Effects on Steroid 5-Alpha Reductase Gene Expression of Thai Rice Bran Extracts and Molecular Dynamics Study on SRD5A2

Steroid 5-alpha reductases (SRD5As) are responsible for the conversion of testosterone to dihydrotestosterone, a potent androgen, which is the aetiologic factor of androgenetic alopecia. This study aimed to compare the SRD5A gene expression suppression activity exerted by Thai rice bran extracts and their components and investigate the interactional mechanism between bioactive compounds and SRD5A2 using molecular dynamics (MD) simulation. Bran of Oryza sativa cv. Tubtim Chumphae (TRB), Yamuechaebia Morchor (YRB), Riceberry (RRB), and Malinil Surin (MRB), all rice milling by-products, was solvent-extracted. The ethanolic extract of TRB had the highest sum of overall bioactive compounds (γ-oryzanol; α-, β-, and γ-tocopherol; phenolics; and flavonoids). Among all extracts, TRB greatly downregulated the expression of SRD5A1, SRD5A2, and SRD5A3; there were no significant differences between TRB and finasteride regarding SRD5A suppression. The linear relationship and principal component analysis supported that the α-tocopherol content was correlated with the SRD5A suppression exerted by TRB. Furthermore, MD simulation demonstrated that α-tocopherol had the highest binding affinity towards SRD5A2 by interacting with residues Phe118 and Trp201. Our findings indicate that α-tocopherol effectively downregulates the expression of SRD5A genes and inhibits SRD5A2 activity, actions that are comparable to standard finasteride. TRB, a source of α-tocopherol, could be developed as an anti-hair loss product.National Research Council of Thailand (NRCT): NRCT5-RRI63004-P05Chiang Mai Universit

Antioxidation, Anti-Inflammation, and Regulation of SRD5A Gene Expression of Oryza sativa cv. Bue Bang 3 CMU Husk and Bran Extracts as Androgenetic Alopecia Molecular Treatment Substances

Acknowledgments: The authors are grateful to the NRCT for supporting research facilities (grant no. NRCT5-RRI63004-P05), Chiang Mai University for the Fundamental Fund 2022, and the partially support grant. We would like to thank Lanna Rice Research Center, Chiang Mai University, and Saleekam Trading Co., Ltd., Thailand, for providing the rice bran and husk samples.Data Availability Statement: The data presented in this study are available on request from the corresponding author.Funding: This research project is supported by National Research Council of Thailand (NRCT): NRCT5-RRI63004-P05, Fundamental Fund 2022, Chiang Mai University, and partially supported by Chiang Mai University.Androgenetic alopecia (AGA), a hair loss disorder, is a genetic predisposition to sensitive androgens, inflammation, and oxidative stress. Unfortunately, current treatments with synthetic medicines contain a restricted mechanism along with side effects, whereas the bioactive constituents of plant extracts are multifunctional, with fewer side effects. The massive amounts of rice husk and bran are agricultural wastes that may cause pollution and environmental problems. Owing to these rationales, the local rice variety, Bue Bang 3 CMU (BB3CMU), which is grown in northern Thailand, was evaluated for the valuable utilization of rice by-products, husk (BB3CMU-H) and bran (BB3CMU-RB) extracts, for AGA treatment regarding antioxidant, anti-inflammatory, anti-androgenic activities, and the characterization of bioactive compounds. Our study verified that BB3CMU-H had the highest level of polyphenols, contributing to its greater antioxidant activity. Conversely, BB3CMU-RB was the predominant source of tocopherols, resulting in better anti-androgenic activities regarding the downregulation of steroid 5α-reductase genes (SRD5A). Notably, anti-inflammation via the attenuation of nitric oxide productions was observed in BB3CMU-H (0.06 ± 0.13 μM) and BB3CMU-RB (0.13 ± 0.01 μM), which were significantly comparable to diclofenac sodium salt (0.13 ± 0.19 μM). Therefore, the combination of BB3CMU-H and BB3CMU-RB could be utilized in cosmeceutical and pharmaceutical applications for AGA patientsNational Research Council of Thailand (NRCT): NRCT5-RRI63004-P05Fundamental Fund 2022Chiang Mai Universit

Mucosal Immune Defence Gene Polymorphisms as Relevant Players in the Pathogenesis of IgA Vasculitis?

This research was funded by European Union FEDER funds and “Fondo de Investigaciones Sanitarias” from “Instituto de Salud Carlos III” (ISCIII, Health Ministry, Spain), grant numbers PI18/00042 and PI21/00042. J.C.B.-L. is a recipient of a PFIS program fellowship from the ISCIII, co-funded by the European Social Fund (‘Investing in your future’), grant number FI22/00020. M.S.M.-G. is supported by funds of “Fondo de Investigaciones Sanitarias” from ISCIII, grant number PI121/00042. R.L.-M. is a recipient of a Miguel Servet type II program fellowship from the ISCIII, co-funded by ESF (“Investing in your future”), grant number CPII21/00004.ITGAM–ITGAX (rs11150612, rs11574637), VAV3 rs17019602, CARD9 rs4077515, DEFA (rs2738048, rs10086568), and HORMAD2 rs2412971 are mucosal immune defence polymorphisms, that have an impact on IgA production, described as risk loci for IgA nephropathy (IgAN). Since IgAN and Immunoglobulin-A vasculitis (IgAV) share molecular mechanisms, with the aberrant deposit of IgA1 being the main pathophysiologic feature of both entities, we assessed the potential influence of the seven abovementioned polymorphisms on IgAV pathogenesis. These seven variants were genotyped in 381 Caucasian IgAV patients and 997 matched healthy controls. No statistically significant differences were observed in the genotype and allele frequencies of these seven polymorphisms when the whole cohort of IgAV patients and those with nephritis were compared to controls. Similar genotype and allele frequencies of all polymorphisms were disclosed when IgAV patients were stratified according to the age at disease onset or the presence/absence of gastrointestinal or renal manifestations. Likewise, no ITGAM–ITGAX and DEFA haplotype differences were observed when the whole cohort of IgAV patients, along with those with nephritis and controls, as well as IgAV patients, stratified according to the abovementioned clinical characteristics, were compared. Our results suggest that mucosal immune defence polymorphisms do not represent novel genetic risk factors for IgAV pathogenesis.European Commission ECInstituto de Salud Carlos III ISCIIIEuropean Social Fund CPII21/00004, FI22/00020, PI121/00042 ESFConsejería de Salud y Familias, Junta de Andalucía PI18/00042, PI21/0004

The molecular basis of defective lens development in the Iberian mole

Background: Fossorial mammals face natural selection pressures that differ from those acting on surface dwelling animals, and these may lead to reduced visual system development. We have studied eye development in a species of true mole, the Iberian mole Talpa occidentalis, and present the molecular basis of abnormal lens development. This is the first embryological developmental study of the eyes of any fossorial mammal at the molecular level. Results: Lens fibre differentiation is not completed in the Iberian mole. Although eye development starts normally (similar to other model species), defects are seen after closure of the lens vesicle. PAX6 is not down-regulated in developing lens fibre nuclei, as it is in other species, and there is ectopic expression of FOXE3, a putative downstream effector of PAX6, in some, but not all lens fibres. FOXE3-positive lens fibres continue to proliferate within the posterior compartment of the embryonic lens, but unlike in the mouse, no proliferation was detected anywhere in the postnatal mole lens. The undifferentiated status of the anterior epithelial cells was compromised, and most of them undergo apoptosis. Furthermore, β-crystallin and PROX1 expression patterns are abnormal and our data suggest that genes encoding β-crystallins are not directly regulated by PAX6, c-MAF and PROX1 in the Iberian mole, as they are in other model vertebrates. Conclusion: In other model vertebrates, genetic pathways controlling lens development robustly compartmentalise the lens into a simple, undifferentiated, proliferative anterior epithelium, and quiescent, anuclear, terminally differentiated posterior lens fibres. These pathways are not as robust in the mole, and lead to loss of the anterior epithelial phenotype and only partial differentiation of the lens fibres, which continue to express 'epithelial' genes. Paradigms of genetic regulatory networks developed in other vertebrates appear not to hold true for the Iberian mole.This work was supported by the Alfonso Martín Escudero Foundation and Junta de Andalucía through Group PAI CVI-109 (BIO-109). Work in JMC's laboratory is supported by Wellcome Trust grant 074127 and BBSRC grant BB/E015840/1

Celiac Disease Is a Risk Factor for Mature T and NK Cell Lymphoma: A Mendelian Randomization Study

Celiac disease (CeD) is an immune-mediated disorder triggered by gluten ingestion that damages the small intestine. Although CeD has been associated with a higher risk for cancer, the role of CeD as a risk factor for specific malignancies, such as enteropathy-associated T-cell lymphoma (EATL), remains controversial. Using two-sample Mendelian randomization (2SMR) methods and the summarized results of large genome-wide association studies from public repositories, we addressed the causal relationship between CeD and eight different malignancies. Eleven non- HLA SNPs were selected as instrumental variables (IVs), and causality estimates were obtained using four 2SMR methods: random-effects inverse variance-weighted, weighted median estimation, MR-Egger regression, and MR pleiotropy residual sum and outlier (MR-PRESSO).We identified a significant causal relationship between CeD and mature T/NK cell lymphomas. Under a multivariate Mendelian randomization model, we observed that the causal effect of CeD was not dependent on other known lymphoma risk factors. We found that the most instrumental IV was located in the TAGAP locus, suggesting that aberrant T cell activation might be relevant in the T/NK cell malignization process. Our findings provide new insights into the connection between immune imbalance and the development of severe comorbidities, such as EATL, in patients with CeD.Ministry of Science and Innovation, Spain (MICINN) IJC2018-038026-IEuropean CommissionSpanish Ministry of Science and Innovation through the Spanish National Plan for Scientific and Technical Research and Innovation PY20_00212Andalusian Government B-CTS-584-UGR20 B-AGR-658FEDER/Junta de Andalucia-Consejeria de Transformacion Economica, Industria, Conocimiento y UniversidadesGrant "Investigation grant program by the Association of Celiacs and Sensitive to Gluten of the Community of Madrid" PID2020-120157RB-I0

Las funciones ejecutivas como predictoras del nivel de pericia en jugadores de baloncesto

Los deportes de interacción se desarrollan en contextos extraordinariamente variables, impredecibles, lo que supone que el nivel de entropía es muy elevado. En estos entornos, donde la toma de decisiones resulta determinante para el éxito deportivo, la participación del ejecutivo central juega un papel fundamental. El objetivo de este estudio fue explorar la importancia que pueden tener las funciones ejecutivas como valor predictivo del nivel de pericia de jugadores de baloncesto. Se evaluaron un total de 34 jugadores de baloncesto masculino, de los cuales 12 pertenecían a un equipo profesional de la liga ACB (M = 25.2 años), 12 a un equipo semiprofesional de liga EBA (M = 20.7 años), y 10 a un equipo amateur de liga regional (M = 22.7 años). Se utilizaron la prueba Design Fluency Test, para la flexibilidad cognitiva y la prueba de interferencia de Stroop, para la capacidad de inhibición. Se encontraron diferencias entre las medias de los jugadores ACB y las de los otros dos grupos, pero no entre semiprofesionales y amateurs. Los resultados muestran una mayor flexibilidad cognitiva de los jugadores de baloncesto profesionales respecto a los jugadores no profesionales pero en cambio no distinguen entre grupos cuando se refiere a la capacidad de inhibición. Teniendo en consideración que la primera de las pruebas mide además memoria de trabajo y capacidad inhibitoria, los resultados en general señalan la importancia de las funciones ejecutivas en el baloncesto y coinciden con los de estudios anteriores que indican que los atletas de élite en comparación con los sub-élite o novatos tienen un rendimiento cognitivo superior, aunque en este caso altamente especializado.Interaction Sports are developed in extremely variable, unpredictable contexts, which means that the level of entropy is very high. In these environments, where decision making is decisive for sporting success, the participation of the central executive plays a key role. The aim of this study was to explore the potential importance of executive functions such as predictive value of the level of expertise of basketball players. A total of 34 men basketball players, of whom 12 belonged to a professional team of the ACB league (M = 25.2 years), 12 a semi-pro team of the EBA league (M = 20.7 years) and 10 of a regional amateur league team (M = 22.7 years) were evaluated. Design Fluency Test was used for cognitive flexibility and Stroop interference test for the inhibitory capacity. Differences between the means of the ACB players and those of the other two groups, but not between semiprofessional and amateurs were found. The results show a greater cognitive flexibility of professional basketball players over non professional players but instead does not distinguish between groups when referring to the inhibitory capacity. Considering that the first test also measures working memory and inhibitory capacity, the overall results point to the importance of executive functions in basketball and are consistent with those of previous studies indicating that elite athletes compared to sub-elite or novice have superior cognitive performance, although in this case highly specialized

Development of Clay Plasters Containing Thermoregulating Microcapsules for Indoor Walls

This work shows the technical feasibility of incorporating phase change materials (PCMs) into clay plastering mortars to improve the thermal properties of the building envelopes. Due to the absence of regulated and internationally agreed-upon norms for clay mortars containing thermoregulating microcapsules (MPCMs), two tests following UNE-EN-998-1:2010 and UNE-EN-1015, were designed to provide the greatest similarity to its final application. Three different dosages 5, 10, and 15 wt% of MPCM relative to the dried mortar weight were used. Fresh mortars were physically characterized to determine its consistency, apparent density, period of workability and open time, and occluded air content. Physical and mechanical characteristics were determined for hardened mortar. The thermal characteristics of the specimens were analysed by using a differential scanning calorimetry, obtaining their apparent specific heat capacities and the enthalpy curves. Building simulation software is a fundamental tool for designing buildings with almost zero energy consumption. In this study, three identical architectural models were simulated. The reference building had inner coatings of clay-based mortar, mortar with 15% added material, and a conventional gypsum mortar. These buildings were subjected to the same exposure and radiation conditions, which allowed the result to be compared to evaluate the effect of incorporating the PCM

Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphism and Infant’s Anthropometry at Birth

This research was funded by the Institute of Health Carlos III (PI13/01559), including the European Regional Development Fund (FEDER) and the Regional Health Council of Andalusia (Spain) (PI-0405-2014).This study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of “Consejería de Salud y Familias, Junta de Andalucía” (PI-0405-2014). and “Consejería de Igualdad, Salud y Políticas Sociales, Junta de Andalucía” (PI13/01559)We follow the standards described in Andalusian and Spanish laws of personal data protection and biomedical research for the treatment of information and biological samples of human origin.Women were informed of all study procedures and gave their informed consent for inclusion before they participated in the study.The authors thank the team of the i-Diet software for their support in the estimation of daily energy and nutrient intake. Likewise, a special mention to the pregnant women who participated in this study and the health professionals from El Poniente Hospital, Almeria.Identification of causal factors that influence fetal growth and anthropometry at birth is of great importance as they provide information about increased risk of disease throughout life. The association between maternal genetic polymorphism MTHFR(677)C>T and anthropometry at birth has been widely studied because of its key role in the one-carbon cycle. MTHFR(677) CT and TT genotypes have been associated with a greater risk of low birth weight, especially in case of deficient intake of folic acid during pregnancy. This study aimed to analyze the association between the maternal MTHFR(677)C>T genetic polymorphism and anthropometry at birth in a population with adequate folate consumption. We included 694 mother-newborn pairs from a prospective population-based birth cohort in Spain, in the Genetics, Early life enviroNmental Exposures and Infant Development in Andalusia (GENEIDA) project. Women were genotyped for MTHFR(677)C>T SNP by Q-PCR using TaqMan (c) probes. Relevant maternal and newborn information was obtained from structured questionnaires and medical records. Results showed that maternal MTHFR(677)C>T genotype was associated with newborn anthropometry. Genotypes CT or CT/TT showed statistically significant associations with increased or decreased risk of large-for-gestational-age (LGA) or small-for-gestational-age (SGA) based on weight and height, depending on the newborn's sex, as well as with SGA in premature neonates. The relationships between this maternal genotype and anthropometry at birth remained despite an adequate maternal folate intake.Instituto de Salud Carlos III PI13/01559European CommissionRegional Health Council of Andalusia (Spain) PI-0405-201

NoMeplot: analysis of DNA methylation and nucleosome occupancy at the single molecule

Supplementary information accompanies this paper at https://doi.org/10.1038/s41598-019-44597-2.We are very grateful to Peter A. Jones for sharing protocols and advice and we thank Serafin Moral for constructive and useful discussion.Recent technical advances highlight that to understand mammalian development and human disease we need to consider transcriptional and epigenetic cell-to-cell differences within cell populations. This is particularly important in key areas of biomedicine like stem cell differentiation and intratumor heterogeneity. The recently developed nucleosome occupancy and methylome (NOMe) assay facilitates the simultaneous study of DNA methylation and nucleosome positioning on the same DNA strand. NOMe-treated DNA can be sequenced by sanger (NOMe-PCR) or high throughput approaches (NOMe-seq). NOMe-PCR provides information for a single locus at the single molecule while NOMe-seq delivers genome-wide data that is usually interrogated to obtain population-averaged measures. Here, we have developed a bioinformatic tool that allow us to easily obtain locus-specific information at the single molecule using genome-wide NOMe-seq datasets obtained from bulk populations. We have used NOMePlot to study mouse embryonic stem cells and found that polycomb-repressed bivalent gene promoters coexist in two different epigenetic states, as defined by the nucleosome binding pattern detected around their transcriptional start site.This study was supported by the Spanish ministry of economy and competitiveness (SAF2013-40891-R; BFU2016-75233-P) and the andalusian regional government (PC-0246-2017). David Landeira is a Ramón y Cajal researcher of the Spanish ministry of economy and competitiveness (RYC-2012- 10019)

Genetic Landscape of Nonobstructive Azoospermia and New Perspectives for the Clinic

We thank Alejandro Fernández Sevilla for his valuable help in the development of Figure 2 of this review. The authors were funded by the Spanish Ministry of Economy and Competitiveness through the Spanish National Plan for Scientific and Technical Research and Innovation (ref. SAF2016-78722-R) and the “Ramón y Cajal” program (ref. RYC-2014-16458).Nonobstructive azoospermia (NOA) represents the most severe expression of male infertility, involving around 1% of the male population and 10% of infertile men. This condition is characterised by the inability of the testis to produce sperm cells, and it is considered to have an important genetic component. During the last two decades, di erent genetic anomalies, including microdeletions of the Y chromosome, karyotype defects, and missense mutations in genes involved in the reproductive function, have been described as the primary cause of NOA in many infertile men. However, these alterations only explain around 25% of azoospermic cases, with the remaining patients showing an idiopathic origin. Recent studies clearly suggest that the so-called idiopathic NOA has a complex aetiology with a polygenic inheritance, which may alter the spermatogenic process. Although we are far from a complete understanding of the molecular mechanisms underlying NOA, the use of the new technologies for genetic analysis has enabled a considerable increase in knowledge during the last years. In this review, we will provide a comprehensive and updated overview of the genetic basis of NOA, with a special focus on the possible application of the recent insights in clinical practice.Funded by the Spanish Ministry of Economy and Competitiveness through the Spanish National Plan for Scientific and Technical Research and Innovation (ref. SAF2016-78722-R) and the “Ramón y Cajal” program (ref. RYC-2014-16458)