bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disruption of the gut microbiota attenuates epithelial ovarian cancer sensitivity to cisplatin therapy
Authors: Chambers Laura M. , Esakov Emily L. , Braley Chad , Trestan Lexie , Alali Zahraa , Bayik Defne , Lathia Justin D. , Sangwan Naseer , Bazeley Peter , Joehlin-Price Amy S. , Dwidar Mohammed , Hajjar Adeline , Ahern Philip P. , Claesen Jan , Rose Peter , Vargas Roberto , Brown J. Mark , Michener Chad , Reizes Ofer 
Published: June 2020

AbstractEpithelial Ovarian Cancer (EOC) is the leading cause of gynecologic cancer death. Despite many patients achieving remission with first-line therapy, up to 80% of patients will recur and require additional treatment. Retrospective clinical analysis of OC patients indicates antibiotic use during chemotherapy treatment is associated with poor overall survival. We assessed whether antibiotic (ABX) therapy would impact growth of EOC and sensitivity to cisplatin in murine models. Immune competent or compromised mice were given control or ABX containing water (metronidazole, ampicillin, vancomycin, and neomycin) before being intraperitoneally injected with murine EOC cells. Stool was collected to confirm microbiome disruption and tumors were monitored, and cisplatin therapy was administered weekly until endpoint. EOC tumor-bearing mice demonstrate accelerated tumor growth and resistance to cisplatin therapy in ABX treated compared with nonABX treatment. Stool analysis indicated most gut microbial species were disrupted by ABX treatment except for ABX resistant bacteria. To test for role of the gut microbiome, cecal microbiome transplants (CMTs) of microbiota derived from ABX or nonABX treated mice were used torecolonize the microbiome of ABX treated mice. nonABX cecal microbiome was sufficient to ameliorate the chemoresistance and survival of ABX treated mice indicative of a gut derived tumor suppressor. Mechanistically, tumors from ABX treated compared to nonABX treated mice contained a high frequency of cancer stem cells that were augmented by cisplatin. These studies indicate an intact microbiome provides a gut derived tumor suppressor and maintains chemosensitivity that is disrupted by ABX treatment.SignificancePlatinum resistance is associated with poor prognosis and reduced therapeutic options for ovarian cancer patients. We identifed a tumor suppressive role of the gut microbiome that is disrupted upon antibiotic therapy.
TranSPHIRE: Automated and feedback-optimized on-the-fly processing for cryo-EM
Authors: Stabrin Markus , Schoenfeld Fabian , Wagner Thorsten , Pospich Sabrina , Gatsogiannis Christos , Raunser Stefan 
Published: June 2020

AbstractSingle particle electron cryomicroscopy (cryo-EM) requires full automation to allow high-throughput structure determination which is especially important for drug discovery research. Although several software packages exist where parts of the cryo-EM pipeline are automated, a complete solution that offers reliable, quality-optimized on-the-fly processing, resulting in a high-resolution three-dimensional reconstruction does not exist. Here we present TranSPHIRE: A software package for fully automated processing of cryo-EM data sets during data acquisition. TranSPHIRE transfers data from the microscope, automatically applies the common pre-processing steps, picks particles, performs 2D clustering, and 3D refinement parallel to image recording. Importantly, TranSPHIRE introduces a machine learning-based feedback loop to re-train its internally used picking model to adapt to any given data set live during processing. This elegant approach enables TranSPHIRE to process data more effectively, producing high-quality particle stacks. TranSPHIRE collects, and displays all microscope settings and metrics generated by its individual tools, in order to allow users to quickly evaluate data during acquisition. TranSPHIRE can run on a single work station and also includes the automated processing of filaments.
Spatiotemporal expression of regulatory kinases directs the transition from mitosis to cellular morphogenesis
Authors: Yang Shuo , McAdow Jennifer , Du Yingqiu , Trigg Jennifer , Taghert Paul H. , Johnson Aaron N. 
Published: June 2020

AbstractEmbryogenesis depends on a tightly regulated balance between mitosis, differentiation, and morphogenesis. Understanding how the embryo uses a relatively small number of proteins to transition between growth and morphogenesis is a central question of developmental biology, but the mechanisms controlling mitosis and differentiation are considered to be fundamentally distinct. Here we show the mitotic kinase Polo, which regulates all steps of mitosis [1–3], also directs cellular morphogenesis after cell cycle exit. In mitotic cells, the Aurora kinases activate Polo to control a cytoskeletal regulatory module that directs cytokinesis [4–6]. We show that in the post-mitotic mesoderm, the control of Polo activity transitions from the Aurora kinases to the uncharacterized kinase Back Seat Driver (Bsd), where Bsd and Polo cooperate to regulate muscle morphogenesis. Polo and its effectors therefore direct mitosis and cellular morphogenesis, but the transition from growth to morphogenesis is determined by the spatiotemporal expression of upstream activating kinases.
Aerobic metabolism inVibrio choleraeis required for population expansion during infection
Authors: Van Alst Andrew J. , DiRita Victor J. 
Published: June 2020

AbstractVibrio choleraeis a bacterial pathogen that replicates to high cell density in the small intestine of human hosts leading to the diarrheal disease cholera. During infection,V. choleraesenses and responds to environmental signals that govern cellular responses. Spatial localization ofV. choleraewithin the intestine affects nutrient availability and therefore the metabolic pathways required for the replicative success of the pathogen. Metabolic processes used byV. choleraeto reach such high cell densities are not fully known. Here we seek to better define the metabolic traits that contribute to high levels ofV. choleraeduring infection by investigating mutant strains in key carbohydrate metabolism pathways. By disrupting the pyruvate dehydrogenase (PDH) complex and pyruvate formate-lyase (PFL), we could differentiate aerobic and anaerobic metabolic pathway involvement inV. choleraeproliferation. We demonstrate that oxidative metabolism is a key contributor to the replicative success ofV. cholerae in vivousing an infant mouse model where PDH mutants were attenuated 100-fold relative to wild type for colonization. Additionally, metabolism of host substrates such as mucin were determined to supportV. choleraegrowthin vitroas a sole carbon source primarily in aerobic growth conditions. Mucin likely contributes to population expansion during human infection as it is a ubiquitous source of carbohydrates. These data highlight the importance of oxidative metabolism in the intestinal environment and warrants further investigation of how oxygen and other host substrates shape the intestinal landscape that ultimately influences bacterial disease. We conclude from our results that oxidative metabolism of host substrates such as mucin is a key driver ofV. choleraegrowth and proliferation during infection, leading to the substantial bacterial burden exhibited in cholera patients.ImportanceVibrio choleraeremains a challenge in the developing world and incidence of the disease it causes, cholera, is anticipated to increase with rising global temperatures and with emergent, highly infectious strains. At present, the underlying metabolic processes that supportV. choleraegrowth during infection are less well understood than specific virulence traits such as production of a toxin or pilus. In this study we determined that oxidative metabolism of host substrates such as mucin contribute significantly toV. choleraepopulation expansionin vivo. Identifying metabolic pathways critical for growth can provide avenues for controllingV. choleraeinfection and the knowledge may be translatable to other pathogens of the gastrointestinal tract.
Rostrocaudal patterning and neural crest differentiation of human pre-neural spinal cord progenitors in vitro
Authors: Cooper Fay , Gentsch George E , Mitter Richard , Bouissou Camille , Healy Lyn , Rodriguez Ana Hernandez , Smith James C , Bernardo Andreia S 
Published: June 2020

ABSTRACTThe spinal cord emerges from a niche of neuromesodermal progenitors (NMPs) formed and maintained by Wnt/FGF signals at the posterior end of the embryo. NMPs can be generated from human pluripotent stem cells and hold promise for spinal cord replacement therapies. However, NMPs are transient, which complicates the full range production of rostrocaudal spinal cord identitiesin vitro. Here we report the generation of NMP-derived pre-neural progenitors (PNPs) with stem cell-like self-renewal capacity. PNPs maintain pre-spinal cord identity by co-expressing the transcription factors SOX2 and CDX2, and lose mesodermal potential by downregulating TBXT. For 7 to 10 passages PNPs divide to self-renew and to make trunk neural crest (NC), while gradually adopting a more posterior identity by activating colinearHOXgene expression. This HOX clock can be halted at the thoracic level for up to 30 passages by blocking the trunk-to-tail transition through GDF11-mediated signal inhibition.
Dynamics of hydraulic and contractile wave-mediated fluid transport duringDrosophilaoogenesis
Authors: Alsous Jasmin Imran , Romeo Nicolas , Jackson Jonathan A. , Mason Frank , Dunkel Jörn , Martin Adam C. 
Published: June 2020

AbstractFrom insects to mice, oocytes develop within cysts alongside nurse-like sister germ cells. Prior to fertilization, the nurse cells’ cytoplasmic contents are transported into the oocyte, which grows as its sister cells regress and die. Although critical for fertility, the biological and physical mechanisms underlying this transport process are poorly understood. Here, we combined live imaging of germline cysts, genetic perturbations, and mathematical modeling to investigate the dynamics and mechanisms that enable directional and complete cytoplasmic transport inDrosophila melanogasteregg chambers. We discovered that during ‘nurse cell (NC) dumping’, most cytoplasm is transported into the oocyte independently of changes in myosin-II contractility, with dynamics instead explained by an effective Young-Laplace’s law, suggesting hydraulic transport induced by baseline cell surface tension. A minimal flow network model inspired by the famous two-balloon experiment and genetic analysis of a myosin mutant correctly predicts the directionality of transport time scale, as well as its intercellular pattern. Long thought to trigger transport through ‘squeezing’, changes in actomyosin contractility are required only once cell volume is reduced by ∼75%, in the form of surface contractile waves that drive NC dumping to completion. Our work thus demonstrates how biological and physical mechanisms cooperate to enable a critical developmental process that, until now, was thought to be a mainly biochemically regulated phenomenon.
AMPlify: attentive deep learning model for discovery of novel antimicrobial peptides effective against WHO priority pathogens
Authors: Li Chenkai , Sutherland Darcy , Hammond S. Austin , Yang Chen , Taho Figali , Bergman Lauren , Houston Simon , Warren René L. , Wong Titus , Hoang Linda M.N. , Cameron Caroline E. , Helbing Caren C. , Birol Inanc 
Published: June 2020

AbstractAntibiotic resistance is a growing global health concern prompting researchers to seek alternatives to conventional antibiotics. Antimicrobial peptides (AMPs) are emerging therapeutic agents with promising utility in this domain and usingin silicomethods to discover novel AMPs is a strategy that is gaining interest. Such methods can filter through large volumes of candidate sequences and reduce lab screening costs. Here we introduce AMPlify, an attentive deep learning model for AMP prediction, and demonstrate its utility in prioritizing peptide sequences derived from theRana [Lithobates] catesbeiana(bullfrog) genome. We tested the bioactivity of our predicted peptides against a panel of bacterial species, including representatives from the World Health Organization’s “priority pathogens” list. Four of our novel AMPs were active against multiple species of bacteria, including a multi-drug resistant isolate of carbapenemase-producingEscherichia coli, demonstrating the utility of tools like AMPlify in our fight against antibiotic resistance.
Ventral hippocampus-lateral septum circuitry promotes foraging-related memory
Authors: Décarie-Spain Léa , Liu Clarissa M. , Lauer Logan Tierno , Subramanian Keshav , Bashaw Alexander G. , Klug Molly E. , Gianatiempo Isabella H. , Suarez Andrea N. , Noble Emily E. , Donohue Kristen N. , Cortella Alyssa M. , Hahn Joel D. , Davis Elizabeth A. , Kanoski Scott E. 
Published: June 2020

SUMMARYRemembering the location of a food or water source is essential for survival. Here we demonstrate that spatial memory for food location is reflected in ventral hippocampus (HPCv) neuron activity and is impaired by HPCv lesion. HPCv mediation of foraging-related memory involves downstream lateral septum (LS) signaling, as both reversible and chronic disconnection of HPCv (field CA1) to LS signaling impairs spatial memory retention for the location of either food or water reinforcement. This neural pathway selectively encodes appetitive spatial memory, as HPCv-LS disconnection does not affect aversive reinforcement-based spatial memory in an escape task using the same apparatus. The selectivity of this pathway in promoting foraging-related memory is further supported by results showing that CA1v-LS disconnection does not affect food intake, motivated operant responses for food, anxiety-like behavior, locomotor activity, or social and olfactory-based appetitive learning. Fluorescent in situ hybridization reveals that LS neurons recruited during the appetitive spatial memory task are primarily GABAergic, and multisynaptic anterograde neural pathway tracing and immediate early gene mapping identify the lateral hypothalamic area as a functional downstream target of this pathway. Collective results reveal a novel neural circuit through which the hippocampus selectively mediates memory for the location of appetitive (food or water) but not aversive (escape) reinforcement.
A method to map and interpret pleiotropic loci using summary statistics of multiple traits
Authors: Lee Cue Hyunkyu , Shi Huwenbo , Pasaniuc Bogdan , Eskin Eleazar , Han Buhm 
Published: June 2020

1AbstractThe identification of pleiotropic loci and the interpretation of the associations at these loci are essential to understand the shared etiology of related traits. A common approach to map pleiotropic loci is to use an existing meta-analysis method to combine summary statistics of multiple traits. This strategy does not take into account the complex genetic architectures of traits such as genetic correlations and heritabilities. Furthermore, the interpretation is challenging because phenotypes often have different characteristics and units. We propose PLEIO, a summary-statistic-based framework to map and interpret pleiotropic loci in a joint analysis of multiple traits. Our method maximizes power by systematically accounting for the genetic correlations and heritabilities of the traits in the association test. Any set of related phenotypes, binary or quantitative traits with differing units, can be combined seamlessly. In addition, our framework offers interpretation and visualization tools to help downstream analyses. Using our method, we combined 18 traits related to cardiovascular disease and identified 20 novel pleiotropic loci, which showed five different patterns of associations. Our method is available athttps://github.com/hanlab-SNU/PLEIO.
Characterization of the evolutionary dynamics of influenza A H3N2 hemagglutinin
Authors: Wang Maggie Haitian , Lou Jingzhi , Cao Lirong , Zhao Shi , Chan Paul KS , Chan Martin Chi-Wai , Chong Marc KC , Wu William KK , Chan Renee WY , Wei Yuchen , Zhang Haoyang , Zee Benny CY , Yeoh Eng-kiong 
Published: June 2020

AbstractVirus evolution drives the annual influenza epidemics in human population worldwide. However, it has been challenging to evaluate the mutation effect of the influenza virus on evading the population immunity. In this study, we introduce a novel statistical and computational approach to measure the dynamic molecular determinants underlying epidemics by the effective mutations (EMs), and account for the time of waning mutation advantage against herd immunity by the effective mutation periods (EMPs). Extensive analysis is performed on the genome and epidemiology data of 13-year worldwide H3N2 epidemics involving nine regions in four continents. We showed that the identified EM processed similar profile in geographically adjacent regions, while only 40% are common to Europe, North America, Asia and Oceania, indicating that the regional specific mutations also contributed significantly to the global H3N2 epidemics. The mutation dynamics calibrated that around 90% of the common EMs underlying global epidemics were originated from South East Asia, led by Thailand and India, and the rest were originated from North America. New Zealand was found to be the dominate sink region of H3N2 circulation, followed by UK. All regions might act as the intersection in the H3N2 transmission network. The proposed methodology provided a way to characterize key amino acids from the genetic epidemiology point of view. This approach is not restricted by the genomic region or type of the virus, and will find broad applications in identifying therapeutic targets for combating infectious diseases.
Towards intervention development to increase the uptake of COVID-19 vaccination among those at high risk: outlining evidence-based and theoretically informed future intervention content
Authors: Williams Lynn , Gallant Allyson J. , Rasmussen Susan , Nicholls Louise A. Brown , Cogan Nicola , Deakin Karen , Young David , Flowers Paul 
Published: June 2020

AbstractObjectivesDevelopment of a vaccine against COVID-19 will be key to controlling the pandemic. We need to understand the barriers and facilitators to receiving a future COVID-19 vaccine so that we can provide recommendations for the design of interventions aimed at maximising public acceptance.DesignCross-sectional UK survey with older adults and patients with chronic respiratory disease.MethodsDuring the UK’s early April 2020 ‘lockdown’ period, 527 participants (311 older adults, mean age = 70.4 years; 216 chronic respiratory participants, mean age = 43.8 years) completed an online questionnaire assessing willingness to receive a COVID-19 vaccine, perceptions of COVID-19, and intention to receive influenza and pneumococcal vaccinations. A free text response (n=502) examined barriers and facilitators to uptake. The Behaviour Change Wheel informed the analysis of these responses, which were coded to the Theoretical Domains Framework (TDF). Behaviour change techniques (BCTs) were identified.ResultsEighty-six percent of respondents want to receive a COVID-19 vaccine. This was positively correlated with the perception that COVID-19 will persist over time, and negatively associated with perceiving the media to have over-exaggerated the risk. The majority of barriers and facilitators were mapped onto the ‘beliefs about consequences’ TDF domain, with themes relating to personal health, health consequences to others, concerns of vaccine safety, and severity of COVID-19.ConclusionsWillingness to receive a COVID-19 vaccination is currently high among high-risk individuals. Mass media interventions aimed at maximising vaccine uptake should utilise the BCTs of information about health, emotional, social and environmental consequences, and salience of consequences.Statement of ContributionWhat is already known on this subject?Uptake of a vaccine for COVID-19 will be vital for controlling the pandemic, but the success of this strategy relies on public acceptance of the vaccine.Uptake of vaccinations and public confidence in vaccines has been falling in recent years.Evidence suggests that 74% of the French population want to receive a COVID-19 vaccination.What does this study add?This study found that 86% of our sample of high-risk participants in the UK are willing to receive a future vaccine for COVID-19.This study showed that perceived barriers and facilitators to uptake of the COVID-19 vaccination concentrated on the ‘beliefs about consequences’ TDF domain.This study suggests that the content of mass media interventions to improve vaccine uptake should focus on the BCTs of information about health, emotional, social and environmental consequences, and salience of consequences. These techniques should be pitched in relation to both self and, most importantly, to others.
Spatio-temporal heterogeneity in hippocampal metabolism in control and epilepsy conditions
Authors: Brancati Giulio E. , Rawas Chahinaz , Ghestem Antoine , Bernard Christophe , Ivanov Anton I. 
Published: June 2020

ABSTRACTThe hippocampus’s dorsal and ventral parts are involved in different operative circuits, which functions vary in time during the night and day cycle. These functions are altered in epilepsy. Since energy production is tailored to function, we hypothesized that energy production would be space- and time-dependent in the hippocampus and that such organizing principle would be modified in epilepsy. Using metabolic imaging and metabolite sensingex vivo, we show that the ventral hippocampus favors aerobic glycolysis over oxidative phosphorylation as compared to the dorsal part in the morning in control mice. In the afternoon, aerobic glycolysis is decreased, and oxidative phosphorylation increased. In the dorsal hippocampus, the metabolic activity varies less between these two times but is weaker than in the ventral. Thus, the energy metabolism is different along the dorsoventral axis and changes as a function of time in control mice. In an experimental model of epilepsy, we find a large alteration of such spatio-temporal organization. In addition to a general hypometabolic state, the dorsoventral difference disappears in the morning, when seizure probability is low. In the afternoon, when seizure probability is high, the aerobic glycolysis is enhanced in both parts, the increase being stronger in the ventral area. We suggest that energy metabolism is tailored to the functions performed by brain networks, which vary over time. In pathological conditions, the alterations of these general rules may contribute to network dysfunctions.SIGNIFICANCE STATEMENTThe dorsal part of the hippocampus is involved in spatial learning and memory processes, while the ventral is implicated in motivational and emotional behavior. These functions change during the night and day cycle, and they are altered in epilepsy. Here we show that energy production (glycolysis versus oxidative phosphorylation) varies along the dorsoventral axis in a circadian mannerex vivoin control mice. These rules are altered in experimental epilepsy. Thus, energy production may be tailored to the function performed by hippocampal subdivisions and to the time of the day. Alterations in epilepsy may contribute to seizure generation and cognitive deficits.