bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prion infection, transmission and cytopathology modelled in a low-biohazard human cell line
Authors: Avar Merve , Heinzer Daniel , Steinke Nicolas , Doğançay Berre , Moos Rita , Lugan Severine , Cosenza Claudia , Hornemann Simone , Andréoletti Olivier , Aguzzi Adriano 
Published: April 2020

AbstractTransmission of prion infectivity to susceptible murine cell lines has simplified prion titration assays and has greatly reduced the need for animal experimentation. However, murine cell models suffer from technical and biological constraints. Human cell lines might be more useful, but they are much more biohazardous and are often poorly infectible. Here we describe the human clonal cell line hovS, which lacks the humanPRNPgene and expresses instead the ovinePRNPVRQ allele. HovS cells were highly susceptible to the PG127 strain of sheep-derived murine prions, reaching up to 90% infected cells in any given culture, and were maintained in a continuous infected state for at least 14 passages. Infected hovS cells produced proteinase K-resistant prion protein (PrPSc), pelletable PrP aggregates andbona fideinfectious prions capable of infecting further generations of naïve hovS cells and mice expressing the VRQ allelic variant of ovine PrPC. Infection in hovS led to prominent cytopathic vacuolation akin to the spongiform changes observed in individuals suffering from prion diseases. In addition to expanding the toolbox for prion research to human experimental genetics, the hovS cell line provides a human-derived system that does not require human prions. Hence, the manipulation of scrapie-infected hovS cells may present fewer biosafety hazards than that of genuine human prions.
Dopaminergic signalling modulates reward-driven music memory consolidation
Authors: Ferreri Laura , Mas-Herrero Ernest , Cardona Gemma , Zatorre Robert J. , Antonijoan Rosa M. , Valle Marta , Riba Jordi , Ripollés Pablo , Rodriguez-Fornells Antoni 
Published: April 2020

AbstractPreviously, we providedcausalevidence for a dopamine-dependent effect of intrinsic reward on memory during self-regulated learning (Ripollés et al., 2016; Ripollés et al., 2018). Here, we further investigated the dopamine-dependent link between reward and memory by focusing on one of the most iconicabstractrewards in humans: music. Twenty-nine healthy participants listened to unfamiliar excerpts—which had to be remembered following a consolidation period—after the intake of a dopaminergic antagonist, a dopaminergic precursor, and a placebo across three separated sessions. The intervention modulated the pleasantness experienced during music-listening and memory recognition of the presented songs (i.e., lower with the antagonist, higher with the precursor) in individuals with higher sensitivity to musical reward. Our work highlights the flexibility of the human dopaminergic system, which is able to enhance memory formation not only through explicit and/or primary reinforcers but also via intrinsic, abstract, or aesthetic rewards of different natures.
A high-density human mitochondrial proximity interaction network
Authors: Antonicka Hana , Lin Zhen-Yuan , Janer Alexandre , Weraarpachai Woranontee , Gingras Anne-Claude , Shoubridge Eric A. 
Published: April 2020

SummaryWe used BioID, a proximity-dependent biotinylation assay, to interrogate 100 mitochondrial baits from all mitochondrial sub-compartments to create a high resolution human mitochondrial proximity interaction network. We identified 1465 proteins, producing 15626 unique high confidence proximity interactions. Of these, 528 proteins were previously annotated as mitochondrial, nearly half of the mitochondrial proteome defined by Mitocarta 2.0. Bait-bait analysis showed a clear separation of mitochondrial compartments, and correlation analysis among preys across all baits allowed us to identify functional clusters involved in diverse mitochondrial functions, and to assign uncharacterized proteins to specific modules. We demonstrate that this analysis can assign isoforms of the same mitochondrial protein to different mitochondrial sub-compartments, and show that some proteins may have multiple cellular locations. Outer membrane baits showed specific proximity interactions with cytosolic proteins and proteins in other organellar membranes, suggesting specialization of proteins responsible for contact site formation between mitochondria and individual organelles. This proximity network will be a valuable resource for exploring the biology of uncharacterized mitochondrial proteins, the interactions of mitochondria with other cellular organelles, and will provide a framework to interpret alterations in sub-mitochondrial environments associated with mitochondrial disease.Bullet pointsWe created a high resolution human mitochondrial protein proximity map using BioIDBait-bait analysis showed that the map has sub-compartment resolution and correlation analysis of preys identified functional clusters and assigned proteins to specific modulesWe identified isoforms of matrix and IMS proteins with multiple cellular localizations and an endonuclease that localizes to both the matrix and the OMMOMM baits showed specific interactions with non-mitochondrial proteins reflecting organellar contact sites and protein dual localization
A quantitative model for metabolic intervention using gut microbes
Authors: Mays Zachary JS , Nair Nikhil U 
Published: April 2020

AbstractAs medicine shifts toward precision-based and personalized therapeutics, utilizing more complex biomolecules to treat increasingly difficult and rare conditions, microorganisms provide an avenue for realizing the production and processing necessary for novel drug pipelines. More so, probiotic microbes can be co-opted to deliver therapeutics by oral administration as living drugs, able to survive and safely transit the digestive tract. As living therapeutics are in their nascency, traditional pharmacokinetic-pharmacodynamic (PK-PD) models for evaluating drug candidates are not appropriate for this novel platform. Using a living therapeutic in late-stage clinical development for phenylketonuria (PKU) as a case study, we adapt traditional oral drug delivery models to properly evaluate and inform the engineering of living therapeutics. We develop theadapted forlivingtherapeuticscompartmentalabsorption andtransit (ALT-CAT) model to provide metrics for drug efficacy across nine age groups of PKU patients and evaluate model parameters that are influenced by patient physiology, microbe selection and therapeutic production, and dosing formulations.ImportanceThis work describes a kinetic model to study the behavior of orally delivered living therapeutics. Such therapeutics are becoming increasingly relevant and are an exciting mode of drug delivery that stems from the growing interest through the convergence of advances in synthetic biology of probiotics and gut microbes as well as microbiome science. In particular, this work describes the development of a mathematical framework (pharmacokinetic-pharmacodynamic, PK-PD) called ALT-CAT to model the behavior of orally delivered engineered bacteria that act as living therapeutics by adapting similar methods that have been developed and widely-used for small molecular drug delivery and absorption.
Multiple freeze-thaw cycles lead to a loss of consistency in poly(A)-enriched RNA sequencing
Authors: Kellman Benjamin P. , Baghdassarian Hratch M. , Pramparo Tiziano , Shamie Isaac , Gazestani Vahid , Begzati Arjana , Li Shengzhong , Nalabolu Srinivasa , Murray Sarah , Lopez Linda , Pierce Karen , Courchesne Eric , Lewis Nathan E. 
Published: April 2020

AbstractRNA-Seq is ubiquitous, but depending on the study, sub-optimal sample handling may be required, resulting in repeated freeze-thaw cycles. However, little is known about how each cycle impacts downstream analyses, due to a lack of study and known limitations in common RNA quality metrics, e.g., RIN, at quantifying RNA degradation following repeated freeze-thaws. Here we quantify the impact of repeated freeze-thaw on the reliability of downstream RNA-Seq analysis. To do so, we developed a method to estimate the relative noise between technical replicates independently of RIN. Using this approach we inferred the effect of both RIN and the number of freeze-thaw cycles on sample noise. We find that RIN is unable to fully account for the change in sample noise due to freeze-thaw cycles. Additionally, freeze-thaw is detrimental to sample quality and differential expression (DE) reproducibility, approaching zero after three cycles for poly(A)-enriched samples, wherein the inherent 3’ bias in read coverage is more exacerbated by freeze-thaw cycles, while ribosome-depleted samples are less affected by freeze-thaws. The use of poly(A)-enrichment for RNA sequencing is pervasive in library preparation of frozen tissue, and thus, it is important during experimental design and data analysis to consider the impact of repeated freeze-thaw cycles on reproducibility.
Genome-wide association study in New YorkPhytophthora capsiciisolates reveals loci involved in mating type and mefenoxam sensitivity
Authors: Vogel Gregory , Gore Michael A. , Smart Christine D. 
Published: April 2020

AbstractPhytophthora capsiciis a soilborne oomycete plant pathogen that causes severe vegetable crop losses in New York (NY) State and worldwide. This pathogen is difficult to manage, in part due to its production of long-lasting sexual spores and its tendency to quickly evolve fungicide resistance. We single-nucleotide polymorphism (SNP) genotyped 252P. capsiciisolates, predominantly from NY, in order to conduct a genome-wide association study for mating type and mefenoxam insensitivity. The population structure and extent of chromosomal copy number variation in this collection of isolates were also characterized. Population structure analyses showed isolates largely clustered by the field site where they were collected, with values of FSTbetween pairs of fields ranging from 0.10 to 0.31. Thirty-three isolates were putative aneuploids, demonstrating evidence for having up to four linkage groups present in more than two copies, and an additional two isolates appeared to be genome-wide triploids. Mating type was mapped to a region on scaffold 4, consistent with previous findings, and mefenoxam insensitivity was associated with several SNP markers at a novel locus on scaffold 62. We identified several candidate genes for mefenoxam sensitivity, including a homolog of yeast ribosome synthesis factor Rrp5, but failed to locate near the scaffold 62 locus any subunits of RNA Polymerase I, the enzyme that has been hypothesized to be the target site of phenylamide fungicides in oomycetes. This work expands our knowledge of the population biology ofP. capsiciand provides a foundation for functional validation of candidate genes associated with epidemiologically important phenotypes.
Admixture has obscured signals of historical hard sweeps in humans
Authors: Souilmi Yassine , Tobler Raymond , Johar Angad , Williams Matthew , Grey Shane T. , Schmidt Joshua , Teixeira João C. , Rohrlach Adam , Tuke Jonathan , Johnson Olivia , Gower Graham , Turney Chris , Cox Murray , Cooper Alan , Huber Christian D. 
Published: April 2020

AbstractThe role of natural selection in shaping biological diversity is an area of intense interest in modern biology. To date, studies of positive selection have primarily relied upon genomic datasets from contemporary populations, which are susceptible to confounding factors associated with complex and often unknown aspects of population history. In particular, admixture between diverged populations can distort or hide prior selection events in modern genomes, though this process is not explicitly accounted for in most selection studies despite its apparent ubiquity in humans and other species. Through analyses of ancient and modern human genomes, we show that previously reported Holocene-era admixture has masked more than 50 historic hard sweeps in modern European genomes. Our results imply that this canonical mode of selection has likely been underappreciated in the evolutionary history of humans and suggests that our current understanding of the tempo and mode of selection in natural populations may be quite inaccurate.
Sufficiency of unidirectional allostery in KaiC in generating the cyanobacterial circadian rhythm
Authors: Koda Shin-ichi , Saito Shinji 
Published: April 2020

AbstractThe clock protein of cyanobacteria KaiC forms a homohexamer with two ring-shaped domains, C1 and C2. These domains undergo several domain-specific conformational transitions and allosterically communicate to generate a circadian rhythm. Interestingly, experiments show a possibility that C2 is independent of C1. However, detailed interplay among them remains elusive. Here we propose a mathematical model, which explicitly considers the interplay. The allostery in KaiC is here modeled to be unidirectional from C2 to C1. We demonstrate that the unidirectional allostery is sufficient for the circadian rhythm by showing the quantitative reproducibility of various experimental data, including temperature dependence of both phosphorylation oscillation and ATPase activity. Based on the present model, we further discuss possible functional roles of the unidirectional allostery particularly in the period robustness against both protein concentration and temperature.
Automatic identification of small molecules that promote cell conversion and reprogramming
Authors: Napolitano Francesco , Rapakoulia Trisevgeni , Annunziata Patrizia , Hasegawa Akira , Cardon Melissa , Napolitano Sara , Vaccaro Lorenzo , Iuliano Antonella , Wanderlingh Luca Giorgio , Kasukawa Takeya , Medina Diego L. , Cacchiarelli Davide , Gao Xin , di Bernardo Diego , Arner Erik 
Published: April 2020

AbstractControlling cell fate has great potential for regenerative medicine, drug discovery, and basic research. Although numerous transcription factors have been discovered that are able to promote cell reprogramming and trans-differentiation, methods based on their up-regulation tend to show low efficiency. The identification of small molecules that can facilitate conversion between cell types can ameliorate this problem working through safe, rapid, and reversible mechanisms. Here we present DECCODE, an unbiased computational method for the identification of such molecules solely based on transcriptional data. DECCODE matches the largest available collection of drug-induced profiles (the LINCS database) for drug treatments against the largest publicly available dataset of primary cell transcriptional profiles (FANTOM5), to identify drugs that either alone or in combination enhance cell reprogramming and cell conversion. Extensivein silicoandin vitrovalidation of DECCODE in the context of human induced pluripotent stem cells (hIPSCs) generation shows that the method is able to prioritize drugs enhancing cell reprogramming. We also generated predictions for cell conversion with single drugs and drug combinations for 145 different cell types and made them available for further studies.
Spatial variability in the risk of death from COVID-19 in 20 regions of Italy
Authors: Mizumoto Kenji , Dahal Sushma , Chowell Gerardo 
Published: April 2020

AbstractObjectivesItaly has been disproportionately affected by the COVID-19 pandemic, becoming the nation with the third highest death toll in the world as of May 10th, 2020. We analyzed the severity of COVID-19 pandemic across 20 Italian regions.MethodWe manually retrieved the daily cumulative numbers of laboratory-confirmed cases and deaths attributed to COVID-19 across 20 Italian regions. For each region, we estimated the crude case fatality ratio and time-delay adjusted case fatality ratio (aCFR). We then assessed the association between aCFR and sociodemographic, health care and transmission factors using multivariate regression analysis.ResultsThe overall aCFR in Italy was estimated at 17.4%. Lombardia exhibited the highest aCFR (24.7%) followed by Marche (19.3%), Emilia Romagna (17.7%) and Liguria (17.6%). Our aCFR estimate was greater than 10% for 12 regions. Our aCFR estimates were statistically associated with population density and cumulative morbidity rate in a multivariate analysis.ConclusionOur aCFR estimates for overall Italy and for 7 out of 20 regions exceeded those reported for the most affected region in China. Our findings highlight the importance of social distancing to suppress incidence and reduce the death risk by preventing saturating the health care system.
The Ecology of Antihypertensives in the United States, 1997-2017
Authors: Johansen Michael E. , Niforatos Joshua D. , Sussman Jeremey B. 
Published: April 2020

AbstractBackgroundAntihypertensives are the most used medication type in the United States, yet there remains uncertainty about the use of different antihypertensives. We sought to characterize use of antihypertensives by and within medication class(es) between 1997-2017.MethodsA repeated cross-sectional study of 493,596 adult individuals using the 1997-2017 Medical Expenditure Panel Survey (MEPS). The Orange Book and published research were used for adjunctive information. The primary outcome was the estimated use by and within anti-hypertensive medication class(es).ResultsThe proportion of individuals taking any antihypertensive during a year increased from 1997 to the early 2010’s and then remained stable. The proportion of the population taking 2 or more medications declined from 2015-2017. The proportion of adults using angiotensin II receptor-blockers (ARBs) and dihydropyridine calcium channel-blockers (CCBs) increased during the study period, while angiotensin-converting enzyme inhibitors (ACE-Is) increased until 2010 after which rates remained stable. Beta-blocker use was similar to ACE-Is with an earlier decline starting in 2012. Thiazide diuretic use increased from 1997-2007, leveled off until 2014, and declined from 2015-2017. Non-dihydropyridine CCBs use declined throughout the study. ACE-Is, ARBs, CCBs, thiazide diuretics, and loop diuretics all had one dominant in-class medication. There was a clear increase in the use of losartan within ARBs, lisinopril within ACE-Is, and amlodipine within CCBs following generic conversion. Furosemide and hydrochlorothiazide started with and maintained a dominant position in their classes. Metoprolol use increased throughout the study and became the dominant beta-blocker, while atenolol peaked around 2005 and then declined thereafter.ConclusionsAntihypertensive classes appear to have a propensity to equilibrate to an individual medication, despite a lack of outcomes based research to compare medications within a class. Future research could focus on comparative effectiveness for within-class medications early in the life cycle of therapeutics that are probable to have wide spread use.
Using influenza surveillance networks to estimate state-specific case detection rates and forecast SARS-CoV-2 spread in the United States
Authors: Silverman Justin D. , Hupert Nathaniel , Washburne Alex D. 
Published: April 2020

AbstractDetection of SARS-CoV-2 infections to date has relied on RT-PCR testing. However, a failure to identify early cases imported to a country, bottlenecks in RT-PCR testing, and the existence of infections which are asymptomatic, sub-clinical, or with an alternative presentation than the standard cough and fever have resulted in an under-counting of the true prevalence of SARS-CoV-2. Here, we show how publicly available CDC influenza-like illness (ILI) outpatient surveillance data can be repurposed to estimate the detection rate of symptomatic SARS-CoV-2 infections. We find a surge of non-influenza ILI above the seasonal average and show that this surge is correlated with COVID case counts across states. By quantifying the number of excess ILI patients in March relative to previous years and comparing excess ILI to confirmed COVID case counts, we estimate the syndromic case detection rate of SARS-CoV-2 in the US to be less than 13%. If only 1/3 of patients infected with SARS-CoV-2 sought care, the ILI surge would correspond to more than 8.7 million new SARS-CoV-2 infections across the US during the three week period from March 8 to March 28. Combining excess ILI counts with the date of onset of community transmission in the US, we also show that the early epidemic in the US was unlikely to be doubling slower than every 4 days. Together these results suggest a conceptual model for the COVID epidemic in the US in which rapid spread across the US are combined with a large population of infected patients with presumably mild-to-moderate clinical symptoms. We emphasize the importance of testing these findings with seroprevalence data, and discuss the broader potential to use syndromic time series for early detection and understanding of emerging infectious diseases.
The scar constituent Collagen I triggers coordinated collective migration and invasion in a 3D spheroid model of early endometriotic lesions
Authors: Stejskalova Anna , Fincke Victoria , Nowak Melissa , Schmidt Yvonne , von Wahlde Marie-Kristin , Schäfer Sebastian D. , Kiesel Ludwig , Greve Burkhard , Götte Martin 
Published: April 2020

AbstractEndometriosis is a painful gynaecological condition characterized by ectopic growth of endometrial cells outside of the uterus. Little is known about the mechanisms by which endometrial fragments invade tissues. This is partially due to a lack of suitable experimental models. In this study, we show that a spheroid 3D model, but not single cells mimic the collective endometrial fragment-like invasion through the extracellular matrix. This model reveals that collagen I, the main constituent of surgical scars, significantly increases the rate of lesion formation by healthy endometrial stromal cells (St-T1b) in vitro compared to the basement membrane-like matrix Matrigel. Stromal cell invasion of collagen I requires MMPs, whereas collective migration of endometriotic epithelial 12Z cells involves Rac-signalling. We show that inhibiting ROCK signalling responsible for actomyosin contraction increases the lesion-size. Moreover, endometriotic epithelial 12Z cells, but not eutopic stromal cells St-T1b migrate on Matrigel. The rate of this migration is decreased by the microRNA miR-200b and increased by miR-145. Our 3D model offers a facile approach to dissect how endometrial fragments invade tissues and is an important step toward developing new personalized therapeutics for endometriosis. Moreover, our model is a suitable tool to screen small molecule drugs and microRNA-based therapeutics.
RANDOMIZE: A Web Server for Data Randomization
Authors: Wani Agaz H , Armstrong D , Dahrendorff Jan , Uddin Monica 
Published: April 2020

AbstractSummaryDNA methylation microarray data may suffer from batch effects due to improper handling of the samples during the plating process. RANDOMIZE is a web-based application designed to perform randomization of relevant metadata to evenly distribute samples across the factors typically responsible for batch effects in DNA methylation microarrays, such as row, chips and plates. Randomization helps to reduce the likelihood of bias and impact of difference among groups.AvailabilityThe tool is freely available online athttps://coph-usf.shinyapps.io/RANDOMIZE/and can be accessed using any web browser. Sample data and tutorial is also available with the tool.Contactahwani@usf.edu