FOXO transcription factors are required for normal somatotrope function and growth

Understanding the molecular mechanisms underlying pituitary organogenesis and function is essential for improving therapeutics and molecular diagnoses for hypopituitarism. We previously found that deletion of the forkhead factor, Foxo1, in the pituitary gland early in development delays somatotrope differentiation. While these mice grow normally, they have reduced growth hormone expression and free serum IGF1 levels, suggesting a defect in somatotrope function. FOXO factors show functional redundancy in other tissues, so we deleted both Foxo1 and its closely related family member, Foxo3, from the primordial pituitary. We find that this results in a significant reduction in growth. Consistent with this, male and female mice in which both genes have been deleted in the pituitary gland (dKO) exhibit reduced pituitary growth hormone expression and serum IGF1 levels. Expression of the somatotrope differentiation factor, Neurod4, is reduced in these mice. This suggests a mechanism underlying proper somatotrope function is the regulation of Neurod4 expression by FOXO factors. Additionally, dKO mice have reduced Lhb expression and females also have reduced Fshb and Prl expression. These studies reveal FOXO transcription factors as important regulators of pituitary gland function.

Alcohol-related family violence in Australia: Secondary data analysis of the National Drug Strategy Household Survey

Aims: Alcohol is a risk factor for family violence that affects partners, parents, children and other relatives. This study aims to provide estimates of the prevalence of alcohol-related family violence reported in 2016 in Australia across numerous socio-demographic groups. Methods: This paper presents secondary data analysis of 23,749 respondents (10,840 men, 12,909 women) from the Australian Institute of Health and Welfare’s 2016 National Drug Strategy Household Survey (NDSHS). Alcohol-related family violence was measured by self-report as being physically or verbally abused or put in fear from a family member or partner deemed by the victim as under the influence of alcohol. Logistic regression was used to analyse which factors were associated with alcohol-related family violence. Findings: Analysis revealed that 5.9% of respondents (7.7% of women and 4.0% of men) reported alcohol-related family violence in the past year from either a partner or another family member. Respondents who were women (vs men), within less advantaged (vs more advantaged) socio-economic groups, risky drinkers (vs non-risky drinkers), residing in outer regional areas (vs major cities), holding a diploma (vs high school education) and single with dependents, reported higher overall rates of alcohol-related family violence. In contrast, respondents aged 55+ had significantly lower odds of experiencing alcohol-related family violence than all other age groups. Conclusions: Alcohol-related family violence was significantly more prevalent amongst respondents in a range of socio-demographic categories. Identification of these groups which are adversely affected by the drinking of family and partners can aid in informing current policy to protect those more vulnerable.

Identification of a shared, common haplotype cosegregating with an SGCB c.544A>C mutation in Indian patients affected with sarcoglycanopathy

Background Sarcoglycanopathies (SG) is the most frequent form of autosomal recessive limb-girdle muscular dystrophies (LGMD) leading to progressive muscle wasting and weakness, predominantly characterized by limb-girdle weakness. LGMDR4 is caused by mutations in SGCB encoding for the beta-sarcoglycan proteins. In this study, we describe a shared, common haplotype cosegregating in 14 SG cases from 13 unrelated families with the likely pathogenic homozygous mutation c.544A>C (p.Thr182Pro) in SGCB. Methods The genotypes of five selected markers (rs10009426, rs6824707, rs2271046, rs35414474 and rs17611952) surrounding the c.544A>C (p.Thr182Pro) were extracted from the variant call format (VCF) generated from whole-exome sequencing (WES) of 14 cases and 14 related family members as controls. The linkage data file was constructed and linkage disequilibrium (LD) plots were generated using HaploView to visualize patterns of LD. Further, haplotype reconstructions based on the 6 markers were conducted using PLINK1.9. using the expectation-maximization (EM) algorithm, an iterative method to find maximum likelihood. Subsequently, the R programming language was used to determine and compare plots of the haplotype frequencies and percentages for both groups to infer the risk haplotypes. Results Four strong LD blocks were identified in control group: rs10009426 to rs6824707 (0.27 kb), rs6824707 to rs2271046 (41.6 kb), rs10009426 to rs2271046 (41.8 kb) and rs35414474 to rs17611952 (0.17 kb) which were absent in the case group. Similarly, a total of nine haplotypes were estimated in cases and controls of which haplotype H1= G, A, T, G, G, T showed significant statistical difference in the frequency between cases and controls. H1 is also observed to cosegregate with c.544A>C (p.Thr182Pro) in the pedigrees of all the cases. Conclusion The identification of c.544A>C (p.Thr182Pro) mutation in 14 cases from India indicates a probable event of founder effect. Further, the H1 haplotype, cosegregating with this mutation, convincingly sheds light on the recent developments in population genetics allowing insights into demographic and population history. This haplotype can also be used as a genetic marker to screen individuals with genetic susceptibility as carriers and provide genetically informed risk stratification and management in the prevention of SG.

Prdm16 and Notch functionally and physically interact during artery development

ABSTRACTRationaleProper functionality of the circulatory system requires correct arteriovenous (AV) endothelial cell (EC) differentiation. While Notch signaling and its downstream effector Hes- Related Family bHLH Transcription Factor with YRPW Motif (Hey)2 favor arterial specification, transcription factor (TF) chicken ovalbumin upstream transcription factor 2 (Coup-TFII) inhibits canonical Notch activity to induce venous identity. However, transcriptional programs that compete with Coup-TFII to orchestrate arterial specification upstream of Notch remain largely unknown. We identified positive regulatory domain-containing protein (Prdm)16 as an arterial EC- specific TF, but its role during arterial EC specification and development remains unexplored.ObjectiveTo unravel the role of Prdm16 during arterial endothelial lineage specification and artery formation.Methods and ResultsTranscriptomic data of freshly isolated arterial and venous ECs from humans and mice revealed that Prdm16 is exclusively expressed by arterial ECs throughout development. This expression pattern was independent of hemodynamic factors and conserved in zebrafish. Accordingly, loss of prdm16 in zebrafish perturbed AV endothelial specification and caused AV malformations in an EC-autonomous manner. This coincided with reduced canonical Notch activity in arterial ECs and was amplified when prdm16 and notch pathway members were concomitantly knocked down. In vitro studies further indicated that Prdm16 not only amplified Notch signaling, but also physically and functionally interacted with Hey2 to drive proper arterial specification.ConclusionWe showed that Prdm16 plays a pivotal role during arterial development through its physical and functional interaction with canonical Notch. As both Hey2 and Prdm16 have been associated with diverse vascular disorders including migraine and atherosclerosis, Prdm16 represents an attractive new target to treat these vascular disorders.

Genome-Wide Identification and Characterization of Soybean GmLOR Gene Family and Expression Analysis in Response to Abiotic Stresses

The LOR (LURP-one related) family genes encode proteins containing a conserved LOR domain. Several members of the LOR family genes are required for defense against Hyaloperonospora parasitica (Hpa) in Arabidopsis. However, there are few reports of LOR genes in response to abiotic stresses in plants. In this study, a genome-wide survey and expression levels in response to abiotic stresses of 36 LOR genes from Glycine max were conducted. The results indicated that the GmLOR gene family was divided into eight subgroups, distributed on 14 chromosomes. A majority of members contained three extremely conservative motifs. There were four pairs of tandem duplicated GmLORs and nineteen pairs of segmental duplicated genes identified, which led to the expansion of the number of GmLOR genes. The expansion patterns of the GmLOR family were mainly segmental duplication. A heatmap of soybean LOR family genes showed that 36 GmLOR genes exhibited various expression patterns in different tissues. The cis-acting elements in promoter regions of GmLORs include abiotic stress-responsive elements, such as dehydration-responsive elements and drought-inducible elements. Real-time quantitative PCR was used to detect the expression level of GmLOR genes, and most of them were expressed in the leaf or root except that GmLOR6 was induced by osmotic and salt stresses. Moreover, GmLOR4/10/14/19 were significantly upregulated after PEG and salt treatments, indicating important roles in the improvement of plant tolerance to abiotic stress. Overall, our study provides a foundation for future investigations of GmLOR gene functions in soybean.

Metabolism of Daidzein and Genistein by Gut Bacteria of the Class Coriobacteriia

The intake of isoflavones is presumed to be associated with health benefits in humans, but also potential adverse effects of isoflavones are controversially discussed. Isoflavones can be metabolized by gut bacteria leading to modulation of the bioactivity, such as estrogenic effects. Especially bacterial strains of the Eggerthellaceae, a well-known bacterial family of the human gut microbiota, are able to convert the isoflavone daidzein into equol. In addition, metabolization of genistein is also described for strains of the Eggerthellaceae. The aim of this study was to identify and investigate gut bacterial strains of the family Eggerthellaceae as well as the narrowly related family Coriobacteriaceae which are able to metabolize daidzein and genistein. This study provides a comprehensive, polyphasic approach comprising in silico analysis of the equol gene cluster, detection of genes associated with the daidzein, and genistein metabolism via PCR and fermentation of these isoflavones. The in silico search for protein sequences that are associated with daidzein metabolism identified sequences with high similarity values in already well-known equol-producing strains. Furthermore, protein sequences that are presumed to be associated with daidzein and genistein metabolism were detected in the two type strains ‘Hugonella massiliensis’ and Senegalimassilia faecalis which were not yet described to metabolize these isoflavones. An alignment of these protein sequences showed that the equol gene cluster is highly conserved. In addition, PCR amplification supported the presence of genes associated with daidzein and genistein metabolism. Furthermore, the metabolism of daidzein and genistein was investigated in fermentations of pure bacterial cultures under strictly anaerobic conditions and proofed the metabolism of daidzein and genistein by the strains ‘Hugonella massiliensis’ DSM 101782T and Senegalimassilia faecalis KGMB04484T.

Assessment of University Students for the Risk Factors and Diabetes Profile in University of Peshawar

Background: Among the non-communicable diseases diabetes is life-threatening condition whose long-time complication causes heart attack, blindness, stroke and kidney failure. The objective was to determine the knowledge, attitude and practice regarding diabetes among the final year students of home economics, university of Peshawar. Methods: This was a descriptive cross-sectional study carried out among final year university students of home economics, university of Peshawar from June to December 2019. Non-probability convenient sampling technique was used for the study. After taking written consent from individual participants a predesigned questionnaire was filled. Data was collected and analyzed by using SPSS version 16. Results: This study included a total of 120 female students of graduate and master level. Among these students 33 (27.5%) were undergraduate and 87 (72.5%) were master level students. It was found that 39 (32.5%) female students were either self-diabetics or one or more close blood related family member were suffering from diabetes. A significantly high proportion 59 (49.2%) and 15 (12.5%) female students were either overweight or obese respectively. About 59 (49.2%) students were with unsatisfactory diabetics practice score, 73 (60.8%) students never checked for sugar and 7 (5.8%) students were found with other chronic diseases status. Interestingly only 28 (23.3%) students know about diabetes and acquired knowledge about diabetes from nutritionists. Conclusion: The increased frequency of obesity & overweight, unsatisfactory diabetes score, unhealthy behavior and suboptimal attitude of female university students provided a threat of potential increase of diabetes among females in future.

Family Function and Child Adjustment Difficulties in the COVID-19 Pandemic: An International Study

To estimate specific proximal and distal effects of COVID-19-related restrictions on families on children’s adjustment problems, we conducted a six-site international study. In total, 2516 parents from Australia, China, Italy, Sweden, the United Kingdom, and the United States of America living with a young child (Mage = 5.77, SD = 1.10, range = 3 to 8 years, 47.9% female) completed an online survey between April and July 2020. The survey included the Strengths and Difficulties Questionnaire and family risk factors (parent distress, parent–child conflict, couple conflict, and household chaos) as well as a scale to index COVID-19-related family disruption. Our analyses also included public data on the stringency of national restrictions. Across the six sites, parental responses indicated elevated levels of hyperactivity, conduct, and emotion problems in children from families characterized by heightened levels of parent distress, parent–child conflict, and household chaos. In contrast, increased peer problems were more strongly related to COVID-19-related social disruption and stringency measures. Mediation models demonstrated that associations between COVID-19 social disruption and child difficulties could be explained by parental distress. Taken together, these results suggest that although the experience of the pandemic differed across countries, associations between COVID-19-related family experiences and child adjustment difficulties were similar in their nature and magnitude across six different contexts. Programs to support family resilience could help buffer the impact of the pandemic for two generations.

Longitudinal associations between family conflict, parent engagement, and metabolic control in children with recent-onset type 1 diabetes

IntroductionWe prospectively investigated the associations between diabetes-related family conflict, parent engagement in child type 1 diabetes (T1D) care, and child glycated hemoglobin (HbA1c) in 127 families of school-age children who we recruited within the first year of their T1D diagnosis.Research design and methodsParents completed the Diabetes Family Conflict Scale-Revised (DFCS-R) to assess for diabetes-related family conflict and the Diabetes Self-Management Questionnaire-Brief (DSMQ-Brief) to assess parent engagement in child T1D care at the initial study visit (T1) and at 12 (T2) and 27 (T3) months later. We also collected child HbA1c at these time points. Our analyses included Pearson correlations and repeated measures linear mixed models controlling for child age, sex, and T1D duration at T1.ResultsParents’ DFCS-R scores negatively correlated with DSMQ-Brief scores (r=−0.13, p<0.05) and positively correlated with children’s HbA1c (r=0.26, p<0.001). In our linear mixed models, parents’ DSMQ-Brief scores were unchanged at T2 (β=−0.71, 95% CI −1.59 to 0.16) and higher at T3 (β=8.01, 95% CI 6.89 to 9.13) compared with T1, and there was an association between increasing DFCS-R and decreasing DSMQ-Brief scores (β=−0.14, 95% CI −0.21 to −0.06). Child HbA1c values were significantly higher at T2 (β=0.66, 95% CI 0.38 to 0.94) and T3 (β=0.95, 95% CI 0.63 to 1.27) compared with T1, and there was an association between increasing DFCS-R scores and increasing child HbA1c (β=0.04, 95% CI 0.02 to 0.06).ConclusionsIncreasing diabetes-specific family conflict early in T1D may associate with decreasing parent engagement in child T1D care and increasing child HbA1c, suggesting a need to assess and intervene on diabetes-specific family conflict.Trial registration numberNCT03698708.

The relevance analysis of GSTP1 rs1695 and lung cancer in the Chinese Han population

Background This study explored the relevance between rs1695 and susceptibility to the lung cancer in the Chinese Han population. Stratification analysis was conducted on the basis of age, gender, smoking status, tumor-related family history, and pathological type to observe relations between rs1695 and susceptibility to lung cancer in the subgroups. Methods A case-control study was performed with 974 lung cancer patients who were pathologically diagnosed and 1005 healthy cases based on physical examination to analyze the association between rs1695 and the risk of lung cancer. Results The frequencies of the AA, GA, and GG genotypes of rs1695 were 68.4%, 28.7%, and 2.9% in cases and 64.8%, 30.8%, and 4.2% in controls, respectively. After adjustment for age, gender, smoking status, and family history, it appears that the rs1695 G allele decreases the risk of lung cancer (OR = 0.811, 95% CI 0.684–0.961, P = 0.016). Moreover, compared with the AA genotype, the GA + GG genotype decreased lung cancer susceptibility (OR = 0.808, 95% CI 0.663–0.985, P = 0.035) and the GG genotype (OR = 0.591, 95% CI 0.347–0.988, P = 0.048). In a stratified analysis, the risk of lung cancer in the G allele carriers decreased among the males, patients without a tumor-related family history, and patients with lung adenocarcinoma, especially in smokers. Conclusion The polymorphism of locus rs1695 is related to the risk of lung cancer and is expected to be a target for the prediction of lung cancer.