bluuebunny/crossref_metadata_2025_split huggingface dataset:
Developmental exposure to the organochlorine pesticide dieldrin causes male-specific exacerbation of α-synuclein-preformed fibril-induced toxicity and motor deficits
Authors: Gezer Aysegul O. , Kochmanski Joseph , VanOeveren Sarah E. , Cole-Strauss Allyson , Kemp Christopher J , Patterson Joseph R. , Miller Kathryn M. , Kuhn Nathan C. , Herman Danielle E. , McIntire Alyssa , Lipton Jack W. , Luk Kelvin C. , Fleming Sheila M. , Sortwell Caryl E. , Bernstein Alison I. 
Published: February 2020

AbstractHuman and animal studies have shown that exposure to the organochlorine pesticide dieldrin is associated with increased risk of Parkinson’s disease (PD). Previous work showed that developmental dieldrin exposure increased neuronal susceptibility to MPTP toxicity in male C57BL/6 mice, possibly via changes in dopamine (DA) packaging and turnover. However, the relevance of the MPTP model to PD pathophysiology has been questioned. We therefore studied dieldrin-induced neurotoxicity in the α-synuclein (α-syn)-preformed fibril (PFF) model, which better reflects the α-syn pathology and toxicity observed in PD pathogenesis. Specifically, we used a “two-hit” model to determine whether developmental dieldrin exposure increases susceptibility to α-syn PFF-induced synucleinopathy. Dams were fed either dieldrin (0.3 mg/kg, every 3-4 days) or vehicle corn oil starting 1 month prior to breeding and continuing through weaning of pups at postnatal day 22. At 12 weeks of age, male and female offspring received intrastriatal PFF or control saline injections. Consistent with the male-specific increased susceptibility to MPTP, our results demonstrate that developmental dieldrin exposure exacerbates PFF-induced toxicity in male mice only. Specifically, in male offspring, dieldrin exacerbated PFF-induced motor deficits on the challenging beam and increased DA turnover in the striatum 6 months after PFF injection. However, male offspring showed neither exacerbation of phosphorylated α-syn (pSyn) aggregation in the substantia nigra (SN) at 1 or 2 months post-PFF injection, nor exacerbation of PFF-induced TH and NeuN loss in the SN 6 months post-PFF injection. Collectively, these data indicate that developmental dieldrin exposure produces a male-specific increase in neuronal vulnerability to synucleinopathy. This sex-specific result is consistent with both previous work in the MPTP model, our previously reported sex-specific effects of this exposure paradigm on the male and female epigenome, and the higher prevalence and more severe course of PD in males. The novel two-hit environmental toxicant/PFF exposure paradigm established in this project can be used to explore the mechanisms by which other PD-related exposures alter neuronal vulnerability to synucleinopathy in sporadic PD.HighlightsDevelopmental dieldrin exposure increases α-syn-PFF-induced motor deficitsDevelopmental dieldrin exposure increases PFF-induced deficits in DA handlingDevelopmental dieldrin exposure does not affect PFF-induced loss of nigral neuronsThis is a novel paradigm modeling how environmental factors increase risk of PDFemale mice show PFF-induced pathology, but no PFF-induced motor deficits.
Exosome-mediated apoptosis pathway during WSSV infection in crustacean mud crab
Authors: Gong Yi , Kong Tongtong , Ren Xin , Chen Jiao , Lin Shanmeng , Zhang Yueling , Li Shengkang 
Published: February 2020

AbstractMicroRNAs are regulatory molecules that can be packaged into exosomes to modulate recipient’s cellular response, while their role during viral infection is beginning to be appreciated. However, the involvement of exosomal miRNAs during immunoregulation in invertebrates has not been addressed. Here, we found that exosomes released from WSSV-injected mud crabs could suppress viral invasion by inducing apoptosis of hemocytes. Besides, miR-137 and miR-7847 were found to be less packaged in mud crab exosomes during viral infection, with both miR-137 and miR-7847 shown to be negative apoptosis regulators by targeting the apoptosis-inducing factor (AIF). Moreover, our data revealed that AIF did not only translocate to the nucleus to induce DNA fragmentation, but could also competitively bind to HSP70 to disintegrate the HSP70-Bax (Bcl-2-associated X protein) complex, which eventually activated the mitochondria apoptosis pathway via free Bax. Therefore, our findings provides a novel mechanism underlying the crosstalk between exosomal miRNAs and apoptosis pathway in innate immunity in invertebrates.
Accuracy of short tandem repeats genotyping tools in whole exome sequencing data
Authors: Halman Andreas , Oshlack Alicia 
Published: February 2020

AbstractBackgroundShort tandem repeats are important source of genetic variation, they are highly mutable and repeat expansions are associated dozens of human disorders, such as Huntington’s disease and spinocerebellar ataxias. Technical advantages in sequencing technology have made it possible to analyse these repeats at large scale, however, accurate genotyping is still a challenging task. We compared four different short tandem repeats genotyping tools on whole exome sequencing data to determine their genotyping performance and limits which will aid other researchers to choose a suitable tool and parameters for analysis.MethodsThe analysis was performed on the Simons Simplex Collection dataset where we used a novel method of evaluation with accuracy determined by the rate of homozygous calls on the X chromosome of male samples. In total we analysed 433 samples and around a million genotypes for evaluating tools on whole exome sequencing data.ResultsWe determined a relatively good performance of all tools when genotyping repeats of 3-6 bp in length which could be improved with coverage and quality score filtering. However, genotyping homopolymers was challenging for all tools and a high error rate was present across different thresholds of coverage and quality scores. Interestingly, dinucleotide repeats displayed a high error rate as well, which was found to be mainly caused by the AC/TG repeats. Overall, LobSTR was able to make the most calls and was also the fastest tool while RepeatSeq and HipSTR exhibited the lowest heterozygous error rate at low coverage.ConclusionsAll tools have different strengths and weaknesses and the choice may depend on the type of analysis. In this analysis we demonstrated the effect of using different filtering parameters and offered recommendations based on the trade-off between the best accuracy of genotyping and the highest number of calls.
ZipSeq : Barcoding for Real-time Mapping of Single Cell Transcriptomes
Authors: Hu Kenneth H. , Eichorst John P. , McGinnis Chris S. , Patterson David M. , Chow Eric D. , Kersten Kelly , Jameson Stephen C. , Gartner Zev J. , Rao Arjun A. , Krummel Matthew F. 
Published: February 2020

ABSTRACTSpatial transcriptomics seeks to integrate single-cell transcriptomic data within the 3-dimensional space of multicellular biology. Current methods use glass substrates pre-seeded with matrices of barcodes or fluorescence hybridization of a limited number of probes. We developed an alternative approach, called ‘ZipSeq’, that uses patterned illumination and photocaged oligonucleotides to serially print barcodes (Zipcodes) onto live cells within intact tissues, in real-time and with on-the-fly selection of patterns. Using ZipSeq, we mapped gene expression in three settings: in-vitro wound healing, live lymph node sections and in a live tumor microenvironment (TME). In all cases, we discovered new gene expression patterns associated with histological structures. In the TME, this demonstrated a trajectory of myeloid and T cell differentiation, from periphery inward. A variation of ZipSeq efficiently scales to the level of single cells, providing a pathway for complete mapping of live tissues, subsequent to real-time imaging or perturbation.
Prestimulus alpha power is related to the strength of stimulus representation
Authors: Barne Louise C. , de Lange Floris P. , Cravo André M. 
Published: February 2020

AbstractSpatial attention can modulate behavioural performance and is associated with several electrophysiological markers. In this study, we used multivariate pattern analysis in electrophysiology data to investigate the effects of covert spatial attention on the quality of stimulus processing and underlying mechanisms. Our results show that covert spatial attention led to (i) an anticipatory alpha power desynchronization; (ii) enhanced stimuli identity information. Moreover, we found that alpha power fluctuations in anticipation of the relevant stimuli boosted and prolonged the coding of stimulus identity.
Multiple links between 5-methylcytosine content of mRNA and translation
Authors: Schumann Ulrike , Zhang He-Na , Sibbritt Tennille , Pan Anyu , Horvath Attila , Gross Simon , Clark Susan J , Yang Li , Preiss Thomas 
Published: February 2020

Abstract5-methylcytosine (m5C) is a prevalent base modification in tRNA and rRNA but it also occurs more broadly in the transcriptome, including in mRNA, where it serves incompletely understood molecular functions. In pursuit of potential links of m5C with mRNA translation, we performed polysome profiling of human HeLa cell lysates and subjected RNA from resultant fractions to efficient bisulfite conversion followed by RNA sequencing (bsRNA-seq). Bioinformatic filters for rigorous site calling were devised to reduce technical noise. We obtained ∼1,000 candidate m5C sites in the wider transcriptome, most of which were found in mRNA. Multiple novel sites were validated by amplicon-specific bsRNA-seq in independent samples of either human HeLa, LNCaP and PrEC cells. Furthermore, RNAi-mediated depletion of either the NSUN2 or TRDMT1 m5C:RNA methyltransferases showed a clear dependence on NSUN2 for the majority of tested sites in both mRNAs and noncoding RNAs. Candidate m5C sites in mRNAs are enriched in 5’UTRs and near start codons, and are commonly embedded in a local context reminiscent of the NSUN2-dependent m5C sites found in the variable loop of tRNA. Analysing mRNA sites across the polysome profile revealed that modification levels, at bulk and for many individual sites, were inversely correlated with ribosome association. Altogether, these findings emphasise the major role of NSUN2 in making this mark transcriptome-wide and further substantiate a functional interdependence of cytosine methylation level with mRNA translation.
Impact of an Oomen feeding with a neonicotinoid on daily activity and colony development of honeybees assessed with an AI based monitoring device
Authors: Gonsior Gundula , Tausch Frederic , Schmidt Katharina , Knäbe Silvio 
Published: February 2020

AbstractFeeding experiments are standard tools in the pollinator risk assessment. The design (Oomen et al 1992) was developed to test insect growth regulators and herbicides. In recent years there was an update (Lückmann & Schmitzer 2015) on the outline in order to also focus on the advantage of different rates making a dose response design possible where exposure levels are known. Additionally, this design gives the possibility to test different rates for honey bee colonies foraging in the same landscape.The main objective of the experiment presented here was to determine the natural variability of foragers losses of hives fed with a sub-lethal neonicotinoid concentration compared to an untreated control. Other objectives were to see if the neurotoxic exposure results in any observable sub-lethal effects and to find out if losses can be correlated to hive development. This was assessed with traditional methods and a novel, visual monitoring device.
Testing structural identifiability by a simple scaling method
Authors: Castro Mario , de Boer Rob J. 
Published: February 2020

AbstractSuccessful mathematical modeling of biological processes relies on the expertise of the modeler to capture the essential mechanisms in the process at hand and on the ability to extract useful information from empirical data. The very structure of the model limits the ability to infer numerical values for the parameters, a concept referred to as structural identifiability. Most of the available methods to test the structural identifiability of a model are either too complex mathematically for the general practitioner to be applied, or require involved calculations or numerical computation for complex non-linear models. In this work, we present a new analytical method to test structural identifiability of models based on ordinary differential equations, based on the invariance of the equations under the scaling transformation of its parameters. The method is based on rigorous mathematical results but it is easy and quick to apply, even to test the identifiability of sophisticated highly non-linear models. We illustrate our method by example and compare its performance with other existing methods in the literature.Author summaryTheoretical Biology is a useful approach to explain, generate hypotheses, or discriminate among competing theories. A well-formulated model has to be complex enough to capture the relevant mechanisms of the problem, and simple enough to be fitted to data. Structural identifiability tests aim to recognize, in advance, if the structure of the model allows parameter fitting even with unlimited high-quality data. Available methods require advanced mathematical skills, or are too costly for high-dimensional non-linear models. We propose an analytical method based on scale invariance of the equations. It provides definite answers to the structural identifiability problem while being simple enough to be performed in a few lines of calculations without any computational aid. It favorably compares with other existing methods.
Exon 13-skipped USH2A protein retains functional integrity in mice, suggesting an exo-skipping therapeutic approach to treat USH2A-associated disease
Authors: Pendse Nachiket , Lamas Veronica , Maeder Morgan , Pawlyk Basil , Gloskowski Sebastian , Pierce Eric A. , Chen Zheng-Yi , Liu Qin 
Published: February 2020

ABSTRACTMutations in theUSH2Agene are the most common cause of non-syndromic inherited retinal degeneration and Usher syndrome, which is characterized by congenital deafness and progressive vision loss. Development of a vector mediated therapy forUSH2A-associated disease has been challenging due to its large size of coding sequence (~15.6kb). Therefore, there is an unmet need to develop alternative therapeutic strategies. The USH2A protein (Usherin) contains many repetitive domains, and it has been hypothesized that some domains may be dispensable with regard to protein function. Here, we show that skipping of exon 13 of the humanUSH2Agene or the equivalent exon 12 of the mouseUsh2agene results in an in-frame transcript that produces functional Usherin protein. This nearly full length Usherin rescues the ciliogenesis inUsh2anull cells as well as the cochlear and retinal phenotypes inUsh2anull mice. Together, our results support the development of exon-skipping strategies to treat both visual and hearing loss in patients withUSH2A-associated disease due to mutations in exon 13.
Warm periods in repeated cold stresses protectDrosophilaagainst ionoregulatory collapse, chilling injury, and reproductive deficits
Authors: El-Saadi Mahmoud I. , Ritchie Marshall W. , Davis Hannah E. , MacMillan Heath A. 
Published: February 2020

AbstractIn many insects, repeated cold stress, characterized by warm periods that interrupt cold periods, have been found to yield survival benefits over continuous cold stress, but at the cost of reproduction. During cold stress, chill susceptible insects likeDrosophila melanogastersuffer from a loss of ion and water balance, and the current model of recovery from chilling posits that re-establishment of ion homeostasis begins upon return to a warm environment, but that it takes minutes to hours for an insect to fully restore homeostasis. Following this ionoregulatory model of chill coma recovery, we predicted that the longer the duration of the warm periods between cold stresses, the better a fly will recover from a subsequent chill coma event and the more likely they will be to survive, but at the cost of fewer offspring. Here, femaleD. melanogasterwere treated to a long continuous cold stress (25 h at 0°C), or experienced the same total time in the cold with repeated short (15 min), or long (120 min) breaks at 23°C. We found that warm periods in general improved survival outcomes, and individuals that recovered for more time in between cold periods had significantly lower rates of injury, faster recovery from chill coma, and produced greater, rather than fewer, offspring. These improvements in chill tolerance were associated with mitigation of ionoregulatory collapse, as flies that experienced either short or long warm periods better maintained low hemolymph [K+]. Thus, warm periods that interrupt cold exposures improve cold tolerance and fertility inD. melanogasterfemales relative to a single sustained cold stress, potentially because this time allows for recovery of ion and water homeostasis.
Genetic Disruption of Serine Biosynthesis is a Key Driver of Macular Telangiectasia Type 2 Etiology and Progression
Authors: Bonelli Roberto , Ansell Brendan R E , Lotta Luca , Scerri Thomas , Clemons Traci E , Leung Irene ,   The MacTel Consortium, Peto Tunde , Bird Alan C , Sallo Ferenc B , Langenberg Claudia , Bahlo Melanie 
Published: February 2020

AbstractPurposeMacular telangiectasia type 2 (MacTel) is a rare, heritable and largely untreatable retinal disorder, often comorbid with diabetes. Genetic risk loci subtend retinal vascular calibre, and glycine/serine/threonine metabolism genes. Serine deficiency may contribute to MacTel via neurotoxic deoxysphingolipid production, however, an independent vascular contribution is also suspected. Here we use statistical genetics to dissect the causal mechanisms underpinning this complex disease.MethodsWe integrated genetic markers for MacTel, vascular, and metabolic traits, and applied Mendelian randomization, MTAG, and conditional/interaction genome-wide association analysis to discover causal contributors to both disease, and spatial retinal imaging sub-phenotypes.ResultsSerine was a key causal driver of disease occurrence and progression, with a lesser contribution to type 2 diabetes risk. Conversely, glycine, threonine and retinal vascular traits are unlikely to be causal for MacTel. Conditional regression analysis resolved three novel disease loci independent of endogenous serine biosynthetic capacity. By aggregating retinal phenotypes into endophenotypes, we demonstrate that SNPs constituting independent risk loci act via related endophenotypes.DiscussionOur findings will aid in early diagnosis and accurate prognosis of MacTel, and improve prospects for effective therapeutic intervention. Our integrative genetics approach also serves as a useful template for post-GWAS analyses in other disorders.
Generating Digital Twins with Multiple Sclerosis Using Probabilistic Neural Networks
Authors: Walsh Jonathan R. , Smith Aaron M. , Pouliot Yannick , Li-Bland David , Loukianov Anton , Fisher Charles K. ,   for the Multiple Sclerosis Outcome Assessments Consortium
Published: February 2020

AbstractMultiple Sclerosis (MS) is a neurodegenerative disorder characterized by a complex set of clinical assessments. We use an unsupervised machine learning model called a Conditional Restricted Boltzmann Machine (CRBM) to learn the relationships between covariates commonly used to characterize subjects and their disease progression in MS clinical trials. A CRBM is capable of generating digital twins, which are simulated subjects having the same baseline data as actual subjects. Digital twins allow for subject-level statistical analyses of disease progression. The CRBM is trained using data from 2395 subjects enrolled in the placebo arms of clinical trials across the three primary subtypes of MS. We discuss how CRBMs are trained and show that digital twins generated by the model are statistically indistinguishable from their actual subject counterparts along a number of measures.
Chromonomer: a tool set for repairing and enhancing assembled genomes through integration of genetic maps and conserved synteny
Authors: Catchen Julian , Amores Angel , Bassham Susan 
Published: February 2020

AbstractThe pace of the sequencing and computational assembly of novel reference genomes is accelerating. Though DNA sequencing technologies and assembly software tools continue to improve, biological features of genomes such as repetitive sequence as well as molecular artifacts that often accompany sequencing library preparation can lead to fragmented or chimeric assemblies. If left uncorrected, defects like these trammel progress on understanding genome structure and function, or worse, positively mislead such research. Fortunately, integration of additional, independent streams of information, such as a genetic map – particularly a marker-dense map from RADseq, for example – and conserved orthologous gene order from related taxa can be used to scaffold together unlinked, disordered fragments and to restructure a reference genome where it is incorrectly joined. We present a tool set for automating these processes, one that additionally tracks any changes to the assembly and to the genetic map, and which allows the user to scrutinize these changes with the help of web-based, graphical visualizations. Chromonomer takes a user-defined reference genome, a map of genetic markers, and, optionally, conserved synteny information to construct an improved reference genome of chromosome models: a “chromonome”. We demonstrate Chromonomer’s performance on genome assemblies and genetic maps that have disparate characteristics and levels of quality.
Entrepreneurial framework conditions and business sustainability among the youth and women entrepreneurs
Authors: Orobia Laura A. , Tusiime Immaculate , Mwesigwa Rogers , Ssekiziyivu Bob 
Published: February 2020

Purpose
This study aims to investigate the relationship between entrepreneurial framework conditions (EFCs) and business sustainability among youth and women entrepreneurs using the institutional theory.

Design/methodology/approach
This study is cross-sectional and follows an explanatory research design using 390 youth and women entrepreneurs in Mbarara district (Uganda). A principal factor analysis was conducted to single out the particular constructs of business sustainability and EFC. Inferential analysis was conducted to test the relationships.

Findings
First, the constructs of business sustainability are stakeholder engagements, people and skills, ecosystem management, market and sales and innovation. Second, the constructs of EFC are education, government program and policies, IT infrastructure, market openness and finance. Finally, finance and IT infrastructure are significant predictors of business sustainability among the youth and women entrepreneurs.

Research limitations/implications
The examination of EFCs from the perspective of the consumers/beneficiaries can offer reasonable results when compared to the national expert perspective.

Originality/value
This study generates initial evidence on the applicability of EFCs from the perspective of the individuals as opposed to the national experts.