Transgenerational inheritance of environmental information in Caenorhabditis elegans

Motivation: In 1906 Luther Burbank, an American botanist, said “Heridity is only the sum of all past environment” (Burbank, 1906). This idea has always been present in spite of being left behind after sustaining that the germline was isolated of the rest of the organism and, therefore, of the environment. With the rediscovery of epigenetics as a regulatory system which controls gene expression without affecting the composition of genes themselves, this idea has regained importance. Not only a great number of cases of environmental changes that influenced the epigenetics in a great variety of species began to be observed; but also the effects of these changes could last for three or more generations. This phenomenon was known as transgenerational epigenetic inheritance (Heard and Martienssen, 2014). This project aims to study the phenomenon of transgenerational epigenetic inheritance in the Caenorhabditis elegans model animal. The idea is to set the parameters where we can identify the phenomenon and reveal the molecular mechanism involved in the process.Methods: We set two different experiments, resistance to pathogen and behavioral respond to the pathogen. For the resistance experiment, plates with Escherichia coli (OP50, main source of nematode's food) and plates with Pseudomonas aeruginosa (PA14, a pathogen) were used to grow mothers and then the percentage of descendants that reach adulthood were scored. For the behavioral experiment, plates with OP50 and plates with both bacteria (PA14 and OP50) were used to grow mothers. Then their eggs were placed on plates containing OP50 and PA14. We counted the percent of worms that went to OP50 and to PA14.Results: It has been observed that individuals whose mothers have been exposed to Pseudomonas aeruginosa are more resistant to it than those whose mothers have never been in contact with the pathogen. On the other hand, it has been observed that this inheritance not only affects the defense mechanisms of the organism, but also influences its behavior. At this time we are studying the genetic pathways involved in this process by using mutants affected in epigenetic and in other candidate pathways.Conclusions: Our results suggest that there is not only an inheritance to stress resistance but also an acquired behavioral inheritance. Genes involved in epigenetic seem to be involved in the process

Azimuthal variations of oxygen abundance profiles in star-forming regions of disc galaxies in EAGLE simulations

The exploration of the spatial distribution of chemical abundances in star-forming regions of galactic discs can help us to understand the complex interplay of physical processes that regulate the star formation activity and the chemical enrichment across a galaxy. We study the azimuthal variations of the normalized oxygen abundance profiles in the highest numerical resolution run of the Evolution and Assembly of GaLaxies and their Environments (EAGLE) Project at z = 0. We use young stellar populations to trace the abundances of star-forming regions. Oxygen profiles are estimated along different line of sights from a centrally located observer. The mean azimuthal variation in the EAGLE discs are ∼0.12 ± 0.03 dex R−1 eff for slopes and ∼0.12 ± 0.03 dex for the zero-points, in agreement with previous works. Metallicity gradients measured along random directions correlate with those determined by averaging over the whole discs, although with a large dispersion. We find a slight trend for higher azimuthal variations in the disc components of low star-forming and bulge-dominated galaxies. We also investigate the metallicity profiles of stellar populations with higher and lower levels of enrichment than the average metallicity profiles, and we find that high star-forming regions with high metallicity tend to have slightly shallower metallicity slopes compared with the overall metallicity gradient. The simulated azimuthal variations in the EAGLE discs are in agreement with observations, although the large variety of metallicity gradients would encourage further exploration of the metal mixing in numerical simulations.Indexación: Scopu

Brain tissue recovery in obstructive congenital hydrocephalus after intraventricular transplantation of mesenchymal stem cells

Introduction: Bone marrow-derived mesenchymal stem cells (BM-MSC) are a potential therapeutic tool due to their ability for migrating and producing neuroprotector factors when transplanted. The aim of this study was to evaluate the short-time effects of a BM-MSC experimental therapy in the hyh mouse model with severe obstructive hydrocephalus. Methods: BM-MSC were characterized in vitro and then injected into the ventricles of hyh mice. Wild-type and saline-injected hyh mice were used as controls. Samples were studied by analyzing and comparing mRNA, protein and metabolites level expression in control and damaged tissue. Results: Undifferentiated BM-MSC were found to: i) spread into the periventricular astrocyte reaction region after four days post-injection, and, ii) be producing neuroprotector factors (GDNF and VEGF). Astrocytes located in periventricular edematous region increased their aquaporin-4 expression, as well as Slit2 expression (neuroprotective and anti-inflammatory molecule). There was also a significant reduction of osmolytes such as taurine and neuroexcytotoxic glutamate. Halved apoptotic cell death was detected in the periventricular walls. Conclusions: BM-MSC lead to recovery of the severe neurodegenerative conditions associated to congenital hydrocephalus mediated by reactive astrocytes.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. Supported by Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech, and PI15/0619 (ISCIII/FEDER)

Metalloproteinase-dependent TLR2 ectodomain shedding is involved in soluble toll-like receptor 2 (sTLR2) production

Toll-like receptor (TLR) 2, a type I membrane receptor that plays a key role in innate immunity, recognizes conserved molecules in pathogens, and triggering an inflammatory response. It has been associated with inflammatory and autoimmune diseases. Soluble TLR2 (sTLR2) variants have been identified in human body fluids, and the TLR2 ectodomain can negatively regulate TLR2 activation by behaving as a decoy receptor. sTLR2 generation does not involve alternative splicing mechanisms, indicating that this process might involve a post-translational modification of the full-length receptor; however, the specific mechanism has not been studied. Using CD14+ peripheral human monocytes and the THP-1 monocytic leukemia-derived cell line, we confirm that sTLR2 generation increases upon treatment with pro-inflammatory agents and requires a post-translational mechanism. We also find that the constitutive and ligand-induced release of sTLR2 is sensitive to pharmacological metalloproteinase activator and inhibitors leading us to conclude that metalloproteinase TLR2 shedding contributes to soluble receptor production. By expressing human TLR2 in ADAM10- or ADAM17-deficient MEF cells, we find both enzymes to be implicated in TLR2 ectodomain shedding. Moreover, using a deletion mutant of the TLR2 juxtamembrane region, we demonstrate that this domain is required for sTLR2 generation. Functional analysis suggests that sTLR2 generated by metalloproteinase activation inhibitsTLR2-induced cytokine production by this monocytic leukemia-derived cell line. The identification of the mechanisms involved in regulating the availability of soluble TLR2 ectodomain and cell surface receptors may contribute further research on TLR2-mediated processes in innate immunity and inflammatory disorders

Clinical Outcomes of Community-Acquired Pneumonia in Patients with Diabetes Mellitus

Background: Studies have found admission hyperglycemia as a predictor of poor outcomes in Community acquired Pneumonia (CAP), whereas others have not. The objective of this study was to evaluate the impact of diabetes mellitus (DM) on mortality as well as Length of stay (LOS) and Time to clinical stability (TCS) of hospitalized patients with CAP. Materials and Methods: Adult patients hospitalized with CAP enrolled at Community-Acquired Pneumonia Organization (CAPO) database with DM were categorized as admission blood glucose ≥ 250 mg/dL (diabetes mellitus blood sugar (BG) \u3e 250) and admission blood glucose ≤ 250 mg/dL (DM BG ≤ 250). CAP outcomes included: all-cause in-hospital mortality, all-cause 28-day mortality, length of stay (LOS) and time to clinical stability (TCS). Results: From a total of 7,303 patients with CAP, 294 (17.7%) had DM; out of whom 960 (13.1%) patients had BG ≤ 250 mg/dL, and 334 (4.6%) patients had BG \u3e 250 mg/dL. The in-hospital mortality was 9.3% for controls, 9.9% for the DM BG ≤ 250 mg/dL group and 13.4% for DM BG \u3e 250 mg/dL group (p = 0.04). Patients with DM BG \u3e 250 mg/dL compared to the control group had a higher risk of in-hospital mortality (Hazard ratio (RR) = 1.32, 95% CI: 1.02-1.72, p = 0.034) and 28-day mortality (RR = 1.31, 95% CI: 1.01-1.71, p = 0.048). Patients in the DM BG ≤ 250 mg/dL group compared to the control group did not have a greater risk for in-hospital mortality (RR = 1.23, 95% CI: 0.16-8.09, p = 0.237), 28-day mortality (RR = 1.09, 95% CI: 0.90-1.32, p = 0.398), LOS (HR = 0.93, 95% CI: 0.85-1.02, p = 0.130), or TCS (HR = 0.95, 95% CI: 0.87-1.05, p = 0.320). Conclusions: DM patients with BG \u3e 250 mg/dL were associated with increased in-hospital mortality and 28-day mortality. Further studies are needed to link the role of hyperglycemia to CAP outcome

The challenge of sustainability: Long-term results from the Fifty-Fifty peer group-based intervention in cardiovascular risk factors.

The Fifty-Fifty trial demonstrated that a peer-group-based intervention was able to improve healthy behaviors in individuals with cardiovascular (CV) risk factors immediately post-intervention. To determine the long-term sustainability of a one-year peer-group-based intervention focused on CV health and behavior. A total of 543 adults aged 25 to 50 years with at least 1 CV risk factor were screened and recruited, received initial training through workshops, and were then randomized 1:1 to a peer-group-based intervention group (IG) or a self-management control group (CG) for 12 months. At a median of 52 months from baseline, 321 participants were re-assessed (~60% retention). The primary outcome was the mean change in a composite health score related to blood pressure, exercise, weight, alimentation, and tobacco use (Fuster-BEWAT score [FBS], range 0-15). Intervention effects were assessed using linear-mixed effects models. The mean age of retained participants was 48.0 years (SD: 5.4), and 73% were female. Consistent with previous results, the change of overall FBS was significantly greater in the IG than in the CG at 12-month follow-up (between-group difference, 0.60 points; 95% CI, 0.08-1.12; P = .025). Assessment of long-term sustainability (52-month follow-up) showed that there were no between-group differences in the mean overall FBS (IG mean score, 8.52; 95% CI, 7.97-9.07 vs CG mean score, 8.51; 95% CI, 7.93-9.10; P = .972) or in the change of overall FBS from screening (IG mean change, 0.64; 95% CI, 0.00-1.28; CG mean change, 0.46; 95% CI, -0.20-1.12; P = .497). A one-year peer-group-based intervention showed favorable results at immediate post-intervention but did not demonstrate significant differences between the IG and CG at 52 months. Combination of an initial training period (workshops) with the maintenance of peer-support groups or other re-intervention strategies may be required to achieve sustained effects on healthy behaviors. ClinicalTrials.gov identifier NCT02367963. Registered (https://clinicaltrials.gov/show/NCT02367963).This study was co-funded by the SHE Foundation -“la Caixa” Foundation (LCF/PR/CE16/10700001 and LCF/PR/MS19/12220001) and the Ministry of Health, Social Services and Equality. R.F-J is recipient of funding from the Instituto de Salud Carlos III-Fondo de Investigacion Sanitaria (PI19/01704) co-funded by the European Regional Development Fund/European Social Fund (“A way to make Europe”/“Investing in your future”). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministry of Science and Innovation, and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505).S

CXCL6 is an important paracrine factor in the pro-angiogenic human cardiac progenitor-like cell secretome

Studies in recent years have established that the principal effects in cardiac cell therapy are associated with paracrine/autocrine factors. We combined several complementary techniques to define human cardiac progenitor cell (CPC) secretome constituted by 914 proteins/genes; 51% of these are associated with the exosomal compartment. To define the set of proteins specifically or highly differentially secreted by CPC, we compared human mesenchymal stem cells and dermal fibroblasts; the study defined a group of growth factors, cytokines and chemokines expressed at high to medium levels by CPC. Among them, IL-1, GROa (CXCL1), CXCL6 (GCP2) and IL-8 are examples whose expression was confirmed by most techniques used. ELISA showed that CXCL6 is significantly overexpressed in CPC conditioned medium (CM) (18- to 26-fold) and western blot confirmed expression of its receptors CXCR1 and CXCR2. Addition of anti-CXCL6 completely abolished migration in CPC-CM compared with anti-CXCR2, which promoted partial inhibition, and anti-CXCR1, which was inefficient. Anti-CXCL6 also significantly inhibited CPC CM angiogenic activity. In vivo evaluation also supported a relevant role for angiogenesis. Altogether, these results suggest a notable angiogenic potential in CPC-CM and identify CXCL6 as an important paracrine factor for CPC that signals mainly through CXCR2.This study was supported by funding from the European Commission (HEALTH-2009_242038) and by grants from the Spanish Ministry of Science and Innovation (SAF2012-34327 and SAF2015-70882-R to AB and BIO2012-37926 and BIO2015-67580-P to JV), the Research Program of the Comunidad Autónoma de Madrid (S2010/BMD-2420) and the Instituto de Salud Carlos III (RETICS-RD12/0019/0018 to AB and RETICS-RD12/0042/0056 to JV).S

Neurocysticercosis, a Persisting Health Problem in Mexico

Human neurocysticercosis is a severe parasitic disease caused by the installation of Taenia solium larvae in the central nervous system. Neurocysticercosis is still deeply rooted in Latin-America, Africa and Asia, where it develops its complete life cycle promoted by poor sanitary conditions. It is also emerging in developed countries due to human migration. Although hard data on the evolution of the disease incidence in endemic countries are lacking, its presence is being obscured by the growth of degenerative and metabolic diseases, creating the illusion of having disappeared

Integration of stool microbiota, proteome and amino acid profiles to discriminate patients with adenomas and colorectal cancer

BACKGROUND: Screening for colorectal cancer (CRC) reduces its mortality but has limited sensitivity and specificity. Aims We aimed to explore potential biomarker panels for CRC and adenoma detection and to gain insight into the interaction between gut microbiota and human metabolism in the presence of these lesions. METHODS: This multicenter case-control cohort was performed between February 2016 and November 2019. Consecutive patients ≥18 years with a scheduled colonoscopy were asked to participate and divided into three age, gender, body-mass index and smoking status-matched subgroups: CRC (n = 12), adenomas (n = 21) and controls (n = 20). Participants collected fecal samples prior to bowel preparation on which proteome (LC-MS/MS), microbiota (16S rRNA profiling) and amino acid (HPLC) composition were assessed. Best predictive markers were combined to create diagnostic biomarker panels. Pearson correlation-based analysis on selected markers was performed to create networks of all platforms. RESULTS: Combining omics platforms provided new panels which outperformed hemoglobin in this cohort, currently used for screening (AUC 0.98, 0.95 and 0.87 for CRC vs controls, adenoma vs controls and CRC vs adenoma, respectively). Integration of data sets revealed markers associated with increased blood excretion, stress- and inflammatory responses and pointed toward downregulation of epithelial integrity. CONCLUSIONS: Integrating fecal microbiota, proteome and amino acids platforms provides for new biomarker panels that may improve noninvasive screening for adenomas and CRC, and may subsequently lead to lower incidence and mortality of colon cancer