Dopaminergic control of ADAMTS2 expression through cAMP/CREB and ERK: molecular effects of antipsychotics

© The Author(s) 2019.A better understanding of the molecular mechanisms that participate in the development and clinical manifestations of schizophrenia can lead to improve our ability to diagnose and treat this disease. Previous data strongly associated the levels of deregulated ADAMTS2 expression in peripheral blood mononuclear cells (PBMCs) from patients at first episode of psychosis (up) as well as in clinical responders to treatment with antipsychotic drugs (down). In this current work, we performed an independent validation of such data and studied the mechanisms implicated in the control of ADAMTS2 gene expression. Using a new cohort of drug-naïve schizophrenia patients with clinical follow-up, we confirmed that the expression of ADAMTS2 was highly upregulated in PBMCs at the onset (drug-naïve patients) and downregulated, in clinical responders, after treatment with antipsychotics. Mechanistically, ADAMTS2 expression was activated by dopaminergic signalling (D1-class receptors) and downstream by cAMP/CREB and mitogen-activated protein kinase (MAPK)/ERK signalling. Incubation with antipsychotic drugs and selective PKA and MEK inhibitors abrogated D1-mediated activation of ADAMTS2 in neuronal-like cells. Thus, D1 receptors signalling towards CREB activation might participate in the onset and clinical responses to therapy in schizophrenia patients, by controlling ADAMTS2 expression and activity. The unbiased investigation of molecular mechanisms triggered by antipsychotic drugs may provide a new landscape of novel targets potentially associated with clinical efficacy.This work was supported by: SAF2016-76046-R and SAF2013-46292-R (MINECO and FEDER) to B.C.F., PI16/00156 (isciii and FEDER) to J.P.V., LUCHAMOS POR LA VIDA project to F.R.J. and J.P.V., SAF2017-83702-R (MINECO and FEDER), Red TERCEL RD12/0019/0024 (ISCIII) and GVA-PROMETEO 2018/041 (Generalitat Valenciana) to S.M. J.P.V. is supported by the RyC research programme (RYC-2013-14097) and F.R.J. by the predoctoral research programme (BES-2014-070615), from MINECO and FEDER

The endocannabinoid system in mental disorders: Evidence from human brain studies

Mental disorders have a high prevalence compared with many other health conditions and are the leading cause of disability worldwide. Several studies performed in the last years support the involvement of the endocannabinoid system in the etiopathogenesis of different mental disorders. The present review will summarize the latest information on the role of the endocannabinoid system in psychiatric disorders, specifically depression, anxiety, and schizophrenia. We will focus on the findings from human brain studies regarding alterations in endocannabinoid levels, cannabinoid receptors and endocannabinoid metabolizing enzymes in patients suffering mental disorders. Studies carried out in humans have consistently demonstrated that the endocannabinoid system is fundamental for emotional homeostasis and cognitive function. Thus, deregulation of the different elements that are part of the endocannabinoid system may contribute to the pathophysiology of several mental disorders. However, the results reported are controversial. In this sense, different alterations in gene and/or protein expression of CB1 receptors have been shown depending on the technical approach used or the brain region studied. Despite the current discrepancies regarding cannabinoid receptors changes in depression and schizophrenia, present findings point to the endocannabinoid system as a pivotal neuromodulatory pathway relevant in the pathophysiology of mental disorders.This study was supported by the Spanish Ministry of Economy and Competitiveness (SAF2015-67457-R, MINECO/FEDER), the Plan Estatal de I+D+i 2013-2016, the Instituto de Salud Carlos III-Subdirección General de Evaluación y Fomento de la Investigación, Spanish Ministry of Economy, FEDER (PI13/01529) and the Basque Government (IT616/13). I I-L is a recipient of a Predoctoral Fellowship from the Basque Government. E F-Z is a recipient of a Predoctoral Fellowship from the University of Cantabria. CM is a recipient of a Postdoctoral Marie Skłodowska-Curie Individual Fellowship (H2020-MSCA-IF-2016, ID 747487)

Setting a baseline for global urban virome surveillance in sewage

The rapid development of megacities, and their growing connectedness across the world is becoming a distinct driver for emerging disease outbreaks. Early detection of unusual disease emergence and spread should therefore include such cities as part of risk-based surveillance. A catch-all metagenomic sequencing approach of urban sewage could potentially provide an unbiased insight into the dynamics of viral pathogens circulating in a community irrespective of access to care, a potential which already has been proven for the surveillance of poliovirus. Here, we present a detailed characterization of sewage viromes from a snapshot of 81 high density urban areas across the globe, including in-depth assessment of potential biases, as a proof of concept for catch-all viral pathogen surveillance. We show the ability to detect a wide range of viruses and geographical and seasonal differences for specific viral groups. Our findings offer a cross-sectional baseline for further research in viral surveillance from urban sewage samples and place previous studies in a global perspective

Bringing severe acute malnutrition treatment close to households through community health workers can lead to early admissions and improved discharge outcomes

Severe acute malnutrition (SAM) affects over 16.6 million children worldwide. The integrated Community Case Management (iCCM) strategy seeks to improve essential health by means of nonmedical community health workers (CHWs) who treat the deadliest infectious diseases in remote rural areas where there is no nearby health center. The objective of this study was to assess whether SAM treatment delivered by CHWs close to families’ locations may improve the early identification of cases compared to outpatient treatment at health facilities (HFs), with a decreased number complicated cases referred to stabilization centers, increased anthropometric measurements at admission (closer to the admission threshold) and similarity in clinical outcomes (cure, death, and default). The study included 930 children aged 6 to 59 months suffering from SAM in the Kita district of the Kayes Region in Mali; 552 children were treated by trained CHWs. Anthropometric measurements, the presence of edema, and other medical signs were recorded at admission, and the length of stay and clinical outcomes were recorded at discharge. The results showed fewer children with edema at admission in the CHW group than in the HF group (0.4% vs. 3.7%; OR = 10.585 [2.222–50.416], p = 0.003). Anthropometric measurements at admission were higher in the CHW group, with fewer children falling into the lowest quartiles of both weight-for-height z-scores (20.2% vs. 31.5%; p = 0.002) and mid-upper arm circumference (18.0% vs. 32.4%; p<0.001), than in the HF group. There was no difference in the length of stay. More children in the CHW group were cured (95.9% vs. 88.7%; RR = 3.311 [1.772–6.185]; p<0.001), and there were fewer defaulters (3.7% vs. 9.8%; RR = 3.345 [1.702–6.577]; p<0.001) than in the HF group. Regression analyses demonstrated that less severe anthropometric measurements at admission resulted in an increased probability of cure at discharge. The study results also showed that CHWs provided more integrated care, as they diagnosed and treated significantly more cases of infectious diseases than HFs (diarrhea: 36.0% vs. 18.3%, p<0.001; malaria: 41.7% vs. 19.8%, p<0.001; acute respiratory infection: 34.8% vs. 25.2%, p = 0.007). The addition of SAM treatment in the curative tasks that the CHWs provided to the families resulted in earlier admission and more integrated care for children than those associated with HFs. CHW treatment also achieved better discharge outcomes than standard community treatment.The Innocent FoundationDepto. de Biodiversidad, Ecología y EvoluciónFac. de Ciencias BiológicasTRUEpu

Gene expression in major depressive disorder

The search for genetic variants underlying major depressive disorder (MDD) has not yet provided firm leads to its underlying molecular biology, A complementary approach is to study gene expression in relation to MDD, We measured gene expression in peripheral blood from 1848 subjects from The Netherlands Study of Depression and Anxiety. Subjects were divided into current MDD (N =882), remitted MDD (N =635) and control (N =331) groups. MDD status and gene expression were measured again 2 years later in 414 subjects. The strongest gene expression differences were between the current MDD and control groups (129 genes at false-discovery rate, FDR <0.1). Gene expression differences across MDD status were largely unrelated to antidepressant use, inflammatory status and blood cell counts. Genes associated with MDD were enriched for interleukin-6 (IL-6)-signaling and natural killer (NK) cell pathways. We identified 13 gene expression clusters with specific clusters enriched for genes involved in NK cell activation (downregulated in current MDD, FDR= 5.8 x 10(-5)) and IL-6 pathways (upregulated in current MDD, FDR= 3.2 x Longitudinal analyses largely confirmed results observed in the cross-sectional data. Comparisons of gene expression results to the Psychiatric Genomics Consortium (PGC) MDD genome-wide association study results revealed overlap with DVL3. In conclusion, multiple gene expression associations with MDD were identified and suggest a measurable impact of current MDD state on gene expression. Identified genes and gene clusters are enriched with immune pathways previously associated with the etiology of MDD, in line with the immune suppression and immune activation hypothesis of MDD