bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel humanized mouse model to study mucosal HIV-1 transmission and prevention
Authors: Vanshylla Kanika , Held Kathrin , Eser Tabea M. , Gruell Henning , Jain Kanika , Weiland Daniela , Muench Jan , Gruettner Berthold , Geldmacher Christof , Klein Florian 
Published: September 2020

AbstractHumanized mice have been critical for HIV-1 research, but are inefficient at mucosal HIV-1 transmission. We present a fetal tissue-independent model called CD34T+ with enhanced human leukocyte levels in the blood and improved T cell homing to the gut-associated lymphoid tissue. CD34T+ mice are highly permissive to intra-rectal HIV-1 infection, which can be prevented by infusion of broadly neutralizing antibodies. Therefore, CD34T+ mice provide a novel platform for mucosal HIV-1 transmission and prevention studies.
Morphological and biochemical repercussions ofToxoplasma gondiiinfection in a 3D human brain neurospheres model
Authors: Corrêa Leite Paulo Emílio , de Araujo Portes Juliana , Pereira Mariana Rodrigues , Russo Fabiele Baldino , Martins-Duarte Erica S. , dos Santos Nathalia Almeida , Attias Marcia , Barrantes Francisco J. , Baleeiro Beltrão-Braga Patricia Cristina , de Souza Wanderley 
Published: September 2020

ABSTRACTBackgroundToxoplasmosis is caused by the parasiteToxoplasma gondiithat can infect the central nervous system (CNS), promoting neuroinflammation, neuronal loss, neurotransmitter imbalance and behavioral alterations.T.gondiiinfection is also related to neuropsychiatric disorders such as schizophrenia. The pathogenicity and inflammatory response in rodents are different to the case of humans, compromising the correlation between the behavioral alterations and physiological modifications observed in the disease. In the present work we used BrainSpheres, a 3D CNS model derived from human pluripotent stem cells (iPSC), to investigate the morphological and biochemical repercussions ofT.gondiiinfection in human neural cells.MethodsWe evaluatedT. gondiiME49 strain proliferation and cyst formation in both 2D cultured human neural cells and BrainSpheres. Aspects of cell morphology, ultrastructure, viability, gene expression of neural phenotype markers, as well as secretion of inflammatory mediators were evaluated for 2 and 4 weeks post infection in BrainSpheres.ResultsT. gondiican infect BrainSpheres, proliferating and inducing cysts formation, neural cell death, alteration in neural gene expression and triggering the release of several inflammatory mediator.ConclusionsBrainSpheres reproduce many aspects ofT. gondiiinfection in human CNS, constituting a useful model to study the neurotoxicity and neuroinflammation mediated by the parasite. In addition, BrainSpheres can be an important tool for better understanding the possible correlation between psychiatric disorders and human CNS infection withT. gondii
Maternal Transfer of Environmentally Relevant Polybrominated Diphenyl Ethers (PBDEs) Produces a Diabetic Phenotype and Disrupts Glucoregulatory Hormones and Hepatic Endocannabinoids in Adult Mouse Female Offspring
Authors: Kozlova Elena V. , Chinthirla Bhuvaneswari D. , Pérez Pedro A. , DiPatrizio Nicholas V. , Argueta Donovan A. , Phillips Allison L. , Stapleton Heather M. , González Gwendolyn M. , Krum Julia M. , Carrillo Valeria , Bishay Anthony E. , Basappa Karthik R. , Currás-Collazo Margarita C. 
Published: September 2020

AbstractPolybrominated diphenyl ethers (PBDEs) are brominated flame retardant chemicals and environmental contaminants with endocrine-disrupting properties that are associated with diabetes and metabolic syndrome in humans. However, their diabetogenic actions are not completely characterized or understood. In this study, we investigated the effects of DE-71, a commercial penta-mixture of PBDEs, on glucose regulatory parameters in a perinatal exposure model using female C57Bl/6 mice. Results fromin vivoglucose and insulin tolerance tests andex vivoanalyses showed that DE-71 produced fasting hyperglycemia, glucose intolerance, reduced sensitivity and delayed glucose clearance after insulin challenge, and exaggerated hepatic endocannabinoid tone in F1 offspring exposed to 0.1 mg/kg DE-71 relative to control. DE-71 effects on F0 dams were more limited indicating that indirect exposure to developing offspring is more detrimental. Otherex vivoglycemic correlates occur more generally in exposed F0 and F1, i.e., reduced plasma insulin and altered glucoregulatory endocrines, exaggerated sympathoadrenal activity, decreased thermogenic brown adipose tissue mass and reduced hepatic glutamate dehydrogenase enzymatic activity. Hepatic PBDE congener analysis indicated maternal transfer of BDE-28 and −153 to F1 at a collective level of 200 ng/g lipid, in range with maximum values detected in serum of human females. Given the persistent diabetogenic phenotype, especially pronounced in female offspring after developmental exposure to environmentally relevant levels of DE-71, additional animal studies should be conducted that further characterize PBDE-induced diabetic pathophysiology and identify critical developmental time windows of susceptibility. Longitudinal human studies should also be conducted to determine the risk of long-lasting metabolic consequences after maternal transfer of PBDEs during early-life development.
CRISPR screens in physiologic medium reveal conditionally essential genes in human cells
Authors: Rossiter Nicholas J. , Huggler Kimberly S. , Adelmann Charles H. , Keys Heather R. , Soens Ross W. , Sabatini David M. , Cantor Jason R. 
Published: September 2020

SUMMARYForward genetic screens across hundreds of diverse cancer cell lines have started to define the genetic dependencies of proliferating human cells and how these vary by genotype and lineage. Most screens, however, have been carried out in culture media that poorly resemble metabolite availability in human blood. To explore how medium composition influences gene essentiality, we performed CRISPR-based screens of human cancer cell lines cultured in traditional versus human plasma-like medium (HPLM). Sets of medium-dependent fitness genes span several cellular processes and can vary with both natural cell-intrinsic diversity and the specific combination of basal and serum components that comprise typical culture media. Notably, we traced the causes for each of three conditional growth phenotypes to the availability of metabolites uniquely defined in HPLM versus traditional media. Our findings reveal the profound impact of medium composition on gene essentiality in human cells, and also suggest general strategies for using genetic screens in HPLM to uncover new cancer vulnerabilities and gene-nutrient interactions.
Updated definitions on piezophily as suggested by hydrostatic pressure dependence on temperature
Authors: Scoma Alberto 
Published: September 2020

AbstractMicrobial preference for elevated hydrostatic pressure (HP) is a recognized key feature of environmental and industrial processes. HP effects on macromolecules and, consequently, cell functionality has been accurately described in the last decades. While there is little debate about the importance of HP in shaping microbial life, a systematic definition of microbial preference for increased HP is missing. The lack of a consensus about ‘true’ piezophiles, and ‘low’ or ‘high’ HP levels, has deleterious repercussions on microbiology and biotechnology. As certain levels are considered ‘low’ they are not applied to assess microbial activity. Most microorganisms collected in deep waters or sediments have not been tested (nor isolated) using the corresponding HP at which they were captured. Microbial response to HP is notoriously dependent on other environmental parameters, most notably temperature, but also on availability of nutrients, growth substrate, pH and salinity. This implies that countless isolates retrieved from ambient pressure conditions may very well require increased HP to grow optimally, as already demonstrated in both Archaea and Bacteria.In the present study, I collected the data from described piezophilic isolates and used the fundamental correlation existing between HP and temperature, as first suggested in seminal works by Yayanos, to update the definition of piezophiles. Thanks to the numerous new piezophilic isolates available since such seminal studies, the present analysis brings forward updated definitions which concern 1) the actual beginning of the piezosphere, the area in the deep sea where piezophiles thrive; 2) the HP thresholds which should be considered low, medium and high HP, and their implications for experimental design in Microbiology; and 3) the nature of obligate piezophiles and their location in the deep sea.
DYRK2 is a ciliary kinase involved in vertebrate Hedgehog signal transduction
Authors: Morante Nicholas , Sigg Monika Abedin , Strauskulage Luke , Raleigh David R. , Reiter Jeremy F. 
Published: September 2020

ABSTRACTPrimary cilia are organelles specialized for signaling. We previously defined the proteomes of sea urchin and sea anemone cilia to identify ciliary proteins that predate the origin of bilateria. This evolutionary perspective on cilia identified DYRK2, a kinase not been previously implicated in ciliary biology. We found that DYRK2 localizes to cilia and that loss of DYRK2 disrupts ciliary morphology. We also found that DYRK2 participates in ciliary Hh signal transduction, communicating between SMO and GLI transcription factors. Mutation of mouseDyrk2resulted in skeletal defects reminiscent of those caused by loss ofIndian hedgehog(Ihh). LikeDyrk2mutations, pharmacological inhibition of DYRK2 dysregulates ciliary length control and attenuates Hedgehog signaling. Thus, DYRK2 is required for ciliary morphology, for Hedgehog signalingin vitro, and for skeletal development. We propose that DYRK2 is part of the mechanism that transduces SMO to activate GLI transcription factors within cilia.
Bioelectrochemical engineering analysis of formate-mediated microbial electrosynthesis
Authors: Abel Anthony J. , Clark Douglas S. 
Published: September 2020

AbstractMediated microbial electrosynthesis (MES) represents a promising strategy for the capture and conversion of CO2into carbon-based products. We describe the development and application of a comprehensive multiphysics model to analyze a formate-mediated MES reactor. The model shows that this system can achieve a biomass productivity of ∼1.7 g L-1hr-1but is limited by a competitive trade-off between O2gas/liquid mass transfer and CO2transport to the cathode. Synthetic metabolic strategies are evaluated for formatotrophic growth, which can enable an energy efficiency of ∼21%, a 30% improvement over the Calvin cycle. However, carbon utilization efficiency is only ∼10% in the best cases due to a futile CO2cycle, so gas recycle will be necessary for greater efficiency. Finally, separating electrochemical and microbial processes into separate reactors enables a higher biomass productivity of ∼2.4 g L-1hr-1. The mediated MES model and analysis presented here can guide process design for conversion of CO2into renewable chemical feedstocks.
SARS-CoV-2 Cell Entry Factors ACE2 and TMPRSS2 are Expressed in the Pancreas but are Not Enriched in Islet Endocrine Cells
Authors: Coate Katie C. , Cha Jeeyeon , Shrestha Shristi , Wang Wenliang , Gonçalves Luciana Mateus , Almaça Joana , Kapp Meghan E. , Fasolino Maria , Morgan Ashleigh , Dai Chunhua , Saunders Diane C. , Bottino Rita , Aramandla Radhika , Jenkins Regina , Stein Roland , Kaestner Klaus H. , Vahedi Golnaz , consortium HPAP , Brissova Marcela , Powers Alvin C. 
Published: September 2020

Summary/AbstractReports of new-onset diabetes and diabetic ketoacidosis in individuals with COVID-19 have led to the hypothesis that SARS-CoV-2, the virus that causes COVID-19, is directly cytotoxic to pancreatic islet β cells. This would require binding and entry of SARS-CoV-2 into host β cells via cell surface co-expression of ACE2 and TMPRSS2, the putative receptor and effector protease, respectively. To define ACE2 and TMPRSS2 expression in the human pancreas, we examined six transcriptional datasets from primary human islet cells and assessed protein expression by immunofluorescence in pancreata from donors with and without diabetes.ACE2andTMPRSS2transcripts were low or undetectable in pancreatic islet endocrine cells as determined by bulk or single cell RNA sequencing, and neither protein was detected in α or β cells from these donors. Instead, ACE2 protein was expressed in the islet and exocrine tissue microvasculature and also found in a subset of pancreatic ducts, whereas TMPRSS2 protein was restricted to ductal cells. The absence of significant ACE2 and TMPRSS2 co-expression in islet endocrine cells reduces the likelihood that SARS-CoV-2 directly infects pancreatic islet β cells through these cell entry proteins.
AKT1 mediates multiple phosphorylation events that functionally promote HSF1 activation
Authors: Lu Wen-Cheng , Omari Ramsey , Ray Haimanti , Williams Imade , Jacobs Curteisha , Hockaden Natasha , Bochman Matthew L. , Carpenter Richard L. 
Published: September 2020

AbstractThe heat stress response activates the transcription factor heat shock factor 1 (HSF1), which subsequently upregulates heat shock proteins to maintain the integrity of the proteome. HSF1 activation requires nuclear localization, trimerization, DNA binding, phosphorylation, and gene transactivation. Phosphorylation at S326 is an important regulator of HSF1 transcriptional activity. Phosphorylation at S326 is mediated by AKT1, mTOR, p38, and MEK1. Here, we observe that AKT1 activates HSF1 independent of mTOR. AKT2 also phosphorylated S326 of HSF1 but showed weak ability to activate HSF1. Similarly, mTOR, p38, and MEK1 all phosphorylated S326 but AKT1 was the more potent activator. Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230, and T527 in addition to S326 whereas the other kinases did not. Subsequent investigation revealed that phosphorylation at T142 is necessary for HSF1 trimerization and that S230, S326, and T527 are required for HSF1 gene transactivation and recruitment of TFIIB and CDK9. This study suggests that HSF1 hyperphosphorylation is targeted and these specific residues have direct function in regulating HSF1 transcriptional activity.
A genetic screen identifies new steps in oocyte maturation that enhance proteostasis in the immortal germ lineage
Authors: Samaddar Madhuja , Goudeau Jérôme , Sanchez Melissa , Hall David H. , Bohnert K. Adam , Ingaramo Maria , Kenyon Cynthia 
Published: September 2020

AbstractSomatic cells age and die, but the germ-cell lineage is immortal. InC. elegans, germline immortality involves proteostasis renewal at the beginning of each new generation, when oocyte-maturation signals from sperm trigger the clearance of carbonylated proteins and protein aggregates. Here, we explore the cell biology of this proteostasis renewal in the context of a whole-genome RNAi screen. Oocyte maturation signals are known to trigger protein-aggregate removal via lysosome acidification. Our findings suggest that lysosomes are acidified as a consequence of changes in ER activity that permit assembly of the lysosomal V-ATPase, which in turn allows lysosomes to clear the aggregates via microautophagy. We define two functions for mitochondria, both of which appear to be independent of ATP generation. Many genes from the screen also regulate lysosome acidification and age-dependent protein aggregation in the soma, suggesting a fundamental mechanistic link between proteostasis renewal in the germline and somatic longevity.
Transcriptional kinetic synergy: a complex landscape revealed by integrating modelling and synthetic biology
Authors: Martinez-Corral Rosa , Park Minhee , Biette Kelly , Friedrich Dhana , Scholes Clarissa , Khalil Ahmad S. , Gunawardena Jeremy , DePace Angela H. 
Published: September 2020

1SummaryGene regulation involves synergistic interactions between transcription factors (TFs). Classical thermodynamic models offer a biophysical understanding of synergy based on binding cooperativity and regulated recruitment of RNA polymerase. However, transcription requires polymerase to transition through multiple states. Accordingly, recent work has suggested that ”kinetic synergy” can arise through TFs differentially regulating distinct steps of the transcription cycle. Disentangling both sources of synergy has been challenging. Here, we combine theory and experiment to analyze TFs binding to a single shared site, thereby removing simultaneous specific DNA binding. Using the graph-based linear framework, we integrate TF binding with regulation of the transcription cycle, and reveal a complex kinetic synergy landscape dependent on TF concentration, DNA binding and transcriptional activity. We exploit synthetic zinc-finger TF fusions to experimentally interrogate these predictions. Our results confirm that transcription cycle regulation must be integrated with recruitment for a quantitative understanding of transcriptional control.
Optimal CD4T Cell Priming in Lymph Nodes Requires Repertoire Scanning by CD301b+Migratory cDC2 Cells
Authors: Tatsumi Naoya , Codrington Alicia L , Kumamoto Yosuke 
Published: September 2020

SummaryActivation of CD4T cells by conventional dendritic cells (cDC) is pivotal in adaptive immunity. However, while the activation mechanism of antigen-specific CD4T cells has been extensively studied, the cellular mechanism that leads to the selection of cognate CD4T cell clones out of the polyclonal pool is incompletely understood. Here, we show that, in the reactive lymph nodes, newly homed naive polyclonal CD4T cells are temporarily retained before leaving the lymph node. This stop-and-go traffic of CD4T cells provides an adequate time window for efficient scanning and timely priming of antigen-specific clones. Mechanistically, upon immunization, CD301b+DCs, a major subset of migratory cDC2 cells, quickly migrate to the draining lymph node and settle in the areas near the high endothelial venules, where they retain incoming polyclonal CD4T cells through MHCII-dependent but antigen-independent mechanisms while concurrently providing cognate stimuli to prime antigen-specific CD4T cells. These results indicate that CD301b+DCs function as an immunological “display window” for CD4T cells to efficiently scan their antigen specificity.Graphical AbstractHighlightsNewly homed polyclonal CD4T cells are temporarily retained in the reactive lymph nodes.Depletion of CD301b+DCs results in shorter dwell time of CD4T cells in the draining lymph node and delayed priming of antigen-specific clones.The transient retention of polyclonal CD4T cells in the draining lymph node requires MHCII expression on CD301b+DCs but not cognate antigen.CD301b+DCs are required for robust expansion of rare antigen-specific CD4T cell clones and their skewing toward Th2 cells.
Cryo-EM reveals species-specific components within theHelicobacter pyloriCag type IV secretion system core complex
Authors: Sheedlo Michael J. , Chung Jeong Min , Sawhney Neha , Durie Clarissa L. , Cover Timothy L. , Ohi Melanie D. , Lacy D. Borden 
Published: September 2020

AbstractThe pathogenesis ofHelicobacter pylori-associated gastric cancer is dependent on delivery of CagA into host cells through a type IV secretion system (T4SS). TheH. pyloriCag T4SS includes a large membrane-spanning core complex containing 5 proteins, organized into an outer membrane cap (OMC), a periplasmic ring (PR) and a stalk. Here, we report cryo-EM reconstructions of a core complex lacking Cag3 and an improved map of the wild-type complex. We define the structures of two unique species-specific components (Cag3 and CagM) and show that Cag3 is structurally similar to CagT. Unexpectedly, components of the OMC are organized in a 1:1:2:2:5 molar ratio (CagY:CagX:CagT:CagM:Cag3). CagX and CagY are components of both the OMC and the PR and bridge the symmetry mismatch between these regions. These results reveal that assembly of theH. pyloriT4SS core complex is dependent on incorporation of interwoven species-specific components.
Reducing the social risks of transnational railway construction: a discussion on the formation mechanism of host country people's coping behaviors
Authors: Li Huaqiang , Zhong Yiting , Fan Chunmei 
Published: September 2020

PurposeThe purpose of this paper is to explore the formation mechanism of the host country people's coping behavior regarding the construction of transnational railways to help engineering managers and decision makers improve their risk management and lead to sustainable transnational railway construction projects.Design/methodology/approachThis paper adopted the grounded theory methodology to analyze the news stories reported by “Belt and Road Portal” and “The New York Times” about eight transnational railways. They were China–Kyrgyzstan–Uzbekistan (Central Asia), Mecca-to-Medina (West Asia), Hungarian–Serbia (Europe), China–Nepal (South Asia), Bi-Oceanic (South America), Mombasa–Nairobi (Africa), China–Laos (Southeast Asia) and Panama railways (North America). The keywords for news search were the names of each railway. After eliminating the problem sentences with semantic repetition and ambiguity, 2,631 effective sentences were formed to screen the information and code. The process included open, axial and selective coding.FindingsIt was concluded that the core structure of the formation mechanism was “situation,” “influence factor,” “cognition” and “coping behavior.” The country-of-origin image has served as an adjustment function in the analysis for the host country people. Governance strategies were suggested focusing on risk prevention, risk mitigation and risk response according to social risk management.Research limitations/implicationsThe rise of transnational railway construction is encouraged by the process of globalization. But during the long construction period, the host country people's coping behavior would develop into social conflicts and mass incidents, becoming a significant obstacle to construction objectives. Thus, studying the formation mechanism of public coping behaviors can better take measures to prevent social risks.Originality/valueThe contributions of this research are three aspects: first, a formation mechanism of the host country people's coping behavior based on grounded theory is presented. Second, the country-of-origin image is found to be a factor that cannot be ignored in a transnational context. The formation mechanism of public coping behaviors is improved compared to risk management in the domestic situation. Finally, the host country people pay more attention to the motivations of country-of-origin's controlling interests and their own emotions compared with internal stakeholders.