Genetic variation modulates susceptibility to aberrant DNA hypomethylation and imprint deregulation in naïve pluripotent stem cells.

Naïve pluripotent stem cells (nPSC) frequently undergo pathological and not readily reversible loss of DNA methylation marks at imprinted gene loci. This abnormality poses a hurdle for using pluripotent cell lines in biomedical applications and underscores the need to identify the causes of imprint instability in these cells. We show that nPSCs from inbred mouse strains exhibit pronounced strain-specific susceptibility to locus-specific deregulation of imprinting marks during reprogramming to pluripotency and upon culture with MAP kinase inhibitors, a common approach to maintain naïve pluripotency. Analysis of genetically highly diverse nPSCs from the Diversity Outbred (DO) stock confirms that genetic variation is a major determinant of epigenome stability in pluripotent cells. We leverage the variable DNA hypomethylation in DO lines to identify several trans-acting quantitative trait loci (QTLs) that determine epigenome stability at either specific target loci or genome-wide. Candidate factors encoded by two multi-target QTLs on chromosomes 4 and 17 suggest specific transcriptional regulators that contribute to DNA methylation maintenance in nPSCs. We propose that genetic variants represent candidate biomarkers to identify pluripotent cell lines with desirable properties and might serve as entry points for the targeted engineering of nPSCs with stable epigenomes. Highlights: Naïve pluripotent stem cells from distinct inbred mouse strains exhibit variable DNA methylation levels at imprinted gene loci.The vulnerability of pluripotent stem cells to loss of genomic imprinting caused by MAP kinase inhibition strongly differs between inbred mouse strains.Genetically diverse pluripotent stem cell lines from Diversity Outbred mouse stock allow the identification of quantitative trait loci controlling DNA methylation stability.Genetic variants may serve as biomarkers to identify naïve pluripotent stem cell lines that are epigenetically stable in specific culture conditions.

Association of the rs4646994 in ACE gene with susceptibility to tuberculosis in a region of the Brazilian Amazon.

Background: Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacterium tuberculosis and represents an important global public health issue. Single-nucleotide polymorphisms and INDELs are common genetic variations that can be located in genes associated with immune response and, therefore, they may have direct implications over the phenotype of susceptibility to infections like tuberculosis. This study aimed to investigate the association between the 17 genetic polymorphisms and susceptibility to tuberculosis in a Brazilian population. Methods: This case-control study enrolled 283 individuals with active tuberculosis and 145 health care workers. Four INDELs and 13 single nucleotide polymorphisms and were genotyped using Multiplex PCR method and TaqMan SNP Genotyping Assays. Group comparisons for categorical variables were performed using the chi-squared test, whilst the t-Student test was used to analyze the continuous variables. Multiple logistic regression analyses were performed to estimate the odds ratio (OR) with 95% confidence intervals (CI). Deviation from Hardy-Weinberg equilibrium was assessed using chi-squared tests with Bonferroni correction. The results were analyzed comparing the genotypic distributions adopting the dominant model and the estimated values ​​of p corrected for multiple tests through FDR (False Discovery Rate) test. Results: The HWE test confirmed that the genotypic frequencies for polymorphisms were balanced. The frequency of Del allele was 73 and 75%, in cases and controls respectively. Frequency of Del allele was significantly higher in the control group than TB group. The homozygous Del/Del genotype was present in 51.6% of cases and 58.6% of controls. The rare Ins/Ins genotype was present in only 7.6% of controls and 6% of cases. The ACE Del/Del genotype was significantly higher in the cases than in controls revealing significant protection for TB in the domain model (OR = 0.465; p < 0.005). Conclusions: The Del/Del genotype of the rs4646994 in ACE gene was associated with susceptibility to tuberculosis. The identification of genetic variants responsible for susceptibility to tuberculosis will allow the development of new diagnostic tools for tuberculosis infection. These studies will help improve control and the future eradication of this disease.

Association between small-for-gestational age and neurocognitive impairment at two years of corrected age among infants born at preterm gestational ages: a cohort study.

OBJECTIVE: To investigate the association between small-for-gestational age (SGA) and neurocognitive impairment at 2 years of corrected age among infants born at preterm gestational ages. STUDY DESIGN: A secondary analysis of a prospectively conducted NICHD/Maternal-Fetal Medicine Units BEAM trial. Non-anomalous pregnancies delivered before 37 weeks of gestation were included in the analysis. Neurocognitive outcomes at 2 years of corrected age were compared between infants who were SGA (<10% for gestational age) and those appropriately grown (AGA). The primary outcome was a severe or moderate neurocognitive impairment at 2 years of corrected age among survivors, defined as either mental (MDI) or psychomotor (PDI) developmental index score <70 for severe and <85 for moderate impairment. RESULTS: Of 2299 preterm neonates 67 (3%) were SGA. SGA infants were more often twin pregnancies (31% vs 17%, P=0.003) and delivered more often by cesarean section (63% vs 40%, P<0.001) at similar gestational ages (30.0±2.6 vs 29.5±2.8 weeks, P=0.11). At 2 years of corrected age, SGA and AGA survivors had similar rates of neurocognitive impairment (MDI <70: 18% vs 18%, P=1.0; MDI <85: 44% vs 46%, P=0.96; PDI <70: 20% vs 15%, P=0.51; PDI <85: 40% vs 34%, P=0.48). CONCLUSION: In this cohort, SGA at preterm gestational ages was associated with similar rates of neurocognitive impairment at two years of corrected age among surviving infants.

Maturação biológica e desempenho físico de jovens atletas de ginástica rítmica / Biological maturation and physical performance of young athletes in rhythmic gymnastics

Objetivo: analisar a maturação biológica e desempenho da força em jovens atletas de ginástica rítmica. Materiais e Métodos: A amostra foi composta por nove moças da seleção paraibana (idade cronológica 12,44±3,00 anos), tempo de prática de 45,66+30,45meses submetidas aos testes físicos de: força de membros inferiores (dinamometria dorsal, salto horizontal e vertical) e membros superiores (dinamometria manual e medicineball) e testes antropométricos de: massa corporal, imc, altura total, envergadura, estatura, estadiamento de maturação sexual (EMS), por meio de auto-avaliação, pelas fotografias de Tanner, maturação óssea pelo método de Greulich-Pyle em Raio X com laudo médico no diagnóstico da idade. Resultados: Encontrou-se: massa corporal 45,9+5,6 kg; estatura 1,56±0,02 m; altura total 2,06±0,04 cm; envergadura 1,63±0,05 cm; IMC 18,6+1,8 kg/m2; idade óssea 15,9±2,2 anos e cronológica de 13,28±12,44 anos, apresentando diferenças significativas (p=0,001); EMS Púbis 2,33±1,22e Mama 3,11±0,93, sem diferenças significativas (p=0,065), sendo 33,3% pré-púberes e 66,7% púberes; o desempenho físico de salto horizontal foi de 150,52±10,01 cm, vertical 217,77±25,55 cm; força de membros superiores: arremesso de medicine ball 221±0,52cm; força em dinamometria manual 22,44±6,89 kg/f e dorsal 54,33±18,44 kg/f. Não foi encontrado diferenças entre os graus de maturação sexual e óssea e desempenho nos testes (p>0,076). Conclusão: A idade óssea é maior do que a cronológica, sendo que as maturações sexuais e ósseas não causaram impacto no desempenho da força.

Objective: To analyze the bone and sexual maturation, and strength performance in young athletes in rhythmic gymnastics. Methods: The sample consisted of nine girls of the Paraiba team (chronological age 12.44 +3.00 years), with practice time of 45.66 +30.45 months, subjected to physical tests: lower limb strength (dorsal dynamometry, horizontal and vertical jump) and upper limbs (handgrip and medicineball) and anthropometric tests: of body mass, BMI, height, wingspan, overall height, stage of sexual maturation (SSM), through self-assessment by photographs of Tanner, bone maturation by the method of Greulich-Pyle in X-ray medical report with the diagnosis of age. Results: There was a body mass 45.9±5.6 kg; height 1.56±0.02 m; overall height of 2.06±0.04 cm; wingspan 1.63±0.05 cm; BMI 18.6±1,8kg/m2, bone age 15.9 ± 2.2 years and chronological 13.28 ± 12.44 years, with significant differences (p=0.001); SSM Pubis 2.33±1.22 and Mama 3,11±0.93, without significant differences (p=0.065), being that 33.3% were prepubertal and 66.7% are pubescent; the physical performance of horizontal jump was 150.52±10.01 cm, Vertical 217.77±25.55 cm; strength of upper limbs: medicine ball throw of 221±0.52 cm; handgrip strength in 22.44±6.89 kg/f and dorsal 54.33±18.44 kg/f. No differenceswere found between the degree of sexual maturation and bone test performance (p> 0.076). Conclusion:The bone age is greater than the chronological, and the sexual maturation and bone caused no impact on the performance of the force.