bluuebunny/crossref_metadata_2025_split huggingface dataset:
Response of human liver tissue to innate immune stimuli
Authors: Wu Xia , Roberto Jessica B. , Knupp Allison , Greninger Alexander L. , Truong Camtu D. , Hollingshead Nicole , Kenerson Heidi L. , Tuefferd Marianne , Chen Antony , Horton Helen , Jerome Keith R. , Polyak Stephen J. , Yeung Raymond S. , Crispe Ian N. 
Published: December 2020

AbstractPrecision-cut human liver slice cultures (PCLS) has become an important alternative immunological platform in preclinical testing. To further evaluate the capacity of PCLS, we investigated the innate immune response to TLR3 agonist (poly-I:C) and TLR4 agonist (LPS) with the normal and pathological liver tissue. Pathological liver tissue was obtained from patients with active chronic HCV infection, and patients with former chronic HCV infection cured by recent Direct-Acting Antiviral (DAA) drug therapy. We found that hepatic innate immunity was not suppressed but enhanced in the HCV-infected tissue, compared with the healthy controls. Furthermore, despite recent HCV elimination, DAA-cured liver tissue manifested ongoing abnormalities in liver immunity. Sustained abnormal immune gene expression in DAA-cured samples were identified from direct ex vivo measurements and with TLR3 and TLR4 stimulation assays. Those genes that were up-regulated in chronic HCV-infected liver tissue were enriched in expression in the liver non-parenchymal cell compartment. These results demonstrated the utility of PCLS in studying the liver pathology and innate immunity.
Host Cell Proteases Drive Early or Late SARS-CoV-2 Penetration
Authors: Koch Jana , Uckeley Zina M , Doldan Patricio , Stanifer Megan , Boulant Steeve , Lozach Pierre-Yves 
Published: December 2020

AbstractSARS-CoV-2 is a newly emerged coronavirus (CoV) that spread through human populations worldwide in early 2020. CoVs rely on host cell proteases for activation and infection. The trypsin-like protease TMPRSS2 at the cell surface, cathepsin L in endolysosomes, and furin in the Golgi have all been implicated in the SARS-CoV-2 proteolytic processing. Whether SARS-CoV-2 depends on endocytosis internalization and vacuolar acidification for infectious entry remains unclear. Here, we examined the dynamics of SARS-CoV-2 activation during the cell entry process in tissue culture. Using four cell lines representative of lung, colon, and kidney epithelial tissues, we found that TMPRSS2 determines the SARS-CoV-2 entry pathways. In TMPRSS2-positive cells, infection was sensitive to aprotinin, a TMPRSS2 inhibitor, but not to SB412515, a drug that impairs cathepsin L. Infectious penetration was marginally dependent on endosomal acidification, and the virus passed the protease-sensitive step within 10 min. In a marked contrast, in TMPRSS2-negative cells cathepsin L and low pH were required for SARS-CoV-2 entry. The cathepsin L-activated penetration occurred within 40-60 min after internalization and required intact endolysosomal functions. Importantly, pre-activation of the virus allowed it to bypass the need for endosomal acidification for viral fusion and productive entry. Overall, our results indicate that SARS-CoV-2 shares with other CoVs a strategy of differential use of host cell proteases for activation and infectious penetration. This study also highlights the importance of TMPRSS2 in dictating the entry pathway used by SARS-CoV-2.SignificancePreventing SARS-CoV-2 spread requires approaches affecting early virus-host cell interactions before the virus enters and infects target cells. Host cell proteases are critical for coronavirus activation and infectious entry. Here, we reconcile apparent contradictory observations from recent reports on endosomal acidification and the role of furin, TMPRSS2, and cathepsin L in the productive entry and fusion process of SARS-CoV-2. Investigating authentic virus in various cell types, we demonstrated that SARS-CoV-2 developed the ability to use different entry pathways, depending on the proteases expressed by the target cell. Our results have strong implications for future research on the apparent broad tropism of the virusin vivo. This study also provides a handle to develop novel antiviral strategies aiming to block virus entry, as illustrated with the several drugs that we identified to prevent SARS-CoV-2 infection, some with low IC50.
No evidence for human monocyte-derived macrophage infection and antibody-mediated enhancement of SARS-CoV-2 infection
Authors: García-Nicolás O , V’kovski P , Zettl F , Zimmer G , Thiel V , Summerfield A 
Published: December 2020

AbstractVaccines are essential to control the spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and to protect the vulnerable population. However, one safety concern of vaccination is the possible development of antibody-dependent enhancement (ADE) of SARS-CoV-2 infection. The potential infection of Fc receptor bearing cells such as macrophages, would support continued virus replication and inflammatory responses, and thereby potentially worsen the clinical outcome of COVID-19. Here we demonstrate that SARS-CoV-2 and SARS-CoV-1 neither infect human monocyte-derived macrophages nor induce inflammatory cytokines in these cells, in sharp contrast to Middle East respiratory syndrome (MERS) coronavirus and the common cold human coronavirus 229E. Furthermore, serum from convalescent COVID-19 patients neither induced enhancement of SARS-CoV-2 infection nor innate immune response in human macrophages. These results support the view that ADE may not be involved in the immunopathological processes associated with COVID-19, however, more studies are necessary to understand the potential contribution of antibodies-virus complexes with other cells expressing FcR receptors.
Sting orchestrates the crosstalk between polyunsaturated fatty acids metabolism and inflammatory responses
Authors: Vila Isabelle K. , Chamma Hanane , Steer Alizée , Taffoni Clara , Reinert Line S. , Turtoi Evgenia , Saccas Mathilde , Marines Johanna , Jin Lei , Bonnefont Xavier , Paludan Soren R. , Vlachakis Dimitrios , Turtoi Andrei , Laguette Nadine 
Published: December 2020

SummaryInflammatory disorders are major health issues in which immune function and metabolic homeostasis are concertedly altered. Yet, the molecular mechanisms coordinating innate and metabolic pathways in homeostatic conditions are poorly understood. Here, we unveil a negative regulatory feedback loop involving the Stimulator of interferon genes (Sting) and the Fatty acid desaturase 2 (Fads2). At steady state, Sting regulates FA metabolism by repressing the activity of the Fads2 enzyme responsible for the desaturation of polyunsaturated FAs (PUFAs). Importantly, Sting activation increased Fads2 activity, while antagonizing Fads2 enhanced Sting activation, promoting the establishment of an anti-viral state. Remarkably, the cross-regulation between Sting and Fads2 is mediated by the cyclic GMP-AMP (cGAMP) Sting agonist and PUFAs. Indeed, we found that PUFAs inhibit Sting activation, while Sting agonists bind Fads2. Thus, our study identifies Sting as a master regulator of FA metabolism, and PUFAs as modulators of Sting-dependent inflammation. The interplay between Fads2 and Sting determines the fine-tuning of inflammatory responses, but comes at the expense of metabolic alterations, which are critical to consider in human pathologies associated with aberrant Sting activation.
WormPaths:Caenorhabditis elegansmetabolic pathway annotation and visualization
Authors: Walker Melissa D. , Giese Gabrielle E. , Holdorf Amy D. , Bhattacharya Sushila , Diot Cédric , García-González Aurian P. , Horowitz Brent , Lee Yong-Uk , Leland Thomas , Li Xuhang , Mirza Zeynep , Na Huimin , Nanda Shivani , Ponomarova Olga , Zhang Hefei , Zhang Jingyan , Yilmaz L. Safak , Walhout Albertha J.M. 
Published: December 2020

AbstractIn our group, we aim to understand metabolism in the nematodeCaenorhabditis elegansand its relationships with gene expression, physiology and the response to therapeutic drugs. On March 15, 2020, a stay-at-home order was put into effect in the state of Massachusetts, USA, to flatten the curve of the spread of the novel SARS-CoV2 virus that causes COVID-19. For biomedical researchers in our state, this meant putting a hold on experiments for nine weeks until May 18, 2020. To keep the lab engaged and productive, and to enhance communication and collaboration, we embarked on an in-lab project that we all found important but that we never had the time for: the detailed annotation and drawing ofC. elegansmetabolic pathways. As a result, we present WormPaths, which is composed of two parts: 1) the careful manual annotation of metabolic genes into pathways, categories and levels, and 2) 66 pathway maps that include metabolites, metabolite structures, genes, reactions, and pathway connections between maps. These maps are available on our WormFlux website. We show that WormPaths provides easy-to-navigate maps and that the different levels in WormPaths can be used for metabolic pathway enrichment analysis of transcriptomic data. In the unfortunate event of additional lockdowns, we envision further developing these maps to be more interactive, with an analogy of road maps that are available on mobile devices.
The schizophrenia-associated variant inSLC39A8alters N-glycosylation in the mouse brain
Authors: Mealer Robert G. , Williams Sarah E. , Noel Maxence , Yang Bo , D’Souza Alexandria , Nakata Toru , Graham Daniel B. , Creasey Elizabeth A. , Cetinbas Murat , Sadreyev Ruslan , Scolnick Edward M. , Woo Christina M. , Smoller Jordan W. , Xavier Ramnik J. , Cummings Richard D. 
Published: December 2020

AbstractA missense mutation (A391T) in the manganese transporterSLC39A8is strongly associated with schizophrenia in genomic studies, though the molecular connection to the brain remains hypothetical. Human carriers of A391T have reduced serum manganese, altered plasma glycosylation, and brain MRI changes consistent with altered metal transport. Here, using a knock-in mouse model homozygous for A391T, we show that the schizophrenia-associated variant changes protein glycosylation in the brain. N-linked glycosylation was most significantly impaired, with effects differing between regions. RNAseq analysis showed negligible regional variation, consistent with changes in the activity of glycosylation enzymes rather than gene expression. Finally, nearly one third of detected glycoproteins were differentially N-glycosylated in the cortex, including members of several pathways previously implicated in schizophrenia such as cell adhesion molecules and neurotransmitter receptors. These findings provide a mechanistic link between a risk allele and biochemical changes in the brain, furthering our molecular understanding of the pathophysiology of schizophrenia.
Profiling diverse sequence tandem repeats in colorectal cancer reveals co-occurrence of microsatellite and chromosomal instability involving Chromosome 8
Authors: Shin GiWon , Greer Stephanie U. , Hopmans Erik , Grimes Susan M. , Lee HoJoon , Zhao Lan , Miotke Laura , Suarez Carlos , Almeda Alison F. , Haraldsdottir Sigurdis , Ji Hanlee P. 
Published: December 2020

ABSTRACTColorectal carcinomas(CRCs)which have lost DNA mismatch repair display hypermutability evident in a molecular phenotype called microsatellite instability(MSI). These mismatch repair deficient tumors are thought to lack widespread genomic instability features, such as copy number changes and rearrangements. To identify MSI for clinical diagnosis, current molecular testing looks for changes in mononucleotide or dinucleotide repeats. However, microsatellites have other types of sequence tandem repeats such as tri- and tetranucleotide motifs. These additional classes of microsatellites are generally not examined for MSI but are known to be unstable in a phenotype known as elevated microsatellite alterations at selected tetranucleotide repeats, orEMAST. We developed a sequencing approach that provides ultra-high coverage (>2500X) of microsatellite targets and cancer genes for profiling genomic instability. We assessed the diverse repeat motifs across 200 microsatellites. Our approach provides highly sensitive detection of MSI with high specificity, evaluates copy number alterations with high accuracy, delineates chromosomal instability(CIN)classification and deconvolutes subclonal architecture. By examining both MSI and CIN, we discovered mutations and copy number alterations that defined mixed genomic instability states of CIN and MSI, which are normally considered exclusive. An increase in copy number of chromosome arm 8q was prevalent among MSI tumors. Moreover, we identified an inter-chromosomal translocation event from a CRC with co-occurrence of MSI. Subclonal analysis demonstrated that mutations which are typically considered to be exclusive in MSI, shows mutual occurrence in MSI tumors with more sensitive characterization. Our approach revealed thatMSH3mutations are a potential source of mixed genomic instability features. Overall, our study demonstrates that some colorectal cancers have features of both microsatellite and chromosomal instability. This result may have implications for immunotherapy treatment.
Biological Correlations and Confounding Variables for Quantification of Retinal Ganglion Cells Based on Optical Coherence Tomography using Diversity Outbred Mice
Authors: Hedberg-Buenz Adam , Meyer Kacie J. , van der Heide Carly J. , Deng Wenxiang , Lee Kyungmoo , Soukup Dana A. , Kettelson Monica , Pellack Danielle , Mercer Hannah , Wang Kai , Garvin Mona K. , Abramoff Michael D. , Anderson Michael G. 
Published: December 2020

AbstractPurposeDespite popularity of optical coherence tomography (OCT) in glaucoma studies, it’s unclear how well OCT-derived metrics compare to traditional measures of retinal ganglion cell (RGC) abundance. Here, Diversity Outbred (J:DO) mice are used to directly compare ganglion cell complex (GCC)-thickness measured by OCT to metrics of retinal anatomy measured ex vivo with retinal wholemounts or optic nerve cross sections.MethodsJ:DO mice (n= 48) underwent OCT and fundoscopic exams, with GCC-thickness measured using automated segmentation. Following euthanasia, RGC axons were quantified from para-phenylenediamine-stained optic nerve cross sections and RGC somas from BRN3A-immunolabeled retinal wholemounts with total cellularity assessed by TO-PRO or hematoxylin nuclear staining.ResultsJ:DO tissues lacked overt disease. GCC-thickness (62.4 ± 3.7 µm), RGC abundance (3,097 ± 515 BRN3A+nuclei/mm2; 45,533 ± 9,077 axons), and total inner retinal cell abundance (6,952 ± 810 nuclei/mm2) varied broadly. GCC-thickness correlated significantly to RGC somal density (r = 0.46) and axon number (r = 0.49), whereas total inner retinal cellularity did not. Retinal area (20.3 ± 2.4 mm2) and optic nerve (0.09 ± 0.02 mm2) cross-sectional area varied widely. Sex did not significantly influence any of these metrics. In bilateral comparisons, GCC-thickness (r = 0.89), inner retinal cellularity (r = 0.47), and RGC axon abundance (r = 0.72) all correlated significantly.ConclusionsAmongst outbred mice with widely variable phenotypes, OCT-derived measurements of GCC thickness correlate significantly to RGC abundance and axon number. The extensive phenotypic variability exhibited by J:DO mice make them a powerful resource for studies of retinal anatomy using quantitative genetics.
GeneNetwork: a continuously updated tool for systems genetics analyses
Authors: Watson Pamela M. , Ashbrook David G. 
Published: December 2020

AbstractGeneNetwork and its earlier iteration, WebQTL, have now been an important database and toolkit for quantitative trait genetics research for two decades. Recent improvements to GeneNetwork have reinvigorated it, including the addition of data from 10 species, multi-omics analysis, updated code, and new tools. The new GeneNetwork is now an exciting resource for predictive medicine and systems genetics, which is constantly being maintained and improved. Here, we give a brief overview of the process for carrying out some of the most common functions on GeneNetwork, as a gateway to deeper analyses, demonstrating how a small number of plausible candidate genes can be found for a typical immune phenotype.
PolyJet 3D Printing of Tissue Mimicking Materials: An Investigation of Characteristic Properties of 3D Printed Synthetic Tissue
Authors: Lee Vania , Severseike Leah , Bakken Chris , Bermel Emily , Bhatia Varun 
Published: December 2020

AbstractCurrent anatomical 3D printing has been primarily used for education, training, and surgical planning purposes. This is largely due to the models being printed in materials which excel at replicating macro-level organic geometries; however, these materials have the drawback of unrealistic mechanical behavior and system properties compared to biological tissue. The new Digital Anatomy (DA) family of materials from Stratasys utilizes composite printed materials to more closely mimic mechanical behavior of biological tissue, potentially allowing more realistic models for design evaluation. Various experimental DA Solid Organ (SO) configurations were quantitatively evaluated under axial loading for comparison with porcine liver in terms of stiffness. Additionally, Structural Heart - Myocardium (Myo) configurations were quantitatively evaluated under different lubricant conditions for comparison with porcine epicardium and aorta in terms of lubricity. Finally, experimental DA Subcutaneous Tissue configurations were qualitatively evaluated by experts with significant pre-clinical implant experience for cutting, tunneling, and puncture procedures.In general, the experimental SO configurations showed promising compliance results when compared to porcine liver. The stiffness of DA configurations was either within the same range or on the lower bound of porcine tissue stiffness values. The lubricity of DA configurations with surface treatments was comparable with porcine epicardium and aorta. In terms of qualitative cutting, DA did not perform well for any of the configurations; however, tunneling and puncture were rated favorably for some of the experimental configurations. Despite some limitations, DA feels closer to real tissue than other commercially available 3D printed materials. Furthermore, the lower sample-to-sample variability of DA allows for repeatability not provided by biological tissue. The promising results and repeatability indicate that DA materials can be used to configure structures with similar characteristic mechanical properties to porcine liver, epicardium, and subcutaneous tissue, adding new value as not only an educational, training, and surgical tool, but also as a research tool.
Genome-wide identification, characterization and expression analysis of the Bcl-2 associated athanogene (BAG) gene family inPhyscomitrium patens
Authors: Castro Alexanda , Saavedra Laura , Ruibal Cecilia , Lascano Ramiro , Vidal Sabina 
Published: December 2020

AbstractThe Bcl-2-associated athanogene (BAG) family is an evolutionarily conserved, multifunctional group of co-chaperones regulators that modulate a number of diverse processes. PlantBAGgenes were identified to play an extensive role in processes of programmed cell death (PCD) ranging from growth and development to stress responses. In this study, we identifiedBAGgenes from different photosynthetic organisms in order to gather evolutionary insights on these proteins followed by anin silicocharacterization of theBAGfamily in the bryophytePhyscomitrium patens. Ten putativePpBAGsharbouring a characteristic BAG domain were grouped into two subfamilies based on the presence of additional conserved domains and phylogenetic distances. Group I consisted of PpBAG4 and PpBAG5, containing an additional ubiquitin-like domain, and PpBAG10 with only the BAG domain. Group II consisted of PpBAG1–3 and PpBAG6-9, containing a calmodulin-binding IQ motif, a novel feature associated with plant BAG proteins. Interestingly, PpBAG9 exhibits an EF-Hand domain, not reported to date in this class of proteins. Caspase cleavage sites in PpBAG1, PpBAG3, PpBAG4-5 and PpBAG9 were predicted.In silicoanalysis ofBAGgenes revealed the presence of stress responsive elements, and a stress-regulated expression pattern which appears to be dependent on specifically organized promoter regulatory elements. According to our analyses, the present data suggest that some members ofP. patens BAGgene family may play a role in heat responses, autophagy and pathogen immunity. Further studies are required to unveil the role of specific members of this gene family in PCD and stress responses inP. patens.Key messageGenome-wide identification and phylogenetic relationships combined within silicogene-expression profiling and protein-interaction analysis of PpBAGs inPhyscomitrium patens, highlight the importance of a particular set in stress tolerance.
cDC1 and interferons promote spontaneous CD4+and CD8+T cell protective responses to breast cancer
Authors: Mattiuz Raphaël , Brousse Carine , Ambrosini Marc , Cancel Jean-Charles , Bessou Gilles , Mussard Julie , Sanlaville Amélien , Caux Christophe , Bendriss-Vermare Nathalie , Valladeau-Guilemond Jenny , Dalod Marc , Crozat Karine 
Published: December 2020

AbstractHere we show that efficient breast cancer immunosurveillance relies on cDC1, conventional CD4+T cells, CD8+cytotoxic T lymphocytes (CTL) and later NK/NK T cells. For this process, cDC1 were required constitutively, but especially during the T cell priming phase. In the tumor microenvironment, cDC1 interacted physically and jointly with both CD4+T cells and tumorspecific CD8+T cells. We found that interferon (IFN) responses were necessary for the rejection of breast cancer, including cDC1-intrinsic signaling by IFN-γ and STAT1. Surprisingly, cell-intrinsic IFN-I signaling in cDC1 was not required. cDC1 and IFNs shaped the tumor immune landscape, notably by promoting CD4+and CD8+T cell infiltration, terminal differentiation and effector functions. XCR1, CXCL9, IL-12 and IL-15 were individually dispensable for breast cancer immunosurveillance. Consistent with our experimental results in mice, high expression in the tumor microenvironment of genes specific to cDC1, CTL, helper T cells or interferon responses are associated with a better prognosis in human breast cancer patients. Our results show that immune control of breast cancer depends on cDC1 and IFNs as previously reported for immunogenic melanoma or fibrosarcoma tumor models, but that the underlying mechanism differ. Revisiting cDC1 functions in the context of spontaneous immunity to cancer should help defining new ways to mobilize cDC1 functions to improve already existing immunotherapies for the benefits of patients.SynopsisType 1 conventional dendritic cells cross-present tumor antigens to CD8+T cells. Understanding the regulation of their antitumor functions is important. Cell-intrinsic STAT1/IFN-γ signaling licenses them for efficient CD4+and CD8+T cell activation during breast cancer immunosurveillance.
The Prevalence of the Val66Met Polymorphism in Musicians: Possible Evidence for Compensatory Neuroplasticity from a pilot study
Authors: Henechowicz T.L. , Chen J.L. , Cohen L.G. , Thaut M.H. 
Published: December 2020

AbstractIt has been reported that MET carriers may express deficits in motor learning and neuroplasticity, possibly deterring musicianship. Here, we compared the prevalence of the Val66Met Brain-derived Neurotrophic Factor single nucleotide polymorphism (rs6265) in a sample of musicians (N=50) and an ethnically matched subset from the 1000 Human Genome Project (N-424). We report no differences in genotype or allele frequencies. Results are consistent with the view that hypothesized Met-dependent deficits in neuroplasticity are either mild or can be overcome by long-term practice.