bluuebunny/crossref_metadata_2025 huggingface dataset:
Donor Characteristics, Recipient Outcomes, and Histologic Findings of Kidney Allografts With Diffuse Donor-derived Glomerular Fibrin Thrombi
Authors: Gao Guofeng , Chen Ling-Xin , Brown Ian E. , De Mattos Angelo , Perez Richard V. , Jen Kuang-Yu
Published: February 2019

Background.

Limited data are available on whether donor kidneys with diffuse glomerular fibrin thrombi (GFT) are safe to use. In this study, the clinicopathologic characteristics of allografts with diffuse donor-derived GFT were examined.

Methods.

All deceased donor kidney transplant implantation biopsies from our institution between July 2011 and February 2018 with diffuse GFT were included. A control group for comparison consisted of all cases with implantation biopsies obtained during the study period without diffuse GFT. Clinical data were extracted from electronic medical records for all study patients, including donor information.

Results.

Twenty-four recipients received kidneys with diffuse GFT from 16 deceased donors. All donors died from severe head trauma. On average, 79% of glomeruli contained fibrin thrombi. Nineteen cases had subsequent biopsy; all revealed resolution of GFT. Compared with the control group, kidneys with diffuse GFT had longer cold ischemia time (34 versus 27 h), were more frequently pumped using machine perfusion (100% versus 81%), and recipients experienced a higher frequency of delayed graft function (58% versus 27%). Only 2 grafts with diffuse GFT failed within the first year. Overall graft survival was similar between the diffuse GFT group and control group.

Conclusions.

Deceased donor kidneys with diffuse GFT appear to be safe to use given that nearly 92% of recipients in this cohort who received such allografts experienced good clinical outcomes. Histologically, GFT demonstrated rapid resolution following transplantation. Interestingly, diffuse GFT only occurred in donors who suffered severe head trauma in this cohort, which may be a predisposing factor.
Evaluation of Accepting Kidneys of Varying Quality for Transplantation or Expedited Placement With Decision Trees
Authors: Kilambi Vikram , Bui Kevin , Hazen Gordon B. , Friedewald John J. , Ladner Daniela P. , Kaplan Bruce , Mehrotra Sanjay
Published: February 2019

Background.

Underutilization of marginal-quality kidneys for transplantation produced ideas of expediting kidney placement for populations with decreased opportunities of receiving transplants. Such policies can be less efficacious for specific individuals and should be scrutinized until the decision-making for accepting marginal-quality organs, which has relied on experiential judgment, is better understood at the individual level. There exist rigorous tools promoting personalized decisions with useful and objective information.

Methods.

This article introduces a decision-tree methodology that analyzes a patient’s dilemma: to accept a kidney offer now or reject it. The methodology calculates the survival benefit of accepting a kidney given a certain quality now and the survival benefit of rejecting it. Survival benefit calculation accounts for patients’ and donors’ characteristics and transplant centers’ and organ procurement organizations’ performances and incorporates patients’ perceived transplant and dialysis utilities. Valuations of rejecting an offer are contingent on future opportunities and subject to uncertainty in the timing of successive kidney offers and their quality and donor characteristics.

Results.

The decision tree was applied to a realistic patient profile as a demonstration. The tool was tested on 1000 deceased-donor kidney offers in 2016. Evaluating up to 1 year of future offers, the tool attains 61% accuracy, with transplant utility of 1.0 and dialysis utility of 0.5. The accuracy reveals potential bias in kidney offer acceptance/rejection at transplant centers.

Conclusions.

The decision-tree tool presented could aid personalized transplant decision-making in the future by providing patients with calculated, individualized survival benefits between accepting and rejecting a kidney offer.
Tolerance Biomarkers in Liver Transplantation: Independent External Validation of the Predictive Strength of SENP6 and FEM1C Gene Expression
Authors: Pérez-Sanz Fernando , Revilla-Nuin Beatriz , Martínez-Alarcón Laura , Herrero José I. , Ramírez Pablo , Pons José A. , Baroja-Mazo Alberto
Published: February 2019

Background.

Numerous studies have emphasized the genetic and phenotypic profiles of tolerant transplant patients. Moreover, different groups have defined several biomarkers, trying to distinguish patients who are going to be tolerant from those who are going to reject. However, most of these biomarkers have not been validated by other groups or even established for clinical practice.

Methods.

We reanalyzed and stratified the predictive capacity of 20 previously described biomarkers for liver transplantation tolerance in a cohort of 17 liver transplant patients subjected to an independent, nonrandomized, prospective study of immunosuppression drug withdrawal.

Results.

Only 4 of the 20 studied biomarkers (expression of SENP6, FEM1C, miR31, and miR95) showed a strong predictive capacity in the present study. miR31 and FEM1C presented an area under the ROC curve of 96.7%, followed by SENP1 with 93.3%. Finally, miR95 had an area under the ROC curve value <86.7%.

Conclusions.

Even though this independent analysis seems to confirm the predictive strength of SENP6 and FEM1C in liver transplantation tolerance, there are also risks in establishing biomarkers for clinical phenotypes without an understanding of how they are biologically relevant. Future collaborations between groups should be promoted so that the most promising biomarkers can be validated and implemented in daily clinical practice.
Continuous Monitoring of Transplant Center Performance: Different Options for Different Goals
Authors: Alexandrine Brian , Savoye Emilie , Pessione Fabienne , Cantrelle Christelle , Jasseron Carine , Santin Gaëlle , Bastien Olivier , Legeai Camille
Published: February 2019

Background.

In France, the need for continuous monitoring of transplant center performance has recently become apparent. Cumulative sum (CUSUM) monitoring of transplantation is already been used to monitor transplant outcomes in the United Kingdom and in the United States. Because CUSUM monitoring can be applied by different methods, the objective was to assess and compare the performance of different CUSUM methods for detecting higher than expected (ie, excessive) graft failure rates.

Methods.

Data come from the French transplant registry. Lung and kidney transplants in 2011-2013 constituted the control cohort, and those in 2014-2016 the observed cohort. The performance of CUSUM monitoring, according to center type and predefined control limits, was measured by simulation. The outcome monitored was 3-month graft failure.

Results.

In a low-volume center with a low failure rate, 3 different types of control limits produced successful detection rates of excessive graft failures of 15%, 62%, and 73% and false alarm rates of 5%, 40%, and 52%, with 3, 1, and 1 excess failures necessary before a signal occurred. In a high-volume center with a high failure rate, successful detection rates were 83%, 93%, and 100% and false alarm rates were 5%, 16%, and 69%, with 6, 13, and 17 excess failures necessary before a signal occurred.

Conclusions.

CUSUM performances vary greatly depending on the type of control limit used. A new control limit set to maximize specificity and sensitivity of detection is an appropriate alternative to those commonly used. Continued attention is necessary for centers with characteristics making it difficult to obtain adequate sensitivity or sufficiently prompt response.
Development of Triazoles based on AZT and their Anti-Viral Activity Against HIV-1
Authors: Alencar Daniel , Gonçalves Juliana , Cerqueira Sofia A. , Soares Helena , Petronilho Ana
Published: February 2019

We report herein a set of 3’-azido-3’-deoxythymidine (AZT) derivatives based on triazoles and triazolium salts for HIV1 infection. Compounds were tested with □using HIV1 pre-exposure prophylaxis experimental model. All compounds were able to decrease infection and two of them were able to clear almost all the infection, suggesting that these drugs could play an important role in pre-exposure prophylaxis therapies.
Feedback training can increase detection of happiness in ambiguous facial expressions in children and adults with autism spectrum disorders
Authors: Griffiths Sarah , Attwood Angela Suzanne , Penton-Voak Ian Scott , Jarrold Christopher , Munafo Marcus R
Published: February 2019

Recognition of subtle emotional facial expressions is challenging for some individuals with autism spectrum disorders (ASD). Training that targets recognition of low intensity emotional expressions may therefore be effective as an intervention to improve social-emotional skills. This paper reports the results of two randomised controlled experiments looking at the effect of a training methodology designed to increase the recognition of happy emotion in low intensity happy facial expressions. The first study implements this training with children with autism spectrum disorder (ASD, N = 14) and the second study implements this training with adults with ASD (N = 27). The training paradigm used images from a morph sequence that mixed a happy expression with a mixed-emotion ‘norm’ expression to create a sequence of varying intensity happy expressions. Participants were asked to say whether or not individual faces from the sequence were happy, to measure their happiness detection threshold. Participants that received active training were given biased feedback to shift their detection threshold, while participants that received control training were given feedback consistent with their baseline threshold. There was some statistical evidence that thresholds in the active training group shifted more than in the control group. This suggests training was successful in increasing the number of expressions that individuals identified as happy. However, there was no evidence that training increased facial expression recognition accuracy, as measured by the Reading the Mind in the Eyes task completed after training (Study 2).
Evolutionary successful strategies in a transparent iterated Prisoner’s Dilemma
Authors: Unakafov Anton M. , Schultze Thomas , Kagan Igor , Moeller Sebastian , Gail Alexander , Treue Stefan , Eule Stephan , Wolf Fred
Published: February 2019

A Transparent game is a game-theoretic setting that takes action visibility into account. In each round, depending on the relative timing of their actions, players have a certain probability to see their partner’s choice before making their own decision. This probability is determined by the level of transparency. At the two extremes, a game with zero transparency is equivalent to the classical simultaneous game, and a game with maximal transparency corresponds to a sequential game. Despite the prevalence of intermediate transparency in many everyday interactions such scenarios have not been sufficiently studied. Here we consider a transparent iterated Prisoner’s dilemma (iPD) and use evolutionary simulations to investigate how and why the success of various strategies changes with the level of transparency. We demonstrate that non-zero transparency greatly reduces the set of successful memory-one strategies compared to the simultaneous iPD. For low and moderate transparency the classical “Win – Stay, Lose – Shift” (WSLS) strategy is the only evolutionary successful strategy. For high transparency all strategies are evolutionary unstable in the sense that they can be easily counteracted, and, finally, for maximal transparency a novel “Leader-Follower” strategy outperforms WSLS. Our results provide a partial explanation for the fact that the strategies proposed for the simultaneous iPD are rarely observed in nature, where high levels of transparency are common.
Mapping changes in the spatiotemporal distribution of lumpy skin disease virus
Authors: Machado G. , Korennoy F. , Alvarez J. , Picasso-Risso C. , Perez A. , VanderWaal K.
Published: February 2019

Lumpy skin disease virus (LSDV) is an infectious disease of cattle transmitted by arthropod vectors which results in substantial economic losses due to impact on production efficiency and profitability, and represents an emerging threat to international trade of livestock products and live animals. Since 2015, the disease has spread across many Eastern European countries as well as Russia and Kazakhstan. This rapid expansion highlights the emergent nature of the virus in more temperate regions than those in which LSDV traditionally occurred. The goal of this study was to assess the risk for further LSDV spread in Eurasia through a) analysis of environmental factors conducive for LSDV and b) estimate of the underlying LSDV risk using a fine spatiotemporally explicit Bayesian hierarchical model on LSDV outbreak occurrence information. We used ecological niche modeling to estimate the potential distribution of LSDV outbreaks for 2014-2016. This analysis resulted in a spatial representation of environmental limits where, if introduced, LSDV is expected to efficiently spread. The Bayesian space-time model incorporated both environmental factors and the changing spatiotemporal distribution of the disease to capture the dynamics of disease spread and predict areas in which there is an increased risk of LSDV occurrence. Variables related to the average temperature, precipitation, wind speed, as well as land cover and host densities were found to be important drivers explaining the observed distribution of LSDV in both modeling approaches. Areas of elevated LSDV risks were identified mainly in Russia, Turkey, Serbia, and Bulgaria. Results suggest that prevailing ecological conditions may be compatible with further spread of LSDV in Eurasia, though models should be continually updated to reflect the current epidemiologic conditions. The results presented here advance our understanding of the ecological requirements of LSDV in temperate regions and may help in the design and implementation of prevention and surveillance strategies in the region.
Dose-specific effectiveness of 7- and 13-valent pneumococcal conjugate vaccines against vaccine-serotype Streptococcus pneumoniae colonization: a matched, case-control study
Authors: Lewnard Joseph A. , Givon-Lavi Noga , Dagan Ron
Published: February 2019

Background

Reduced-dose pneumococcal conjugate vaccine (PCV) schedules are under consideration in countries where children are currently recommended to receive three PCV doses. However, dose-specific PCV effectiveness against vaccine-serotype colonization is uncertain.

Methods

From 2009-2016, we conducted surveillance of pneumococcal carriage in southern Israel, where PCV is administered at ages 2, 4, and 12 months (2+1 schedule). We obtained nasopharyngeal swabs and vaccination histories from 4245 children ages 0-59 months without symptoms of diseases that could be caused by pneumococci. In a case-control analysis, we measured protection against vaccine-serotype colonization as one minus the matched odds ratio for PCV doses received.

Results

At ages 5-12 months, a second PCV7/13 dose increased protection against PCV7-serotype carriage from –23.6% (95%CI: –209.7-39.1%) to 27.1% (–69.2-64.5%), and a second PCV13 dose increased protection against carriage of all PCV13 serotypes from –54.8% (–404.3-39.1%) to 23.4% (– 128.5-67.1%). At ages 13-24 months, a third PCV7/13 dose increased protection against PCV7-serotype carriage from 32.4% (–8.4-58.0%) to 74.1% (58.4-84.6%), and a third PCV13 dose increased protection against carriage of all PCV13 serotypes from –50.0% (–194.0-42.7%) to 49.7% (15.8-83.3%). On average, each PCV13 dose conferred 37.7% (7.0-61.8%) greater protection against carriage of serotypes 1, 5, 6A, 7F, and 19A than carriage of serotype 3. PCV13-derived protection against carriage of serotypes 1, 5, 6A, 7F, and 19A was equivalent to PCV7/13-derived protection against carriage of PCV7 serotypes.

Conclusions

In a setting implementing a 2+1 PCV schedule, protection against vaccine-serotype colonization is sustained primarily by the third dose.
Upscaling the surveillance of tick-borne pathogens in the French Caribbean islands
Authors: Gondard Mathilde , Delannoy Sabine , Pinarello Valérie , Aprelon Rosalie , Devillers Elodie , Galon Clémence , Pradel Jennifer , Vayssier-Taussat Muriel , Albina Emmanuel , Moutailler Sara
Published: February 2019

Despite the high burden of vector-borne disease in (sub)-tropical areas, few information are available regarding the diversity of tick and tick-borne pathogens circulating in the Caribbean. Management and control of vector-borne disease require actual epidemiological data to better assess and anticipate the risk of (re)-emergence of tick-borne diseases in the region. To simplify and reduce the costs of such large-scale surveys, we implemented a high-throughput microfluidic real-time PCR system suitable for the screening of the main bacterial and parasitic genera involved in tick-borne disease and potentially circulating in the area. We used the new screening tool to perform an exploratory epidemiological study on 132 specimens of Amblyomma variegatum and 446 of Rhipicephalus microplus collected in Guadeloupe and Martinique. Not only the system was able to detect the main pathogens of the area– Ehrlichia ruminantium, Rickettsia africae, Anaplasma marginale, Babesia bigemina, Babesia bovis– but the system also provided evidence of unsuspected microorganisms in Caribbean ticks, belonging to the Anaplasma, Ehrlichia, Borrelia and Leishmania genera. Our study demonstrated how high-throughput microfluidic real-time PCR technology can assist large-scale epidemiological studies, providing a rapid overview of tick-borne pathogen and microorganism diversity, and opening up new research perspectives for the epidemiology of tick-borne pathogens.
HIV infection and incidence of cardiovascular diseases: an analysis of a large healthcare database
Authors: Alonso Alvaro , Barnes A. Elise , Guest Jodie L. , Shah Amit , Shao Iris Yuefan , Marconi Vincent
Published: February 2019

Background

Persons living with HIV (PLWH) experience higher risk of cardiovascular diseases (CVD) such as myocardial infarction (MI) and heart failure (HF) compared to uninfected individuals. Risk of other CVDs in PLWH has received less attention.

Methods

We studied 19,798 PLWH and 59,302 age and sex-matched uninfected individuals identified from the MarketScan Commercial and Medicare databases in the period 2009-2015. Incidence of CVDs, including MI, HF, atrial fibrillation (AF), peripheral artery disease (PAD), stroke and any CVD-related hospitalization, were identified using validated algorithms. We used adjusted Cox models to estimate hazard ratios (HR) and 95% confidence interval (95%CI) of CVD endpoints and performed probabilistic bias analysis to control for unmeasured confounding by race.

Results

After a mean (median) follow-up of 20 (17) months, study patients experienced 154 MIs, 223 HF, 93 stroke, 397 AF, 98 PAD and 935 CVD hospitalizations. HR (95%CI) comparing PLWH to uninfected controls were 1.3 (0.9, 1.9) for MI, 3.2 (2.4, 4.2) for HF, 2.7 (1.7, 4.0) for stroke, 1.2 (1.0, 1.5) for AF, 1.1 (0.7, 1.7) for PAD, and 1.7 (1.5, 2.0) for any CVD-related hospitalization. Adjustment for unmeasured confounding led to similar associations [1.2 (0.8, 1.8) for MI, 2.8 (2.0, 3.8) for HF, 2.3 (1.5, 3.6) for stroke, 1.3 (1.0, 1.7) for AF, 0.9 (0.5, 1.4) for PAD, and 1.6 (1.3, 1.9) for CVD hospitalization].

Conclusion

Using a large health insurance database, we showed that PLWH have an elevated risk of CVD, particularly HF and stroke. With the aging of the HIV population, developing interventions for cardiovascular health promotion and CVD prevention is imperative.
Subcortical Shape Alterations in Major Depressive Disorder: Findings from the ENIGMA Major Depressive Disorder Working Group
Authors: Ho Tiffany C. , Gutman Boris , Pozzi Elena , Grabe Hans J. , Hosten Norbert , Wittfeld Katharina , Völzke Henry , Baune Bernhard , Dannlowski Udo , Förster Katharina , Grotegerd Dominik , Redlich Ronny , Jansen Andreas , Kircher Tilo , Krug Axel , Meinert Susanne , Nenadic Igor , Opel Nils , Dinga Richard , Veltman Dick J. , Schnell Knut , Veer Ilya , Walter Henrik , Gotlib Ian H. , Sacchet Matthew D. , Aleman André , Groenewold Nynke A. , Stein Dan J. , Li Meng , Walter Martin , Jahanshad Neda , Thompson Paul M. , Sämann Philipp G. , Schmaal Lianne
Published: February 2019

Alterations in regional subcortical brain volumes have been widely investigated as part of the efforts of an international consortium, ENIGMA, to determine reliable structural brain signatures for Major Depressive Disorder (MDD). Given that subcortical structures are comprised of distinct subfields, we sought to build significantly from prior work to precisely map localized MDD-related differences in subcortical regions using shape analysis. In this meta-analysis of subcortical shape from the ENIGMA-MDD working group, we compared 1,781 patients with MDD and 2,953 healthy controls (CTL) on individual measures of shape metrics (thickness and surface area) on the surface of seven bilateral subcortical structures: nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus. Harmonized data processing and statistical analyses were conducted locally at each site, and findings were aggregated by meta-analysis. Relative to CTL, patients with MDD had lower surface area in the subiculum of the hippocampus, the basolateral amygdala, and the nucleus accumbens shell. Relative to CTL, patients with adolescent-onset MDD (≤ 21 years) had lower thickness and surface area of the subiculum of the hippocampus and the basolateral amygdala. Relative to first-episode MDD, recurrent MDD patients had lower thickness and surface area in the CA1 of the hippocampus and the basolateral amygdala. Our results suggest that previously reported MDD-associated volumetric differences may be localized to specific subfields of these structures that have been shown to be sensitive to the effects of stress, with important implications for mapping treatments to patients based on specific neural targets and key clinical features.
Global variability of the human IgG glycome
Authors: Štambuk Jerko , Nakić Natali , Vučković Frano , Pučić-Baković Maja , Razdorov Genadij , Trbojević-Akmačić Irena , Novokmet Mislav , Keser Toma , Vilaj Marija , Pavić Tamara , Gudelj Ivan , Šimurina Mirna , Song Manshu , Wang Hao , Salihović Marijana Peričić , Campbell Harry , Rudan Igor , Kolčić Ivana , Eller Leigh Anne , McKeigue Paul , Robb Merlin L. , Halfvarson Jonas , Kurtoglu Metin , Annese Vito , Škarić-Jurić Tatjana , Molokhia Mariam , Polašek Ozren , Hayward Caroline , Kibuuka Hannah , Thaqi Kujtim , Primorac Dragan , Gieger Christian , Nitayaphan Sorachai , Spector Tim , Wang Youxin , Tillin Therese , Chaturvedi Nish , Wilson James F. , Schanfield Moses , Filipenko Maxim , Wang Wei , Lauc Gordan
Published: February 2019

Immunoglobulin G (IgG) is the most abundant serum antibody and is a key determinant of the humoral immune response. Its structural characteristics and effector functions are modulated through the attachment of various sugar moieties called glycans. IgG N-glycome patterns change with the age of individual and in different diseases. Variability of IgG glycosylation within a population is well studied and is affected by a combination of genetic and environmental factors. However, global inter-population differences in IgG glycosylation have never been properly addressed. Here we present population-specific N-glycosylation patterns of whole IgG, analysed in 5 different populations totalling 10,482 IgG glycomes, and of IgG’s fragment crystallisable region (Fc), analysed in 2,530 samples from 27 populations sampled across the world. We observed that country of residence associates with many N-glycan features and is a strong predictor of monogalactosylation variability. IgG galactosylation also strongly correlated with the development level of a country, defined by United Nations health and socioeconomic development indicators. We found that subjects from developing countries had low IgG galactosylation levels, characteristic for inflammation and ageing. Our results suggest that citizens of developing countries may be exposed to country-specific environmental factors that can cause low-grade chronic inflammation and the apparent increase in biological age.
Occupation and Parkinson disease in Women’s Health Initiative Observational Study
Authors: Burstyn Igor , LaCroix Andrea Z. , Litvan Irene , Wallace Robert B. , Checkoway Harvey
Published: February 2019

Introduction

There is a lack of consistency in associations between workplace factors and risk of Parkinson disease (PD), and paucity of such data on women. We took a classic occupational epidemiology approach that assesses associations with occupational groups in order to derive insights about potential occupation-specific exposures that may be causal.

Methods

The Women’s Health Initiative (WHI-OS) is a prospective cohort that enrolled 91,627 postmenopausal women, 50 to 79 years of age from 10/01/93 to 12/31/98, at 40 clinical centers across the US with average follow-up of 11 years, who reported up to three paid jobs held the longest since age 18; these jobs were coded and duration of employment calculated. We defined the case by self-report of doctor-diagnosed PD (at baseline or follow-up), death attributed to PD, or medication consistent with PD.

Results

Among 2,590 cases, we report evidence of excess risk among “counselors, social workers, and other community and social service specialists”. There was a suggestion of increase in risk among post-secondary teachers, and “building and grounds cleaning and maintenance”. There was also evidence of deficit in risk among women who worked in sales.

Results with ever-employed and duration were similar, except for evidence of excess of risk among “health technologists and technicians” with more than 20 years of employment. Longer duration of life on a farm was associated with higher risk.

Conclusion

Our findings paint a largely reassuring picture of occupational risks for PD among US women, especially for trades largely unaffected by recent technological advances.
Computational analysis of molecular networks using spectral graph theory, complexity measures and information theory
Authors: Huang Chien-Hung , Tsai Jeffrey J. P. , Kurubanjerdjit Nilubon , Ng Ka-Lok
Published: February 2019

Molecular networks are described in terms of directed multigraphs, so-called network motifs. Spectral graph theory, reciprocal link and complexity measures were utilized to quantify network motifs. It was found that graph energy, reciprocal link and cyclomatic complexity can optimally specify network motifs with some degree of degeneracy. Biological networks are built up from a finite number of motif patterns; hence, a graph energy cutoff exists and the Shannon entropy of the motif frequency distribution is not maximal. Also, frequently found motifs are irreducible graphs. Network similarity was quantified by gauging their motif frequency distribution functions using Jensen-Shannon entropy. This method allows us to determine the distance between two networks regardless of their nodes’ identities and network sizes.

This study provides a systematic approach to dissect the complex nature of biological networks. Our novel method different from any other approach. The findings support the view that there are organizational principles underlying molecular networks.
LuxUS: DNA Methylation Analysis Using Generalized Linear Mixed Model with Spatial Correlation
Authors: Halla-aho Viivi , Lähdesmäki Harri
Published: February 2019

Abstract

Motivation

DNA methylation is an important epigenetic modification, which has multiple functions. DNA methylation and its connections to diseases have been extensively studied in recent years. It is known that DNA methylation levels of neighboring cytosines are correlated and that differential DNA methylation typically occurs rather as regions instead of individual cytosine level.

Results

We have developed a generalized linear mixed model, LuxUS, that makes use of the correlation between neighboring cytosines to facilitate analysis of differential methylation. LuxUS implements a likelihood model for bisulfite sequencing data that accounts for experimental variation in underlying biochemistry. LuxUS can model both binary and continuous covariates, and mixed model formulation enables including replicate and cytosine random effects. Spatial correlation is included to the model through a cytosine random effect correlation structure. We show with simulation experiments that by utilizing the spatial correlation we gain more power to the statistical testing of differential DNA methylation. Results with real bisulfite sequencing data set show that LuxUS is able to detect biologically significant differentially methylated cytosines.

Availability

The tool is available at https://github.com/hallav/LuxUS.

Supplementary information

Supplementary data are available at bioRxiv.
Dystrophin and calcium current are decreased in cardiomyocytes expressing Cre enzyme driven by αMHC but not TNT promoter
Authors: Gillet Ludovic , Guichard Sabrina , Essers Maria C. , Rougier Jean-Sébastien , Abriel Hugues
Published: February 2019

Background

The Cre/lox system is a potent technology to control gene expression in mouse tissues. However, cardiac alterations following cardiac-specific Cre enzyme expression in non-loxP-flanked genome heart have been reported. Recently, many loxP like sites have been identified in the wild-type mouse genome. Interestingly one of them is localized in the Dmd gene encoding the dystrophin protein known to be crucial for stabilization of cardiac voltage-gated ion channels Nav1.5 and Cav1.2.

Aim

Here, we studied the potential alteration of dystrophin expression in adult alpha-myosin heavy chain (MHC)-Cre mice, which are extensively used for cardiac-specific recombination, and investigated Troponin T (TNT)-Cre mice as a potential alternative.

Methods

Cardiac-specific MHC-Cre and TNT-Cre mouse lines expressing Cre recombinase under the control of the cardiac-specific alpha-myosin-heavy chain, and rat cardiac troponin T2 promoter respectively were used. Western blots, quantitative RT-PCR, immunostainings, and patch-clamp experiments were performed to characterize MHC-Cre and TNT-Cre mouse hearts and cardiomyocytes.

Results

Dystrophin protein level was decreased in hearts from 12-week-old MHC-Cre+ mice compared to MHC-Cre-. Reduction of dystrophin was more pronounced with age. No significant difference was observed between 8-week-old MHC-Cre+ mice and MHC-Cre-. Immunostainings performed on cardiac sections showed reduced dystrophin signal at the lateral membrane of MHC-Cre+ cardiomyocytes. Quantitative RT-PCR showed decreased mRNA levels of Dmd gene encoding dystrophin. Finally, patch-clamp experiments showed a significant decrease in calcium current (ICaL) in adult MHC-Cre+ cardiomyocytes compared to MHC-Cre-. Neither dystrophin nor ICaL was reduced in adult TNT-Cre+ mouse hearts compared to TNT-Cre-.

Conclusion

In contrary to TNT-Cre+ mice, the sole expression of Cre recombinase can alter the cardiac phenotype of MHC-Cre+ mice. Thus, researchers should include the “Cre-only” condition as control condition when designing experiments with Cre mouse strains.
Horizontally transmitted symbiont populations in deep-sea mussels are genetically isolated
Authors: Picazo Devani Romero , Dagan Tal , Ansorge Rebecca , Petersen Jillian M. , Dubilier Nicole , Kupczok Anne
Published: February 2019

Eukaryotes are habitats for bacterial organisms where the host colonization and dispersal among individual hosts have consequences for the bacterial ecology and evolution. Vertical symbiont transmission leads to geographic isolation of the microbial population and consequently to genetic isolation of microbiotas from individual hosts. In contrast, the extent of geographic and genetic isolation of horizontally transmitted microbiota is poorly characterized. Here we show that chemosynthetic symbionts of individual Bathymodiolus brooksi mussels constitute genetically isolated populations. The reconstruction of core genome-wide strain sequences from high-resolution metagenomes revealed distinct phylogenetic clades. Nucleotide diversity and strain composition vary along the mussel lifespan and individual hosts show a high degree of genetic isolation. Our results suggest that the uptake of environmental bacteria is a restricted process in B. brooksi, where self-infection of the gill tissue results in serial founder effects during symbiont evolution. We conclude that bacterial colonization dynamics over the host life-cycle is thus an important determinant of population structure and genome evolution of horizontally transmitted symbionts.
Hif-1α stabilisation polarises macrophages via cyclooxygenase/prostaglandin E2in vivo
Authors: Lewis Amy , Elks Philip M.
Published: February 2019

Macrophage subtypes are poorly characterised in disease systemsin vivo. The initial innate immune response to injury and infectious stimuli through M1 polarisation is important for the outcome of disease. Appropriate macrophage polarisation requires complex coordination of local microenvironmental cues and cytokine signalling to influence immune cell phenotypes. If the molecular mechanisms behind macrophage polarisation were better understood then macrophages could be pharmacologically tuned to better deal with bacterial infections, for example tuberculosis. Here, using zebrafishtnfa:GFPtransgenic lines asin vivoreadouts of M1 macrophages, we show that hypoxia and stabilisation of Hif-1α polarises macrophages to atnfaexpressing phenotype. We demonstrate a novel mechanism of Hif-1α mediated macrophagetnfaupregulation via a cyclooxygenase/prostaglandin E2 axis, a mechanism that is conserved in human primary macrophages. These findings uncover a novel macrophage HIF/COX/TNF axis that links microenvironmental cues to macrophage phenotype that may have implications in inflammation, infection and cancer, where hypoxia is a common microenvironmental feature and where cyclooxygenase and Tnfa are major mechanistic players.
Mito-SinCe2 Approach to Quantify Relationships between Mitochondrial Dynamics and Energetics status
Authors: Spurlock Brian , Gupta Priyanka , Basu Malay Kumar , Mukherjee Avik , Hjelmeland Anita B , Darley-Usmar Victor , Parker Danitra , Foxall McKenzie E , Mitra Kasturi
Published: February 2019

Mitochondrial dynamics primarily refers to the opposing fission and fusion events between individual mitochondria, which maintains steady-state mitochondrial morphology in cells. The details of the bidirectional relationship between mitochondrial dynamics and energetics are unclear as the methods to integrate these mitochondrial aspects are lacking. To study the quantitative relationship between mitochondrial dynamics (fission, fusion, matrix continuity and diameter) and energetics (ATP and redox), we have developed and validated an analytical approach, mito-SinCe2. Application of this approach led to the hypothesis that mitochondria-dependent ovarian tumor initiating cells interconvert between 3 states with distinct relationships between mitochondrial energetics and dynamics. Interestingly, fusion and ATP increase linearly with each other only once a certain level of fusion is attained. Moreover, mitochondrial dynamics status changes linearly either with ATP or with redox, but not simultaneously with both. Furthermore, mito-SinCe2 analyses can potentially predict new quantitative features of the opposing fission vs. fusion relationship and classify cells into functional classes based on their mito-SinCe2 states.
Blood-brain barrier dysfunction in aging induces hyper-activation of TGF-beta signaling and chronic yet reversible neural dysfunction
Authors: Senatorov V.V. , Friedman A.R. , Milikovsky D.Z. , Ofer J. , Saar-Ashkenazy R. , Charbash A. , Jahan N. , Chin G. , Mihaly E. , Lin J.M. , Ramsay H.J. , Moghbel A. , Preininger M.K. , Eddings C.R. , Harrison H.V. , Patel R. , Shen Y. , Ghanim H. , Sheng H. , Veksler R. , Sudmant P.H. , Becker A. , Hart B. , Rogawski M.A. , Dillin A. , Friedman A. , Kaufer D.
Published: February 2019

Aging involves a decline in neural function that contributes to cognitive impairment and disease. However, the mechanisms underlying the transition from a young-and-healthy to aged-and-dysfunctional brain are not well understood. Here, we report breakdown of the vascular blood-brain barrier (BBB) in aging humans and rodents, which begins as early as middle age and progresses to the end of the lifespan. Gain-of-function and loss-of-function manipulations show that this BBB dysfunction triggers hyperactivation of transforming growth factor β (TGFβ) signaling in astrocytes, which is necessary and sufficient to cause neural dysfunction and age-related pathology. Specifically, infusion of the serum protein albumin into the young brain (mimicking BBB leakiness) induced astrocytic TGFβ signaling and an aged brain phenotype including aberrant electrocorticographic activity, vulnerability to seizures, and cognitive impairment. Furthermore, conditional genetic knockdown of astrocytic TGFβ receptors, or pharmacological inhibition of TGFβ signaling, reversed these symptomatic outcomes in aged mice. Finally, we found that this same signaling pathway is activated in aging human subjects with BBB dysfunction. Our study identifies dysfunction in the neurovascular unit as one of the earliest triggers of neurological aging, and demonstrates that the aging brain may retain considerable latent capacity which can be revitalized by therapeutic inhibition of TGFβ signaling.
The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders
Authors: Miller-Rhodes Patrick , Kong Cuicui , Baht Gurpreet S. , Rodriguiz Ramona M. , Wetsel William C. , Gelbard Harris A. , Terrando Niccolò
Published: February 2019

Perioperative neurocognitive disorders (PND), including delirium and postoperative cognitive dysfunction, are serious complications that afflict up to 50% of surgical patients and for which there are no disease-modifying therapeutic options. Here, we test whether prophylactic treatment with the broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents surgery-induced neuroinflammation and cognitive impairment in a translational model of orthopedic surgery-induced PND. We used a combination of two-photon scanning laser microscopy and CLARITY with light-sheet microscopy to define surgery-induced changes in microglial dynamics and morphology. Orthopedic surgery induced widespread microglial activation in the hippocampus and cortex that accompanied impairments in episodic memory. URMC-099 prophylaxis prevented these neuropathological sequelae without impacting bone fracture healing. Together, these findings provide compelling evidence for the advancement of URMC-099 as a therapeutic option for PND.
Resilient Living Materials Built By Printing Bacterial Spores
Authors: González Lina M. , Voigt Christopher A.
Published: February 2019

A route to advanced multifunctional materials is to embed them with living cells that can perform sensing, chemical production, energy scavenging, and actuation. A challenge in realizing this potential is that the conditions for keeping cells alive are not conducive to materials processing and require a continuous source of water and nutrients. Here, we present a 3D printer that can mix material and cell streams in a novel printhead and build 3D objects (up to 2.5 cm by 1 cm by 1 cm). Hydrogels are printed using 5% agarose, which has a low melting temperature (65°C) consistent with thermophilic cells, a rigid storage modulus (G’= 6.5 × 104), exhibits shear thinning, and can be rapidly hardened upon cooling to preserve structural features. Spores ofB. subtilisare printed within the material and germinate on its exterior, including spontaneously in cracks and new surfaces exposed by tears. By introducing genetically engineered bacteria, the materials can sense chemicals (IPTG, xylose, or vanillic acid). Further, we show that the spores are resilient to extreme environmental stresses, including desiccation, solvents (ethanol), high osmolarity (1.5 mM NaCl), 365 nm UV light, and γ-radiation (2.6 kGy). The construction of 3D printed materials containing spores enables the living functions to be used for applications that require long-term storage, in-field functionality, or exposure to uncertain environmental stresses.
Obesity alters mobility and adult neurogenesis, but not hippocampal dependent learning in ob/ob mice
Authors: Bracke Alexander , Domanska Grazyna , Bracke Katharina , Harzsch Steffen , van den Brandt Jens , Bröker Barbara , von Bohlen und Halbach Oliver
Published: February 2019

Abstracts

Background

Obesity has become a severe problem among the world’s population with clearly increasing prevalence over the last decades. Because obesity is associated with several comorbidities (e.g. hypertension or cancer) it constitutes an increasing burden for the health care system. Correlations between obesity and cognition have been studied in humans with ambivalent results. Here, we studied the effects of obesity on hippocampus dependent learning and memory and cell morphology in a mouse model of obesity.

Methods

The body mass of male and female Lep+/+(wt) and Lepob/ob(ob/ob) animals with access to food and water ad libitum was measured between postnatal day 60-200 and animals with clear adiposity (4-6 months) were further analyzed. Adult hippocampal neurogenesis in the dentate gyrus was examined using phosphohistone H3 as a marker for proliferation, doublecortin as a marker for differentiation and caspase3 as a marker for apoptosis. Moreover, the density of dendritic spines on apical and basal dendrites of pyramidal neurons of the cornu ammonis 1 (CA1) were analyzed using Golgi impregnation. In addition, mice were subjected to the open field and Morris water maze test in order to analyze locomotor activity and spatial learning.

Results

The body weight of ob/ob mice nearly doubled during the first 120 postnatal days. Adult hippocampal neurogenesis was reduced in ob/ob mice due to reduced cell proliferation. Dendritic spine densities in the hippocampal area CA1 were not altered in ob/ob mice. Four to six months old ob/ob mice showed reduced locomotor activity in the open field test but similar performance in the Morris water maze compared to control mice.

Conclusion

Our data show that alterations in adult neurogenesis in leptin-deficient mice are not associated with an impairment in spatial learning abilities. Moreover, ob/ob mice are inconspicuous in the Morris water maze and do not display altered spine densities in the hippocampus, suggesting that obesity does not have a severe impact upon hippocampal neuronal plasticity and spatial learning.
Determinants of the population health distribution, or why are risk factor-body mass index associations larger at the upper end of the BMI distribution?
Authors: Bann David , Fitzsimons Emla , Johnson Will
Published: February 2019

Most epidemiological studies examine how risk factors relate to average difference in outcomes (linear regression) or odds a binary outcome (logistic regression); they do not explicitly examine whether risk factors are associated differentially across the distribution of the health outcome investigated. This paper documents a phenomenon found repeatedly in the minority of epidemiological studies which do this (via quantile regression) -associations between a range of established risk factors and body mass index (BMI) are progressively stronger in the upper ends of the BMI distribution. In this paper, we document this finding and provide illustrative evidence of it in a single dataset (the 1958 British birth cohort study). Associations of low childhood socioeconomic position, high maternal weight, low childhood general cognition and adult physical inactivity with higher BMI are larger at the upper end of the BMI distribution, on both absolute and relative scales. For example, effect estimates for socioeconomic position and childhood cognition were around three times larger at the 90th compared with 10th quantile, while effect estimates for physical inactivity were increasingly larger from the 50th-90th quantiles, yet null at lower quantiles. We provide potential explanations for these findings and discuss possible research and policy implications. We conclude by stating that tools such as quantile regression may be useful to better understand how risk factors relate to the distribution of health -particularly so in obesity research given conventional reliance on cut-points -yet for other outcomes in addition given the continuous nature of population health.
A pivotal role for Nrf2 in endothelial detachment- implications for endothelial erosion of stenotic plaques
Authors: Satta Sandro , McElroy Michael , Langford Smith Alex , Ferris Glenn R , Teasdale Jack , Kim Yongcheol , Niccoli Giampaolo , Tanjeko Ajime Tom , Serré Jef , Hazell Georgina , Sala Newby Graciela , Wang Ping , Johnson Jason L , Humphries Martin J , Gayan-Ramirez Ghislaine , Libby Peter , Crea Filippo , Degens Hans , Gijsen Frank , Johnson Thomas , Keshmiri Amir , Alexander Yvonne , Newby Andrew C , White Stephen J
Published: February 2019

Endothelial erosion of atherosclerotic plaques and resulting thrombosis causes approximately 30% of acute coronary syndromes (ACS). As changes in the haemodynamic environment strongly influence endothelial function and contribute to plaque development, we reconstructed the coronary artery geometries of plaques with thrombi overlying intact fibrous caps from 17 ACS patients and performed computational fluid dynamic analysis. The results demonstrated that erosions frequently occur within areas of stenosis exposed to elevated flow. We recapitulated this flow environment in vitro, exposing human coronary artery endothelial cells to elevated flow and modelled smoking (a risk factor for erosion) by exposure to a combination of aqueous cigarette smoke extract and TNFα. This treatment induced endothelial detachment, which increased with pharmacological activation of the antioxidant system controlled by transcription factor Nrf2 (encoded by NFE2L2). The expression of Oxidative Stress Growth INhibitor genes OSGIN1 and OSGIN2 increased under these conditions and also in the aortas of mice exposed to cigarette smoke. Sustained high level expression of OSGIN1+2 resulted in cell cycle arrest, induction of senescence, loss of focal adhesions and actin stress fibres, and dysregulation of autophagy. Overexpression of either Nrf2 or OSGIN1+2 induced cell detachment, which did not depend on apoptosis, and could be partially rescued by inhibition of HSP70 using VER-155008, or AMP kinase activation using metformin. These findings demonstrate that under elevated flow, smoking-induced hyperactivation of Nrf2 can trigger endothelial cell detachment, highlighting a novel mechanism that could contribute to ACS involving endothelial erosion overlying stenotic plaques.