bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical outcomes three-year after revascularization with biodegradable polymer stents: ultrathin-strut sirolimus-eluting stent versus biolimus-eluting stent: from the Scandinavian organization for randomized trials with clinical outcome VII trial
Authors: Ellert Julia , Maeng Michael , Raungaard Bent , Hansen Knud Nørregaard , Kahlert Johnny , Jensen Svend Eggert , Bøtker Hans Erik , Hansen Henrik Steen , Lassen Jens Flensted , Christiansen Evald Høj , Jensen Lisette Okkels
Published: April 2020

Background

Drug-eluting stents with biodegradable polymers have been designed to improve safety and efficacy. However, drug-eluting stents with biodegradable polymers may not be a class effect, as stent strut thickness, polymer coating, and drug resorption differ between these groups of stents. Twelve months results of Scandinavian Organization for Randomized Trials With Clinical Outcome VII showed that ultrathin-strut sirolimus-eluting Orsiro stent was noninferior to the biolimus-eluting Nobori stent. The sirolimus-eluting Orsiro stent was associated with a reduced risk of definite stent thrombosis.

Methods

The Scandinavian Organization for Randomized Trials With Clinical Outcome VII trial is a prospective multicenter randomized clinical trial comparing sirolimus-eluting Orsiro stent and biolimus-eluting Nobori stent in all-comers patients. The endpoint target lesion failure was a composite of cardiac death, myocardial infarction (not related to other than index lesion) and target lesion revascularization.

Results

A total of 1261 patients were randomized to treatment with sirolimus-eluting Orsiro stent and 1264 patients to biolimus-eluting Nobori stent and followed for 3 years. At 3-year the target lesion failure was comparable for sirolimus-eluting Orsiro stent (9.0%) and the biolimus-eluting Nobori stent (9.1%), (rate ratio, 0.99; 95% confidence interval, 0.77–1.29). Cardiac death (sirolimus-eluting Orsiro stent 3.0% vs. biolimus-eluting Nobori stent 2.6% [rate ratio, 1.16; 95% confidence interval, 0.73–1.86]), target lesion revascularization (sirolimus-eluting Orsiro stent 5.2% vs. biolimus-eluting Nobori stent 5.9% [rate ratio, 0.90; 95% confidence interval, 0.64–1.25]), myocardial infarction (sirolimus-eluting Orsiro stent 4.7% vs. biolimus-eluting Nobori stent 4.5% [rate ratio, 1.04; 95% confidence interval, 0.72–1.50]), and definite stent thrombosis (sirolimus-eluting Orsiro stent 1.0% vs. biolimus-eluting Nobori stent 1.7% [rate ratio, 0.59; 95% confidence interval, 0.30–1.18]) did not differ significantly between the two groups.

Conclusion

At 3-year follow-up, target lesion failure did not differ among ultrathin-strut sirolimus-eluting Orsiro stent and biolimus-eluting Nobori stent with biodegradable polymers.
Adolescents' Perceptions of Childbirth
Authors: Anderson Cheryl Ann , Baker Kathy , Harter Lindsay
Published: April 2020

Purpose:

The purpose of this study was to describe adolescents' perception of birth within the first 72 hours postpartum.

Study Design & Methods:

A thematic analysis using qualitative data captured via one overarching question about labor expectations as part of a larger, parent quantitative study exploring psychological birth trauma.

Results:

Forty-two percent (n = 128) of adolescents ages 13 to 19 in the original study responded in writing to one overarching question concerning birth expectations. Four major themes were identified including pain, support, personal control, and fear, with three subthemes. Pain was expressed as a primary theme for all age adolescents and had an impact on all other themes. Expressed fear was general and specific including a fear of dying that emerged as a subtheme along with labor information and emotions.

Clinical Implications:

Lacking a positive birth experience has been linked with poor mental health outcomes (depression and posttraumatic stress) postpartum. Findings offer a guide for nurses and other healthcare providers to promote a positive birth experience for adolescents. Pain management is foremost to adolescents and requires healthcare providers' continued attention. Working together with adolescents to identify and monitor level of pain; assess support needs, feelings of loss of personal control, and signs or verbal expressions of fear; and offer ongoing information about labor progress and necessary procedures can help strengthen bonds between teens and their healthcare provider and create a positive birth experience.
Mattering: How Organizations, Patients, and Peers Can Affect Nurse Burnout and Engagement
Authors: Haizlip Julie , McCluney Courtney , Hernandez Morela , Quatrara Beth , Brashers Valentina
Published: April 2020

OBJECTIVE

The aim of this study was to explore professional mattering in a broad cohort of nurses.

BACKGROUND

Mattering is a construct from social psychology that describes the feeling that one makes a difference in the lives of others and has significance in one's community.

METHODS

A cross-sectional survey assessing mattering, meaning, social support, burnout, and engagement was administered to nurses and nurse practitioners working in various specialties in the United States.

RESULTS

Higher levels of mattering at work were associated with lower burnout and higher engagement. Mattering was correlated with perceived social support from one's organization, supervisor, peers, and subordinates. Open-ended responses describing experiences of mattering at work included demonstrating professional competence, positive interactions with patients and interprofessional peers, and receiving recognition from one's organization.

CONCLUSIONS

A perception of mattering at work is associated with lower levels of burnout. Our data suggest that affirming interactions with other healthcare team members promote a sense of mattering.
Adult Glioma WHO Classification Update, Genomics, and Imaging
Authors: Bai James , Varghese Jerrin , Jain Rajan
Published: April 2020

Recent advances in the understanding of the genetic makeup of gliomas have led to a paradigm shift in the diagnosis and classification of these tumors. Driven by these changes, the World Health Organization (WHO) introduced an update to its classification system of central nervous system (CNS) tumors in 2016. The updated glioma classification system incorporates molecular markers into tumor subgrouping, which has been shown to better correlate with tumor biology and behavior as well as patient prognosis than the previous purely histology-based classification system. Familiarity with this new classification scheme, the individual molecular markers, and corresponding imaging findings is critical for the radiologists who play an important role in diagnostic and surveillance imaging of patients with CNS tumors. The goals of this article are to review these updates to the WHO classification of CNS tumors with a focus on adult gliomas, provide an overview of key genomic markers of gliomas, and review imaging features pertaining to various genomic subgroups of adult gliomas.
Sequence-based prediction of vaccine targets for inducing T cell responses to SARS-CoV-2 utilizing the bioinformatics predictor RECON
Authors: Poran Asaf , Harjanto Dewi , Malloy Matthew , Rooney Michael S. , Srinivasan Lakshmi , Gaynor Richard B.
Published: April 2020

Background

The ongoing COVID-19 pandemic has created an urgency to identify novel vaccine targets for protective immunity against SARS-CoV-2. Consistent with observations for SARS-CoV, a closely related coronavirus responsible for the 2003 SARS outbreak, early reports identify a protective role for both humoral and cell-mediated immunity for SARS CoV-2.

Methods

In this study, we leveraged HLA-I and HLA-II T cell epitope prediction tools from RECON® (Real-time Epitope Computation for ONcology), our bioinformatic pipeline that was developed using proteomic profiling of individual HLA-I and HLA-II alleles to predict rules for peptide binding to a diverse set of such alleles. We applied these binding predictors to viral genomes from theCoronaviridaefamily, and specifically to identify SARS-CoV-2 T cell epitopes.

Results

To test the suitability of these tools to identify viral T cell epitopes, we first validated HLA-I and HLA-II predictions onCoronaviridaefamily epitopes deposited in the Virus Pathogen Database and Analysis Resource (ViPR) database. We then use our HLA-I and HLA-II predictors to identify 11,776 HLA-I and 7,991 HLA-II candidate binding peptides across all 12 open reading frames (ORFs) of SARS-CoV-2. This extensive list of identified candidate peptides is driven by the length of the ORFs and the significant number of HLA-I and HLA-II alleles that we are able to predict (74 and 83, respectively), providing over 99% coverage for the US, European and Asian populations, for both HLA-I and HLA-II. From our SARS-CoV-2 predicted peptide-HLA-I allele pairs, 368 pairs identically matched previously reported pairs in the ViPR database, originating from other forms of coronaviruses. 320 of these pairs (89.1%) had a positive MHC-binding assay result. This analysis reinforces the validity our predictions.

Conclusions

Using this bioinformatic platform, we identify multiple putative epitopes for CD4+and CD8+T cells whose HLA binding properties cover nearly the entire population and thus may be effective when included in prophylactic vaccines against SARS-CoV-2 to induce broad cellular immunity.
Rapid, field-deployable nucleobase detection and identification using FnCas9
Authors: Azhar Mohd. , Phutela Rhythm , Ansari Asgar Hussain , Sinha Dipanjali , Sharma Namrata , Kumar Manoj , Aich Meghali , Sharma Saumya , Rauthan Riya , Singhal Khushboo , Lad Harsha , Patra Pradeep Kumar , Makharia Govind , Chandak Giriraj Ratan , Chakraborty Debojyoti , Maiti Souvik
Published: April 2020

Detection of pathogenic sequences or variants in DNA and RNA through a point-of-care diagnostic approach is valuable for rapid clinical prognosis. In recent times, CRISPR based detection of nucleic acids has provided an economical and quicker alternative to sequencing-based platforms which are often difficult to implement in the field. Here, we present FnCas9 Editor Linked Uniform Detection Assay (FELUDA) that employs a highly accurate enzymatic readout for detecting nucleotide sequences, identifying nucleobase identity and inferring zygosity with precision. We demonstrate that FELUDA output can be adapted to multiple signal detection platforms and can be quickly designed and deployed for versatile applications including rapid diagnosis during infectious disease outbreaks like COVID-19.
Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high fat diet
Authors: Kellard Joely A. , Rorsman Nils J. G. , Hill Thomas G. , Armour Sarah L , van der Bunt Martijn , Rorsman Patrik , Knudsen Jakob G. , Briant Linford J. B.
Published: April 2020

Elevated plasma glucagon is an early symptom of diabetes, occurring in subjects with impaired glucose regulation. Here we explored alpha-cell function in female mice fed a high fat diet (HFD) – a widely used mouse model of pre-diabetes.In vivo, HFD-fed mice have increased fed plasma glucagon levels that are unaffected by elevation of plasma glucose. To explore the underlying mechanisms, we conducted experiments on isolated islets and in the perfused pancreas. In both experimental models, glucagon secretion under both hypo- and hyperglycaemic conditions was elevated. Because Ca2+is an important intracellular regulator of glucagon release in alpha-cells, we fed mice expressing the Ca2+indicator GCaMP3 specifically in alpha-cells the HFD. In mice fed a control (CTL) diet, increasing glucose reduced intracellular Ca2+([Ca2+]i) (oscillation frequency and amplitude). This effect was not observed in HFD mice where both the frequency and amplitude of the [Ca2+]ioscillations were higher than in CTL alpha-cells. Given that alpha-cells are under strong paracrine control from neighbouring somatostatin-secreting delta-cells, we hypothesised that this elevation of alpha-cell output was due to a lack of somatostatin (SST) secretion. Indeed, SST secretion in isolated islets from HFD mice was reduced but exogenous SST also failed to suppress glucagon secretion and Ca2+activity from HFD alpha-cells, in contrast to observations in CTL mice. These findings suggest that reduced delta-cell function, combined with intrinsic changes in alpha-cell sensitivity to somatostatin, accounts for the hyperglucagonaemia in mice fed a HFD.
The IMPDH inhibitor merimepodib suppresses SARS-CoV-2 replicationin vitro
Authors: Bukreyeva Natalya , Mantlo Emily K. , Sattler Rachel A. , Huang Cheng , Paessler Slobodan , Zeldis Jerry
Published: April 2020

The ongoing COVID-19 pandemic continues to pose a major public health burden around the world. The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected over one million people worldwide as of April, 2020, and has led to the deaths of nearly 300,000 people. No approved vaccines or treatments in the USA currently exist for COVID-19, so there is an urgent need to develop effective countermeasures. The IMPDH inhibitor merimepodib (MMPD) is an investigational antiviral drug that acts as a noncompetitive inhibitor of IMPDH. It has been demonstrated to suppress replication of a variety of emerging RNA viruses. We report here that MMPD suppresses SARS-CoV-2 replication in vitro. After overnight pretreatment of Vero cells with 10 μM of MMPD, viral titers were reduced by 4 logs of magnitude, while pretreatment for 4 hours resulted in a 3-log drop. The effect is dose-dependent, and concentrations as low as 3.3 μM significantly reduced viral titers when the cells were pretreated prior to infection. The results of this study provide evidence that MMPD may be a viable treatment option for COVID-19.
Feedback Between Coevolution and Epidemiology Can Help or Hinder the Maintenance of Genetic Variation in Host-Parasite Models
Authors: MacPherson Ailene , Keeling Matthew J. , Otto Sarah P.
Published: April 2020

Understanding if and when coevolution helps maintains genetic variation in hosts of a directly-transmissible pathogen is fundamental to quantifying the prevalence and impact of coevolution on disease epidemiology. Here, we extend our previous work on the maintenance of genetic variation in a classic matching-alleles coevolutionary model by exploring the effects of ecological and epidemiological feedbacks, where both allele frequencies and population sizes are allowed to vary over time. In general, we find that coevolution rarely maintains more host genetic variation than expected under neutral genetic drift alone. When and if coevolution maintains or depletes genetic variation relative to neutral drift is determined, predominantly, by two factors: the deterministic stability of the Red Queen allele frequency cycles and the frequency at which pathogen fixation occurs, as this results in directional selection and the depletion of genetic variation in the host. Compared to purely coevolutionary models with constant host and pathogen population sizes, ecological and epidemiological feedbacks stabilize Red Queen cycles deterministically, but population fluctuations in the pathogen increase the rate of pathogen fixation, especially in epidemiological models. Taken together our results illustrate the importance of considering the ecological and epidemiological context in which coevolution occurs when examining the impact of Red Queen cycles on genetic variation.
Prolonged exposure to constant environmental conditions prompts nonrandom genetic variation
Authors: Catania Francesco , Hagen Rebecca , Vitali Valerio
Published: April 2020

Long-term environmental exposure under selection-free conditions has no consequences for fitness under the neo-Darwinian paradigm but it may provoke adaptive developmental buffering if environmental pressures foster directional organismal changes. To test this hypothesis, we revisited a Mutation Accumulation (MA) experiment where isogenic lines of the ciliateParameciumwere propagated for >40 sexual cycles (∼4 years) in a nearly selection-free and nutrient-rich environment. We find that these MA lines’ somatic genome is enriched with intervening segments of DNA (IESs), which are normally eliminated during germline-soma differentiation. Across independent replicate MA lines, an excess of these somatic IESs fall into a class of epigenetically controlled sequences, map to the same genomic locations, and preferentially disrupt loci that regulate nutrient metabolism. Although further work is needed to assess the phenotypic consequences of somatic IESs, these findings support a model where environmentally induced developmental variants may restore an adaptive fit between phenotype and environment. In this model, positive selection is surprisingly dispensable for adaptation.
Gene knockdown via electroporation of short hairpin RNAs in embryos of the marine hydroidHydractinia symbiolongicarpus
Authors: Quiroga-Artigas Gonzalo , Duscher Alexandrea , Lundquist Katelyn , Waletich Justin , Schnitzler Christine E.
Published: April 2020

Performing gene function analyses in a broad range of research organisms is crucial for understanding the biological functions of genes and their evolution. Recent studies have shown that short hairpin RNAs (shRNAs) can induce gene-specific knockdowns in two cnidarian species. We have developed a detailed, straightforward, and scalable method to deliver shRNAs into fertilized eggs of the hydrozoan cnidarianHydractinia symbiolongicarpusvia electroporation, yielding gene-targeted knockdowns that can be assessed throughout embryogenesis, larval settlement, and metamorphosis. Our electroporation protocol allows for the transfection of shRNAs into hundreds of fertilizedH.symbiolongicarpuseggs simultaneously with minimal embryo death and no long-term harmful consequences on the developing animals. We show RT-qPCR and detailed phenotypic evidence of our method successfully inducing significant knockdowns of an exogenous gene (eGFP) and an endogenous gene (Nanos2). We also provide visual confirmation of successful shRNA transfection inside embryos through electroporation. This is the first time that electroporation as a delivery system has been developed forHydractinia. Our detailed protocol for electroporation of shRNAs inH. symbiolongicarpusembryos constitutes an important experimental resource for the hydrozoan community while also serving as a successful model for the development of similar methods for interrogating gene function in other marine invertebrates.
IDseq – An Open Source Cloud-based Pipeline and Analysis Service for Metagenomic Pathogen Detection and Monitoring
Authors: Kalantar Katrina L. , Carvalho Tiago , de Bourcy Charles F.A. , Dimitrov Boris , Dingle Greg , Egger Rebecca , Han Julie , Holmes Olivia B. , Juan Yun-Fang , King Ryan , Kislyuk Andrey , Mariano Maria , Reynoso Lucia V. , Cruz David Rissato , Sheu Jonathan , Tang Jennifer , Wang James , Zhang Mark A. , Zhong Emily , Ahyong Vida , Lay Sreyngim , Chea Sophana , Bohl Jennifer A. , Manning Jessica E. , Tato Cristina M. , DeRisi Joseph L.
Published: April 2020

Background

Metagenomic next generation sequencing (mNGS) has enabled the rapid, unbiased detection and identification of microbes without pathogen-specific reagents, culturing, ora prioriknowledge of the microbial landscape. mNGS data analysis requires a series of computationally intensive processing steps to accurately determine the microbial composition of a sample. Existing mNGS data analysis tools typically require bioinformatics expertise and access to local server-class hardware resources. For many research laboratories, this presents an obstacle, especially in resource limited environments.

Findings

We present IDseq, an open source cloud-based metagenomics pipeline and service for global pathogen detection and monitoring (https://idseq.net). The IDseq Portal accepts raw mNGS data, performs host and quality filtration steps, then executes an assembly-based alignment pipeline which results in the assignment of reads and contigs to taxonomic categories. The taxonomic relative abundances are reported and visualized in an easy-to-use web application to facilitate data interpretation and hypothesis generation. Furthermore, IDseq supports environmental background model generation and automatic internal spike-in control recognition, providing statistics which are critical for data interpretation. IDseq was designed with the specific intent of detecting novel pathogens. Here, we benchmark novel virus detection capability using both synthetically evolved viral sequences, and real-world samples, including IDseq analysis of a nasopharyngeal swab sample acquired and processed locally in Cambodia from a tourist from Wuhan, China, infected with the recently emergent SARS-CoV-2.

Conclusion

The IDseq Portal reduces the barrier to entry for mNGS data analysis and enables bench scientists, clinicians, and bioinformaticians to gain insight from mNGS datasets for both known and novel pathogens.
Sampling requirements and approaches to detect ecosystem shifts
Authors: Bruel Rosalie , White Easton R.
Published: April 2020

Environmental monitoring is a key component of understanding and managing ecosystems. Given that most monitoring efforts are still expensive and time-consuming, it is essential that monitoring programs are designed to be efficient and effective. In many situations, the expensive part of monitoring is not sample collection, but instead sample processing, which leads to only a subset of the samples being processed. For example, sediment or ice cores can be quickly obtained in the field, but they require weeks or months of processing in a laboratory setting. Standard sub-sampling approaches often involve equally-spaced sampling. We use simulations to show how many samples, and which types of sampling approaches, are the most effective in detecting ecosystem change. We test these ideas with a case study of Cladocera community assemblage reconstructed from a sediment core. We demonstrate that standard approaches to sample processing are less efficient than an iterative approach. For our case study, using an optimal sampling approach would have resulted in savings of 195 person-hours—thousands of dollars in labor costs. We also show that, compared with these standard approaches, fewer samples are typically needed to achieve high statistical power. We explain how our approach can be applied to monitoring programs that rely on video records, eDNA, remote sensing, and other common tools that allow re-sampling.
Lithium directs embryonic stem cell differentiation versus hemogenic endothelium
Authors: Mnatsakanyan Hayk , Salmeron-Sanchez Manuel , Rico Patricia
Published: April 2020

The discovery that the definitive hematopoietic stem cells (HSCs) derive from specialized regions of the endothelium, known as thehemogenic endothelium(HE), shed a good deal of light on HSC embryonic developmental processes. This knowledge opened up new possibilities for the design of new strategies to obtain HSCsin vitrofrom pluripotent stem cells (PSCs). Previous advances in this field have shown that the Wnt/β-catenin signaling pathway plays a key role in PSC-derived HSC formation. In this work, we identified lithium, a GSK3 inhibitor, as an element capable of stabilizing β-catenin and inducing ESC differentiation in the mesoderm lineage and subsequently in the HE, highly consistent with the role of Wnt agonists on ESC differentiation. ESCs treated with 10 mM lithium express CD31+, Sca-1+, Nkx2-5+ and Runx1+ cells characteristic of HE cells. The ability of lithium-treated ESCs to further derive into HSCs was confirmed after defined maturation, resulting in rounded cell aggregates positive for fetal and mature HSCs markers, confirming the endothelial to hematopoietic transition. Our results represent a novel strategy for generating HSCin vitroas a multipotent source of stem cells for blood and muscle disease therapies.
Chromosome 1 trisomy overcomes the block of sphingolipid biosynthesis caused by aureobasidin A and confers pleiotropic effects on susceptibility to antifungals inCandida albicans
Authors: Xu Yi , Yang Feng
Published: April 2020

Sphingolipids are important membrane lipid components of eukaryotic cells. InCandida albicans, chromosome 1 trisomy not only overcame the block of sphingolipid biosynthesis caused by aureobasidin A, but also altered tolerance to three of the four major classes of antifungal drugs. Two haploinsufficient genes on chromosome 1,PDR16andIPT1, were associated with tolerance to aureobasidin A. This study illustrates an example of multi-drug tolerance caused by aneuploidy in the human fungal pathogenC. albicans.
Unravelling the effect of a potentiating anti-Factor H antibody on atypical hemolytic uremic syndrome associated factor H variants
Authors: Dekkers Gillian , Brouwer Mieke , Jeremiasse Jorn , Kamp Angela , Biggs Robyn M. , van Mierlo Gerard , Lauder Scott , Katti Suresh , Kuijpers Taco W. , Rispens Theo , Jongerius Ilse
Published: April 2020

The complement system plays an important role in our innate immune system. Complement activation results in clearance of pathogens, immune complex and apoptotic cells. The host is protected from complement-mediated damage by several complement regulators. Factor H (FH) is the most important fluid-phase regulator of the alternative pathway of the complement system. Heterozygous mutations in FH are associated with complement-related diseases such as atypical hemolytic uremic syndrome (aHUS) and age-related macular degeneration.

We recently described an agonistic anti-FH monoclonal antibody that can potentiate the regulatory function of FH. This antibody could serve as a potential new drug for aHUS patients and alternative to C5 blockade by Eculizumab. However, it is unclear whether this antibody can potentiate FH mutant variants in addition to wild type FH. Here, the functionality and potential of the agonistic antibody in the context of pathogenic aHUS-related FH mutant proteins was investigated. The binding affinity of recombinant WT FH, and the FH variants, W1183L, V1197A, R1210C, and G1194D to C3b was increased upon addition of the potentiating antibody and similarly, the decay accelerating activity of all mutants is increased. The potentiating anti-FH antibody is able to restore the surface regulatory function of most of the tested FH mutants to WT FH levels. In conclusion, our potentiating anti-FH is broadly active and able to enhance both WT FH function as well as most aHUS-associated FH variants tested in this study.
Phage and bacteria diversification through a prophage acquisition ratchet
Authors: Anthenelli Maxwell , Jasien Emily , Edwards Robert , Bailey Barbara , Felts Ben , Katira Parag , Nulton James , Salamon Peter , Rohwer Forest , Silveira Cynthia B. , Luque Antoni
Published: April 2020

Lysogeny is prevalent in the microbial-dense mammalian gut. This contrasts the classical view of lysogeny as a refuge used by phages under poor host growth conditions. Here we hypothesize that as carrying capacity increases, lysogens escape phage top-down control through superinfection exclusion, overcoming the canonical trade-off between competition and resistance. This hypothesis was tested by developing an ecological model that combined lytic and lysogenic communities and a diversification model that estimated the accumulation of prophages in bacterial genomes. The ecological model sampled phage-bacteria traits stochastically for communities ranging from 1 to 1000 phage-bacteria pairs, and it included a fraction of escaping lysogens proportional to the increase in carrying capacity. The diversification model introduced new prophages at each diversification step and estimated the distribution of prophages per bacteria using combinatorics. The ecological model recovered the range of abundances and sublinear relationship between phage and bacteria observed across eleven ecosystems. The diversification model predicted an increase in the number of prophages per genome as bacterial abundances increased, in agreement with the distribution of prophages on 833 genomes from marine and human-associated bacteria. The study of lysogeny presented here offers a framework to interpret viral and microbial abundances and reconciles the Kill-the-Winner and Piggyback-the-Winner paradigms in viral ecology.
Normative models of enhancer function
Authors: Grah Rok , Zoller Benjamin , Tkačik Gašper
Published: April 2020

In prokaryotes, thermodynamic models of gene regulation provide a highly quantitative mapping from promoter sequences to gene expression levels that is compatible within vivoandin vitrobio-physical measurements. Such concordance has not been achieved for models of enhancer function in eukaryotes. In equilibrium models, it is difficult to reconcile the reported short transcription factor (TF) residence times on the DNA with the high specificity of regulation. In non-equilibrium models, progress is difficult due to an explosion in the number of parameters. Here, we navigate this complexity by looking for minimal non-equilibrium enhancer models that yield desired regulatory phenotypes: low TF residence time, high specificity and tunable cooperativity. We find that a single extra parameter, interpretable as the “linking rate” by which bound TFs interact with Mediator components, enables our models to escape equilibrium bounds and access optimal regulatory phenotypes, while remaining consistent with the reported phenomenology and simple enough to be inferred from upcoming experiments. We further find that high specificity in non-equilibrium models is in a tradeoff with gene expression noise, predicting bursty dynamics — an experimentally-observed hallmark of eukaryotic transcription. By drastically reducing the vast parameter space to a much smaller subspace that optimally realizes biological function prior to inference from data, our normative approach holds promise for mathematical models in systems biology.
BSAseq: an interactive and integrated web-based workflow for identification of causal mutations in bulked F2 populations
Authors: Wang Liya , Lu Zhenyuan , Regulski Michael , Jiao Yinping , Chen Junping , Ware Doreen , Xin Zhanguo
Published: April 2020

With the advance of next-generation sequencing (NGS) technologies and reductions in the costs of these techniques, bulked segregant analysis (BSA) has become not only a powerful tool for mapping quantitative trait loci (QTL) but also a useful way to identify causal gene mutations underlying phenotypes of interest. However, due to the presence of background mutations and errors in sequencing, genotyping, and reference assembly, it is often difficult to distinguish true causal mutations from background mutations. In this study, we developed the BSAseq workflow, which includes an automated bioinformatics analysis pipeline with a probabilistic model for estimating the segregation region and an interactive Shiny web application for visualizing the results. We deeply sequenced a male sterile parental line (ms8) to capture the majority of background mutations in our bulked F2 data. We applied the workflow to 11 bulked F2 populations and identified the true causal mutation in each population. The workflow is intuitive and straightforward, facilitating its adoption by users without bioinformatics analysis skills. We anticipate that BSAseq will be broadly applicable to the identification of causal mutations for many phenotypes of interest.

Availability

BSAseq is freely available onhttps://www.sciapps.org/page/bsa

Contact

liya.wang@cshl.edu,ware@cshl.edu,zhanguo.xin@ars.usda.gov
Mortality and coexistence time both cause changes in predator-prey co-evolutionary dynamics
Authors: Scheuerl Thomas , Kaitala Veijo
Published: April 2020

All organisms are sensitive to the abiotic environment, and in multispecies communities a deteriorating environment increasing mortality and limiting coexistence time can cause ecological changes. When interaction within the community is changed this can impact co-evolutionary processes. Here we use a mathematical model to predict ecological and evolutionary changes in a simple predator-prey community under different mortality rates and times of coexistence, both controlled by various transfer volume and transfer interval. In the simulated bacteria-ciliate system, we find species densities to be surprisingly robust under changed mortality rates and times both species coexist, resulting in stable densities. Confirming a theoretical prediction however, the evolution of anti-predator defence in the bacteria and evolution of predation efficiency in ciliates relax under high mortalities and limited times both partners interact. In contrast, evolutionary trajectories intensify when global mortalities are low, and the predator-prey community has more time for close interaction. These results provide testable hypotheses for future studies of predator-prey systems and we hope this work will help to bridge the gap in our knowledge how ecological and evolutionary process together shape composition of microbial communities.
Unique Evolution of Antiviral Tetherin in Bats
Authors: Hayward Joshua A. , Tachedjian Mary , Johnson Adam , Irving Aaron T. , Gordon Tamsin B. , Cui Jie , Nicolas Alexis , Smith Ina , Boyd Victoria , Marsh Glenn A. , Baker Michelle L. , Wang Lin-Fa , Tachedjian Gilda
Published: April 2020

Bats are recognised as important reservoirs of viruses deadly to other mammals, including humans. These infections are typically non-pathogenic in bats raising questions about host response differences that might exist between bats and other mammals. Tetherin is a restriction factor which inhibits the release of a diverse range of viruses from host cells, including retroviruses, coronaviruses, filoviruses, and paramyxoviruses, some of which are deadly to humans and transmitted by bats. Here we characterise the tetherin genes from 27 species of bats, revealing that they have evolved under strong selective pressure, and that fruit bats and vesper bats express unique structural variants of the tetherin protein. Tetherin was widely and variably expressed across fruit bat tissue-types and upregulated in spleen tissue when stimulated with Toll-like receptor agonists. The expression of two computationally predicted splice isoforms of fruit bat tetherin was verified. We identified an additional third unique splice isoform which includes a C-terminal region that is not homologous to known mammalian tetherin variants but was functionally capable of restricting the release of filoviral virus-like particles. We also report that vesper bats possess and express at least five tetherin genes, including structural variants, a greater number than any other mammal reported to date. These findings support the hypothesis of differential antiviral gene evolution in bats relative to other mammals.
Clonal thermal preferences affect the strength of the temperature-size rule
Authors: Stuczyńska Anna , Sobczyk Mateusz , Fiałkowska Edyta , Kocerba-Soroka Wioleta , Pajdak-Stós Agnieszka , Starzycka Joanna , Walczyńska Aleksandra
Published: April 2020

Genetically similar organisms act as a powerful study system for the subtle differences in various aspects of life histories. The issue of trade-offs among traits is of special interest. We used six parthenogenetic rotifer clones previously exposed to different thermal laboratory conditions. Interclonal differences in female body size were examined in common garden conditions. We estimated the population growth rate and strength of the size-to-temperature response across four thermal regimes. We tested hypotheses on the existence of the relationships between (i) thermal acclimation and species body size, (ii) thermal specialization and fitness and (iii) thermal specialization and strength of the temperature-size rule. Positive verification of (i) would make it justifiable to refer the other investigated traits to thermal preference and, further, to thermal specialization. Addressing the issues (ii) and (iii) is our pioneering contribution to the question on the strength of size-to-temperature response as differing across life strategies. We hypothesized that this plastic response may be affected by the level of thermal specialization and that this pattern may be traded off with the temperature-dependent potential for population growth rate. Additionally, we investigated the differences in reproductive strategy (number of eggs laid by a female and female lifetime duration) in one temperature assumed optimal, which acts as an important supplement to the general clonal life strategy. We confirmed that the thermal acclimation of a clone is related to body size, with clones acclimated to higher temperatures being smaller. We also found that warm-acclimated clones have a narrower thermal range (= are more specialized), and that the temperature-size rule is stronger in rotifers acclimated to intermediate thermal conditions than in specialists. Our results contribute into the issue of trade-offs between generalist and specialist strategies, in the context of plastic body size respone to different temperatures.
Delay-dependent cholinergic modulation of visual short-term memory in rhesus macaques
Authors: Knakker Balázs , Oláh Vilmos , Trunk Attila , Lendvai Balázs , Lévay György , Hernádi István
Published: April 2020

Cholinergic neuromodulation is known to play a key role in visual working memory (VWM) – keeping relevant stimulus representations available for cognitive processes for short time periods up to a few minutes. Despite the growing body of evidence on how the neural and cognitive mechanisms of VWM dynamically change over retention time, there is mixed evidence available on cholinergic effects as a function of VWM delay period in non-human primates. Using the delayed matching to sample VWM task in rhesus macaques (N=6), we aimed to characterize VWM maintenance in terms of performance changes as a function of delay duration (across a wide range of delays from 1 to 76 s). Then, we studied how cholinergic neuromodulation influences VWM maintenance using the muscarinic receptor antagonist scopolamine administered alone as transient amnestic treatment, and in combination with two doses of the acetylcholinesterase inhibitor donepezil, a widely used Alzheimer’s medication probing for the reversal of scopolamine-induced impairments. Results indicate that scopolamine-induced impairments of VWM maintenance are delay-dependent and specifically affect the 15-33 s time range, suggesting that scopolamine worsens the normal decay of VWM with the passage of time. Donepezil partially rescued the observed scopolamine-induced impairments of VWM performance. These results provide strong behavioral evidence for the role of increased cholinergic tone and muscarinic neuromodulation in the maintenance of VWM beyond a few seconds, in line with our current knowledge on the role of muscarinic acetylcholine receptors in sustained neural activity during VWM delay periods.
Topographic Connectivity in a Duration Selective Cortico-Cerebellar Network
Authors: Protopapa Foteini , Hayashi Masamichi J. , Kanai Ryota , Bueti Domenica
Published: April 2020

How does the human brain represent millisecond unit of time? A recent neuroimaging study revealed the existence in the human premotor cortex of a topographic representation of time i.e., neuronal units selectively responsive to specific durations and topographically organized on the cortical surface. By using high resolution functional Magnetic Resonance Images here, we go futher this previous work, showing duration preferences across a wide network of cortical and subcortical brain areas: from cerebellum to primary visual, parietal, premotor and prefrontal cortices. Most importantly, we identify the functional connectivity structure between these different brain areas and their duration selective neural units. The results highlight the role of the cerebellum as the network hub and that of medial premotor cortex as the final stage of duration recognition. Interstingly, when a specific duration is presented, only the communication between the units selective to that duration become particularly “active”. These findings identify duration tuning and topographic connectivity as possible mechanisms underlying our capacity of telling time.
Neural harmonics of syntactic structure
Authors: Tavano Alessandro , Blohm Stefan , Knoop Christine A. , Muralikrishnan R , Fink Lauren , Scharinger Mathias , Wagner Valentin , Thiele Dominik , Ghitza Oded , Ding Nai , Menninghaus Winfried , Poeppel David
Published: April 2020

Can neural rhythms reflect purely internal syntactic processes in multi-word constructions? To test this controversial conjecture - relevant to language in particular and cognition more broadly - we recorded electroencephalographic and behavioural data as participants listened to isochronously presented sentences of varying in syntactic complexity. Each trial comprised ten concatenated sentences and was either fully grammatical (regular) or rendered ungrammatical via randomly distributed word order violations. We found that attending the regular repetition of abstract syntactic categories (phrases and sentences) generates neural rhythms whose harmonics are mathematically independent of word rate. This permits to clearly separate endogenous syntactic rhythms from exogenous speech rhythms. We demonstrate that endogenous but not exogenous rhythms predict participants’ grammaticality judgements, and allow for the neural decoding of regular vs. irregular trials. Neural harmonic series constitute a new form of behaviourally relevant evidence for syntactic competence.
SweetOrigins: Extracting Evolutionary Information from Glycans
Authors: Bojar Daniel , Powers Rani K. , Camacho Diogo M. , Collins James J.
Published: April 2020

Glycans, the most diverse biopolymer and crucial for many biological processes, are shaped by evolutionary pressures stemming in particular from host-pathogen interactions. While this positions glycans as being essential for understanding and targeting host-pathogen interactions, their considerable diversity and a lack of methods has hitherto stymied progress in leveraging their predictive potential. Here, we utilize a curated dataset of 12,674 glycans from 1,726 species to develop and apply machine learning methods to extract evolutionary information from glycans. Our deep learning-based language model SweetOrigins provides evolution-informed glycan representations that we utilize to discover and investigate motifs used for molecular mimicry-mediated immune evasion by commensals and pathogens. Novel glycan alignment methods enable us to identify and contextualize virulence-determining motifs in the capsular polysaccharide ofStaphylococcus aureusandAcinetobacter baumannii. Further, we show that glycan-based phylogenetic trees contain most of the information present in traditional 16S rRNA-based phylogenies and improve on the differentiation of genetically closely related but phenotypically divergent species, such asBacillus cereusandBacillus anthracis. Leveraging the evolutionary information inherent in glycans with machine learning methodology is poised to provide further – critically needed – insights into host-pathogen interactions, sequence-to-function relationships, and the major influence of glycans on phenotypic plasticity.
Whole-genome analysis of noncoding genetic variations identifies multigranular regulatory element perturbations associated with Hirschsprung disease
Authors: Fu Alexander Xi , Lui Kathy Nga-Chu , Tang Clara Sze-Man , Ng Ray Kit , Lai Frank Pui-Ling , Lau Sin-Ting , Li Zhixin , Gracia-Barcelo Maria-Mercè , Sham Pak-Chung , Tam Paul Kwong-Hang , Ngan Elly Sau-Wai , Yip Kevin Y.
Published: April 2020

It is widely recognized that the missing heritability of many human diseases is partially due to noncoding genetic variants, but there are multiple challenges that hinder the identification of functional disease-associated noncoding variants. The number of noncoding variants can be many times of coding variants; many of them are not functional but in linkage disequilibrium with the functional ones; different variants can have epistatic effects; different variants can affect the same genes or pathways in different individuals, and some variants are related to each other not by affecting the same gene but by affecting the binding of the same upstream regulator. To overcome these difficulties, we propose a novel analysis framework that considers convergent impacts of different genetic variants on protein binding, which provides multi-granular information about disease-associated perturbations of regulatory elements, genes, and pathways. Applying it to our whole-genome sequencing data of 918 short-segment Hirschsprung disease patients and matched controls, we identify various novel genes not detected by standard single-variant and region-based tests, functionally centering on neural crest migration and development. Our framework also identifies upstream regulators whose binding is influenced by the noncoding variants. Using human neural crest cells, we confirm cell-stage-specific regulatory roles three top novel regulatory elements on our list, respectively in theRET, RASGEF1AandPIK3C2Bloci. In thePIK3C2Bregulatory element, we further show that a noncoding variant found only in the affects the binding of the gliogenesis regulator NFIA, with a corresponding down-regulation of multiple genes in the same topologically associating domain.
Identification of Stem Cells from Large Cell Populations with Topological Scoring
Authors: Sardiu Mihaela E. , Andrew Box C. , Haug Jeff , Washburn Michael P.
Published: April 2020

Machine learning and topological analysis methods are becoming increasingly used on various large-scale omics datasets. Modern high dimensional flow cytometry data sets share many features with other omics datasets like genomics and proteomics. For example, genomics or proteomics datasets can be sparse and have high dimensionality, and flow cytometry datasets can also share these features. This makes flow cytometry data potentially a suitable candidate for employing machine learning and topological scoring strategies, for example, to gain novel insights into patterns within the data. We have previously developed the Topological Score (TopS) and implemented it for the analysis of quantitative protein interaction network datasets. Here we show that the TopS approach for large scale data analysis is applicable to the analysis of a previously described flow cytometry sorted human hematopoietic stem cell dataset. We demonstrate that TopS is capable of effectively sorting this dataset into cell populations and identify rare cell populations. We demonstrate the utility of TopS when coupled with multiple approaches including topological data analysis, X-shift clustering, and t-Distributed Stochastic Neighbor Embedding (t-SNE). Our results suggest that TopS could be effectively used to analyze large scale flow cytometry datasets to find rare cell populations.
Identifying stem cell numbers and functional heterogeneities during post-embryonic organ growth
Authors: Danciu Diana-Patricia , Stolper Julian , Centanin Lázaro , Marciniak-Czochra Anna
Published: April 2020

Uncovering the number of stem cells necessary to grow an organ has been challenging in most vertebrate systems. Here, we have developed a mathematical model that we use to characterise stem cells in the fish gill, an organ that displays non-exhaustive growth. Our work employs a Markov model, first stochastically simulated via an adapted Gillespie algorithm, and further improved by using probability theory. The stochastic algorithm produces a simulated data set for comparison with experimental data by inspecting quantifiable properties, while the analytical approach skips the step ofin silicodata generation and goes directly to the quantification, being more abstract and very efficient. By applying the model to a large clonal experimental dataset, we report that a reduced number of stem cells are responsible for growing and maintaining the fish gill. The model also highlights a functional heterogeneity among the stem cells involved, where activation and quiescence phases determine their relative growth contribution. Overall, our work presents an easy-to-apply algorithm to infer the number of stem cells functionally required in a life-long growing system.