bluuebunny/crossref_metadata_2025_split huggingface dataset:
Freewater EstimatoR using iNtErpolated iniTialization (FERNET): Toward Accurate Estimation of Free Water in Peritumoral Region Using Single-Shell Diffusion MRI Data
Authors: Ould Ismail Abdol Aziz , Parker Drew , Hernandez-Fernandez Moises , Wolf Ronald , Brem Steven , Alexander Simon , Hodges Wes , Pasternak Ofer , Caruyer Emmanuel , Verma Ragini 
Published: October 2019

ABSTRACTCharacterization of healthy versus pathological tissue is a key concern when modeling tissue microstructure in the peritumoral area, confounded by the presence of free water (e.g., edema). Most methods that model tissue microstructure are either based on advanced acquisition schemes not readily available in the clinic, or are not designed to address the challenge of edema. This underscores the need for a robust free water elimination (FWE) method that estimates free water in pathological tissue but can be used with clinically prevalent single-shell diffusion tensor imaging data. FWE in single-shell data requires the fitting of a bi-compartment model, which is an ill-posed problem. Its solution requires optimization, which relies on an initialization step. We propose a novel initialization approach for FWE, FERNET, which improves the estimation of free water in edematous and infiltrated peritumoral regions, using single-shell diffusion MRI data. The method has been extensively investigated on simulated data and healthy and brain tumor datasets, demonstrating its applicability on clinically acquired data. Additionally, it has been applied to data from brain tumor patients to demonstrate the improvement in tractography in the peritumoral region.
An amygdala circuit mediates experience-dependent momentary exploratory arrests
Authors: Botta Paolo , Fushiki Akira , Vicente Ana Mafalda , Hammond Luke A. , Mosberger Alice C. , Gerfen Charles R. , Peterka Darcy , Costa Rui M. 
Published: October 2019

SummaryExploration of novel environments ensures survival and evolutionary fitness. This behavior is expressed through exploratory bouts and arrests, which change dynamically based on experience. Neural circuits mediating exploratory behavior should therefore integrate experience and use it to select the proper behavioral output. Using a spatial exploration assay, we uncovered an experience-dependent increase of momentary arrests in visited locations where animals previously arrested. Quantitative analyses of neuronal calcium activity in freely-exploring mice revealed that a large neuronal ensemble in basolateral amygdala is active during self-paced behavioral arrests. This ensemble was recruited in an experience-dependent manner, and closed-loop optogenetic manipulation of these neurons revealed that they are sufficient and necessary to drive experience-dependent arrests. Additionally, we found that neurons in the basolateral amygdala projecting to central amygdala mediate these momentary arrests. These findings uncover an amygdala circuit that mediates momentary exploratory arrests in familiar places, without changing place preference or anxiety/fear-like behaviors.
Structure of E3 ligase E6AP with a novel proteasome-binding site provided by substrate receptor hRpn10
Authors: Buel Gwen R. , Chen Xiang , Chari Raj , O’Neill Maura J. , Ebelle Danielle L. , Jenkins Conor , Sridharan Vinidhra , Tarasov Sergey G. , Tarasova Nadya I. , Andresson Thorkell , Walters Kylie J. 
Published: October 2019

AbstractRegulated proteolysis by the proteasome involves ∼800 enzymes for substrate modification with ubiquitin, of which ∼600 are E3 ligases. We report here that E6AP/UBE3A is distinguished from other ubiquitin E3 ligases by having a 12 nM binding site at the proteasome contributed by substrate receptor hRpn10/PSMD4/S5a. Intrinsically disordered by itself, and previously uncharacterized, this domain in hRpn10 locks into a novel well-defined helical structure to form an intermolecular 4-helix bundle with the E6AP AZUL domain, which is unique to this E3. We thus name the hRpn10AZUL-binding domain RAZUL. We further find in human cells that loss of RAZUL by CRISPR-based gene editing leads to loss of E6AP at the proteasome, where associated ubiquitin is correspondingly reduced, suggesting that E6AP ubiquitinates substrates at or for the proteasome. Altogether, our findings indicate E6AP to be a privileged E3 for the proteasome, with a dedicated, high affinity binding site contributed by hRpn10.
Examining go-or-grow using fluorescent cell-cycle indicators and cell cycle-inhibiting drugs
Authors: Vittadello Sean T. , McCue Scott W. , Gunasingh Gency , Haass Nikolas K. , Simpson Matthew J. 
Published: October 2019

AbstractThe go-or-grow hypothesis states that adherent cells undergo reversible phenotype switching between migratory and proliferative states, with cells in the migratory state being more motile than cells in the proliferative state. Here we examine go-or-grow in 2-D in vitro assays using melanoma cells with fluorescent cell-cycle indicators and cell cycle-inhibiting drugs. We analyse the experimental data using single-cell tracking to calculate mean diffusivities, and compare motility between cells in different cell-cycle phases and in cell-cycle arrest. Unequivocally, our analysis does not support the go-or-grow hypothesis. We present clear evidence that cell motility is independent of the cell-cycle phase, and non-proliferative arrested cells have the same motility as cycling cells.
Unconstrained multivariate EEG decoding can help detect lexical-semantic processing in individual children
Authors: Petit Selene , Badcock Nicholas A. , Grootswagers Tijl , Woolgar Alexandra 
Published: October 2019

AbstractIn conditions such as minimally-verbal autism, standard assessments of language comprehension are often unreliable. Given the known heterogeneity within the autistic population, it is crucial to design tests of semantic comprehension that are sensitive in individuals. Recent efforts to develop neural signals of language comprehension have focused on the N400, a robust marker of lexical-semantic violation at the group level. However, homogeneity of response in individual neurotypical children has not been established. Here, we presented 20 neurotypical children with congruent and incongruent visual animations and spoken sentences while measuring their neural response using EEG. Despite robust group-level responses, we found high inter-individual variability in response to lexico-semantic anomalies. To overcome this, we analysed our data using temporally and spatially unconstrained MVPA, supplemented by descriptive analyses to examine the timecourse, topography, and strength of the effect. Our results show that neurotypical children exhibit heterogenous responses to lexical-semantic violation, implying that any application to heterogenous disorders such as ASD will require individual-subject analyses that are robust to variation in topology and timecourse of neural responses.
Systems-level physiology of the human red blood cell is computed from metabolic and macromolecular mechanisms
Authors: Yurkovich James T. , Yang Laurence , Palsson Bernhard O. 
Published: October 2019

ABSTRACTThe human red blood cell has served as a starting point for the application and development of systems biology approaches due to its simplicity, intrinsic experimental accessibility, and importance in human health applications. Here, we present a multi-scale computational model of the human red blood cell that accounts for the full metabolic network, key proteins (>95% of proteome mass fraction), and several macromolecular mechanisms. Proteomics data are used to place quantitative constraints on individual protein complexes that catalyze metabolic reactions, as well as a total proteome capacity constraint. We explicitly describe molecular mechanisms—such as hemoglobin binding and the formation and detoxification of reactive oxygen species—and takes standard hematological variables (e.g., hematocrit, hemoglobin concentration) as input, allowing for personalized physiological predictions. This model is built from first principles and allows for direct computation of physiologically meaningful quantities such as the oxygen dissociation curve and an accurate computation of the flux state of the metabolic network. More broadly, this work represents an important step toward including the proteome and its function in whole-cell models of human cells.
Regime shifts in a phage-bacterial ecosystem and strategies for its control
Authors: Maslov Sergei , Sneppen Kim 
Published: October 2019

ABSTRACTThe competition between bacteria often involves both nutrients and phage predators and may give rise to abrupt regime shifts between the alternative stable states characterized by different species compositions. While such transitions have been previously studied in the context of competition for nutrients, the case of phage-induced bistability between competing bacterial species has not been considered yet. Here we demonstrate a possibility of regime shifts in well-mixed phage-bacterial ecosystems. In one of the bistable states the fast-growing bacteria competitively exclude the slow-growing ones by depleting their common nutrient. Conversely, in the second state the slow-growing bacteria with a large burst size generate such a large phage population that the other species cannot survive. This type of bistability can be realized as the competition between a strain of bacteria protected from phage by abortive infection and another strain with partial resistance to phage. It is often desirable to reliably control the state of microbial ecosystems, yet bistability significantly complicates this task. We discuss successes and limitations of one control strategy in which one adds short pulses to populations of individual species. Our study proposes a new type of phage therapy, where introduction of the phage is supplemented by addition of a partially resistant host bacteria.IMPORTANCEPhage-microbial communities play an important role in human health as well as natural and industrial environments. Here we show that these communities can assume several alternative species compositions separated by abrupt regime shifts. Our model predicts these regime shifts in the competition between bacterial strains protected by two different phage defense mechanisms: abortive infection/CRISPR and partial resistance. The history dependence caused by regime shifts greatly complicates the task of manipulation and control of a community. We propose and study a successful control strategy via short population pulses aimed at inducing the desired regime shifts. In particular, we predict that a fast-growing pathogen could be eliminated by a combination of its phage and a slower-growing susceptible host.
Hif-1alpha stabilisation is protective against infection in a zebrafish model of comorbidity
Authors: Schild Yves , Mohamed Abdirizak , Wootton Edward J. , Lewis Amy , Elks Philip M. 
Published: October 2019

AbstractMulti-drug resistant tuberculosis is a worldwide problem and there is an urgent need for host-derived therapeutic targets, circumventing emerging drug resistance. We have previously shown that hypoxia inducible-1α (Hif-1α) stabilisation helps the host to clear mycobacterial infection via neutrophil activation. However, Hif-1α stabilisation has also been implicated in chronic inflammatory diseases caused by prolonged neutrophilic inflammation. Comorbid infection and inflammation can be found together in disease settings, so it is unclear as to whether Hif-1α stabilisation would be beneficial in a holistic disease setting. Here, we set out to understand the effects of Hif-1α on neutrophil behaviour in disease-relevant settings by combining two well-characterisedin vivozebrafish models: TB infection (Mycobacterium marinuminfection) and wounding (tailfin transection). We demonstrate during systemic infection, that wounding leads to increased infection burden, but the protective effect of Hif-1α stabilisation remains. A local Mm infection near to the tailfin wound site caused neutrophil migration between sites that was reduced by Hif-1α stabilisation. Our data indicate that the protective effect of Hif-1α against Mm is maintained in the presence of inflammation, highlighting its potential as a host-derived target against TB infection in a disease relevant setting.
The challenge of heterogeneous evidence in conservation
Authors: Christie Alec P. , Amano Tatsuya , Martin Philip A. , Petrovan Silviu O. , Shackelford Gorm E. , Simmons Benno I. , Smith Rebecca K. , Williams David R. , Wordley Claire F. R. , Sutherland William J. 
Published: October 2019

AbstractConservation efforts to tackle the current biodiversity crisis need to be as efficient and effective as possible. To inform decision-makers of the most effective conservation actions, it is important to identify biases and gaps in the conservation literature to prioritize future evidence generation. We assessed the state of this global literature base using the Conservation Evidence database, a comprehensive collection of quantitative tests of conservation actions (interventions) from the published literature. For amphibians and birds, we investigated the nature of Conservation Evidence spatially and taxonomically, as well as by biome, effectiveness metrics, and study design. Studies were heavily concentrated in Western Europe and North America for birds and particularly amphibians. Studies that used the most robust study designs - Before-After Control-Impact and Randomized Controlled Trials - were also the most geographically restricted. Furthermore, there was no relationship between the number of studies in each 1×1 degree grid cell and the number of species, threatened species or data-deficient species. Taxonomic biases and gaps were apparent for amphibians and birds - some orders were absent from the evidence base and others were poorly represented relative to the proportion of threatened species they contained. Temperate forest and grassland biomes were highly represented, which reinforced observed geographic biases. Various metrics were used to evaluate the effectiveness of a given conservation action, potentially making studies less directly comparable and evidence synthesis more difficult. We also found that the least robust study designs were the most commonly used; studies using robust designs were scarce. Future research should prioritize testing conservation actions on threatened species outside of Western Europe and North America. Standardizing metrics and improving the robustness of study designs used to test conservation actions would also improve the quality of the evidence base for synthesis and decision-making.
Quantifying the relative importance of competition, predation, and environmental variation for species coexistence
Authors: Shoemaker Lauren G. , Barner Allison K. , Bittleston Leonora S. , Teufel Ashley I. 
Published: October 2019

1AbstractCoexistence theory and food web theory are two cornerstones of the longstanding effort to understand how species coexist. Although competition and predation are known to act simultaneously in communities, theory and empirical study of the two processes continue to be developed independently. Here, we integrate modern coexistence theory and food web theory to simultaneously quantify the relative importance of predation, competition, and environmental fluctuations for species coexistence. We first examine coexistence in a classic multi-trophic model, adding complexity to the food web using a novel machine learning approach. We then apply our framework to a parameterized rocky intertidal food web model, partitioning empirical coexistence dynamics. We find that both environmental fluctuation and variation in predation contribute substantially to species coexistence. Unexpectedly, covariation in these two forces tends to destabilize coexistence, leading to new insights about the role of bottom-up versus top-down forces in both theory and the rocky intertidal ecosystem.
In Vivo Study of Key Transcription Factors in Muscle Satellite Cells by CRISPR/Cas9/AAV9-sgRNA Mediated Genome Editing
Authors: He Liangqiang , Ding Yingzhe , Zhao Yu , So Karl K. , Peng Xianlu L. , Li Yuying , Yuan Jie , Sun Hao , Wang Huating 
Published: October 2019

ABSTRACTSkeletal muscle satellite cells (SCs) are adult muscle stem cells responsible for injury induced muscle regeneration. Despite advances in the knowledge of molecular mechanisms regulating SC lineage progression, our understanding of key transcription factors (TFs) and their regulatory functions in SCs in particularly the quiescent and early activation stages remains incomplete due to the lack of efficient method to screen and investigate the stage-specific key TFs. In this study, we succeeded in defining a distinct list of key TFs in early stages of SC fate transition using the paradigm of super enhancers (SEs). Particularly, leveraging the Cre-dependent Cas9 knockin mice and AAV9 mediated sgRNAs delivery, we generated a facile muscle specific genome editing system which allows gene depletion in SCs in vivo. Using MyoD locus as a proof of concept, we demonstrated that this CRISPR/Cas9/AAV9-sgRNA system can efficiently introduce mutagenesis at target locus and recapture the phenotypes reported in knockout mice. Further application of the system on key TFs, Myc, Bcl6 and Pknox2, revealed their distinct functions in the early stage of SC activation and damage induced muscle regeneration. Altogether our findings have proven the CRISPR/Cas9/AAV9-sgRNA system as a robust way for in vivo genome editing and elucidation of key factors governing SC activities.
Validating metabarcoding-based biodiversity assessments with multi-species occupancy models: a case study using coastal marine eDNA
Authors: McClenaghan Beverly , Compson Zacchaeus G. , Hajibabaei Mehrdad 
Published: October 2019

AbstractEnvironmental DNA (eDNA) metabarcoding is an increasingly popular method for rapid biodiversity assessment. As with any ecological survey, false negatives can arise during sampling and, if unaccounted for, lead to biased results and potentially misdiagnosed environmental assessments. We developed a multi-scale, multi-species occupancy model for the analysis of community biodiversity data resulting from eDNA metabarcoding; this model accounts for imperfect detection and additional sources of environmental and experimental variation. We present methods for model assessment and model comparison and demonstrate how these tools improve the inferential power of eDNA metabarcoding data using a case study in a coastal, marine environment. Using occupancy models to account for factors often overlooked in the analysis of eDNA metabarcoding data will dramatically improve ecological inference, sampling design, and methodologies, empowering practitioners with an approach to wield the high-resolution biodiversity data of next-generation sequencing platforms.
Genotype imputation using the Positional Burrows Wheeler Transform
Authors: Rubinacci Simone , Delaneau Olivier , Marchini Jonathan 
Published: October 2019

AbstractGenotype imputation is the process of predicting unobserved genotypes in a sample of individuals using a reference panel of haplotypes. In the last 10 years reference panels have increased in size by more than 100 fold. Increasing reference panel size improves accuracy of markers with low minor allele frequencies but poses ever increasing computational challenges for imputation methods.Here we present IMPUTE5, a genotype imputation method that can scale to reference panels with millions of samples. This method continues to refine the observation made in the IMPUTE2 method, that accuracy is optimized via use of a custom subset of haplotypes when imputing each individual. It achieves fast, accurate, and memory-efficient imputation by selecting haplotypes using the Positional Burrows Wheeler Transform (PBWT). By using the PBWT data structure at genotyped markers, IMPUTE5 identifies locally best matching haplotypes and long identical by state segments. The method then uses the selected haplotypes as conditioning states within the IMPUTE model.Using the HRC reference panel, which has ~65,000 haplotypes, we show that IMPUTE5 is up to 30x faster than MINIMAC4 and up to 3x faster than BEAGLE5.1, and uses less memory than both these methods. Using simulated reference panels we show that IMPUTE5 scales sub-linearly with reference panel size. For example, keeping the number of imputed markers constant, increasing the reference panel size from 10,000 to 1 million haplotypes requires less than twice the computation time. As the reference panel increases in size IMPUTE5 is able to utilize a smaller number of reference haplotypes, thus reducing computational cost.Author summaryGenome-wide association studies (GWAS) typically use microarray technology to measure genotypes at several hundred thousand positions in the genome. However reference panels of genetic variation consist of haplotype data at >100 fold more positions in the genome. Genotype imputation makes genotype predictions at all the reference panel sites using the GWAS data. Reference panels are continuing to grow in size and this improves accuracy of the predictions, however methods need to be able to scale to increased size. We have developed a new version of the popular IMPUTE software than can handle referenece panels with millions of haplotypes, and has better performance than other published approaches. A notable property of the new method is that it scales sub-linearly with reference panel size. Keeping the number of imputed markers constant, a 100 fold increase in reference panel size requires less than twice the computation time.
Phytoene Synthase 2 Can Compensate for the Absence of Psy1 in Pepper Fruit (Capsicum annuum)
Authors: Jang So-Jeong , Jeong Hyo-Bong , Jung Ayoung , Kang Min-Young , Kim Suna , Ha Sun-Hwa , Kwon Jin-Kyung , Kang Byoung-Cheorl 
Published: October 2019

AbstractPhytoene synthase 1 (PSY1) and Capsanthin-capsorubin synthase (CCS) are two major genes responsible for fruit color variation in pepper (Capsicum spp.), although fruit colors cannot be explained by variations in these two genes alone. Furthermore, the role of PSY2 in fruit color development in pepper is unknown. Here, we used a systemic approach to discover the genetic factors responsible for the yellow fruit color of C. annuum ‘MicroPep Yellow’ (MY) and to reveal the role of PSY2 in fruit color. We detected a complete deletion of PSY1 and a retrotransposon insertion in CCS in MY. Despite the loss of PSY1 and CCS function, the MY and mutant F2 plants from a cross between MY and the MicroPep Red (MR) accumulated basal levels of carotenoids, indicating that other PSY genes may complement the loss of PSY1. A qRT-PCR analysis demonstrated that PSY2 is constitutively expressed in both MR and MY fruits, and a color complementation assay using Escherichia coli revealed that PSY2 is capable of biosynthesizing a carotenoid. Virus-induced gene silencing of PSY2 in MY resulted in white fruits. These findings suggest that PSY2 can compensate for the absence of PSY1 in fruit, resulting in the yellow color of MY fruits.HighlightWe reveal the novel function of PSY2 in the development of yellow pepper fruit coloration using a psy1 knockout mutant. This gene function was not previously identified in solanaceous crops.