Biliary Bicarbonate Secretion Constitutes a Protective Mechanism against Bile Acid-Induced Injury in Man

Background: Cholangiocytes expose a striking resistance against bile acids: while other cell types, such as hepatocytes, are susceptible to bile acid-induced toxicity and apoptosis already at micromolar concentrations, cholangiocytes are continuously exposed to millimolar concentrations as present in bile. We present a hypothesis suggesting that biliary secretion of HCO(3)(-) in man serves to protect cholangiocytes against bile acid-induced damage by fostering the deprotonation of apolar bile acids to more polar bile salts. Here, we tested if bile acid-induced toxicity is pH-dependent and if anion exchanger 2 (AE2) protects against bile acid-induced damage. Methods: A human cholangiocyte cell line was exposed to chenodeoxycholate (CDC), or its glycine conjugate, from 0.5 mM to 2.0 mM at pH 7.4, 7.1, 6.7 or 6.4, or after knockdown of AE2. Cell viability and apoptosis were determined by WST and caspase-3/-7 assays, respectively. Results: Glycochenodeoxycholate (GCDC) uptake in cholangiocytes is pH-dependent. Furthermore, CDC and GCDC (pK(a) 4-5) induce cholangiocyte toxicity in a pH-dependent manner: 0.5 mM CDC and 1 mM GCDC at pH 7.4 had no effect on cell viability, but at pH 6.4 decreased viability by >80% and increased caspase activity almost 10- and 30-fold, respectively. Acidification alone had no effect. AE2 knockdown led to 3- and 2-fold enhanced apoptosis induced by 0.75 mM CDC or 2 mM GCDC at pH 7.4. Discussion: These data support our hypothesis of a biliary HCO(3)(-) umbrella serving to protect human cholangiocytes against bile acid-induced injury. AE2 is a key contributor to this protective mechanism. The development and progression of cholangiopathies, such as primary biliary cirrhosis, may be a consequence of genetic and acquired functional defects of genes involved in maintaining the biliary HCO(3)(-) umbrella. Copyright (C) 2011 S. Karger AG, Base

The relative abundance of fecal bacterial species belonging to the Firmicutes and Bacteroidetes phyla is related to plasma levels of bile acids in young adults

The online version contains supplementary material available at https://doi.org/10.1007/s11306-023-02016-8.Funding for open access publishing: Universidad de Granada/CBUA. The study was supported by the Spanish Ministry of Economy and Competitiveness via Fondo de Investigacion Sanitaria del Instituto de Salud Carlos III (PI13/01393) and PTA 12264-I, Retos de la Sociedad (DEP2016-79512-R), and European Regional Development Funds (ERDF), by the Spanish Ministry of Education (FPU16/05159, FPU16/02828, FPU17/01523 and FPU19/01609), the Fundacion Iberoamericana de Nutricion (FINUT), the University of Granada Plan Propio de Investigacion 2016-Excellence actions: Unit of Excellence on Exercise and Health (UCEES), AstraZeneca HealthCare Foundation, and by the Junta de Andalucia, Consejeria de Economia, Conocimiento, Empresas y Universidad (ref. P18-RT-4455), the Chinese Scholarship Council (CSC, No. 201707060012 to XD), Fundacion Alfonso Martin Escudero and Maria Zambrano fellowship by the Ministerio de Universidades y la Union Europea -NextGenerationEU (RR_C_2021_04). We would like to thank the team of Data Integration Center of University Medicine Magdeburg for local data-analysis solutions; they are supported by MIRACUM and funded by the German Federal Ministry of Education and Research (BMBF) within the "Medical Informatics Funding Scheme" (FKZ 01ZZ1801H). This study is part of a Ph.D. thesis conducted within the Biomedicine Doctoral Studies Program of the University of Granada, Spain. AL was supported by the funds from European Commission through the "European funds for regional development" (EFRE) Project ID: ZS/2018/11/95324.Background Gut bacteria play a crucial role in the metabolism of bile acids (BA). Whether an association exists between the fecal microbiota composition and circulating BA levels in humans is poorly understood. Here, we investigated the relationship between fecal microbiota diversity and composition with plasma levels of BA in young adults. Methods Fecal microbiota diversity/composition was analyzed with 16S rRNA sequencing in 80 young adults (74% women; 21.9 +/- 2.2 years old). Plasma levels of BA were measured using liquid chromatography-tandem mass spectrometry. PERMANOVA and Spearman correlation analyses were used to investigate the association between fecal microbiota parameters and plasma levels of BA. Results Fecal microbiota beta (P = 0.025) and alpha diversity indexes of evenness (rho = 0.237, P = 0.033), Shannon (rho = 0.313, P = 0.004), and inverse Simpson (rho = 0.283, P = 0.010) were positively associated with plasma levels of the secondary BA glycolithocholic acid (GLCA). The relative abundance of genera belonging to the Firmicutes and Bacteroidetes phyla was positively correlated with plasma levels of GLCA (all rho = 0.225, P = 0.049). However, the relative abundance of species from Firmicutes and Bacteroidetes phyla were negatively correlated with plasma levels of primary and secondary BA (all rho = - 0.220, P = 0.045), except for the relative abundance of Bacteroides vulgatus, Alistipes onderdonkii, and Bacteroides xylanisolvens species (Bacteroidetes phylum) that were positively correlated with the plasma levels of GLCA. Conclusions The relative abundance of specific fecal bacteria species is associated with plasma levels of BA in young adults. However, further investigations are required to validate whether the composition of the gut microbiota can regulate the plasma concentrations of BA in humans.Universidad de Granada/CBUASpanish Ministry of Economy and Competitiveness via Fondo de Investigacion Sanitaria del Instituto de Salud Carlos III PI13/01393Retos de la Sociedad DEP2016-79512-REuropean CommissionSpanish Government FPU16/05159, FPU16/02828, FPU17/01523, FPU19/01609Fundacion Iberoamericana de Nutricion (FINUT)University of Granada Plan Propio de Investigacion 2016-Excellence actions: Unit of Excellence on Exercise and Health (UCEES)AstraZenecaJunta de Andalucia P18-RT-4455China Scholarship Council 201707060012Ministerio de Universidades y la Union Europea -Next Generation EU RR_C_2021_04MIRACUMFederal Ministry of Education & Research (BMBF) FKZ 01ZZ1801HUniversity of Granada, SpainEuropean Commission Joint Research Centre ZS/2018/11/9532

Theoretical characterization of transition state dynamical resonances in heavy-light-heavy reactions

The resonant reactivity of three elementary Heavy-Light-Heavy reactions is presented and discussed. Collinear reactivity, in which a vibrational adiabatic model is constructed, is used for a detailed analysis of resonance phenomena, which appear as a direct consequence of transition state metastable states in the strong interaction region of the potential energy surface. Their influence on the detailed mechanism of the elementary process is also discussed. The shape of the resonant peak, and the phase and the Argand plot of the S-matrix are used for a further characterization.Three-dimensional approximate calculations are used to test the evolution of the energy dependent structure present in detailed quantities when sums and integrations over all partial waves contributing to reaction are taken into account to obtain the usual averaged global quantities such as integral state-to-state cross sections

The Use of Urine Proteomic and Metabonomic Patterns for the Diagnosis of Interstitial Cystitis and Bacterial Cystitis

The advent of systems biology approaches that have stemmed from the sequencing of the human genome has led to the search for new methods to diagnose diseases. While much effort has been focused on the identification of disease-specific biomarkers, recent efforts are underway toward the use of proteomic and metabonomic patterns to indicate disease. We have developed and contrasted the use of both proteomic and metabonomic patterns in urine for the detection of interstitial cystitis (IC). The methodology relies on advanced bioinformatics to scrutinize information contained within mass spectrometry (MS) and high-resolution proton nuclear magnetic resonance (1H-NMR) spectral patterns to distinguish IC-affected from non-affected individuals as well as those suffering from bacterial cystitis (BC). We have applied a novel pattern recognition tool that employs an unsupervised system (self-organizing-type cluster mapping) as a fitness test for a supervised system (a genetic algorithm). With this approach, a training set comprised of mass spectra and 1H-NMR spectra from urine derived from either unaffected individuals or patients with IC is employed so that the most fit combination of relative, normalized intensity features defined at precise m/z or chemical shift values plotted in n-space can reliably distinguish the cohorts used in training. Using this bioinformatic approach, we were able to discriminate spectral patterns associated with IC-affected, BC-affected, and unaffected patients with a success rate of approximately 84%

Lithium and Halpha in stars and brown dwarfs of sigma Orionis

We present intermediate- and low-resolution optical spectra around Halpha and LiI 6708 A for a sample of 25 low mass stars and 2 brown dwarfs with confirmed membership in the pre-main sequence stellar sigma Orionis cluster. Our observations are intended to investigate the age of the cluster. The spectral types derived for our target sample are found to be in the range K6-M8.5, which corresponds to a mass interval of roughly 1.2-0.02 Msun on the basis of state-of-the-art evolutionary models. Radial velocities (except for one object) are found to be consistent with membership in the Orion complex. All cluster members show considerable Halpha emission and LiI in absorption, which is typical of very young ages. We find that our pseudo-equivalent widths appear rather dispersed (and intense in the case of Halpha) for objects cooler than M3.5 spectral class, occurring at the approximate mass where low mass stars are expected to become fully convective. The least massive brown dwarf in our sample, SOri 45 (M8.5, ~0.02 Msun), displays variable Halpha emission and a radial velocity that differs from the cluster mean velocity. Tentative detection of forbidden lines in emission indicates that this brown dwarf may be accreting mass from a surrounding disk. We also present recent computations of LiI curves of growth for low gravities and for the temperature interval (about 4000-2600 K) of our sample. The comparison of our observations to these computations allows us to infer that no lithium depletion has yet taken place in sigma Orionis, and that the observed pseudo-equivalent widths are consistent with a cluster initial lithium abundance close to the cosmic value. Hence, the upper limit to the sigma Orionis cluster age can be set at 8 Myr, with a most likely value around 2-4 Myr.Comment: 17 pages (figures included). Accepted for publication in A&

Suicide Attempts Among a Cohort of Transgender and Gender Diverse People

INTRODUCTION: Transgender and gender diverse people often face discrimination and may experience disproportionate emotional distress that leads to suicide attempts. Therefore, it is essential to estimate the frequency and potential determinants of suicide attempts among transgender and gender diverse individuals. METHODS: Longitudinal data on 6,327 transgender and gender diverse individuals enrolled in 3 integrated healthcare systems were analyzed to assess suicide attempt rates. Incidence was compared between transmasculine and transfeminine people by age and race/ethnicity and according to mental health status at baseline. Cox proportional hazards models examined rates and predictors of suicide attempts during follow-up. Data were collected in 2016, and analyses were conducted in 2019. RESULTS: During follow-up, 4.8% of transmasculine and 3.0% of transfeminine patients had at least 1 suicide attempt. Suicide attempt rates were more than 7 times higher among patients aged45 years, more than 3 times higher among patients with previous history of suicide ideation or suicide attempts than among those with no such history, and 2-5 times higher among those with 1-2 mental health diagnoses and more than 2 mental health diagnoses at baseline than among those with none. CONCLUSIONS: Among transgender and gender diverse individuals, younger people, people with previous suicidal ideation or attempts, and people with multiple mental health diagnoses are at a higher risk for suicide attempts. Future research should examine the impact of gender-affirming healthcare use on the risk of suicide attempts and identify targets for suicide prevention interventions among transgender and gender diverse people in clinical settings

Habitat filtering and inferred dispersal ability condition across-scale species turnover and rarity in Macaronesian island spider assemblages

Publisher Copyright: © 2021 The Authors. Journal of Biogeography published by John Wiley & Sons Ltd.Aim: Habitat diversity has been linked to the diversity and structure of island communities, however, little is known about patterns and processes within habitats. Here we aim to determine the contributions of habitat type and inferred dispersal frequency to the differences in taxonomic structure between assemblages in the same island habitat. Location: The Macaronesian archipelagos (Azores, Madeira, the Canary Islands and Cabo Verde). Taxon: Spiders (Araneae). Methods: We established forest and dry habitat sites (each with five plots) on two islands per archipelago. We collected spiders using standardised sampling protocols. We tested the differences in beta diversity separately for each habitat and for each inferred category of ballooning (an aerial dispersal strategy) frequency across geographic scales through nested non-parametric permutational multivariate analyses of variance. We then tested whether ballooning and habitat influenced heterogeneity in species composition (dispersion in beta diversity) in the two habitat types. We analysed the effects of habitat and ballooning on species abundance distribution (SAD) and rarity by fitting Gambin models and evaluating the contribution of ballooning categories to SAD. Results: Communities of the same archipelago and habitat were taxonomically more similar, and beta diversity increased with geographic scale, being greater in dry habitats. There was greater species replacement among assemblages in dry habitats than in forests, with greater differences for rare ballooners. There were no differences in SAD between habitats although dry habitat sites seemed to harbour more species with low abundances (rare species) than forests. Main conclusions: Habitat type does not only condition the differences between spider assemblages of the same habitat but also the scale at which they occur. These differences may be determined by the heterogeneity in the physical structure of each habitat as well as how much this structure facilitates aerial dispersal (ballooning), and should be considered in theories/hypotheses on island community assembly as well as in conservation strategies.Peer reviewe

Site-Specific Integration of Foreign DNA into Minimal Bacterial and Human Target Sequences Mediated by a Conjugative Relaxase

This is an open-access article distributed under the terms of the Creative Commons Attribution License.[Background]: Bacterial conjugation is a mechanism for horizontal DNA transfer between bacteria which requires cell to cell contact, usually mediated by self-transmissible plasmids. A protein known as relaxase is responsible for the processing of DNA during bacterial conjugation. TrwC, the relaxase of conjugative plasmid R388, is also able to catalyze site-specific integration of the transferred DNA into a copy of its target, the origin of transfer (oriT), present in a recipient plasmid. This reaction confers TrwC a high biotechnological potential as a tool for genomic engineering. [Methodology/Principal Findings]: We have characterized this reaction by conjugal mobilization of a suicide plasmid to a recipient cell with an oriT-containing plasmid, selecting for the cointegrates. Proteins TrwA and IHF enhanced integration frequency. TrwC could also catalyze integration when it is expressed from the recipient cell. Both Y18 and Y26 catalytic tyrosil residues were essential to perform the reaction, while TrwC DNA helicase activity was dispensable. The target DNA could be reduced to 17 bp encompassing TrwC nicking and binding sites. Two human genomic sequences resembling the 17 bp segment were accepted as targets for TrwC-mediated site-specific integration. TrwC could also integrate the incoming DNA molecule into an oriT copy present in the recipient chromosome. [Conclusions/Significance]: The results support a model for TrwC-mediated site-specific integration. This reaction may allow R388 to integrate into the genome of non-permissive hosts upon conjugative transfer. Also, the ability to act on target sequences present in the human genome underscores the biotechnological potential of conjugative relaxase TrwC as a site-specific integrase for genomic modification of human cells.This work was supported by grant BIO2008-00133 from the Spanish Ministry of Science and Innovation to ML. CGP was a recipient of a predoctoral fellowship from the University of Cantabria, Spain.Peer reviewe

Height and timing of growth spurt during puberty in young people living with vertically acquired HIV in Europe and Thailand.

OBJECTIVE: The aim of this study was to describe growth during puberty in young people with vertically acquired HIV. DESIGN: Pooled data from 12 paediatric HIV cohorts in Europe and Thailand. METHODS: One thousand and ninety-four children initiating a nonnucleoside reverse transcriptase inhibitor or boosted protease inhibitor based regimen aged 1-10 years were included. Super Imposition by Translation And Rotation (SITAR) models described growth from age 8 years using three parameters (average height, timing and shape of the growth spurt), dependent on age and height-for-age z-score (HAZ) (WHO references) at antiretroviral therapy (ART) initiation. Multivariate regression explored characteristics associated with these three parameters. RESULTS: At ART initiation, median age and HAZ was 6.4 [interquartile range (IQR): 2.8, 9.0] years and -1.2 (IQR: -2.3 to -0.2), respectively. Median follow-up was 9.1 (IQR: 6.9, 11.4) years. In girls, older age and lower HAZ at ART initiation were independently associated with a growth spurt which occurred 0.41 (95% confidence interval 0.20-0.62) years later in children starting ART age 6 to 10 years compared with 1 to 2 years and 1.50 (1.21-1.78) years later in those starting with HAZ less than -3 compared with HAZ at least -1. Later growth spurts in girls resulted in continued height growth into later adolescence. In boys starting ART with HAZ less than -1, growth spurts were later in children starting ART in the oldest age group, but for HAZ at least -1, there was no association with age. Girls and boys who initiated ART with HAZ at least -1 maintained a similar height to the WHO reference mean. CONCLUSION: Stunting at ART initiation was associated with later growth spurts in girls. Children with HAZ at least -1 at ART initiation grew in height at the level expected in HIV negative children of a comparable age

No evidence of brown adipose tissue activation after 24 weeks of supervised exercise training in young sedentary adults in the ACTIBATE randomized controlled trial

Exercise modulates both brown adipose tissue (BAT)metabolismand white adipose tissue (WAT) browning in murine models. Whether this is true in humans, however, has remained unknown. An unblinded randomized controlled trial (ClinicalTrials.gov ID: NCT02365129) was therefore conducted to study the effects of a 24-week supervised exercise intervention, combining endurance and resistance training, on BAT volume and activity (primary outcome). The study was carried out in the Sport and Health University Research Institute and the Virgen de las Nieves University Hospital of the University of Granada (Spain). One hundred and forty-five young sedentary adults were assigned to either (i) a control group (no exercise, n = 54), (ii) a moderate intensity exercise group (MOD-EX, n = 48), or (iii) a vigorous intensity exercise group (VIG-EX n = 43) by unrestricted randomization. No relevant adverse events were recorded. 97 participants (34 men, 63 women) were included in the final analysis (Control; n = 35, MOD-EX; n=31, and VIG-EX; n=31).We observed no changes in BAT volume (Δ Control: −22.2 ± 52.6ml; Δ MOD-EX: −15.5 ± 62.1ml, Δ VIG-EX: −6.8 ± 66.4 ml; P = 0.771) or 18F-fluorodeoxyglucose uptake (SUVpeak Δ Control: −2.6 ± 3.1ml; Δ MOD-EX: −1.2 ± 4.8, Δ VIG-EX: −2.2 ± 5.1; p = 0.476) in either the control or the exercise groups. Thus, we did not find any evidence of an exercise-induced change on BAT volume or activity in young sedentary adults.Spanish Government PI13/01393Retos de la Sociedad DEP2016-79512-R PTA-12264IEuropean CommissionSpanish Government FPU13/04365 FPU14/04172 FPU15/04059 FPU16/03653 FPU19/01609Consejo Nacional de Ciencia y Tecnologia (CONACyT) 440575Fundacion Iberoamericana de Nutricion (FINUT)Redes Tematicas de Investigacion Cooperativa RETIC Red SAMID RD16/0022AstraZenecaUniversity of Granada Plan Propio de Investigacion 2016 -Excellence actions: Unit of Excellence on Exercise and Health (UCEES)Plan Propio de Investigacion 2018 -Programa Contratos-PuentePrograma Perfecionamiento de DoctoresJunta de Andalucia Consejeria de Conocimiento, Investigacion y Universidades (ERDF) SOMM17/6107/UGRJunta de Andalucia P18-RT-4455Fundacion Alfonso Martin EscuderoMaria Zambrano fellowship by the Ministerio de Universidades y la Union Europea-NextGenerationEU RR_C_2021_04Novo Nordisk FoundationNovocure Limited NNF18OC003239