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The majority of human genomic research studies have been conducted in European-ancestry cohorts, reducing the likelihood of detecting potentially novel and globally impactful findings. Here, we present mid-pass whole-genome sequencing data and a genome-wide association study in a cohort of 264 self-reported Malagasy individuals from three locations on the island of Madagascar. We describe genetic variation in this Malagasy cohort, providing insight into the shared and unique patterns of genetic variation across the island. We observe phenotypic variation by location, and find high rates of hypertension particularly in the Southern Highlands sampling site as well as elevated self-reported malaria prevalence in the West Coast site relative to other sites. After filtering to a subset of 214 minimally-related individuals, we find a number of genetic associations with body composition traits, including many variants that are only observed in African populations or populations with admixed African ancestry from the 1000 Genomes Project. This study highlights the importance of including diverse populations in genomic research for the potential to gain novel insights, even with small cohort sizes. This project was conducted in partnership and consultation with local stakeholders in Madagascar and serves as an example of genomic research that prioritizes community engagement and that has potential impacts on our understanding of human health and disease.
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BACKGROUND: Tuberous sclerosis complex (TSC) is a multi-system genetic disease that causes benign tumors in the brain and other vital organs. The most debilitating symptoms result from involvement of the central nervous system and lead to a multitude of severe symptoms including seizures, intellectual disability, autism, and behavioral problems. TSC is caused by heterozygous mutations of either the TSC1 or TSC2 gene and dysregulation of mTOR kinase with its multifaceted downstream signaling alterations is central to disease pathogenesis. Although the neurological sequelae of the disease are well established, little is known about how these mutations might affect cellular components and the function of the blood-brain barrier (BBB). METHODS: We generated TSC disease-specific cell models of the BBB by leveraging human induced pluripotent stem cell and microfluidic cell culture technologies. RESULTS: Using microphysiological systems, we demonstrate that a BBB generated from TSC2 heterozygous mutant cells shows increased permeability. This can be rescued by wild type astrocytes or by treatment with rapamycin, an mTOR kinase inhibitor. CONCLUSION: Our results demonstrate the utility of microphysiological systems to study human neurological disorders and advance our knowledge of cell lineages contributing to TSC pathogenesis and informs future therapeutics.
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Barreira Hematoencefálica , Células-Tronco Pluripotentes Induzidas , Proteína 2 do Complexo Esclerose Tuberosa , Esclerose Tuberosa , Esclerose Tuberosa/fisiopatologia , Esclerose Tuberosa/genética , Humanos , Barreira Hematoencefálica/fisiopatologia , Proteína 2 do Complexo Esclerose Tuberosa/genética , Sirolimo/farmacologia , Astrócitos/metabolismoRESUMO
BACKGROUND: Vertical sleeve gastrectomy (SGx) is a type of bariatric surgery to treat morbid obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). The molecular mechanisms of SGx to improve MASLD are unclear, but increased bile acids (BAs) and FGF19 (mouse FGF15) were observed. FGF15/19 is expressed in the ileum in response to BAs and is critical in not only suppressing BA synthesis in the liver but also promoting energy expenditure. We hypothesized the reduction of obesity and resolution of MASLD by SGx may be mediated by FGF15/19. METHODS: First, we conducted hepatic gene expression analysis in obese patients undergoing SGx, with the results showing increased expression of FGF19 in obese patients' livers. Next, we used wild-type and intestine-specific Fgf15 knockout mice (Fgf15ile-/-) to determine the effects of FGF15 deficiency on improving the metabolic effects. RESULTS: SGx improved metabolic endpoints in both genotypes, evidenced by decreased obesity, improved glucose tolerance, and reduced MASLD progression. However, Fgf15ile-/- mice showed better improvement compared to wild-type mice after SGx, suggesting that other mediators than FGF15 are also responsible for the beneficial effects of FGF15 deficiency. Further gene expression analysis in brown adipose tissue suggests increased thermogenesis. CONCLUSIONS: FGF15 deficiency, the larger BA pool and higher levels of secondary BAs may increase energy expenditure in extrahepatic tissues, which may be responsible for improved metabolic functions following SGx.
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Fígado Gorduroso , Fatores de Crescimento de Fibroblastos , Gastrectomia , Obesidade Mórbida , Adulto , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Cirurgia Bariátrica , Ácidos e Sais Biliares/metabolismo , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Gastrectomia/métodos , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade Mórbida/cirurgia , Obesidade Mórbida/genética , Obesidade Mórbida/metabolismoRESUMO
BACKGROUND: Gout is the most common cause of inflammatory arthritis worldwide, particularly in Pacific regions. We aimed to establish the prevalence of gout and hyperuricaemia in French Polynesia, their associations with dietary habits, their comorbidities, the prevalence of the HLA-B*58:01 allele, and current management of the disease. METHODS: The Ma'i u'u survey was epidemiological, prospective, cross-sectional, and gout-focused and included a random sample of adults from the general adult population of French Polynesia. It was conducted and data were collected between April 13 and Aug 16, 2021. Participants were randomly selected to represent the general adult population of French Polynesia on the basis of housing data collected during the 2017 territorial census. Each selected household was visited by a research nurse from the Ma'i u'u survey who collected data via guided, 1-h interviews with participants. In each household, the participant was the individual older than 18 years with the closest upcoming birthday. To estimate the frequency of HLA-B*58:01, we estimated HLA-B haplotypes on individuals who had whole-genome sequencing to approximately 5× average coverage (mid-pass sequencing). A subset of individuals who self-reported Polynesian ancestry and not European, Chinese, or other ancestry were used to estimate Polynesian-ancestry specific allele frequencies. Bivariate associations were reported for weighted participants; effect sizes were estimated through the odds ratio (OR) of the association calculated on the basis of a logistic model fitted with weighted observations. FINDINGS: Among the random sample of 2000 households, 896 participants were included, 140 individuals declined, and 964 households could not be contacted. 22 participants could not be weighted due to missing data, so the final weighted analysis included 874 participants (449 [51·4%] were female and 425 [48·6%] were male) representing the 196â630 adults living in French Polynesia. The estimated prevalence of gout was 14·5% (95% CI 9·9-19·2), representing 28â561 French Polynesian adults, that is 25·5% (18·2-32·8) of male individuals and 3·5% (1·0-6·0) of female individuals. The prevalence of hyperuricaemia was estimated at 71·6% (66·7-76·6), representing 128â687 French Polynesian adults. In multivariable analysis, age (OR 1·5, 95% CI 1·2-1·8 per year), male sex (10·3, 1·8-60·7), serum urate (1·6, 1·3-2·0 per 1 mg/dL), uraturia (0·8, 0·8-0·8 per 100 mg/L), type 2 diabetes (2·1, 1·4-3·1), BMI more than 30 kg/m2 (1·1, 1·0-1·2 per unit), and percentage of visceral fat (1·7, 1·1-2·7 per 1% increase) were associated with gout. There were seven heterozygous HLA-B*58:01 carriers in the full cohort of 833 individuals (seven [0·4%] of 1666 total alleles) and two heterozygous carriers in a subset of 696 individuals of Polynesian ancestry (two [0·1%]). INTERPRETATION: French Polynesia has an estimated high prevalence of gout and hyperuricaemia, with gout affecting almost 15% of adults. Territorial measures that focus on increasing access to effective urate-lowering therapies are warranted to control this major public health problem. FUNDING: Variant Bio, the French Polynesian Health Administration, Lille Catholic University Hospitals, French Society of Rheumatology, and Novartis.
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Diabetes Mellitus Tipo 2 , Gota , Hiperuricemia , Adulto , Humanos , Masculino , Feminino , Hiperuricemia/epidemiologia , Hiperuricemia/genética , Ácido Úrico , Estudos Transversais , Estudos Prospectivos , Gota/epidemiologia , Gota/genética , Polinésia/epidemiologia , Antígenos HLA-BRESUMO
Survivors of campus sexual assault are often tasked with healing while sharing an environment with their perpetrators. However, little is known about the effects of a shared environment on survivor well-being. A qualitative thematic analysis design was employed to address this gap. We conducted semi-structured interviews with nine female survivors who identified their perpetrators as fellow students at a large state university in the southeastern U.S. The five themes that emerged are situated within an ecological framework, which is also used to guide our recommendations for supporting survivors' well-being within higher education.
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Vítimas de Crime , Delitos Sexuais , Humanos , Feminino , Universidades , Sudeste dos Estados Unidos , SobreviventesRESUMO
Tuberous Sclerosis Complex (TSC) is a debilitating developmental disorder characterized by a variety of clinical manifestations. TSC is caused by mutations in the TSC1 or TSC2 genes, which encode the hamartin/tuberin proteins respectively. These proteins function as a heterodimer that negatively regulates the mechanistic Target of Rapamycin Complex 1 (mTORC1). TSC research has focused on the effects of mTORC1, a critical signaling hub, on regulation of diverse cell processes including metabolism, cell growth, translation, and neurogenesis. However, non-canonical functions of TSC2 are not well studied, and the potential disease-relevant biological mechanisms of mutations affecting these functions are not well understood. We observed aberrant multipolar mitotic division, a novel phenotype, in TSC2 mutant iPSCs. The multipolar phenotype is not meaningfully affected by treatment with the inhibitor rapamycin. We further observed dominant negative activity of the mutant form of TSC2 in producing the multipolar division phenotype. These data expand the knowledge of TSC2 function and pathophysiology which will be highly relevant to future treatments for patients with TSC.
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Transdução de Sinais , Proteínas Supressoras de Tumor , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteínas Mutantes , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
Reactivation and dysregulation of the mTOR signaling pathway are a hallmark of aging and chronic lung disease; however, the impact on microvascular progenitor cells (MVPCs), capillary angiostasis, and tissue homeostasis is unknown. While the existence of an adult lung vascular progenitor has long been hypothesized, these studies show that Abcg2 enriches for a population of angiogenic tissue-resident MVPCs present in both adult mouse and human lungs using functional, lineage, and transcriptomic analyses. These studies link human and mouse MVPC-specific mTORC1 activation to decreased stemness, angiogenic potential, and disruption of p53 and Wnt pathways, with consequent loss of alveolar-capillary structure and function. Following mTOR activation, these MVPCs adapt a unique transcriptome signature and emerge as a venous subpopulation in the angiodiverse microvascular endothelial subclusters. Thus, our findings support a significant role for mTOR in the maintenance of MVPC function and microvascular niche homeostasis as well as a cell-based mechanism driving loss of tissue structure underlying lung aging and the development of emphysema.
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Pulmão , Serina-Treonina Quinases TOR , Camundongos , Humanos , Animais , Pulmão/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Células-Tronco/metabolismo , Via de Sinalização Wnt , Envelhecimento/genéticaRESUMO
Pregnancy embodiment describes the way a pregnant individual inhabits their body, including disconnection and connection, likely influencing both distress and well-being. Emerging work indicates that acceptance of pregnancy-related bodily change may support well-being, particularly when co-occurring with self-care behaviors. Yet, specific associations of pregnant embodiment and intentional, individualized self-care practices (mindful self-care; MSC) with well-being and distress remain unexamined. The present study tested independent and interactive associations between MSC and positive embodiment (body agency), and negative embodiment (body estrangement), respectively, with maternal distress and well-being in a sample of US pregnant women (N = 179; Mage = 31.3 years, aged 21-43; 85.6 % White, 4.9 % Hispanic/Latinx). Challenge and threat/harm appraisals of the COVID-19 pandemic were included in the model to represent responses to the unique sociohistorical context. Measurement-corrected path analytic models explained a substantial proportion of variation in well-being and a smaller proportion in prenatal distress. Among those with higher MSC, the association between body estrangement and prenatal distress was weaker. Results support mindful self-care as protective for pregnancy distress in the setting of body disconnection. Future individualized health promotion might consider how high-stress contexts influence application of self-care practices and impact distress and well-being during pregnancy.
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COVID-19 , Pandemias , Feminino , Gravidez , Humanos , Autocuidado , COVID-19/epidemiologia , Imagem Corporal/psicologia , GestantesRESUMO
The effects of exposure to Myclobutanil, a triazole fungicide, on the development and progression of nonalcoholic fatty liver disease (NAFLD) are unclear, but activation of nuclear receptors (NRs) is a known mechanism of azole-induced liver toxicity. Farnesoid X receptor (FXR) is a NR and is highly expressed in the liver and intestine. Activation of FXR tightly regulates bile acid (BA), lipid and glucose homeostasis, and inflammation partly through the induction of fibroblast growth factor 15 (FGF15; human ortholog FGF19). FXR activation is downregulated during NAFLD and agonists are currently being explored as potential therapeutic strategy. In this study, we aimed to clarify the effects of Myclobutanil exposure on FXR activation and NAFLD development. Reporter assay showed Myclobutanil treatment, following FXR activation with potent FXR agonist (GW4064), resulted in a dose-dependent decrease of FXR activity. Furthermore, a 10-day study in male mice demonstrated that cotreatment with Myclobutanil led to an 80% reduction of GW4064-induced ileal expression of Fgf15. In a diet-induced NAFLD study, low-fat diet (LFD) fed mice administered myclobutanil displayed decreased FXR activity in the liver and ileum, while high-fat-high-sugar-diet (HFHSD) fed mice showed an increase in hepatic FXR activity and an induction of target genes regulated by constitutive androstane receptor and/or pregnane X receptor. Our work demonstrates Myclobutanil inhibits FXR activity and modulates FXR activity differentially in mice fed LFD or HFHSD. Our studies suggest the importance of understanding how Myclobutanil could contribute to BA dysregulation in disease states such as NAFLD.
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Hepatopatia Gordurosa não Alcoólica , Triazóis , Animais , Humanos , Masculino , Camundongos , Ácidos e Sais Biliares/metabolismo , Intestinos/metabolismo , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Nitrilas/farmacologia , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteínas de Ligação a RNA/metabolismo , Triazóis/toxicidade , Triazóis/metabolismoRESUMO
Tuberous sclerosis complex (TSC) is a multi-system genetic disease that causes benign tumors in the brain and other vital organs. The most debilitating symptoms result from involvement of the central nervous system and lead to a multitude of severe symptoms including seizures, intellectual disability, autism, and behavioral problems. TSC is caused by heterozygous mutations of either the TSC1 or TSC2 gene. Dysregulation of mTOR kinase with its multifaceted downstream signaling alterations is central to disease pathogenesis. Although the neurological sequelae of the disease are well established, little is known about how these mutations might affect cellular components and the function of the blood-brain barrier (BBB). We generated disease-specific cell models of the BBB by leveraging human induced pluripotent stem cell and microfluidic cell culture technologies. Using these microphysiological systems, we demonstrate that the BBB generated from TSC2 heterozygous mutant cells shows increased permeability which can be rescued by wild type astrocytes and with treatment with rapamycin, an mTOR kinase inhibitor. Our results further demonstrate the utility of microphysiological systems to study human neurological disorders and advance our knowledge of the cell lineages contributing to TSC pathogenesis.
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To date, there are no brief child self-report coping measures for the pandemic and other major societal events resulting in social or learning disruptions for children. Ignoring the voice of children can ultimately result in programs or services that fail to meet their needs. Thus, a child self-report measure called the 3Cs (Children's Crisis Coping) was developed and underwent pilot evaluation. This measure was designed in collaboration with key stakeholders using a Knowledge Translation-Integrated development framework. Some of the primary concerns that were relevant in the literature for the development of a pandemic coping measure included stress, worries, loneliness, and unpredictable school changes. The completed 4-item measure, grounded in these concerns, demonstrated good internal consistency reliability, as well as convergent validity with mental health and meaning mindset. A Second Wave Positive Psychology framework is presented concerning a spiritual concept called "meaning mindset" and it's association with positive societal crisis coping (i.e., pandemic coping in the present study).
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Farnesoid X receptor (FXR) is a nuclear receptor known to markedly alter expression of major transporters and enzymes in the liver. However, its effects toward organic anion transporting polypeptides (OATP) 1B1 and 1B3 remain poorly characterized. Therefore, the present study was aimed at determining the effects of chenodeoxycholic acid (CDCA), a naturally occurring FXR agonist, on OATP1B expression in cynomolgus monkeys. Multiple administrations of 50 and 100 mg/kg of CDCA were first shown to significantly repress mRNA expression of SLCO1B1/3 approximately 60% to 80% in monkey livers. It also suppressed cytochrome P450 (CYP)7A1-mRNA and induced OSTα/ß-mRNA, which are well known targets of FXR and determinants of bile acid homeostasis. CDCA concomitantly decreased OATP1B protein abundance by approximately 60% in monkey liver. In contrast, multiple doses of 15 mg/kg rifampin (RIF), a pregnane X receptor agonist, had no effect on hepatic OATP1B protein, although it induced the intestinal P-glycoprotein and MR2 proteins by â¼2-fold. Moreover, multiple doses of CDCA resulted in a steady â¼2- to 10-fold increase of the OATP1B biomarkers coproporphyrins (CPs) in the plasma samples collected prior to each CDCA dose. Additionally, 3.4- to 11.2-fold increases of CPI and CPIII areas under the curve were observed after multiple administrations compared with the single dose and vehicle administration dosing groups. Taken together, these data suggest that CDCA represses the expression of OATP1B1 and OATP1B3 in monkeys. Further investigation of OATP1B downregulation by FXR in humans is warranted, as such downregulation effects may be involved in bile acid homeostasis and potential drug interactions in man. SIGNIFICANCE STATEMENT: Using gene expression and proteomics tools, as well as endogenous biomarker data, for the first time, we have demonstrated that OATP1B expression was suppressed and its activity was reduced in the cynomolgus monkeys following oral administration of 50 and 100 mg/kg/day of chenodeoxycholic acid (CDCA), a Farnesoid X receptor agonist, for 8 days. These results lead to a better understanding of OATP1B downregulation by CDCA and its role on bile acid and drug disposition.
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Ácido Quenodesoxicólico , Coproporfirinas , Transportador 1 de Ânion Orgânico Específico do Fígado , Animais , Ácidos e Sais Biliares , Biomarcadores/metabolismo , Ácido Quenodesoxicólico/metabolismo , Ácido Quenodesoxicólico/farmacologia , Coproporfirinas/sangue , Coproporfirinas/metabolismo , Regulação para Baixo , Interações Medicamentosas , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Macaca fascicularis/metabolismo , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , RNA MensageiroRESUMO
PURPOSE: The study objective was to develop and validate a measure of parent perception of child weight-related risk, the Child Weight Risk Questionnaire (CWRQ), among a sample of US parents. METHODS: A cross-sectional survey was conducted in a sample of 216 parents of 6- to 12-year-old children who were overweight. The CWRQ was used to assess parent beliefs about their child's susceptibility to physical, social-emotional, and behavioral health problems due to weight. RESULTS: Confirmatory factor analysis supported the three-factor structure of the CWRQ and acceptable fit was achieved. The internal consistency of the measure was excellent. Convergent, discriminant, and incremental validity analyses provided initial evidence for CWRQ validity. CONCLUSION: The CWRQ is a reliable and valid instrument for assessing parent perception of child weight-related risk. This measure could be utilized in research and applied settings to capture the multifaceted nature of parent risk perception and support efforts to tailor family weight interventions in ways that align with parent beliefs. LEVEL OF EVIDENCE: Level V, cross-sectional, descriptive study.
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Sobrepeso , Pais , Criança , Estudos Transversais , Análise Fatorial , Humanos , Pais/psicologia , Inquéritos e QuestionáriosRESUMO
The present study examined the effects of data-guided innovations on students' social-emotional (SE) development within prekindergarten settings. Specifically, this study examined the effects of a pilot effort that sought to improve instructional quality through the use of structured classroom observations by coaches to help support teacher implementation of curricula and evidence-based practices. In addition, teachers used formative assessments of students' SE functioning to guide and individualize their instruction. To examine the effects of the multicomponent intervention, this study compared the SE functioning of students across three conditions: (1) students whose teachers received no data-guided innovations; (2) students whose teachers received SE formative assessments; and (3) students whose teachers received both SE formative assessments and performance-based feedback using structured classroom observations. Students whose teachers received both SE formative assessments and performance-based feedback using structured classroom observations evidenced significantly greater SE competencies than those in the control group. Additionally, students whose teachers just received SE formative assessments evidenced greater SE competencies than those in the control group, however, the differences were not significant. Results indicate the potential value of these data-guided innovations for improving prekindergarten student outcomes such as SE development and point to the next steps for future research.
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Professores Escolares , Instituições Acadêmicas , Emoções , Humanos , Mudança Social , Estudantes/psicologiaRESUMO
In standard times, approximately 20% of children and youth experience significant emotional, behavioral, or social challenges. During COVID-19, however, over half of parents have reported mental health symptoms in their children. Specifically, depressive symptoms, anxiety, contamination obsessions, family well-being challenges, and behavioral concerns have emerged globally for children during the pandemic. Without treatment or prevention, such concerns may hinder positive development, personal life trajectory, academic success, and inhibit children from meeting their potential. A school-based resiliency program for children (DREAM) for children was developed, and the goal of this study was to collaborate with stakeholders to translate it into an online-live hybrid. Our team developed a methodology to do this based on Knowledge Translation-Integration (KTI), which incorporates stakeholder engagement throughout the entire research to action process. KTI aims to ensure that programs are acceptable, sustainable, feasible, and credible. Through collaboration with parents and school board members, qualitative themes of concerns, recommendations and validation were established, aiding in meaningful online-live translation. Even though the original program was developed for intellectually gifted children, who are at greater risk for mental health concerns, stakeholders suggested using the program for both gifted and non-gifted children, given the universal applicability of the tools, particularly during this pandemic time period when mental health promotion is most relevant. An online-live approach would allow students studying at home and those studying in the classroom to participate in the program. Broader implications of this study include critical recommendations for the development of both online-live school programs in general, as well as social-emotional literacy programs for children.
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There is a need for valves and pumps that operate at the microscale with precision and accuracy, are versatile in their application, and are easily fabricated. To that end, we developed a new rotary planar multiport valve to faithfully select solutions (contamination = 5.22 ± 0.06 ppb) and a rotary planar peristaltic pump to precisely control fluid delivery (flow rate = 2.4 ± 1.7 to 890 ± 77 µL/min). Both the valve and pump were implemented in a planar format amenable to single-layer soft lithographic fabrication. These planar microfluidics were actuated by a rotary motor controlled remotely by custom software. Together, these two devices constitute an innovative microformulator that was used to prepare precise, high-fidelity mixtures of up to five solutions (deviation from prescribed mixture = ±|0.02 ± 0.02| %). This system weighed less than a kilogram, occupied around 500 cm3, and generated pressures of 255 ± 47 kPa. This microformulator was then combined with an electrochemical sensor creating a microclinical analyzer (µCA) for detecting glutamate in real time. Using the chamber of the µCA as an in-line bioreactor, we compared glutamate homeostasis in human astrocytes differentiated from human-induced pluripotent stem cells (hiPSCs) from a control subject (CC-3) and a Tuberous Sclerosis Complex (TSC) patient carrying a pathogenic TSC2 mutation. When challenged with glutamate, TSC astrocytes took up less glutamate than control cells. These data validate the analytical power of the µCA and the utility of the microformulator by leveraging it to assess disease-related alterations in cellular homeostasis.
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Homozygosity for the SERPINA1 Z allele causes α1-antitrypsin deficiency, a rare condition that can cause lung and liver disease. However, the effects of Z allele heterozygosity on nonrespiratory phenotypes, and on lung function in the general population, remain unclear. We conducted a large, population-based study to determine Z allele effects on >2400 phenotypes in the UK Biobank (N=303â353). Z allele heterozygosity was strongly associated with increased height (ß=1.02â cm, p=3.91×10-68), and with other nonrespiratory phenotypes including increased risk of gall bladder disease, reduced risk of heart disease and lower blood pressure, reduced risk of osteoarthritis and reduced bone mineral density, increased risk of headache and enlarged prostate, as well as with blood biomarkers of liver function. Heterozygosity was associated with higher height-adjusted forced expiratory volume in 1â s (FEV1) (ß=19.36â mL, p=9.21×10-4) and FEV1/forced vital capacity (ß=0.0031, p=1.22×10-5) in nonsmokers, whereas in smokers, this protective effect was abolished. Furthermore, we show for the first time that sex modifies the association of the Z allele on lung function. We conclude that Z allele heterozygosity and homozygosity exhibit opposing effects on lung function in the UK population, and that these associations are modified by smoking and sex. In exploratory analyses, heterozygosity for the Z allele also showed pleiotropic associations with nonrespiratory health-related traits and disease risk.
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CONTEXT: Glycogen storage diseases are rare. Increased glycogen in the liver results in increased attenuation. OBJECTIVE: Investigate the association and function of a noncoding region associated with liver attenuation but not histologic nonalcoholic fatty liver disease. DESIGN: Genetics of Obesity-associated Liver Disease Consortium. SETTING: Population-based. MAIN OUTCOME: Computed tomography measured liver attenuation. RESULTS: Carriers of rs4841132-A (frequency 2%-19%) do not show increased hepatic steatosis; they have increased liver attenuation indicative of increased glycogen deposition. rs4841132 falls in a noncoding RNA LOC157273 ~190 kb upstream of PPP1R3B. We demonstrate that rs4841132-A increases PPP1R3B through a cis genetic effect. Using CRISPR/Cas9 we engineered a 105-bp deletion including rs4841132-A in human hepatocarcinoma cells that increases PPP1R3B, decreases LOC157273, and increases glycogen perfectly mirroring the human disease. Overexpression of PPP1R3B or knockdown of LOC157273 increased glycogen but did not result in decreased LOC157273 or increased PPP1R3B, respectively, suggesting that the effects may not all occur via affecting RNA levels. Based on electronic health record (EHR) data, rs4841132-A associates with all components of the metabolic syndrome (MetS). However, rs4841132-A associated with decreased low-density lipoprotein (LDL) cholesterol and risk for myocardial infarction (MI). A metabolic signature for rs4841132-A includes increased glycine, lactate, triglycerides, and decreased acetoacetate and beta-hydroxybutyrate. CONCLUSIONS: These results show that rs4841132-A promotes a hepatic glycogen storage disease by increasing PPP1R3B and decreasing LOC157273. rs4841132-A promotes glycogen accumulation and development of MetS but lowers LDL cholesterol and risk for MI. These results suggest that elevated hepatic glycogen is one cause of MetS that does not invariably promote MI.
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Doença de Depósito de Glicogênio/etiologia , Glicogênio Hepático/metabolismo , Síndrome Metabólica/etiologia , Infarto do Miocárdio/prevenção & controle , Polimorfismo de Nucleotídeo Único , Proteína Fosfatase 1/genética , Adulto , Idoso , Biomarcadores/análise , Feminino , Seguimentos , Doença de Depósito de Glicogênio/metabolismo , Doença de Depósito de Glicogênio/patologia , Humanos , Masculino , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Pessoa de Meia-Idade , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Prognóstico , Estudos ProspectivosRESUMO
The development of social-emotional competencies in early childhood is essential for long-term health and wellbeing, and these skills are particularly critical for children from disadvantaged backgrounds to set the foundation for success in school and in life. The present study examined the effects of an intervention to support prekindergarten (pre-k) teachers' ability to address the specific social-emotional needs of their students. Teachers in a publicly funded pre-k program completed the Devereux Early Childhood Assessment (DECA; LeBuffe & Naglieri, 1999; LeBuffe & Shapiro, 2004) to measure social-emotional functioning. "Intervention" teachers received summaries of their students' social-emotional strengths and needs based on the DECA and packets providing teaching strategies they could use to target the social-emotional domains assessed by the DECA. Teachers were encouraged to work with their coaches to interpret their classroom summaries and implement strategies to address their students' needs. Multilevel modeling revealed that students whose teachers received social-emotional feedback (classroom summaries and strategy packets) showed significantly greater social-emotional gains (across multiple domains) over the school year compared to students whose teachers did not receive feedback. Our findings suggest that having teachers complete social-emotional assessments of their students at the beginning of the school year and providing teachers with data-based feedback may build teachers' capacity to promote social-emotional development for children from disadvantaged backgrounds. We discuss the potential to build on this data-guided approach to better prepare children to succeed in elementary school and beyond. (PsycInfo Database Record (c) 2021 APA, all rights reserved).