bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pigs as a new behavioral model for studying Pavlovian eyeblink conditioning
Authors: Boele Henk-Jan , Joung Sangyun , Fil Joanne E. , Mudd Austin T. , Fleming Stephen A. , Koekkoek Sebastiaan K. E. , Dilger Ryan N. 
Published: April 2021

AbstractIntroPigs have been an increasingly popular preclinical model in nutritional neuroscience, as their anatomy, physiology, and nutrition requirements are highly comparable to those of humans. Eyeblink conditioning is one of the most well-validated behavioral paradigms in neuroscience to study underlying mechanisms of learning and memory formation in the cerebellum. Eyeblink conditioning has been performed in many species but has never been done on young pigs. Therefore, our aim here was to develop and validate an eyeblink conditioning paradigm in young pigs.MethodEighteen intact male pigs were artificially reared from postnatal day 2 to 30. The eyeblink conditioning setup consisted of a sound-damping box with a hammock that pigs were placed in, which allowed the pig to remain comfortable yet maintain a typical range of head motion. In a delay conditioning paradigm, the conditional stimulus (CS) was a 550 ms blue light-emitting diode (LED), the unconditional stimulus (US) was a 50 ms eye air-puff, the CS-US interval was 500 ms. Starting at postnatal day 14, pigs were habituated for five days to the eyeblink conditioning setup, followed by 5 daily sessions of acquisition training (40 paired CS-US trials each day).ResultsThe group-averaged amplitude of eyelid responses gradually increased over the course of the five days of training, indicating that pigs learned to make the association between the LED light CS and the air-puff US. A similar increase was found for the conditioned response (CR) probability: the group-averaged CR probability on session 1 was about 12% and reached a CR probability of 55% on day 5. The latency to CR peak time lacked a temporal preference in the first session, but clearly showed preference from the moment that animals started to show more CRs in session 2 and onwards whereby the eyelid was maximally closed exactly at the moment that the US would be delivered.ConclusionWe concluded that 4-week-old pigs have the capability of performing in a cerebellar classical association learning task, demonstrating for the first time that eyeblink conditioning in young pigs has the potential to be a valuable behavioral tool to measure neurodevelopment.
Redundant mechanisms driven independently by RUNX1 and GATA2 for hematopoietic development
Authors: Bresciani Erica , Carrington Blake , Yu Kai , Kim Erika M. , Zhen Tao , Guzman Victoria Sanchez , Broadbridge Elizabeth , Bishop Kevin , Kirby Martha , Harper Ursula , Wincovitch Stephen , Dell’Orso Stefania , Sartorelli Vittorio , Sood Raman , Liu Paul 
Published: April 2021

AbstractRUNX1 is essential for the generation of hematopoietic stem cells (HSCs).Runx1null mouse embryos lack definitive hematopoiesis and die in mid-gestation. However, even though zebrafish embryos with arunx1W84X mutation have defects in early definitive hematopoiesis, somerunx1W84X/W84Xembryos can develop to fertile adults with blood cells of multi-lineages, raising the possibility that HSCs can emerge without RUNX1. Here, using three new zebrafishrunx1-/-lines we uncovered the compensatory mechanism forrunx1-independent hematopoiesis. We show that, in the absence of a functionalrunx1, acd41-GFP+population of hematopoietic precursors still emerge from the hemogenic endothelium and can colonize the hematopoietic tissues of the mutant embryos. Single-cell RNA sequencing of thecd41-GFP+cells identified a set ofrunx1-/--specific signature genes during hematopoiesis. Significantly,gata2b, which normally acts upstream ofrunx1for the generation of HSCs, was increased in thecd41-GFP+cells inrunx1- /-embryos. Interestingly, genetic inactivation of bothgata2band its paralog,gata2a, did not affect hematopoiesis. However, knocking outrunx1and any three of the four alleles ofgata2aandgata2babolished definitive hematopoiesis.Gata2expression was also upregulated in hematopoietic cells inRunx1-/-mice, suggesting the compensatory mechanism is conserved. Our findings indicate that RUNX1 and GATA2 serve redundant roles for HSC production, acting as each other’s safeguard.Key pointsExistence of RUNX1-independent mechanisms for the generation of HSCs and the development of functional definitive hematopoietic cellsGATA2 and RUNX1 functionally complement each other for their respective roles during hematopoiesis
Stratification of Risk of Progression to Colectomy in Ulcerative Colitis using Measured and Predicted Gene Expression
Authors: Mo Angela , Nagpal Sini , Gettler Kyle , Haritunians Talin , Giri Mamta , Haberman Yael , Karns Rebekah , Prince Jarod , Arafat Dalia , Hsu Nai-Yun , Chuang Ling-Shiang , Argmann Carmen , Kasarskis Andrew , Suarez-Farinas Mayte , Gotman Nathan , Mengesha Emebet , Venkateswaran Suresh , Rufo Paul A. , Baker Susan S. , Sauer Cary G. , Markowitz James , Pfefferkorn Marian D. , Rosh Joel R. , Boyle Brendan M. , Mack David R. , Baldassano Robert N. , Shah Sapana , LeLeiko Neal S. , Heyman Melvin B. , Griffiths Anne M. , Patel Ashish S. , Noe Joshua D. , Thomas Sonia Davis , Aronow Bruce J. , Walters Thomas D. , McGovern Dermot P. B. , Hyams Jeffrey S. , Kugathasan Subra , Cho Judy H. , Denson Lee A. , Gibson Greg 
Published: April 2021

SUMMARYAn important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of ulcerative colitis (UC) patients require colectomy within five years of diagnosis, but polygenic risk scores (PRS) utilizing findings from GWAS are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn’s disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a Transcriptional Risk Score (TRS). Here we demonstrate that both measured (TRS) and polygenic predicted gene expression (PPTRS) identify UC patients at 5-fold elevated risk of colectomy with data from the PROTECT clinical trial and UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with transcriptome-wide association studies to stratify risk of disease complications.
Gene expression inLucilia sericata(Diptera: Calliphoridae) larvae exposed toPseudomonas aeruginosaandAcinetobacter baumaniiidentifies shared and microbe-specific induction of immune genes
Authors: McKenna C.H. , Asgari D. , Crippen T.L. , Zheng L. , Sherman R.A. , Tomberlin J.K. , Meisel R.P. , Tarone A.M. 
Published: April 2021

AbstractAntibiotic resistance is a continuing challenge in medicine. There are various strategies for expanding antibiotic therapeutic repertoires, including the use of blow flies. Their larvae exhibit strong antibiotic and antibiofilm properties that alter microbiome communities. One species,Lucilia sericata, is used to treat problematic wounds due to its debridement capabilities and its excretions and secretions that kill some pathogenic bacteria. There is much to be learned about howL. sericatainteracts with microbiomes at the molecular level. To address this deficiency, gene expression was assessed after feeding exposure (1 hour or 4 hours) to two clinically problematic pathogens:Pseudomonas aeruginosaandAcinetobacter baumanii. The results identified immunity related genes that were differentially expressed when exposed to these pathogens, as well as non-immune genes possibly involved in gut responses to bacterial infection. There was a greater response toP. aeruginosathat increased over time, while few genes responded toA. baumaniiexposure and expression was not time-dependent. The response to feeding on pathogens indicates a few common responses and features distinct to each pathogen, which is useful in improving wound debridement therapy and helps develop biomimetic alternatives.
Guidelines for obtaining an absolute blood flow index with laser speckle contrast imaging
Authors: Sunil Smrithi , Zilpelwar Sharvari , Boas David A. , Postnov Dmitry D. 
Published: April 2021

ABSTRACTLaser speckle contrast imaging (LSCI) is a technique broadly applied in research and clinical settings for full-field characterization of tissue perfusion. It is based on the analysis of speckle pattern contrast, which can be theoretically related to the decorrelation time - a quantitative measure of dynamics. A direct contrast to decorrelation time conversion, however, requires prior knowledge of specific parameters of the optical system and scattering media and thus is often impractical. For this reason, and because of the nature of some of the most common applications, LSCI is historically used to measurerelativeblood flow change. Over time, the belief that the absolute blood flow index measured with LSCI is not a reliable metric and thus should not be used has become more widespread. This belief has resulted from the use of LSCI to compare perfusion in different animal models and to obtain longitudinal blood flow index observations without proper consideration given to the stability of the measurement. Here, we aim to clarify the issues that give rise to variability in the repeatability of the quantitative blood flow index and to present guidelines on how to make robust absolute blood flow index measurements with conventional single-exposure LSCI. We also explain how to calibrate contrast to compare measurements from different systems and show examples of applications that are enabled by high repeatability.
Quantitative resistance loci to southern rust mapped in a temperate maize diversity panel
Authors: Sun Guangchao , Mural Ravi V. , Turkus Jonathan D. , Schnable James C. 
Published: April 2021

ABSTRACTSouthern rust is a severe foliar disease of maize resulting from infection with the obligate biotrophic fungus,Puccinia polysora. The disease reduces photosynthetic productivity which reduces yields with the greatest yield losses (up to 50%) associated with earlier onset infections.Puccinia polysoraurediniospores overwinter only in tropical and subtropical regions but cause outbreaks when environmental conditions favor initial infection. Increased temperatures and humidity during the growing season, combined with an increased frequency of moderate winters are likely to increase the frequency of severe southern rust outbreaks in the US corn belt. In summer 2020, a severe outbreak of Southern Rust was observed in eastern Nebraska (NE), USA. Disease incidence severity showed significant variation among maize genotypes. A replicated maize association panel planted in Lincoln, NE was scored for disease severity. Genome wide association studies identified four loci associated with significant quantitative variation in disease severity which were associated with candidate genes with plausible links to quantitative disease resistance and a transcriptome wide association study conducted identified additional associated genes. Together these results indicate substantial diversity in resistance to southern rust exists among current temperate adapted maize germplasm, including several candidate loci which may explain observed variation in resistance to southern rust.
Discovery of Latent Drivers from Double Mutations in Pan-Cancer Data Reveal their Clinical Impact
Authors: Yavuz Bengi Ruken , Tsai Chung-Jung , Nussinov Ruth , Tuncbag Nurcan 
Published: April 2021

AbstractBackgroundTransforming patient-specific molecular data into clinical decisions is fundamental to personalized medicine. Despite massive advancements in cancer genomics, to date driver mutations whose frequencies are low, and their observable transformation potential is minor have escaped identification. Yet, when paired with other mutationsin cis, such ‘latent driver’ mutations can drive cancer. Here, we discover potential ‘latent driver’ double mutations.MethodWe applied a statistical approach to identify significantly co-occurring mutations in the pan-cancer data of mutation profiles of ∼80,000 tumor sequences from the TCGA and AACR GENIE databases. The components of same gene doublets were assessed as potential latent drivers. We merged the analysis of the significant double mutations with drug response data of cell lines and patient derived xenografts (PDXs). This allowed us to link the potential impact of double mutations to clinical information and discover signatures for some cancer types.ResultsOur comprehensive statistical analysis identified 228 same gene double mutations of which 113 mutations are cataloged as latent drivers. Oncogenic activation of a protein can be through either single or multiple independent mechanisms of action. Combinations of a driver mutation with either a driver, a weak driver, or a strong latent driver have the potential of a single gene leading to a fully activated state and high drug response rate. Tumor suppressors require higher mutational load to coincide with double mutations compared to oncogenes which implies their relative robustness to losing their functions. Evaluation of the response of cell lines and patient-derived xenograft data to drug treatment indicate that in certain genes double mutations can increase oncogenic activity, hence a better drug response (e.g. in PIK3CA), or they can promote resistance to the drugs (e.g. in EGFR).ConclusionOur comprehensive analysis of same allele double mutations in cancer genome landscapes emphasizes that interrogation of big genomic data and integration with the results of large-scale small-molecule sensitivity data can provide deep patterns that are rare; but can still result in dramatic phenotypic alterations, and provide clinical signatures for some cancer types.
Roads as ecological traps for giant anteaters
Authors: Noonan Michael J. , Ascensão Fernando , Yogui Débora R. , Desbiez Arnaud L.J. 
Published: April 2021

AbstractWildlife-vehicle collisions (WVC) represent a serious source of mortality for many species, threatening local populations’ persistence while also carrying a high economic and human safety cost. Animals may adapt their behaviour to road associated threats, but roadside resources can act as attractants, providing misleading signals about the quality of roadside habitats, ultimately acting as an ecological trap. Yet, the extent to which individuals modify their behaviour and space use to roads is largely unknown for most taxa. Using fine-scale movement data from 41 giant anteaters (Myrmecophaga tridactyla), tracked in the Brazilian Cerrado, we aimed to identify facets of movement behaviour that might exhibit plasticity to roads and traffic volume. Specifically, the analysis of daily and instantaneous movement speeds, home range characteristics, and crossing rates/times, allowed us to test for an effect of road proximity, traffic volume and natural linear features on movement behaviour. We found no effect of road proximity or traffic volume on space use or movement behaviour. While individuals tended to reduce their movement speed when approaching roads and crossed roads ~3 times less than would have been expected by random chance, none of the highways we monitored were impervious. The majority of tracked anteaters living near roads (<2km) crossed them, with higher crossing rates for males. Consequently, habitat near roads may function as an ecological trap where healthy individuals occupy the territories nearby or bisected by roads but eventually are road-killed given their regular crossings, leaving the territory vacant for subsequent occupation. Crucially, we found no evidence that anteaters actively searched for passage structures to cross the roads. This suggests that crossing structures alone are unlikely to mitigate WVC induced mortality. Our research reinforces the need to implement fencing, properly linked to existing passages, and minimising the amount of night-time driving to reduce the number of WVCs.Article Impact StatementAnalyses of giant anteater movement show how roads act as ecological traps, reinforcing the need for fencing and reduced night-time driving.
Modeling The Effect of Background Sounds on Human Focus Using Brain Decoding Technology
Authors: Haruvi Aia , Kopito Ronen , Brande-Eilat Noa , Kalev Shai , Kay Eitan , Furman Daniel 
Published: April 2021

AbstractThe goal of this study was to investigate the effect of sounds on human focus and to identify the properties that contribute most to increasing and decreasing focus in people within their natural, everyday environment. Participants (N=62, 18-65y) performed various tasks on a tablet computer while listening to either no background sounds (silence), popular music playlists designed to increase focus (pre-recorded songs in a particular sequence), or engineered soundscapes that were personalized to individual listeners (digital audio composed in real-time based on input parameters such as heart rate, time of day, location, etc.). Sounds were delivered to participants through headphones while simultaneously their brain signals were recorded by a portable electroencephalography headband. Participants completed four one-hour long sessions at home during which different sound content played continuously. Using brain decoding technology, we obtained individual participant focus levels over time and used this data to analyze the effects of various properties of sound. We found that while participants were working, personalized soundscapes increased their focus significantly above silence (p=0.008), while music playlists did not have a significant effect. For the young adult demographic (18-36y), all sound content tested was significantly better than silence at producing focus (p=0.001-0.009). Personalized soundscapes increased focus the most relative to silence, but playlists of pre-recorded songs also increased focus significantly during specific time intervals. Ultimately we found that it is possible to accurately predict human focus levels that will be experienced in response to soundsa prioribased on the sound’s physical properties. We then applied this finding to compare between music genres and revealed that classical music, engineered soundscapes, and natural sounds were the best genres for increasing focus, while pop and hip-hop were the worst. These insights can enable human and artificial intelligence composers to produce increases or decreases in listener focus with high temporal (millisecond) precision. Future research will include real-time adaptation of sound libraries for other functional objectives beyond affecting focus, such as affecting listener enjoyment, stress, and memory.
Structure and dynamics of SARS-CoV-2 proofreading exoribonuclease ExoN
Authors: Moeller Nicholas H. , Shi Ke , Demir Özlem , Banerjee Surajit , Yin Lulu , Belica Christopher , Durfee Cameron , Amaro Rommie E. , Aihara Hideki 
Published: April 2021

AbstractHigh-fidelity replication of the large RNA genome of coronaviruses (CoVs) is mediated by a 3′-to-5′ exoribonuclease (ExoN) in non-structural protein 14 (nsp14), which excises nucleotides including antiviral drugs mis-incorporated by the low-fidelity viral RNA-dependent RNA polymerase (RdRp) and has also been implicated in viral RNA recombination and resistance to innate immunity. Here we determined a 1.6-Å resolution crystal structure of SARS-CoV-2 ExoN in complex with its essential co-factor, nsp10. The structure shows a highly basic and concave surface flanking the active site, comprising several Lys residues of nsp14 and the N-terminal amino group of nsp10. Modeling suggests that this basic patch binds to the template strand of double-stranded RNA substrates to position the 3′ end of the nascent strand in the ExoN active site, which is corroborated by mutational and computational analyses. Molecular dynamics simulations further show remarkable flexibility of multi-domain nsp14 and suggest that nsp10 stabilizes ExoN for substrate RNA-binding to support its exoribonuclease activity. Our high-resolution structure of the SARS-CoV-2 ExoN-nsp10 complex serves as a platform for future development of anti-coronaviral drugs or strategies to attenuate the viral virulence.
UnMICST: Deep learning with real augmentation for robust segmentation of highly multiplexed images of human tissues
Authors: Yapp Clarence , Novikov Edward , Jang Won-Dong , Vallius Tuulia , Chen Yu-An , Cicconet Marcelo , Maliga Zoltan , Jacobson Connor A. , Wei Donglai , Santagata Sandro , Pfister Hanspeter , Sorger Peter K. 
Published: April 2021

ABSTRACTNewly developed technologies have made it feasible to routinely collect highly multiplexed (20-60 channel) images at subcellular resolution from human tissues for research and diagnostic purposes. Extracting single cell data from such images requires efficient and accurate image segmentation, a challenging problem that has recently benefited from the use of deep learning. In this paper, we demonstrate two approaches to improving tissue segmentation that are applicable to multiple deep learning frameworks. The first uses “real augmentations” that comprise defocused and saturated image data collected on the same instruments as the actual data; using real augmentation improves model accuracy to a significantly greater degree than computational augmentation (Gaussian blurring). The second involves imaging the nuclear envelope to better identify nuclear outlines. The two approaches cumulatively and substantially improve segmentation on a wide range of tissue types and provide a set of improved segmentation models. We speculate that the use of real augmentations may have applications in image processing outside of microscopy.
Unbiased clade age estimation using a Bayesian Brownian Bridge
Authors: Silvestro Daniele , Bacon Christine D. , Ding Wenna , Zhang Qiuyue , Donoghue Philip C. J. , Antonelli Alexandre , Xing Yaowu 
Published: April 2021

AbstractIn a recent paper1we presented a new model, the Bayesian Brownian Bridge (BBB), to infer clade age based on fossil evidence and modern diversity. We benchmarked the method with extensive simulations, including a wide range of diversification histories and sampling heterogeneities that go well beyond the necessarily simplistic model assumptions. Applying BBB to 198 angiosperm families, we found that their fossil record is compatible with clade origins earlier than most contemporary palaeobotanical interpretations. In particular, we estimated with high probability that crown-angiosperms originated before the Cretaceous (> 145 Ma). Budd and colleagues2critique our study, arguing that the BBB model is biased towards older estimates when fossil data are scarce or absent, that our underlying fossil dataset is unsound, that our clade age estimates are therefore biased by early diverging lineages that are underrepresented in the fossil record, and that pooling of fossil data for analysis at higher taxonomic ranks overcomes these biases. Here, we explore their points and perform new simulations to show that their critique has no merit.