bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of an Antiepileptogenesis Drug Screening Platform: Effects of Everolimus and Phenobarbital
Authors: Barker-Haliski Melissa , Knox Kevin , Zierath Dannielle , Koneval Zachery , Metcalf Cameron , Wilcox Karen S. , White H. Steve 
Published: December 2020

SummaryObjectiveThe kainic acid (KA)-induced status epilepticus (SE) model in rats is an etiologically-relevant animal model of epileptogenesis. Just as in patients, who develop temporal lobe epilepsy (TLE) following SE, this rat model of KA-induced SE very closely recapitulates many of the clinical and pathological characteristics of human TLE that arise following SE or another neurological insult. Spontaneous recurrent seizures (SRS) in TLE can present after a latent period following a neurological insult (TBI, SE event, viral infection, etc.). Moreover, this rat model of TLE is ideally suited for preclinical studies to evaluate the long-term process of epileptogenesis and screen putative disease-modifying/antiepileptogenic agents. This report details the pharmacological characterization and methodological refinement of a moderate-throughput drug screening program using the post KA-induced SE model of epileptogenesis in male Sprague Dawley rats to identify potential agents that may prevent or modify the onset or severity of SRS. Specifically, we sought to demonstrate whether our protocol could prevent the development of SRS, or lead to a reduced frequency/severity of SRS.MethodsRats were administered everolimus (2-3 mg/kg, P.O. commencing at 1, 2, or 24-hrs after SE onset) or phenobarbital (60 mg/kg, beginning 1 hr after SE onset). The rats in all studies (n=12/treatment dose/study) were then followed intermittently by video-EEG monitoring; i.e., 2-weeks on/2-weeks off, 2-weeks on epochs to determine latency to onset of SRS, and disease burden following SRS onset.ResultsWhile there were no adverse side effects observed in any of our studies, no treatment conferred a significant disease modifying effect, nor did any agent prevent the presentation of SRS by 6 weeks post-SE onset.ConclusionsWhile neither phenobarbital nor everolimus administered at several time points post-SE onset prevented the development of SRS, we herein demonstrate a moderate-throughput screen for potential antiepileptogenic agents in an etiologically-relevant rodent model of TLE.Key PointsDisease-modifying therapies are needed to prevent or attenuate the burden of epilepsy in at-risk individuals.We report a moderate-throughput screening protocol to identify disease-modifying agents in a rat post-kainic acid status epilepticus model.Everolimus was administered at multiple time points post-status epilepticus with no effect on spontaneous seizures up to 6 weeks later.Repeated administration of phenobarbital also did not prevent the development of spontaneous recurrent seizures up to 6 weeks post SE.While we did not identify any effect of either agent, our approach provides a moderate-throughput screen for antiepileptogenesis.
Safeguarding pollinators requires specific habitat prescriptions and substantially more land area than current policy suggests
Authors: Pindar Alana , Hogg Adam , Raine Nigel E. 
Published: December 2020

AbstractHabitat loss and fragmentation are major drivers of global pollinator declines, yet even after recent unprecedented periods of anthropogenic land-use intensification the amount of habitat needed to support pollinators remains unknown. Here we use comprehensive datasets to determine the extent and amount of habitat needed. Safeguarding wild bee communities in a Canadian landscape requires 11.6-16.7% land-cover from a diverse range of habitats (~1.8-3.6x current policy guidelines), irrespective of whether conservation aims are enhancing species richness or abundance. Sensitive habitats, like tallgrass woodlands and wetlands, were important predictors of bee biodiversity. Conservation strategies that under-estimate the extent of habitat, spatial scale and specific habitat needs of functional guilds are unlikely to protect bee communities and the essential pollination services they provide to crops and wild plants.One sentence summarySafeguarding wild bee communities requires 11.6-16.7% of the area in common North American landscapes to provide targeted habitat prescriptions for different functional guilds over a variety of spatial scales.
Scalable Analysis of Multi-Modal Biomedical Data
Authors: Smith Jaclyn , Shi Yao , Benedikt Michael , Nikolic Milos 
Published: December 2020

Targeted diagnosis and treatment options are dependent on insights drawn from multi-modal analysis of large-scale biomedical datasets. Advances in genomics sequencing, image processing, and medical data management have supported data collection and management within medical institutions. These efforts have produced large-scale datasets and have enabled integrative analyses that provide a more thorough look of the impact of a disease on the underlying system. The integration of large-scale biomedical data commonly involves several complex data transformation steps, such as combining datasets to build feature vectors for learning analysis. Thus, scalable data integration solutions play a key role in the future of targeted medicine. Though large-scale data processing frameworks have shown promising performance for many domains, they fail to support scalable processing of complex datatypes. To address these issues and achieve scalable processing of multi-modal biomedical data, we present TraNCE, a framework that automates the difficulties of designing distributed analyses with complex biomedical data types. We outline research and clinical applications for the platform, including data integration support for building feature sets for classification. We show that the system is capable of outperforming the common alternative, based on “flattening” complex data structures, and runs efficiently when alternative approaches are unable to perform at all.Key PointsModern biomedical analyses are integrated pipelines of data access mechanisms and analysis components that operate on and produce datasets in a variety of complex, domain specific formats.Scalable data integration and aggregation solutions that support joint inference on such large-scale datasets play a key role advancing biomedical analysis.Query compilation techniques that optimize nested data processing are essential for scaling multi-modal, biomedical analysis.
Longitudinal profiling of the macaque vaginal microbiome reveals similarities to diverse human vaginal communities: implications for use as a pre-clinical model for bacterial vaginosis
Authors: Rhoades Nicholas S. , Hendrickson Sara M. , Gerken Danielle R. , Martinez Kassandra , Slayden Ov D. , Slifka Mark K. , Messaoudi Ilhem 
Published: December 2020

ABSTRACTThe vaginal microbiota plays an important role in women’s reproductive and urogenital health. Disturbances in this microbial community can lead to several adverse outcomes including pelvic inflammatory disease, bacterial vaginosis (BV) as well as increased susceptibility to sexually transmitted infections, miscarriage, and pre-term births. It is now well accepted that while the microbiome of healthy women in the developed world is dominated byLactobacillusspecies, vaginal communities in asymptomatic women, especially those in the developing world, can be comprised of a diverse set of micro-organisms. The presence of a diverse vaginal microbiome has been associated with increased susceptibility to HIV infection but their implications for women’s health remain poorly understood. Rhesus macaques are an excellent translational animal model due to significant physiological and genetic homology with humans. In this study, we performed a longitudinal analysis of clinical and microbiome data from 16 reproductive age female rhesus macaques. Many animals showed hallmarks of BV, including Nugent scores above 7 and high vaginal pH. At both the taxonomic and functional level, the rhesus macaque vaginal microbiome was most similar to that of women who harbor a diverse vaginal community associated with asymptomatic/symptomatic bacterial vaginosis. Specifically, rhesus macaque vaginal microbiomes harbored a diverse set of anaerobic gram-negative bacteria, including;Snethia,Prevotella, Porphyromonas, andMobilluncus. Interestingly, some animals were transiently colonized byLactobacillusand some withGardnerella. Our in-depth and comprehensive analysis highlights the importance of the model to test interventions for manipulating the vaginal microbiome.IMPORTANCEIt is widely accepted that the “healthy” vaginal microbiome of the majority of women in the developed world is dominated byLactobacillusspecies. However, in the developing world, a majority of women are colonized by diverse microbial communities, typically associated with bacterial vaginosis, but remain asymptomatic. Many questions remain about the drivers of this disparity and potential interventions to alter the vaginal microbiome. Rhesus macaques provide an excellent translational model due to significant physiological and genetic homology with humans. In this study, we performed a longitudinal analysis of clinical and microbiome data from a large cohort of reproductive age rhesus macaques. At the taxonomic, genomic, and functional level, the rhesus macaque vaginal microbiome was most similar to that of humans who harbor a diverse vaginal community associated with asymptomatic/symptomatic bacterial vaginosis. Our in-depth and comprehensive analysis highlights the utility of macaques to test interventions for manipulating the vaginal microbiome.
Minor pilin genes are involved in motility and natural competence inSynechocystissp. PCC 6803
Authors: Oeser Sabrina , Wallner Thomas , Bučinská Lenka , Bähre Heike , Schürgers Nils , Wilde Annegret 
Published: December 2020

AbstractCyanobacteria synthesize type IV pili, which are known to be essential for motility, adhesion and natural competence. They consist of long flexible fibres that are primarily composed of the major pilin PilA1 inSynechocystissp. PCC 6803. In addition,Synechocystisencodes less abundant pilin-like proteins, which are known as minor pilins. The transcription of the minor pilin genespilA5, pilA6andpilA9-pilA11is inversely regulated in response to different conditions. In this study, we show that the minor pilin PilA5 is essential for natural transformation but is dispensable for motility and flocculation. In contrast, a set of minor pilins encoded by thepilA9-slr2019transcriptional unit are necessary for motility but are dispensable for natural transformation. NeitherpilA5-pilA6norpilA9-slr2019are essential for pilus assembly as mutant strains showed type IV pili on the cell surface. Microarray analysis demonstrated that the transcription levels of known and newly predicted minor pilin genes change in response to surface contact. A total of 120 genes were determined to have altered transcription between planktonic and surface growth. Among these genes, 13 are located on the pSYSM plasmid. The results of our study indicate that different minor pilins facilitate distinct pilus functions.
A nuclear role for ARGONAUTE-2 in regulation of neuronal alternative polyadenylation
Authors: Ravid Revital , Siany Aviad , Rivkin Natalia , Eitan Chen , Marmor-Kollet Hagai , Yanowski Eran , Savidor Alon , Levin Yishai , Rot Gregor , Meister Gunter , Hornstein Eran 
Published: December 2020

AbstractArgonaute 2 (AGO2), the effector protein partner of microRNAs (miRNAs) in the cytoplasmic RNA induced silencing complex, is further involved in nuclear RNA processing. However, a role for AGO2 in regulation of alternative polyadenylation was not yet demonstrated. Here, we reveal unexpected abundance of AGO2 in mouse neuronal nuclei and characterize nuclear AGO2 interactors by mass spectrometry. We discover that AGO2 broadly regulated alternative polyadenylation (APA) in neuronal cells. Specifically, we demonstrate how two isoforms ofRetmRNA, which encodes a receptor tyrosine kinase are regulated by AGO2-depenent APA, affecting downstream GDNF signaling in primary motor neurons.
Immunogenomic profile of colorectal cancer response to immune checkpoint blockade
Authors: Bortolomeazzi Michele , Keddar Mohamed Reda , Montorsi Lucia , Acha-Sagredo Amelia , Benedetti Lorena , Temelkovski Damjan , Choi Subin , Petrov Nedyalko , Todd Katrina , Wai Patty , Kohl Jonny , Denner Tamara , Nye Emma , Goldstone Robert , Ward Sophia , Wilson Gareth A. , Al Bakir Maise , Swanton Charles , John Susan , Miles James , Larijani Banafshe , Kunene Victoria , Fontana Elisa , Arkenau Hendrik-Tobias , Parker Peter J. , Rodriguez-Justo Manuel , Shiu Kai-Keen , Spencer Jo , Ciccarelli Francesca D. 
Published: December 2020

ABSTRACTColorectal cancers (CRCs) show variable response to immune checkpoint blockade, which can only partially be explained by the variability of tumour mutational burden. To dissect the cellular and molecular determinants of response we performed a multi-omic screen of 721 cancer regions from patients treated with Pembrolizumab (KEYNOTE 177 clinical trial) or Nivolumab. Multi-regional whole exome, RNA and T-cell receptor sequencing show that, within hypermutated CRCs, response to both anti-PD1 agents is not positively associated with tumour mutational burden but with high clonality of immunogenic mutations, expanded T cells, low activation of the WNT pathway and active immune escape mechanisms. Coupling high-dimensional imaging mass cytometry with multiplexed immunofluorescence and computational spatial analysis, we observe that responsive hypermutated CRCs are rich in cytotoxic and proliferating PD1-expressing CD8 cells interacting with high-density clusters of PDL1-expressing antigen presenting macrophages. We propose that anti-PD1 agents release the PD1-PDL1 interaction between CD8 T cells and macrophages thus promoting cytotoxic anti-tumour activity.
Oncogene-induced cardiac neoplasia shares similar mechanisms with heart regeneration in zebrafish
Authors: Pfefferli Catherine , Bonvin Marylène , Robatel Steve , Perler Julien , König Désirée , Jaźwińska Anna 
Published: December 2020

AbstractThe human heart is a poorly regenerative organ and cardiac tumors are extremely rare. The zebrafish heart can restore its damaged myocardium through cardiomyocyte proliferation. Whether this endogenous capacity causes a susceptibility to neoplasia remains unknown. Here, we established a strategy to conditionally express the HRASG12Voncogene in zebrafish cardiomyocytes. The induction of this transgene in larvae or adult animals resulted in heart overgrowth with abnormal histology. The malformed ventricle displayed similar characteristics to the regenerative myocardium, such as enhanced cell-cycle entry, incomplete differentiation, reactivation of cardiac embryonic programs, expression of regeneration genes, oxidative metabolism changes, intramyocardial matrix remodeling and leucocyte recruitment. We found that oncogene-mediated cardiac tumorigenesis and cryoinjury-induced regeneration involve TOR signaling, as visualized by phosphorylation of its target ribosomal protein S6. The inhibition of TOR by rapamycin impaired regeneration and rescued from neoplasia. These findings demonstrate the existence of common mechanisms underlying the proliferative plasticity of zebrafish cardiomyocytes during advantageous organ restoration and detrimental tumorigenesis.
No detectable signal for ongoing genetic recombination in SARS-CoV-2
Authors: Richard Damien , Owen Christopher J. , van Dorp Lucy , Balloux François 
Published: December 2020

AbstractThe COVID-19 pandemic has led to an unprecedented global sequencing effort of its viral agent SARS-CoV-2. The first whole genome assembly of SARS-CoV-2 was published on January 5 2020. Since then, over 150,000 high-quality SARS-CoV-2 genomes have been made available. This large genomic resource has allowed tracing of the emergence and spread of mutations and phylogenetic reconstruction of SARS-CoV-2 lineages in near real time. Though, whether SARS-CoV-2 undergoes genetic recombination has been largely overlooked to date. Recombination-mediated rearrangement of variants that arose independently can be of major evolutionary importance. Moreover, the absence of recombination is a key assumption behind the application of phylogenetic inference methods. Here, we analyse the extant genomic diversity of SARS-CoV-2 and show that, to date, there is no detectable hallmark of recombination. We assess our detection power using simulations and validate our method on the related MERS-CoV for which we report evidence for widespread genetic recombination.
CRISPR knockdown of GABAAalpha3 subunits on thalamic reticular neurons enhances deep sleep
Authors: Uygun David S. , Yang Chun , Tilli Elena R. , Katsuki Fumi , McKenna James T. , McNally James M. , Brown Ritchie E. , Basheer Radhika 
Published: December 2020

AbstractIdentification of mechanisms which increase deep sleep could lead to novel treatments which promote the restorative effects of sleep. Here, knockdown of the α3 GABAA-receptor subunit from parvalbumin neurons in the thalamic reticular nucleus using CRISPR-Cas9 gene editing increased the thalamocortical delta oscillations implicated in many health-promoting effects of sleep. Inhibitory synaptic currents were strongly reducedin vitro. Effects were most pronounced in the mouse sleep (light) period. Further analysis identified a novel deep-sleep state in mice prior to NREM-REM transitions which was preferentially affected by deletion of α3 subunits. Our results identify a functional role for GABAAreceptors on Thalamic Reticular Nucleus neurons and suggest antagonism of α3 subunits as a strategy to enhance deep sleep.One Sentence SummarySelective genetic knockdown of the major α subunit of GABAAreceptors present in the thalamic reticular nucleus enhanced deep sleep in mice.
A diencephalic circuit for opioid analgesia but not positive reinforcement
Authors: Waung Maggie W. , Maanum Kayla A. , Cirino Thomas J. , Driscoll Joseph R. , O’Brien Chris , Bryant Svetlana , Mansourian Kasra A. , Morales Marisela , Barker David J. , Margolis Elyssa B. 
Published: December 2020

AbstractMu opioid receptor (MOR) agonists are potent analgesics, but also cause sedation, respiratory depression, and addiction risk. The epithalamic lateral habenula (LHb) signals aversive states including pain and we found it is a potent site for MOR-agonist analgesia. Importantly, LHb MOR activation is not reinforcing in the absence of noxious input. The LHb receives excitatory inputs from multiple sites including the ventral tegmental area, lateral hypothalamus, entopeduncular nucleus, and the lateral preoptic area of the hypothalamus (LPO). Here we report that LHb-projecting glutamatergic LPO neurons are excited by noxious stimulation and are preferentially inhibited by MOR selective agonists. Critically, optogenetic stimulation of LHb-projecting LPO neurons produces an aversive state that is relieved by LHb MOR activation, and optogenetic inhibition of LHb-projecting LPO neurons relieves the aversiveness of ongoing pain. Therefore, targeting this MOR sensitive forebrain circuit can relieve pain yet lower the risk of misuse by pain free individuals.
Vaginal squamous cell carcinoma develops in mice withArid1aloss and gain of oncogenicKras
Authors: Wang Xiyin , Praça Mariana S. L. , Wendel Jillian R. H. , Emerson Robert E. , DeMayo Francesco J. , Lydon John P. , Hawkins Shannon M. 
Published: December 2020

AbstractRecent sequencing studies showed that loss-of-function mutations inARID1A(AT-rich interactive domain 1a) were enriched in gynecologic malignancies. However, multiple mouse models with deletion ofArid1adid not exhibit gynecologic malignancy. OncogenicKRASmutations are a common finding in endometrial cancers. However, expression of oncogenic Kras (KrasG12D) in the uterus was not sufficient to develop endometrial cancer. These results suggest that both ARID1A deletion and oncogenic KRAS require additional hits before driving gynecologic malignancy. To determine the role of the combination effects of deletion ofArid1aand oncogenicKras, Arid1aflox/floxmice were crossed toKrasLox-Stop-Lox-G12D/+mice using progesterone receptor Cre (PgrCre/+). Survival studies, histology, and immunohistochemistry were used to characterize the phenotype. Hormone dependence was evaluated by ovarian hormone depletion and estradiol replacement.Arid1aflox/flox;KrasLox-Stop-Lox-G12D/+;PgrCre/+(AKP) mice exhibited early euthanasia due to large vaginal tumors, which were invasive squamous cell carcinoma. Younger mice exhibited precancerous intraepithelial lesions that progressed to invasive squamous cell carcinoma with age. Immunohistochemistry supported the pathological diagnosis with abnormal expression and localization of cytokeratin 5, tumor protein P63, cyclin dependent kinase inhibitor 2A (CDKN2A or p16), and marker of proliferation Ki-67. Vaginal lesions in AKP mice were hormone dependent. Ovarian hormone deletion in AKP mice resulted in atrophic vaginal epithelium without evidence of vaginal tumors. Estradiol replacement in ovarian hormone depleted AKP mice resulted in lesions that resembled the squamous cell carcinoma in intact mice. AKP mice did not develop endometrial cancer.Arid1adeletion withKrasG12Dexpression drives invasive vaginal squamous cell carcinoma. This mouse can be used to study the transition from benign precursor lesions into invasive vaginal squamous cell carcinoma offering insights into progression.
Three decades of green advertising – a review of literature and bibliometric analysis
Authors: Agarwal Neha Dhruv , Kumar V.V. Ravi 
Published: December 2020

PurposeThe purpose of this paper is to present an overview of the research which has been done during the past three decades on the topic of green advertising and identify gaps for future research.Design/methodology/approachThe methodology that has been adopted for analysis is two-pronged – the first being a literature review with tabulation of data using excel sheets and bar graphs and the second being a bibliometric review using the software VOSviewer. Both approaches analyze the number of citations, keywords, authors, journals and countries. A database of 113 articles from 1990 to 2020 is generated from Web of Science.FindingsMajor contributors to the topic of green advertising research have been identified. Thematic classification is created to understand the subtopics of green advertising. Under this classification, nine subtopics have been identified. Six core research gaps have been identified for future research in the area of green advertising.Practical implicationsThe study helps identify where green advertising research is being conducted, its growth potential and future prospects. This research work will enable the industry to gain new insights into this emerging field of green advertising for incorporating the same in their advertising campaigns in view of growing consumer concerns on environment.Originality/valueThe paper provides a comprehensive overview of the current status of research in green advertising. The paper is unique as it is the only review on the topic of green advertising. Given the increasing trend of going green among consumers, the paper adds tremendous value to the field of green advertising.