs, should be designed to confirm these results and achieve a deeper understanding of the genetic mechanisms underlying fat deposition in suckling lambs.

Phenotypic variation in milk fatty acid composition and its association with stearoyl-CoA desaturase 1 (SCD1) gene polymorphisms in Gir cows.

Individual variation in milk fatty acid (FA) composition has been partially attributed to stearoyl-CoA desaturase 1 (SCD1) gene polymorphisms in taurine breeds, but much less is known for Zebu breeds. This study investigated the phenotypic variation in milk FA composition, and the influence of SCD1 variants on this trait and on milk fat desaturase indices (DI) in Gir cows. The functional impact of SCD1 variants was predicted using bioinformatics tools. Milk and blood samples were collected from 312 cows distributed in 10 herds from five states of Brazil. SCD1 variants were identified through target sequencing, and milk FA composition was determined by gas chromatography. Phenotypic variation in milk FA composition fell within the range reported for taurine breeds, with SCD18 index showing the lowest variation among the DI. Fourteen SCD1 variants were identified, six of which not previously described. Regarding the A293V polymorphism, all cows were homozygous for the C allele (coding for alanine), whereas all genotypes were detected for the second SNP affecting the 293 codon (G > A), with compelling evidence for functional effects. Significant associations (based on raw p-values) were found between this SNP and C12:0, cis-9, trans-11 CLA and short-chain FA, and between another SNP (rs523411937) and C15:0 and odd-chain linear FA. A new SNP on Chr26:21277069 was associated with trans-11 C18:1, cis-9, trans-11 CLA, C18:3 n-3 and n-3 FA. These findings indicate that SCD1 polymorphisms also contributes to the phenotypic variation in milk FA composition of Gir cows, with potential use in their breeding programmes.

Intergenerational impact of dietary protein restriction in dairy ewes on epigenetic marks in the perirenal fat of their suckling lambs.

In sheep, nutrition during the prepubertal stage is essential for growth performance and mammary gland development. However, the potential effects of nutrient restriction in a prepuberal stage over the progeny still need to be better understood. Here, the intergenerational effect of maternal protein restriction at prepubertal age (2 months of age) on methylation patterns was evaluated in the perirenal fat of Assaf suckling lambs. In total, 17 lambs from ewes subjected to dietary protein restriction (NPR group, 44% less protein) and 17 lambs from control ewes (C group) were analyzed. These lambs were ranked based on their carcass proportion of perirenal and cavitary fat and classified into HighPCF and LowPCF groups. The perirenal tissue from 4 NPR-LowPCF, 4 NPR-HighPCF, 4 C-LowPCF, and 4 C-HighPCF lambs was subjected to whole-genome bisulfite sequencing and differentially methylated regions (DMRs) were identified. Among other relevant processes, these DMRs were mapped in genes responsible for regulating the transition of brown to white adipose tissue and nonshivering thermoregulation, which might be associated with better adaptation/survival of lambs in the perinatal stage. The current study provides important biological insights about the intergenerational effect on the methylation pattern of an NPR in replacement ewes.

Testicular hypoplasia in Nellore Cattle: Genetic analysis and functional analysis of genome-wide association study results.

Characterized by the incomplete development of the germinal epithelium of the seminiferous tubules, Testicular hypoplasia (TH) leads to decreased sperm concentration, increased morphological changes in sperm and azoospermia. Economic losses resulting from the disposal of affected bulls reduce the efficiency of meat production systems. A genome-wide association study and functional analysis were performed to identify genomic windows and the underlying positional candidate genes associated with TH in Nellore cattle. Phenotypic and pedigree data from 207,195 animals and genotypes (461,057 single nucleotide polymorphism, SNP) from 17,326 sires were used in this study. TH was evaluated as a binary trait measured at 18 months of age. A possible correlated response on TH resulting from the selection for scrotal circumference was evaluated by using a two-trait analysis. Thus, estimated breeding values were calculated by fitting a linear-threshold animal model in a Bayesian approach. The SNP effects were estimated using the weighted single-step genomic BLUP method. Twelve non-overlapping windows of 20 adjacent SNP that explained more than 1% of the additive genetic variance were selected for candidate gene annotation. Functional and gene prioritization analysis of the candidate genes identified genes (KHDRBS3, GPX5, STAR, ERLIN2), which might play an important role in the expression of TH due to their known roles in the spermatogenesis process, synthesis of steroids and lipid metabolism.

Underlying genetic architecture of resistance to mastitis in dairy cattle: A systematic review and gene prioritization analysis of genome-wide association studies.

Mastitis, the most frequent disease in dairy cattle. Resistance to mastitis is a complex, polygenic trait controlled by several genes, each with small effects. Genome-wide association studies have been widely used to identify genomic variants associated with complex traits, including resistance to mastitis, to elucidate the underlying genetic architecture of the trait. However, no systematic review and gene prioritization analysis have been conducted to date on GWAS results for resistance to mastitis in dairy cattle. Hence, the objective was to perform a systematic review and gene prioritization analysis of GWAS studies to identify potential functional candidate genes associated with resistance to mastitis-related traits in dairy cattle. Four electronic databases were searched from inception to December 2020, supplemented with multiple sources of gray literature, to identify eligible articles. Annotation for genes and quantitative trait loci (QTL), and QTL enrichment analysis were conducted using GALLO. Gene prioritization analysis was performed by a guilty-by-association approach using GUILDify and ToppGene. From 52 articles included within this systematic review, 30 articles were used for further functional analyses. Gene and QTL annotation resulted in 9,125 and 43,646 unique genes and QTL, respectively, from 39 studies. In general, overlapping of genes across studies was very low (mean ± SD = 0.02% ± 0.07%). Most annotated genes were associated with somatic cell count-related traits and the Holstein breed. Within all annotated genes, 74 genes were shared among Holstein, Jersey, and Ayrshire breeds. Approximately 7.5% of annotated QTL were related to QTL class "health." Within the health QTL class, 2.6 and 2.2% of QTL were associated with clinical mastitis and somatic cell count-related traits. Enrichment analysis of QTL demonstrated that many enriched QTL were associated with somatic cell score located in Bos taurus autosomes 5, 6, 16, and 20. The prioritization analysis resulted in 427 significant genes after multiple test correction (false discovery rate of 5%) from 26 studies. Most prioritized genes were located in Bos taurus autosomes 19 and 7, and most top-ranked genes were from the cytokine superfamily (e.g., chemokines, interleukins, transforming growth factors, and tumor necrosis factor genes). Although most prioritized genes (397) were associated with somatic cell count-related traits, only 54 genes were associated with clinical mastitis-related traits. Twenty-four genes (ABCC9, ACHE, ADCYAP1, ARC, BCL2L1, CDKN1A, EPO, GABBR2, GDNF, GNRHR, IKBKE, JAG1, KCNJ8, KCNQ1, LIFR, MC3R, MYOZ3, NFKB1, OSMR, PPP3CA, PRLR, SHARPIN, SLC1A3, and TNFRSF25) were reported for both somatic cell count and clinical mastitis-related traits. Prioritized genes were mainly associated with immune response, regulation of secretion, locomotion, cell proliferation, and development. In conclusion, this study provided a fine-mapping of previously identified genomic regions associated with resistance to mastitis and identified key functional candidate genes for resistance to mastitis, which can be used to develop enhanced genomic strategies to combat mastitis by increasing mastitis resistance through genetic selection.

Unravelling the genetics of non-random fertilization associated with gametic incompatibility.

In the dairy industry, mate allocation is dependent on the producer's breeding goals and the parents' breeding values. The probability of pregnancy differs among sire-dam combinations, and the compatibility of a pair may vary due to the combination of gametic haplotypes. Under the hypothesis that incomplete incompatibility would reduce the odds of fertilization, and complete incompatibility would lead to a non-fertilizing or lethal combination, deviation from Mendelian inheritance expectations would be observed for incompatible pairs. By adding an interaction to a transmission ratio distortion (TRD) model, which detects departure from the Mendelian expectations, genomic regions linked to gametic incompatibility can be identified. This study aimed to determine the genetic background of gametic incompatibility in Holstein cattle. A total of 283,817 genotyped Holstein trios were used in a TRD analysis, resulting in 422 significant regions, which contained 2075 positional genes further investigated for network, overrepresentation, and guilt-by-association analyses. The identified biological pathways were associated with immunology and cellular communication and a total of 16 functional candidate genes were identified. Further investigation of gametic incompatibility will provide opportunities to improve mate allocation for the dairy cattle industry.

Deviations from Mendelian Inheritance on Bovine X-Chromosome Revealing Recombination, Sex-of-Offspring Effects and Fertility-Related Candidate Genes.

Transmission ratio distortion (TRD), or significant deviations from Mendelian inheritance, is a well-studied phenomenon on autosomal chromosomes, but has not yet received attention on sex chromosomes. TRD was analyzed on 3832 heterosomal single nucleotide polymorphisms (SNPs) and 400 pseudoautosomal SNPs spanning the length of the X-chromosome using 436,651 genotyped Holstein cattle. On the pseudoautosomal region, an opposite sire-TRD pattern between male and female offspring was identified for 149 SNPs. This finding revealed unique SNPs linked to a specific-sex (Y- or X-) chromosome and describes the accumulation of recombination events across the pseudoautosomal region. On the heterosomal region, 13 SNPs and 69 haplotype windows were identified with dam-TRD. Functional analyses for TRD regions highlighted relevant biological functions responsible to regulate spermatogenesis, development of Sertoli cells, homeostasis of endometrium tissue and embryonic development. This study uncovered the prevalence of different TRD patterns across both heterosomal and pseudoautosomal regions of the X-chromosome and revealed functional candidate genes for bovine reproduction.

Integrated analyses of the methylome and transcriptome to unravel sex differences in the perirenal fat from suckling lambs.

In sheep, differences were observed regarding fat accumulation and fatty acid (FA) composition between males and females, which may impact the quality and organoleptic characteristics of the meat. The integration of different omics technologies is a relevant approach for investigating biological and genetic mechanisms associated with complex traits. Here, the perirenal tissue of six male and six female Assaf suckling lambs was evaluated using RNA sequencing and whole-genome bisulfite sequencing (WGBS). A multiomic discriminant analysis using multiblock (s)PLS-DA allowed the identification of 314 genes and 627 differentially methylated regions (within these genes), which perfectly discriminate between males and females. These candidate genes overlapped with previously reported QTLs for carcass fat volume and percentage of different FAs in milk and meat from sheep. Additionally, differentially coexpressed (DcoExp) modules of genes between males (nine) and females (three) were identified that harbour 22 of these selected genes. Interestingly, these DcoExp were significantly correlated with fat percentage in different deposits (renal, pelvic, subcutaneous and intramuscular) and were associated with relevant biological processes for adipogenesis, adipocyte differentiation, fat volume and FA composition. Consequently, these genes may potentially impact adiposity and meat quality traits in a sex-specific manner, such as juiciness, tenderness and flavour.

Unrevealing functional candidate genes for bovine fertility through RNA sequencing meta-analysis and regulatory elements networks of co-expressed genes and lncRNAs.

The high genetic heterogeneity and environmental effects of subfertility in livestock species make the elucidation of the genetic mechanisms associated with reproductive efficiency a difficult task. Network and co-expression network meta-analyses were applied alongside genetic variant calling and long non-coding RNA (lncRNA) characterization to identify functionally relevant target genes and regulatory subnetworks associated with fertility in dairy cattle. In total, 505 lncRNAs (441 previously annotated in the bovine reference genome ARS-UCD 1.2 and 64 novel lncRNAs) were identified. Seven differentially expressed genes between high-fertile (HF) and sub-fertile (SF) Holstein cows were identified in the network meta-analysis (CA5A, ENSBTAG00000051149, ENSBTAG00000003272, DEFB7, DIO2, TRPV3, and COL4A4). Additionally, seven functional candidate differentially co-expressed (DcoExp) modules with a differential regulatory pattern (|z-score|>2) were identified between HF and SF cows. The functional candidate genes and DcoExp modules identified were associated with fertility relevant processes such as the regulation of embryonic implantation and proliferation, interaction and molecule transfer between the fetus and the cow, and the immune system. These results help to better understand the genetic mechanisms associated with reproductive efficiency in dairy cattle through the identification of potential biomarkers and genetic variants associated with differentially expressed regulatory gene and lncRNAs regulatory element networks.

Working memory and arithmetic impairments in children with FMR1 premutation and gray zone alleles.

Expansive mutations in familial mental retardation 1 (FMR1) gene have been associated with different phenotypes. Full mutations are associated with intellectual disability and autism spectrum disorder; premutations are associated with math learning difficulties and working memory impairments. In gray zone, neuropsychological development has not yet been described. Objectives: This study aimed to describe the frequency of FMR1 premutation and gray zone alleles in a school population sample representing a broad spectrum of variation in math achievement and detail school achievement and cognitive performance in the children identified with FMR1 premutation or gray zone alleles. Methods: We described a two-phase study. In the first phase, 2,195 school-age children were screened for math achievement. In the second phase, 378 children with normal intelligence were neuropsychologically assessed and genotyped for FMR1. Of these, 121 children (61 girls) performed below percentile 25 in mathematics (MD group) and 257 children (146 girls) performed above percentile 25 (control group). Results: Four pupils presented expanded alleles, one premutation and three gray zone alleles. The girl with the premutation and one boy with a gray zone allele presented impairments in working memory and arithmetic performance below percentile 6, compatible with the diagnosis of developmental dyscalculia. These children's difficulties were not associated with inaccuracy of nonsymbolic number representations or literacy impairments. Dyscalculia in these children seems to be associated mainly with working memory impairments. Conclusions: FMR1 expansions in the gray zone may contribute to dyscalculia in otherwise healthy and normally intelligent children.

Mutações expansivas no gene FMR1 têm sido associadas a diferentes fenótipos. Mutações completas estão associadas a deficiência intelectual e transtorno do espectro do autismo; pré-mutações, com dificuldades de aprendizagem de matemática e comprometimentos de memória de trabalho. Na zona cinzenta o desenvolvimento neuropsicológico ainda não foi descrito. Objetivos: Descrever a frequência de alelos pré-mutados e zona cinzenta em uma amostra escolar que representa amplo espectro de variação do desempenho em Matemática e detalhar o desempenho escolar e cognitivo em crianças identificadas com alelos pré-mutados ou zona cinzenta. Métodos: Aqui, descrevemos um estudo de duas fases. Na primeira fase, 2.195 crianças em idade escolar foram selecionadas para desempenho em Matemática. Na segunda fase, 378 crianças com inteligência normal foram avaliadas neuropsicologicamente e, em seguida, por genotipagem FMR1. Resultados: Tiveram desempenho abaixo do percentil 25 em Matemática (grupo DM) 121 crianças (61 meninas), e tiveram desempenho acima do percentil 25 (grupo controle) 257 crianças (146 meninas). Quatro alunos apresentaram alelos expandidos, sendo uma pré-mutação e três alelos da zona cinza. A menina com a pré-mutação e um menino com o alelo da zona cinza apresentaram prejuízos na memória de trabalho e desempenho aritmético abaixo do percentil 6, compatíveis com o diagnóstico de discalculia do desenvolvimento. As dificuldades dessas crianças não foram associadas à imprecisão de representações não simbólicas de números ou deficiências de alfabetização. A discalculia nessas crianças parece estar associada principalmente a deficiências da memória de trabalho. Conclusões: Em conclusão, expansões na zona cinzenta do FMR1 podem contribuir para a discalculia em crianças saudáveis com inteligência normal.

Emerging Blood-Based Biomarkers for Predicting Immunotherapy Response in NSCLC.

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has demonstrated a profitable performance for Non-Small Cell Lung Cancer (NSCLC) cancer treatment in some patients; however, there is still a percentage of patients in whom immunotherapy does not provide the desired results regarding beneficial outcomes. Therefore, obtaining predictive biomarkers for ICI response will improve the treatment management in clinical practice. In this sense, liquid biopsy appears as a promising method to obtain samples in a minimally invasive and non-biased way. In spite of its evident potential, the use of these circulating biomarkers is still very limited in the real clinical practice, mainly due to the huge heterogeneity among the techniques, the lack of consensus, and the limited number of patients included in these previous studies. In this work, we review the pros and cons of the different proposed biomarkers, such as soluble PD-L1, circulating non-coding RNA, circulating immune cells, peripheral blood cytokines, and ctDNA, obtained from liquid biopsy to predict response to ICI treatment at baseline and to monitor changes in tumor and tumor microenvironment during the course of the treatment in NSCLC patients.

NAToRA, a relatedness-pruning method to minimize the loss of dataset size in genetic and omics analyses.

Genetic and omics analyses frequently require independent observations, which is not guaranteed in real datasets. When relatedness cannot be accounted for, solutions involve removing related individuals (or observations) and, consequently, a reduction of available data. We developed a network-based relatedness-pruning method that minimizes dataset reduction while removing unwanted relationships in a dataset. It uses node degree centrality metric to identify highly connected nodes (or individuals) and implements heuristics that approximate the minimal reduction of a dataset to allow its application to complex datasets. When compared with two other popular population genetics methodologies (PLINK and KING), NAToRA shows the best combination of removing all relatives while keeping the largest possible number of individuals in all datasets tested and also, with similar effects on the allele frequency spectrum and Principal Component Analysis than PLINK and KING. NAToRA is freely available, both as a standalone tool that can be easily incorporated as part of a pipeline, and as a graphical web tool that allows visualization of the relatedness networks. NAToRA also accepts a variety of relationship metrics as input, which facilitates its use. We also release a genealogies simulator software used for different tests performed in this study.

Genome-wide association study for meat tenderness in beef cattle identifies patterns of the genetic contribution in different post-mortem stages.

The beef tenderization process during the post-mortem period is one of the most important sensorial attributes and it is well-established. The aim of this study was to identify the genetic contribution pattern to meat tenderness at 7-(LMD7), 14-(LMD14), and 21-(LMD21) days post-mortem. The heritabilities for LMD7 (0.194), LMD14 (0.142) and LMD21 (0.048) are well established in the population evaluated here. However, its genetic contribution in terms of genomic candidate regions is still poorly understood. Tenderness was measured in the Longissiums thoracis using Warner-Bratzler shear force in the three post-mortem periods. A total of 4323 crossbred beef cattle were phenotyped and genotyped using the Illumina BovineSNP50K. The percentage of the total genetic variance was estimated using the weighted single-step genomic best linear unbiased prediction method. The main candidate windows for LMD7 were associated with proteolysis of myofibrillar structures and the weakening endomysium and perimysium. Candidate windows for LMD14 and LMD21 were mapped in bovine QTLs for body composition, height and growth. Results presented herein highlight, the largest contribution of proteolysis related processes before 14-days post-mortem and body composition characteristics in later stages for meat tenderness.

A global agenda for advancing freshwater biodiversity research.

Global freshwater biodiversity is declining dramatically, and meeting the challenges of this crisis requires bold goals and the mobilisation of substantial resources. While the reasons are varied, investments in both research and conservation of freshwater biodiversity lag far behind those in the terrestrial and marine realms. Inspired by a global consultation, we identify 15 pressing priority needs, grouped into five research areas, in an effort to support informed stewardship of freshwater biodiversity. The proposed agenda aims to advance freshwater biodiversity research globally as a critical step in improving coordinated actions towards its sustainable management and conservation.

Identification and in silico characterization of structural and functional impacts of genetic variants in milk protein genes in the Zebu breeds Guzerat and Gyr.

Whole genome sequencing of bovine breeds has allowed identification of genetic variants in milk protein genes. However, functional repercussion of such variants at a molecular level has seldom been investigated. Here, the results of a multistep Bioinformatic analysis for functional characterization of recently identified genetic variants in Brazilian Gyr and Guzerat breeds is described, including predicted effects on the following: (i) evolutionary conserved nucleotide positions/regions; (ii) protein function, stability, and interactions; (iii) splicing, branching, and miRNA binding sites; (iv) promoters and transcription factor binding sites; and (v) collocation with QTL. Seventy-one genetic variants were identified in the caseins (CSN1S1, CSN2, CSN1S2, and CSN3), LALBA, LGB, and LTF genes. Eleven potentially regulatory variants and two missense mutations were identified. LALBA Ile60Val was predicted to affect protein stability and flexibility, by reducing the number the disulfide bonds established. LTF Thr546Asn is predicted to generate steric clashes, which could mildly affect iron coordination. In addition, LALBA Ile60Val and LTF Thr546Asn affect exonic splicing enhancers and silencers. Consequently, both mutations have the potential of affecting immune response at individual level, not only in the mammary gland. Although laborious, this multistep procedure for classifying variants allowed the identification of potentially functional variants for milk protein genes.