Chromatin regulation by Histone H4 acetylation at Lysine 16 during cell death and differentiation in the myeloid compartment

Histone H4 acetylation at Lysine 16 (H4K16ac) is a key epigenetic mark involved in gene regulation, DNA repair and chromatin remodeling, and though it is known to be essential for embryonic development, its role during adult life is still poorly understood. Here we show that this lysine is massively hyperacetylated in peripheral neutrophils. Genome-wide mapping of H4K16ac in terminally differentiated blood cells, along with functional experiments, supported a role for this histone post-translational modification in the regulation of cell differentiation and apoptosis in the hematopoietic system. Furthermore, in neutrophils, H4K16ac was enriched at specific DNA repeats. These DNA regions presented an accessible chromatin conformation and were associated with the cleavage sites that generate the 50 kb DNA fragments during the first stages of programmed cell death. Our results thus suggest that H4K16ac plays a dual role in myeloid cells as it not only regulates differentiation and apoptosis, but it also exhibits a non-canonical structural role in poising chromatin for cleavage at an early stage of neutrophil cell death

Neutrophil count is associated with reduced gray matter and enlarged ventricles in first-episode psychosis

Although there is recent evidence that cells from the peripheral immune system can gain access to the central nervous system in certain conditions such as multiple sclerosis, their role has not been assessed in psychosis. Here, we aimed to explore whether blood cell count was associated with brain volume and/or clinical symptomatology. A total of 218 participants (137 first-episode psychosis patients [FEP] and 81 healthy controls [HC]) were included in the study. For each participant, a T1 structural image was acquired, from which brain tissue volumes were calculated. We found that, in FEP, neutrophil count was associated with reduced gray matter (GM) volume (ß = -0.117, P < .001) and increased cerebrospinal fluid volume (ß = 0.191, P = .007). No associations were observed in HC. GM reduction was generalized but more prominent in certain regions, notably the thalamus, the anterior insula, and the left Heschl''s gyrus, among many others. Neutrophil count was also associated with the total PANSS score (ß = 0.173, P = .038), including those items assessing hallucinations (ß = 0.182, P = .028) and avolition (ß = 0.197, P = .018). Several confounders, such as antipsychotic medication, body mass index, and smoking, were controlled for. Overall, the present study may represent the first indirect evidence of brain tissue loss associated with neutrophils in psychosis, and lends support to the hypothesis of a dysregulated immune system. Higher neutrophil count was also associated with more severe clinical symptomatology, which renders it a promising indicator of schizophrenia severity and could even give rise to new therapies

Effectiveness of a strategy that uses educational games to implement clinical practice guidelines among Spanish residents of family and community medicine (e-EDUCAGUIA project):A clinical trial by clusters

This study was funded by the Fondo de Investigaciones Sanitarias FIS Grant Number PI11/0477 ISCIII.-REDISSEC Proyecto RD12/0001/0012 AND FEDER Funding.Background: Clinical practice guidelines (CPGs) have been developed with the aim of helping health professionals, patients, and caregivers make decisions about their health care, using the best available evidence. In many cases, incorporation of these recommendations into clinical practice also implies a need for changes in routine clinical practice. Using educational games as a strategy for implementing recommendations among health professionals has been demonstrated to be effective in some studies; however, evidence is still scarce. The primary objective of this study is to assess the effectiveness of a teaching strategy for the implementation of CPGs using educational games (e-learning EDUCAGUIA) to improve knowledge and skills related to clinical decision-making by residents in family medicine. The primary objective will be evaluated at 1 and 6months after the intervention. The secondary objectives are to identify barriers and facilitators for the use of guidelines by residents of family medicine and to describe the educational strategies used by Spanish teaching units of family and community medicine to encourage implementation of CPGs. Methods/design: We propose a multicenter clinical trial with randomized allocation by clusters of family and community medicine teaching units in Spain. The sample size will be 394 residents (197 in each group), with the teaching units as the randomization unit and the residents comprising the analysis unit. For the intervention, both groups will receive an initial 1-h session on clinical practice guideline use and the usual dissemination strategy by e-mail. The intervention group (e-learning EDUCAGUIA) strategy will consist of educational games with hypothetical clinical scenarios in a virtual environment. The primary outcome will be the score obtained by the residents on evaluation questionnaires for each clinical practice guideline. Other included variables will be the sociodemographic and training variables of the residents and the teaching unit characteristics. The statistical analysis will consist of a descriptive analysis of variables and a baseline comparison of both groups. For the primary outcome analysis, an average score comparison of hypothetical scenario questionnaires between the EDUCAGUIA intervention group and the control group will be performed at 1 and 6months post-intervention, using 95% confidence intervals. A linear multilevel regression will be used to adjust the model. Discussion: The identification of effective teaching strategies will facilitate the incorporation of available knowledge into clinical practice that could eventually improve patient outcomes. The inclusion of information technologies as teaching tools permits greater learning autonomy and allows deeper instructor participation in the monitoring and supervision of residents. The long-term impact of this strategy is unknown; however, because it is aimed at professionals undergoing training and it addresses prevalent health problems, a small effect can be of great relevance. Trial registration: ClinicalTrials.gov: NCT02210442.Publisher PDFPeer reviewe

Evolution of a New Function by Degenerative Mutation in Cephalochordate Steroid Receptors

Gene duplication is the predominant mechanism for the evolution of new genes. Major existing models of this process assume that duplicate genes are redundant; degenerative mutations in one copy can therefore accumulate close to neutrally, usually leading to loss from the genome. When gene products dimerize or interact with other molecules for their functions, however, degenerative mutations in one copy may produce repressor alleles that inhibit the function of the other and are therefore exposed to selection. Here, we describe the evolution of a duplicate repressor by simple degenerative mutations in the steroid hormone receptors (SRs), a biologically crucial vertebrate gene family. We isolated and characterized the SRs of the cephalochordate Branchiostoma floridae, which diverged from other chordates just after duplication of the ancestral SR. The B. floridae genome contains two SRs: BfER, an ortholog of the vertebrate estrogen receptors, and BfSR, an ortholog of the vertebrate receptors for androgens, progestins, and corticosteroids. BfSR is specifically activated by estrogens and recognizes estrogen response elements (EREs) in DNA; BfER does not activate transcription in response to steroid hormones but binds EREs, where it competitively represses BfSR. The two genes are partially coexpressed, particularly in ovary and testis, suggesting an ancient role in germ cell development. These results corroborate previous findings that the ancestral steroid receptor was estrogen-sensitive and indicate that, after duplication, BfSR retained the ancestral function, while BfER evolved the capacity to negatively regulate BfSR. Either of two historical mutations that occurred during BfER evolution is sufficient to generate a competitive repressor. Our findings suggest that after duplication of genes whose functions depend on specific molecular interactions, high-probability degenerative mutations can yield novel functions, which are then exposed to positive or negative selection; in either case, the probability of neofunctionalization relative to gene loss is increased compared to existing models

J-PLUS: The javalambre photometric local universe survey

ABSTRACT: TheJavalambrePhotometric Local UniverseSurvey (J-PLUS )isanongoing 12-band photometricopticalsurvey, observingthousands of squaredegrees of theNorthernHemispherefromthededicated JAST/T80 telescope at the Observatorio Astrofísico de Javalambre (OAJ). The T80Cam is a camera with a field of view of 2 deg2 mountedon a telescopewith a diameter of 83 cm, and isequippedwith a uniquesystem of filtersspanningtheentireopticalrange (3500–10 000 Å). Thisfiltersystemis a combination of broad-, medium-, and narrow-band filters, optimallydesigned to extracttherest-framespectralfeatures (the 3700–4000 Å Balmer break region, Hδ, Ca H+K, the G band, and the Mg b and Ca triplets) that are key to characterizingstellartypes and delivering a low-resolutionphotospectrumforeach pixel of theobservedsky. With a typicaldepth of AB ∼21.25 mag per band, thisfilter set thusallowsforanunbiased and accuratecharacterization of thestellarpopulation in our Galaxy, itprovidesanunprecedented 2D photospectralinformationforall resolved galaxies in the local Universe, as well as accuratephoto-z estimates (at the δ z/(1 + z)∼0.005–0.03 precisionlevel) formoderatelybright (up to r ∼ 20 mag) extragalacticsources. Whilesomenarrow-band filters are designedforthestudy of particular emissionfeatures ([O II]/λ3727, Hα/λ6563) up to z < 0.017, theyalsoprovidewell-definedwindowsfortheanalysis of otheremissionlines at higherredshifts. As a result, J-PLUS has thepotential to contribute to a widerange of fields in Astrophysics, both in thenearbyUniverse (MilkyWaystructure, globular clusters, 2D IFU-likestudies, stellarpopulations of nearby and moderate-redshiftgalaxies, clusters of galaxies) and at highredshifts (emission-line galaxies at z ≈ 0.77, 2.2, and 4.4, quasi-stellarobjects, etc.). Withthispaper, wereleasethefirst∼1000 deg2 of J-PLUS data, containingabout 4.3 millionstars and 3.0 milliongalaxies at r <  21mag. With a goal of 8500 deg2 forthe total J-PLUS footprint, thesenumbers are expected to rise to about 35 millionstars and 24 milliongalaxiesbytheend of thesurvey.Funding for the J-PLUS Project has been provided by the Governments of Spain and Aragón through the Fondo de Inversiones de Teruel, the Spanish Ministry of Economy and Competitiveness (MINECO; under grants AYA2017-86274-P, AYA2016-77846-P, AYA2016-77237-C3-1-P, AYA2015-66211-C2-1-P, AYA2015-66211-C2-2, AYA2012-30789, AGAUR grant SGR-661/2017, and ICTS-2009-14), and European FEDER funding (FCDD10-4E-867, FCDD13-4E-2685

RICORS2040 : The need for collaborative research in chronic kidney disease

Chronic kidney disease (CKD) is a silent and poorly known killer. The current concept of CKD is relatively young and uptake by the public, physicians and health authorities is not widespread. Physicians still confuse CKD with chronic kidney insufficiency or failure. For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. Thus health authorities may consider CKD a non-issue: very few persons eventually need KRT and, for those in whom kidneys fail, the problem is 'solved' by dialysis or kidney transplantation. However, KRT is the tip of the iceberg in the burden of CKD. The main burden of CKD is accelerated ageing and premature death. The cut-off points for kidney function and kidney damage indexes that define CKD also mark an increased risk for all-cause premature death. CKD is the most prevalent risk factor for lethal coronavirus disease 2019 (COVID-19) and the factor that most increases the risk of death in COVID-19, after old age. Men and women undergoing KRT still have an annual mortality that is 10- to 100-fold higher than similar-age peers, and life expectancy is shortened by ~40 years for young persons on dialysis and by 15 years for young persons with a functioning kidney graft. CKD is expected to become the fifth greatest global cause of death by 2040 and the second greatest cause of death in Spain before the end of the century, a time when one in four Spaniards will have CKD. However, by 2022, CKD will become the only top-15 global predicted cause of death that is not supported by a dedicated well-funded Centres for Biomedical Research (CIBER) network structure in Spain. Realizing the underestimation of the CKD burden of disease by health authorities, the Decade of the Kidney initiative for 2020-2030 was launched by the American Association of Kidney Patients and the European Kidney Health Alliance. Leading Spanish kidney researchers grouped in the kidney collaborative research network Red de Investigación Renal have now applied for the Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) call for collaborative research in Spain with the support of the Spanish Society of Nephrology, Federación Nacional de Asociaciones para la Lucha Contra las Enfermedades del Riñón and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

Mapping genomic loci prioritises genes and implicates synaptic biology in schizophrenia

Schizophrenia has a heritability of 60–80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies