bluuebunny/crossref_metadata_2025_split huggingface dataset:
Post-outbreak surveillance strategies to support proof of freedom from foot-and-mouth disease
Authors: Bradhurst Richard , Garner Graeme , East Iain , Death Clare , Dodd Aaron , Kompas Tom 
Published: April 2021

AbstractWhilst emergency vaccination may help contain foot-and-mouth disease in a previously FMD-free country, its use complicates post-outbreak surveillance and the recovery of FMD-free status. A structured surveillance program is required that can distinguish between vaccinated and residually infected animals, and provide statistical confidence that the virus is no longer circulating in previously infected areas.Epidemiological models have been well-used to investigate the potential benefits of emergency vaccination during a control progam and when/where/whom to vaccinate in the face of finite supplies of vaccine and personnel. Less well studied are post-outbreak issues such as the management of vaccinated animals and the implications of having used vaccination during surveillance regimes to support proof-of-freedom. This paper presents enhancements to the Australian Animal Disease Model (AADIS) that allow comparisons of different post-outbreak surveillance sampling regimes for establishing proof-of-freedom from FMD.A case study is provided that compares a baseline surveillance sampling regime (derived from current OIE guidelines), with an alternative less intensive sampling regime. It was found that when vaccination was not part of the control program, a reduced sampling intensity significantly reduced the number of samples collected and the cost of the post-outbreak surveillance program, without increasing the risk of missing residual infected herds.
Th17 T cells and immature dendritic cells are the preferential initial targets after rectal challenge with an SIV-based replication-defective dual-reporter vector
Authors: Maric Danijela , Grimm Wesley A. , Greco Natalie , McRaven Michael D. , Fought Angela J. , Veazey Ronald S. , Hope Thomas J. 
Published: April 2021

ABSTRACTUnderstanding the earliest events of HIV sexual transmission is critical to develop and optimize HIV prevention strategies. To gain insights into the earliest steps of HIV rectal transmission, including cellular targets, rhesus macaques were intra-rectally challenged with a single-round SIV-based dual reporter that expresses luciferase and iRFP670 upon productive transduction. The vector was pseudotyped with the HIV-1 envelope JRFL. Regions of tissue containingfociof luminescent, transduced cells were identified macroscopically using anin vivoimaging system, and individual transduced cells expressing fluorescent protein were identified and phenotyped microscopically. This system revealed that anal and rectal tissues are both susceptible to transduction 48 hours after the rectal challenge. Detailed phenotypic analysis revealed that on average, 62% of transduced cells are CCR6+T cells—the vast majority of which express RORγT, a Th17 lineage-specific transcription factor. The second most common target cells were immature dendritic cells at 20%. These two cell types were transduced at the rates that are four to five times higher than their relative abundances indicate. Our work demonstrates that Th17 T and immature dendritic cells are preferential initial targets of HIV/SIV rectal transmission.IMPORTANCEMen and women who participate in unprotected receptive anal intercourse are at high risk for acquiring HIV. Whilein vitrodata have developed a framework for understanding HIV cell tropism, the initial target cells in the rectal mucosa have not been identified. In this study, we identify these early host cells by using an innovative rhesus macaque rectal challenge model and methodology, which we previously developed. Thus, by shedding light on these early HIV/SIV transmission events, this study provides a specific cellular target for future prevention strategies.
Sewage PromotesVibrio vulnificusGrowth and Alters Gene Expression
Authors: Conrad James W. , Harwood Valerie J. 
Published: April 2021

AbstractVibrio vulnificusis a naturally-occurring, potentially lethal pathogen found in coastal waters, fish, and shellfish. Sewage spills in coastal waters occur when infrastructure fails due to severe storms or age, and may affect bacterial populations by altering nutrient levels. This study investigated effects of sewage on clonal and naturalV. vulnificuspopulations in microcosms. Addition of 1% sewage to estuarine water caused the density of a pure culture ofV. vulnificusCMCP6 and a naturalV. vulnificuspopulation to increase significantly, whether measured by qPCR or culture. Changes in the transcription of six virulence- and survival-associated genes in response to sewage were assessed using continuous culture. Exposure to sewage affected transcription of genes that may be associated with virulence. Specifically, sewage modulated the oxidative stress response by altering superoxide dismutase transcription, significantly increasingsodBtranscription while repressingsodA. Sewage also repressed transcription ofnptA, which encodes a sodium-phosphate cotransporter. Sewage had no effect onsodCtranscription or the putative virulence-associated geneshupAorwza. The effects of environmentally relevant levels of sewage onV. vulnificuspopulations and gene transcription suggest that sewage spills that impact warm coastal waters could lead to an increased risk ofV. vulnificusinfections.ImportanceVibrio vulnificusinfections have profound impacts such as limb amputation and death for individuals with predisposing conditions. The warming climate is contributing to risingV. vulnificusprevalence in waters that were previously too cold to support high levels of the pathogen. Climate change is also expected to increase precipitation in many regions, which puts more pressure on wastewater infrastructure and will result in more frequent sewage spills. The finding that 1% wastewater in estuarine water leads to tenfold to 1000-fold greaterV. vulnificusconcentrations suggests that human exposure to oysters and estuarine water could have greater health impacts in the future. Further, wastewater had a significant effect on gene transcription and has the potential to affect virulence during the initial environment-to-host transition.
Quantitative systems pharmacology modeling of avadomide-induced neutropenia enables virtual clinical dose and schedule finding studies
Authors: Abbiati Roberto A. , Pourdehnad Michael , Carrancio Soraya , Pierce Daniel W. , Kasibhatla Shailaja , McConnell Mark , Trotter Matthew W. B. , Loos Remco , Santini Cristina C. , Ratushny Alexander V. 
Published: April 2021

AbstractAvadomide is a cereblon E3 ligase modulator and a potent antitumor and immunomodulatory agent. Avadomide trials are challenged by neutropenia as a major adverse event and a dose-limiting toxicity. Intermittent dosing schedules supported by preclinical data provide a strategy to reduce frequency and severity of neutropenia, however the identification of optimal dosing schedules remains a clinical challenge.Quantitative Systems Pharmacology (QSP) modeling offers opportunities for virtual screening of efficacy and toxicity levels produced by alternative dose and schedule regimens, thereby supporting decision-making in translational drug development.We formulated a QSP model to capture the mechanism of avadomide-induced neutropenia, which involves cereblon-mediated degradation of transcription factor Ikaros, resulting in a maturation block of the neutrophil lineage.The neutropenia model was integrated with avadomide-specific pharmacokinetic and pharmacodynamic models to capture dose-dependent effects. Additionally, we generated a disease-specific virtual patient population to represent the variability in patient characteristics and response to treatment observed for a diffuse large B-cell lymphoma trial cohort.Model utility was demonstrated by simulating avadomide effect in the virtual population for various dosing schedules and determining the incidence of high-grade neutropenia, its duration, and the probability of recovery to low grade-neutropenia.
Lizard feeding enhancesIxodes pacificusvector competency
Authors: Ring Kacie , Couper Lisa , Sapiro Anne L. , Yarza Fauna , Yang X. Frank , Clay Keith , Mateusiak Chase , Chou Seemay , Swei Andrea 
Published: April 2021

AbstractA vector’s susceptibility and ability to transmit a pathogen— termed vector competency—determines disease outcomes, yet the ecological factors influencing tick vector competency remain largely unknown.Ixodes pacificus, the vector ofBorrelia burgdorferi(Bb) in the western U.S., feeds on rodents, birds, and lizards. While rodents and birds are reservoirs forBband infect juvenile ticks, lizards areBb-refractory. DespiteI. pacificusfeeding on a range of hosts, it is undetermined how larval host bloodmeal identity affects future nymphal vector competency. We experimentally evaluate the influence of larval host bloodmeal onBbacquisition by nymphalI. pacificus. LarvalI. pacificuswere fed on either lizards or mice and after molting, nymphs were fed onBb-infected mice. We found that lizard-fed larvae were significantly more likely to become infected withBbduring their next bloodmeal than mouse-fed larvae. We also conducted the first RNA-seq analysis on whole-bodiedI. pacificusand found significant upregulation of antioxidants and antimicrobial peptides in the lizard-fed group. Our results indicate that the lizard bloodmeal significantly alters vector competency and gene regulation in ticks, highlighting the importance of host bloodmeal identity in disease transmission and upends prior notions about the role of lizards in Lyme disease transmission.
Social steerability modulates perceptual biases
Authors: Anlló Hernán , Watanabe Katsumi , Sackur Jérôme , de Gardelle Vincent 
Published: April 2021

AbstractVerbal hints can bias perceptual decision-making, even when the information they provide is false. Whether individuals may be more or less susceptible to such perceptual influences, however, remains unclear. We asked naive participants to indicate the dominant color in a series of stimuli, after giving them a false statement about which color would likely dominate. As anticipated, this statement biased participants’ perception of the dominant color, as shown by a correlated shift of their perceptual decisions, confidence judgments and response times. Crucially, this perceptual bias was more pronounced in participants with higher levels of susceptibility to social influence, as measured by a standard suggestibility scale. Together, these results indicate that even without much apparatus, simple verbal hints can affect our perceptual reality, and that social steerability can determine how much they do so. Susceptibility to suggestion might thus be considered an integral part of perceptual processing.Statement of relevanceAt a time when fake news soar, understanding the role that simple verbal descriptions play in how we perceive the world around us is paramount. Extensive research has shown that perception is permeable to well-orchestrated manipulation. Comparatively less attention has been paid to the perceptual impact of false information when the latter is imparted simply and straightforwardly, through short verbal hints and instructions. Here we show that even a single sentence suffices to bias perceptual decision-making, and that critically, this bias varies across individuals as a function of susceptibility to social influence. Considering how here perception was biased by a single, plain sentence, we argue that researchers, communicators and policy-makers should pay careful attention to the role that social suggestibility plays in how we build our perceptual reality.
Clonal inactivation of telomerase promotes accelerated stem cell differentiation
Authors: Hasegawa Kazuteru , Zhao Yang , Garbuzov Alina , Corces M. Ryan , Chen Lu , Cheung Peggie , Wei Yuning , Chang Howard Y. , Artandi Steven E. 
Published: April 2021

SummaryTelomerase is intimately associated with stem cells and upregulated in cancer, where it serves essential roles through its catalytic action in elongating telomeres, nucleoprotein caps that protect chromosome ends1. Overexpression of the telomerase reverse transcriptase (TERT) enhances cell proliferation through telomere-independent means, yet definitive evidence for such a direct role in stem cell function has yet to be revealed through loss-of-function studies. Here, we show that conditional deletion of TERT in spermatogonial stem cells (SSCs) markedly impairs competitive clone formation. Using lineage-tracing from theTertlocus, we find that TERT-expressing SSCs yield long-lived clones, but that selective TERT-inactivation in SSCs causes accelerated stem cell differentiation thereby disrupting clone formation. This requirement for TERT in clone formation is bypassed by expression of a catalytically inactive TERT transgene and occurs independently of the canonical telomerase complex. TERT inactivation induces a genome-wide reduction in open chromatin evident in purified SSCs, but not in committed progenitor cells. Loss of TERT causes reduced activity of the MYC oncogene and transgenic expression of MYC in TERT-deleted SSCs efficiently rescues clone formation. These data reveal a required catalytic activity-independent role for TERT in preventing stem cell differentiation, forge a genetic link between TERT and MYC and suggest new means by which TERT may promote tumorigenesis.
Benchmarking a highly selective USP30 inhibitor for enhancement of mitophagy and pexophagy
Authors: Rusilowicz-Jones Emma V. , Barone Francesco G. , Lopes Fernanda Martins , Stephen Elizabeth , Mortiboys Heather , Urbé Sylvie , Clague Michael J. 
Published: April 2021

AbstractThe deubiquitylase USP30 is an actionable target considered for treatment of conditions associated with defects in the PINK1/Parkin pathway leading to mitophagy. These include Parkinson’s disease and pulmonary fibrosis. We provide a detailed cell biological characterisation of a benzenesulphonamide molecule, compound 39, that has previously been reported to inhibit USP30 in anin vitroenzymatic assay. The current compound offers increased selectivity over previously described inhibitors. It enhances mitophagy and generates a signature response for USP30 inhibition following mitochondrial depolarisation. This includes enhancement of TOM20 and SYNJ2BP ubiquitylation and phosphoubiquitin accumulation, alongside increased mitophagy. In dopaminergic neurons, generated from Parkinson’s disease patients carrying loss of function Parkin mutations, compound 39 could significantly restore mitophagy to a level approaching control values. USP30 is located on both mitochondria and peroxisomes and has also been linked to the PINK1 independent pexophagy pathway. Using a fluorescence reporter of pexophagy expressed in U20S cells, we observe increased pexophagy upon application of compound 39 that recapitulates the previously described effect for USP30 depletion. This provides the first pharmacological intervention with a synthetic molecule to enhance peroxisome turnover.
DTI-Voodoo: machine learning over interaction networks and ontology-based background knowledge predicts drug–target interactions
Authors: Hinnerichs Tilman , Hoehndorf Robert 
Published: April 2021

AbstractMotivationIn silicodrug–target interaction (DTI) prediction is important for drug discovery and drug repurposing. Approaches to predict DTIs can proceed indirectly, top-down, using phenotypic effects of drugs to identify potential drug targets, or they can be direct, bottom-up and use molecular information to directly predict binding potentials. Both approaches can be combined with information about interaction networks.ResultsWe developed DTI-Voodoo as a computational method that combines molecular features and ontology-encoded phenotypic effects of drugs with protein–protein interaction networks, and uses a graph convolutional neural network to predict DTIs. We demonstrate that drug effect features can exploit information in the interaction network whereas molecular features do not. DTI-Voodoo is designed to predict candidate drugs for a given protein; we use this formulation to show that common DTI datasets contain intrinsic biases with major affects on performance evaluation and comparison of DTI prediction methods. Using a modified evaluation scheme, we demonstrate that DTI-Voodoo improves significantly over state of the art DTI prediction methods.AvailabilityDTI-Voodoo source code and data necessary to reproduce results are freely available athttps://github.com/THinnerichs/DTI-VOODOO.Contacttilman.hinnerichs@kaust.edu.saSupplementary informationSupplementary data are available athttps://github.com/THinnerichs/DTI-VOODOO.
Highly variable fidelity drives symbiont community composition in an obligate symbiosis
Authors: Mankowski Anna , Kleiner Manuel , Erséus Christer , Leisch Nikolaus , Sato Yui , Volland Jean-Marie , Hüttel Bruno , Wentrup Cecilia , Woyke Tanja , Wippler Juliane , Dubilier Nicole , Gruber-Vodicka Harald 
Published: April 2021

AbstractMany animals are obligately associated with microbial symbionts that provide essential services such as nutrition or protection against predators. It is assumed that in such obligate associations fidelity between the host and its symbionts must be high to ensure the evolutionary success of the symbiosis. We show here that this is not the case in marine oligochaete worms, despite the fact that they are so dependent on their bacterial symbionts for their nutrition and waste recycling that they have lost their digestive and excretory systems. Our metagenomic analyses of 64 gutless oligochaete species from around the world revealed highly variable levels of fidelity not only across symbiont lineages, but also within symbiont clades. We hypothesize that in gutless oligochaetes, selection within host species for locally adapted and temporally stable symbiont communities leads to varying levels of symbiont fidelity and shuffles the composition of symbiont assemblages across geographic and evolutionary scales.
Adhesion-growth factor crosstalk regulates AURKB activation and ERK signaling in re-adherent fibroblasts
Authors: Inchanalkar Siddhi , Balasubramanian Nagaraj 
Published: April 2021

AbstractAurora kinases despite their similarity have distinct roles in the cell cycle, which is regulated by cell-matrix adhesion and growth factors. This study reveals loss of adhesion and re-adhesion to differentially regulate Aurora kinases. AURKB activation that drops on the loss of adhesion recovers on re-adhesion in serum-deprived conditions but not in the presence of serum growth factors. A rapid 30min serum treatment of serum-deprived cells blocks the adhesion-dependent recovery of AURKB, which negatively corelates with Erk activation. AZD mediated inhibition of AURKB in serum-deprived re-adherent cells promotes Erk activation and membrane ruffling, comparable to presence of serum. These studies thus define a novel adhesion-growth factor-dependent regulation of AURKB that controls adhesion-dependent Erk activation in re-adherent fibroblasts.
The evolution of regulatory elements in the emerging promoter variant strains of HIV-1
Authors: Bhange Disha , Prasad Nityanand , Singh Swati , Prajapati Harshit Kumar , Maurya Shesh Prakash , Gopalan Bindu Parachalil , Nadig Sowmya , Chaturbhuj Devidas , Boobalan Jayaseelan , Dinesha Thongadi Ramesh , Ahamed Syed Fazil , Singh Navneet , Brahmaiah Anangi , Mehta Kavita , Gohil Yuvrajsinh , Balakrishnan Pachamuthu , Das Bimal Kumar , Dias Mary , Gangakhedkar Raman , Mehendale Sanjay , Paranjape Ramesh , Saravanan Shanmugam , Shet Anita , Solomon Sunil Suhas , Thakar Madhuri , Ranga Udaykumar 
Published: April 2021

AbstractIn a multicentric, observational, investigator-blinded, and longitudinal clinical study of 764 ART-naïve subjects, we identified nine different promoter-variant strains of HIV-1 subtype C (HIV-1C) emerging in the Indian population, with some of these variants being reported for the first time. Unlike several previous studies, our work here focuses on the evolving viral regulatory elements, not coding sequences. The emerging viral strains contain additional copies of the existing transcription factor binding sites (TFBS), including TCF-1α/LEF-1, RBEIII, AP-1, and NF-κB, created by sequence duplication. The additional TFBS are genetically diverse and may blur the distinction between the modulatory region of the promoter and the viral enhancer. In a follow-up analysis, we found trends, but not significant associations between any specific variant promoter and prognostic markers, probably because the emerging viral strains might not have established mono infections yet. Illumina sequencing of four clinical samples containing a co-infection indicated the domination of one strain over the other and establishing a stable ratio with the second strain at the follow-up time-points. Since a single promoter regulates viral gene expression and constitutes the master regulatory circuit with Tat, the acquisition of additional and variant copies of the TFBS may significantly impact viral latency and latent reservoir characteristics. Further studies are urgently warranted to understand how the diverse TFBS profiles of the viral promoter may modulate the characteristics of the latent reservoir, especially following the initiation of antiretroviral therapy.Significance StatementA unique conglomeration of TFBS enables the HIV-1 promoter to accomplish two diametrically opposite functions – transcriptional activation and transcriptional silencing. The various phases of viral latency -establishment, maintenance, and reversal -collectively determine the replication fitness of individual viral strains. A profound variation in the TFBS composition of the viral promoter may significantly alter the viral latency properties and the latent reservoir characteristics. Although the duplication of certain TFBS remains a quality unique to HIV-1C, the high-level genetic recombination of HIV-1 may promote the transfer of such molecular properties to the other HIV-1 subtypes. The emergence of several promoter-variant viral strains may make the task of a ‘functional cure’ more challenging in HIV-1C.
Judgments of agency are affected by sensory noise without recruiting metacognitive processing
Authors: Constant Marika , Salomon Roy , Filevich Elisa 
Published: April 2021

AbstractJudgments of agency, our sense of control over our actions and the environment, often occur in noisy conditions. We examined the computations underlying judgments of agency, in particular under the influence of sensory noise. Building on previous literature, we studied whether judgments of agency incorporate uncertainty in the same way that confidence judgments do, which would imply that the former share computational mechanisms with metacognitive judgments. In two tasks, participants rated agency, or confidence in a decision about their agency, over a virtual hand that tracked their movements, either synchronously or with a delay and either under high or low noise. We compared the predictions of two computational models to participants’ ratings and found that agency ratings, unlike confidence, were best explained by a model involving no estimates of sensory noise. We propose that agency judgments reflect first-order measures of the internal signal, without involving metacognitive computations, challenging the assumed link between the two cognitive processes.