bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antigenic assessment of the H3N2 component of the 2019-2020 Northern Hemisphere influenza vaccine
Authors: Gouma Sigrid , Weirick Madison , Hensley Scott E. 
Published: January 2020

AbstractThe 2019-2020 Northern Hemisphere influenza vaccine includes antigens from 3c3.A H3N2 viruses; however, over half of circulating H3N2 viruses belong to subclade 3c2.A1b. Here, we analyzed antibody responses elicited by the egg-adapted 3c3.A H3N2 vaccine strain in ferrets and humans. We found that this vaccine strain elicits antibodies that have reduced reactivity to a wild-type 3c3.A strain and very limited reactivity to 3c2.A strains, including the currently circulating 3c2.A1b strain.
Antimicrobial treatment impacts resistance in off-target populations of a nosocomial bacterial pathogen: a case-control study
Authors: Kinnear Clare L. , Hansen Elsa , Forstchen Meghan , Read Andrew F. , Woods Robert J. 
Published: January 2020

AbstractThe antimicrobial resistance crisis has persisted despite broad attempts at intervention. Detailed studies of the population dynamics that lead to resistance could identify additional intervention points. An important driver of resistance in the most concerning antibiotic resistant pathogens can be selection imposed on bacterial populations that are not the intended target of antimicrobial therapy. Here we focus on the important nosocomial pathogen Enterococcus faecium in a hospital system where resistance to daptomycin is evolving despite standard interventions. We hypothesized that the intravenous use of daptomycin generates off-target selection for resistance in transmissible gastrointestinal (carriage) populations of E. faecium. We performed a case-control study in which the daptomycin resistance of E. faecium isolated from rectal swabs from daptomycin-exposed patients was compared to a control group of patients exposed to linezolid, a drug with similar indications. In the daptomycin-exposed group, daptomycin resistance of E. faecium from the off-target population was on average 50% higher than resistance in the control group (n=428 independent E. faecium clones from 22 patients). There was also greater phenotypic diversity in daptomycin resistance within daptomycin-exposed patients. Multiple samples over time were available from a subset of patients, and these demonstrate wide variability in temporal dynamics, from long-term maintenance of resistance to rapid return to sensitivity after daptomycin treatment stopped. Our results demonstrate that off-target gastrointestinal populations rapidly respond to intravenous antibiotic exposure. Gastrointestinal populations are the source for faecal transmission and so can be the driver for hospital-wide population level increases in resistance. Focusing on the off-target evolutionary dynamics may offer novel avenues to slow the spread of antibiotic resistance.
An empirical attack tolerance test alters the structure and species richness of plant-pollinator networks
Authors: Biella Paolo , Akter Asma , Ollerton Jeff , Nielsen Anders , Klečka Jan 
Published: January 2020

AbstractEcological network theory hypothesizes a link between structure and stability, but this has mainly been investigatedin-silico. In an experimental manipulation, we sequentially removed four generalist plants from real plant-pollinator networks and explored the effects on, and drivers of, species and interaction extinctions, network structure and interaction rewiring. Our results indicate that cumulative species and interaction extinctions increased faster with generalist plant loss than what was expected by co-extinction models, which predicted the survival or extinction of many species incorrectly. In addition, network nestedness decreased, modularity increased, and opportunistic random interactions and structural unpredictability emerged, which are all indicators of network instability and fragility. Conversely, interaction reorganization (rewiring) was high, asymmetries between network levels emerged as plants increased their centrality. From the experimental manipulations of real networks, our study shows how plant-pollinator network structure has low stability and changes towards a more fragile state when generalist plants are lost.
Outer membrane permeabilization by the membrane attack complex sensitizes Gram-negative bacteria to antimicrobial proteins in serum and phagocytes
Authors: Heesterbeek Dani A. C. , Muts Remy M. , van Hensbergen Vincent P. , de Saint Aulaire Pieter , Wennekes Tom , Bardoel Bart W. , van Sorge Nina M. , Rooijakkers Suzan H.M. 
Published: January 2020

AbstractInfections with Gram-negative bacteria form an increasing risk for human health, which is mainly due to the increase in antibiotic resistance. The cell envelope of Gram-negative bacteria consists of an inner membrane, a peptidoglycan layer and an outer membrane, which forms an impermeable barrier to many antibiotics and antimicrobial proteins. The complement system is an important factor of the human immune system that can efficiently kill Gram-negative bacteria via the formation of large pores in the bacterial outer membrane, called Membrane Attack Complexes (MACs). To better understand how these MAC pores damage the complex cell envelope of Gram-negative bacteria, we recently developed a fluorescent reporter system to study membrane damage inE. coli. Here, we used a similar experimental setup in combination with flow cytometry, confocal microscopy and conventional plating assays to elucidate how different components of the immune system act synergistically to effectively clear invading bacteria. We demonstrate how MAC-dependent outer membrane damage enhances the susceptibility ofE. colito further degradation of the cell envelope by lysozyme, leading to drastic changes in the morphology of these bacteria. Furthermore, we elucidate that the MAC enhances the susceptibility ofE. colito phospholipases, and to degradation and killing inside human neutrophils. Altogether, this study provides a detailed overview on how different players of the human immune system work closely together to degrade the complex cell envelope of Gram-negative bacteria. This knowledge may facilitate the development of new antimicrobials that could stimulate, or work synergistically with the immune system.
Copy number variants outperform SNPs to reveal genotype-temperature association in a marine species
Authors: Dorant Yann , Cayuela Hugo , Wellband Kyle , Laporte Martin , Rougemont Quentin , Mérot Claire , Normandeau Eric , Rochette Rémy , Bernatchez Louis 
Published: January 2020

AbstractCopy number variants (CNVs) are a major component of genotypic and phenotypic variation in genomes. To date, our knowledge of genotypic variation and evolution has largely been acquired by means of single nucleotide polymorphism (SNPs) analyses. Until recently, the adaptive role of structural variants (SVs) and particularly that of CNVs has been overlooked in wild populations, partly due to their challenging identification. Here, we document the usefulness of Rapture, a derived reduced-representation shotgun sequencing approach, to detect and investigate copy number variants (CNVs) alongside SNPs in American lobster (Homarus americanus) populations. We conducted a comparative study to examine the potential role of SNPs and CNVs in local adaptation by sequencing 1,141 lobsters from 21 sampling sites within the southern Gulf of St. Lawrence, which experiences the highest yearly thermal variance of the Canadian marine coastal waters. Our results demonstrated that CNVs accounts for higher genetic differentiation than SNP markers. Contrary to SNPs, for which no significant genetic-environment association was found, 48 CNV candidates were significantly associated with the annual variance of sea surface temperature, leading to the genetic clustering of sampling locations despite their geographic separation. Altogether, we provide a strong empirical case that CNVs putatively contribute to local adaptation in marine species and unveil stronger spatial signal of population structure than SNPs. Our study provides the means to study CNVs in non-model species and highlights the importance of considering structural variants alongside SNPs to enhance our understanding of ecological and evolutionary processes shaping adaptive population structure.
Implications of genetic heterogeneity for plant translocation during ecological restoration
Authors: Crow Taylor M. , Buerkle C. Alex , Runcie Daniel E. , Hufford Kristina M. 
Published: January 2020

AbstractEcological restoration often requires translocating plant material from distant sites. Yet published guidelines for seed transfer are available for very few species. Accurately predicting how plants will perform when transferred requires multi-year and multi-environment field trials and comprehensive follow-up work. In this study, we analyzed the genetic structure of an important shrub used in ecological restorations in the Southern Rocky Mountains called alder-leaf mountain mahogany (Cercocarpus montanus). We sequenced DNA from 1440 plants in 48 populations across a broad geographic range. We found that genetic heterogeneity among populations reflected the complex climate and topography across which the species is distributed. We identified several temperature and precipitation variables that were useful predictors of genetic differentiation and can be used to generate seed transfer recommendations. These results will be valuable for defining management and restoration practices for mountain mahogany and other widespread montane plant species.
Serine Phosphorylation Regulates the P-type Potassium pump KdpFABC
Authors: Sweet Marie E. , Dubey Vikas , Zhang Xihui , Erdjument-Bromage Hediye , Neubert Thomas A. , Pedersen Bjørn P. , Khandelia Himanshu , Stokes David L. 
Published: January 2020

AbstractKdpFABC is an ATP-dependent K+pump that ensures bacterial survival in K+-deficient environments. Whereas transcriptional activation of kdpFABC expression is well studied, a mechanism for down regulation when K+levels are restored has not been described. Here we show that KdpFABC is inhibited when cells return to a K+-rich environment. The mechanism of inhibition involves phosphorylation of Ser162 on KdpB, which can be reversed in vitro by treatment with serine phosphatase. Mutating Ser162 to Alanine produces constitutive activity, whereas the phosphomimetic Ser162Asp mutation inactivates the pump. Analyses of the transport cycle show that serine phosphorylation uncouples the pump and blocks the cycle after formation of the catalytic aspartyl phosphate intermediate (E1∼P). Molecular dynamics simulations show that serine phosphorylation has allosteric effects that potentially explain the uncoupling. This regulatory mechanism, unique amongst P-type pumps, furthers our understanding of how bacteria control potassium homeostasis to maintain cell volume and osmotic potential.
StoHi-C: Using t-Distributed Stochastic Neighbor Embedding (t-SNE) to predict 3D genome structure from Hi-C Data
Authors: MacKay Kimberly , Kusalik Anthony 
Published: January 2020

ABSTRACTIn order to comprehensively understand the structure-function relationship of the genome, 3D genome structures must first be predicted from biological data (like Hi-C) using computational tools. Many of these existing tools rely partially or completely on multi-dimensional scaling (MDS) to embed predicted structures in 3D space. MDS is known to have inherent problems when applied to high-dimensional datasets like Hi-C. Alternatively, t-Distributed Stochastic Neighbor Embedding (t-SNE) is able to overcome these problems but has not been applied to predict 3D genome structures. In this manuscript, we present a new workflow called StoHi-C (pronounced "stoic") that uses t-SNE to predict 3D genome structure from Hi-C data. StoHi-C was used to predict 3D genome structures for multiple, independent existing fission yeast Hi-C datasets. Overall, StoHi-C was able to generate 3D genome structures that more clearly exhibit the established principles of fission yeast 3D genomic organization.
Encoding Innately Recognized Odors via a Generalized Population Code
Authors: Qiu Qiang , Wu Yunming , Ma Limei , Yu C. Ron 
Published: January 2020

SummaryOdors carrying intrinsic values often trigger instinctive aversive or attractive responses. It is not known how innate valence is encoded. An intuitive model suggests that the information is conveyed through specific channels in hardwired circuits along the olfactory pathway, insulated from influences of other odors, to trigger innate responses. Here we show that in mice, mixing innately aversive or attractive odors with a neutral odor, and surprisingly, mixing two odors with the same valence, abolish the innate behavioral responses. Recordings from the olfactory bulb indicate that odors are not masked at the level of peripheral activation and glomeruli independently encode components in the mixture. In contrast, crosstalk among the mitral/tufted cells changes their patterns of activity such that those elicited by the mixtures can no longer be linearly decoded as separate components. The changes in behavioral and mitral/tufted cell responses are associated with reduced activation of brain areas linked to odor preferences. Thus, crosstalk among odor channels at the earliest processing stage in the olfactory pathway leads to re-coding of odor identity to abolish valence associated with the odors. These results are inconsistent with insulated labeled lines and support a model of a common mechanism of odor recognition for both innate and learned valence associations.
Quantitativein vivoanalyses reveal a complex pharmacogenomic landscape in lung adenocarcinoma
Authors: Li Chuan , Lin Wen-Yang , Rizvi Hira , Cai Hongchen , McFarland Christopher D. , Rogers Zoë N. , Yousefi Maryam , Winters Ian P. , Rudin Charles M. , Petrov Dmitri A. , Winslow Monte M. 
Published: January 2020

Abstract:The lack of knowledge about the relationship between tumor genotypes and therapeutic responses remains one of the most important gaps in enabling the effective use of cancer therapies. Here, we couple a multiplexed and quantitative platform with robust statistical methods to enable pharmacogenomic mapping of lung cancer treatment responsesin vivo. We uncover a surprisingly complex map of genotype-specific therapeutic responses, with over 20% of possible interactions showing significant resistance or sensitivity. We validate one of these interactions - the resistance of Keap1 mutant tumors to platinum therapy - using a large patient response dataset. Our results highlight the importance of understanding the genetic determinants of treatment responses in the development of precision therapies and define a strategy to identify such determinants.
Acoustic Ejection Mass Spectrometry for High-Throughput Analysis
Authors: Zhang Hui , Liu Chang , Hua Wenyi , Ghislain Lucien P. , Liu Jianhua , Aschenbrenner Lisa , Noell Stephen , Dirico Kenneth , Lanyon Lorraine F. , Steppan Claire M. , Arnold Don W. , Covey Thomas R. , Datwani Sammy S. , Troutman Matthew D. 
Published: January 2020

AbstractWe describe a mass spectrometry (MS) analytical platform resulting from the novel integration of acoustic droplet ejection (ADE) technology, an open-port interface (OPI), and electrospray ionization (ESI) MS that creates a transformative system enabling high-speed sampling and label-free analysis. The ADE technology delivers nanoliter droplets in a touchless manner with high speed, precision and accuracy; subsequent sample dilution within the OPI, in concert with the capabilities of modern ESI-MS, eliminates the laborious sample preparation and method development required in current approaches. This platform is applied to a variety of experiments, including high-throughput (HT) pharmacology screening, label-free in situ enzyme kinetics, in vitro and in vivo adsorption, distribution, metabolism, elimination, pharmacokinetic (PK) and biomarker analysis, and HT parallel medicinal chemistry.One Sentence SummaryADE-OPI-MS is a transformational analytical platform that increases mass spectrometry utility via sub-second speed and non-contact sampling.
Incidence and Risk Factors of Second Primary Cancer after the Initial Primary Human Papillomavirus Related Neoplasms
Authors: Shen Jiayi , Zhou Huaqiang , Liu Jiaqing , Zhang Zhonghan , Fang Wenfeng , Yang Yunpeng , Hong Shaodong , Ma Yuxiang , Zhou Ting , Zhang Yaxiong , Zhao Hongyun , Huang Yan , Zhang Li 
Published: January 2020

AbstractBackgroundHuman papillomavirus (HPV)-related cancers are nowadays associated with better survival. However, comprehensive studies in second primary cancer (SPC) after the initial primary HPV-related cancer still remain warranted. Therefore, this study was designed to analyse the incidence and risk factors of SPC after HPV-related cancer.MethodsWe identified 86,790 patients diagnosed with initial primary HPV-related cancer between 1973 and 2010 in the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) 9 database. Standardized incidence ratio (SIR) and cumulative incidence were calculated to assess the risk of SPC after HPV-related cancer. Subdistribution hazard regression was also conducted to figure out the risk factors.ResultsSIR of SPC after HPV-related cancer was 1.60 (95% confidence interval [CI] 1.55-1.65) for male and 1.25 (95% CI 1.22-1.28) for female. SIR of second primary HPV-related cancer (7.39 [95% CI 6.26-8.68] male and 4.35 [95% CI 4.04-4.67] female) was obviously higher than that of second primary HPV-unrelated cancer (1.54 [95% CI 1.49-1.60] male and 1.16 [95% CI 1.13-1.19] female). 5-year cumulative incidence of SPC was 7.22% (95% CI 6.89%-7.55%) for male and 3.72% (95% CI 3.58%-3.88%) for female. Risk factors of SPC included being married and initial primary cancer (IPC) diagnosed at earlier stage for both gender, and IPC diagnosed at older age as well as surgery performed for female only.ConclusionPatients diagnosed with HPV-related cancer are more likely to develop another primary cancer, as compared with the age-specific reference population. Patients with the risk factors claimed in this study are suggested to screen for SPC regularly. According to the elevation of SIR of HPV-related SPC, it is suggested that part of the HPV-related SPC cases may be caused by the persistent infection of HPV.
Genomic determination of relative risks for Clostridioides difficile infection from asymptomatic carriage in ICU patients
Authors: Worley Jay , Delaney Mary L. , Cummins Christopher K. , DuBois Andrea , Klompas Michael , Bry Lynn 
Published: January 2020

AbstractBackgroundClostridioides difficile infections (CDIs) are among the most prevalent hospital-associated infections (HAIs), particularly for intensive care unit (ICU) patients. The risks for developing active CDI from asymptomatic carriage of C. difficile are not well understood.MethodsWe identified asymptomatic C. difficile carriage among 1897 ICU patients, using rectal swabs from an existing ICU vancomycin-resistant Enterococci (VRE) surveillance program. C. difficile isolates from VRE swabs, and from C. difficile-positive stool samples, were genome sequenced to assess clonal relationships among isolates from asymptomatic carriers and CDI patients. Integrated genomic and epidemiologic analyses identified multiple cases of asymptomatic carriers who developed CDI, and of asymptomatic transmission of C. difficile to naïve patients.ResultsGenomic analyses identified diverse strains in infected patients and asymptomatic carriers. 7.4% of ICU patients asymptomatically carried C. difficile. 69% of isolates carried an intact toxin locus. In contrast, 96% of C. difficile stool isolates were toxigenic. CDI rates in asymptomatic carriers of toxigenic strains were 5.3%, versus 0.57% in non-carriers. The relative risk for CDI with asymptomatic carriage of a toxigenic strain was 9.32 (95% CI=3.25-26.7). Genomic identification of clonal clusters supported epidemiologic analyses for asymptomatic transmission events, with spatial-temporal overlaps identified in 13 of 28 cases.ConclusionsOur studies provide the first genomically-confirmed assessments of CDI relative risk from asymptomatic carriage of toxigenic strains and highlight the complex dynamics of asymptomatic transmission in ICUs. C. difficile screening can be implemented within existing HAI surveillance programs and, with isolation of asymptomatic carriers, has potential to reduce these risks.SummaryRelative risks for C. difficile infections rise to 9.32 in asymptomatic ICU patients carrying toxigenic strains. Integrated genomic and epidemiologic analyses illustrate functional use of C. difficile genomic data to identify asymptomatic transmission events and assist in outbreak investigations.
Spatio-temporal Proteomic Analysis of Stress Granule Disassembly Using APEX Reveals Regulation by SUMOylation and Links to ALS Pathogenesis
Authors: Marmor-Kollet Hagai , Siany Aviad , Kedersha Nancy , Knafo Naama , Rivkin Natalia , Danino Yehuda M. , Olender Tsviya , Cohen Nir , Moens Thomas , Higginbottom Adrian , Knock John Cooper- , Eitan Chen , Cohen Beata Toth , Van Den Bosch Ludo , Anderson Paul , Ivanov Pavel , Geiger Tamar , Hornstein Eran 
Published: January 2020

SummaryCytoplasmic stress granules (SG) form in response to a variety of cellular stresses by phase-separation of proteins associated with non-translating mRNAs. SG provide insight into the biology of neurodegeneration, including amyotrophic lateral sclerosis (ALS) because they approximate some of the molecular conditions for nucleation of insoluble aggregates in neuropathological inclusions. Whereas much has been learned about SG formation, a major gap remains in understanding the compositional changes SG undergo during normal disassembly and under disease conditions. Here, we address this gap by proteomic dissection of SG temporal disassembly sequence, using multi-bait APEX proximity-proteomics. We discover 109 novel SG-proteins and characterize at proteomic resolution two biophysically distinct SG substructures. We further demonstrate that dozens of additional proteins are recruited to SG specifically during disassembly, indicating that it is a highly regulated process. The involved proteins link SG disassembly, to mitochondrial biology and the cytoskeleton. Parallel analysis with C9ORF72-associated dipeptides, which are found in patients with ALS and frontotemporal dementia, demonstrated compositional changes in SG during the course of disassembly and focused our attention on the roles SUMOylation in SG disassembly. We demonstrate that broad SUMOylation of SG-proteins is required for SG disassembly and is impaired by C9ORF72-associated dipeptides, representing an unexplored potential molecular mechanism of neurodegeneration. Altogether, out study fundamentally increases the knowledge about SG composition in human cells by dissecting the SG spatio-temporal proteomic landscape, provides an in-depth resource for future work on SG function and reveals basic and disease-relevant mechanisms of SG disassembly.HighlightsMulti bait APEX proximity labelling reveals 109 novel SG proteins and two distinct SG substructures.Proteomic dissection of SG temporal disassembly under basal conditions and with a model of neurodegeneration.Disassembly-engaged proteins (DEPs) include SUMO ligases that are recruited during normal disassembly and dysregulated in ALS-like conditions.Pervasive SG protein SUMOylation during SG disassembly is impaired by ALS-like conditions.Abstract Figure