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.

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.

Genetic variants of VWF gene in type 2 von Willebrand disease.

INTRODUCTION: von Willebrand disease (VWD) is the most common inherited bleeding disorder. Few studies have explored the molecular basis of type 2 VWD. AIM: This study aimed to identify variants associated with type 2 VWD. METHODS: We collected clinical and laboratory data, as well as response to desmopressin and bleeding assessment tool (BAT) score in patients diagnosed with type 2 VWD. We sequenced exons 17, 18, 20 and 28 of the VWF gene. RESULTS: We identified 19 different variants in 40 unrelated patients (47.5%). Most of the variants (84.2%) were found in exon 28. A total of 10/19 variants (52.6%) were identified as "likely causative" in 17/40 patients (42.5%), according to the ISTH-SSC and EAHAD VWF gene mutations databases. Nine variants were initially identified as potentially benign. However, through analyses in silico, four of these variants were reclassified as "likely pathogenic" (Ile1380Val, Asn1435Ser, Ser1486Leu and Tyr1584Cys). Response to desmopressin was associated with three variants: Met740Ile, Arg1597Gln and Tyr1584Cys. Major bleeding was associated with variants related to VWD subtypes 2B and 2M. CONCLUSION: In conclusion, we identified 19 variants, of which 14 are "likely pathogenic" and therefore associated with VWD. We suggest a possible association of pathogenic variants with major bleeding, response to desmopressin and BAT score ≥10, although this requires further confirmation.

Evidence for a Role of ACTN3 R577X Polymorphism in Football Player's Career Progression.

The aim was to investigate a possible role of the ACTN3 R577X polymorphism in a Brazilian football player's career progression. 2 questions were formulated: 1. Does ACTN3 polymorphism affect the probability of an individual being a professional football player? 2. Does this polymorphism affect the progression of the athlete throughout his career? The study included 353 players from first division Brazilian football clubs in the following categories: under-14 (U-14), U-15, U-17, U-20, and professional (PRO). The control group (CON) was composed of 100 healthy non-athletes. The chi-squared test was used to assess differences between the allele and genotype frequencies. Comparing football categories, the XX genotype was less frequent among professional players than in the U-20 (p<0.05) or the U-15 category (p<0.05). The RX genotype also presented more frequently in the PRO category than the U-14 category (p<0.05). Moreover, a trend towards a higher frequency of the RX genotype and a lower frequency of the XX genotype was observed in the professional category compared to U-20. These results suggest that the genotype in the ACTN3 polymorphism affects the probability of a football player progressing throughout his career and becoming professional, meaning that playing football selects against the ACTN3 XX genotype.

Whole genome sequencing of Guzerá cattle reveals genetic variants in candidate genes for production, disease resistance, and heat tolerance.

In bovines, artificial selection has produced a large number of breeds which differ in production, environmental adaptation, and health characteristics. To investigate the genetic basis of these phenotypical differences, several bovine breeds have been sequenced. Millions of new SNVs were described at every new breed sequenced, suggesting that every breed should be sequenced. Guzerat or Guzerá is an indicine breed resistant to drought and parasites that has been the base for some important breeds such as Brahman. Here, we describe the sequence of the Guzerá genome and the in silico functional analyses of intragenic breed-specific variations. Mate-paired libraries were generated using the ABI SOLiD system. Sequences were mapped to the Bos taurus reference genome (UMD 3.1) and 87% of the reference genome was covered at a 26X. Among the variants identified, 2,676,067 SNVs and 463,158 INDELs were homozygous, not found in any database searched, and may represent true differences between Guzerá and B. taurus. Functional analyses investigated with the NGS-SNP package focused on 1069 new, non-synonymous SNVs, splice-site variants (including acceptor and donor sites, and the conserved regions at both intron borders, referred to here as splice regions) and coding INDELs (NS/SS/I). These NS/SS/I map to 935 genes belonging to cell communication, environmental adaptation, signal transduction, sensory, and immune systems pathways. These pathways have been involved in phenotypes related to health, adaptation to the environment and behavior, and particularly, disease resistance and heat tolerance. Indeed, 105 of these genes are known QTLs for milk, meat and carcass, production, reproduction, and health traits. Therefore, in addition to describing new genetic variants, our approach provided groundwork for unraveling key candidate genes and mutations.

Are 22q11.2 distal deletions associated with math difficulties?

Approximately 6% of school-aged children have math difficulties (MD). A neurogenetic etiology has been suggested due to the presence of MD in some genetic syndromes such as 22q11.2DS. However, the contribution of 22q11.2DS to the MD phenotype has not yet been investigated. This is the first population-based study measuring the frequency of 22q11.2DS among school children with MD. Children (1,564) were identified in the schools through a screening test for language and math. Of these children, 152 (82 with MD and 70 controls) were selected for intelligence, general neuropsychological, and math cognitive assessments and for 22q11.2 microdeletion screening using MLPA. One child in the MD group had a 22q11.2 deletion spanning the LCR22-4 to LCR22-5 interval. This child was an 11-year-old girl with subtle anomalies, normal intelligence, MD attributable to number sense deficit, and difficulties in social interactions. Only 19 patients have been reported with this deletion. Upon reviewing these reports, we were able to characterize a new syndrome, 22q11.2 DS (LCR22-4 to LCR22-5), characterized by prematurity; pre- and postnatal growth restriction; apparent hypotelorism, short/upslanting palpebral fissures; hypoplastic nasal alae; pointed chin and nose; posteriorly rotated ears; congenital heart defects; skeletal abnormalities; developmental delay, particularly compromising the speech; learning disability (including MD, in one child); intellectual disability; and behavioral problems. These results suggest that 22q11.2 DS (LCR22-4 to LCR22-5) may be one of the genetic causes of MD.

Novel SNPs and INDEL polymorphisms in the 3'UTR of DGAT1 gene: in silico analyses and a possible association.

Diacylglycerol-O-acyltransferase (DGAT1) gene encodes the rate-limiting enzyme of triglyceride synthesis. A polymorphism in this gene, DGAT1 K232A, has been associated with milk production and composition in taurine breeds. However, this polymorphism is not a good tool for ascertaining the effects of this QTL in Bos indicus (Zebu), since the frequency of the DGAT1 232A allele is too low in these breeds. We sequenced the 3'-untranslated region of DGAT1 gene in a sample of bulls of the breeds Guzerá (Bos indicus) and Holstein (Bos taurus) and, using in silico analysis, we searched for genetic variation, evolutionary conservation, regulatory elements, and possible substitution effects. Six single nucleotide (SNPs) and one insertion-deletion (INDEL) polymorphisms were found in the Guzerá bulls. Additionally, we developed a preliminary association study, using this INDEL polymorphism as a genetic marker. A significant association was detected (P ≤ 0.05) between the INDEL (DGAT1 3'UTR INDEL) and the breeding values (BV) for protein, fat, and milk yields over a 305-day lactation period. The DGAT1 3' UTR INDEL genotype I/I (I, for insertion) was associated with lower BVs (-38.77 kg for milk, -1.86 kg for fat, and -1.48 kg for protein yields), when compared to the genotype I/D (D, for deletion). I/D genotype was lower D/D genotype (-34.98 kg milk, -1.73 kg fat, and -1.09 kg protein yields). This study reports the first polymorphism of DGAT1 3'UTR in the Guzerá breed, as well as its association with BV for milk protein, fat, and milk yields.

Metformin safety in the management of gestational diabetes.

OBJECTIVE: The use of metformin in pregnant women is still controversial, despite the increasing reports on metformin's safety and effectiveness. We aimed to evaluate the maternal and neonatal safety of metformin in subjects with gestational diabetes mellitus (GDM). METHODS: We retrospectively reviewed the clinical records of 186 pregnancies complicated with GDM surveilled at Hospital de Santa Maria, Lisboa, between 2011 and 2012. The maternal and neonatal outcomes of 32 females who took metformin during pregnancy were compared with 121 females controlled with diet and 33 insulin-treated females. RESULTS: Of the 186 GDM subjects, 32 (17.2%) received metformin during pregnancy. No statistical differences between the diet and metformin groups were found with regard to the rates of abortion, prematurity, preeclampsia, macrosomy, small-for-gestational-age (SGA) or large-for-gestational-age (LGA) newborns, cesarean deliveries, neonatal intensive care unit (NICU) admissions, and birth malformations or neonatal injuries. Similarly, there were no differences between the metformin and insulin groups with regard to the referred outcomes. No abortions or perinatal deaths were recorded in the metformin group. Ten out of 32 metformin patients required additional insulin. CONCLUSION: This retrospective study suggests that metformin is a safe alternative or additional treatment to insulin in females with GDM. Metformin was not associated with a higher risk of maternal or neonatal complications when compared to the insulin or diet groups.

In deep bioinformatic characterization of a novel fumarate hydratase variant FH c.199T > G; (p.Tyr67Asp) in hereditary leiomyomatosis and renal cell carcinoma.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare, autosomal dominant tumor predisposition syndrome characterized by variable development of multiple skin and uterus leiomyomas and aggressive forms of renal cell carcinoma (RCC). Mutations in fumarate hydratase (FH), one of the proteins in homologous recombination repair, precede the development of HLRCC with high penetrance. Considering the risk of early metastasis of RCC, FH has been included in mutation screening panels. The identification of a pathogenic FH variant guides the screening for tumors in the carriers. However, variants of uncertain significance (VUS) are frequent findings, limiting the clinical value of the mutation screening. Here, we describe the associated phenotype and an in-depth, multi-step Bioinformatic evaluation of the germline FH c.199T > G (p.Tyr67 > Asp) variant segregated in an HLRCC family. Evidence for FH c.199T > G; (p.Tyr67Asp) pathogenicity includes the variant segregation with the disease in three affected family members, its absence in populational databases, and the deep evolutionary conservation of the Tyr67 residue. At the protein level, this residue substitution causes the loss of molecular bonds and ionic interactions, affecting molecular dynamics and protein stability. Considering ACMG/AMP criteria, we propose the reclassification of the FH c.199T > G; (p.Tyr67Asp) variant to "likely pathogenic". In addition, the in-depth, in silico approach used here allowed us to understand how and why FH c.199T > G; (p.Tyr67Asp) could cause HLRCC. This could help in clinical management decisions concerning the monitoring of unaffected family members having this variant.

2023 UPDATE: Luso-Brazilian evidence-based guideline for the management of antidiabetic therapy in type 2 diabetes.

BACKGROUND: The management of antidiabetic therapy in people with type 2 diabetes (T2D) has evolved beyond glycemic control. In this context, Brazil and Portugal defined a joint panel of four leading diabetes societies to update the guideline published in 2020. METHODS: The panelists searched MEDLINE (via PubMed) for the best evidence from clinical studies on treating T2D and its cardiorenal complications. The panel searched for evidence on antidiabetic therapy in people with T2D without cardiorenal disease and in patients with T2D and atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), or diabetic kidney disease (DKD). The degree of recommendation and the level of evidence were determined using predefined criteria. RESULTS AND CONCLUSIONS: All people with T2D need to have their cardiovascular (CV) risk status stratified and HbA1c, BMI, and eGFR assessed before defining therapy. An HbA1c target of less than 7% is adequate for most adults, and a more flexible target (up to 8%) should be considered in frail older people. Non-pharmacological approaches are recommended during all phases of treatment. In treatment naïve T2D individuals without cardiorenal complications, metformin is the agent of choice when HbA1c is 7.5% or below. When HbA1c is above 7.5% to 9%, starting with dual therapy is recommended, and triple therapy may be considered. When HbA1c is above 9%, starting with dual therapyt is recommended, and triple therapy should be considered. Antidiabetic drugs with proven CV benefit (AD1) are recommended to reduce CV events if the patient is at high or very high CV risk, and antidiabetic agents with proven efficacy in weight reduction should be considered when obesity is present. If HbA1c remains above target, intensification is recommended with triple, quadruple therapy, or even insulin-based therapy. In people with T2D and established ASCVD, AD1 agents (SGLT2 inhibitors or GLP-1 RA with proven CV benefit) are initially recommended to reduce CV outcomes, and metformin or a second AD1 may be necessary to improve glycemic control if HbA1c is above the target. In T2D with HF, SGLT2 inhibitors are recommended to reduce HF hospitalizations and mortality and to improve HbA1c. In patients with DKD, SGLT2 inhibitors in combination with metformin are recommended when eGFR is above 30 mL/min/1.73 m2. SGLT2 inhibitors can be continued until end-stage kidney disease.

The ACTN3 genotype in soccer players in response to acute eccentric training.

Genetic factors can interfere with sporting performance. The identification of genetic predisposition of soccer players brings important information to trainers and coaches for individual training loads adjustment. Different responses to eccentric training could be observed by the genotype referred to as α-actinin-3 (ACTN3) in biomarkers of muscle damage, hormones and inflammatory responses. The aim of this study was to compare acute inflammatory responses, muscle damage and hormonal variations according to the eccentric training in soccer professional athletes with different genetic profiles of ACTN3 (XX, RX and RR). 37 soccer professional athletes (9 XX, 13 RX, 15 RR) were randomly divided into five stations associated to eccentric muscle contraction and plyometrics. Blood samples were taken from athletes pre-eccentric training, immediately after (post), 2- and 4-h post-eccentric training to determine hormone responses (cortisol and testosterone), muscle damage (CK and α-actin), and inflammatory responses (IL-6). After eccentric training, athletes XX presented higher levels for CK (4-h post), α-actin (post and 2-h post) and cortisol (post) compared to RR and RX athletes. However, RR and RX athletes presented higher levels of testosterone (post) and IL-6 (2 h post and 4 h post) compared to athletes XX. The main conclusion of this study is that professional soccer athletes homozygous to ACTN3XX gene are more susceptible to eccentric damage and present a higher catabolic state, demonstrated by metabolic, hormonal and immune responses post an eccentric training, in comparison to ACTN3RR and ACTN3RX groups.

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.

Do boys with MAOA_LPR*2R allele present cognitive and learning impairments?

Monoamine oxidase A (MAOA) polymorphisms have been associated with antisocial disorders. Less attention has been paid to the cognitive functioning of individuals with different MAOA alleles. No study has described the cognitive phenotype associated with the less frequent, low enzyme activity allele, MAOA_LPR*2R. Objective: We describe the cognitive correlates of boys having MAOA_LPR*2R allele, ascertained in a sample of school children with normal intelligence, not referred for behavioral disorders. Methods: Participants were eight boys, attending from the second to fifth grades in state-run schools. They were identified among 712 children with typical general cognitive ability, genotyped for MAOA_LPR polymorphism. Participants were assessed with general intelligence, mathematics and spelling achievement, and verbal and visuospatial working memory tests. Neuropsychological performance was compared to published standards, using 1 SD below the mean as a cutoff value for low performance. Results: Intelligence of boys with MAOA_LPR*2R allele varied from above average (N=2) to low average in the other children. Five out of eight boys with the MAOA_LPR*2R allele had low mathematics achievement, and three presented additional difficulties with spelling. Four out of eight children had low short-term and working memory performance. Discussion: This is the first study describing cognitive correlates and school performance in boys having the MAOA_LPR*2R allele. Having this allele, and therefore, probably low MAO-A activity, does not necessarily imply low intelligence or low school performance. However, learning difficulties, particularly in math, and low working memory performance were observed in boys having this allele. This suggests a role of MAOA in learning difficulties.

Polimorfismos da monoaminoxidase A (MAOA) são associados a transtornos antissociais. Menos atenção tem sido dada ao funcionamento cognitivo de indivíduos com diferentes alelos de MAOA. Nenhum estudo descreveu o fenótipo cognitivo associado ao alelo menos frequente, de baixa atividade enzimática, MAOA_LPR*2R. Objetivo: Descrevemos os correlatos cognitivos de meninos com o alelo MAOA_LPR*2R, identificados em uma amostra de escolares com inteligência normal, não encaminhados por transtornos de comportamento. Métodos: Oito meninos com o alelo MAOA_LPR*2R foram identificados entre 712 crianças genotipadas, com inteligência típica, que cursavam do 2º ao 5º ano em escolas públicas. Foram avaliados: inteligência, desempenho em matemática e ortografia, memória de trabalho verbal e visuoespacial. O desempenho foi comparado a normas publicadas, utilizando-se 1 desvio padrão (DP) abaixo da média como ponto de corte para desempenho rebaixado. Resultados: A inteligência dos meninos com alelo MAOA_LPR*2R variou de acima da média (N=2) a médio-inferior nas demais crianças. Cinco dos oito meninos com alelo MAOA_LPR*2R apresentaram desempenho rebaixado em matemática e três apresentaram dificuldades adicionais em ortografia. Quatro dos oito meninos apresentaram baixo desempenho de memória de curto prazo e de trabalho. Discussão: Este é o primeiro estudo a descrever os correlatos cognitivos e o desempenho escolar em meninos com alelo MAOA_LPR*2R. Ter esse alelo não significa necessariamente baixa inteligência ou baixo desempenho escolar. No entanto, dificuldades de aprendizagem, principalmente em matemática, e desempenho rebaixado da memória de trabalho foram observados em mais da metade dos meninos com esse alelo. Isso sugere um papel do MAOA nas dificuldades de aprendizagem.

MAOA-LPR polymorphism and math anxiety: A marker of genetic susceptibility to social influences in girls?

Math anxiety (MA) seems to result from an interaction of genetic vulnerability with negative experiences learning mathematics. Although mathematics achievement does not substantially differ between the sexes, MA levels are usually higher in girls. Molecular genetic markers of MA vulnerability have been seldom explored. This article examines the contribution of the monoamine oxidase A gene (MAOA) to MA and to sex differences in MA. Five hundred and sixty-eight third to fifth graders were genotyped for the MAOA-LPR polymorphism (a repetitive element in MAOA promoter that has been associated with MAOA enzymatic activity), and assessed on general cognitive ability, mathematics achievement, and the cognitive and affective dimensions of MA. MAOA-LPR genotypes were classified as high (MAOA-H) or low (MAOA-L) according to their predicted enzymatic activity. Mixed models controlling for effects of school, sex, general cognitive ability, and mathematics achievement were evaluated. The best fitting model included school, math achievement, sex, MAOA-LPR, and the MAOA-LPR by sex interaction. This indicated that under the MAOA-H dominant model, anxiety toward mathematics interacted with the MAOA genotype: girls with an MAOA-L genotype exhibited higher levels of MA, with a small but significant effect. The association between MAOA-L genotype and MA in girls may represent an example of developmental plasticity.

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.

Allele distribution of six STR/miniSTR loci (CD4, FABP2, D12S391, D14S1434, D22S1045 and D10S1248) for forensic purposes in Southeastern Brazil.

BACKGROUND: Allele frequencies for six STR/miniSTR loci were determined in a sample of unrelated individuals from Southeastern Brazil. METHODS AND RESULTS: No significant deviations from Hardy-Weinberg equilibrium proportions were observed for the loci investigated (p-values ≥ 0.2320). Statistical parameters of forensic interest such as heterozygosity (H), power of discrimination (PD) and power of exclusion (PE) were estimated. Except for marker FABP2, all STR/miniSTRs tested showed observed heterozygosities over 0.66.Combined power of discrimination and power of exclusion were 0.9999993 and 0.9925, respectively. CONCLUSIONS: Due to their ease of analysis and high informativity, these new STR multiplexes will be useful for extending current marker sets for forensic and paternity purposes.

Genetic Diversity and Population Genetic Structure of a Guzerá (Bos indicus) Meta-Population.

The Brazilian Guzerá population originated from a few founders introduced from India. These animals adapted well to the harsh environments in Brazil, were selected for beef, milk, or dual-purpose (beef and milk), and were extensively used to produce crossbred animals. Here, the impact of these historical events with regard to the population structure and genetic diversity in a Guzerá meta-population was evaluated. DNA samples of 744 animals (one dairy, nine dual-purpose, and five beef herds) were genotyped for 21 microsatellite loci. Ho, He, PIC, Fis, Fit, and Fst estimates were obtained considering either farms or lineages as subpopulations. Mean Ho (0.73) and PIC (0.75) suggest that genetic diversity was efficiently conserved. Fit, Fis and Fst values (95% CI) pointed to a low fixation index, and large genetic diversity: Fit (Farms = 0.021-0.100; lineages = 0.021-0.100), Fis (Farms = -0.007-0.076; lineages = -0.014-0.070), and Fst (Farms = 0.0237-0.032; lineages = 0.029-0.038). The dual-purpose herds/selection lines are the most uniform subpopulation, while the beef one preserved larger amounts of genetic diversity among herds. In addition, the dairy herd showed to be genetically distant from other herds. Taken together, these results suggest that this Guzerá meta-population has high genetic diversity, a low degree of population subdivision, and a low inbreeding level.

The quandary of diagnosing mathematical difficulties in a generally low performing population.

Brazilian students' mathematical achievement was repeatedly observed to fall below average levels of mathematical attainment in international studies such as PISA. OBJECTIVE: In this article, we argue that this general low level of mathematical attainment may interfere with the diagnosis of developmental dyscalculia when a psychometric criterion is used establishing an arbitrary cut-off (e.g., performance

O desempenho em matemática dos estudantes brasileiros mostra-se consistentemente abaixo da média mundial em estudos internacionais como o PISA. OBJETIVO: No presente artigo, argumenta-se que um baixo desempenho geral na matemática, a exemplo dos estudantes brasileiros, pode interferir no diagnóstico de discalculia do desenvolvimento quando um critério puramente psicométrico é usado para estabelecer um ponto de corte arbitrário (por exemplo, desempenho

Mutational analysis of two boys with the severe perinatally lethal Melnick-Needles syndrome.

Melnick-Needles syndrome (MNS) (OMIM 309350) is a rare, X-linked dominant condition, caused by mutations in the filamin A gene (FLNA, on Xq28). In females, the syndrome presents with bone dysplasia and characteristic facial changes. Affected males may show two different phenotypes. One is similar to the female phenotype and is seen in children born to unaffected mothers and suggesting new mutations. Alternatively, males born to affected mothers have an embryonic or perinatally lethal disorder. It has been claimed that MNS constitutes part of a spectrum including frontometaphyseal dysplasia, otopalatodigital syndrome type 1 (OPD1) and otopalatodigital syndrome type 2 (OPD2). These conditions are produced by different mutations in the filamin A gene (FLNA). MNS is caused by three different mutations in FLNA exon 22, to date detected only in females. We describe the clinical manifestations and present the results of FLNA exon 22 mutations screening in two boys with the perinatally lethal form of MNS and their affected mothers. In order to obtain DNA amplification from paraffin-embedded tissues, we designed a new method based on hemi-nested PCR. One of the children (and his mother) had a previously undescribed mutation produced by a double SNP in the positions 3776 and 3777 of the gene and leading to an amino acid substitution (NP_001447:p.[Gly1176Asp]). The second child (and his mother) had an already known mutation (NP_001447.2:p[.Ser1199Leu]). This is the first report confirming the presence FLNA mutations in boys with the perinatally lethal phenotype of MNS. (

Alpha blockade with doxazosin in pheochromocytoma--report of three cases.

Pheochromocytoma is a catecholamine-secreting tumor, for which the treatment of choice is complete surgical resection, when possible. Some form of preoperative pharmacological preparation is indicated. Most centers use alpha blockade, phenoxybenzamine being the preferred drug. There is little experience with the use of other alpha-blocking agents. The authors report three different cases in which doxazosin was used: as preoperative preparation of a patient with pheochromocytoma, as preparation for therapy in I-131-MIBG of a patient with a malignant pheochromocytoma, and as a pre-cesarean preparation in a pregnant woman with multiple endocrine neoplasia type 2A (MEN-2A). Doxazosin provided a safe alternative to phenoxybenzamine in the three cases described, with some advantages that the authors summarize.