bluuebunny/crossref_metadata_2025_split huggingface dataset:
Subtherapeutic doses of vancomycin synergize with bacteriophages for treatment of experimental methicillin-resistant Staphylococcus aureus infective endocarditis
Authors: Save Jonathan , Que Yok-Ai , M. Entenza José , Resch Grégory 
Published: June 2022

AbstractBackgroundRecurrent therapeutic failures reported for treatment of methicillin-resistant Staphylococcus aureus (MRSA) infective endocarditis (IE) with vancomycin may be due to poor bactericidal activity. Alternative antibacterial approaches using bacteriophages may overcome this limitation.ObjectiveAn experimental rat model of MRSA IE (EE) was used to examine the efficacy of vancomycin combined with a 1:1 bacteriophage cocktail composed of Herelleviridae vB_SauH_2002 and Podoviridae 66.MethodsSix hours after inoculation with ca. 5 log10 CFU of MRSA strain AW7, animals were treated with either: (i) saline, (ii) an equimolar two-phage cocktail (bolus of 1 mL followed by a 0.3 mL/h continuous infusion of 10 log10PFU/mL phage suspension), (iii) vancomycin (at a dose mimicking the kinetics in humans of 0.5 g b.i.d.), or (iv) a combination of both. Bacterial loads in vegetations, and phage loads in vegetations, liver, kidney, spleen, and blood, were measured outcomes.ResultsPhage cocktail alone was unable to control growth of strain AW7 in cardiac vegetations. However, when combined with subtherapeutic doses of vancomycin, a statistically significant decrease of Δ4.05 ± 0.94 log10 CFU/g at 24 h compared to placebo was detected (p < 0.001). Administration of vancomycin was found to significantly impact local concentrations of phages in the vegetations and in the organs examined.ConclusionsLytic bacteriophages as an adjunct treatment to standard of care antibiotics could potentially improve management of MRSA IE. Further studies are needed to investigate the impact of antibiotics on phage replication in vivo.
COVID-19 Endemic Plan: Impact of Vaccination and Non-pharmaceutical Interventions with Viral Variants and Waning Immunity Using an Agent-Based Simulation
Authors: Lee Serin , Zabinsky Zelda B. , Wasserheit Judith N. , Ross Jennifer M. , Chen Shi , Liu Shan 
Published: June 2022

AbstractBackgroundsDespite the widespread distribution of SARS-CoV-2 vaccines, the COVID-19 pandemic continues with highly contagious variants and waning immunity. Low disease severity of the Omicron variant gives society hope that the COVID-19 pandemic could end.MethodsWe develop an agent-based simulation to explore the impact of COVID-19 vaccine willingness, booster vaccination schedule, vaccine effectiveness, and non-pharmaceutical interventions (NPIs) on reducing COVID-19 deaths while considering immunity duration and disease severity against the Omicron variant. The model is calibrated to the greater Seattle in year 2020 by observing local epidemic data. The simulation is run to the end of year 2024 to observe long-term effects.ResultsResults show that an NPI policy that maintains low levels of NPIs can reduce mortality by 35.1% compared to fully opening the society. A threshold NPI policy is especially helpful when the disease severity of the Omicron variant is high, or booster vaccines are not scheduled. A periodic booster schedule is needed to achieve the goal of lowering the number of deaths from COVID-19 to the level of influenza and pneumonia. Except for one scenario, 80% or more vaccine willingness is also needed to achieve this goal.ConclusionsWe find that a periodic booster vaccination schedule and mild disease severity of the Omicron variant play a crucial role in reducing deaths by the end of year 2024. If a booster schedule is not planned and the Omicron variant is not mild, NPI policies that limit society from fully opening are required to control the outbreak.
Human hematopoietic stem cell vulnerability to ferroptosis
Authors: Zhao Jiawei , Jia Yuemeng , Mahmut Dilnar , Deik Amy A. , Jeanfavre Sarah , Clish Clary B. , Sankaran Vijay G. 
Published: June 2022

SummaryHematopoietic stem cells (HSCs) have a number of unique physiologic adaptations that enable lifelong maintenance of blood cell production, including a highly regulated rate of protein synthesis. Yet the precise vulnerabilities that arise from such adaptations have not been fully characterized. Here, inspired by a bone marrow failure disorder due to loss of the histone deubiquitinase MYSM1, characterized by selectively disadvantaged HSCs, we show how reduced protein synthesis in HSCs results in increased ferroptosis. HSC maintenance can be fully rescued by blocking ferroptosis, despite no alteration in protein synthesis rates. Importantly, this selective vulnerability to ferroptosis not only underlies HSC loss in MYSM1 deficiency, but also characterizes a broader liability of human HSCs. Increasing protein synthesis rates via MYSM1 overexpression makes HSCs less susceptible to ferroptosis, more broadly illuminating the selective vulnerabilities that arise in somatic stem cell populations as a result of physiologic adaptations.
Portrait of a genus: genome sequencing reveals evidence of adaptive variation inZea
Authors: Chen Lu , Luo Jingyun , Jin Minliang , Yang Ning , Liu Xiangguo , Peng Yong , Li Wenqiang , Philips Alyssa , Cameron Brenda , Bernal Julio , Rellán-Álvarez Rubén , Sawers Ruairidh JH , Qing Liu , Yin Yuejia , Ye Xinnan , Yan Jiali , Zhang Qinghua , Zhang Xiaoting , Wu Shenshen , Gui Songtao , Wei Wenjie , Wang Yuebin , Luo Yun , Jiang Chengling , Deng Min , Jin Min , Jian Liumei , Yu Yanhui , Zhang Maolin , Yang Xiaohong , Hufford Matthew B. , Fernie Alisdair R. , Warburton Marilyn L. , Ross-Ibarra Jeffrey , Yan Jianbing 
Published: June 2022

AbstractMaize is a globally valuable commodity and one of the most extensively studied genetic model organisms. However, we know surprisingly little about the extent and potential utility of the genetic variation found in the wild relatives of maize. Here, we characterize a high-density genomic variation map from 744 genomes encompassing maize and all wild taxa of the genusZea, identifying over 70 million single nucleotide polymorphisms (SNPs) and nearly 9 million Insertion/Deletion (InDel) polymorphisms. The variation map reveals evidence of selection within taxa displaying novel adaptations to traits such as waterlogging, perenniality and regrowth. We focus in detail on adaptive alleles in highland teosinte and temperate maize and highlight the key role of flowering time related pathways in highland and high latitude adaptation. To show how this data can identify useful genetic variants, we generated and characterized novel mutant alleles for two flowering time candidate genes. This work provides the most extensive sampling to date of the genetic diversity of the genusZea, resolving questions on evolution and identifying adaptive variants for direct use in modern breeding.
FAK drives resistance to therapy in HPV-negative head and neck cancer in a p53-dependent manner
Authors: Pifer Phillip M. , Yang Liangpeng , Kumar Manish , Xie Tongxin , Frederick Mitchell , Hefner Andrew , Beadle Beth , Molkentine David , Molkentine Jessica , Dhawan Annika , Abdelhakiem Mohamed , Osman Abdullah A. , Myers Jeffrey N. , Pickering Curtis R. , Sandulache Vlad C. , Heymach John , Skinner Heath D. 
Published: June 2022

AbstractRadiation and platinum-based chemotherapy form the backbone of therapy in HPV-negative head and neck squamous cell carcinoma (HNSCC). We have correlated focal adhesion kinase (FAK/PTK2) expression with radioresistance and worse outcome in these patients. However, the importance of FAK in driving radioresistance and its effects on chemoresistance in these patients remain unclear. We performed an in vivo shRNA screen using targetable libraries to address these questions and identified FAK as an excellent target for both radio- and chemosensitization. Because TP53 is mutated in over 80% of HPV-negative HNSCC, we hypothesized that mutant TP53 may facilitate FAK-mediated therapy resistance. FAK inhibitor increased sensitivity to radiation, increased DNA damage and repressed homologous recombination and non-homologous end joining repair in mutant, but not wild-type, TP53 HPV-negative HNSCC cell lines. Mutant TP53 cisplatin-resistant cell line had increased FAK phosphorylation compared to wild-type, and FAK inhibition partially reversed cisplatin resistance. To validate these findings, we utilized a HNSCC cohort to show that FAK copy number and gene expression were associated with worse disease-free survival in mutant TP53, but not wild-type TP53, HPV-negative HNSCC tumors. Thus, FAK may represent a targetable therapeutic sensitizer linked to a known genomic marker of resistance.
Single-cell RNA-sequencing data analysis reveals a highly correlated triphasic transcriptional response to SARS-CoV-2 infection
Authors: Gutiérrez Pablo A. , Elena Santiago F. 
Published: June 2022

ABSTRACTSingle-cells RNA sequencing (scRNA-seq) is currently one of the most powerful techniques available to study the transcriptional response of cells to external perturbations. However, the use of conventional bulked RNA-seq analysis methods can miss important patterns underlying in the scRNA-seq data. Here, we present a reanalysis of scRNA-seq data from human bronchial epithelial cells and colon and ileum organoids using pseudo-time profiles based on the degree of virus accumulation which reflect the progress of infection. Our analysis revealed a transcriptional response to infection characterized by three distinct up- and down-regulatory phases, that cannot be detected using classical two-group comparisons. Interrogation of results, focused on genes involved in interferon-response, transcription factors and RNA-binding proteins, suggests a highly correlated transcriptional response for most genes. In addition, correlation network analysis revealed a distinct response of genes involved in translation and mitochondrially-encoded genes. Based on our data, we propose a model where modulation of nucleocytoplasmic traffic by the viral protein nsp1 explains the triphasic transcriptional response to SARS-CoV-2 infection.
Bumetanide increases microglia-interneuron contact following traumatic brain injury
Authors: Tessier Marine , Garcia Marta Saez , Goubert Emmanuelle , Tian Li , Molinari Florence , Blasco Edith , Laurin Jerome , Guillemot François , Hübner Christian , Pellegrino Christophe , Rivera Claudio 
Published: June 2022

AbstractObjectiveThe Na-K-Cl cotransporter (NKCC1) inhibitor bumetanide has prominent positive effects on the pathophysiology of many neurological disorders. Here we studied whether bumetanide could influence post-traumatic cognitive decline and inflammatory processes by regulating astrocyte and microglia activation.MethodControlled cortical impacted (CCI) animals were treated with bumetanide during the first post-CCI week. Immunochemistry, flow cytometry, immunoassay, and in vivo imaging were used to study astrocytic and microglial morphology and phenotype as well as adult neurogenesis. Telemetric electroencephalograms and cognitive behavioral test were performed at one-month post CCI.ResultsBumetanide prevented CCI-induced decrease in hippocampal neurogenesis and parvalbumin positive interneuron loss. Deletion of NKCC1 in astrocytes neither rescued interneurons nor promote neurogenesis. Interestingly, bumetanide had a strong effect on microglial activation by inducing polarization towards the M1-like phenotype 3 days post-CCI and the M2-like phenotype 7 days post-CCI. Bumetanide increased microglial Brain-derived neurotrophic factor (BDNF) expression and interaction with parvalbumin interneurons. The early treatment with bumetanide resulted in improvements in working and episodic memory, one-month post-CCI, as well as the normalization of theta band oscillations.InterpretationHere, we disclose a novel mechanism for the neuroprotective action of bumetanide mediated by an acceleration of microglial activation dynamics that leads to an increase of parvalbumin interneuron survival following CCI, possibly resulting from increased microglial BDNF expression and contact with interneurons. Salvage of interneurons may normalize ambient gamma-aminobutyric acid (GABA) resulting in the preservation of adult neurogenesis processes as well as contributing to bumetanide-mediated improvement of cognitive performance.
Comparative analysis of the caecal tonsil transcriptome in two hen lines experimentally infected withSalmonellaEnteritidis
Authors: Cazals Anaïs , Rau Andrea , Estellé Jordi , Bruneau Nicolas , Coville Jean-Luc , Menanteau Pierrette , Rossignol Marie-Noëlle , Jardet Deborah , Bevilacqua Claudia , Bed’hom Bertrand , Velge Philippe , Calenge Fanny 
Published: June 2022

AbstractManagingSalmonella entericaEnteritidis (SE) carriage in chicken is necessary to ensure human food safety and enhance chicken breeding viability.Salmonellacan contaminate poultry products, causing human foodborne disease and economic losses for farmers. Both genetic selection for a decreased carriage and gut microbiota modulation strategies could reduceSalmonellapropagation in farms.Two-hundred and twenty animals from the White Leghorn inbred lines N and 61were raised together on floor, infected by SE at 7 days of age, transferred into isolators to prevent oro-fecal recontamination and euthanized at 19 days. Caecal content DNA was used to measure individualSalmonellacounts (ISC) by droplet digital PCR. A RNA sequencing approach was used to measure gene expression levels in caecal tonsils after infection of 48 chicks with low or high ISC.The analysis between lines identified 7516 differentially expressed genes (DEGs) corresponding to 62 enriched Gene Ontology (GO) Biological Processes (BP) terms. A comparison between low and high carriers allowed us to identify 97 DEGs and 23 enriched GO BP terms within line 61, and 1034 DEGs and 288 enriched GO BP terms within line N. Among these genes, we identified several candidate genes based on their putative functions, includingFUT2orMUC4, which could be involved in the control of SE infection, maybe through interactions with commensal bacteria. Altogether, we were able to identify several genes and pathways associated with differences in SE carriage level. These results are discussed in relation to individual caecal microbiota compositions, obtained for the same animals in a previous study, which may interact with host gene expression levels for the control of the caecal SE load.
Mixed origin of juvenile Atlantic cod (Gadus morhua) along the Swedish west coast
Authors: Henriksson Simon , Pereyra Ricardo T. , Sodeland Marte , Ortega-Martinez Olga , Knutsen Halvor , Wennhage Håkan , André Carl 
Published: June 2022

AbstractCryptic population structure in exploited fish species poses a major challenge for fisheries management. Atlantic cod (Gadus morhua) is a species in which the presence of sympatric ecotypes has been known for a long time, for instance off the coast of Northern Norway. More recently, two sympatric ecotypes of cod have also been documented in the Skagerrak and Kattegat; one ecotype is of an apparent offshore origin and undertakes spawning migrations to the North Sea, and the other is resident at the coast throughout its life. However, their relative contributions of juveniles to the Swedish west coast remain poorly understood. The lack of adult cod along the Skagerrak and Kattegat coasts in recent years has led to the hypothesis that the offshore ecotype is the main source of juveniles to the area, but recent studies have shown large proportions of coastal cod inside Norwegian Skagerrak fjords. In this study, juvenile cod were collected at a high spatial resolution along the Swedish west coast, and genetically assigned to each of the two ecotypes. The results reveal that there is a considerable proportion of juvenile coastal cod in the southern Kattegat, Öresund, and in inshore Swedish Skagerrak, but that the offshore ecotype dominates in offshore areas. Model selection suggests that differences in bottom depth, rather than distance from the open sea, may explain the heterogenous spatial distribution of the two ecotypes. In addition, the two ecotypes displayed differences at loci known to be associated with environmental adaptation, suggesting that their spatial distribution is maintained by natural selection in response to specific environmental conditions.
Lower air humidity reduced both the plant growth and activities of photosystems I and II under prolonged heat stress
Authors: Lysenko Eugene A. , Kozuleva Marina. A. , Klaus Alexander A. , Pshybytko Natallia L. , Kusnetsov Victor V. 
Published: June 2022

AbstractThe warming is global problem. In natural environments, a heat stress is accompanied with a drought usually. The effect of lower air humidity remains obscure. Maize and barley plants were supplied with an unlimited source of water for the root uptake and undergone to heat stress for 48 h at contrast conditions of air humidity. The lower air humidity decreased photochemical activities of photosystem I and photosystem II. The small effect was revealed in control. The temperature elevation to 37°C and 42°C increased relative activities of the both photosystems; the photosystem II was activated more. The effect of air humidity disappeared at 37°C; at 42°C, the effect was small. At 46°C, lower air humidity magnified substantially the inhibitory effect of heat. Consequently, the maximal and relative activities of the both photosystems were decreased in maize and barley; the plant growth was reduced greatly. The photosystem II was inhibited more. At 46°C, maize plants increased water uptake by roots at lower air humidity and survived; barley plants were unable to increase water uptake and died. Therefore, air humidity is the important component of environmental heat stress influencing activities of photosystem I and photosystem II and thereby plant growth and viability.HighlightThe effect of severe heat stress was magnified with lower air humidity. At 46°C, their mutual action inhibited photosystem I and II and reduced greatly the plant growth and viability.
Integrative signatures of signaling pathway response increase robustness and accuracy of pathway predictions
Authors: Clark Nicholas A. , Ren Yan , Plas David R. , Sivaganesan Siva , Medvedovic Mario 
Published: June 2022

AbstractMotivationAberrant cell signaling is known to drive progression of cancer and many other diseases. The study of signaling pathways within cells is central to identifying drugs that seek to modulate these pathways. Expression of pathway genes (i.e. genes that code for pathway proteins) correlates poorly with signaling pathway activity, making prediction of signaling pathway activity changes based on transcriptional disease signatures a challenging problem. Pathway architecture and response also varies across cell lines, which reflects how drug response varies across a patient population.ResultsHere, we present a transcriptional footprinting framework for predicting changes in activity of signaling pathway by integrating transcriptional signatures of genetic perturbations of pathway genes over a diverse set of cell lines into a integrative Pathway Activity Signature (iPAS). We use an unsupervised multi-task learning approach to create pathway signatures across 12 cell lines using genetic loss of function data from the LINCS project. We also use supervised learning to construct an optimal predictor based on the ensemble of 12 cell line signatures. Our methods achieve a sizeable increase in performance, as measured by prediction of pathways targeted by LINCS chemical perturbagens.AvailabilityOpen source R package iPAS is available at https://github.com/uc-bd2k/iPAS.Contactmedvedm@ucmail.uc.eduSupplementary informationSupplementary data are available online.
Tubule jamming in the developing mouse kidney creates cyclical mechanical stresses in nephron-forming niches
Authors: Viola John M. , Liu Jiageng , Prahl Louis S. , Huang Aria , Chan Trevor J. , Hayward-Lara Gabriela , Porter Catherine M. , Shi Chenjun , Zhang Jitao , Hughes Alex J. 
Published: June 2022

AbstractThe kidney develops through branching of progressively crowded ureteric bud (UB) tubules at the organ surface. The elongating tubule tips are surrounded by traveling cap mesenchyme niches consisting of nephron progenitors and separated by stromal boundaries. Dynamic interactions between these tissues coordinate a balance between UB tip branching, elongation, and nephron induction that sets nephron numbers for life, impacting the likelihood of adult disease. Such a crowded tissue environment could place geometric limits on the number of niches that can be formed while maintaining mechanical integrity of the tissue. Since space is at a premium, crowding could also force a given niche to prioritize between nephron formation or UB branching differently depending on its spatial context. Here we study the geometric and mechanical consequences of tubule tip crowding at the embryonic kidney surface. Organ curvature reduces and tubule ‘tip domain’ niches pack more closely over developmental time. These together create a semi-crystalline geometry of tips at the kidney surface and a rigidity transition to more solid-like tissue properties at later developmental stages. To infer mechanical dynamics over the branching timescale, we define a new method to infer tip domain ‘ages’ relative to their most recent branch events from fixed kidneys. We find that new tip domains overcome mechanical resistance as they branch and displace close-packed neighbors, transiently increasing mechanical stress in the niche. Ongoing efforts to understand geometric and mechanical effects on niche regulation will clarify variation in kidney tissue composition and advance engineering control strategies for synthetic regenerative tissues.