bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using a supervised principal components analysis for variable selection in high-dimensional datasets reduces false discovery rates
Authors: Ullah Insha , Mengersen Kerrie , Pettitt Anthony , Liquet Benoit 
Published: May 2020

AbstractHigh-dimensional datasets, where the number of variables ‘p’ is much larger compared to the number of samples ‘n’, are ubiquitous and often render standard classification and regression techniques unreliable due to overfitting. An important research problem is feature selection — ranking of candidate variables based on their relevance to the outcome variable and retaining those that satisfy a chosen criterion. In this article, we propose a computationally efficient variable selection method based on principal component analysis. The method is very simple, accessible, and suitable for the analysis of high-dimensional datasets. It allows to correct for population structure in genome-wide association studies (GWAS) which otherwise would induce spurious associations and is less likely to overfit. We expect our method to accurately identify important features but at the same time reduce the False Discovery Rate (FDR) (the expected proportion of erroneously rejected null hypotheses) through accounting for the correlation between variables and through de-noising data in the training phase, which also make it robust to outliers in the training data. Being almost as fast as univariate filters, our method allows for valid statistical inference. The ability to make such inferences sets this method apart from most of the current multivariate statistical tools designed for today’s high-dimensional data. We demonstrate the superior performance of our method through extensive simulations. A semi-real gene-expression dataset, a challenging childhood acute lymphoblastic leukemia (CALL) gene expression study, and a GWAS that attempts to identify single-nucleotide polymorphisms (SNPs) associated with the rice grain length further demonstrate the usefulness of our method in genomic applications.Author summaryAn integral part of modern statistical research is feature selection, which has claimed various scientific discoveries, especially in the emerging genomics applications such as gene expression and proteomics studies, where data has thousands or tens of thousands of features but a limited number of samples. However, in practice, due to unavailability of suitable multivariate methods, researchers often resort to univariate filters when it comes to deal with a large number of variables. These univariate filters do not take into account the dependencies between variables because they independently assess variables one-by-one. This leads to loss of information, loss of statistical power (the probability of correctly rejecting the null hypothesis) and potentially biased estimates. In our paper, we propose a new variable selection method. Being computationally efficient, our method allows for valid inference. The ability to make such inferences sets this method apart from most of the current multivariate statistical tools designed for today’s high-dimensional data.
Transcriptomics and methylomics study on the effect of iodine-containing drug FS-1 onEscherichia coliATCC BAA-196
Authors: Korotetskiy Ilya S. , Jumagaziyeva Ardak B. , Shilov Sergey V. , Kuznetsova Tatyana V. , Myrzabayeva Auyes N. , Iskakbayeva Zhanar A. , Ilin Aleksandr I. , Joubert Monique , Taukobong Setshaba , Reva Oleg N. 
Published: May 2020

AbstractBackgroundRecent studies showed promising results on application of iodine-containing nanomicelles, FS-1, against antibiotic resistant pathogens. The effect was studied onEscherichia coliATCC BAA-196.Materials & methodsRNA sequencing for transcriptomics and the complete genome sequencing by SMRT PacBio RS II technology followed by genome assembly and methylomics study were performed.Results & conclusionsFS-1 treatedE. colishowed an increased susceptibility to antibiotics ampicillin and gentamicin. The analysis of differential gene regulation showed that possible targets of iodine-containing particles are cell membrane fatty acids and proteins, particularly cytochromes, that leads to oxidative, osmotic and acidic stresses. Cultivation with FS-1 caused gene expression alterations towards anaerobic respiration, increased anabolism and inhibition of many nutrient uptake systems. Identification of methylated nucleotides showed an altered pattern in the FS-1 treated culture. Possible role of transcriptional and epigenetic modifications in the observed increase in susceptibility to gentamicin and ampicillin were discussed.Lay abstractNew approaches of combatting drug resistance infections are in demand as the development of new antibiotics is in a deep crisis. This study was set out to investigate molecular mechanisms of action of new iodine-containing nano-micelle drug FS-1, which potentially may improve the antibiotic therapy of drug resistant infections. Iodine is one of the oldest antimicrobials and until now there were no reports on development of resistance to iodine. Recent studies showed promising results on application of iodine-containing nano-micelles against antibiotic resistant pathogens as a supplement to antibiotic therapy. The mechanisms of action, however, remain unclear. The collection strainEscherichia coliATCC BAA-196 showing an extended spectrum of resistance to beta-lactam and aminoglycoside antibiotics was used in this study as a model organism. Antibiotic resistance patterns, whole genomes and total RNA sequences of the FS-1 treated (FS) and negative control (NC) variants ofE. coliBAA-196 were obtained and analyzed. FS culture showed an increased susceptibility to antibiotics associated with profound gene expression alterations switching the bacterial metabolism to anaerobic respiration, increased anabolism, osmotic stress response and inhibition of many nutrient uptake systems. Nucleotide methylation pattern were identified in FS and NC cultures. While the numbers of methylated sites in both genomes remained similar, some peculiar alterations were observed in their distribution along chromosomal and plasmid sequences.
CRISPRCasTyper: An automated tool for the identification, annotation and classification of CRISPR-Cas loci
Authors: Russel Jakob , Pinilla-Redondo Rafael , Mayo-Muñoz David , Shah Shiraz A. , Sørensen Søren J. 
Published: May 2020

AbstractCRISPR-Cas loci encode for highly diversified prokaryotic adaptive defense systems that have recently become popular for their applications in gene editing and beyond. The increasing demand for bioinformatic tools that systematically detect and classify CRISPR-Cas systems has been largely challenged by their complex dynamic nature and rapidly expanding classification. Here, we developed CRISPRCasTyper, a new automated software tool with improved capabilities for identifying and typing CRISPR arrays andcasloci across prokaryotic sequences, based on the latest classification and nomenclature (39 subtypes/variants) (Makarova et al. 2020; Pinilla-Redondo et al. 2019). As a novel feature, CRISPRCasTyper uses a machine learning approach to subtype CRISPR arrays based on the sequences of the direct repeats. This allows the typing of orphan and distant arrays which, for example, are commonly observed in fragmented metagenomic assemblies. Furthermore, the tool provides a graphical output, where CRISPRs andcasoperon arrangements are visualized in the form of colored gene maps, thus aiding annotation of partial and novel systems through synteny. Moreover, CRISPRCasTyper can resolve hybrid CRISPR-Cas systems and detect loci spanning the ends of sequences with a circular topology, such as complete genomes and plasmids. CRISPRCasTyper was benchmarked against a manually curated set of 31 subtypes/variants with a median accuracy of 98.6%. Altogether, we present an up-to-date and freely available software pipeline for significantly improved automated predictions of CRISPR-Cas loci across genomic sequences.ImplementationCRISPRCasTyper is available through conda and PyPi under the MIT license (https://github.com/Russel88/CRISPRCasTyper), and is also available as a web server (http://cctyper.crispr.dk).
JAG1-NOTCH4 Mechanosensing Drives Atherosclerosis
Authors: Souilhol Celine , Li Xiuying , Canham Lindsay , Roddie Hannah , Pirri Daniela , Ayllon Blanca Tardajos , Chambers Emily V , Dunning Mark J , Ariaans Mark , Li Jin , Fang Yun , Fragiadaki Maria , Ridger Victoria , Serbanovic-Canic Jovana , de Val Sarah , Francis Sheila E. , Chico Timothy JA , Evans Paul C 
Published: May 2020

AbstractEndothelial cell (EC) sensing of fluid shear stress regulates atherosclerosis, a disease of arteries that causes heart attack and stroke. Atherosclerosis preferentially develops at regions of arteries exposed to low oscillatory shear stress (LOSS), whereas high shear regions are protected. We show using inducible EC-specific genetic deletion in hyperlipidaemic mice that the Notch ligands JAG1 and DLL4 have opposing roles in atherosclerosis. While endothelialJag1promoted atherosclerosis at sites of LOSS, endothelialDll4was atheroprotective. Analysis of porcine and murine arteries and cultured human coronary artery EC exposed to experimental flow revealed that JAG1 and its receptor NOTCH4 are strongly upregulated by LOSS. Functional studies in cultured cells and in mice with EC-specific deletion ofJag1show that JAG1-NOTCH4 signalling drives vascular dysfunction by repressing endothelial repair. These data demonstrate a fundamental role for JAG1-NOTCH4 in sensing LOSS during disease, and suggest therapeutic targeting of this pathway to treat atherosclerosis.
Polarized endosome dynamics engage cytosolic Par-3 and dynein during asymmetric division
Authors: Zhao Xiang , Tong Kai , Chen Xingye , Yang Bin , Li Qi , Dai Zhipeng , Shi Xiaoyu , Seiple Ian B. , Huang Bo , Guo Su 
Published: May 2020

AbstractAsymmetric cell division (ACD), which produces two daughters with different fates, is fundamental for generating cellular diversity. In the developing embryos of both invertebrates and vertebrates, asymmetrically dividing progenitors generate daughter cells with differential activity of Notch signaling1–7, a key regulator of cell fate decisions8,9. The cell polarity regulator Par-3 is critical for establishing this Notch asymmetry1,4,6, but the underlying mechanisms are not understood. Here, employingin vivotime-lapse imaging in the developing zebrafish forebrain during the mitotic cycle of radial glia, the principal vertebrate neural stem cells10,11, we show that during ACD, endosomes containing the Notch ligand Delta D (Dld) undergo convergent movement toward the cleavage plane, followed by preferential segregation into the posterior (and subsequently basal) Notchhidaughter. This asymmetric segregation requires the activity of Par-3 and the dynein motor complex. Employing label-retention expansion microscopy, we further detect Par-3 in the cytosol in association with the dynein light intermediate chain 1 (DLIC1) on Dld endosomes, suggesting a direct involvement of Par-3 in dynein-mediated polarized transport of Notch signaling endosomes. Our data reveal an unanticipated mechanism by which Par-3 regulates cell fate decision by directly polarizing Notch signaling components during ACD.
The FDA-approved drug Nelfinavir inhibits lytic cell-free transmission of human adenoviruses
Authors: Georgi Fanny , Andriasyan Vardan , Witte Robert , Murer Luca , Hemmi Silvio , Yu Lisa , Grove Melanie , Meili Nicole , Kuttler Fabien , Yakimovich Artur , Turcatti Gerardo , Greber Urs F 
Published: May 2020

AbstractAdenoviruses (AdVs) are prevalent and give rise to chronic and recurrent disease. The human AdV (HAdV) species B and C, such as HAdV-C2, C5 and B14, cause respiratory disease, and constitute a health threat for immuno-compromised individuals. HAdV-Cs are well known for lysing cells, owing to the E3 CR1-β-encoded adenovirus death protein (ADP). We previously reported a high-throughput image-based screening framework and identified an inhibitor of HAdV-C2 multi-round infection, Nelfinavir Mesylate. Nelfinavir is the active ingredient of Viracept, an FDA-approved inhibitor of the human immuno-deficiency virus (HIV) aspartyl protease, and used to treat acquired immunodeficiency syndrome (AIDS). It is not effective against single round HAdV infections. Here, we show that Nelfinavir inhibits the lytic cell-free transmission of HAdV, indicated by the suppression of comet-shaped infection foci in cell culture. Comet-shaped foci occur upon convection-based transmission of cell-free viral particles from an infected cell to neighbouring uninfected cells. HAdV lacking ADP was insensitive to Nelfinavir, but gave rise to comet-shaped foci indicating that ADP enhances but is not required for cell lysis. This was supported by the notion that HAdV-B14 and B14p1 lacking ADP were highly sensitive to Nelfinavir, although HAdV-A31, B3, B7, B11, B16, B21, D8, D30 or D37 were less sensitive. Conspicuously, Nelfinavir uncovered slow-growing round-shaped HAdV-C2 foci, independent of neutralizing antibodies in the medium, indicative of non-lytic cell-to-cell transmission. Our study demonstrates the repurposing potential of Nelfinavir with post-exposure efficacy against different HAdVs, and describes an alternative non-lytic cell-to-cell transmission mode of HAdV.Graphical AbstractFigure 1.
β-catenin perturbations control differentiation programs in mouse embryonic stem cells
Authors: Pedone Elisa , Failli Mario , Gambardella Gennaro , De Cegli Rossella , La Regina Antonella , di Bernardo Diego , Marucci Lucia 
Published: May 2020

AbstractThe Wnt/β-catenin pathway is involved in development, cancer and embryonic stem cell (ESC) maintenance; its dual role in stem cell self-renewal and differentiation is still controversial. Here, by applying anin vitrosystem enabling inducible gene expression control, we report that moderate induction of transcriptionally active exogenous β- catenin in β-catenin null mouse ESCs promotes epiblast-like cell (EpiLC) derivationin vitro. Instead, in wild type cells moderate chemical pre-activation of the Wnt/β-catenin pathway promotes EpiLCin vitroderivation. Finally, we suggest that moderate β- catenin levels in β-catenin null mouse ESCs favour early stem cell commitment towards mesoderm if the exogenous protein is induced only in the ‘ground state’ of pluripotency condition, or endoderm if the induction is maintained during the differentiation. Overall, our results confirm previous findings about the role of β-catenin in pluripotency and differentiation, while indicating a role for its doses in promoting specific differentiation programs.
Spider viscid silk sticks better to superhydrophobic surfaces
Authors: Alicea-Serrano Angela M. , Htut K Zin , Coonfield Alissa J. , Karkosiak Katherine , Dhinojwala Ali , Blackledge Todd A. 
Published: May 2020

ABSTRACTIn a likely coevolutionary arms race, insects evolved a variety of counter strategies to avoid capture by spider webs, while spiders’ evolved innovations web structure and especially their adhesive silks. For instance, insects’ cuticles employ a variety of potential anti-adhesion mechanisms such as the detachable scales of moths and surface waxes and superhydrophobic structures that might resist spreading of glues. In contrast, the viscid capture threads of most spider orb webs are covered with aggregate glue droplets that absorb atmospheric water, tuning glue viscosity to balance the competing demands of surface spreading versus maintaining strong bulk cohesion. Here, we test the hypothesis that superhydrophobicity in insects acts as an anti-adhesion defense against spider silk. We used lotus leaves as a model substrate because its superhydrophobicity outperforms most known insect surfaces. The adhesion of spider capture silk from the web of Larinioides cornutus was studied against three substrates: raw lotus leaves, oxygen plasma treated lotus leaves (hydrophilic lotus), and smooth glass, differing in roughness and chemistry. We found that spider capture silk sticks better to the superhydrophobic lotus than to other surfaces. Both chemistry and physical properties of the leaves contribute to higher adhesion, as raw lotus showed a mean increase in adhesion of 74 % compared to glass, while the similar surface roughness of the hydrophilic lotus increased adhesion by 64 % compared to glass. Thus, evolving a hydrophobic cuticle is unlikely to be a defensive trait used to mitigate the effectiveness of spider webs.
Selective B cell depletion upon intravenous infusion of replication-incompetent anti-CD19 CAR lentivirus
Authors: Rive Craig M. , Yung Eric , Dreolini Lisa , Brown Scott D. , May Christopher G. , Woodsworth Daniel J. , Holt Robert A. 
Published: May 2020

AbstractAnti-CD19 CAR-T therapy for B cell malignancies has shown clinical success, but a major limitation is the logistical complexity and high cost of manufacturing autologous cell products. If engineered for improved safety, direct infusion of viral gene transfer vectors to initiatein vivoCAR-T transduction, expansion and anti-tumor activity could provide an alternative, universal approach. To explore this approach we administered approximately 20 million replication-incompetent VSV-G lentiviral particles carrying an anti-CD19CAR-2A-GFP transgene comprising either an FMC63 (human) or 1D3 (murine) anti-CD19 binding domain, or a GFP-only control transgene, to wild-type C57BL/6 mice by tail vein infusion. The dynamics of immune cell subsets isolated from peripheral blood were monitored at weekly intervals. We saw emergence of a persistent CAR-transduced CD3+T cell population beginning week 3-4 that reached a maximum of 13.5 +/-0.58% (mean +/-SD) and 7.8 +/-0.76% of the peripheral blood CD3+T cell population in mice infused with ID3-CAR or FMC63-CAR lentivector, respectively, followed by a rapid decline in each case of the B cell content of peripheral blood. Complete B cell aplasia was apparent by week 5 and was sustained until the end of the protocol (week 8). No significant CAR positive populations were observed within other immune cell subsets or other tissues. These results indicate that direct IV infusion of conventional VSV-G pseudotyped lentiviral particles carrying a CD19 CAR transgene can transduce T cells that then fully ablate endogenous B cells in wild type mice.
Clonal Heterogeneity Supports Mitochondrial Metabolism in Pancreatic Cancer
Authors: Halbrook Christopher J. , Thurston Galloway , McCarthy Amy , Nelson Barbara S. , Sajjakulnukit Peter , Krall Abigail S. , Mullen Peter J. , Zhang Li , Batra Sandeep , Viale Andrea , Stanger Ben Z. , Christofk Heather R. , Zhang Ji , di Magliano Marina Pasca , Jorgensen Claus , Lyssiotis Costas A. 
Published: May 2020

SummaryPancreatic ductal adenocarcinoma (PDA) is characterized by a heterogenous and densely fibrotic microenvironment. This limits functional vasculature and diffusion of nutrients through the tumor1,2. Accordingly, pancreatic cancer cells develop numerous metabolic adaptations to survive and proliferate in nutrient austere conditions3-7. Subtypes of PDA have been characterized by transcriptional and functional differences8-12, which have been reported to exist within the same tumor13-15. However, it remains unclear if this diversity extends to metabolic programming. Here, using a combination of metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses within neoplastic populations isolated from a single pancreatic tumor. Furthermore, these populations are poised for metabolic crosstalk, and in examining this, we find an unexpected role for asparagine in maintaining cell proliferation following mitochondrial inhibition. Functionally, when challenged by mitochondrial inhibition, asparagine supplementation increases intracellular levels of asparagine and aspartate, a rate limiting biosynthetic precursor16-18. Conversely, depletion of extracellular asparagine with PEG-asparaginase sensitizes pancreatic tumors to mitochondrial targeting with phenformin. Together, these data extend the concept of metabolic diversity to neoplastic populations within individual tumors, while illustrating a new method of intratumoral communication that supports tumor fitness19,20. Finally, the combination of asparaginase with mitochondrial inhibition could provide a powerful new strategy for this difficult to treat disease.
Polymer modelling unveils the roles of heterochromatin and nucleolar organizing regions in shaping 3D genome organization in Arabidopsis thaliana
Authors: Di Stefano Marco , Nützmann Hans-Wilhelm , Marti-Renom Marc A. , Jost Daniel 
Published: May 2020

ABSTRACTThe 3D genome is characterized by a complex organization made of genomic and epigenomic layers with profound implications on gene regulation and cell function. However, the understanding of the fundamental mechanisms driving the crosstalk between nuclear architecture and (epi)genomic information is still lacking. The plantArabidopsis thalianais a powerful model organism to address these questions owing to its compact genome for which we have a rich collection of microscopy, Chromosome Conformation Capture (Hi-C), and ChIP-seq experiments. Using polymer modelling, we investigate the roles of nucleolus formation and epigenomics-driven interactions in shaping the 3D genome ofA. thaliana. By validation of several predictions with published data, we demonstrate that self-attracting nucleolar organizing regions and repulsive constitutive heterochromatin are major mechanisms to regulate the organization of chromosomes. Simulations also suggest that interphase chromosomes maintain a partial structural memory of the V-shapes, typical of (sub)metacentric chromosomes in anaphase. Additionally, self-attraction between facultative heterochromatin regions facilitates the formation of Polycomb bodies hosting H3K27me3-enriched gene-clusters. Since nucleolus and heterochromatin are highly-conserved in eukaryotic cells, our findings pave the way for a comprehensive characterization of the generic principles that are likely to shape and regulate the 3D genome in many species.
MEKK3-MEK5-ERK5 Signaling Promotes Mitochondrial Degradation
Authors: Craig Jane E. , Miller Joseph N. , Rayavarapu Raju R. , Hong Zhenya , Bulut Gamze B. , Zhuang Wei , Sakurada Sadie Miki , Temirov Jamshid , Low Jonathan A. , Chen Taosheng , Pruett-Miller Shondra M. , Huang Lily Jun-shen , Potts Malia B. 
Published: May 2020

AbstractMitochondria are vital organelles that coordinate cellular energy homeostasis and have important roles in cell death. Therefore, the removal of damaged or excessive mitochondria is critical for maintaining proper cellular function. The PINK1-Parkin pathway removes acutely damaged mitochondria through a well-characterized mitophagy pathway, but basal mitochondrial turnover occurs via distinct and less well-understood mechanisms. Here we report that the MEKK3-MEK5-ERK5 kinase cascade is required for mitochondrial degradation in the absence of exogenous damage. We demonstrate that genetic or pharmacological inhibition of the MEKK3-MEK5-ERK5 pathway increases mitochondrial content by reducing lysosome-mediated degradation of mitochondria under basal conditions. We show that the MEKK3-MEK5-ERK5 pathway plays a selective role in basal mitochondrial degradation but is not required for non-selective bulk autophagy, damage-induced mitophagy, or restraint of mitochondrial biogenesis. This illuminates the MEKK3-MEK5-ERK5 pathway as a positive regulator of mitochondrial degradation that acts independently of exogenous mitochondrial stressors.