bluuebunny/crossref_metadata_2025_split huggingface dataset:
PHERI - Phage Host Exploration pipeline
Authors: Baláž Andrej , Kajsík Michal , Budiš Jaroslav , Szemeš Tomáš , Turňa Ján 
Published: May 2020

AbstractAntibiotic resistance is becoming a common problem in medicine, food, and industry, with multi-resistant bacterial strains occurring in all world regions. One of the possible future solutions is the use of bacteriophages in therapy. Bacteriophages are the most abundant form of life in the biosphere, so we can highly likely purify a specific phage against each target bacterium. The identification and consistent characterization of individual phages was a common form of phage work and included determining bacteriophages’ host-specificity. With the advent of new modern sequencing methods, there was a problem with the detailed characterization of phages in the environment identified by metagenome analysis. The solution to this problem may be to use a bioinformatic approach in the form of prediction software capable of determining a bacterial host based on the phage whole-genome sequence. The result of our research is the machine learning algorithm based tool called PHERI. PHERI predicts suitable bacterial host genus for purification of individual viruses from different samples. Besides, it can identify and highlight protein sequences that are important for host selection. PHERI is available athttps://hub.docker.com/repository/docker/andynet/pheri. The source code for the model training is available athttps://github.com/andynet/pheri_preprocessing, and the source code for the tool is available athttps://github.com/andynet/pheri.
A point mutation inTtc26causes lumbar spinal cord fusion and synchronous hind-limb locomotion inhopmice
Authors: Bernhardt Nadine , Memic Fatima , Velica Anna , Tran Michelle A. , Vieillard Jennifer , Chersa Taha , Andersson Leif , Whelan Patrick J. , Boije Henrik , Kullander Klas 
Published: May 2020

AbstractIdentifying the spinal circuits controlling locomotion is critical for unravelling the mechanisms controlling the production of gaits. Development of the circuits governing left-right coordination relies on axon guidance molecules such as ephrins and netrins. To date, no other class of proteins have been shown to play a role during this process. Here we have analyzedhopmice, which walk with a characteristic hopping gait using their hind legs in synchrony. Fictive locomotion experiments suggest that a local defect in the ventral spinal cord contributes to the aberrant locomotor phenotype.Hopmutant spinal cords had severe morphological defects, including the absence of the ventral midline and a poorly defined border between white and grey matter. Thehopmice represent the first model where the left and right central pattern generators (CPGs) are fused to form one central CPG, with a synchronous gait as a functional consequence. These defects were exclusively found in the lumbar domain and were associated with abnormal developmental processes, including a misplaced notochord and reduced induction of ventral progenitor domains. While the underlying mutation inhopmice has been suggested to lie withinTtc26, other genes in close vicinity have been associated with gait defects. By replicating the point mutation withinTtc26, employing CRISPR technology, we observed mice with an identical phenotype, thereby verifying the hop mutation. Thus, we show that the assembly of the lumbar CPG network is dependent on a fully functional TTC26 protein.
Dynamic phenotypic heterogeneity generated by delayed genetic oscillations
Authors: Peña-Miller R. , Arnoldini M. , Ackermann M. , Beardmore R. E. 
Published: May 2020

ABSTRACTEukaryotes and prokaryotes exploit the ability of genetically identical cells to exhibit different phenotypes in order to enhance their survival. However, the mechanisms by which cells transition from one phenotype to another remain unclear. Canonical models of this dynamic posit that molecular fluctuations provide the noise that drives the cell out of one stable state and into another. Stochastic processes generated by canonical models should, therefore, be good descriptors of phenotype dynamics and between-state transitions should become more likely at greater noise amplitude, for instance at higher extracellular temperatures. To test these predictions, we observed temporal expression dynamics of the promoter of a flagellum gene,fliC, in a microfluidic device usingSalmonella entericaserovar Typhimurium and green fluorescent protein (GFP). Our observations show that while cells can exhibit multistable phenotypes, including stablefliC-OFF andfliC-ON states characterised by low and high GFP levels, respectively, between-state transitions can exhibit oscillatory dynamics whose return statistics do not conform to canonical theories. For example, here thefliC-ON state was more frequent following a temperature increase. To better understand our data we developed different dynamical frameworks to predictfliCexpression data. We conclude that a stochastic dynamical system tailored to the genetic network offliCis better suited to our data than prior theories where dynamical features, like oscillations and pulsing, are driven by inevitable delays in the post-translational regulation offliC. Thus, while transcriptional noise promotes phenotypic heterogeneity, as we show here, regular features like oscillatory heterogeneity can result from delays that fundamental molecular processes impose upon a cell’s gene regulatory architecture.
Discovery of repurposing drug candidates for the treatment of diseases caused by pathogenic free-living amoebae
Authors: Rice Christopher A. , Colon Beatrice L. , Chen Emily , Hull Mitchell V. , Kyle Dennis E. 
Published: May 2020

AbstractDiseases caused by pathogenic free-living amoebae include primary amoebic meningoencephalitis (Naegleria fowleri), granulomatous amoebic encephalitis (Acanthamoebaspp.),Acanthamoebakeratitis, andBalamuthiaamoebic encephalitis (Balamuthia mandrillaris). Each of these are difficult to treat and have high morbidity and mortality rates due to lack of effective therapeutics. In pursuit of repurposing drugs for chemotherapies, we conducted a high throughput phenotypic screen of 12,000 compounds from the Calibr ReFRAME library. We discovered a total of 58 potent inhibitors (IC50<1 μM) againstN. fowleri(n=19),A. castellanii(n=12), andB. mandrillaris(n=27) plus an additional 90 micromolar inhibitors. Of these, 113 inhibitors have never been reported to have activity againstNaegleria,AcanthamoebaorBalamuthia. Rapid onset of action is important for new anti-amoeba drugs and we identified 19 compounds that inhibitN. fowleri in vitrowithin 24 hours (halofuginone, NVP-HSP990, fumagillin, bardoxolone, belaronib, and BPH-942, solithromycin, nitracrine, quisinostat, pabinostat, pracinostat, dacinostat, fimepinostat, sanguinarium, radicicol, acriflavine, REP3132, BC-3205 and PF-4287881). These compounds inhibitN. fowleri in vitrofaster than any of the drugs currently used for chemotherapy. The results of these studies demonstrate the utility of phenotypic screens for discovery of new drugs for pathogenic free-living amoebae, includingAcanthamoebafor the first time. Given that many of the repurposed drugs have known mechanisms of action, these compounds can be used to validate new targets for structure-based drug design.Author SummaryFree-living amoebae (FLA) are ubiquitous in soil and freshwater and most are non-pathogenic to people; however, three different pathogenic FLA have been found to cause severe, most often fatal diseases in humans. Due to poor detection and inadequate treatment options available for pathogenic FLA, the fatality rates are still > 90% for the diseases caused byBalamuthia mandrillaris,Naegleria fowleri, andAcanthamoebaspp. With hundreds of cases in the United States and many more cases reported worldwide, there is still an urgent clinical need for effective diagnosis and specific treatments discovered against these opportunistic parasites. Drug repurposing is a powerful approach for drug-discovery because it significantly improves the discovery time, reduces the amount of resources, and decreases costs required to advance lead candidate drugs of interest into the clinic. This is extremely helpful for neglected diseases including pathogenic FLA where there is a need for new active therapies with limited budgets. This report addresses the discovery of new active drugs with potential for repurposing, multiple new drug classes that inhibit pathogenic FLA, and numerous putative drug targets that can be used as tools for further investigation and structure-based drug design.
Iterative point set registration for aligning scRNA-seq data
Authors: Alavi Amir , Bar-Joseph Ziv 
Published: May 2020

AbstractSeveral studies profile similar single cell RNA-Seq (scRNA-Seq) data using different technologies and platforms. A number of alignment methods have been developed to enable the integration and comparison of scRNA-Seq data from such studies. While each performs well on some of the datasets, to date no method was able to both perform the alignment using the original expression space and generalize to new data. To enable such analysis we developed Single Cell Iterative Point set Registration (SCIPR) which extends methods that were successfully applied to align image data to scRNA-Seq. We discuss the required changes needed, the resulting optimization function, and algorithms for learning a transformation function for aligning data. We tested SCIPR on several scRNA-Seq datasets. As we show it successfully aligns data from several different cell types, improving upon prior methods proposed for this task. In addition, we show the parameters learned by SCIPR can be used to align data not used in the training and to identify key cell type-specific genes.Author SummaryIntegrating single cell expression data (scRNA-Seq) across labs, platforms, and technologies is a major challenge. Current methods for addressing this problem attempt to align cells in one study to match cells in another. While successful, current methods are unable to learn a general alignment ingene spacethat can be used to process new or additional data not used in the learning. Here we show that the scRNA-Seq alignment problem resembles a well known problem in the field of computer vision and robotics: point-cloud registration. We next extend traditional iterative rigid-object alignment methods for scRNA-seq while satisfying a set of unique constraints that distinguishes our solution from past methods. Analysis of transcriptomics data demonstrates that our method can accurately align scRNA-seq data, can generalize to unseen datasets, and can provide useful insights about genes active in the cells being studied.
Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells
Authors: Wood Katherine A. , Rowlands Charlie F. , Thomas Huw B. , Woods Steven , O’Flaherty Julieta , Douzgou Sofia , Kimber Susan J. , Newman William G. , O’Keefe Raymond T. 
Published: May 2020

ABSTRACTThe craniofacial developmental disorder Burn-McKeown Syndrome (BMKS) is caused by biallelic variants in the pre-messenger RNA splicing factor geneTXNL4A/DIB1. The majority of affected individuals with BMKS have a 34 base pair deletion in the promoter region of one allele ofTXNL4Acombined with a loss-of-function variant on the other allele, resulting in reducedTXNL4Aexpression. However, it is unclear how reduced expression of this ubiquitously expressed spliceosome protein results in craniofacial defects during development. Here we reprogrammed peripheral mononuclear blood cells from a BMKS patient and her unaffected mother into induced pluripotent stem cells (iPSCs) and differentiated the iPSCs into induced neural crest cells (iNCCs), the key cell type required for correct craniofacial development. BMKS patient-derived iPSCs proliferated more slowly than both mother- and unrelated control-derived iPSCs, and RNA-Seq analysis revealed significant differences in gene expression and alternative splicing. Patient iPSCs displayed defective differentiation into iNCCs compared to maternal and unrelated control iPSCs, in particular a delay in undergoing an epithelial-to-mesenchymal transition (EMT). RNA-Seq analysis of differentiated iNCCs revealed widespread gene expression changes and mis-splicing in genes relevant to craniofacial and embryonic development that highlight a dampened response to WNT signalling, the key pathway activated during iNCC differentiation. Furthermore, we identified the mis-splicing ofTCF7L2exon 4, a key gene in the WNT pathway, as a potential cause of the downregulated WNT response in patient cells. Additionally, mis-spliced genes shared common sequence properties such as length, splice site strengths and sequence motifs, suggesting that splicing of particular subsets of genes is particularly sensitive to changes inTXNL4Aexpression. Together, these data provide the first insight into how reducedTXNL4Aexpression in BMKS patients might compromise splicing and NCC function, resulting in defective craniofacial development in the embryo.
Human dental pulp stem cells: a sanctuary for relapsingBartonella quintana
Authors: Hama Hamadou Oumarou , Hamada Attoumani , Aboudharam Gérard , Ghigo Éric , Drancourt Michel 
Published: May 2020

ABSTRACTBartonella quintanais a facultative intracellular bacterium responsible for relapsing fever, an example of non-sterilizing immunity. The cellular sanctuary ofB. quintanain-between febrile relapses remains unknown but repeated detection ofB. quintanain dental pulp specimens suggested long-term half-life dental pulp stem cells (DPSCs) as candidates. As the capacity of DPSCs to internalize microscopic particles was unknown, we confirmed that DPSCs internalizedB. quintanabacteria: Gimenez staining and fluorescence microscopy localizedB. quintanabacteria inside DPSCs and this internalization did not affect the cellular multiplication of DPSCs during a one-month follow-up despite the increase in the bacterial load.B. quintana-infected DPSCs did not produce Tumor Necrosis Factor-α whereas an important production of Monocytes Chemoattractant Protein-1 was observed. These unprecedented observations suggested the possibility that DPSCs were shelters for the long-term persistence ofB. quintanain the host, warranting further experimental and clinical investigations.
Oligomycins Inhibit Magnaporthe oryzae Triticum and suppress wheat blast disease
Authors: Chakraborty Moutoshi , Mahmud Nur Uddin , Muzahid Abu Naim Md. , Rabby S. M. Fajle , Islam Tofazzal 
Published: May 2020

AbstractOligomycins are macrolide antibiotics, produced by Streptomyces spp., show biological activities to several microorganisms like bacteria, fungi, nematodes and peronosporomycetes. Conidiogenesis, germination of conidia and formation of appressoria are crucial for a successful disease cycle and pathogenicity of the filamentous fungal phytopathogen. The goal of this research was to evaluate the effects of two oligomycins, oligomycin B and oligomycin F along with a commercial fungicide Nativo® 75WG on hyphal growth, conidiogenesis, conidia germination, appressoria formation, and disease development of a worrisome wheat blast fungus, Magnaporthe oryzae Triticum (MoT) pathotype. Both oligomycins suppressed the growth of MoT mycelia depending on the dose. Between the two natural products, oligomycin F displayed the maximum inhibition of MoT hyphal growth accompanied by oligomycin B with minimum inhibitory concentrations (MICs) of 0.005 and 0.05 μg/disk, respectively. The application of the compounds also completely halted the conidia formation in the MoT mycelia in agar medium. A further bioassay showed that these compounds significantly inhibited MoT conidia germination and induced lysis; if germinated, induced abnormal germ tube and suppressed appressoria formation. Interestingly, the application of these macrolides significantly inhibited wheat blast disease on detached leaves of wheat. This is a first report on the inhibition of mycelial growth, process of conidia formation, germination of conidia, morphological changes in germinated conidia, and suppression of blast disease of wheat by oligomycins from Streptomyces spp. A further study is needed to evaluate the mode of action and field trials of these natural compounds to consider them as biopesticides for controlling this devastating wheat killer.
Ancient mitochondrial DNA pathogenic variants putatively associated with mitochondrial disease
Authors: Toncheva Draga , Serbezov Dimitar , Karachanak-Yankova Sena , Nesheva Desislava 
Published: May 2020

AbstractMitochondrial DNA variants associated with diseases are widely studied in contemporary populations, but their prevalence has not yet been investigated in ancient populations. The publicly available AmtDB database contains 1443 ancient mtDNA Eurasian genomes from different periods. The objective of this study was to use this data to establish the presence of pathogenic mtDNA variants putatively associated with mitochondrial diseases in ancient populations. The clinical significance, pathogenicity prediction and contemporary frequency of mtDNA variants were determined using online platforms. The analyzed ancient mtDNAs contain six variants designated as being “confirmed pathogenic” in modern patients. The oldest of these, m.7510T>C in theMT-TS1gene, was found in a sample from the Neolithic period dated 5800-5400 BCE. All six have well established clinical association, and their pathogenic effect is corroborated by very low population frequencies in contemporary populations. In addition, ten variants designated as possibly or likely pathogenic were detected. The oldest of these were two variants in theMT-TDgene, m.7543A>G and m.7554G>A, from Neolithic samples dated 8205-7700 BCE. A novel mutation in contemporary populations, m.4440G>A in theMT-TMgene, is established in 12 ancient mtDNA samples from different periods ranging from 2800 BCE to 920 CE. The pathogenic effect of these possibly/likely pathogenic mutations is not yet well established, and further research is warranted. All detected mutations putatively associated with mitochondrial disease in ancient mtDNA samples are in tRNA coding genes. Most of these mutations are in a mt-tRNA type (Model 2) that is characterized by loss of D-loop/T-loop interaction. Seven mutations are located in CS-Anticodon stem, 4 are located in AS-Acceptor stem, 2 in TS-TΨC stem, and single mutations are found in DL-Dihydrouridine Loop, CL-Anticodon Loop and DS-Dihydrouridine stem. Exposing pathogenic variants in ancient human populations expands our understanding of their origin.
Heterogeneity in clone dynamics within and adjacent to intestinal tumours identified by Dre-mediated lineage tracing
Authors: Thorsen Ann-Sofie , Khamis Doran , Kemp Richard , Colombé Mathilde , Lourenço Filipe C. , Morrissey Edward , Winton Douglas 
Published: May 2020

AbstractSomatic models of tissue pathology commonly utilise induction of gene specific mutations in mice mediated by spatiotemporal regulation of Cre recombinase. Subsequent investigation of the onset and development of disease can be limited by the inability to track changing cellular behaviours over time. Here a lineage tracing approach based on ligand dependent activation of Dre recombinase that can be employed independently of Cre is described. The clonal biology of intestinal epithelium following Cre-mediated stabilisation of ß-catenin reveals that within tumours many new clones rapidly become extinct. Surviving clones show accelerated population of tumour glands compared to normal intestinal crypts but in a non-uniform manner indicating that intra-tumour glands follow heterogeneous dynamics. In tumour adjacent epithelium clone sizes are smaller than in the background epithelium as a whole. This suggests a zone of around 5 crypt diameters within which clone expansion is inhibited by tumours and that may facilitate their growth.
Genome Analysis of SARS-CoV-2 Isolate from Bangladesh
Authors: Hasan Saam , Khan Salim , Ahsan Giasuddin , Hossain Muhammad Maqsud 
Published: May 2020

AbstractRecently the first genome sequence for a Severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2 isolate from Bangladesh became available. The sequencing was carried out by the Child Health Research Foundation and provided the first insight into the genetic details of the viral strain responsible for the SARS-CoV-2 infections in Bangladesh. Here we carried out a comparative study were we explored the phylogenetic relationship between the Bangladeshi isolate with other isolates from different parts of the world. Afterwards we identified single nucleotide variants in the Bangladeshi isolate, using the Wuhan virus reference sequence. We found a total of 9 variants in the Bangladeshi isolate using 2 separate tools. Barring 2, the rest of these variants were also observed in other isolates from different countries. Most of the variants occurred in the ORF1ab gen. Another noteworthy finding was a sequence of three consecutive variants in the N protein gene that were observed in other isolates as well. Lastly the phylogenetic analysis revealed a close relationship between the Bangladeshi isolate and those from Taiwan, Kazakhstan, Greece, California, Spain, Israel, and Sri Lanka.
Live Imaging of Intracranial Lymphatics in the Zebrafish
Authors: Castranova Daniel , Samasa Bakary , Galanternik Marina Venero , Jung Hyun Min , Pham Van N. , Weinstein Brant M. 
Published: May 2020

ABSTRACTRationaleThe recent discovery of meningeal lymphatics in mammals is reshaping our understanding of fluid homeostasis and cellular waste management in the brain, but visualization and experimental analysis of these vessels is challenging in mammals. Although the optical clarity and experimental advantages of zebrafish have made this an essential model organism for studying lymphatic development, the existence of meningeal lymphatics has not yet been reported in this species.ObjectiveExamine the intracranial space of larval, juvenile, and adult zebrafish to determine whether and where intracranial lymphatic vessels are present.Methods and ResultsUsing high-resolution optical imaging of the meninges in living animals, we show that zebrafish possess a meningeal lymphatic network comparable to that found in mammals. We confirm that this network is separate from the blood vascular network and that it drains interstitial fluid from the brain. We document the developmental origins and growth of these vessels into a distinct network separated from the external lymphatics. Finally we show that these vessels contain immune cells and perform live imaging of immune cell trafficking and transmigration in meningeal lymphatics.ConclusionsThis discovery establishes the zebrafish as a important new model for experimental analysis of meningeal lymphatic development, and opens up new avenues for probing meningeal lymphatic function in health and disease.
Cell-type-specific synaptic imbalance and disrupted homeostatic plasticity in cortical circuits of ASD-associatedChd8haploinsufficient mice
Authors: Ellingford Robert A. , de Meritens Emilie Rabeshala , Shaunak Raghav , Naybour Liam , Basson M. Albert , Andreae Laura C. 
Published: May 2020

AbstractHeterozygous mutation of chromodomain helicase DNA binding protein 8 (CHD8) is strongly associated with autism spectrum disorder (ASD) and results in dysregulated expression of neurodevelopmental and synaptic genes during brain development. To reveal how these changes affect ASD-associated cortical circuits, we studied synaptic transmission in the prefrontal cortex of a haploinsufficientChd8mouse model. We report profound alterations to both excitatory and inhibitory synaptic transmission onto deep layer projection neurons, resulting in a reduced excitatory:inhibitory balance, which were found to vary dynamically across neurodevelopment and result from distinct effects of reducedChd8expression within individual neuronal subtypes. These changes were associated with disrupted regulation of homeostatic plasticity mechanisms operating via spontaneous neurotransmission. These findings therefore directly implicateCHD8mutation in the disruption of ASD-relevant circuits in the cortex.