bluuebunny/crossref_metadata_2025 huggingface dataset:
Application of Next-Generation Sequencing for Characterization of Surveillance and Clinical Trial Isolates: Analysis of the Distribution of β-lactamase Resistance Genes and Lineage Background in the United States
Authors: Mendes Rodrigo E , Jones Ronald N , Woosley Leah N , Cattoir Vincent , Castanheira Mariana
Published: March 2019

Background

Sequencing technologies and techniques have seen remarkable transformation and innovation that have significantly affected sequencing capability. Data analyses have replaced sequencing as the main challenge. This paper provides an overview on applying next-generation sequencing (NGS) and analysis and discusses the benefits and challenges. In addition, this document shows results from using NGS and bioinformatics tools to screen for β-lactamase genes and assess the epidemiological structure of Escherichia coli– and Klebsiella pneumoniae–causing bloodstream (BSIs) and urinary tract (UTIs) infections in patients hospitalized in the United States during the SENTRY Antimicrobial Surveillance Program for 2016.

Methods

A total of 3525 isolates (2751 E. coli and 774 K. pneumoniae) causing BSIs (n = 892) and UTIs (n = 2633) in hospitalized patients in the United States were included. Isolates were tested for susceptibility by broth microdilution, and those that met a minimum inhibitory concentration (MIC)–based screening criteria had their genomes sequenced and analyzed.

Results

A total of 11.6% and 16.1% of E. coli–causing UTIs and BSIs, respectively, met the MIC-based criteria, whereas 11.0% and 13.7% of K. pneumoniae isolates causing UTIs and BSIs, respectively, met the criteria. Among E. coli, blaCTX-M variants (87.6% overall) prevailed (60.5% of CTX-M group 1 and 26.9% of group 9). A total of 60.3% of K. pneumoniae isolates carried blaCTX-M variants (52.7% and 7.6% of groups 1 and 9, respectively). Two E. coli (0.6%) and 13 K. pneumoniae (12.9%) isolates harbored blaKPC. Among KPC-producing K. pneumoniae (2 from BSIs and 11 from UTIs), 84.6% (11/13) were ST258 (CC258). Seventeen and 38 unique clonal complexes (CCs) were noted in E. coli that caused BSIs and UTIs, respectively, and CC131 (or ST131) was the most common CC among BSI (53.6%) and UTI (58.2%) isolates. Twenty-three and 26 CCs were noted among K. pneumoniae–causing BSIs and UTIs, respectively. CC258 (28.3%) prevailed in UTI pathogens, whereas CC307 (15.0%) was the most common CC among BSI isolates.

Conclusions

This study provides a benchmark for the distribution of β-lactamase genes and the population structure information for the most common Enterobacteriaceae species responsible for BSIs and UTIs in US medical centers during the 2016 SENTRY Program.
Social inclusion in the knowledge economy: unions’ strategies and institutional change in the Austrian and German training systems
Authors: Durazzi Niccolo , Geyer Leonard
Published: March 2019

As skill formation systems are increasingly under pressure from de-industrialization and the rise of knowledge economies, their ability to include the low-skilled has been strained. But what determines how skill formation systems adjust to this challenge? By explaining the divergence of two most-similar systems, those of Austria and Germany, the article highlights the key role of trade unions and of the institutional resources and legacies available to them. Where institutional resources are high and legacies positive, as in Austria, unions were crucial in setting an inclusive pathway of reform of the training system. Where, on the contrary, institutional resources are low and legacies negative, as in Germany, unions’ strategies for inclusion failed, paving the way to a dualizing outcome. The article therefore provides a novel analysis of institutional change in skill formation systems, while also offering broader insights on the relationship between coordinated and egalitarian capitalism in post-industrial knowledge-based economies.
Dosing Time Matters
Authors: Ruben Marc D. , Smith David F. , FitzGerald Garret A. , Hogenesch John B.
Published: March 2019

Trainees in medicine are taught to diagnose and administer treatment as needed; time-of-day is rarely considered. Yet accumulating evidence shows that ∼half of human genes and physiologic functions follow daily rhythms. Circadian medicine aims to incorporate knowledge of these rhythms to enhance diagnosis and treatment. Interest in this approach goes back at least six decades, but the path to the clinic has been marked by starts, stops, and ambiguity. How do we move the field forward to impact clinical practice? To gain insight into successful strategies, we studied the results of more than 100 human trials that evaluated time-of-administration of drugs.
Performance of the Maxim and Sedia Limiting Antigen Avidity assays for population-level HIV incidence surveillance
Authors: Sempa Joseph B. , Welte Alex , Busch Michael P. , Hall Jake , Hampton Dylan , Keating Sheila M. , Facente Shelley N. , Marson Kara , Parkin Neil , Pilcher Christopher D. , Murphy Gary , Grebe Eduard ,   on behalf of the Consortium for the Evaluation and Performance of HIV Incidence Assays (CEPHIA)
Published: March 2019

Background

Two manufacturers, Maxim Biomedical and Sedia Biosciences Corporation, supply US CDC-approved versions of the HIV-1 Limiting Antigen Avidity EIA (LAg assay) for detecting ‘recent’ HIV infection in cross-sectional incidence estimation. This study assesses and compares the performance of the Maxim and Sedia LAg assays for incidence surveillance.

Methods

We ran both assays on a panel of 2,500 well-characterized HIV-1-infected specimens, most with estimated dates of (detectable) infection. We analysed concordance of assay results, assessed reproducibility using repeat testing and estimated the critical performance characteristics of a test for recent infection—mean duration of recent infection (MDRI) and false-recent rate (FRR)—for a range of normalized optical density (ODn) recency discrimination thresholds, alone and in combination with viral load thresholds. We further defined three hypothetical surveillance scenarios and evaluated overall performance for incidence surveillance, defined as the precision of incidence estimates, by estimating context-specific performance characteristics.

Results

The Maxim assay produced lower ODn values than the Sedia assay on average, largely as a result of higher calibrator readings (mean calibrator OD of 0.749 vs. 0.643). Correlation of non-normalized OD readings was greater (R2 = 0.938) than those of ODn readings (R2 = 0.908), and the slope was closer to unity (1.054 vs. 0.899). Reproducibility of repeat testing of three blinded control specimens (25 replicates each) was slightly better for the Maxim assay (CV 8.9% to 14.8% vs. 13.2% to 15.0%). The MDRI of a Maxim-based algorithm at the ‘standard’ recency discrimination threshold in combination with viral load (ODn ≤1.5 & VL >1,000) was 201 days (95% CI: 180,223) and for Sedia was 171 days (95% CI: 152,191). Commensurately, the Maxim algorithm had a higher FRR in treatment-naive subjects (1.7% vs. 1.1%). We observed statistically significant differences in MDRI using the ODn alone (≤1.5) and in combination with viral load (>1,000). Under three fully-specified hypothetical surveillance scenarios (comparable to South Africa, Kenya and a concentrated epidemic), recent infection testing algorithms based on the two assays produced similar precision of incidence estimates.

Conclusions

Differences in ODn measurements between the Maxim and Sedia LAg assays on the same specimens largely resulted from differences in the reactivity of calibrators supplied by the manufacturers. Performance for surveillance purposes was extremely similar, although different ODn thresholds were optimal and different values of MDRI and FRR were appropriate for use in survey planning and incidence estimation.
Making Pastoralists Count: Geospatial Methods for the Health Surveillance of Nomadic Populations
Authors: Wild Hannah , Glowacki Luke , Maples Stace , Mejía-Guevara Iván , Krystosik Amy , Bonds Matthew H. , Hiruy Abiy , Desiree LaBeaud A. , Barry Michele
Published: March 2019

Nomadic pastoralists are among the world’s hardest-to-reach and least-served populations. Pastoralist communities are difficult to capture in household surveys due to factors including their high degree of mobility over remote terrain, fluid domestic arrangements, and cultural barriers. Most surveys utilize census-based sampling frames which do not accurately capture the demographic and health parameters of nomadic populations. As a result, pastoralists are “invisible” in population data such as the Demographic and Health Surveys (DHS). By combining remote sensing and geospatial analysis, we developed a sampling strategy designed to capture the current distribution of nomadic populations.

We then implemented this sampling frame to survey a population of mobile pastoralists in southwest Ethiopia, focusing on maternal and child health (MCH) indicators. Using standardized instruments from DHS questionnaires, we draw comparisons with regional and national data finding disparities with DHS data in core MCH indicators including vaccination coverage, skilled birth attendance, and nutritional status. Our field validation demonstrates that this method is a logistically feasible alternative to conventional sampling frames and may be used at the population level. Geospatial sampling methods provide cost-affordable and logistically feasible strategies for sampling mobile populations, a crucial first step towards reaching these groups with health services.
Evolution of Phototransduction Genes in Lepidoptera
Authors: Macias-Muñoz Aide , Rangel Olguin Aline G. , Briscoe Adriana D.
Published: March 2019

Vision is underpinned by phototransduction, a signaling cascade that converts light energy into an electrical signal. Among insects, phototransduction is best understood inDrosophila melanogaster.A survey of phototransduction genes in four insect genomes found gains and losses betweenD. melanogasterand other insects; this study did not include lepidopterans. Diurnal butterflies and nocturnal moths occupy different light environments and have distinct eye morphologies, which might impact the expression of their phototransduction genes. Here, we used transcriptomics and phylogenetics to identify phototransduction genes that vary betweenD. melanogasterand Lepidoptera, and between moths and butterflies. Most phototransduction genes were conserved betweenD. melanogasterand Lepidoptera, with some exceptions. We found two lepidopteran opsins lacking aD. melanogasterortholog, and using antibodies found that one, a candidate retinochrome which we name unclassified opsin (UnRh), is expressed in the crystaline cone cells and the pigment cells of the butterflyHeliconius melpomene. We also found differences between Lepidoptera andD. melanogasterphototransduction in diacylglycerol regulation where a lepidopteran paralog, DAGβ, may be taking on a role in vision. Lastly, butterflies express similar amounts oftrpandtrplchannel mRNAs, while moths express approximately 50x lesstrp. Since TRP/TRPL channels allow Ca2+and Na+influx this might explain why moths appear to express lessCalxandNckx30CNa+/Ca2+channel mRNAs. Our findings suggest that while many single-copyD. melanogasterphototransduction genes are conserved in lepidopterans, phototransduction gene expression differences exist between moths and butterflies that may be linked to their visual light environment.
Deep Learning with Multimodal Representation for Pancancer Prognosis Prediction
Authors: Cheerla Anika , Gevaert Olivier
Published: March 2019

Estimating the future course of cancer is invaluable to physicians; however, current clinical methods fail to effectively use the vast amount of multimodal data that is available for cancer patients.

To tackle this problem, we constructed a deep neural network based model to predict the survival of patients for 20 different cancer types using gene expressions, microRNA data, clinical data and histopathology whole slide images (WSIs). We developed an unsupervised encoder to compress these four data modalities into a single feature vector for each patient, handling missing data through a resilient, multimodal dropout method. Encoding methods were tailored to each data type - using deep highway networks to extract features from genomic and clinical data, and convolutional neural networks extract features from pathology images. We then used these feature encodings trained on pancancer data to predict pancancer and single cancer survival data, achieving a C-index of 0.784 overall.

This work shows that it is possible to build a pancancer model for prognosis that also predicts prognosis in single cancer sites. Furthermore, our model handles multiple data modalities, efficiently analyzes WSIs, and summarizes patient details flexibly into an unsupervised, informative profile. We thus present a powerful automated tool to accurately determine prognosis, a key step towards personalized treatment for cancer patients.
Effectiveness and selectivity of a heroin conjugate vaccine to attenuate heroin, 6-acetylmorphine, and morphine antinociception in rats: Comparison with naltrexone
Authors: Schwienteck Kathryn L. , Blake Steven , Bremer Paul T. , Poklis Justin L. , Townsend E. Andrew , Negus S. Stevens , Banks Matthew L.
Published: March 2019

Background

One emerging strategy to address the opioid crisis includes opioid-targeted immunopharmacotherapies. This study compared effectiveness of a heroin-tetanus toxoid (TT) conjugate vaccine to antagonize heroin, 6-acetylmorphine (6-AM), morphine, and fentanyl antinociception in rats.

Methods

Adult male and female Sprague Dawley rats received three doses of active or control vaccine at weeks 0, 2, and 4. Vaccine pharmacological selectivity was assessed by comparing opioid dose-effect curves in 50°C warm-water tail-withdrawal procedure before and after active or control heroin-TT vaccine. Route of administration [subcutaneous (SC) vs. intravenous [IV)] was also examined as a determinant of vaccine effectiveness. Continuous naltrexone treatment (0.0032-0.032 mg/kg/h) effects on heroin, 6-AM, and morphine antinociceptive potency was also determined as a benchmark for minimal vaccine effectiveness.

Results

The heroin-TT vaccine decreased potency of SC heroin (5-fold), IV heroin (3-fold), and IV 6-AM (3-fold) for several weeks without affecting IV morphine or SC and IV fentanyl potency. The control vaccine did not alter potency of any opioid. Naltrexone dose-dependently decreased antinociceptive potency of SC heroin, and treatment with 0.01 mg/kg/h naltrexone produced similar, approximate 8-fold decreases in potencies of SC and IV heroin, IV 6-AM, and IV morphine. The combination of naltrexone and active vaccine was more effective than naltrexone alone to antagonize SC heroin but not IV heroin.

Conclusions

The heroin-TT vaccine formulation examined is less effective, but more selective, than chronic naltrexone to attenuate heroin antinociception in rats. Furthermore, these results provide an empirical framework for future preclinical opioid vaccine research to benchmark effectiveness against naltrexone.
Constructing a Draft Map of the Cannabis Proteome
Authors: Jenkins Conor , Orsburn Ben
Published: March 2019

Recently we have seen a relaxing on the historic restrictions on the use and subsequent research on the cannabis plants, generally classified as Cannabis sativa and Cannabis indica. What research has been performed to date has centered on chemical analysis of plant flower products, namely cannabinoids and various terpenes that directly contribute to phenotypic characteristics of the female flowers. In addition, we have seen many groups recently completing genetic profiles of various plants of commercial value. To date, no comprehensive attempt has been made to profile the proteomes of these plants. In this study we present our initial findings consisting of the identification of 17,269 unique proteins identified from Cannabis plant materials, as well as 6,110 post-translational modifications identified on these proteins. The results presented demonstrate the first steps toward constructing a complete draft map of the Cannabis proteome.
Marine sediments illuminate Chlamydiae diversity and evolution
Authors: Dharamshi Jennah E. , Tamarit Daniel , Eme Laura , Stairs Courtney , Martijn Joran , Homa Felix , Jørgensen Steffen L. , Spang Anja , Ettema Thijs J. G.
Published: March 2019

The bacterial phylum Chlamydiae, which is so far comprised of obligate symbionts of eukaryotic hosts, are well-known as human and animal pathogens1-3. However, the Chlamydiae also include so-called environmental lineages4-6that primarily infect microbial eukaryotes7. Studying environmental chlamydiae, whose genomes display extended metabolic capabilities compared to their pathogenic relatives8-10has provided first insights into the evolution of the pathogenic and obligate intracellular lifestyle that is characteristic for this phylum. Here, we report an unprecedented relative abundance and diversity of novel lineages of the Chlamydiae phylum, representing previously undetected, yet potentially important, community members in deep marine sediments. We discovered that chlamydial lineages dominate the microbial communities in the Arctic Mid-Ocean Ridge11, which revealed the dominance of chlamydial lineages at anoxic depths, reaching relative abundances of up to 43% of the bacterial community, and a maximum diversity of 163 different species-level taxonomic unit. Using genome-resolved metagenomics, we reconstructed 24 draft chlamydial genomes, thereby dramatically expanding known interspecies genomic diversity in this phylum. Phylogenomic and comparative analyses revealed several deep-branching Chlamydiae clades, including a sister clade of the pathogenic Chlamydiaceae. Altogether, our study provides new insights into the diversity, evolution and environmental distribution of the Chlamydiae.
Depiction of secondary metabolites and antifungal activity of Bacillus velezensis DTU001
Authors: Devi Sagarika , Kiesewalter Heiko T. , Kovács Renátó , Frisvad Jens Christian , Weber Tilmann , Larsen Thomas Ostenfeld , Kovács Ákos T. , Ding Ling
Published: March 2019

For a safe and sustainable environment, effective microbes as biocontrol agents are in high demand. We have isolated a new Bacillus velezensis strain DTU001, investigated its antifungal spectrum, sequenced its genome, and uncovered the production of lipopeptides in HPLC-HRMS analysis. To test the antifungal efficacy, extracts of B. velezensis DTU001 was tested against a range of twenty human or plant pathogenic fungi. We demonstrate that inhibitory potential of B. velezensis DTU001 against selected fungi is superior in comparison to single lipopeptide, either iturin or fengycin. The isolate showed analogous biofilm formation to other closely related Bacilli. To further support the biocontrol properties of the isolate, coculture with Candida albicans demonstrated that B. velezensis DTU001 exhibited excellent antiproliferation effect against C. albicans. In summary, the described isolate is a potential antifungal agent with a broad antifungal spectrum that might assist our aims to avoid hazardous pathogenic fungi and provide alternative to toxicity caused by chemicals.
Recent global changes have decoupled species richness from specialization patterns in North American birds
Authors: Mimet Anne , Buitenwerf Robert , Sandel Brody , Svenning Jens-Christian , Normand Signe
Published: March 2019

Aim

Theory suggests that increasing productivity and climate stability toward the tropics can explain the latitudinal richness gradient by favouring specialization. A positive relationship between species richness and specialization should thus emerge as a fundamental biogeographic pattern. However, land use and climate change disproportionally increase the local extirpation risk for specialists, potentially impacting this pattern. Here, we empirically quantify the richness-specialization prediction and test how 50 years of climate and land use change has affected the richness-specialization relationship.

Location

USA

Time period

1966-2015

Major taxa studied

Birds

Methods

We used the North American breeding bird survey to quantify bird community richness and specialization to habitat and climate. We assess i) temporal change in the slope of the richness-specialization relationship, using a Generalized Mixed Model; ii) temporal change in spatial covariation of richness and specialization as driven by local environmental conditions, using Generalized Additive Models; and iii) land use, climate and topographic drivers of the spatio-temporal changes in the relationship, using a multivariate method.

Results

We found evidence for a positive richness-specialization relationship in bird communities. However, the slope of the relationship declined strongly over time. Richness spatially covaried with specialization following a unimodal pattern. The peak of the unimodal pattern shifted toward less specialized communities over time. These temporal changes were associated with precipitation change, decreasing temperature stability and land use.

Main conclusions

Recent climate and land use changes induced two antagonist types of community responses. In human-dominated areas, the decoupling of richness and specialization drove a general biotic homogenization trend. In human-preserved areas under increasing climate harshness, specialization increased while richness decreased in a “specialization” trend. Our results offer new support for specialization as a key driver of macroecological diversity patterns, and show that global changes are erasing this fundamental macroecological pattern.

Biosketch

Anne Mimet is a postdoctoral researcher interested in the understanding of human impacts on biodiversity through land use and climate changes, at various spatio-temporal scales. She is interested in embracing the complexity of socio-ecological systems, and in the understanding of biodiversity trends in a human-dominated world in the context of the general theories of ecology.
Cannabis-associated symptom profiles in patients with first episode psychosis and population controls
Authors: Quattrone Diego , Ferraro Laura , Tripoli Giada , Cascia Erika La , Quigley Harriet ,   EU-GEI group, Gayer-Anderson Charlotte , Jones Peter B. , Kirkbride James B. , Barbera Daniele La , Tarricone Ilaria , Lynskey Michael T. , Freeman Tom P. , Sham Pak C. , Cardno Alaistar , Vassos Evangelos , van Os Jim , Morgan Craig , Reininghaus Ulrich , Lewis Cathryn M. , Murray Robin M. , Di Forti Marta
Published: March 2019

Objective

The evidence is mixed on whether cannabis use is associated with a particular symptomatology in first episode psychosis (FEP) patients.

The authors set out to investigate a) patterns of association between cannabis use and transdiagnostic symptom dimensions; b) whether the extent of use of cannabis contributes to the variation in clinical and subclinical symptom profiles.

Method

The authors analysed data from 901 patients and 1235 controls recruited across six countries, as part of the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. Item response modelling was used to estimate two bifactor models, which included general and specific dimensions of psychotic symptoms in patients and psychotic experiences in controls. The associations between these dimensions and cannabis use was evaluated using linear mixed effects models analyses.

Results

In patients, there was a linear relationship between the positive symptom dimension and the extent of lifetime exposure to cannabis, with daily users of high potency cannabis having the highest score (B=0.35; 95%CI 0.14 to 0.56). Moreover, negative symptoms were more common among patients who never used cannabis compared with those with any pattern of use (B=-0.27; 95%CI −0.42 to −0.12).

In controls, psychotic experiences were associated with current use of cannabis but not with the extent of lifetime use.

Neither patients nor controls presented differences in the depressive dimension related to cannabis use.

Conclusions

The extent of use of cannabis explains part of the heterogeneous distribution of positive and negative symptoms of FEP patients.
Prenatal thyroid hormone exposure increases growth but not oxidative stress in a wild passerine species
Authors: Sarraude Tom , Hsu Bin-Yan , Groothuis Ton G.G. , Ruuskanen Suvi
Published: March 2019

Hormones transferred from mothers to their offspring are thought to be a maternal tool for mothers to prepare their progeny for expected environmental conditions, thus increasing fitness. Thyroid hormones (THs) are crucial across vertebrates for embryonic and post-natal development and metabolism. Nevertheless, the studies that investigated the consequences of maternal hormones have mostly focused on steroid hormones and ignored maternally-derived thyroid hormones. In this study, we experimentally elevated yolk thyroid hormones in a wild population of a migratory passerine, the European Pied flycatcherFicedula hypoleuca. We injected eggs with a mixture of T4and T3within the natural range of the species to assess its effects on hatching success, nestling survival, growth and oxidative status (antioxidant enzyme activity, lipid peroxidation and oxidative balance). We found no effects of yolk THs on egg hatchability or nestling survival. Yolk THs increased nestling growth during the second week post hatching, but this potentially beneficial effect did not incur any costs in terms of oxidative stress. The results should stimulate more research on thyroid hormone mediated maternal effects, further studies into the underlying mechanistic pathways for these effects and how they translate into adulthood and fitness.

Summary statement

Thyroid hormones have been overlooked in the context of hormone-mediated maternal effects. We found that yolk thyroid hormones in a wild bird species increase growth without incurring oxidative stress.
HSC70 regulates cold-induced caspase-1 hyperactivation by an autoinflammation-causing mutant of cytoplasmic immune receptor NLRC4
Authors: Raghawan Akhouri Kishore , Ramaswamy Rajashree , Radha Vegesna , Swarup Ghanshyam
Published: March 2019

NLRC4 is an innate immune receptor, which upon detection of certain pathogens or internal distress signal, initiates caspase-1 mediated inflammatory response. A gain-of-function mutation, H443P in NLRC4, causes familial cold autoinflammatory syndrome (FCAS) characterized by cold-induced hyperactivation of caspase-1 and inflammation. Here, we show that heat shock cognate protein 70 (HSC70) complexes with NLRC4 and negatively regulates caspase-1 activation by NLRC4-H443P. Compared to NLRC4, the structurally altered NLRC4-H443P shows enhanced interaction with HSC70. Knockdown of HSC70 or inhibition of its ATPase activity enhances caspase-1 activation by NLRC4-H443P. Exposure to subnormal temperature resulted in reduced interaction of NLRC4-H443P with HSC70, and an increase in its ability to form ASC-specks and activate caspase-1. By demonstrating that HSC70 differentially interacts with NLRC4-H443P mutant in a temperature-dependent manner to regulate caspase-1 activation, we provide a mechanism for cold-induced inflammation seen in FCAS patients with NLRC4-H443P mutation.
Interplay of primary bovine lymphocytes and Mycobacterium avium subsp. paratuberculosis shows distinctly different proteome changes and immune pathways in host-pathogen interaction
Authors: Kleinwort Kristina J.H. , Hauck Stefanie M. , Degroote Roxane L. , Scholz Armin M. , Hölzel Christina , Märtlbauer Erwin P. , Deeg Cornelia A.
Published: March 2019

Mycobacterium avium subsp. paratuberculosis (MAP) is a pathogen causing paratuberculosis in cattle and small ruminants. During the long asymptomatic subclinical stage, high numbers of MAP are excreted and can be transmitted to food, where they survive many of the standard techniques of food decontamination. If these MAP are harmful to the consumers is currently under debate. In general, there is a lack of information regarding interaction of the hosts immune system with MAP.

In this study, we tested the interaction of peripheral blood lymphocytes (PBL) from cattle with MAP in their exoproteomes/secretomes. Because in other mycobacterial infections, the immune phenotype correlates with susceptibility, we additionally tested the interaction of MAP with recently detected immune deviant cows.

In PBL, different biological pathways were enhanced in response to MAP dependent on the immune phenotype of the host. PBL of control cows activated members of cell activation and chemotaxis of leukocytes pathway as well as IL-12 mediated signaling. In contrast, in ID cows CNOT1 was detected as highly abundant protein, pointing to a different immune response, which could be favorable for MAP. Additionally, MAP reacted different to the hosts. Their exoproteomes differed in either GroEL1 or DnaK abundance, depending on the interacting immune response.

These findings point to an interdependent, tightly regulated response of MAP and the immune system.
Zika virus seroprevalence declines and neutralization antibodies wane in adults following outbreaks in French Polynesia and Fiji
Authors: Henderson Alasdair D , Aubry Maite , Kama Mike , Vanhomwegen Jessica , Teissier Anita , Mariteragi-Helle Teheipuaura , Paoaafaite Tuterarii , Manuguerra Jean-Claude , Edmunds W John , Whitworth Jimmy , Watson Conall H , Lau Colleen L , Cao-Lormeau Van-Mai , Kucharski Adam J
Published: March 2019

Background

Serosurveys published following major outbreaks of Zika virus (ZIKV) have so far shown a high level of seroprevalence from samples collected within 12 months of the first confirmed case. A common assumption is that ZIKV infection confers long-term protection against reinfection, preventing ZIKV from re-emerging in previously affected areas for many years. However, the long-term immune response to ZIKV following an outbreak remains poorly documented.

Methods

We compared results from eight serological surveys, with sample sizes ranging from 49 to 700, before and after known ZIKV outbreaks in the Pacific region: five from cross-sectional studies of schoolchildren and the general population in French Polynesia over a seven-year period; and three from a longitudinal cohort in Fiji over a four-year period.

Findings

We found strong evidence of a decline in seroprevalence in both countries over a two-year period following first reported ZIKV transmission. In the cohort in Fiji, there was also a significant decline in antibody titres against ZIKV. However, the decline in seroprevalence was concentrated in adults, while high seroprevalence persisted in children.

Interpretation

The observed patterns of long-term anti-ZIKV antibody levels following outbreaks in the Pacific could be an early indication of the dynamics of population immunity in Latin America. Given that ZIKV antibody levels can wane substantially over time, follow-up seroprevalence studies and prospective clinical trial designs in Latin America may need to be revised, and assumptions about the potential for ZIKV to re-emerge may need to be revisited.

Funding

Pacific Funds, ANR, MRC, Wellcome, Royal Society.
Effect of Antimicrobial Peptides HNP-1 and hBD-1 on Staphylococcus aureus Clinical Strains in vitro and in vivo
Authors: Bolatchiev Albert , Baturin Vladimir , Bazikov Igor , Maltsev Alexander , Kunitsina Elena
Published: March 2019

The aims of this study were: (1) To investigate the activity of recombinant AMPs HNP-1 and hBD-1 in combination with cefotaxime against Staphylococcus aureus clinical strains (MSSA and MRSA) in vitro using checkerboard method; (2) To investigate the activity of HNP-1 and hBD-1 encapsulated in silicon nanoparticles (niosomes) in the treatment of MRSA-infected wound in rats. For this S. aureus clinical strains (MSSA and MRSA) were isolated from patients with diabetic foot infection. Cefotaxime, recombinant HNP-1 and hBD-1 (in all possible combinations with each other) were used for testing by the checkerboard method. Two niosomal topical gels with HNP-1/hBD-1 were prepared to treat MRSA-infected wounds in rats. Gels were administered once a day, the control group – without treatment. Wound healing rate was calculated on the 4th, 9th and 16th days of the experiment and compared using one-way ANOVA with Bonferroni correction. MIC of HNP-1 for MSSA and MRSA was the same – 1 mg/L. MIC of hBD-1 for MSSA and MRSA was also the same – 0.5 mg/L. Topical gels with niosomal HNP-1 (or hBD-1) showed a significantly faster wound healing in comparison with the control. The data obtained open up prospects for use of AMPs encapsulated in silica nanoparticles for the development of new antibiotics.
Tricalbin-mediated contact sites control ER curvature to maintain plasma membrane integrity
Authors: Collado Javier , Kalemanov Maria , Martínez-Sánchez Antonio , Campelo Felix , Baumeister Wolfgang , Stefan Christopher J. , Fernández-Busnadiego Ruben
Published: March 2019

Membrane contact sites (MCS) between the endoplasmic reticulum (ER) and the plasma membrane (PM) play fundamental roles in all eukaryotic cells. ER-PM MCS are particularly abundant in S. cerevisiae, where approximately half of the PM surface is covered by cortical ER (cER). Several proteins, including Ist2, Scs2/22 and Tcb1/2/3 are implicated in cER formation, but the specific roles of these molecules are poorly understood. Here we use cryo-electron tomography to show that ER-PM tethers are key determinants of cER morphology. In particular, Tcb proteins form peaks of extreme curvature on the cER membrane facing the PM. Semi-quantitative modeling and functional assays suggest that Tcb-mediated cER peaks facilitate the transport of lipids from the cER to the PM, necessary to maintain PM integrity under stress conditions. ER peaks were also present at other MCS, implying that membrane curvature enforcement may be a widespread mechanism to expedite lipid transport at MCS.
The Hidden Repertoire of Brain Dynamics and Dysfunction
Authors: McIntosh Anthony R. , Jirsa Viktor K.
Published: March 2019

The purpose of this paper is to describe a framework for the understanding of rules that govern how neural system dynamics are coordinated to produce behavior. The framework, structured flows on manifolds (SFM), posits that neural processes are flows depicting system interactions that occur on relatively low-dimension manifolds, which constrain possible functional configurations. Although this is a general framework, we focus on the application to brain disorders. We first explain the Epileptor, a phenomenological computational model showing fast and slow dynamics, but also a hidden repertoire whose expression is similar to refractory status epilepticus. We suggest that epilepsy represents an innate brain state whose potential may be realized only under certain circumstances. Conversely, deficits from damage or disease processes, such as stroke or dementia, may reflect both the disease process per se and the adaptation of the brain. SFM uniquely captures both scenarios.

The Hidden Repertoire of Brain Dynamics and Dysfunction
Proteome-wide signatures of function in highly diverged intrinsically disordered regions
Authors: Zarin Taraneh , Strome Bob , Nguyen Ba Alex N , Alberti Simon , Forman-Kay Julie D , Moses Alan M
Published: March 2019

Intrinsically disordered regions make up a large part of the proteome, but the sequence-to-function relationship in these regions is poorly understood, in part because the primary amino acid sequences of these regions are poorly conserved in alignments. Here we use an evolutionary approach to detect molecular features that are preserved in the amino acid sequences of orthologous intrinsically disordered regions. We find that most disordered regions contain multiple molecular features that are preserved, and we define these as “evolutionary signatures” of disordered regions. We demonstrate that intrinsically disordered regions with similar evolutionary signatures can rescue functionin vivo,and that groups of intrinsically disordered regions with similar evolutionary signatures are strongly enriched for functional annotations and phenotypes. We propose that evolutionary signatures can be used to predict function for many disordered regions from their amino acid sequences.
Spatial integration of mechanical forces by alpha-actinin establishes actin network symmetry
Authors: Senger Fabrice , Pitaval Amandine , Ennomani Hajer , Kurzawa Laetitia , Blanchoin Laurent , Théry Manuel
Published: March 2019

Cell and tissue morphogenesis depend on the production and spatial organization of tensional forces in the actin cytoskeleton. Actin network architecture is complex because it is made of distinct modules in which filaments adopt a variety of organizations. The assembly and dynamics of these modules is well described but the self-organisation rules directing the global network architecture are much less understood. Here we investigated the mechanism regulating the interplay between network architecture and the geometry of cell’s extracellular environment. We found that α-actinin, a filament crosslinker, is essential for network symmetry to be consistent with extracellular microenvironment symmetry. It appeared to be required for the interconnection of transverse arcs with radial fibres to ensure an appropriate balance between forces at cell adhesions and across the entire actin network. Furthermore, the connectivity of the actin network appeared necessary for the cell ability to integrate and adapt to complex patterns of extracellular cues as they migrate. Altogether, our study has unveiled a role of actin-filament crosslinking in the physical integration of mechanical forces throughout the entire cell, and the role of this integration in the establishment and adaptation of intracellular symmetry axes in accordance with the geometry of extracellular cues.
Inferring biophysical models of evolution from genome-wide patterns of codon usage
Authors: Kion-Crosby Willow B. , Manhart Michael , Morozov Alexandre V.
Published: March 2019

Frequencies of synonymous codons are typically non-uniform, despite the fact that such codons correspond to the same amino acid in the genetic code. This phenomenon, known as codon bias, is broadly believed to be due to a combination of factors including genetic drift, mutational biases, and selection for speed and accuracy of codon translation; however, quantitative modeling of codon bias has been elusive. We have developed a biophysical population genetics model which explains genome-wide codon frequencies observed across 20 organisms. We assume that codons evolve independently of each other under the influence of mutation and selection forces, and that the codon population has reached evolutionary steady state. Our model implements codon-level treatment of mutations with transition/transversion biases, and includes two contributions to codon fitness which describe codon translation speed and accuracy. Furthermore, our model includes wobble pairing – the possibility of codon-anticodon base pairing mismatches at the 3’ nucleotide position of the codon. We find that the observed patterns of genome-wide codon usage are consistent with a strong selective penalty for mistranslated amino acids. Thus codons undergo purifying selection and their relative frequencies are affected in part by mutational robustness. We find that the dependence of codon fitness on translation speed is weaker on average compared to the strength of selection against mistranslation. Although no constraints on codon-anticodon pairing are imposeda priori, a reasonable hierarchy of pairing rates, which conforms to the wobble hypothesis and is consistent with available structural evidence, emerges spontaneously as a model prediction. Finally, treating the translation process explicitly in the context of a finite ribosomal pool has allowed us to estimate mutation rates per nucleotide directly from the coding sequences. Reminiscent of Drake’s observation that mutation rates are inversely correlated with the genome size, we predict that mutation rates are inversely proportional to the number of genes. Overall, our approach offers a unified biophysical and population genetics framework for studying codon bias across all domains of life.
A geometric characterization of population coding in the prefrontal cortex and hippocampus during a paired-associate learning task
Authors: Liu Yue , Brincat Scott L , Miller Earl K , Hasselmo Michael E
Published: March 2019

Large-scale neuronal recording techniques have enabled discoveries of population-level mechanisms for neural computation. However it is not clear how these mechanisms form by trial and error learning. In this paper we present an initial effort to characterize the population activity in monkey prefrontal cortex (PFC) and hippocampus (HPC) during the learning phase of a paired-associate task. To analyze the population data, we introduce the normalized distance, a dimensionless metric that describes the encoding of cognitive variables from the geometrical relationship among neural trajectories in state space. It is found that PFC exhibits a more sustained encoding of task-relevant variables whereas HPC only transiently encodes the identity of the stimuli. We also found partial evidence on the learning-dependent changes for some of the task variables. This study shows the feasibility of using normalized distance as a metric to characterize and compare population level encoding of task variables, and suggests further directions to explore the learning-dependent changes in the population activity.
Myosin II isoforms play distinct roles in adherens junction biogenesis
Authors: Heuzé Mélina L. , Sankara Gautham , Dang Tien , d’Alessandro Joseph , Cellerin Victor , Williams David S. , van Hest Jan C. M. , Marcq Philippe , Mège René-Marc , Ladoux Benoît
Published: March 2019

Adherens junction (AJ) assembly under force is essential for many biological processes like epithelial monolayer bending, collective cell migration, cell extrusion and wound healing. The acto-myosin cytoskeleton acts as a major force-generator during the de novo formation and remodelling of AJ. Here, we investigated the role of myosinII isoforms in epithelial junction assembly. Myosin IIA (NMIIA) and Myosin IIB (NMIIB) differentially regulate biogenesis of adherens junction through association with distinct actin networks. Analysis of junction dynamics, actin organization, and mechanical forces of control and knockdown cells for myosins revealed that NMIIA provides the mechanical tugging force necessary for cell-cell junction reinforcement and maintenance. NMIIB is involved in E-cadherin clustering, maintenance of a branched actin layer connecting E-cadherin complexes and perijunctional actin fibres leading to the building-up of anisotropic stress. These data reveal unanticipated complementary functions of NMIIA and NMIIB in the biogenesis and integrity of AJ.
Somatic mutations in miRNA genes in lung cancer – potential functional consequences of non-coding sequence variants
Authors: Galka-Marciniak Paulina , Urbanek-Trzeciak Martyna Olga , Nawrocka Paulina Maria , Dutkiewicz Agata , Giefing Maciej , Lewandowska Marzena Anna , Kozlowski Piotr
Published: March 2019

A growing body of evidence indicates that miRNAs may either drive or suppress oncogenesis. However, little is known about somatic mutations in miRNA genes. To determine the frequency and potential consequences of miRNA gene mutations, we analyzed whole exome sequencing datasets of ∼500 lung adenocarcinoma (LUAD) and ∼500 lung squamous cell carcinoma (LUSC) samples generated in the TCGA. Altogether, we identified >1000 mutations affecting ∼500 different miRNA genes and showed that half of all cancers had at least one such mutation. Mutations occurred in most crucial parts of miRNA precursors, including mature miRNA and seed sequences. We showed that seed mutations strongly affected miRNA:target interactions, drastically changing the pool of predicted targets. Mutations may also affect miRNA biogenesis by changing the structure of miRNA precursors, DROSHA and DICER cleavage sites, and regulatory sequence/structure motifs. We identified 10 significantly overmutated hotspot miRNA genes, including themiR-379gene in LUAD enriched in mutations in the mature miRNA and regulatory sequences. The occurrence of mutations in the hotspot miRNA genes was also shown experimentally. We present a comprehensive analysis of somatic mutations in miRNA genes and show that some of these genes are mutational hotspots, suggesting their potential role in cancer.
Reduced insulin and IGF-1 signalling synergistically extend healthspan in male mice
Authors: Walker Andrew MN , Watt Nicole T , Warmke Nele , Yuldasheva Nadira Y , Drozd Michael , Haywood Natalie J , Skromna Anna , Makava Natasha , Wheatcroft Stephen B , Kearney Mark T , Cubbon Richard M
Published: March 2019

Reduced IGF-1 signalling is an evolutionarily conserved mediator of longevity, yet the magnitude of this effect is substantially larger in organisms retaining a common insulin and IGF-1 receptor. Whether this discrepancy reflects the failure to simultaneously reduce IGF-1 and insulin signalling in mammalian model systems remains unexplored. Moreover, studies of invertebrates cannot ascertain whether substantial effects upon lifespan are associated with preserved cognitive performance, a crucial component of healthspan. We compared the healthspan of male mice with haploinsufficiency of the insulin receptor (IRKO), IGF-1 receptor (IGF-1RKO), or both (DKO), with wildtype (WT) littermates. DKO mice survived longer than WT, with IRKO and IGF-1RKO being intermediate. At 2 years of age, DKO also exhibited preserved nesting behaviour in contrast with all other genotypes. Differential insulin sensitivity or weight gain during ageing did not explain the preserved healthspan of DKO, since these were comparable to IRKO littermates. These data provide the first demonstration that reduced insulin and IGF-1 signalling have synergistic effects upon healthspan in a mammalian model system, suggesting future mechanistic and translational studies should target insulin and IGF-1 signalling.
Rod-shaped tricalbins contribute to PM asymmetry at curved ER-PM contact sites
Authors: Hoffmann Patrick C. , Bharat Tanmay A. M. , Wozny Michael R. , Miller Elizabeth A. , Kukulski Wanda
Published: March 2019

Lipid flow between cellular organelles occurs via membrane contact sites that form dynamic conduits. Extended-synaptotagmins, known as tricalbins in yeast, mediate lipid transfer between the endoplasmic reticulum (ER) and plasma membrane (PM). How these proteins regulate the membrane architecture to transport lipids across the aqueous space between bilayers remains unknown. Using correlative microscopy, electron cryo-tomography and high-throughput genetics we address this interplay of architecture and function in budding yeast. We find that ER-PM contacts are diverse in protein composition and membrane morphology, not in intermembrane distance. In situ cryo-EM of tricalbins reveals their molecular organisation that suggests an unexpected structural framework for lipid transfer. Genetic analysis identifies functional redundancies, both for tricalbin domains and cellular lipid routes, and points to tricalbin function in maintenance of PM asymmetry. These results uncover a modularity of molecular and structural functions of tricalbins, and of their roles within the network of cellular lipid fluxes.