The glucose transporter GLUT12, a new actor in obesity and cancer.

Obesity constitutes a global health epidemic which worsens the main leading death causes such as type 2 diabetes, cardiovascular diseases, and cancer. Changes in the metabolism in patients with obesity frequently lead to insulin resistance, along with hyperglycemia, dyslipidemia and low-grade inflammation, favoring a more aggressive tumor microenvironment. One of the hallmarks of cancer is the reprogramming of the energy metabolism, in which tumor cells change oxidative phosphorylation to aerobic glycolysis or "Warburg effect". Aerobic glycolysis is faster than oxidative phosphorylation, but less efficient in terms of ATP production. To obtain sufficient ATP, tumor cells increase glucose uptake by the glucose transporters of the GLUT/SLC2 family. The human glucose transporter GLUT12 was isolated from the breast cancer cell line MCF7. It is expressed in adipose tissue, skeletal muscle and small intestine, where insulin promotes its translocation to the plasma membrane. Moreover, GLUT12 over-expression in mice increases the whole-body insulin sensitivity. Thus, GLUT12 has been proposed as a second insulin-responsive glucose transporter. In obesity, GLUT12 is downregulated and does not respond to insulin. In contrast, GLUT12 is overexpressed in human solid tumors such as breast, prostate, gastric, liver and colon. High glucose concentration, insulin, and hypoxia upregulate GLUT12 both in adipocytes and tumor cells. Inhibition of GLUT12 mediated Warburg effect suppresses proliferation, migration, and invasion of cancer cells and xenografted tumors. This review summarizes the up-to-date information about GLUT12 physiological role and its implication in obesity and cancer, opening new perspectives to consider this transporter as a therapeutic target.

Complete male-to-female sex reversal in XY mice lacking the miR-17~92 cluster.

Mammalian sex determination is controlled by antagonistic gene cascades operating in embryonic undifferentiated gonads. The expression of the Y-linked gene SRY is sufficient to trigger the testicular pathway, whereas its absence in XX embryos leads to ovarian differentiation. Yet, the potential involvement of non-coding regulation in this process remains unclear. Here we show that the deletion of a single microRNA cluster, miR-17~92, induces complete primary male-to-female sex reversal in XY mice. Sry expression is delayed in XY knockout gonads, which develop as ovaries. Sertoli cell differentiation is reduced, delayed and unable to sustain testicular development. Pre-supporting cells in mutant gonads undergo a transient state of sex ambiguity which is subsequently resolved towards the ovarian fate. The miR-17~92 predicted target genes are upregulated, affecting the fine regulation of gene networks controlling gonad development. Thus, microRNAs emerge as key components for mammalian sex determination, controlling Sry expression timing and Sertoli cell differentiation.

Maresin 1 Exerts a Tissue-Specific Regulation of Adipo-Hepato-Myokines in Diet-Induced Obese Mice and Modulates Adipokine Expression in Cultured Human Adipocytes in Basal and Inflammatory Conditions.

This study analyses the effects of Maresin 1 (MaR1), a docosahexaenoic acid (DHA)-derived specialized proresolving lipid mediator with anti-inflammatory and insulin-sensitizing actions, on the expression of adipokines, including adiponectin, leptin, dipeptidyl peptidase 4 (DPP-4), cardiotrophin-1 (CT-1), and irisin (FNDC5), both in vitro and in in vivo models of obesity. The in vivo effects of MaR1 (50 µg/kg, 10 days, oral gavage) were evaluated in epididymal adipose tissue (eWAT), liver and muscle of diet-induced obese (DIO) mice. Moreover, two models of human differentiated primary adipocytes were incubated with MaR1 (1 and 10 nM, 24 h) or with a combination of tumor necrosis factor-α (TNF-α, 100 ng/mL) and MaR1 (1-200 nM, 24 h) and the expression and secretion of adipokines were measured in both models. MaR1-treated DIO mice exhibited an increased expression of adiponectin and Ct-1 in eWAT, increased expression of Fndc5 and Ct-1 in muscle and a decreased expression of hepatic Dpp-4. In human differentiated adipocytes, MaR1 increased the expression of ADIPONECTIN, LEPTIN, DPP4, CT-1 and FNDC5. Moreover, MaR1 counteracted the downregulation of ADIPONECTIN and the upregulation of DPP-4 and LEPTIN observed in adipocytes treated with TNF-α. Differential effects for TNF-α and MaR1 on the expression of CT-1 and FNDC5 were observed between both models of human adipocytes. In conclusion, MaR1 reverses the expression of specific adipomyokines and hepatokines altered in obese mice in a tissue-dependent manner. Moreover, MaR1 regulates the basal expression of adipokines in human adipocytes and counteracts the alterations of adipokines expression induced by TNF-α in vitro. These actions could contribute to the metabolic benefits of this lipid mediator.

Cell adhesion and immune response, two main functions altered in the transcriptome of seasonally regressed testes of two mammalian species.

In species with seasonal breeding, male specimens undergo substantial testicular regression during the nonbreeding period of the year. However, the molecular mechanisms that control this biological process are largely unknown. Here, we report a transcriptomic analysis on the Iberian mole, Talpa occidentalis, in which the desquamation of live, nonapoptotic germ cells is the major cellular event responsible for testis regression. By comparing testes at different reproductive states (active, regressing, and inactive), we demonstrate that the molecular pathways controlling the cell adhesion function in the seminiferous epithelium, such as the MAPK, ERK, and TGF-ß signaling, are altered during the regression process. In addition, inactive testes display a global upregulation of genes associated with immune response, indicating a selective loss of the "immune privilege" that normally operates in sexually active testes. Interspecies comparative analyses using analogous data from the Mediterranean pine vole, a rodent species where testis regression is controlled by halting meiosis entry, revealed a common gene expression signature in the regressed testes of these two evolutionary distant species. Our study advances in the knowledge of the molecular mechanisms associated to gonadal seasonal breeding, highlighting the existence of a conserved transcriptional program of testis involution across mammalian clades.

The impact of COVID-19 pandemic on the quality of life of healthcare workers and the associated factors: A systematic review.

Introduction: The COVID-19 pandemic has exacerbated health issues in healthcare workers which in turn impacts their quality of life. Objective: This review aimed to (i) analyze the impact of the COVID-19 pandemic on the quality of life of healthcare professionals and (ii) identify the associated factors with quality of life. Materials and methods: We conducted a systematic review using the PRISMA guidelines previously registered in PROSPERO (CRD42021253075). The searched in Web of Science, Scopus, MEDLINE and EMBASE databases included original articles published till May 2021. Results: We found 19 articles and 14,352 professionals in total, the median age ranged from 29 to 42.5 years and 37% of the studies used the WHOQOL-BREF instrument to assess the outcome. The report was heterogeneous, 7 studies described global scores and 9 by domains. Depression, anxiety and stress were commonly reported factors affecting professional's quality of life and this was significantly lower among professionals working with COVID-19 patients compared to their counterparts. Conclusion: COVID-19 frontline workers perceived lower quality of life, which was mainly associated with psychological states such as the aforementioned besides to working conditions like not being previously trained in COVID-19 cases. On the other hand, social support, resilience and active coping could improved their quality of life.

Introducción: La pandemia de COVID-19 ha agravado los problemas de salud del personal sanitario, lo que a su vez repercute en su calidad de vida. Objetivo: Esta revisión tiene como objetivo: (a) Analizar el impacto de la pandemia COVID-19 en la calidad de vida de los profesionales sanitarios y (2) Identificar los factores asociados a su calidad de vida. Materiales y métodos: Se realizó una revisión sistemática utilizando las pautas PRISMA previamente registradas en PROSPERO (CRD42021253075). La búsqueda en las bases de datos Web of Science, Scopus, MEDLINE y EMBASE incluyó artículos originales publicados hasta mayo de 2021. Resultados: Se encontraron 19 artículos y 14.352 profesionales en total, la mediana de edad osciló entre 29 y 42,5 años y el 37% de los estudios utilizaron el instrumento WHOQOL-BREF para evaluar el resultado. El informe fue heterogéneo, 7 estudios describieron puntuaciones globales y 9 por dominios. La depresión, la ansiedad y el estrés fueron los factores comúnmente reportados que afectan a la calidad de vida del profesional, y esta fue significativamente menor entre los profesionales que trabajan con pacientes de COVID-19 en comparación con sus homólogos. Conclusión: Los trabajadores de primera línea de COVID-19 percibieron una menor calidad de vida, que se asoció principalmente a estados psicológicos como los mencionados, además de a condiciones de trabajo como no haber recibido formación previa en casos de COVID-19. Por otro lado, el apoyo social, la resiliencia y el afrontamiento activo mejoraron su calidad de vida.

The Biology and Evolution of Fierce Females (Moles and Hyenas).

Talpid moles and spotted hyenas have become the paradigms of anatomical and behavioral female masculinization. Females of many mole species develop ovotestes that produce testosterone, show external genitalia that resemble that of males, and close their vaginal orifice after every estrus, and female spotted hyenas lack an external vaginal orifice and develop a pseudoscrotum and a large pseudopenis through which they urinate, mate, and give birth. We review current knowledge about several significant aspects of the biology and evolution of these females, including (a) their specific study methods; (b) their unique anatomical features, and how these peculiarities influence certain physiological functions; and (c) the role that steroid hormones as well as genetic and environmental factors may have in urogenital system development, aggressive behavior, and social dominance. Nevertheless, both mole and hyena females are exceptionally efficient mothers, so their peculiar genitalia should not call into question their femininity.

Immune and spermatogenesis-related loci are involved in the development of extreme patterns of male infertility.

We conducted a genome-wide association study in a large population of infertile men due to unexplained spermatogenic failure (SPGF). More than seven million genetic variants were analysed in 1,274 SPGF cases and 1,951 unaffected controls from two independent European cohorts. Two genomic regions were associated with the most severe histological pattern of SPGF, defined by Sertoli cell-only (SCO) phenotype, namely the MHC class II gene HLA-DRB1 (rs1136759, P = 1.32E-08, OR = 1.80) and an upstream locus of VRK1 (rs115054029, P = 4.24E-08, OR = 3.14), which encodes a protein kinase involved in the regulation of spermatogenesis. The SCO-associated rs1136759 allele (G) determines a serine in the position 13 of the HLA-DRß1 molecule located in the antigen-binding pocket. Overall, our data support the notion of unexplained SPGF as a complex trait influenced by common variation in the genome, with the SCO phenotype likely representing an immune-mediated condition.

Common genetic variation in KATNAL1 non-coding regions is involved in the susceptibility to severe phenotypes of male infertility.

BACKGROUND: Previous studies in animal models evidenced that genetic mutations of KATNAL1, resulting in dysfunction of its encoded protein, lead to male infertility through disruption of microtubule remodelling and premature germ cell exfoliation. Subsequent studies in humans also suggested a possible role of KATNAL1 single-nucleotide polymorphisms in the development of male infertility as a consequence of severe spermatogenic failure. OBJECTIVES: The main objective of the present study is to evaluate the effect of the common genetic variation of KATNAL1 in a large and phenotypically well-characterised cohort of infertile men because of severe spermatogenic failure. MATERIALS AND METHODS: A total of 715 infertile men because of severe spermatogenic failure, including 210 severe oligospermia and 505 non-obstructive azoospermia patients, as well as 1058 unaffected controls were genotyped for three KATNAL1 single-nucleotide polymorphism taggers (rs2077011, rs7338931 and rs2149971). Case-control association analyses by logistic regression assuming different models and in silico functional characterisation of risk variants were conducted. RESULTS: Genetic associations were observed between the three analysed taggers and different severe spermatogenic failure groups. However, in all cases, the haplotype model (rs2077011*C | rs7338931*T | rs2149971*A) better explained the observed associations than the three risk alleles independently. This haplotype was associated with non-obstructive azoospermia (adjusted p = 4.96E-02, odds ratio = 2.97), Sertoli-cell only syndrome (adjusted p = 2.83E-02, odds ratio = 5.16) and testicular sperm extraction unsuccessful outcomes (adjusted p = 8.99E-04, odds ratio = 6.13). The in silico analyses indicated that the effect on severe spermatogenic failure predisposition could be because of an alteration of the KATNAL1 splicing pattern. CONCLUSIONS: Specific allelic combinations of KATNAL1 genetic polymorphisms may confer a risk of developing severe male infertility phenotypes by favouring the overrepresentation of a short non-functional transcript isoform in the testis.

Common Variation in the PIN1 Locus Increases the Genetic Risk to Suffer from Sertoli Cell-Only Syndrome.

We aimed to analyze the role of the common genetic variants located in the PIN1 locus, a relevant prolyl isomerase required to control the proliferation of spermatogonial stem cells and the integrity of the blood-testis barrier, in the genetic risk of developing male infertility due to a severe spermatogenic failure (SPGF). Genotyping was performed using TaqMan genotyping assays for three PIN1 taggers (rs2287839, rs2233678 and rs62105751). The study cohort included 715 males diagnosed with SPGF and classified as suffering from non-obstructive azoospermia (NOA, n = 505) or severe oligospermia (SO, n = 210), and 1058 controls from the Iberian Peninsula. The allelic frequency differences between cases and controls were analyzed by the means of logistic regression models. A subtype specific genetic association with the subset of NOA patients classified as suffering from the Sertoli cell-only (SCO) syndrome was observed with the minor alleles showing strong risk effects for this subset (ORaddrs2287839 = 1.85 (1.17-2.93), ORaddrs2233678 = 1.62 (1.11-2.36), ORaddrs62105751 = 1.43 (1.06-1.93)). The causal variants were predicted to affect the binding of key transcription factors and to produce an altered PIN1 gene expression and isoform balance. In conclusion, common non-coding single-nucleotide polymorphisms located in PIN1 increase the genetic risk to develop SCO.

Antitumoral Activity of a CDK9 PROTAC Compound in HER2-Positive Breast Cancer.

Cyclin-dependent kinases (CDKs) are a broad family of proteins involved in the cell cycle and transcriptional regulation. In this article, we explore the antitumoral activity of a novel proteolysis-targeting chimera (PROTAC) compound against CDK9. Breast cancer cell lines from different subtypes were used. Transcriptomic mapping of CDKs in breast cancer demonstrated that the expression of CDK9 predicted a detrimental outcome in basal-like tumors (HR = 1.51, CI = 1.08-2.11, p = 0.015) and, particularly, in the luminal B subtype with HER2+ expression (HR = 1.82, CI = 1.17-2.82, p = 0.0069). The novel CDK9 PROTAC, THAL-SNS-032, displayed a profound inhibitory activity in MCF7, T47D, and BT474 cells, with less effect in SKBR3, HCC1569, HCC1954, MDA-MB-231, HS578T, and BT549 cells. The three cell lines with HER2 overexpression and no presence of ER, SKBR3, HCC1569, and HCC1954 displayed an EC50 three times higher compared to ER-positive and dual ER/HER2-positive cell lines. BT474-derived trastuzumab-resistant cell lines displayed a particular sensitivity to THAL-SNS-032. Western blot analyses showed that THAL-SNS-032 caused a decrease in CDK9 levels in BT474, BT474-RH, and BT474-TDM1R cells, and a significant increase in apoptosis. Experiments in animals demonstrated an inverse therapeutic index of THAL-SNS-032, with doses in the nontherapeutic and toxic range. The identified toxicity was mainly due to an on-target off-tumor effect of the compound in the gastrointestinal epithelium. In summary, the potent and efficient antitumoral properties of the CDK9 PROTAC THAL-SNS-032 opens the possibility of using this type of compound in breast cancer only if specifically delivered to cancer cells, particularly in ER/HER2-positive and HER2-resistant tumors.

Validation of the medium and short version of CENSOPAS-COPSOQ: a psychometric study in the Peruvian population.

BACKGROUND: The presence of psychosocial risks at work are associated with mental and physical health issues in workers. The study aim was to adapt the COPSOQ-ISTAS21 (Spanish version of the Copenhagen Psychosocial Questionnaire and Union Institute of Work, Environment and Health) Medium-Version to the Peruvian context and to develop a Short-Version of the instrument. METHOD: Cross-sectional design study. The COPSOQ-ISTAS21 Medium Version was used. A confirmatory factor analysis was performed to determine the internal structure of each subdimension (first-order) and dimension (second-order) using the Robust Maximum Likelihood estimation method, and classic fit indices in the literature (CFI, SRMR, RMSEA). Internal consistency was evaluated using the alpha and omega coefficients. A short version was developed based on the items with the highest factorial load and that reduce the factorial complexity. RESULTS: A total of 1707 participants were evaluated. In the confirmatory factor analysis, the goodness-of-fit indices for seventeen of the 20 one-dimensional models (subdimensions) were identified; two subdimensions could not be evaluated because they presented only two items. When conducting a multidimensional analysis, we identified that all second-order models presented optimal goodness-of-fit indices, except "psychological demands at work". Finally, a short version of only 31 items was designed from the items with optimal fit indices. CONCLUSIONS: The new adapted versions of COPSOQ-ISTAS21 were renamed CENSOPAS-COPSOQ (National center of occupational health and environment protection for health -in Spanish- and Copenhagen Psychosocial Questionnaire). The CENSOPAS-COPSOQ is an instrument with sufficient evidence of validity and reliability in its medium and short version, which is why its use is recommended in Peruvian work centers to identify the evaluation and prevention of psychosocial risks at work in Peru.

Sox9 Is Required for Nail-Bed Differentiation and Digit-Tip Regeneration.

The nail organ is a specialized appendage in which several ectodermal tissues coordinately function to sustain nail growth, a process that is coupled to digit regeneration. In this study, we show that the transcription factor Sox9 is expressed in several cell populations in the mouse digit tip. We found a SOX9+ cell population in the nail bed, and genetic lineage tracing showed that this is a transient cell population differentiated from matrix nail stem cells. In the absence of Sox9, nail matrix stem cells fail to differentiate into epithelial nail-bed cells and proliferate, thus expanding distally and following the corneocyte fate, which results in outlandishly large fingernails. In addition, the tip of the underlying terminal phalanx undergoes bone regression. Sox9-lineage tracing also revealed the existence of a continuous cell supply from a Sox9-expressing population residing in the basal layers to the entire hyponychium epidermis. Furthermore, digit-tip regeneration is compromised in Sox9-knockout mice, revealing an essential role for the gene during this process. These results will contribute to understand the cellular and molecular basis of mammalian nail organ homeostasis and disease and digit-tip regeneration and will help to design new treatment strategies for patients with nail diseases or amputation.

Prognostic value of the immune target CEACAM6 in cancer: a meta-analysis.

BACKGROUND: Identification of membrane proteins differentially expressed on tumor cells is a key step in drug development. The carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is a cell adhesion protein belonging to the immunoglobulin superfamily. Here, we explore the prognostic role CEACAM6 expression on patient outcome in cancer. METHODS: A systematic search for studies evaluating the association between tumor expression of CEACAM6 and overall survival (OS) and disease-free survival (DFS) was performed. Hazard ratios (HR) were pooled in a meta-analysis using generic inverse variance and random effect modeling. Subgroup analyses were conducted based on tumor type and method of HR extraction. RESULTS: Sixteen studies met the inclusion criteria. CEACAM6 expression was associated with worse OS [HR = 1.96, 95% confidence interval (CI) = 1.51-2.53], and DFS (HR = 2.49, 95% CI = 2.01-3.07) with subgroup analysis showing no significant differences between disease site subgroups. CONCLUSIONS: High expression of CEACAM6 is associated with worse OS and DFS in different malignancies. CEACAM6 is a target for the future development of novel therapeutics.

Contribution of TEX15 genetic variants to the risk of developing severe non-obstructive oligozoospermia.

Background: Severe spermatogenic failure (SPGF) represents one of the most relevant causes of male infertility. This pathological condition can lead to extreme abnormalities in the seminal sperm count, such as severe oligozoospermia (SO) or non-obstructive azoospermia (NOA). Most cases of SPGF have an unknown aetiology, and it is known that this idiopathic form of male infertility represents a complex condition. In this study, we aimed to evaluate whether common genetic variation in TEX15, which encodes a key player in spermatogenesis, is involved in the susceptibility to idiopathic SPGF. Materials and Methods: We designed a genetic association study comprising a total of 727 SPGF cases (including 527 NOA and 200 SO) and 1,058 unaffected men from the Iberian Peninsula. Following a tagging strategy, three tag single-nucleotide polymorphisms (SNPs) of TEX15 (rs1362912, rs323342, and rs323346) were selected for genotyping using TaqMan probes. Case-control association tests were then performed by logistic regression models. In silico analyses were also carried out to shed light into the putative functional implications of the studied variants. Results: A significant increase in TEX15-rs1362912 minor allele frequency (MAF) was observed in the group of SO patients (MAF = 0.0842) compared to either the control cohort (MAF = 0.0468, OR = 1.90, p = 7.47E-03) or the NOA group (MAF = 0.0472, OR = 1.83, p = 1.23E-02). The genotype distribution of the SO population was also different from those of both control (p = 1.14E-02) and NOA groups (p = 4.33-02). The analysis of functional annotations of the human genome suggested that the effect of the SO-associated TEX15 variants is likely exerted by alteration of the binding affinity of crucial transcription factors for spermatogenesis. Conclusion: Our results suggest that common variation in TEX15 is involved in the genetic predisposition to SO, thus supporting the notion of idiopathic SPGF as a complex trait.

Políticas de vigilancia, prevención y control de la COVID-19 en trabajadores del sector salud en el Perú / Surveillance, prevention, and control policies of COVID-19 in health sector workers in Peru

Antecedentes: El Perú ha sido uno de los países con mayor carga de enfermedad por la COVID-19. El Gobierno del Perú ha establecido pautas básicas para la elaboración y registro de los planes para la vigilancia, prevención y control de la COVID-19 en el trabajo (PVPC) de las instituciones del Perú. Objetivo: Caracterizar los PVPC de instituciones del sector salud del Perú. Material y Métodos: Estudio descriptivo retrospectivo de base de datos secundaria. Se evaluaron los PVPC del sector salud registrados en la plataforma SISCOVID-Empresas del Ministerio de Salud del Perú, registro obligatorio para la reactivación de actividades durante la pandemia por la COVID-19. Resultados: Se analizaron 1263 registros PVPC del sector salud registrados en la plataforma SISCOVID-Empresas. El 5,8% de empresas no cuenta con supervisor o comité de seguridad y salud en el trabajo, y 38,6% de empresas con más de 20 trabajadores no cuenta con profesional de salud. Conclusiones: Se identificó un elevado incumplimiento de lo requerido en los PVPC en instituciones del sector salud peruano. Se requiere reforzar y fiscalizar el cumplimiento adecuado de los PVPC en estas instituciones (AU)

Background: Peru has been one of the countries with the highest burden of disease due to COVID-19. The Government of Peru has established basic guidelines for the preparation and registration of plans for the surveillance, prevention, and control of COVID-19 at work (PVPC) of Peruvian institutions. Objective: To characterize the PVPC of health sector institutions in Peru. Materials and Methods: retrospective descriptive secondary database study. The PVPCs of the health sector registered in the SISCOVID-Empresas platform of the Ministry of Health of Peru, mandatory registration for the reactivation of activities during the COVID-19 pandemic, were evaluated. Results: 1263 PVPC records from the health sector registered on the SISCOVID-Empresas platform were analyzed. Of the registered PVPCs, 5.8% of companies do not have a supervisor or committee for occupational safety and health, and 38.6% of companies with more than 20 workers do not have a health professional. Conclusions: A high non-compliance with what is required in the PVPCs in institutions of the Peruvian health sector was identified. It is necessary to reinforce and supervise the adequate fulfillment of the PVPC in these institutions (AU)

Non-Coding RNAs: lncRNAs, miRNAs, and piRNAs in Sexual Development.

Non-coding RNAs (ncRNAs) are a group of RNAs that do not encode functional proteins, including long non-coding RNAs (lncRNAs), microRNAs (miRNAs), PIWI-interacting RNAs (piRNAs), and short interfering RNAs (siRNAs). In the last 2 decades an effort has been made to uncover the role of ncRNAs during development and disease, and nowadays it is clear that these molecules have a regulatory function in many of the developmental and physiological processes where they have been studied. In this review, we provide an overview of the role of ncRNAs during gonad determination and development, focusing mainly on mammals, although we also provide information from other species, in particular when there is not much information on the function of particular types of ncRNAs during mammalian sexual development.

Sex Maintenance in Mammals.

The crucial event in mammalian sexual differentiation occurs at the embryonic stage of sex determination, when the bipotential gonads differentiate as either testes or ovaries, according to the sex chromosome constitution of the embryo, XY or XX, respectively. Once differentiated, testes produce sexual hormones that induce the subsequent differentiation of the male reproductive tract. On the other hand, the lack of masculinizing hormones in XX embryos permits the formation of the female reproductive tract. It was long assumed that once the gonad is differentiated, this developmental decision is irreversible. However, several findings in the last decade have shown that this is not the case and that a continuous sex maintenance is needed. Deletion of Foxl2 in the adult ovary lead to ovary-to-testis transdifferentiation and deletion of either Dmrt1 or Sox9/Sox8 in the adult testis induces the opposite process. In both cases, mutant gonads were genetically reprogrammed, showing that both the male program in ovaries and the female program in testes must be actively repressed throughout the individual's life. In addition to these transcription factors, other genes and molecular pathways have also been shown to be involved in this antagonism. The aim of this review is to provide an overview of the genetic basis of sex maintenance once the gonad is already differentiated.

Mediterranean Pine Vole, Microtus duodecimcostatus: A Paradigm of an Opportunistic Breeder.

Most mammalian species of the temperate zones of the Earth reproduce seasonally, existing a non-breeding period in which the gonads of both sexes undergo functional regression. It is widely accepted that photoperiod is the principal environmental cue controlling these seasonal changes, although several exceptions have been described in other mammalian species in which breeding depends on cues such as food or water availability. We studied the circannual reproductive cycle in males of the Mediterranean pine vole, Microtus duodecimcostatus, in the Southeastern Iberian Peninsula. Morphological, hormonal, functional, molecular and transcriptomic analyses were performed. As reported for populations of other species from the same geographic area, male voles captured in wastelands underwent seasonal testis regression in summer whereas, surprisingly, those living either in close poplar plantations or in our animal house reproduced throughout the year, showing that it is the microenvironment of a particular vole subpopulation what determines its reproductive status and that these animals are pure opportunistic, photoperiod-independent breeders. In addition, we show that several molecular pathways, including MAPK, are deregulated and that the testicular "immune privilege" is lost in the inactive testes, providing novel mechanisms linking seasonal testosterone reduction and testis regression.

Effect and in silico characterization of genetic variants associated with severe spermatogenic disorders in a large Iberian cohort.

BACKGROUND: Severe spermatogenic failure (SpF) represents the most extreme manifestation of male infertility, as it decreases drastically the semen quality leading to either severe oligospermia (SO, <5 million spermatozoa/mL semen) or non-obstructive azoospermia (NOA, complete lack of spermatozoa in the ejaculate without obstructive causes). OBJECTIVES: The main objective of the present study is to analyze in the Iberian population the effect of 6 single-nucleotide polymorphisms (SNPs) previously associated with NOA in Han Chinese through genome-wide association studies (GWAS) and to establish their possible functional relevance in the development of specific SpF patterns. MATERIALS AND METHODS: We genotyped 674 Iberian infertile men (including 480 NOA and 194 SO patients) and 1058 matched unaffected controls for the GWAS-associated variants PRMT6-rs12097821, PEX10-rs2477686, CDC42BPA-rs3000811, IL17A-rs13206743, ABLIM1-rs7099208, and SOX5-rs10842262. Their association with SpF, SO, NOA, and different NOA phenotypes was evaluated by logistic regression models, and their functional relevance was defined by comprehensive interrogation of public resources. RESULTS: ABLIM1-rs7099208 was associated with SpF under both additive (OR = 0.86, p = 0.036) and dominant models (OR = 0.78, p = 0.026). The CDC42BPA-rs3000811 minor allele frequency was significantly increased in the subgroup of NOA patients showing maturation arrest (MA) of germ cells compared to the remaining NOA cases under the recessive model (OR = 4.45, p = 0.044). The PEX10-rs2477686 SNP was associated with a negative testicular sperm extraction (TESE) outcome under the additive model (OR = 1.32, p = 0.034). The analysis of functional annotations suggested that these variants affect the testis-specific expression of nearby genes and that lincRNA may play a role in SpF. CONCLUSIONS: Our data support the association of three previously reported NOA risk variants in Asians (ABLIM1-rs7099208, CDC42BPA-rs3000811, and PEX10-rs2477686) with different manifestations of SpF in Iberians of European descent, likely by influencing gene expression and lincRNA deregulation.

MZ1 co-operates with trastuzumab in HER2 positive breast cancer.

BACKGROUND: Although the anti-HER2 antibody trastuzumab augments patient survival in HER2+ breast cancer, a relevant number of patients progress to this treatment. In this context, novel drug combinations are needed to increase its antitumor activity. In this work, we have evaluated the efficacy of proteolysis targeting chimera (PROTAC) compounds based on BET inhibitors (BETi) to augment the activity of trastuzumab in HER2+ breast cancer models. METHODS: BT474 and SKBR3 HER2+ breast cancer cell lines were used. The effects of trastuzumab and the BET-PROTAC MZ1 either alone or in combination, were evaluated using MTT proliferation assays, three-dimensional invasion and adhesion cultures, flow cytometry, qPCR and Western blot. In vivo studies were carried out in a xenografted model in mice. Finally, a Clariom_S_Human transcriptomic array was applied to identify deregulated genes after treatments. RESULTS: MZ1 induced a higher antiproliferative effect compared to the BETi JQ1. The combination of MZ1 and -trastuzumab significantly decreased cell proliferation, the formation of three-dimensional structures and cellular invasion compared to either of the drugs alone. Evaluation of apoptosis resulted in an increase of cell death following treatment with the combination, and biochemical studies displayed modifications of apoptosis and DNA damage components. In vivo administration of agents alone or combined, to tumors orthotopically xenografted in mice, resulted in a decrease of the tumor volume only after MZ1-Trastuzumab combination treatment. Results from a transcriptomic array indicated a series of newly described transcription factors including HOXB7, MEIS2, TCERG1, and DNAJC2, that were associated to poor outcome in HER2+ breast cancer subtype and downregulated by the MZ1-trastuzumab combination. CONCLUSIONS: We describe an active novel combination that includes the BET-PROTAC MZ1 and trastuzumab, in HER2+ tumors. Further studies should be performed to confirm these findings and pave the way for their future clinical development.