A Yap-dependent mechanoregulatory program sustains cell migration for embryo axis assembly

The assembly of the embryo’s primary axis is a fundamental landmark for the establishment of the vertebrate body plan. Although the morphogenetic movements directing cell convergence towards the midline have been described extensively, little is known on how gastrulating cells interpret mechanical cues. Yap proteins are well-known transcriptional mechanotransducers, yet their role in gastrulation remains elusive. Here we show that the double knockout of yap and its paralog yap1b in medaka results in an axis assembly failure, due to reduced displacement and migratory persistence in mutant cells. Accordingly, we identified genes involved in cytoskeletal organization and cell-ECM adhesion as potentially direct Yap targets. Dynamic analysis of live sensors and downstream targets reveal that Yap is acting in migratory cells, promoting cortical actin and focal adhesions recruitment. Our results indicate that Yap coordinates a mechanoregulatory program to sustain intracellular tension and maintain the directed cell migration for embryo axis development

Moderate exercise reveals the influence of ACTN3 R577X and ACE I/D polymorphisms on physical performance in non-athlete active subjects

Genome variations contribute to the vast majority of interindividual differences and may decisively influence sports capability. This study was conceived as a means of finding out when exactly polymorphisms start being physically discriminative. The polymorphisms we studied were two of the best characterized ones: ACE I/D and ACTN3 R577X. These germline variants were determined in a cohort of 200 healthy volunteers from the university environment who underwent a series of physical evaluations that included a Cooper test, a 20-meter sprint test and a vertical jump test. Initially, no statistical association was found because the genetic effect was masked by those subjects with sedentary lifestyles. But when only physically active volunteers were considered, the ACE and ACTN3 genotypes were found to have an impact on heart rate after the Cooper test (p-value = 0.033 and 0.032 respectively) and ACTN3 was found to correlate with the total distance covered in the same test (p-value = 0.051). This can therefore be considered a paradigmatic example in which the environment might hide the genetic effect, with genotypic differences arising only upon training. © 2022No hubo patrocinadores externo

Analysis of gene network bifurcation during optic cup morphogenesis in zebrafish

Sight depends on the tight cooperation between photoreceptors and pigmented cells, which derive from common progenitors through the bifurcation of a single gene regulatory network into the neural retina (NR) and retinal-pigmented epithelium (RPE) programs. Although genetic studies have identified upstream nodes controlling these networks, their regulatory logic remains poorly investigated. Here, we characterize transcriptome dynamics and chromatin accessibility in segregating NR/RPE populations in zebrafish. We analyze cis-regulatory modules and enriched transcription factor motives to show extensive network redundancy and context-dependent activity. We identify downstream targets, highlighting an early recruitment of desmosomal genes in the flattening RPE and revealing Tead factors as upstream regulators. We investigate the RPE specification network dynamics to uncover an unexpected sequence of transcription factors recruitment, which is conserved in humans. This systematic interrogation of the NR/RPE bifurcation should improve both genetic counseling for eye disorders and hiPSCs-to-RPE differentiation protocols for cell-replacement therapies in degenerative diseases.This work is supported by the following grants: (I) To J.-R.M.-M.: From the Spanish Ministry of Science, Innovation, and Universities (MICINN): BFU2017-86339P with FEDER funds, MDM-2016-0687 and PY20_00006/Junta de Andalucía. (II) To O.B. Australian Research Council (ARC) Discovery Project (DP190103852). (III) To F.-J.D.-C.: Andalusian Ministry of Health, Equality and Social Policies (PI-0099-2018). (IV) To P.B.: BFU2016-75412-R with FEDER funds; PCIN-2015-176-C02-01/ERA-Net Neuron ImprovVision, and a CBMSO Institutional grant from the Fundación Ramón Areces. (V) To both J.-R.M.-M. and P.B.: BFU2016-81887-REDT, as well as Fundación Ramón Areces-2016 (Supporting L.B.)

Mutation of vsx genes in zebrafish highlights the robustness of the retinal specification network

Genetic studies in human and mice have established a dual role for Vsx genes in retina development: an early function in progenitors' specification, and a later requirement for bipolar-cells fate determination. Despite their conserved expression patterns, it is currently unclear to which extent Vsx functions are also conserved across vertebrates, as mutant models are available only in mammals. To gain insight into vsx function in teleosts, we have generated vsx1 and vsx2 CRISPR/Cas9 double knockouts (vsxKO) in zebrafish. Our electrophysiological and histological analyses indicate severe visual impairment and bipolar cells depletion in vsxKO larvae, with retinal precursors being rerouted toward photoreceptor or Müller glia fates. Surprisingly, neural retina is properly specified and maintained in mutant embryos, which do not display microphthalmia. We show that although important cis-regulatory remodelling occurs in vsxKO retinas during early specification, this has little impact at a transcriptomic level. Our observations point to genetic redundancy as an important mechanism sustaining the integrity of the retinal specification network, and to Vsx genes regulatory weight varying substantially among vertebrate species

A Functional Pipeline of Genome-Wide Association Data Leads to Midostaurin as a Repurposed Drug for Alzheimer’s Disease

Genome-wide association studies (GWAS) constitute a powerful tool to identify the different biochemical pathways associated with disease. This knowledge can be used to prioritize drugs targeting these routes, paving the road to clinical application. Here, we describe DAGGER (Drug Repositioning by Analysis of GWAS and Gene Expression in R), a straightforward pipeline to find currently approved drugs with repurposing potential. As a proof of concept, we analyzed a meta-GWAS of 1.6 × 107 single-nucleotide polymorphisms performed on Alzheimer’s disease (AD). Our pipeline uses the Genotype-Tissue Expression (GTEx) and Drug Gene Interaction (DGI) databases for a rational prioritization of 22 druggable targets. Next, we performed a two-stage in vivo functional assay. We used a C. elegans humanized model over-expressing the Aβ1-42 peptide. We assayed the five top-scoring candidate drugs, finding midostaurin, a multitarget protein kinase inhibitor, to be a protective drug. Next, 3xTg AD transgenic mice were used for a final evaluation of midostaurin’s effect. Behavioral testing after three weeks of 20 mg/kg intraperitoneal treatment revealed a significant improvement in behavior, including locomotion, anxiety-like behavior, and new-place recognition. Altogether, we consider that our pipeline might be a useful tool for drug repurposing in complex diseases.This work was mainly financed by Programa Operativo FEDER funds from the European Union through grant UMA20-FEDERJA-133. We thank Fundacion SantÁngela for co-funding with grant 83/23.04.2021. P.G.-G. is supported by the CIBERNED employment plan CNV-304-PRF-866. CIBERNED is integrated into Instituto de Salud Carlos III. I.d.R is supported by a national grant from the Instituto de Salud Carlos III FI20/00215. A.R. is supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240, and PI19/01301. A.M.B.-L. and M.J.M. were funded by grant PID2020-120463RB-I00 funded by the Spanish Ministerio de Ciencia e Innovación. A.C.-Z. holds a postdoctoral research contract from Secretaría General de Universidades, Investigación y Tecnología–Junta de Andalucía (POSTDOC21_00365). B.P.S (IFI21/00024) holds an “iPFIS” predoctoral contract from the National System of Health, EU-ERDF-ISCIII. M.d.C.M.-P. holds predoctoral grants from the Spanish Ministry of Science, Innovation and Universities (FPU17/00276). P.R. (CP19/00068) holds a “Miguel Servet” research contract from the National System of Health, ISCIII co-funded by the European Social Fund, “Investing in your future,” Gobierno de España. This research was funded by Delegación del Gobierno para el Plan Nacional sobre Drogas, Ministerio de Salud, Gobierno de España (PND2020/048). Ethovision XT software v17 (Noldus, Wageningen, The Netherlands) funded by Plan Propio, Universidad de Málaga

A Functional Pipeline of Genome-Wide Association Data Leads to Midostaurin as a Repurposed Drug for Alzheimer’s Disease

Genome-wide association studies (GWAS) constitute a powerful tool to identify the different biochemical pathways associated with disease. This knowledge can be used to prioritize drugs targeting these routes, paving the road to clinical application. Here, we describe DAGGER (Drug Repositioning by Analysis of GWAS and Gene Expression in R), a straightforward pipeline to find currently approved drugs with repurposing potential. As a proof of concept, we analyzed a meta-GWAS of 1.6 × 107 single-nucleotide polymorphisms performed on Alzheimer’s disease (AD). Our pipeline uses the Genotype-Tissue Expression (GTEx) and Drug Gene Interaction (DGI) databases for a rational prioritization of 22 druggable targets. Next, we performed a two-stage in vivo functional assay. We used a C. elegans humanized model over-expressing the Aβ1-42 peptide. We assayed the five top-scoring candidate drugs, finding midostaurin, a multitarget protein kinase inhibitor, to be a protective drug. Next, 3xTg AD transgenic mice were used for a final evaluation of midostaurin’s effect. Behavioral testing after three weeks of 20 mg/kg intraperitoneal treatment revealed a significant improvement in behavior, including locomotion, anxiety-like behavior, and new-place recognition. Altogether, we consider that our pipeline might be a useful tool for drug repurposing in complex diseases.Department of Surgery, Biochemistry and Immunology, School of Medicine, University of Malaga, Boulevard Louis Pasteur s/n, 29071 Malaga, Spain Departamento de Biología Molecular e Ingeniería Bioquímica, Centro Andaluz de Biología del Desarrollo (CABD), Universidad Pablo de Olavide (UPO), UPO/CSIC/JA, Ctra Utrera Km1, 41013 Sevilla, Spain Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), 28029 Madrid, Spain Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Malaga, Spain Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Facultad de Psicología, Universidad de Málaga, 29071 Malaga, Spain Research Center and Memory Clinic, Ace Alzheimer Center Barcelona—Universitat Internacional de Catalunya, 08017 Barcelona, Spain Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), National Institute of Health Carlos III, 28029 Madrid, Spain Unidad de Gestion Clinica de Salud Mental, Hospital Universitario Regional de Malaga, 29010 Malaga, Spain Funding for open Access charge: Universidad de Málaga / CBU

Nanoestructuras biocidas

Esta invención se refiere a un procedimiento de obtención de nanoestructuras que comprende las siguientes etapas: a) preparación de una suspensión que comprende al menos un óxido metálico semiconductor, carbón activo y al menos un compuesto de un metal noble; y b) adición de un agente reductor a la suspensión obtenida en la etapa (a).Peer reviewedUniversidad Pablo de Olavide, Consejo Superior de Investigaciones CientíficasA1 Solicitud de patente con informe sobre el estado de la técnic

Nanoestructuras biocidas

Esta invención se refiere a un procedimiento de obtención de nanoestructuras que comprende las siguientes etapas: a) preparación de una suspensión que comprende al menos un óxido metálico semiconductor, carbón activo y al menos un compuesto de un metal noble; y b) adición de un agente reductor a la suspensión obtenida en la etapa (a).Peer reviewedUniversidad Pablo de Olavide, Consejo Superior de Investigaciones CientíficasB1 Patente sin examen previ

Maob rs3027452 modifies mood improvement after tryptophan supplementation

© 2021 Gonzalez et al.[Purpose]: Tryptophan is the only precursor of serotonin, the hormone which helps regulate key human functions such as appetite, memory, mood, and sexual behavior. Connections have been identified between serotonin system dysfunction and the molecular etiology and treatment of mood disorders in a wide range of studies. Proposals have been put forward to co-administer tryptophan supplementation together with serotonin reuptake inhibitors in major depression patients, and also to exploit the sub-therapeutic depressive status in healthy populations. The reported responses, however, have been very dissimilar and this uneven effect may largely be explained by interindividual genetic differences.[Materials and Methods]: We studied mood change in 138 healthy subjects using both Goldberg’s General Health Questionnaire and the Profile of Mood States Questionnaire to determine the effects of a daily supplementation of 1g of tryptophan or placebo. Buccal DNA samples were provided and TPH1 (rs1800532), MAOA (rs3788862 and rs979605), MAOB (rs3027452), and COMT (rs6269 and rs4680) variants were genotyped.[Results]: MAOB rs3027452 was equally associated with tryptophan supplementation efficacy in the depression subscales of both questionnaires (ΔT-Score.D; ΔT-Score.TMD and ΔPOMS.D p-values < 0.01).[Conclusion]: Here we provide evidence that tryptophan supplementation has an uneven effect on mood improvement in the general population

Dysmorphic contribution of neurotransmitter and neuroendocrine system polymorphisms to subtherapeutic mood states

© The Author(s).[Objective]: From an evolutionary perspective, emotions emerged as rapid adaptive reactions that increase survival rates. Current psychobiology includes the consideration that genetic changes affecting neuroendocrine and neurotransmission pathways may also be affecting mood states. Following this hypothesis, abnormal levels of any of the aminergic neurotransmitters would be of considerable importance in the development of a pathophysiological state. [Materials and Methods]: A total of 668 students from the School of Medicine of the University of Malaga (Average = 22.41 ± 3; 41% men) provided self‐report measures of mood states using POMS and GHQ‐28 questionnaires and buccal cells for genotyping 19 polymorphisms from 14 selected neurotransmitter pathways genes (HTR1A; HTR2A; HTR2C; HTR3B; TPH1; SLC18A1; SLC18A2; COMT; MAOA; MAOB) and neuroendocrine system (AVPR1B; OPRM1; BDNF; OXTR). [Results]: MAOA rs3788862 genotype correlates with decreasing levels of Tension among females (beta = −0.168, p‐value = 0.003) but it is neutral among males in this subscale. On the contrary, it correlates with lower GHQ‐28 depression scores among males (beta = −0.196, p‐value = 0.008). Equivalently, SLC18A1 and HTR2A variants correlated with anger and vigor scores, only among males. From the neuroendocrine system, OPRM1 rs1799971 correlated increasing levels of female's Anxiety, depression and Social Dysfunction scores. [Conclusion]: Our findings suggest that these polymorphisms contribute to define general population mood levels, although exhibiting a clear sexual dimorphism