bluuebunny/crossref_metadata_2025_split huggingface dataset:
Learning epistatic gene interactions from perturbation screens
Authors: Elmes Kieran , Schmich Fabian , Szczurek Ewa , Jenkins Jeremy , Beerenwinkel Niko , Gavryushkin Alex 
Published: August 2020

AbstractThe treatment of complex diseases often relies on combinatorial therapy, a strategy where drugs are used to target multiple genes simultaneously. Promising candidate genes for combinatorial perturbation often constitute epistatic genes, i.e., genes which contribute to a phenotype in a non-linear fashion. Experimental identification of the full landscape of genetic interactions by perturbing all gene combinations is prohibitive due to the exponential growth of testable hypotheses. Here we present a model for the inference of pairwise epistatic, including synthetic lethal, gene interactions from siRNA-based perturbation screens. The model exploits the combinatorial nature of siRNA-based screens resulting from the high numbers of sequence-dependent off-target effects, where each siRNA apart from its intended target knocks down hundreds of additional genes. We show that conditional and marginal epistasis can be estimated as interaction coefficients of regression models on perturbation data. We compare two methods, namelyglinternetandxyz, for selecting non-zero effects in high dimensions as components of the model, and make recommendations for the appropriate use of each. For data simulated from real RNAi screening libraries, we show thatglinternetsuccessfully identifies epistatic gene pairs with high accuracy across a wide range of relevant parameters for the signal-to-noise ratio of observed phenotypes, the effect size of epistasis and the number of observations per double knockdown.xyzis also able to identify interactions from lower dimensional data sets (fewer genes), but is less accurate for many dimensions. Higher accuracy ofglinternet, however, comes at the cost of longer running time compared toxyz. The general model is widely applicable and allows mining the wealth of publicly available RNAi screening data for the estimation of epistatic interactions between genes. As a proof of concept, we apply the model to search for interactions, and potential targets for treatment, among previously published sets of siRNA perturbation screens on various pathogens. The identified interactions include both known epistatic interactions as well as novel findings.
The 3’UTR of theorb2gene encoding theDrosophilaCPEB translation factor plays a critical role in spermatogenesis
Authors: Gilmutdinov Rudolf A. , Kozlov Eugene N. , Olenina Ludmila V. , Kotov Alexei A. , Barr Justinn , Zhukova Mariya V. , Schedl Paul , Shidlovskii Yulii V. 
Published: August 2020

AbstractCPEB proteins are conserved translation regulators involved in multiple biological processes. One of these proteins inDrosophila, Orb2, is a principal player in spermatogenesis. It is required for meiosis and spermatid differentiation. During the later processorb2mRNAs and proteins are localized within the developing spermatid. To evaluate the role oforb2mRNA 3’UTR in spermatogenesis, we used the CRISPR/Cas9 system to generate a deletion of theorb23’UTR,orb2R. This deletion disrupts the process of spermatid differentiation, but has no apparent effect on meiosis. While this deletion appears to destabilize theorb2mRNA and reduce the levels of Orb2 protein, this is not the primary cause of the differentiation defects. Instead, differentiation appears to be disrupted becauseorb2mRNAs and proteins are not properly localized within the differentiating spermatids. Other transcripts and proteins involved in spermatogenesis are also mislocalized inorb2Rspermatids.Author summaryThe conserved family of cytoplasmic polyadenylation element binding (CPEB) proteins can activate or repress translation of target mRNAs, depending on the specific biological context, through interaction with special cytoplasmic polyadenylation element (CPE) sequences. These proteins function mainly in highly polarized cells. Orb2, one of the twoDrosophila melanogasterCPEB proteins, is predominantly expressed in the testes and is crucial for spermatogenesis. The 3’UTR oforb2transcript contains multiple CPE-like motifs, which is indicative oforb2self-regulation. We have generated a deletion that removes the greater portion of 3’UTR. While this deletion causes a reduction in the levels oforb2mRNA and the protein, this does not appear to be responsible for the defects in spermatogenesis observed in the deletion mutant. Instead, it is the mislocalization of the mRNA and protein in the developing spermatids.
Protected areas network is not adequate to protect a critically endangered East Africa Chelonian: Modelling distribution of pancake tortoise, Malacochersus tornieri under current and future climates
Authors: Eustace Abraham , Esser Luíz Fernando , Mremi Rudolf , Malonza Patrick K. , Mwaya Reginald T. 
Published: August 2020

ABSTRACTWhile the international pet trade and habitat destruction have been extensively discussed as major threats to the survival of the pancake tortoise (Malacochersus tornieri), the impact of climate change on the species remains unknown. In this study, we used species distribution modelling to predict the current and future distribution of pancake tortoises in Zambezian and Somalian biogeographical regions. We used 224 pancake tortoise occurrences obtained from Tanzania, Kenya and Zambia to estimate suitable and stable areas for the pancake tortoise in all countries present in these regions. We also used a protected area network to assess how many of the suitable and stable areas are protected for the conservation of this critically endangered species. Our model predicted the expansion of climatically suitable habitats for pancake tortoises from four countries and a total area of 90,668.75 km2to ten countries in the future and an area of 343,459.60 - 401,179.70 km2. The model also showed that a more significant area of climatically suitable habitat for the species lies outside of the wildlife protected areas. Based on our results, we can predict that pancake tortoises may not suffer from habitat constriction. However, the species will continue to be at risk from the international pet trade, as most of the identified suitable habitats remain outside of protected areas. We suggest that efforts to conserve the pancake tortoise should not only focus on protected areas but also areas that are unprotected, as these comprise a large proportion of the suitable and stable habitats available following predicted future climate change.
Comparison of antimicrobial activity between intraoperatively soaked bacitracin sutures and triclosan coated suture
Authors: Musick Shane T. , Adkins Jeremy M. , Al-Ahmar Roy , Yu Hongwei D. , Alberico Anthony M. 
Published: August 2020

AbstractWith the easily available option for surgeons to soak their suture in anti-biotic irrigating solution intraoperatively in mind, this study was designed to evaluate the ability of suture soaked in bacitracin irrigating solution to inhibit the growth ofStaphylococcus aureusandMethicillin-resistant Staphylococcus aureus. Using standard experimental procedure, sterile suture was soaked in Bacitracin suture, and dried for 10 minutes or 6 hours, incubated for 24 h on inoculated plates, and examined for zone of inhibition around the suture. This was compared to control unsoaked suture and antimicrobial suture (AMS) currently on the market to determine if the minor intra operative procedural change of placing suture in antibiotic irrigation solution instead of on the sterile table could confer some antimicrobial activity. The study found the Bacitracin soaked suture (BSS) consistently inhibited the growth of the test organisms. For both organisms, the BSS exhibited a significantly larger zone of inhibition compared to the unsoaked control suture. However, the AMS currently on the market exhibited a larger zone of inhibition compared to the BSS. Placing sutures in a bacitracin irrigation solution intraoperatively instead of directly on the sterile table can achieve some of the in vitro antimicrobial effect seen from AMS currently on the market. This may result in reduced rates of SSIs and associated costs without major procedural change and at reduced overhead.
A compelling symmetry: The extended fetuses-at-risk perspective on modal, optimal and relative birthweight and gestational age
Authors: Joseph K.S. 
Published: August 2020

AbstractBackgroundThe relationship between several intriguing perinatal phenomena, namely, modal, optimal, and relative birthweight and gestational age, remains poorly understood, especially the mechanism by which relative birthweight and gestational age resolve the paradox of intersecting perinatal mortality curves.MethodsBirthweight and gestational age distributions and birthweight- and gestational age-specific perinatal death rates of low- and high-risk cohorts in the United States, 2004-2015, were estimated using births-based and extended fetuses-at-risk formulations. The relationships between these births-based distributions and rates, and the first derivatives of fetuses-at-risk birth and perinatal death rates were examined in order to assess how the rate of change in fetuses-at-risk rates affects gestational age distributions and births-based perinatal death rate patterns.ResultsModal gestational age typically exceeded optimal gestational age because both were influenced by the peak in the first derivative of the birth rate, while optimal gestational age was additionally influenced by the point at which the first derivative of the fetuses-at-risk perinatal death rate showed a sharp increase in late gestation. The clustering and correlation between modal and optimal gestational age within cohorts, the higher perinatal death rate at optimal gestational age among higher-risk cohorts, and the symmetric left-shift in births-based gestational age-specific perinatal death rates in higher-risk cohorts explained how relative gestational age resolved the paradox of intersecting perinatal mortality curves.ConclusionsChanges in the first derivative the fetuses-at-risk birth and perinatal death rates underlie several births-based perinatal phenomena and this explanation further unifies the fetuses-at-risk and births-based models of perinatal death.
Profiles of expression pattern and tissue distribution of host defense peptides genes in different chicken (Gallus gallus) breeds related to body weight
Authors: Li Zhengtian , Ahmed Irfan , Xu Zhiqiang , Sun Shuai , Li Tao , Gu Dahai , Liu Yong , Zhang Xia , Yan Shixiong , Hu Wenyuan , Jiang Ziqing , Duan Xiaohua , Li Qihua , Liu Lixian , Rong Hua , Wang Kun , Abdulwahid Alsoufi Mohammed , Dou Tengfei , Wang Shanrong , Su Zhengchang , Ge Changrong , te Pas Marinus F.W. , Jia Junjing , Huang Ying 
Published: August 2020

AbstractHost defense peptides(HDPs) are an important first line of defense with antimicrobial and immunomodulatory properties. Selection for increased body weight is suggested to be related to reduced immune response. We studied the relationships among body weight, age, and theHDPexpression patterns in intestine and immune organs. We used chickens with marked differences of body sizes. The non-selected Daweishan mini chickens showed the highest indexes of immune organs and the lowest concentrations of the plasma immune parameters C3, C4, IgA, and IgY, while the commercial Avian broiler showed the opposite results. The Daweishan mini chickens showed the highest mRNA expressions ofHDPgenes in small intestine followed by the semi-selected Wuding chickens. Compared with local breeds, broiler chickens showed higher mRNA expression ofHDPgenes in spleen, thymus, and bursa. Body weight andHDPexpression levels were negatively correlated in the intestine and positively in the immune organs. These results indicated that theHDPimmune regulatory roles in small intestine acted as first line of defense in innate immunity in local breeds, and as an adaptive immunity in broiler chickens. Selection was associated with the expression profiles ofHDPgenes in a chicken, age, and organ-specific manner.
Identification of split-GAL4 drivers and enhancers that allow regional cell type manipulations of theDrosophila melanogasterintestine
Authors: Ariyapala Ishara S. , Holsopple Jessica M. , Popodi Ellen M. , Hartwick Dalton G. , Kahsai Lily , Cook Kevin R. , Sokol Nicholas S. 
Published: August 2020

ABSTRACTThe Drosophila adult midgut is a model epithelial tissue composed of a few major cell types with distinct regional identities. One of the limitations to its analysis is the lack of tools to manipulate gene expression based on these regional identities. To overcome this obstacle, we applied the intersectional split-GAL4 system to the adult midgut and report 653 driver combinations that label cells by region and cell type. We first identified 424 split-GAL4 drivers with midgut expression from over 7,300 drivers screened, and then evaluated the expression patterns of each of these 424 when paired with three reference drivers that report activity specifically in progenitor cells, enteroendocrine cells, or enterocytes. We also evaluated a subset of the drivers expressed in progenitor cells for expression in enteroblasts using another reference driver. We show that driver combinations can define novel cell populations by identifying a driver that marks a distinct subset of enteroendocrine cells expressing genes usually associated with progenitor cells. The regional cell type patterns associated with the entire set of driver combinations are documented in a freely available website, providing information for the design of thousands of additional driver combinations to experimentally manipulate small subsets of intestinal cells. In addition, we show that intestinal enhancers identified with the split-GAL4 system can confer equivalent expression patterns on other transgenic reporters. Altogether, the resource reported here will enable more precisely targeted gene expression for studying intestinal processes, epithelial cell functions, and diseases affecting self-renewing tissues.
Olfactory host entry supports herpesvirus recombination
Authors: Xie Wanxiaojie , Bruce Kimberley , Farrell Helen E. , Stevenson Philip G. 
Published: August 2020

AbstractHerpesvirus genomes record abundant recombination. Its impact on infection remains ill-defined. When co-infecting mice by the natural olfactory route, individually incapacitated Murid Herpesvirus-4 (MuHV-4) mutants routinely recombined to restore normal host colonization. Lung infection rescued much less well. Murine cytomegalovirus mutants deficient in salivary gland colonization also showed rescue via the nose but not the lungs. As nose and lung infections show similar spread, efficient recombination seemed specific to olfactory entry. Rescue of replication-deficient MuHV-4 implied co-infection of the first encountered cells, and this worked also with asynchronous inoculation, suggesting that latent virus could lie in wait for later reactivation. Inhaled MuHV-4 is commonly caught on respiratory mucus, which epithelial cilia push back towards the olfactory surface, and infection was correspondingly frequent at the anterior olfactory edge. Thus olfactory entry provides a general means for herpesviruses to meet.Author summaryInter-strain recombination allows viruses to optimise infection in diverse hosts. Many herpesviruses show past recombination. Yet they are ancient pathogens, so this past may be remote and recombination rare. Diverse herpesviruses enter new hosts via olfactory cells. We show that such entry routinely allows recombination between co-infecting virus strains, even when one strain cannot spread. Recombination was contrastingly rare after lung infection. Thus, entry via olfactory cells specifically supports frequent herpesvirus recombination.
Reconstructing the lineage histories and differentiation trajectories of individual cancer cells inJAK2-mutant myeloproliferative neoplasms
Authors: Van Egeren Debra , Escabi Javier , Nguyen Maximilian , Liu Shichen , Reilly Christopher R. , Patel Sachin , Kamaz Baransel , Kalyva Maria , DeAngelo Daniel J. , Galinsky Ilene , Wadleigh Martha , Winer Eric S. , Luskin Marlise R. , Stone Richard M. , Garcia Jacqueline S. , Hobbs Gabriela S. , Camargo Fernando D. , Michor Franziska , Mullally Ann , Cortes-Ciriano Isidro , Hormoz Sahand 
Published: August 2020

ABSTRACTSome cancers originate from a single mutation event in a single cell. For example, blood cancers known as myeloproliferative neoplasms (MPN) are thought to originate through the acquisition of a driver mutation (most commonlyJAK2-V617F) in a hematopoietic stem cell (HSC). However, when the mutation first occurs in individual patients and how it impacts the behavior of HSCs in their native context is not known. Here we quantified the impact of theJAK2-V617F mutation on the proliferation dynamics of HSCs and the differentiation trajectories of their progenies in individual MPN patients. We reconstructed the lineage history of individual HSCs obtained from MPN patients using the patterns of spontaneous somatic mutations accrued in their genomes over time. Strikingly, we found that theJAK2-V617F mutation occurred in a single HSC several decades before MPN diagnosis — at age 9±2 years in a 34-year-old patient, and at age 19±3 years in a 63-year-old patient. For each patient, we inferred the number of mutated HSCs over time and computed their fitness. The population ofJAK2-mutated HSCs grew exponentially by 63±15% and 44±13% every year in the two patients, respectively. To contrast the differentiation trajectories of theJAK2-mutated HSCs with those of healthy HSCs, we simultaneously measured the full transcriptome and somatic mutations in single hematopoietic stem and progenitor cells (HSPCs). We found that the fraction ofJAK2-mutant HSPCs varied significantly across different myeloid cell types within the same patient. The erythroid progenitor cells were often entirelyJAK2-mutant, even when the peripheral bloodJAK2-V617F allele burden was low. The novel biological insights uncovered by this work have implications for the prevention and treatment of MPN, as well as the accurate assessment of disease burden in patients. The technology platforms and computational frameworks developed here are broadly applicable to other types of hematological malignancies and cancers.
Induction of SARS-CoV-2 protein S-specific CD8+ T cells in the lungs of gp96-Ig-S vaccinated mice
Authors: Fisher Eva , Padula Laura , Podack Kristin , O’Neill Katelyn , Seavey Matthew M , Jayaraman Padmini , Jasuja Rahul , Strbo Natasa 
Published: August 2020

AbstractGiven the aggressive spread of COVID-19-related deaths, there is an urgent public health need to support the development of vaccine candidates to rapidly improve the available control measures against SARS-CoV-2. To meet this need, we are leveraging our existing vaccine platform to target SARS-CoV-2. Here, we generated cellular heat shock chaperone protein, glycoprotein 96 (gp96), to deliver SARS-CoV-2 protein S (spike) to the immune system and to induce cell-mediated immune responses. We showed that our vaccine platform effectively stimulates a robust cellular immune response against protein S. Moreover, we confirmed that gp96-Ig, secreted from allogeneic cells expressing full-length protein S, generates powerful, protein S polyepitope-specific CD4+ and CD8+ T cell responses in both lung interstitium and airways. These findings were further strengthened by the observation that protein-S -specific CD8+ T cells were induced in human leukocyte antigen (HLA)-A2-02-01 transgenic mice thus providing encouraging translational data that the vaccine is likely to work in humans, in the context of SARS-CoV-2 antigen presentation.
Embedding covariate adjustments in tree-based automated machine learning for biomedical big data analyses
Authors: Manduchi Elisabetta , Fu Weixuan , Romano Joseph D. , Ruberto Stefano , Moore Jason H. 
Published: August 2020

AbstractBackgroundA typical task in bioinformatics consists of identifying which features are associated with a target outcome of interest and building a predictive model. Automated machine learning (AutoML) systems such as the Tree-based Pipeline Optimization Tool (TPOT) constitute an appealing approach to this end. However, in biomedical data, there are often baseline characteristics of the subjects in a study or batch effects that need to be adjusted for in order to better isolate the effects of the features of interest on the target. Thus, the ability to perform covariate adjustments becomes particularly important for applications of AutoML to biomedical big data analysis.ResultsWe present an approach to adjust for covariates affecting features and/or target in TPOT. Our approach is based on regressing out the covariates in a manner that avoids ‘leakage’ during the cross-validation training procedure. We then describe applications of this approach to toxicogenomics and schizophrenia gene expression data sets. The TPOT extensions discussed in this work are available athttps://github.com/EpistasisLab/tpot/tree/v0.11.1-resAdj.ConclusionsIn this work, we address an important need in the context of AutoML, which is particularly crucial for applications to bioinformatics and medical informatics, namely covariate adjustments. To this end we present a substantial extension of TPOT, a genetic programming based AutoML approach. We show the utility of this extension by applications to large toxicogenomics and differential gene expression data. The method is generally applicable in many other scenarios from the biomedical field.
An evolutionarily conserved Lhx2-Ldb1 interaction regulates the acquisition of hippocampal cell fate and regional identity
Authors: Kinare Veena , Iyer Archana , Padmanabhan Hari , Godbole Geeta , Khan Tooba , Khatri Zeba , Maheshwari Upasana , Muralidharan Bhavana , Tole Shubha 
Published: August 2020

AbstractProtein cofactor Ldb1 regulates cell fate specification by interacting with LIM-homeodomain (LIM-HD) proteins in a tetrameric complex consisting of an LDB:LDB dimer that bridges two LIM-HD molecules, a mechanism first demonstrated in theDrosophilawing disc. Here, we demonstrate conservation of this interaction in the regulation of mammalian hippocampal development, which is profoundly defective upon loss of eitherLhx2orLdb1. Electroporation of a chimeric construct that encodes the Lhx2-HD and Ldb1-DD (dimerization domain) in a single transcript cell-autonomously rescues a comprehensive range of hippocampal deficits in the mouseLdb1mutant, including the acquisition of field-specific molecular identity and the regulation of the neuron-glia cell fate switch. This demonstrates that the LHX:LDB complex is an evolutionarily conserved molecular regulatory device that controls complex aspects of regional cell identity in the developing brain.Summary statementSimilar to an Apterous-Chip mechanism that patterns the Drosophila wing blade, interaction between mammalian orthologs Lhx2 and Ldb1 regulates multiple aspects of hippocampal development in the mouse.