Characterization of cytomegalovirus lung infection in non-HIV infected children

Cytomegalovirus (CMV) is a prevalent pathogen in the immunocompromised host and invasive pneumonia is a feared complication of the virus in this population. In this pediatric case series we characterized CMV lung infection in 15 non-HIV infected children (median age 3 years; IQR 0.2–4.9 years), using current molecular and imaging diagnostic modalities, in combination with respiratory signs and symptoms. The most prominent clinical and laboratory findings included cough (100%), hypoxemia (100%), diffuse adventitious breath sounds (100%) and increased respiratory effort (93%). All patients had abnormal lung images characterized by ground glass opacity/consolidation in 80% of cases. CMV was detected in the lung either by CMV PCR in bronchoalveolar lavage (82% detection rate) or histology/immunohistochemistry in lung biopsy (100% detection rate). CMV caused respiratory failure in 47% of children infected and the overall mortality rate was 13.3%. Conclusion: CMV pneumonia is a potential lethal disease in non-HIV infected children that requires a high-index of suspicion. Common clinical and radiological patterns such as hypoxemia, diffuse adventitious lung sounds and ground-glass pulmonary opacities may allow early identification of CMV lung infection in the pediatric population, which may lead to prompt initiation of antiviral therapy and better clinical outcomes

Comparative description of ten transcriptomes of newly sequenced invertebrates and efficiency estimation of genomic sampling in non-model taxa

Traditionally, genomic or transcriptomic data have been restricted to a few model or emerging model organisms, and to a handful of species of medical and/or environmental importance. Next-generation sequencing techniques have the capability of yielding massive amounts of gene sequence data for virtually any species at a modest cost. Here we provide a comparative analysis of de novo assembled transcriptomic data for ten non-model species of previously understudied animal taxa.Peer reviewe

Pranlukast Antagonizes CD49f and Reduces Sternness in Triple-Negative Breast Cancer Cells

Introduction: Cancer stem cells (CSCs) drive the initiation, maintenance, and therapy response of breast tumors. CD49f is expressed in breast CSCs and functions in the maintenance of stemness. Thus, blockade of CD49f is a potential therapeutic approach for targeting breast CSCs. In the present study, we aimed to repurpose drugs as CD49f antagonists. Materials and Methods: We performed consensus molecular docking using a subdomain of CD49f that is critical for heterodimerization and a collection of pharmochemicals clini-cally tested. Molecular dynamics simulations were employed to further characterize drug-target binding. Using MDA-MB-231 cells, we evaluated the effects of potential CD49f antagonists on 1) cell adhesion to laminin; 2) mammosphere formation; and 3) cell viability. We analyzed the effects of the drug with better CSC-selectivity on the activation of CD49f-downstream signaling by Western blot (WB) and co-immunoprecipitation. Expressions of the stem cell markers CD44 and SOX2 were analyzed by flow cytometry and WB, respectively. Transactivation of SOX2 promoter was evaluated by luciferase reporter assays. Changes in the number of CSCs were assessed by limiting-dilution xenotransplantation. Results: Pranlukast, a drug used to treat asthma, bound to CD49f in silico and inhibited the adhesion of CD49f+ MDA-MB-231 cells to laminin, indicating that it antagonizes CD49f-containing integrins. Molecular dynamics analysis showed that pranlukast binding induces con-formational changes in CD49f that affect its interaction with β1-integrin subunit and constrained the conformational dynamics of the heterodimer. Pranlukast decreased the clonogenicity of breast cancer cells on mammosphere formation assay but had no impact on the viability of bulk tumor cells. Brief exposure of MDA-MB-231 cells to pranlukast altered CD49f-dependent signaling, reducing focal adhesion kinase (FAK) and phosphatidylinositol 3-kinase (PI3K) activation. Further, pranlukast-treated cells showed decreased CD44 and SOX2 expression, SOX2 promoter transacti-vation, and in vivo tumorigenicity, supporting that this drug reduces the frequency of CSC. Conclusion: Our results support the function of pranlukast as a CD49f antagonist that reduces the CSC population in triple-negative breast cancer cells. The pharmacokinetics and toxicology of this drug have already been established, rendering a potential adjuvant therapy for breast cancer patients

miR-146a is a pivotal regulator of neutrophil extracellular trap formation promoting thrombosis.

Neutrophil extracellular traps (NETs) induce a procoagulant response linking inflammation and thrombosis. Low levels of miR-146a, a brake of inflammatory response, are involved in higher risk for cardiovascular events, but the mechanisms explaining how miR-146a exerts its function remain largely undefined. The aim of this study was to explore the impact of miR-146a deficiency in NETosis both, in sterile and non-sterile models in vivo, and to inquire into the underlying mechanism. Two models of inflammation were performed: 1) Ldlr-/- mice transplanted with bone marrow from miR-146a-/- or wild type (WT) were fed high-fat diet, generating an atherosclerosis model; and 2) an acute inflammation model was generated by injecting lipopolysaccharide (LPS) (1 mg/Kg) into miR-146a-/- and WT mice. miR-146a deficiency increased NETosis in both models. Accordingly, miR-146a-/- mice showed significant reduced carotid occlusion time and elevated levels of NETs in thrombi following FeCl3-induced thrombosis. Infusion of DNAse I abolished arterial thrombosis in WT and miR-146a-/- mice. Interestingly, miR-146a deficient mice have aged, hyperreactive and pro-inflammatory neutrophils in circulation that are more prone to form NETs independently of the stimulus. Furthermore, we demonstrated that community acquired pneumonia (CAP) patients with reduced miR-146a levels associated with the T variant of the functional rs2431697, presented an increased risk for cardiovascular events due in part to an increased generation of NETs.This work was supported by research grants from Instituto de Salud Carlos III (ISCIII), Fondo Europeo de Desarrollo Regional “Investing in your future” (PI17/00051 y PI17/01421) (PFIS18/0045: A.M. de los Reyes-García) (CD18/00044: S. Águila), and Fundación Séneca (19873/GERM/15). The CNIC is supported by the ISCIII, the Ministerio de Ciencia, Innovación y Universidades (MCIU), and the Fundación Pro CNIC, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). A.B. Arroyo has a research fellowship from Sociedad Española de Trombosis y Hemostasia (SETH). The MCIU supported A.dM. (predoctoral contract BES-2014-067791).S

Looking for Crumbs in the Obesity Forest: Anti-obesity Interventions and Obesity-Associated Cardiometabolic Traits in the Mexican Population. History and Systematic Review With Meta-Analyses

Mexicans and Mexican Americans share culture, genetic background, and predisposition for chronic complications associated with obesity and diabetes making imperative efficacious treatments and prevention. Obesity has been treated for centuries focused-on weight loss while other treatments on associated conditions like gout, diabetes (T2D), and hypertriglyceridemia. To date, there is no systematic review that synthesizes the origin of obesity clinics in Mexico and the efforts to investigate treatments for obesity tested by randomized clinical trials (RCT). We conducted systematic searches in Pubmed, Scopus, and Web of Science to retrieve anti-obesity RCT through 2019 and without an inferior temporal limit. The systematic review included RCT of anti-obesity treatments in the Mexican adult population, covering alternative medicine, pharmacological, nutritional, behavioral, and surgical interventions reporting metabolism-associated traits such as BMI, weight, waist circumference, triglycerides, glucose, among others. Only the studies with at least 3 months of treatment were included in the meta-analyses in order to reduce placebo effects. We found 634 entries, after removal of duplicates and screening the studies based on eligibility criteria, we analyzed 43 national, and 2 multinational-collaborative studies. Most of the national studies had small sample sizes, and the implemented strategies do not have replications in the population. The nutrition/behavioral interventions were difficult to blind, and most studies have medium-to-high risk of bias. Nutritional/behavioral interventions and medications showed effects on BMI, waist circumference, and blood pressure. Simple measures like pure water instead of sweet beverages decrease triglycerides and systolic blood pressure. Dark chocolate showed the highest effect for BMI and high blood pressure, and treatment with insulin increased weight in those with T2D. The study of obesity in Mexico has been on-going for more than four decades, the interest on RCT just increased until this millennium, but with small sample sizes and lack of replication. The interventions affect different cardiometabolic associated traits, which should be analyzed in detail in the population living near the Mexico-U.S. border; therefore, bi-national collaboration is desirable to disentangle the cultural effects on this population\u27s treatment response

Gene-environment interaction analysis of redox-related metals and genetic variants with plasma metabolic patterns in a general population from Spain: The Hortega Study

Background: Limited studies have evaluated the joint influence of redox-related metals and genetic variation on metabolic pathways. We analyzed the association of 11 metals with metabolic patterns, and the interacting role of candidate genetic variants, in 1145 participants from the Hortega Study, a population-based sample from Spain. Methods: Urine antimony (Sb), arsenic, barium (Ba), cadmium (Cd), chromium (Cr), cobalt (Co), molybdenum (Mo) and vanadium (V), and plasma copper (Cu), selenium (Se) and zinc (Zn) were measured by ICP-MS and AAS, respectively. We summarized 54 plasma metabolites, measured with targeted NMR, by estimating metabolic principal components (mPC). Redox-related SNPs (N = 291) were measured by oligo-ligation assay. Results: In our study, the association with metabolic principal component (mPC) 1 (reflecting non-essential and essential amino acids, including branched chain, and bacterial co-metabolism versus fatty acids and VLDL subclasses) was positive for Se and Zn, but inverse for Cu, arsenobetaine-corrected arsenic (As) and Sb. The association with mPC2 (reflecting essential amino acids, including aromatic, and bacterial co-metabolism) was inverse for Se, Zn and Cd. The association with mPC3 (reflecting LDL subclasses) was positive for Cu, Se and Zn, but inverse for Co. The association for mPC4 (reflecting HDL subclasses) was positive for Sb, but inverse for plasma Zn. These associations were mainly driven by Cu and Sb for mPC1; Se, Zn and Cd for mPC2; Co, Se and Zn for mPC3; and Zn for mPC4. The most SNP-metal interacting genes were NOX1, GSR, GCLC, AGT and REN. Co and Zn showed the highest number of interactions with genetic variants associated to enriched endocrine, cardiovascular and neurological pathways. Conclusions: Exposures to Co, Cu, Se, Zn, As, Cd and Sb were associated with several metabolic patterns involved in chronic disease. Carriers of redox-related variants may have differential susceptibility to metabolic alterations associated to excessive exposure to metals.This work was supported by the Strategic Action for Research in Health sciences [CP12/03080, PI15/00071, PI10/0082, PI13/01848, PI14/00874, PI16/01402, PI21/00506 and PI11/00726], CIBER Fisio patología Obesidad y Nutrición (CIBEROBN) (CIBER-02-08-2009, CB06/03 and CB12/03/30,016), the State Agency for Research (PID2019-108973RB- C21 and C22), the Valencia Government (GRUPOS 03/101; PROMETEO/2009/029 and ACOMP/2013/039, IDI FEDER/2021/072 and GRISOLIAP/2021/119), the Castilla-Leon Government (GRS/279/A/08) and European Network of Excellence Ingenious Hypercare (EPSS-037093) from the European Commission. The Strategic Action for Research in Health sciences, CIBERDEM and CIBEROBN are initiatives from Carlos III Health Institute Madrid and cofunded with European Funds for Regional Development (FEDER). The State Agency for Research and Carlos III Health Institute belong to the Spanish Ministry of Science and Innovation. ADR received the support of a fellowship from “la Caixa” Foundation (ID 100010434) (fellowship code “LCF/BQ/DR19/11740016”). MGP received the support of a fellowship from “la Caixa” Foundation (ID 100010434, fellowship code LCFLCF/BQ/DI18/11660001). The funding bodies had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.S

Nanoinformatics: developing new computing applications for nanomedicine

Nanoinformatics has recently emerged to address the need of computing applications at the nano level. In this regard, the authors have participated in various initiatives to identify its concepts, foundations and challenges. While nanomaterials open up the possibility for developing new devices in many industrial and scientific areas, they also offer breakthrough perspectives for the prevention, diagnosis and treatment of diseases. In this paper, we analyze the different aspects of nanoinformatics and suggest five research topics to help catalyze new research and development in the area, particularly focused on nanomedicine. We also encompass the use of informatics to further the biological and clinical applications of basic research in nanoscience and nanotechnology, and the related concept of an extended ?nanotype? to coalesce information related to nanoparticles. We suggest how nanoinformatics could accelerate developments in nanomedicine, similarly to what happened with the Human Genome and other -omics projects, on issues like exchanging modeling and simulation methods and tools, linking toxicity information to clinical and personal databases or developing new approaches for scientific ontologies, among many others

Angiocrine polyamine production regulates adiposity.

Reciprocal interactions between endothelial cells (ECs) and adipocytes are fundamental to maintain white adipose tissue (WAT) homeostasis, as illustrated by the activation of angiogenesis upon WAT expansion, a process that is impaired in obesity. However, the molecular mechanisms underlying the crosstalk between ECs and adipocytes remain poorly understood. Here, we show that local production of polyamines in ECs stimulates adipocyte lipolysis and regulates WAT homeostasis in mice. We promote enhanced cell-autonomous angiogenesis by deleting Pten in the murine endothelium. Endothelial Pten loss leads to a WAT-selective phenotype, characterized by reduced body weight and adiposity in pathophysiological conditions. This phenotype stems from enhanced fatty acid β-oxidation in ECs concomitant with a paracrine lipolytic action on adipocytes, accounting for reduced adiposity. Combined analysis of murine models, isolated ECs and human specimens reveals that WAT lipolysis is mediated by mTORC1-dependent production of polyamines by ECs. Our results indicate that angiocrine metabolic signals are important for WAT homeostasis and organismal metabolism.We thank members of the Endothelial Pathobiology and Microenvironment Group for helpful discussions. We thank the CERCA Program/Generalitat de Catalunya and the Josep Carreras Foundation for institutional support. The research leading to these results has received funding from la Fundación BBVA (Ayuda Fundacion BBVA a Equipos de Investigación Científica 2019, PR19BIOMET0061) and from SAF2017-82072-ERC from Ministerio de Ciencia, Innovación y Universidades (MCIU) (Spain). The laboratory of M.G. is also supported by the research grants SAF2017-89116R-P (FEDER/EU) co-funded by European Regional Developmental Fund (ERDF), a Way to Build Europe and PID2020-116184RB-I00 from MCEI; by the Catalan Government through the project 2017-SGR; PTEN Research Foundation (BRR-17-001); La Caixa Foundation (HR19-00120 and HR21-00046); by la Asociación Española contra el Cancer-Grupos Traslacionales (GCTRA18006CARR, also to A.C.); European Foundation for the Study of Diabetes/Lilly research grant, also to M.C.); and by the People Programme (Marie Curie Actions; grant agreement 317250) of the European Union’s Seventh Framework Programme FP7/2007-2013 and the Marie Skłodowska-Curie (grant agreement 675392) of the European Union’s Horizon 2020 research. The laboratory of A.C. is supported by the Basque Department of Industry, Tourism and Trade (Elkartek) and the department of education (IKERTALDE IT1106-16), the MCIU (PID2019-108787RB-I00 (FEDER/ EU); Severo Ochoa Excellence Accreditation SEV-2016-0644; Excellence Networks SAF2016-81975-REDT), La Caixa Foundation (ID 100010434), under the agreement LCF/PR/HR17, the Vencer el Cancer foundation and the European Research Council (ERC) (consolidator grant 819242). CIBERONC was co-funded with FEDER funds and funded by Instituto de Salud Carlos III (ISCIII). The laboratory of M.C. is supported by the ERC under the European Union’s Horizon 2020 research and innovation programme (grant agreement 725004) and CERCA Programme/Generalitat de Catalunya (M.C.). The laboratory of D.S. is supported by research grants from MINECO (SAF2017- 83813-C3-1-R, also to L.H., cofounded by the ERDF), CIBEROBN (CB06/03/0001), Government of Catalonia (2017SGR278) and Fundació La Marató de TV3 (201627- 30). The laboratory of R.N. is supported by FEDER/Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación (RTI2018-099413-B-I00 and and RED2018-102379-T), Xunta de Galicia (2016-PG057 and 2020-PG015), ERC under the European Union’s Horizon 2020 research and innovation programme (grant agreement 810331), Fundación BBVA, Fundacion Atresmedia and CIBEROBN, which is an initiative of the ISCIII of Spain, which is supported by FEDER funds. The laboratory of J.A.V. is supported by research grants from MICINN (RTI2018-099250-B100) and by La Caixa Foundation (ID 100010434, LCF/PR/HR17/52150009). P.M.G.-R. is supported by ISCIII grant PI15/00701 cofinanced by the ERDF, A Way to Build Europe. Personal support was from Marie Curie ITN Actions (E.M.), Juan de la Cierva (IJCI-2015-23455, P.V.), CONICYT fellowship from Chile (S.Z.), Vetenskapsradet (Swedish Research Council, 2018-06591, L.G.) and NCI K99/R00 Pathway to Independence Award (K99CA245122, P. Castel).S

Effectiveness of rotavirus vaccination in Spain

With the aim of determining rotavirus vaccine effectiveness (RVVE) in Spain, from Oct-2008/Jun-2009, 467 consecutive children below 2 years old with acute gastroenteritis (AGE) were recruited using a pediatric research network (ReGALIP-www.regalip.org) that includes primary, emergency and hospital care settings. Of 467 enrolled children, 32.3% were rotavirus positive and 35.0% had received at least one dose of any rotavirus vaccine. RRVE to prevent any episode of rotavirus AGE was 91.5% (95% CI: 83.7%-95.6%). RVVE to prevent hospitalization by rotavirus AGE was 95.6% (85.6-98.6%). No differences in RVVE were found regarding the vaccine used. Rotavirus vaccines have showed an outstanding effectiveness in Spain

Randomized Clinical Trials of obesity treatments in Mexican population. Systematic Review and Meta-Analysis

Background: Mexicans and Mexican Americans share similar culture, genetic background, and predisposition for obesity and diabetes. Randomized clinical trials (RCT) assessing obesity treatments (ObT) are reliable to assess efficacy. To date, there is no systematic review to investigate ObT tested by RCT in Mexican adults. Methods: We conducted systematic searches in Pubmed, Scopus, and Web of Science to retrieve ObT RCT from 1990 to 2019. The ObT included alternative medicine, pharmacological, nutritional, behavioral, and surgical interventions. The analyzed RCT were at least three months of duration, and reported: BMI, weight, waist circumference, triglycerides, glucose and blood pressure. Results: We found 634 entries; after removal of duplicates and exclusions based on eligibility criteria, we analyzed 43 and 2 multinational-collaborative studies. Most of the national studies had small sample sizes, and did not have replications from other studies. The nutrition/behavioral interventions were difficult to blind, and most studies had medium to high risk of bias. Random effects meta-analysis of nutritional/behavioral interventions and medications showed effects on BMI, waist circumference, and blood pressure. Simple measures like plain water instead of sweet beverages decreased triglycerides and systolic blood pressure. Participants with obesity and hypertension had beneficial effects with antioxidants, and the treatment with insulin increased weight in those with T2D. Conclusions: The RCT’s in Mexico reported effects on metabolic components despite small sample sizes and lack of replication. In the future we should analyze ObT in population living on the U.S.-Mexico border; therefore, bi-national collaboration is desirable to disentangle cultural effects on ObT response