bluuebunny/crossref_metadata_2025_split huggingface dataset:
Social Stress Alters Immune Response and Results in Higher Viral Load During Acute SIV Infection in a Pigtailed Macaque Model of HIV
Authors: Guerrero-Martin Selena M. , Rubin Leah H. , McGee Kirsten M. , Shirk Erin N. , Queen Suzanne E. , Li Ming , Bullock Brandon , Carlson Bess W. , Adams Robert J. , Gama Lucio , Graham David R. , Zink Christine , Clements Janice E. , Mankowski Joseph L. , Metcalf Pate Kelly A. 
Published: April 2020

AbstractWhile social distancing is a key public health response during viral pandemics, social stress, which can be induced by social isolation, has been implicated in adverse health outcomes in general1and in the context of infectious disease, such as HIV2,3. A comprehensive understanding of the direct pathophysiologic effects of social stress on viral pathogenesis is needed to provide strategic and comprehensive care to patients with viral infection. To determine the effect of social stress on HIV pathogenesis during acute viral infection without sociobehavioral confounders inherent in human cohorts, we compared commonly measured parameters of HIV progression between singly and socially housed SIV-infected pigtailed macaques (Macaca nemestrina). Singly housed macaques had a higher viral load in the plasma and cerebrospinal fluid and demonstrated greater CD4 T cell declines and greater CD4 and CD8 T cell activation compared to socially housed macaques throughout acute infection. These data demonstrate that social stress directly impacts the pathogenesis of acute HIV infection and imply that social stress may act as an integral variable in the progression of HIV infection and potentially of other viral infections.
Mechanism of life-long maintenance of neuron identity despite molecular fluctuations
Authors: Traets Joleen J. H. , van der Burght Servaas N. , Jansen Gert , van Zon Jeroen S. 
Published: April 2020

SummaryCell fate is maintained over long timescales, yet molecular fluctuations can lead to spontaneous loss of this differentiated state. We uncovered a mechanism that explains life-long maintenance of ASE neuron fate inC. elegansby the terminal selector transcription factor CHE-1. Fluctuations in CHE-1 level are buffered by the reservoir of CHE-1 bound at its target promoters, which ensure continuedche-1expression by preferentially binding theche-1promoter. We validated this mechanism by showing thatche-1expression was resilient to induced transient CHE-1 depletion, while both expression of CHE-1 targets and ASE function were lost. We identified a 130 bpche-1promoter fragment responsible for this resilience, with deletion of a homeodomain binding site in this fragment causing stochastic loss of ASE identity long after its determination. Because network architectures that support this mechanism are highly conserved in cell differentiation, it may explain stable cell fate maintenance in many systems.
The CRP-family transcriptional regulator DevH regulates expression of heterocyst-specific genes at the later stage of differentiation in the cyanobacteriumAnabaenasp. strain PCC 7120
Authors: Kurio Yohei , Koike Yosuke , Kanesaki Yu , Watanabe Satoru , Ehira Shigeki 
Published: April 2020

SummaryHeterocysts are terminally differentiated cells of filamentous cyanobacteria, which are specialized for nitrogen fixation. Because nitrogenase, an enzyme for nitrogen fixation, is easily inactivated by oxygen, the intracellular environment of heterocysts is kept microoxic. In heterocysts, the oxygen-evolving photosystem II is inactivated, a heterocyst-specific envelope with an outer polysaccharide layer and an inner glycolipid layer is formed to limit oxygen entry, and oxygen consumption is activated. Heterocyst differentiation, which is accompanied by drastic morphological and physiological changes, requires strictly controlled gene expression systems. Here, we investigated the functions of a CRP-family transcriptional regulator, DevH, in the process of heterocyst differentiation. AdevH-knockdown strain, devHKD, was created by replacing the original promoter with thegifApromoter, which is repressed during heterocyst differentiation. Although devHKD formed morphologically distinct cells with the heterocyst envelope polysaccharide layer, it was unable to grow diazotrophically. Genes involved in construction of the microoxic environment, such ascoxoperons and thehglisland, were not upregulated in devHKD. Moreover, expression of thenifgene cluster was completely abolished. Even under anaerobic conditions, thenifgene cluster was not induced in devHKD. Thus, DevH is necessary for the establishment of a microoxic environment and induction of nitrogenase in heterocysts.
Zinc oxide nanoparticles modulate the gene expression of ZnT1and ZIP8to manipulate zinc homeostasis and stress-induced cytotoxicity in human neuroblastoma SH-SY5Y cells
Authors: Pan Chien-Yuan , Lin Fang-Yu , Kao Lung-Sen , Huang Chien-Chang , Liu Pei-Shan 
Published: April 2020

AbstractZinc ions (Zn2+) are important messenger molecules involved in various physiological functions. To maintain the homeostasis of cytosolic Zn2+concentration ([Zn2+]c), Zrt/Irt-related proteins (ZIPs) and Zn2+transporters (ZnTs) are the two families of proteins responsible for decreasing and increasing the [Zn2+]c, respectively, by fluxing Zn2+across the membranes of the cell and intracellular compartments in opposite directions. Most studies focus on the cytotoxicity incurred by a high concentration of [Zn2+]cand less investigate the [Zn2+]cat physiological levels. Zinc oxide-nanoparticle (ZnO-NP) is blood brain barrier-permeable and elevates the [Zn2+]cto different levels according to the concentrations of ZnO-NP applied. In this study, we mildly elevated the [Zn2+]cby zinc oxide-nanoparticles (ZnO-NP) at concentrations below 1 μg/ml, which had little cytotoxicity, in cultured human neuroblastoma SH-SY5Y cells and characterized the importance of Zn2+transporters in 6-hydroxy dopamine (6-OHDA)-induced cell death. The results show that ZnO-NP at low concentrations elevated the [Zn2+]ctransiently in 6 hr, then declined gradually to a basal level in 24 hr. Knocking down the expression levels ofZnT1(mostly at the plasma membrane) andZIP8(present in endosomes and lysosomes) increased and decreased the ZnO-NP-induced elevation of [Zn2+]c, respectively. ZnO-NP treatment reduced the basal levels of reactive oxygen species andBax/Bcl-2mRNA ratios; in addition, ZnO-NP decreased the 6-OHDA-induced ROS production,p53expression, and cell death. Therefore, mild elevations in [Zn2+]cinduced by ZnO-NP activate beneficial effects in reducing the 6-OHDA-induced cytotoxic effects. Therefore, brain-delivery of ZnO-NP can be regarded as a potential therapy for neurological disease.
In silicodiscovery and biological validation of ligands of FAD synthase, a promising new antimicrobial target
Authors: Lans Isaias , Anoz-Carbonell Ernesto , Palacio-Rodríguez Karen , Aínsa José Antonio , Medina Milagros , Cossio Pilar 
Published: April 2020

AbstractNew treatments for diseases caused by antimicrobial-resistant microorganisms can be developed by identifying unexplored therapeutic targets and by designing efficient drug screening protocols. In this study, we have screened a library of compounds to find ligands for the flavin-adenine dinucleotide synthase (FADS) -a potential target for drug design against tuberculosis and pneumonia- by implementing a new and efficient virtual screening protocol. The protocol has been developed for thein silicosearch of ligands of unexplored therapeutic targets, for which limited information about ligands or ligand-receptor structures is available. It implements an integrative funnel-like strategy with filtering layers that increase in computational accuracy. The protocol starts with a pharmacophore-based virtual screening strategy that uses ligand-free receptor conformations from molecular dynamics (MD) simulations. Then, it performs a molecular docking stage using several docking programs and an exponential consensus ranking strategy. The last filter, samples the conformations of compounds bound to the target using MD simulations. The MD conformations are scored using several traditional scoring functions in combination with a newly-proposed score that takes into account the fluctuations of the molecule with a Morse-based potential. The protocol was optimized and validated using a compound library with known ligands of theCorynebacterium ammoniagenesFADS. Then, it was used to find new FADS ligands from a compound library of 14,000 molecules. A small set of 17in silicofiltered molecules were tested experimentally. We identified five inhibitors of the activity of the flavin adenylyl transferase mononucleotide of the FADS, and some of them were able to inhibit growth of three bacterial species:Corynebacterium ammoniagenes, Mycobacterium tuberculosis, andStreptococcus pneumoniae, where the former two are human pathogens. Overall, the results show that the integrative VS protocol is a cost-effective solution for the discovery of ligands of unexplored therapeutic targets.Author summaryDeveloping cures for antimicrobial-resistant microorganisms is a pressing necessity. Addressing this problem requires the discovery of novel therapeutic targets -for example, bacterial proteins with no human homologues- and the development of cost-effective drug screening protocols. In this work, we tackled the problem on both sides. We developed an efficient and successful integrative computational protocol for screening inhibitory-molecules for unexplored targets. We used it to discover five novel inhibitors of flavin-adenine dinucleotide synthase (FADS), a promising protein target of pathogens causingtuberculosisandpneumonia.
Exploration of bacterial bottlenecks andStreptococcus pneumoniaepathogenesis by CRISPRi-seq
Authors: Liu Xue , Kimmey Jacqueline M. , de Bakker Vincent , Nizet Victor , Veening Jan-Willem 
Published: April 2020

AbstractStreptococcus pneumoniaeis a commensal bacterium of the human nasopharynx, but can cause harmful infections if it spreads to other parts of the body, such as pneumonia, sepsis or meningitis. To facilitate pathogenesis studies, we constructed a doxycycline-inducible pooled CRISPR interference (CRISPRi) library targeting all operons in protypicalS. pneumoniaestrain D39V. Our library design allows fitness within the pool to be assessed by a one-step PCR reaction directly followed by Illumina sequencing (CRISPRi-seq). The doxycycline-inducible CRISPRi system is tightly controllable and suitable for both bottleneck exploration and evaluation of gene fitnessin vitroandin vivo. Here, we applied CRISPRi-seq to identify genetic factors important for causing pneumococcal pneumonia. Mice were infected intratracheally with our CRISPRi library and bacteria collected at 24 h (from lung) and 48 h (from both lung and blood) post-infection. CRISPRi-seq showed a critical bottleneck at 48 h after intratracheal infection, with only a few bacteria surviving the brunt of the innate immune response to cause systemic infection. However, earlier at 24 h post-infection, many significant differences in gene fitness cost betweenin vitroandin vivoconditions were identified, including genes encoding known and putative novel virulence factors, genes essential onlyin vivo, and genes essential onlyin vitro. A key advantage of CRISPRi-seq over traditional transposon-based genetic screens is that all genes, including essential genes, can be tested for their role in virulence and pathogenicity. The approaches developed here should be generally applicable to study infection bottlenecks andin vivofitness for other important human and animal pathogens.
Multiscale cardiac imaging to capture the whole heart and its internal cellular architecture, with applications to congenital heart disease
Authors: Rykiel Graham , López Claudia S. , Riesterer Jessica L. , Fries Ian , Deosthali Sanika , Courchaine Katherine , Maloyan Alina , Thornburg Kent , Rugonyi Sandra 
Published: April 2020

AbstractEfficient cardiac pumping depends on the morphological structure of the heart, but also on its sub-cellular (ultrastructural) architecture, which enables cardiac contraction. In cases of congenital heart defects, localized sub-cellular disruptions in architecture that increase the risk of heart failure are only starting to be discovered. This is in part due to a lack of technologies that can image the three dimensional (3D) heart structure, assessing malformations; and its ultrastructure, assessing disruptions. We present here a multiscale, correlative imaging procedure that achieves high-resolution images of the whole heart, using 3D micro-computed tomography (micro-CT); and its ultrastructure, using 3D scanning electron microscopy (SEM). This combination of technologies has not been possible before in imaging the same cardiac sample due to the heart large size, even when studying small fetal and neonatal animal models (~5×5×5mm3). Here, we achieved uniform fixation and staining of the whole heart, without losing ultrastructural preservation (at the nm resolution range). Our approach enables multiscale studies of cardiac architecture in models of congenital heart disease and beyond.
The SCF/KIT pathway implements self-organised epithelial patterning by cell movement
Authors: Chuyen Alexandre , Rulquin Charlotte , Thomé Virginie , Clément Raphaël , Kodjabachian Laurent , Pasini Andrea 
Published: April 2020

SUMMARYHow individual cell behaviours lead to the emergence of global patterns is poorly understood. In theXenopusembryonic epidermis, multiciliated cells (MCCs) are born in a random pattern within an inner mesenchymal layer, and subsequently intercalate at regular intervals into an outer epithelial layer. Using both experiments and mathematical modelling, we show that this transition from chaotic to ordered distribution relies on mutual repulsion among motile immature MCCs, and affinity towards outer-layer intercellular junctions. Consistently, ARP2/3-mediated actin remodelling is required for MCC pattern emergence. Using multiple functional approaches, we show that the Kit tyrosine kinase receptor, expressed in MCCs, and its ligand Scf, expressed in outer-layer cells, are both required for regular MCC distribution. While Scf behaves as a potent adhesive cue for MCCs, Kit expression is sufficient to confer order to a disordered heterologous cell population. Our work reveals how a single signalling system can implement self-organised large-scale patterning.Highlights- Immature multiciliated cells transit from a disordered to an ordered pattern- The transition is a self-organising process based on repulsive and affinity movements- ARP2/3-dependent actin remodelling is required for pattern emergence- The SCF/KIT pathway promotes both repulsion and affinity movementseTOC blurbIn developingXenopusepidermis, immature multiciliated cells (MCCs), initially chaotically distributed within an inner layer, emerge in an orderly pattern among cells of the outer layer. This process involves MCC mutual repulsion and affinity towards outer-layer intercellular junctions. The SCF/KIT signalling pathway promotes both properties to allow regular MCC distribution.
FAM111A regulates replication origin activation and cell fitness
Authors: Rios-Szwed Diana O. , Garcia-Wilson Elisa , Sanchez-Pulido Luis , Alvarez Vanesa , Jiang Hao , Bandau Susanne , Lamond Angus , Ponting Chris P. , Alabert Constance 
Published: April 2020

ABSTRACTFAM111A is a replisome associated protein and dominant mutations within its trypsin-like peptidase domain are linked to severe human developmental syndromes. However, FAM111A functions and its putative substrates remain largely unknown. Here, we showed that FAM111A promotes origin activation and interacts with the putative peptidase FAM111B, and we identified the first potential FAM111A substrate, the suicide enzyme HMCES. Moreover, unrestrained expression of FAM111A wild-type and patient mutants impaired DNA replication and caused cell death only when the peptidase domain remained intact. Altogether our data reveal how FAM111A promotes DNA replication in normal conditions and becomes harmful in a disease context.
Identification of essential genes forEscherichia coliaryl polyene biosynthesis and function in biofilm formation
Authors: Johnston Isabel , Osborn Lucas J , Markley Rachel L , McManus Elizabeth A , Kadam Anagha , Schultz Karlee B , Nagajothi Nagashreyaa , Ahern Philip P , Brown J Mark , Claesen Jan 
Published: April 2020

ABSTRACTAryl polyenes (APEs) are specialized polyunsaturated carboxylic acids that were identifiedin silicoas the product of the most widespread family of bacterial biosynthetic gene clusters (BGCs). They are present in several Gram-negative host-associated bacteria, including multi-drug resistant human pathogens. Here, we characterize a biological function of APEs, focusing on the BGC from a uropathogenicEscherichia coli(UPEC) strain. We first perform a genetic deletion analysis to identify the essential genes required for APE biosynthesis. Next, we show that APEs function as fitness factors that increase protection from oxidative stress and contribute to biofilm formation. Together, our study highlights key steps in the APE biosynthesis pathway that can be explored as potential drug targets for complementary strategies to reduce fitness and prevent biofilm formation of multi-drug resistant pathogens.
Axin-mediated regulation of lifespan and muscle health inC. elegansinvolves AMPK-FOXO signaling
Authors: Mallick Avijit , Ranawade Ayush , Gupta Bhagwati P 
Published: April 2020

SUMMARYAging is a significant risk factor for several diseases. Studies have uncovered multiple signaling pathways that modulate the process of aging including the Insulin/IGF-1 signaling (IIS). InC. elegansthe key regulator of IIS is DAF-16/FOXO whose activity is regulated by phosphorylation. A major kinase involved in DAF-16-mediated lifespan extension is the AMPK catalytic subunit homolog, AAK-2. In this study, we demonstrate a novel role of PRY-1/Axin in AAK-2 activation to regulate DAF-16 function. Thepry-1transcriptome contains many genes associated with aging and muscle function. Consistent with this,pry-1is strongly expressed in muscles and muscle-specific overexpression ofpry-1extends the lifespan, delays muscle aging, and improves mitochondrial morphology in DAF-16-dependent manner. Furthermore, PRY-1 is necessary for AAK-2 phosphorylation. Together, our data demonstrate a crucial role of PRY-1 in maintaining the lifespan and muscle health. Since muscle health declines with age, our study offers new possibilities to manipulate Axin function to delay muscle aging and improve lifespan.
Host association induces genome changes inCandida albicanswhich alters its virulence
Authors: Smith Amanda C. , Hickman Meleah A. 
Published: April 2020

AbstractCandida albicansis an opportunistic fungal pathogen of humans that is typically diploid yet, has a highly labile genome that is tolerant of large-scale perturbations including chromosomal aneuploidy and loss-of-heterozygosity events. The ability to rapidly generate genetic variation is crucial forC. albicansto adapt to changing or stress environments, like those encountered in the host. Genetic variation occurs via stress-induced mutagenesis or can be generated through its parasexual cycle, which includes mating between diploids or stress-induced mitotic defects to produce tetraploids and non-meiotic ploidy reduction. However, it remains largely unknown how genetic background contributes toC. albicansgenome instabilityin vitroorin vivo.Here, we tested how genetic background, ploidy and host environment impactC. albicansgenome stability. We found that host association induced both loss-of-heterozygosity events and genome size changes, regardless of genetic background or ploidy. However, the magnitude and types of genome changes varied acrossC. albicansstrains. We also assessed whether host-induced genomic changes resulted in any consequences on growth rate and virulence phenotypes and found that many host derived isolates had significant changes compared to their parental strains. Interestingly, host derivatives from diploidC. albicanspredominantly displayed increased virulence, whereas host derivatives from tetraploidC. albicanshad mostly reduced virulence. Together, these results are important for understanding how host-induced genomic changes inC. albicansalter the relationship between the host andC. albicans.
BLOS1 mediates kinesin switch during endosomal recycling of LDL receptor
Authors: Zhang Chang , Hao Chanjuan , Shui Guanghou , Li Wei 
Published: April 2020

AbstractLow-density lipoprotein receptor (LDLR) in hepatocytes plays a key role in normal clearance of circulating LDL and in whole body cholesterol homeostasis. The trafficking of LDLR is highly regulated in clathrin-dependent endocytosis, endosomal recycling and lysosomal degradation. Current studies have been focusing on its endocytosis and degradation. However, the detailed molecular and cellular mechanisms underlying its endosomal recycling are largely unknown. We found that BLOS1, a shared subunit of BLOC-1 and BORC, is involved in LDLR endosomal recycling. Loss of BLOS1 leads to less membrane LDLR and impairs LDL clearance from plasma in hepatocyte-specific BLOS1 knockout mice. BLOS1 interacts with kinesin-3, and that BLOS1 acts as a new adaptor for kinesin-2 to coordinate kinesin-3 and kinesin-2 during the long-range transport of recycling endosomes (REs) to plasma membrane along microtubule tracks to overcome hurdles at microtubule intersections. These findings provide new insights into RE’s anterograde transport and the pathogenesis of dyslipidemia.
Regulation of blood cell transdifferentiation by oxygen sensing neurons
Authors: Corcoran Sean , Mase Anjeli , Hashmi Yousuf , Ouyang Debra , Augsburger Jordan , Jacobs Thea , Kukar Katelyn , Brückner Katja 
Published: April 2020

SummaryTransdifferentiation generates specialized cell types independent of stem or progenitor cells. Despite the unique process, it remains poorly understood how transdifferentiation is regulated in vivo. Here we reveal a mechanism of environmental control of blood cell transdifferentiation in aDrosophilamodel of hematopoiesis. Functional lineage tracing provides evidence for transdifferentiation from macrophage-like plasmatocytes to crystal cells that execute melanization. Interestingly, this transdifferentiation is promoted by neuronal activity of a specific subset of sensory neurons, in the caudal sensory cones of the larva. Crystal cells develop from plasmatocyte clusters surrounding the sensory cones, triggered by environmental conditions: oxygen sensing, and the atypical guanylyl cyclase Gyc88E specifically expressed in the sensory cone neurons, drive plasmatocyte-to-crystal cell transdifferentiation. Our findings reveal an unexpected functional and molecular link of environment-monitoring sensory neurons that govern blood cell transdifferentiation in vivo, suggesting similar principles in vertebrate systems where environmental sensors and blood cell populations coincide.HighlightsFunctional lineage tracing reveals in vivo transdifferentiation in aDrosophilamodel of hematopoiesisActive sensory neurons of the caudal sensory cones promote blood cell transdifferentiation in theDrosophilalarvaEnvironmental oxygen sensing and atypical guanylyl cyclase activity in sensory cone neurons drive blood cell transdifferentiation