bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2–Priming Protease TMPRSS2
Authors: Azouz Nurit P. , Klingler Andrea M. , Callahan Victoria , Akhrymuk Ivan V. , Elez Katarina , Raich Lluís , Henry Brandon M. , Benoit Justin L. , Benoit Stefanie W. , Noé Frank , Kehn-Hall Kylene , Rothenberg Marc E. 
Published: May 2020

AbstractHost proteases have been suggested to be crucial for dissemination of MERS, SARS-CoV, and SARS-CoV-2 coronaviruses, but the relative contribution of membrane versus intracellular proteases remains controversial. Transmembrane serine protease 2 (TMPRSS2) is regarded as one of the main proteases implicated in the coronavirus S protein priming, an important step for binding of the S protein to the angiotensin-converting enzyme 2 (ACE2) receptor before cell entry. The main cellular location where the SARS-CoV-2 S protein priming occurs remains debatable, therefore hampering the development of targeted treatments. Herein, we identified the human extracellular serine protease inhibitor (serpin) alpha 1 antitrypsin (A1AT) as a novel TMPRSS2 inhibitor. Structural modeling revealed that A1AT docked to an extracellular domain of TMPRSS2 in a conformation that is suitable for catalysis, resembling similar serine protease–inhibitor complexes. Inhibitory activity of A1AT was established in a SARS-CoV-2 viral load system. Notably, plasma A1AT levels were associated with COVID-19 disease severity. Our data support the key role of extracellular serine proteases in SARS-CoV-2 infections and indicate that treatment with serpins, particularly the FDA-approved drug A1AT, may be effective in limiting SARS-CoV-2 dissemination by affecting the surface of the host cells.SummaryDelivery of extracellular serine protease inhibitors (serpins) such as A1AT has the capacity to reduce SARS-CoV-2 dissemination by binding and inhibiting extracellular proteases on the host cells, thus, inhibiting the first step in SARS-CoV-2 cell cycle (i.e. cell entry).
SARS-CoV-2 Spike Glycoprotein Receptor Binding Domain is Subject to Negative Selection with Predicted Positive Selection Mutations
Authors: Li You , Wang Ye , Qiu Yaping , Gong Zhen , Deng Lei , Pan Min , Yang Huiping , Xu Jianan , Yang Li , Li Jin 
Published: May 2020

AbstractCOVID-19 is a highly contagious disease caused by a novel coronavirus SARS-CoV-2. The interaction between SARS-CoV-2 spike protein and the host cell surface receptor ACE2 is responsible for mediating SARS-CoV-2 infection. By analyzing the spike-hACE2 interacting surface, we predicted many hot spot residues that make major contributions to the binding affinity. Mutations on most of these residues are likely to be deleterious, leading to less infectious virus strains that may suffer from negative selection. Meanwhile, several residues with mostly advantageous mutations have been predicted. It is more probable that mutations on these residues increase the transmission ability of the virus by enhancing spike-hACE2 interaction. So far, only a limited number of mutations has been reported in this region. However, the list of hot spot residues with predicted downstream effects from this study can still serve as a tracking list for SARS-CoV-2 evolution studies. Coincidentally, one advantageous mutation, p.476G>S, started to surge in the last couple of weeks based on the data submitted to the public domain, indicating that virus strains with increased transmission ability may have already spread.
Translation-associated mutational U-pressure in the first ORF of SARS-CoV-2 and other coronaviruses
Authors: Victorovich Khrustalev Vladislav , Rajanish Giri , Aleksandrovna Khrustaleva Tatyana , Krishna Kapuganti Shivani , Nicolaevich Stojarov Aleksander , Vitoldovich Poboinev Victor 
Published: May 2020

AbstractWithin four months of the ongoing COVID-19 pandemic caused by SARS-CoV-2, more than 250 nucleotide mutations have been detected in the ORF1 of the virus isolated from different parts of the globe. These observations open up an obvious question about the rate and direction of mutational pressure for further vaccine and therapeutics designing. In this study, we did a comparative analysis of ORF1a and ORF1b by using the first isolate (Wuhan strain) as the parent sequence. We observed that most of the nucleotide mutations are C to U transitions. The rate of synonymous C to U transitions is significantly higher than the rate of nonsynonymous ones, indicating negative selection on amino acid substitutions. Further, trends in nucleotide usage bias have been investigated in 49 coronaviruses species. A strong bias in nucleotide usage in fourfold degenerated sites towards uracil residues is seen in ORF1 of all the studied coronaviruses. A more substantial mutational U pressure is observed in ORF1a than in ORF1b owing to the translation of ORF1ab via programmed ribosomal frameshifting. Unlike other nucleotide mutations, mutational U pressure caused by cytosine deamination, mostly occurring in the RNA-plus strand, cannot be corrected by the proof-reading machinery of coronaviruses. The knowledge generated on the direction of mutational pressure during translation of viral RNA-plus strands has implications for vaccine and nucleoside analogue development for treating covid-19 and other coronavirus infections.
A first perturbome ofPseudomonas aeruginosa: Identification of core genes related to multiple perturbations by a machine learning approach
Authors: Mora Jose Arturo Molina , Montero-Manso Pablo , Batán Raquel García , Sánchez Rebeca Campos , Fernández Jose Vilar , Santamaría Fernando García 
Published: May 2020

AbstractTolerance to stress conditions is vital for organismal survival, including bacteria under specific environmental conditions, antibiotics, and other perturbations. Some studies have described common modulation and shared genes during stress response to different types of disturbances (termed as perturbome), leading to the idea of central control at the molecular level. We implemented a robust machine learning approach to identify and describe genes associated with multiple perturbations or perturbome in aPseudomonas aeruginosaPAO1 model.Using microarray datasets from the Gene Expression Omnibus (GEO), we evaluated six approaches to rank and select genes: using two methodologies, data single partition (SP method) or multiple partitions (MP method) for training and testing datasets, we evaluated three classification algorithms (SVM Support Vector Machine, KNN K-Nearest neighbor and RF Random Forest). Gene expression patterns and topological features at the systems level were included to describe the perturbome elements.We were able to select and describe 46 core response genes associated with multiple perturbations inP. aeruginosaPAO1 and it can be considered a first report of theP. aeruginosaperturbome. Molecular annotations, patterns in expression levels, and topological features in molecular networks revealed biological functions of biosynthesis, binding, and metabolism, many of them related to DNA damage repair and aerobic respiration in the context of tolerance to stress. We also discuss different issues related to implemented and assessed algorithms, including data partitioning, classification approaches, and metrics. Altogether, this work offers a different and robust framework to select genes using a machine learning approach.
Test Agreement Between Roche Cobas 6800 and Cepheid GeneXpert Xpress SARS-CoV-2 Assays at High Cycle Threshold Ranges
Authors: Broder Kari , Babiker Ahmed , Myers Charles , White Terri , Jones Heather , Cardella John , Burd Eileen M. , Hill Charles E. , Kraft Colleen S. 
Published: May 2020

AbstractThe SARS-CoV-2 pandemic has changed the face of the globe and upended the daily lives of billions. In an effort to bring mass-testing to as many as possible, multiple diagnostic tests including molecular, antigen detection and serological assays have been rapidly developed. However, there is very little information on positive test agreement across modalities, especially for lower viral loads. Thirty-five nasopharyngeal samples that had cycle threshold (Ct) values greater than 30.0 from the Roche cobas 6800 assay were run on the Cepheid GeneXpert Xpress SARS-CoV-2 assay. Ct values ranged from 30.1 to 37.9 (mean 36.7 ± 1.9) on the Roche cobas 6800 assay and 24.6 to 42.4 (mean 32.8±4.1) on the Cepheid assay. There was a bias of 0.33 ± 3.21, (mean difference −1.59, 95% limits of agreement −5.97, 6.63) signifying close agreement between the 2 instruments with a high standard deviation. The close test agreement between the cobas 6800 and GeneXpert at high Ct values allows for utilization of both assays interchangeable in accordance with testing algorithms.
Proteomic profiling of peripheral blood mononuclear cells isolated from patients with tuberculosis and diabetes copathogenesis -A pilot study
Authors: Kundu Jyoti , Bakshi Shikha , Joshi Himanshu , Bhadada Sanjay K , Verma Indu , Sharma Sadhna 
Published: May 2020

AbstractBackgroundDiabetes is an important risk factor for developing tuberculosis. This association leads to exacerbation of tuberculosis symptoms and delayed treatment of both the diseases. Molecular mechanism and biomarkers/drug targets related to copathogenesis of tuberculosis and diabetes, however, still remains to be poorly understood. In this study, proteomics based 2D-MALDI/MS approach was employed to identify host signature proteins which are altered during copathogenesis of tuberculosis and diabetes.MethodsComparative proteome of human peripheral blood mononuclear cells (PBMCs) from healthy controls, tuberculosis and diabetes patients in comparison to comorbid diabetes and tuberculosis patients was analyzed. Gel based proteomics approach followed by in gel trypsin digestion and peptide identification by mass spectrometry was used for signature protein identification.ResultsTotal of 18 protein spots with differential expression in TBDM patients in comparison to other groups were identified. These include Vimentin, tubulin beta chain protein, superoxide dismutase, Actin related protein 2/3 complex subunit 2, PDZ LIM domain protein, Rho-GDP dissociation inhibitor, Ras related protein Rab, dCTPpyrophosphatase 1, Transcription initiation factor TFIID subunit 12, coffilin 1, three isoforms of Peptidylprolylcis-trans isomerase A, three isoforms of Protein S100A9, Protein S100A8 and SH3 domain containing protein. These proteins belonged to four functional categories i.e. structural, cell cycle/growth regulation, signaling and intermediary metabolism.ConclusionProteins identified to be differentially expressed in TBDM patient can act as potent biomarkers and as predictors for copathogenesis of tuberculosis and diabetes.
Phylogenetic analysis of HIV-1 archived DNA in blood and gut-associated lymphoid tissue in patients receiving antiretroviral therapy: a study from Provir/Latitude45 project
Authors: Recordon-Pinson Patricia , Tumiotto Camille , Bellecave Pantxika , Salin Franck , Thebault Patricia , Gosselin Annie , Ancuta Petronela , Soares Marcelo , Routy Jean-Pierre , Fleury Hervé 
Published: May 2020

AbstractOne of the approaches to cure HIV is the use of therapeutic vaccination. We have launched the Provir/Latitude 45 study to identify conserved CTL epitopes in archived HIV-1 DNA according to the HLA class I alleles in aviremic patients under antiretroviral therapy (ART). A HIV-1 polypeptidic therapeutic vaccine based on viral sequence data obtained from circulating blood was proposed; here, our aim was to compare the proviral DNA in blood and gut-associated lymphoid tissue (GALT) at two different levels : nucleotide sequences and potential CTL epitopes. The reverse transcriptase was sequenced in both compartments using next generation sequencing (NGS) in samples from nine individuals, two of which had also single genome sequencing (SGS) performed; phylogenetic trees were established and compared; CTL epitopes were also identified according to their potential affinity for the HLA alleles. The proviral sequences of both compartments intra-patient exhibited a very low genetic divergence while it was possible to differentiate the sequences inter-patients; SGS analysis of two couples of samples confirmed that there was not a compartmentalization of the sequences intra-patient.When we simulated the CTL epitopes which can be presented by the corresponding HLA alleles in both compartments, no significant difference was observed. We conclude that the proviral DNA sequences in blood and GALT are similar and that the epitope analysis in blood can be considered as relevant to that observed in the GALT, a hard-to-reach major compartment, and can therefore be used for therapeutic vaccine approaches.
Myosin-X and talin modulate integrin activity at filopodia tips
Authors: Miihkinen Mitro , Grönloh Max L.B. , Vihinen Helena , Jokitalo Eija , Goult Benjamin T. , Ivaska Johanna , Jacquemet Guillaume 
Published: May 2020

AbstractFilopodia assemble unique integrin-adhesion complexes to sense the extracellular matrix. However, the mechanisms of integrin localization and regulation in filopodia are poorly defined. Here, we observed that active integrins accumulate at the tip of myosin-X(MYO10)-positive filopodia while inactive integrins are uniformly distributed. RNAi depletion of 10 integrin activity modulators identified talin as the principal integrin activator in filopodia. Deletion of the MYO10-FERM domain, or mutation of the β1-integrin-binding residues within, revealed MYO10 as facilitating integrin activation but not transport in filopodia. However, MYO10-FERM alone could not activate integrins, potentially due to dual binding to both a- and β-integrin tails. As swapping MYO10-FERM with talin-FERM enabled integrin activation in filopodia, our data indicate that an integrin-binding FERM domain coupled to a myosin motor is a core requirement for integrin activation in filopodia. Therefore, we propose a two-step integrin activation model in filopodia: receptor tethering by MYO10 followed by talin-mediated integrin activation.
PI31 expression prevents neuronal degeneration in a mouse Parkinson Disease model
Authors: Minis Adi , Steller Hermann 
Published: May 2020

AbstractAge-related neurodegenerative diseases pose a major unmet health need since no effective treatment strategies are currently available. These disorders are defined by the accumulation of abnormal protein aggregates that impair synaptic function and cause progressive neuronal degeneration. Therefore, stimulating protein clearance mechanisms may be neuro-protective. The proteasome regulator PI31 promotes local protein degradation at synapses by mediating fast proteasome transport in neurites, and loss of PI31 function causes neuronal degeneration. Here we show that transgenic expression of PI31 in a mouse Parkinson’s Disease model preserves neuronal function and greatly extends animal health and lifespan. These results indicate that targeting the PI31-pathway may have therapeutic value for treating neurodegenerative disorders.
Selectomic and Evolvability Analyses of the Highly Pathogenic Betacoronaviruses SARS-CoV-2, SARS-CoV, and MERS-CoV
Authors: May Meghan , Rostama Bahman , Relich Ryan F. 
Published: May 2020

AbstractSARS-CoV-2, the causative agent of COVID-19, is widespread in several countries around the world following its late-2019 emergence in the human population. Rapid development of molecular diagnostic tests and subunit vaccines have been prioritized, and as such evaluating the SARS-CoV-2 genomic plasticity and evolutionary dynamics is an urgent need. We determined the SARS-CoV-2 selectome by calculating rates of pervasive and episodic diversifying selection for every amino acid coding position in the SARS-CoV-2 genome. To provide context for evolutionary dynamics of a highly pathogenic betacoronavirus following a zoonotic spillover into human hosts, we also determined the selectomes of SARS-CoV and MERS-CoV, and performed evolvability calculations for SARS-CoV-2 based on SARS-CoV. These analyses identify the amino acid sites within each coding sequence that have been subjected to pervasive diversifying selection or episodic diversifying selection, and report significantly evolvable sites in the ORF1a polyprotein, the spike protein, and the membrane protein of SARS-CoV-2. These findings provide a comprehensive view of zoonotic, highly pathogenic betacoronavirus evolutionary dynamics that can be directly applied to diagnostic assay and vaccine design for SARS-CoV-2.
Interhemispheric callosal projections enforce response fidelity and frequency tuning in auditory cortex
Authors: Slater Bernard J. , Isaacson Jeffry S. 
Published: May 2020

AbstractSensory cortical areas receive glutamatergic callosal projections that link information processing between brain hemispheres. However, the role of interhemispheric projections in sensory processing is unclear. Here we use single unit recordings and optogenetic manipulations in awake mice to probe how callosal inputs modulate spontaneous and tone-evoked activity in primary auditory cortex (A1). Although activation of callosal fibers increased firing of some pyramidal cells, the majority of responsive cells were suppressed. In contrast, callosal stimulation consistently increased fast spiking (FS) cell activity and brain slice recordings indicated that parvalbumin (PV)-expressing cells receive stronger callosal input than pyramidal cells or other interneuron subtypes.In vivosilencing of the contralateral cortex revealed that callosal inputs linearly modulate tone-evoked pyramidal cell activity via both multiplicative and subtractive operations. These results suggest that callosal input regulates both the salience and tuning sharpness of tone responses in A1 via PV cell-mediated feedforward inhibition.
Tuba1a is uniquely important for axon guidance through midline commissural structures
Authors: Buscaglia Georgia , Aiken Jayne , Hoff Katelyn J. , Northington Kyle R. , Bates Emily A. 
Published: May 2020

AbstractDeveloping neurons undergo dramatic morphological changes to appropriately migrate and extend axons to make synaptic connections. The microtubule cytoskeleton, made of α/β-tubulin dimers, drives neurite outgrowth, promotes neuronal growth cone responses, and facilitates intracellular transport of critical cargoes during neurodevelopment.TUBA1Aconstitutes the majority of α-tubulin in the developing brain and mutations toTUBA1Ain humans cause severe brain malformations accompanied by varying neurological defects, collectively termed tubulinopathies. Studies ofTUBA1Afunctionin vivohave been limited by the presence of multiple genes encoding highly similar tubulin proteins, which prevents TUBA1A-specific antibody generation and makes genetic manipulation challenging. Here we present a novel tagging method for studying and manipulatingTUBA1Ain cells without impairing tubulin function. Using this tool, we show that aTUBA1Aloss-of-function mutationTUBA1AN102D(TUBA1AND), reduced the amount of TUBA1A protein and prevented incorporation of TUBA1A into microtubule polymers. Reduced Tuba1a α-tubulin in heterozygousTuba1aND/+mice significantly impacted axon extension and impaired formation of forebrain commissures. Neurons with reduced Tuba1a caused byTuba1aNDhad altered microtubule dynamics and slower neuron outgrowth compared to controls. Neurons deficient in Tuba1a failed to localize microtubule associated protein-1b (Map1b) to the developing growth cone, likely impacting reception of developmental guidance cues. Overall, we show that reduced Tuba1a is sufficient to support neuronal migration, but not axon guidance, and provide mechanistic insight as to howTUBA1Atunes microtubule function to support neurodevelopment.
LaTe1.82(1): modulated crystal structure and chemical bonding of a chalcogen-deficient rare earth metal polytelluride
Authors: Poddig Hagen , Finzel Kati , Doert Thomas 
Published: May 2020

Crystals of the rare earth metal polytelluride LaTe1.82(1), namely, lanthanum telluride (1/1.8), have been grown by molten alkali halide flux reactions and vapour-assisted crystallization with iodine. The two-dimensionally incommensurately modulated crystal structure has been investigated by X-ray diffraction experiments. In contrast to the tetragonal average structure with unit-cell dimensions ofa= 4.4996 (5) andc= 9.179 (1) Å at 296 (1) K, which was solved and refined in the space groupP4/nmm(No. 129), the satellite reflections are not compatible with a tetragonal symmetry but enforce a symmetry reduction. Possible space groups have been derived by group–subgroup relationships and by consideration of previous reports on similar rare earth metal polychalcogenide structures. Two structural models in the orthorhombic superspace group,i.e.Pmmn(α,β,1 \over 2)000(−α,β,1 \over 2)000 (No. 59.2.51.39) andPm21n(α,β,1 \over 2)000(−α,β,1 \over 2)000 (No. 31.2.51.35), with modulation wave vectorsq1 = αa* + βb* + 1 \over 2c* andq2= −αa* + βb* + 1 \over 2c* [α = 0.272 (1) and β = 0.314 (1)], have been established and evaluated against each other. The modulation describes the distribution of defects in the planar [Te] layer, coupled to a displacive modulation due to the formation of different Te anions. The bonding situation in the planar [Te] layer and the different Te anion species have been investigated by density functional theory (DFT) methods and an electron localizability indicator (ELI-D)-based bonding analysis on three different approximants. The temperature-dependent electrical resistance revealed a semiconducting behaviour with an estimated band gap of 0.17 eV.
A new monoclinic structure type for ternary gallide MgCoGa2
Authors: Pavlyuk Nazar , Dmytriv Grygoriy , Pavlyuk Volodymyr , Rozdzynska-Kielbik Beata , Nitek Wojciech , Lasocha Wieslaw , Chumak Ihor , Ehrenberg Helmut 
Published: May 2020

The crystal structure of MgCoGa2 (magnesium cobalt digallide) was solved by direct methods and refined in two space groups as P21/c (standard choice) and P21/n (non-standard choice). The refined lattice parameters for the standard choice are a = 5.1505 (2), b = 7.2571 (2), c = 8.0264 (3) Å and β = 125.571 (3)°, and for the non-standard choice are a = 5.1505 (2), b = 7.2571 (2), c = 6.5464 (2) Å and β = 94.217 (3)°. All parameters for MgCoGa2 refined to R
1 = 0.027 and wR
2 = 0.042 using 594 reflections. The crystal structure peculiarities of this compound are discussed. Particular attention has been given to relationships with other similar structures, such as YPd2Si and Fe3C. Crystallographic analysis, together with linear muffin-tin orbital electronic structure calculations, reveals the presence of three-dimensional polyatomic nets with partial covalent bonding between the Ga atoms.