OSR1 disruption contributes to uterine factor infertility via impaired Müllerian duct development and endometrial receptivity.

Three sisters, born from consanguineous parents, manifested a unique Müllerian anomaly characterized by uterine hypoplasia with thin estrogen-unresponsive endometrium and primary amenorrhea, but with spontaneous tubal pregnancies. Through whole-exome sequencing followed by comprehensive genetic analysis, a missense variant was identified in the OSR1 gene. We therefore investigated OSR1/OSR1 expression in postpubertal human uteri, and the prenatal and postnatal expression pattern of Osr1/Osr1 in murine developing Müllerian ducts (MDs) and endometrium, respectively. We then investigated whether Osr1 deletion would affect MD development, using WT and genetically engineered mice. Human uterine OSR1/OSR1 expression was found primarily in the endometrium. Mouse Osr1 was expressed prenatally in MDs and Wolffian ducts (WDs), from rostral to caudal segments, in E13.5 embryos. MDs and WDs were absent on the left side and MDs were rostrally truncated on the right side of E13.5 Osr1-/- embryos. Postnatally, Osr1 was expressed in mouse uteri throughout their lifespan, peaking at postnatal days 14 and 28. Osr1 protein was present primarily in uterine luminal and glandular epithelial cells and in the epithelial cells of mouse oviducts. Through this translational approach, we demonstrated that OSR1 in humans and mice is important for MD development and endometrial receptivity and may be implicated in uterine factor infertility.

Effects of exercise on human energy metabolism in high temperature and high humidity environment / Efeitos do exercício sobre o metabolismo energético humano em ambientes de alta temperatura e umidade / Efectos del ejercicio sobre el metabolismo energético humano en ambientes de alta temperatura y humedad

ABSTRACT Introduction Many exercise enthusiasts have started participating in sports in the high-temperature environment in recent years due to the increasing popularity of these sports habits. However, their scientific studies still have a gap in their safety and effectiveness. Objective Measure the energy supply characteristics of fat and sugar oxidation during exercise in different high-temperature and humidity environments. Methods 20 healthy adult subjects were exposed to fixed-intensity exercise for 20 minutes at 30-33 oC, 20% relative humidity (RH), and 50% RH, respectively. Results Under the silent exposure condition, compared with RH 20% and RH 50% under high temperature, sugar oxidation was significantly increased (P<0.01), while fat oxidation was significantly reduced (P<0.01), and total energy consumption was significantly increased (P<0.01). Under the condition of 65% VO2 max exercise, compared with RH 20% and RH 50% at high temperatures, the amount of sugar oxidation was significantly reduced (P<0.05), and the total energy consumption was significantly reduced (P<0.05). Conclusion Under 65% exercise under VO2 max in the high temperature and humidity-controlled environment, the high temperature and medium humidity (RH 50%) environment consumes more energy, and there is a greater amount of sugar oxidation. Level of evidence II; Therapeutic studies - investigating treatment outcomes.

RESUMO Introdução Muitos entusiastas do exercício físico começaram a participar de esportes no ambiente de altas temperaturas nos últimos anos devido a crescente popularidade desses hábitos esportivos, embora seus estudos científicos ainda apresentem uma lacuna sobre sua segurança e efetividade. Objetivo Comparar as características do fornecimento de energia de oxidação de gordura e açúcar durante o exercício em ambientes de alta temperatura e umidade diferentes. Métodos Um total de 20 sujeitos adultos saudáveis foram expostos a exercícios de intensidade fixa durante 20 minutos a 30-33 oC, 20% de umidade relativa (RH) e 50% de RH, respectivamente. Resultados Sob a condição de exposição silenciosa, comparado com RH 20% e RH 50% sob alta temperatura, a oxidação do açúcar foi significativamente aumentada (P<0,01), enquanto a oxidação da gordura foi significativamente reduzida (P<0,01), e o consumo total de energia foi significativamente incrementado (P<0,01). Sob a condição de 65% de exercício de VO2max, comparado com RH 20% e RH 50% a altas temperaturas, a quantidade de oxidação do açúcar foi significativamente reduzida (P<0,05), e o consumo total de energia foi significativamente reduzido (P<0,05). Conclusão Sob a condição de 65% de exercício sob VO2max, no ambiente de alta temperatura e umidade controlados, o ambiente de alta temperatura e umidade média (RH 50%) consome mais energia, havendo uma maior quantidade de oxidação de açúcar. Nível de evidência II; Estudos terapêuticos - investigação dos resultados do tratamento.

RESUMEN Introducción En los últimos años, muchos aficionados al ejercicio han comenzado a practicar deportes en el entorno de altas temperaturas debido a la creciente popularidad de estos hábitos deportivos, aunque sus estudios científicos aún presentan lagunas sobre su seguridad y eficacia. Objetivo Comparar las características de suministro energético de la oxidación de grasas y azúcares durante el ejercicio en diferentes entornos de alta temperatura y humedad. Métodos Un total de 20 sujetos adultos sanos fueron expuestos a ejercicio de intensidad fija durante 20 minutos a 30-33 oC, 20% de humedad relativa (HR) y 50% de HR, respectivamente. Resultados Bajo la condición de exposición silenciosa, en comparación con RH 20% y RH 50% bajo alta temperatura, la oxidación de azúcar se incrementó significativamente (P<0.01), mientras que la oxidación de grasa se redujo significativamente (P<0.01), y el consumo total de energía se incrementó significativamente (P<0.01). Bajo la condición de ejercicio VO2max 65%, en comparación con RH 20% y RH 50% a alta temperatura, la cantidad de oxidación de azúcar se redujo significativamente (P<0,05), y el consumo total de energía se redujo significativamente (P<0,05). Conclusión Bajo la condición de 65% de ejercicio bajo VO2max en el ambiente controlado de alta temperatura y humedad, el ambiente de alta temperatura y humedad media (RH50%) consume más energía y hay una mayor cantidad de oxidación de azúcar. Nivel de evidencia II; Estudios terapéuticos - investigación de los resultados del tratamiento.

Covariance-based sample selection for heterogeneous data: Applications to gene expression and autism risk gene detection.

Risk for autism can be influenced by genetic mutations in hundreds of genes. Based on findings showing that genes with highly correlated gene expressions are functionally interrelated, "guilt by association" methods such as DAWN have been developed to identify these autism risk genes. Previous research analyze the BrainSpan dataset, which contains gene expression of brain tissues from varying regions and developmental periods. Since the spatiotemporal properties of brain tissue is known to affect the gene expression's covariance, previous research have focused only on a specific subset of samples to avoid the issue of heterogeneity. This analysis leads to a potential loss of power when detecting risk genes. In this article, we develop a new method called COBS (COvariance-Based sample Selection) to find a larger and more homogeneous subset of samples that share the same population covariance matrix for the downstream DAWN analysis. To demonstrate COBS's effectiveness, we use genetic risk scores from two sequential data freezes obtained in 2014 and 2020. We show COBS improves DAWN's ability to predict risk genes detected in the newer data freeze when using the risk scores of the older data freeze as input.

Evolutionary and functional genomics of DNA methylation in maize domestication and improvement.

DNA methylation is a ubiquitous chromatin feature, present in 25% of cytosines in the maize genome, but variation and evolution of the methylation landscape during maize domestication remain largely unknown. Here, we leverage whole-genome sequencing (WGS) and whole-genome bisulfite sequencing (WGBS) data on populations of modern maize, landrace, and teosinte (Zea mays ssp. parviglumis) to estimate epimutation rates and selection coefficients. We find weak evidence for direct selection on DNA methylation in any context, but thousands of differentially methylated regions (DMRs) are identified population-wide that are correlated with recent selection. For two trait-associated DMRs, vgt1-DMR and tb1-DMR, HiChIP data indicate that the interactive loops between DMRs and respective downstream genes are present in B73, a modern maize line, but absent in teosinte. Our results enable a better understanding of the evolutionary forces acting on patterns of DNA methylation and suggest a role of methylation variation in adaptive evolution.

Aliskiren attenuates cardiac dysfunction by modulation of the mTOR and apoptosis pathways.

Aliskiren (ALS) is well known for its antihypertensive properties. However, the potential underlying the molecular mechanism and the anti-hypertrophic effect of ALS have not yet been fully elucidated. The aim of the present study was to investigate the role of ALS in mammalian target of rapamycin (mTOR) and apoptosis signaling using in vivo and in vitro models of cardiac hypertrophy. A rat model of cardiac hypertrophy was induced by isoproterenol treatment (5 mg·kg-1·day-1) for 4 weeks, with or without ALS treatment at 20 mg·kg-1·day-1. The expression of hypertrophic, fibrotic, and apoptotic markers was determined by RT-qPCR. The protein expression of apoptotic markers mTOR and p-mTOR was assessed by western blot analysis. The proliferation of H9C2 cells was monitored using the MTS assay. Cell apoptosis was analyzed using flow cytometry. In vivo, isoproterenol-treated rats exhibited worse cardiac function, whereas ALS treatment reversed these dysfunctions, which were associated with changes in p-mTOR, Bcl-2, Bax, and cleaved caspase-3 expression, as well as the number of apoptotic cells. In vitro, H9C2 cardiomyocyte viability was significantly inhibited and cardiac hypertrophy was induced by Ang II administration, but ALS reversed Ang II-induced H9C2 cardiomyocyte hypertrophy and death. Furthermore, Ang II triggered the activation of the mTOR and apoptosis pathways in hypertrophic cardiomyocytes that were inhibited by ALS treatment. These results indicated that ALS alleviated cardiac hypertrophy through inhibition of the mTOR and apoptosis pathways in cardiomyocytes.

Aliskiren attenuates cardiac dysfunction by modulation of the mTOR and apoptosis pathways

Aliskiren (ALS) is well known for its antihypertensive properties. However, the potential underlying the molecular mechanism and the anti-hypertrophic effect of ALS have not yet been fully elucidated. The aim of the present study was to investigate the role of ALS in mammalian target of rapamycin (mTOR) and apoptosis signaling using in vivo and in vitro models of cardiac hypertrophy. A rat model of cardiac hypertrophy was induced by isoproterenol treatment (5 mg·kg-1·day-1) for 4 weeks, with or without ALS treatment at 20 mg·kg-1·day-1. The expression of hypertrophic, fibrotic, and apoptotic markers was determined by RT-qPCR. The protein expression of apoptotic markers mTOR and p-mTOR was assessed by western blot analysis. The proliferation of H9C2 cells was monitored using the MTS assay. Cell apoptosis was analyzed using flow cytometry. In vivo, isoproterenol-treated rats exhibited worse cardiac function, whereas ALS treatment reversed these dysfunctions, which were associated with changes in p-mTOR, Bcl-2, Bax, and cleaved caspase-3 expression, as well as the number of apoptotic cells. In vitro, H9C2 cardiomyocyte viability was significantly inhibited and cardiac hypertrophy was induced by Ang II administration, but ALS reversed Ang II-induced H9C2 cardiomyocyte hypertrophy and death. Furthermore, Ang II triggered the activation of the mTOR and apoptosis pathways in hypertrophic cardiomyocytes that were inhibited by ALS treatment. These results indicated that ALS alleviated cardiac hypertrophy through inhibition of the mTOR and apoptosis pathways in cardiomyocytes.

Morphological characteristics of the cranial base of early Angle's class II division 1 malocclusion in permanent teeth / Características morfológicas de la base de cráneo en la maloclusión temprana clase II división 1 de Angle en dientes permanentes

To investigate the effects of morphological characteristics of cranial base on malocclusion by analyzing characteristics of sagittal and vertical facial types of Angle's class II division 1 malocclusion so as to provide theoretical references for clinical diagnosis and correction of early Angle's class II division 1 malocclusion in permanent teeth. We randomly selected lateral radiographs of the skull of 80 patients at the age of 12­14 years old from the Department of Orthodontics, Stomatological Hospital, Shanxi Medical University, China. There were 20 cases of Angle's class I malocclusion with average angle, 20 cases of Angle's class II division 1 malocclusion with average angle, 20 cases of Angle's class II division 1 malocclusion with low angle, and 20 cases of Angle's class II division 1 malocclusion with high angle. Winceph 8.0 software was used to measure 39 hard tissue markers and 13 indicators reflecting the characteristics of cranial base structure. One-way t-test was used in the average-angle class II division 1 group and average-angle class I group. Least significantdifference was utilized in patients with different vertical types of class II division 1 malocclusion.nterior (S-N) and posterior (S-Ba) cranial base lengths,and total cranial base length(Ba-N) were significantly longer in the class II division 1 patients compared with the class I patients. Significant differences in anterior cranial floor base angle (CF-PM), middle cranial floor base angle (Ba-SE-PM), and posterior cranial base inclination (SBa-FH) were determined between class II division 1 malocclusion and class I malocclusion patients. CF-PM angle and SBa-FH were smaller in class II division 1 subjects than in class I subjects. Ba-SE-PM angle and cranial floor base angle (Ba-SE-FMS) were larger in class II division 1 subjects than in class I subjects. No significant difference in cranial base angle (N-S-Ba) and anterior cranial base inclination (SN-FH) was detected between class II division 1 subjects and class I subjects. Morphology of cranial base and cranial floor base has a significant effect on sagittal and vertical facial types of Angle's class II division 1 malocclusion. The changes in the length of the posterior skull base and the inclination of the anterior skull base are mainly presented in the sagittal direction. Angle of cranial base and cranial floor base plays a certain role in vertical facial type of Angle's class II division 1 malocclusion.

El objetivo de este trabajo consistió en investigar los efectos de las características morfológicas de la base craneal sobre la maloclusión, a través del análisis de los siferentes tipos faciales de maloclusión Clase II de Angle (sagital y vertical), para proporcionar referencias teóricas para el diagnóstico clínico y la corrección temprana de la maloclusión de clase II división 1 de Angle en dientes permanentes. Se seleccionaron al azar radiografías laterales de cráneo de 80 pacientes, entre 12-14 años de edad, del Departamento de Ortodoncia, Hospital de Estomatología, Universidad Médica de Shanxi, China. Hubo 20 casos de maloclusión clase I de Angle con ángulo promedio, 20 casos de maloclusión clase II de Angle con ángulo promedio, 20 casos de maloclusión Clase II de Angle con ángulo bajo y 20 casos de maloclusión clase 1 de Angle con ángulo alto. Se utilizó el software Winceph 8.0 para medir 39 marcadores de tejido duro y 13 indicadores que reflejan las características de la estructura de la base de cráneo. Se usó la prueba t de una vía en el grupo clase II de división 1 con ángulo promedio y el grupo clase I con ángulo promedio. Se detectaron diferencias mínimas significativas en pacientes con diferentes tipos verticales de maloclusión clase II división 1. Las longitudes de la base de cráneo posterior (SN) y posterior (S-Ba), y la longitud total de la base craneal (Ba-N) fueron significativamente mayores en la clase II, en comparación con los pacientes de la clase I. Se determinaron diferencias significativas en el ángulo de la base del piso craneal anterior (CF-PM), el ángulo de la base del piso craneal medio (Ba-SE-PM) y la inclinación de la base craneana posterior (SBa-FH) entre la maloclusión clase II división 1 y los pacientes con maloclusión de clase I. Los ángulos de CF-PM y SBa-FH fueron más pequeños en la clase II división 1 que en la clase I. El ángulo de Ba-SE-PM y el ángulo de base del piso craneal (Ba-SE-FMS) fueron mayores en sujetos de clase II división 1 que en sujetos de clase I. No se detectaron diferencias significativas en el ángulo de la base craneana (N-S-Ba) y la inclinación de la base craneal anterior (SN-FH) entre los sujetos de la clase II división 1 y los de la clase I. La morfología de la base craneal y de la base del suelo craneal tiene un efecto significativo en los tipos faciales sagital y vertical de maloclusión Clase II división 1 de Angle. Los cambios en la longitud de la base posterior del cráneo y la inclinación de la base anterior del cráneo se presentaron principalmente en la dirección sagital. El ángulo de la base craneal y la base del suelo craneal tiene cierto rol en el tipo facial vertical de la clase II de Angle.

Atopic diathesis in patients with Kawasaki disease.

OBJECTIVE: To determine the association between Kawasaki disease (KD) and atopic diathesis (atopic dermatitis [AD], allergic rhinitis, and asthma) in children younger than 5 years of age. STUDY DESIGN: In this nationwide study, we aimed to analyze the association and temporal relationship between KD and atopic diathesis. Data were obtained from the National Health Insurance Research Database of Taiwan from 1997 to 2010. In total, 200 patients with KD younger than 5 years of age and 800 age- and sex-matched control subjects were enrolled. RESULTS: In the whole study population, an increased risk of any concomitant atopic diseases was observed in patients with KD (OR 1.61, 95% CI 1.15-2.26). The risk of AD was increased in male patients between 1 and 5 years of age (OR 3.02, 95% CI 1.22-7.50). More than 60% of the patients developed atopic diseases after the diagnosis of KD. CONCLUSION: There appears to be an association between KD and risk of AD. Most of the atopic diseases occurred after the episode of KD.

Chronic hepatitis virus infection in patients with multiple myeloma: clinical characteristics and outcomes.

OBJECTIVES: Cytotoxic agents and steroids are used to treat lymphoid malignancies, but these compounds may exacerbate chronic viral hepatitis. For patients with multiple myeloma, the impact of preexisting hepatitis virus infection is unclear. The aim of this study is to explore the characteristics and outcomes of myeloma patients with chronic hepatitis virus infection. METHODS: From 2003 to 2008, 155 myeloma patients were examined to determine their chronic hepatitis virus infection statuses using serologic tests for the hepatitis B (HBV) and C viruses (HCV). Clinical parameters and outcome variables were retrieved via a medical chart review. RESULTS: The estimated prevalences of chronic HBV and HCV infections were 11.0% (n = 17) and 9.0% (n = 14), respectively. The characteristics of patients who were hepatitis virus carriers and those who were not were similar. However, carrier patients had a higher prevalence of conventional cytogenetic abnormalities (64.3% vs. 25.0%). The cumulative incidences of grade 3-4 elevation of the level of alanine transaminase, 30.0% vs. 12.0%, and hyperbilirubinemia, 20.0% vs. 1.6%, were higher in carriers as well. In a Kaplan-Meier analysis, carrier patients had worse overall survival (median: 16.0 vs. 42.4 months). The prognostic value of carrier status was not statistically significant in the multivariate analysis, but an age of more than 65 years old, the presence of cytogenetic abnormalities, a beta-2-microglobulin level of more than 3.5 mg/L, and a serum creatinine level of more than 2 mg/ dL were independent factors associated with poor prognosis. CONCLUSION: Myeloma patients with chronic hepatitis virus infections might be a distinct subgroup, and close monitoring of hepatic adverse events should be mandatory.

Chronic hepatitis virus infection in patients with multiple myeloma: clinical characteristics and outcomes

OBJECTIVES: Cytotoxic agents and steroids are used to treat lymphoid malignancies, but these compounds may exacerbate chronic viral hepatitis. For patients with multiple myeloma, the impact of preexisting hepatitis virus infection is unclear. The aim of this study is to explore the characteristics and outcomes of myeloma patients with chronic hepatitis virus infection. METHODS: From 2003 to 2008, 155 myeloma patients were examined to determine their chronic hepatitis virus infection statuses using serologic tests for the hepatitis B (HBV) and C viruses (HCV). Clinical parameters and outcome variables were retrieved via a medical chart review. RESULTS: The estimated prevalences of chronic HBV and HCV infections were 11.0 percent (n = 17) and 9.0 percent (n = 14), respectively. The characteristics of patients who were hepatitis virus carriers and those who were not were similar. However, carrier patients had a higher prevalence of conventional cytogenetic abnormalities (64.3 percent vs. 25.0 percent). The cumulative incidences of grade 3-4 elevation of the level of alanine transaminase, 30.0 percent vs. 12.0 percent, and hyperbilirubinemia, 20.0 percent vs. 1.6 percent, were higher in carriers as well. In a Kaplan-Meier analysis, carrier patients had worse overall survival (median: 16.0 vs. 42.4 months). The prognostic value of carrier status was not statistically significant in the multivariate analysis, but an age of more than 65 years old, the presence of cytogenetic abnormalities, a beta-2-microglobulin level of more than 3.5 mg/L, and a serum creatinine level of more than 2 mg/ dL were independent factors associated with poor prognosis. CONCLUSION: Myeloma patients with chronic hepatitis virus infections might be a distinct subgroup, and close monitoring of hepatic adverse events should be mandatory.