bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selective antibiofilm properties and biocompatibility of nano-ZnO and nano-ZnO/Ag coated surfaces
Authors: Rosenberg M. , Visnapuu M. , Vija H. , Kisand V. , Kasemets K. , Kahru A. , Ivask A. 
Published: March 2020

ABSTRACTSpread of pathogenic microbes and antibiotic-resistant bacteria in health-care settings and public spaces is a serious public health challenge. Materials that prevent solid surface colonization or impede touch-transfer of viable microbes could provide means to decrease pathogen transfer from high-touch surfaces in critical applications. ZnO and Ag nanoparticles have shown great potential in antimicrobial applications. Less is known about nano-enabled surfaces. Here we demonstrate that surfaces coated with nano-ZnO or nano-ZnO/Ag composites are not cytotoxic to human keratinocytes and possess species-selective medium-dependent antibiofilm activity againstEscherichia coli, Staphylococcus aureusandCandida albicans. Colonization of nano-ZnO and nano-ZnO/Ag surfaces byE. coliandS. aureuswas decreased in static oligotrophic conditions (no planktonic growth). Moderate to no effect was observed for bacterial biofilms in growth medium (supporting exponential growth). Inversely, nano-ZnO surfaces enhanced biofilm formation byC. albicansin oligotrophic conditions. However, enhancedC. albicansbiofilm formation on nano-ZnO surfaces was effectively counteracted by the addition of Ag. Possible selective enhancement of biofilm formation by the yeastC. albicanson Zn-enabled surfaces should be taken into account in antimicrobial surface development. Our results also indicated the importance of the use of application-appropriate test conditions and exposure medium in antimicrobial surface testing.
Dynamin-related Irgm proteins modulate LPS-induced caspase-4 activation and septic shock
Authors: Finethy Ryan , Dockterman Jacob , Kutsch Miriam , Orench-Rivera Nichole , Wallace Graham , Piro Anthony S. , Luoma Sarah , Haldar Arun K. , Hwang Seungmin , Martinez Jennifer , Kuehn Meta J. , Taylor Gregory A. , Coers Jörn 
Published: March 2020

ABSTRACTInflammation associated with gram-negative bacterial infections is often instigated by the bacterial cell wall component lipopolysaccharide (LPS). LPS-induced inflammation and resulting life-threatening sepsis are mediated by the two distinct LPS receptors TLR4 and caspase-4. Whereas the regulation of TLR4 activation by extracellular and phago-endosomal LPS has been studied in great detail, auxiliary host factors that specifically modulate recognition of cytosolic LPS by caspase-4 are largely unknown. This study identifies dynamin-related membrane remodeling proteins belonging to the family of Immunity related GTPases M clade (IRGM) as negative regulators of caspase-4 activation in macrophages. Phagocytes lacking expression of mouse isoform Irgm2 aberrantly activate caspase-4-dependent inflammatory responses when exposed to extracellular LPS, bacterial outer membrane vesicles or gram-negative bacteria. Consequently, Irgm2-deficient mice display increased susceptibility to caspase-4-mediated septic shockin vivo.ThisIrgm2phenotype is partly reversed by the simultaneous genetic deletion of the two additionalIrgmparalogsIrgm1andIrgm3,indicating that dysregulated Irgm isoform expression disrupts intracellular LPS processing pathways that limit LPS availability for caspase-4 activation.
Identification of an antiretroviral small molecule that appears to be a host-targeting inhibitor of HIV-1 assembly
Authors: Reed Jonathan C. , Solas Dennis , Kitaygorodskyy Anatoliy , Freeman Beverly , Ressler Dylan T. B. , Phuong Daryl J. , Swain J. Victor , Matlack Kent , Hurt Clarence R. , Lingappa Vishwanath R. , Lingappa Jaisri R. 
Published: March 2020

ABSTRACTGiven the projected increase in multidrug resistant HIV-1, there is an urgent need for development of antiretrovirals that act on virus life-cycle stages that are not targeted by antiretrovirals currently in use. Host-targeting drugs are of particular interest because they can offer a high barrier to resistance. Here we report identification of two related small molecules that inhibit HIV-1 late events, a stage of the HIV-1 life cycle for which potent and specific inhibitors are lacking. This chemotype was discovered using cell-free protein synthesis and assembly systems that recapitulate intracellular host-catalyzed viral capsid assembly pathways. These compounds inhibit replication of HIV-1 in human T cell lines and PBMCs and are effective against a primary isolate. They reduce virus production, likely by inhibiting a post-translational step in HIV-1 Gag assembly. Notably, the compound colocalizes with HIV-1 Gagin situ; however, unexpectedly, selection experiments failed to identify compound-specific resistance mutations ingagorpol, even though known resistance mutations developed in a parallel nelfinavir selection. Thus, we hypothesized that instead of binding to Gag directly, these compounds might localize to assembly intermediates, the intracellular multiprotein complexes containing Gag and host factors that are formed during immature HIV-1 capsid assembly. Indeed, imaging of infected cells showed colocalization of the compound with two host enzymes found in assembly intermediates, ABCE1 and DDX6. While the exact target and mechanism of action of this chemotype remain to be determined, these findings suggest that these compounds represent first-in-class, host-targeting inhibitors of intracellular events in HIV-1 assembly.IMPORTANCEThe success of antiretroviral treatment for HIV-1 is at risk of being undermined by the growing problem of drug resistance. Thus, there is a need to identify antiretrovirals that act on viral life cycle stages not targeted by drugs in use, such as the events of HIV-1 Gag assembly. To address this gap, we developed a compound screen that recapitulates the intracellular events of HIV-1 assembly, including viral-host interactions that promote assembly. This effort led to identification of a new chemotype that inhibits HIV-1 replication at nanomolar concentrations by inhibiting virus production. This compound colocalized with Gag and two host enzymes that facilitate capsid assembly but resistance selection did not result in compound-specific mutations ingag,suggesting that the chemotype does not directly target Gag. We hypothesize that this chemotype may represent a first-in-class inhibitor of virus production that acts by targeting a viral-host complex important for HIV-1 Gag assembly.
Mixed method estimation of population level HIV viral suppression rate in the Western Cape, South Africa
Authors: Mukonda Elton , Hsiao Nei-Yuan , Vojnov Lara , Myer Landon , Lesosky Maia 
Published: March 2020

AbstractIntroductionThere are few population-wide data on viral suppression (VS) that can be used to monitor programmatic targets in sub-Saharan Africa. We describe how routinely collected viral load (VL) data from ART programmes can be extrapolated to estimate population VS and validate this using a combination of empiric and model-based estimates.MethodsVL test results from were matched using a record linkage algorithm to obtain linked results for individuals. Test- and individual-level VS rates were based on test VL values <1000 cps/ml, and individual VL <1000 cps/mL in a calendar year, respectively. We calculated population VS among people living with HIV (PLWH) in the province by combining census-derived mid-year population estimates, HIV prevalence estimates and individual level VS estimates from routine VL data.ResultsApproximately 1.9 million VL test results between 2008 – 2018 were analysed. Among individuals in care, VS increased from 85.5% in 2008 to 90% in 2018. Population VS among all PLWH in the province increased from 12.2% in 2008 to 51.0% in 2017. The estimates derived from this method are comparable to those from other published studies. Sensitivity analyses showed that the results are robust to variations in linkage method, but sensitive to the extreme combinations of assumed ART coverage and population HIV prevalence.ConclusionWhile validation of this method in other settings is required, this approach provides a simple, robust method for estimating population VS using routine data from ART services that can be employed by national programmes in high-burden settings.
Simulating Emergency Department Boarding Using a Difference Equation
Authors: Brown Edward G. , Howard Patricia K. , Moore Daniel 
Published: March 2020

AbstractBackgroundThis paper aims to provide a model that can be used to simulate the effect of patient presentation counts on ED boarder counts and investigate strategies that might be used for managing ED boarding levels.MethodsA boarding simulation model is constructed using a random variable and two regressions that are linked together in a difference equation. The simulation is run under varying constraints, including time interval, presentation counts, and boarder count threshold. Bootstrapping is used to run the simulation a large number of times so that mean and medians can be calculated along with confidence intervals.ResultsThe method outlined in this paper can be used to simulate the effect of presentation levels on ED boarder counts. Using these methods one can derive quantifiable estimates of time that an emergency department might meet or exceed a particular boarder count threshold.ConclusionsThese simulation methods can help an emergency department understand the dynamics of the system in the status quo of normal operations and quantify the relationship of presentation counts and throughput to the hospital. We are hopeful that others may use these methods, adapting, developing, and testing for their own institutions.
Complement active human and porcine serum induces natural competence for genetic transformation in the emerging zoonotic pathogenStreptococcus suis
Authors: Ferrando Maria Laura , Gussak Alex , Mentink Saskia , van Baarlen Peter , Wells Jerry Mark 
Published: March 2020

AbstractThe acquisition of novel genetic traits by natural competence is a strategy used by bacteria in microbe-rich environments including animal or human hosts where microbial competition, antibiotics and host immune defences threaten their survival. We show here that several virulent strains ofStreptococcus suis, an important porcine pathogen and zoonotic agent, become naturally competent for genetic transformation with plasmid or genomic DNA when cultured in active porcine and human serum, but not when it is pre-heated for 30 minutes at 56°C to inactivate complement. Competence is also not induced in active fetal bovine serum, which contains less complement factors and immunoglobulins than adult serum. Late competence genes, encoding the uptake machinery for environmental DNA, were highly upregulated in active serum. Competence development was independent of the early competence regulatory switch suggesting the presence of an alternative stress-induced pathway for regulation of the transformasome, a type 4-like pilus DNA binding and transport apparatus.
An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 and multiple endemic, epidemic and bat coronavirus
Authors: Sheahan Timothy P. , Sims Amy C. , Zhou Shuntai , Graham Rachel L. , Hill Collin S. , Leist Sarah R. , Schäfer Alexandra , Dinnon Kenneth H. , Montgomery Stephanie A. , Agostini Maria L. , Pruijssers Andrea J. , Chapell James D. , Brown Ariane J. , Bluemling Gregory R. , Natchus Michael G. , Saindane Manohar , Kolykhalov Alexander A. , Painter George , Harcourt Jennifer , Tamin Azaibi , Thornburg Natalie J. , Swanstrom Ronald , Denison Mark R. , Baric Ralph S. 
Published: March 2020

AbstractCoronaviruses (CoVs) traffic frequently between species resulting in novel disease outbreaks, most recently exemplified by the newly emerged SARS-CoV-2. Herein, we show that the ribonucleoside analog β-D-N4-hydroxycytidine (NHC, EIDD-1931) has broad spectrum antiviral activity against SARS-CoV 2, MERS-CoV, SARS-CoV, and related zoonotic group 2b or 2c Bat-CoVs, as well as increased potency against a coronavirus bearing resistance mutations to another nucleoside analog inhibitor. In mice infected with SARS-CoV or MERS-CoV, both prophylactic and therapeutic administration of EIDD-2801, an orally bioavailable NHC-prodrug (b-D-N4-hydroxycytidine-5’-isopropyl ester), improved pulmonary function, and reduced virus titer and body weight loss. Decreased MERS-CoV yieldsin vitroandin vivowere associated with increased transition mutation frequency in viral but not host cell RNA, supporting a mechanism of lethal mutagenesis. The potency of NHC/EIDD-2801 against multiple coronaviruses, its therapeutic efficacy, and oral bioavailabilityin vivo, all highlight its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic coronaviruses.
Size aftereffect is non-local
Authors: Altan Ecem , Boyaci Huseyin 
Published: March 2020

AbstractIt is well known that prolonged exposure to a certain size stimulus alters the perceived size of a subsequently presented stimulus at the same location. How the rest of the visual space is affected by this size adaptation, however, has not been systematically studied before. Here, to fill this gap in literature, we tested size adaptation at the adapter location as well as the rest of the visual space. We used peripherally presented solid discs (Experiment 1) and rings (Experiment 2) as adapter and target (test) stimuli. Observers adapted to a mid-sized stimulus and judged the size of the subsequently presented smaller or larger target stimuli. Results showed that the perceived sizes of target stimuli were repelled away from the adapter size, not only at the adapter location but also at distant locations. These findings demonstrate that size adaptation causes widespread distortion of the visual space and alters perceived size. We discuss possible computational models that may underpin the perceptual effect.
Sparse long-range connections in visual cortex for cost-efficient small-world networks
Authors: Baek Seungdae , Park Youngjin , Paik Se-Bum 
Published: March 2020

AbstractThe brain performs visual object recognition using much shallower hierarchical stages than artificial deep neural networks employ. However, the mechanism underlying this cost-efficient function is elusive. Here, we show that cortical long-range connectivity(LRC) may enable this parsimonious organization of circuits for balancing cost and performance. Using model network simulations based on data in tree shrews, we found that sparse LRCs, when added to local connections, organize a small-world network that dramatically enhances object recognition of shallow feedforward networks. We found that optimization of the ratio between LRCs and local connections maximizes the small-worldness and task performance of the network, by minimizing the total length of wiring needed for integration of the global information. We also found that the effect of LRCs varies by network size, which explains the existence of species-specific LRCs in mammalian visual cortex of various sizes. Our results demonstrate a biological strategy to achieve cost-efficient brain circuits.HighlightsLong-range connections (LRCs) enhance the object recognition of shallow networksSparse LRCs added to dense local connections organize a small-world type networkSmall-worldness of networks modulates the balance between performance and wiring costDistinct LRCs in various species are due to the size-dependent effect of LRCsSignificance statementThe hierarchical depth of the visual pathway in the brain is constrained by biological factors, whereas artificial deep neural networks consist of super-deep structures (i.e., as deep as computational power allows). Here, we show that long-range horizontal connections (LRCs) observed in mammalian visual cortex may enable shallow biological networks to perform cognitive tasks that require deeper artificial structures, by implementing cost-efficient organization of circuitry. Using model simulations based on anatomical data, we found that sparse LRCs, when added to dense local circuits, organize “small-world” type networks and that this dramatically enhances image classification performance by integrating both local and global components of visual stimulus. Our findings show a biological strategy of brain circuitry to balance sensory performance and wiring cost in the networks.One sentence summaryCortical long-range connections organize a small-world type network to achieve cost-efficient functional circuits under biological constraints
PacBio SMRT-based full-length transcriptome data ofAscosphaera apismycelium and spore
Authors: Du Yu , Wang Jie , Chen Huazhi , Fan Xiaoxue , Zhu Zhiwei , Fan Yuanchan , Jiang Haibin , Xiong Cuiling , Zheng Yanzhen , Chen Dafu , Guo Rui 
Published: March 2020

ABSTRACTAscosphaera apisis an entomopathogenic fungus that exclusively infects honeybee larvae, resulting in chalkbrood disease, a widespread fungal disease damaging the beekeeping industry all over the world. In this article, purified mycelia (Aam) and spores (Aas) ofA. apispure culture under lab condition were sequenced using PacBio Sequel platform. In total, 13,302,489 and 9,911,345 subreads were yielded from Aam and Aas, respectively; 394,142 and 274,928 circular consensus sequence (CCS) reads were identified as being full-length non-chimeric (FLNC) reads, with a mean length of 2820 bp and 2602 bp, respectively. Furthermore, 174,095 and 103,845 corrected isoforms were identified, with a N50 length of 3543 bp and 3262 bp, respectively. The reported full-length transcriptome data ofA. apismycelium and spore will provide a valuable resource for improvement of genome and transcriptome annotations as well as better understanding of transcript structure such as alternative splicing and polyadenylation.Value of the dataCurrent dataset offers a set of high-quality full-length transcripts ofA. apis.The data can facilitate the improvement ofA. apisgenome and transcriptome annotations.This dataset benefits further exploration of alternative splicing and polyadenylation ofA. apismRNAs.
The pregnant myometrium is epigenetically activated at contractility-driving gene loci prior to the onset of labor in mice
Authors: Shchuka Virlana M. , Abatti Luis E. , Hou Huayun , Dorogin Anna , Wilson Michael D. , Shynlova Oksana , Mitchell Jennifer A. 
Published: March 2020

AbstractDuring gestation, uterine smooth muscle cells transition from a state of quiescence to one of contractility, but the molecular mechanisms underlying this transition at a genomic level are not well-known. To better understand these events, we evaluated the epigenetic landscape of the mouse myometrium during pregnancy, labor and post-partum. We established gestational timepoint-specific enrichment profiles involving histone H3K27 acetylation (H3K27ac), H3K4 tri-methylation (H3K4me3), and RNA polymerase II (RNAPII) occupancy by chromatin immunoprecipitation sequencing (ChIP-seq), as well as gene expression profiles by total RNA-sequencing (RNA-seq). Our findings reveal that 533 genes, including known contractility-driving genes (Gja1, Fos, Oxtr, Ptgs2), are upregulated during active labor due to an increase in transcription at gene bodies. Their promoters and putative intergenic enhancers, however, are epigenetically activated by H3K27ac as early as day 15, four days prior to the onset of active labor on day 19. In fact, we find that the majority of genome-wide H3K27ac or H3K4me3 peaks identified during active labor are present in the myometrium on day 15. Despite the early presence of H3K27ac at labor-associated genes, both an increase in non-coding enhancer RNA (eRNA) production, and in recruitment of RNAPII to corresponding genes occur during active labor, at labor upregulated gene loci. Our findings indicate that epigenetic activation of the myometrial genome precedes active labor by at least four days in the mouse model, suggesting the myometrium is poised for rapid activation of contraction-associated genes in order to exit the state of quiescence.
A Sec14-like Phosphatidylinositol Transfer Protein Paralog Defines a Novel Class of Heme-binding Proteins With An Unusual Heme Coordination Mechanism
Authors: Khan Danish , Lee Dongju , Gulten Gulcin , Aggarwal Anup , Wofford Joshua , Krieger Inna , Tripathi Ashutosh , Patrick John W. , Eckert Debra M. , Laganowsky Arthur , Sacchettini James , Lindahl Paul , Bankaitis Vytas A. 
Published: March 2020

AbstractYeast Sfh5 is an unusual member of the Sec14-like phosphatidylinositol transfer protein (PITP) family. Whereas PITPs are defined by their abilities to transfer phosphatidylinositol between membranes in vitro, and to stimulate phosphoinositide signaling in vivo, Sfh5 does not exhibit these activities. Rather, Sfh5 is a redox-active penta-coordinate high spin FeIIIheme-binding protein with an unusual heme-binding arrangement that involves a co-axial tyrosine/histidine coordination strategy and a complex electronic structure connecting the open shell irond-orbitals with three aromatic ring systems. That Sfh5 is not a PITP is supported by demonstrations that heme is not a readily exchangeable ligand, and that phosphatidylinositol-exchange activity is resuscitated in heme binding-deficient Sfh5 mutants. The collective data identify Sfh5 as the prototype of a new class of fungal hemoproteins, and emphasize the versatility of the Sec14-fold as scaffold for translating the binding of chemically distinct ligands to the control of diverse sets of cellular activities.
Investigation of ACE2 N-terminal fragments binding to SARS-CoV-2 Spike RBD
Authors: Zhang G. , Pomplun S. , Loftis A. R. , Tan X. , Loas A. , Pentelute B. L. 
Published: March 2020

AbstractCoronavirus disease 19 (COVID-19) is an emerging global health crisis. With over 7 million confirmed cases to date, this pandemic continues to expand, spurring research to discover vaccines and therapies. SARS-CoV-2 is the novel coronavirus responsible for this disease. It initiates entry into human cells by binding to angiotensin-converting enzyme 2 (ACE2) via the receptor binding domain (RBD) of its spike protein (S). Disrupting the SARS-CoV-2-RBD binding to ACE2 with designer drugs has the potential to inhibit the virus from entering human cells, presenting a new modality for therapeutic intervention. Peptide-based binders are an attractive solution to inhibit the RBD-ACE2 interaction by adequately covering the extended protein contact interface. Using molecular dynamics simulations based on the recently solved cryo-EM structure of ACE2 in complex with SARS-CoV-2-RBD, we observed that the ACE2 peptidase domain (PD) α1 helix is important for binding SARS-CoV-2-RBD. Using automated fast-flow peptide synthesis, we chemically synthesized a 23-mer peptide fragment of the ACE2 PD α1 helix (SBP1) composed entirely of proteinogenic amino acids. Chemical synthesis of SBP1 was complete in 1.5 hours, and after work up and isolation >20 milligrams of pure material was obtained. Bio-layer interferometry (BLI) revealed that SBP1 associates with micromolar affinity to insect-derived SARS-CoV-2-RBD protein obtained from Sino Biological. Association of SBP1 was not observed to an appreciable extent to HEK cell-expressed SARS-CoV-2-RBD proteins and insect-derived variants acquired from other vendors. Moreover, competitive BLI assays showed SBP1 does not outcompete ACE2 binding to Sino Biological insect-derived SARS-CoV-2-RBD. Further investigations are ongoing to gain insight into the molecular and structural determinants of the variable binding behavior to different SARS-CoV-2-RBD protein variants.