The enzymes LSD1 and Set1A cooperate with the viral protein HBx to establish an active hepatitis B viral chromatin state

Indexación: Web of ScienceWith about 350 million people chronically infected around the world hepatitis B is a major health problem. Template for progeny HBV synthesis is the viral genome, organized as a minichromosome (cccDNA) inside the hepatocyte nucleus. How viral cccDNA gene expression is regulated by its chromatin structure; more importantly, how the modulation of this structure impacts on viral gene expression remains elusive. Here, we found that the enzyme SetDB1 contributes to setting up a repressed cccDNA chromatin state. This repressive state is activated by the histone lysine demethylase-1 (LSD1). Consistently, inhibiting or reducing LSD1 levels led to repression of viral gene expression. This correlates with the transcriptionally repressive mark H3K9 methylation and reduction on the activating marks H3 acetylation and H3K4 methylation on viral promoters. Investigating the importance of viral proteins we found that LSD1 recruitment to viral promoters was dependent on the viral transactivator protein HBx. Moreover, the histone methyltransferase Set1A and HBx are simultaneously bound to the core promoter, and Set1A expression correlates with cccDNA H3K4 methylation. Our results shed light on the mechanisms of HBV regulation mediated by the cccDNA chromatin structure, offering new therapeutic targets to develop drugs for the treatment of chronically infected HBV patients.http://www.nature.com/articles/srep2590

Propuesta de un modelo de mesa de partes virtual (MPV) para las entidades de la administraci?n p?blica

Dentro del contexto del Estado de Emergencia Sanitaria como consecuencia del COVID-19 y como parte de las medidas destinadas para modernizar la gesti?n en las entidades de la Administraci?n P?blica, la investigaci?n busca analizar si existerelaci?n entrela implementaci?n de una mesa de partes virtual est?ndar para todas las entidades de la Administraci?n P?blica y el desarrollo de los procesos de simplificaci?n administrativa, con el prop?sito de brindar valor p?blico a los ciudadanos en sus relaciones con las entidades estatales, de todos los niveles de gobierno.La existencia de un marco normativo que regula la implementaci?n de esta soluci?n no es suficiente, ya que las mesas de partes virtuales existentes difieren entre s?, dificultando el acceso a los ciudadanos a este canal de atenci?n, por lo que, luego de analizar c?mo es que los lineamientos para la implementaci?n de una mesa de partes virtual est?ndar influyen positivamenteen la simplificaci?n administrativa en las entidades p?blicasy de concluir en la existencia de una relaci?n entre ambos conceptos, se incluye una propuesta y los beneficios que se espera conseguir con su puesta en funcionamiento

Exposure to widespread drinking water chemicals, blood inflammation markers, and colorectal cancer

Background: Trihalomethanes (THMs) and nitrate are widespread chemicals in drinking water associated with colorectal cancer risk but mechanisms are not well understood. Objectives: We explored the association between exposure to THMs and nitrate in drinking water and inflammation markers, and the link with colorectal cancer risk. Methods: A subset of 198 colorectal cancer cases and 205 controls from the multicase-control study MCC-Spain were included. Average concentration of THMs (chloroform, bromodichloromethane, dibromochloromethane, bromoform) and nitrate in tap water at the residence was estimated from age 18 until 2 years before the interview ("long term") and for a recent period (3 years before diagnosis). Serum levels of EGF, eotaxin, G-CSF, IL-17E, IL-1rA, IL-8, IP-10, MDC, MPO, periostin, VEGF, and C-reactive protein (CRP) were measured. We estimated the linear association between inflammation markers and exposure among controls, and the odds ratio of colorectal cancer associated with THM and nitrate exposure, and inflammation markers. A mediation analysis was conducted to identify inflammation markers in the pathway between THM/nitrate exposure and colorectal cancer. Results: Serum concentrations of EGF, IL-8, IL-17E and eotaxin increased with recent residential levels of brominated THMs, chloroforom and/or total THM. No associations were observed for nitrate and for long-term residential THM levels. All residential exposures except chloroform were positively associated with colorectal cancer. Serum concentrations of VEGF and periostin were positively associated with colorectal cancer, while EGF was inversely associated. One protein-exposure combination (periostin-recent ingested brominated THMs) slightly mediated the association with colorectal cancer risk. Discussion: Results suggest that estimated THM exposure is involved in inflammation processes. However, the study design was limited to stablish etiologically relevant associations between the protein levels and colorectal cancer risk. The lack of association between nitrate exposure and inflammation markers suggests other biological mechanisms are involved in the link with colorectal cancer.Acknowledgements: We acknowledge support from the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019-2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. This work was funded by the 7th Framework Programme EXPOSOMICS Project (grant agreement 308610), the Acci´on Transversal del C´ancer del Consejo de Ministros del 11/10/2007, and the Instituto de Salud Carlos III-FEDER (PI08/1770, PI08/0533, PI11/00226) FIS grants

Value of adenosine infusion for infarct size determination using real-time myocardial contrast echocardiography

BACKGROUND: Myocardial contrast echocardiography has been used for determination of infarct size (IS) in experimental models. However, with intermittent harmonic imaging, IS seems to be underestimated immediately after reperfusion due to areas with preserved, yet dysfunctional, microvasculature. The use of exogenous vasodilators showed to be useful to unmask these infarcted areas with depressed coronary flow reserve. This study was undertaken to assess the value of adenosine for IS determination in an open-chest canine model of coronary occlusion and reperfusion, using real-time myocardial contrast echocardiography (RTMCE). METHODS: Nine dogs underwent 180 minutes of coronary occlusion followed by reperfusion. PESDA (Perfluorocarbon-Exposed Sonicated Dextrose Albumin) was used as contrast agent. IS was determined by RTMCE before and during adenosine infusion at a rate of 140 mcg·Kg(-1)·min(-1). Post-mortem necrotic area was determined by triphenyl-tetrazolium chloride (TTC) staining. RESULTS: IS determined by RTMCE was 1.98 ± 1.30 cm(2 )and increased to 2.58 ± 1.53 cm(2 )during adenosine infusion (p = 0.004), with good correlation between measurements (r = 0.91; p < 0.01). The necrotic area determined by TTC was 2.29 ± 1.36 cm(2 )and showed no significant difference with IS determined by RTMCE before or during hyperemia. A slight better correlation between RTMCE and TTC measurements was observed during adenosine (r = 0.99; p < 0.001) then before it (r = 0.92; p = 0.0013). CONCLUSION: RTMCE can accurately determine IS in immediate period after acute myocardial infarction. Adenosine infusion results in a slight better detection of actual size of myocardial damage

Effect of human leukocyte antigen heterozygosity on infectious disease outcome: The need for allele-specific measures

BACKGROUND: Doherty and Zinkernagel, who discovered that antigen presentation is restricted by the major histocompatibility complex (MHC, called HLA in humans), hypothesized that individuals heterozygous at particular MHC loci might be more resistant to particular infectious diseases than the corresponding homozygotes because heterozygotes could present a wider repertoire of antigens. The superiority of heterozygotes over either corresponding homozygote, which we term allele-specific overdominance, is of direct biological interest for understanding the mechanisms of immune response; it is also a leading explanation for the observation that MHC loci are extremely polymorphic and that these polymorphisms have been maintained through extremely long evolutionary periods. Recent studies have shown that in particular viral infections, heterozygosity at HLA loci was associated with a favorable disease outcome, and such findings have been interpreted as supporting the allele-specific overdominance hypothesis in humans. METHODS: An algebraic model is used to define the expected population-wide findings of an epidemiologic study of HLA heterozygosity and disease outcome as a function of allele-specific effects and population genetic parameters of the study population. RESULTS: We show that overrepresentation of HLA heterozygotes among individuals with favorable disease outcomes (which we term population heterozygote advantage) need not indicate allele-specific overdominance. On the contrary, partly due to a form of confounding by allele frequencies, population heterozygote advantage can occur under a very wide range of assumptions about the relationship between homozygote risk and heterozygote risk. In certain extreme cases, population heterozygote advantage can occur even when every heterozygote is at greater risk of being a case than either corresponding homozygote. CONCLUSION: To demonstrate allele-specific overdominance for specific infections in human populations, improved analytic tools and/or larger studies (or studies in populations with limited HLA diversity) are necessary

Dissemination of Metarhizium anisopliae of low and high virulence by mating behavior in Aedes aegypti

<p>Abstract</p> <p>Background</p> <p>Dengue is a viral disease transmitted by <it>Aedes </it>mosquitoes. It is a threat for public health worldwide and its primary vector <it>Aedes aegypti </it>is becoming resistant to chemical insecticides. These factors have encouraged studies to evaluate entomopathogenic fungi against the vector. Here we evaluated mortality, infection, insemination and fecundity rates in <it>A. aegypti </it>females after infection by autodissemination with two Mexican strains of <it>Metarhizium anisopliae</it>.</p> <p>Methods</p> <p>Two <it>M. anisopliae </it>strains were tested: The Ma-CBG-1 least virulent (lv), and the Ma-CBG-2 highly virulent (hv) strain. The lv was tested as non mosquito-passed (NMP), and mosquito-passed (MP), while the hv was examined only as MP version, therefore including the control four treatments were used. In the first bioassay virulence of fungal strains towards female mosquitoes was determined by indirect exposure for 48 hours to conidia-impregnated paper. In the second bioassay autodissemination of fungal conidia from fungus-contaminated males to females was evaluated. Daily mortality allowed computation of survival curves and calculation of the LT₅₀by the Kaplan-Meier model. All combinations of fungal sporulation and mating insemination across the four treatments were analyzed by χ². The mean fecundity was analyzed by ANOVA and means contrasted with the Ryan test.</p> <p>Results</p> <p>Indirect exposure to conidia allowed a faster rate of mortality, but exposure to a fungal-contaminated male was also an effective method of infecting female mosquitoes. All females confined with the hv strain-contaminated male died in fifteen days with a LT₅₀of 7.57 (± 0.45) where the control was 24.82 (± 0.92). For the lv strain, it was possible to increase fungal virulence by passing the strain through mosquitoes. 85% of females exposed to hv-contaminated males became infected and of them just 10% were inseminated; control insemination was 46%. The hv strain reduced fecundity by up to 99%, and the lv strain caused a 40% reduction in fecundity.</p> <p>Conclusions</p> <p>The hv isolate infringed a high mortality, allowed a low rate of insemination, and reduced fecundity to nearly zero in females confined with a fungus-contaminated male. This pathogenic impact exerted through sexual transmission makes the hv strain of <it>M. anisopliae </it>worthy of further research.</p

Normalization in MALDI-TOF imaging datasets of proteins: practical considerations

Normalization is critically important for the proper interpretation of matrix-assisted laser desorption/ionization (MALDI) imaging datasets. The effects of the commonly used normalization techniques based on total ion count (TIC) or vector norm normalization are significant, and they are frequently beneficial. In certain cases, however, these normalization algorithms may produce misleading results and possibly lead to wrong conclusions, e.g. regarding to potential biomarker distributions. This is typical for tissues in which signals of prominent abundance are present in confined areas, such as insulin in the pancreas or β-amyloid peptides in the brain. In this work, we investigated whether normalization can be improved if dominant signals are excluded from the calculation. Because manual interaction with the data (e.g., defining the abundant signals) is not desired for routine analysis, we investigated two alternatives: normalization on the spectra noise level or on the median of signal intensities in the spectrum. Normalization on the median and the noise level was found to be significantly more robust against artifact generation compared to normalization on the TIC. Therefore, we propose to include these normalization methods in the standard “toolbox” of MALDI imaging for reliable results under conditions of automation

Human cell dedifferentiation in mesenchymal condensates through controlled autophagy

Tissue and whole organ regeneration is a dramatic biological response to injury that occurs across different plant and animal phyla. It frequently requires the dedifferentiation of mature cells to a condensed mesenchymal blastema, from which replacement tissues develop. Human somatic cells cannot regenerate in this way and differentiation is considered irreversible under normal developmental conditions. Here, we sought to establish in vitro conditions to mimic blastema formation by generating different three-dimensional (3D) condensates of human mesenchymal stromal cells (MSCs). We identified specific 3D growth environments that were sufficient to dedifferentiate aged human MSCs to an early mesendoderm-like state with reversal of age-associated cell hypertrophy and restoration of organized tissue regenerating capacity in vivo. An optimal auophagic response was required to promote cytoplasmic remodeling, mitochondrial regression, and a bioenergetic shift from oxidative phosphorylation to anaerobic metabolism. Our evidence suggests that human cell dedifferentiation can be achieved through autonomously controlled autophagic flux

Comparison of hemodynamic, biochemical and hematological parameters of healthy pregnant women in the third trimester of pregnancy and the active labor phase

<p>Abstract</p> <p>Background</p> <p>Pregnancy is accompanied by several hemodynamic, biochemical and hematological changes which revert to normal values after labor. The mean values of these parameters have been reported for developed countries, but not for Mexican women. Furthermore, labor constitutes a stress situation, in which these factors may be altered. It is known that serologic increase of heat shock protein (Hsp) 70 is associated with abnormal pregnancies, presenting very low level in normal pregnant women. Nevertheless, there are no studies where these measurements are compared in healthy pregnant women at their third trimester of pregnancy (3TP) and the active labor phase (ActLP).</p> <p>Methods</p> <p>Seventy five healthy Mexican pregnant women were included. Hemodynamic, biochemical and hematological parameters were obtained in all cases, and serum Hsp70 levels were measured in a sample of 15 women at 3TP and at ActLP.</p> <p>Results</p> <p>Significant differences were found in most analysis performed and in Hsp70 concentration at 3TP as compared to ActLP, however all were within normal range in both conditions, supporting that only in pathological pregnancies Hsp70 is drastically increased.</p> <p>Conclusion</p> <p>Results obtained indicate that 3TP and ActLP have clinical similarities in normal pregnancies, therefore if abnormalities are found during 3TP, precautions should be taken before ActLP.</p