bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety, Immunogenicity and Efficacy of a Recombinant Vesicular Stomatitis Virus Vectored Vaccine Against Severe Fever with Thrombocytopenia Syndrome Virus and Heartland Bandaviruses
Authors: Hicks Philip , Westover Jonna B. , Manzoni Tomaz B. , Roper Brianne , Rock Gabrielle L. , Boardman Kirsten M. , Blotbter Dallan J. , Gowen Brian B. , Bates Paul 
Published: December 2021

AbstractSevere fever with thrombocytopenia syndrome virus (SFTSV) is a recently emerged tickborne virus in east Asia with over 8,000 confirmed cases. With a high case fatality ratio, SFTSV has been designated a high priority pathogen by the WHO and the NIAID. Despite this, there are currently no approved therapies or vaccines to treat or prevent SFTS. Vesicular stomatitis virus (VSV) represents an FDA-approved vaccine platform that has been considered for numerous viruses due to its low sero-prevalence in humans, ease in genetic manipulation and promiscuity in incorporating foreign glycoproteins into its virions. In this study, we developed a recombinant VSV (rVSV) expressing the SFTSV glycoproteins Gn/Gc (rVSV-SFTSV) and assessed its safety, immunogenicity and efficacy in mice. We demonstrate that rVSV-SFTSV is safe when given to immunocompromised animals and is not neuropathogenic when injected intracranially into young immunocompetent mice. Immunization of Ifnar-/- mice with rVSV-SFTSV resulted in high levels of neutralizing antibodies and protection against lethal SFTSV challenge. Additionally, passive transfer of sera from immunized Ifnar-/- mice into naïve animals was protective when given pre- or post-exposure. Finally, we demonstrate that immunization with rVSV-SFTSV cross protects mice against challenge with the closely related Heartland virus despite low neutralizing titers to the virus. Taken together, these data suggest that rVSV-SFTSV is a promising vaccine candidate.ImportanceTick borne diseases are a growing threat to human health. Severe fever with thrombocytopenia syndrome (SFTS) and Heartland viruses are recently recognized, highly-pathogenic, tick-transmitted viruses. The fatality rates for individuals infected with SFTSV or HRTV are high and there are no therapeutics or vaccines available. The recent introduction of the tick vector for SFTSV (Haemaphysalis longicornis) to the eastern half of the United States and Austrailia raises concerns for SFTSV outbreaks outside East Asia. Here we report the development of a potential vaccine for SFTSV and HRTV based on the viral vector platform that has been successfully used for an Ebola vaccine. We demonstrate that the rVSV-SFTSV protects from lethal SFTSV or HRTV challenge when given as a single dose. We evaluated possible pathogenic effects of the vaccine and show that it is safe in immune compromised animlas and when introduced into the central nervous system.
Microbial cysteine degradation is a source of hydrogen sulfide in oxic freshwater lakes
Authors: Tran Patricia Q. , Bachand Samantha C. , Hotvedt Jacob C. , Kieft Kristopher , McDaniel Elizabeth A. , McMahon Katherine D. , Anantharaman Karthik 
Published: December 2021

AbstractThe sulfur-containing amino acid cysteine is abundant in the environment including in freshwater lakes. Biological cysteine degradation can result in hydrogen sulfide (H2S), a toxic and ecologically relevant compound that is a central player in biogeochemical cycling in aquatic environments. Here, we investigated the ecological significance of cysteine in oxic freshwater lake environments, using isolated cultures, controlled growth experiments, and multi-omics. We screened bacterial isolates enriched from natural lake water for their ability to produce H2S when provided cysteine. In total, we identified 29 isolates that produced H2S and belonged to the phyla Bacteroidetes, Proteobacteria, and Actinobacteria. To understand the genomic and genetic basis for cysteine degradation and H2S production, we further characterized 3 freshwater isolates using whole-genome sequencing (using a combination of short-read and long-read sequencing), and quantitatively tracked cysteine and H2S levels over their growth ranges: Stenotrophomonas maltophilia (Gammaproteobacteria), Stenotrophomonas bentonitica (Gammaproteobacteria) and Chryseobacterium piscium (Bacteroidetes). We observed a decrease in cysteine and increase in H2S, and identified genes involved in cysteine degradation in all 3 genomes. Finally, to assess the presence of these organisms and genes in the environment, we surveyed a five-year time series of metagenomic data from the same isolation source (freshwater Lake Mendota, WI, USA) and identified their presence throughout the time series. Overall, our study shows that sulfur-containing amino acids can drive microbial H2S production in oxic environments. Future considerations of sulfur cycling and biogeochemistry in oxic environments should account for H2S accumulation from degradation of organosulfur compounds.ImportanceHydrogen sulfide (H2S), a naturally occurring gas with biological origins, can be toxic to living organisms. In aquatic environments, H2S production typically originates from anoxic (lacking oxygen) environments such as sediments, or the bottom layers of thermally stratified lakes. However, the degradation of sulfur-containing amino acids such as cysteine, which all cells and life forms rely on, can be a source of ammonia and H2S in the environment. Unlike other approaches for biological H2S production such as dissimilatory sulfate reduction, cysteine degradation can occur in the presence of oxygen. Yet, little is known about how cysteine degradation influences sulfur availability and cycling in freshwater lakes. In our study, we identified diverse bacteria from a freshwater lake that can produce H2S in the presence of O2. Our study highlights the ecological importance of oxic H2S production in natural ecosystems and necessitates a change in our outlook of sulfur biogeochemistry.
Continuum Theory for Planar Cell Polarity
Authors: Rizvi Mohd Suhail , Singh Divyoj , Jolly Mohit K. 
Published: December 2021

AbstractPlanar Cell Polarity (PCP), characterized by asymmetric localization of proteins at the cell membrane within the epithelial plane, plays essential roles in embryonic development and physiological functions. The significance of PCP can be appreciated by the outcomes of its failure in the form of defects in neural tube formation, tracheal malfunctions, organ shape misregulation, hair follicle misalignment etc. Extensive experimental works on PCP in fruit fly Drosophila melanogaster have classified the proteins involved in PCP into a ‘core’ module, acting locally by inter-cellular protein interactions, and a ‘global’ module, responsible for the alignment of cell polarities with that of the tissue axis. Despite the involvement of different molecular players the asymmetric localization of the proteins of the two modules on cell membrane primarily involves inter-cellular dimer formations. We have developed a continuum model of the localization of PCP proteins on the cell membrane and its regulation via intra- and inter-cellular protein-protein interactions. We have identified the conditions for the asymmetric protein localization, or PCP establishment, for uniform and graded protein expression levels in the tissue. We have found that in the absence of any tissue level expression gradient polarized state of the tissue does not arise. However, in the presence of tissue-level expression gradients of proteins the polarized state remains stable. We have also looked at the influence of the loss of PCP proteins from a select region of the tissue on the polarization of the cells outside of that region. This continuum theory of planar cell polarity can be coupled with active-matter hydrodynamics to study cell flows and their regulation by genetic machinery.
Replication Study: RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth
Authors: Pelech Steven , Gallagher Curtis , Sutter Catherine , Yue Lambert , Kerwin John , Bhargava Ajay , Iorns Elizabeth , Tsui Rachel , Denis Alexandria , Perfito Nicole , Errington Timothy M. 
Published: December 2021

AbstractAs part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Bhargava et al., 2016) that described how we intended to replicate selected experiments from the paper “RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth” (Hatzivassiliou et al., 2010). Here we report the results. We found two unrelated RAF inhibitors, PLX4720 or GDC-0879, selectively inhibited BRAF(V600E) cell proliferation, while the MEK inhibitor, PD0325901, inhibited BRAF(V600E), wild-type RAF/RAS, and mutant RAS cancer cell proliferation, similar to the original study (Figure 1A; Hatzivassiliou et al., 2010). We found knockdown of CRAF, but not BRAF, in mutant RAS cells attenuated the phospho-MEK induction observed after PLX4720 treatment, similar to the original study (Figure 2B; Hatzivassiliou et al., 2010). The original study reported analogous results with GDC-0879, which was not observed in this replication, although unexpected control results confound the interpretation. We also attempted a replication of an assay with recombinant proteins to test the differential effect of RAF inhibitors on BRAF-CRAF heterodimerization (Figure 4A; Hatzivassiliou et al., 2010). Although we were unable to conduct the experiment as planned, we observed differential binding of BRAF by RAF inhibitors; however, it was between BRAF and beads, independent of CRAF. While these data were unable to address whether, under the conditions of the original study, the same observations could be observed, we discuss key differences between the original study and this replication that are important to consider for further experiments. Finally, where possible, we report meta-analyses for each result.
Gut transcriptome reveals differential gene expression and enriched pathways linked to immune activation in response to weaning in pigs
Authors: Le Bon M. , Tötemeyer S. , Emes R. D. , Mellits K. H. 
Published: December 2021

AbstractWeaning represents one of the most critical periods in pig production associated with increase in disease risk, reduction in performance and economic loss. Physiological changes faced by piglets during the weaning period have been well characterised, however little is currently known about the underlying molecular pathways involved in these processes. As pig meat remains one of the most consumed sources of protein worldwide, understanding how these changes are mediated is critical to improve pig production and consequently sustainable food production globally. In this study, we evaluated the effect of weaning on transcriptomic changes in the colon of healthy piglets over time using an RNA-sequencing approach.The findings revealed a complex and coordinated response to weaning with the majority of genes found to be rapidly differentially expressed within one day post weaning. Multiple genes and pathways affected by weaning in the colon were associated with immune regulation, cell signalling and bacterial defence. NOD-like receptors, Toll-like receptor and JAK-STAT signalling pathways were amongst the pathways significantly enriched. Immune activation was evidenced by the enrichment of pathways involved in interferon response, cytokines interactions, oxidoreductase activities and response to microbial invasion. Biosynthesis of amino acids, in particular arginine, was also amongst the most enriched KEGG pathways in weaned pigs, reinforcing the critical role of arginine in gut homeostasis under stress conditions.Overall, transcriptomic and physiological results suggest that pigs going through the weaning transition undergo a transient period of inflammatory state with a temporary breakdown of barrier functions in the gut. These findings could provide valuable tools to monitor host response post weaning, and may be of particular relevance for the investigation and development of intervention strategies aimed to reduce antibiotic use and improve pig health and performance.
Genetic assimilation of ancestral plasticity during parallel adaptation
Authors: Wood Daniel P. , Holmberg Jon A. , Osborne Owen G. , Helmstetter Andrew J. , Dunning Luke T. , Ellison Amy R. , Smith Rhian J. , Lighten Jackie , Papadopulos Alexander S.T. 
Published: December 2021

AbstractPhenotypic plasticity in ancestral populations is hypothesised to facilitate adaptation, but evidence supporting its contribution is piecemeal and often contradictory. Further, whether ancestral plasticity increases the probability of parallel genetic and phenotypic adaptive changes has not been explored. The most general finding is that nearly all ancestral gene expression plasticity is reversed following adaptation, but this is usually examined transcriptome-wide rather than focused on the genes directly involved in adaptation. We investigated the contribution of ancestral plasticity to adaptive evolution of gene expression in two independently evolved lineages of zinc-tolerant Silene uniflora. We found that the general pattern of reversion is driven by the absence of a widespread stress response in zinc-adapted plants compared to ancestral, zinc-sensitive plants. Our experiments show that reinforcement of ancestral plasticity plays an influential role in the evolution of plasticity in derived populations and, surprisingly, one third of constitutive differences between ecotypes are the result of genetic assimilation of ancestral plasticity. Ancestral plasticity also increases the chance that genes are recruited repeatedly during adaptation. However, despite a high degree of convergence in gene expression levels between independently adapted lineages, genes with ancestral plasticity are as likely to have similar expression levels in adapted populations as genes without. Overall, these results demonstrate that ancestral plasticity does play an important role in adaptive parallel evolution, particularly via genetic assimilation across evolutionary replicates.
Uveal Melanoma: a miR-16 disease?
Authors: Quéméner Anaïs M. , Bachelot Laura , Aubry Marc , Avner Stéphane , Leclerc Delphine , Salbert Gilles , Cabillic Florian , Decaudin Didier , Mari Bernard , Mouriaux Frédéric , Galibert Marie-Dominique , Gilot David 
Published: December 2021

AbstractUveal melanoma (UM), the most common primary intraocular tumor in adults, has been extensively characterized by omics technologies during the last 5 years. Despite the discovery of gene signatures, the molecular actors driving the cancer aggressiveness are not fully understood and UM is still associated to a dismal overall survival at metastatic stage. Here, we showed that microRNA-16 (miR-16) is involved in uveal melanoma by an unexpected mechanism. By defining the miR-16-interactome, we revealed that miR-16 mainly interacts via non-canonical base-pairing to a subset of RNAs, promoting their expression levels (sponge RNAs). Consequently, the canonical miR-16 activity, involved in the RNA decay of oncogenes such as cyclin D1 and D3, is impaired. This miR-16 non-canonical base-pairing to sponge RNAs can explain both the derepression of miR-16 targets and the promotion of oncogenes expression observed for patients with poor overall survival in two cohorts. miR-16 activity assessment using our sponge-signature discriminates the patient’s overall survival as efficiently as the current method based on copy number variations and driver mutations detection. To conclude, miRNA loss of function due to miRNA sequestration seems to promote cancer burden by two combined events – “loss of brake and an acceleration”. Our results highlight the oncogenic role of the non-canonical base-pairing between miRNAs/mRNAs in uveal melanoma.
Efficient targeting of NY-ESO-1 tumor antigen to human cDC1s by lymphotactin results in cross-presentation and antigen-specific T cell expansion
Authors: Le Gall Camille M. , Cammarata Anna , de Haas Lukas , Ramos-Tomillero Iván , Cuenca-Escalona Jorge , Wijfjes Zacharias , Becker Anouk M.D. , Dölen Yusuf , de Vries I. Jolanda M. , Figdor Carl G. , Flórez-Grau Georgina , Verdoes M. 
Published: December 2021

ABSTRACTType 1 conventional dendritic cells (cDC1s) are characterized by their ability to induce potent CD8+T cell responses. In efforts to generate novel vaccination strategies, notably against cancer, human cDC1s emerge as an ideal target to deliver antigens. cDC1s uniquely express XCR1, a seven transmembrane G protein-coupled receptor (GPCR). Due to its restricted expression and endocytic nature, XCR1 represents an attractive receptor to mediate antigen-delivery to human cDC1s. To explore tumor antigen delivery to human cDC1s, we used an engineered version of XCR1-binding lymphotactin (XCL1), XCL1(CC3). Site-specific sortase-mediated transpeptidation was performed to conjugate XCL1(CC3) to an analog of the HLA-A*02:01 epitope of the cancer testis antigen New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1). While poor epitope solubility prevented isolation of stable XCL1-antigen conjugates, incorporation of a single polyethylene glycol (PEG) chain upstream of the epitope-containing peptide enabled generation of soluble XCL1(CC3)-antigen fusion constructs. Binding and chemotactic characteristics of the XCL1-antigen conjugate, as well as its ability to induce antigen-specific CD8+T cell activation by cDC1s, was assessed. PEGylated XCL1(CC3)-antigen conjugates retained binding to XCR1, and induced cDC1 chemoattractionin vitro. The model epitope was efficiently cross-presented by human cDC1s to activate NY-ESO-1-specific CD8+T cells. Importantly, vaccine activity was increased by targeting XCR1 at the surface of cDC1s. Our results present a novel strategy for the generation of targeted vaccines fused to insoluble antigens. Moreover, our data emphasize the potential of targeting XCR1 at the surface of primary human cDC1s to induce potent CD8+T cell responses.
Dihydroartemisinin broke immune evasion through YAP1/JAK1/STAT1, 3 pathways to enhance anti-PD-1 therapy in hepatocellular carcinoma
Authors: Peng Qing , Li Shenghao , Shi Xinli , Guo Yinglin , Hao Liyuan , Zhang Zhiqin , Ji Jingmin , Zhao Yanmeng , Li Caige , Xue Yu , Liu Yiwei 
Published: December 2021

AbstractThe efficacy of anti-PD-1 therapy is not as expected in patients with hepatocellular carcinoma (HCC). Yes-associated protein 1 (YAP1) was overexpressed and activated in HCC. This study aimed to investigate the potential mechanism and inhibitor of YAP1 on immune evasion, and promote anti-PD-1 therapy in HCC. Here, we showed that dihydroartemisinin (DHA), an FDA approved drug, directly suppressed YAP1 expression, leading to break immune evasion in liver tumor niche, characterized by decreased PD-L1 in liver tumor cells and increased CD8+ T cell infiltration. Mechanismly, YAP1 is not only directly related to PD-L1, but also involved in activating the JAK1/STAT1, 3 pathways. Moreover, Yap1 knockout elevated CD4+ and CD8+ T cells in liver tumor niche of Yap1LKO mice. Consistently, verteporfin, YAP1 inhibitor, decreased TGF-β in liver tumor niche and exhausted CD8+ T cells in spleen. Furthermore, DHA combined with anti-PD-1 treatment promoted CD4+ T cell infiltration in the spleen and CD8+ T cells in tumor tissues. Thus, we provide a new combined therapeutic strategy for anti-PD-1 with DHA, a potent YAP1 inhibitor, in HCC.
Convergent Cerebrospinal Fluid Proteomes and Metabolic Ontologies in Humans and Animal Models of Rett Syndrome
Authors: Zlatic Stephanie A. , Duong Duc , Gadalla Kamal K.E. , Murage Brenda , Ping Lingyan , Shah Ruth , Khwaja Omar , Swanson Lindsay C. , Sahin Mustafa , Rayaprolu Sruti , Kumar Prateek , Rangaraju Srikant , Bird Adrian , Tarquinio Daniel , Cobb Stuart , Faundez Victor 
Published: December 2021

AbstractMECP2 loss-of-function mutations cause Rett syndrome, a disorder that results from a disrupted brain transcriptome. How these transcriptional defects are decoded into a disease proteome remains unknown. We studied the proteome in Rett syndrome cerebrospinal fluid (CSF) across vertebrates. We identified a consensus proteome and ontological categories shared across Rett syndrome cerebrospinal fluid (CSF) from three species, including humans. Rett CSF proteomes enriched proteins annotated to HDL lipoproteins, complement, mitochondria, citrate/pyruvate metabolism, as well as synapse compartments. We used these prioritized and shared ontologies to select analytes for orthogonal quantification. These studies independently validated our proteome and ontologies. Ontologically selected CSF hits had genotypic discriminatory capacity as determined by Receiver Operating Characteristic (ROC) analysis and distinguished Rett from a related neurodevelopmental disorder, CDKL5 deficiency disorder. We propose that Mecp2 mutant CSF proteomes and ontologies inform novel putative mechanisms and biomarkers of disease. We suggest that Rett syndrome is a metabolic disorder impacting synapse function.
Optogenetic operated probiotics to regulate host metabolism by mimicking enteroendocrine
Authors: Zhang Xinyu , Ma Ning , Ling Wei , Pang Gaoju , Sun Tao , Liu Jing , Pan Huizhuo , Cui Meihui , Han Chunli , Yang Chun , Chang Jin , Huang Xian , Wang Hanjie 
Published: December 2021

AbstractThe enteroendocrine system plays an important role in metabolism. The gut microbiome regulates enteroendocrine in an extensive way, arousing attention in biomedicine. However, conventional strategies of enteroendocrine regulation via gut microbiome are usually non-specific or imprecise. Here, an optogenetic operated probiotics system was developed combining synthetic biology and flexible electronics to achieve in situ controllable secretion to mimic enteroendocrine. Firstly, optogenetic engineered Lactococcus lactis (L. lactis) were administrated in the intestinal tract. A wearable optogenetic device was designed to control optical signals remotely. Then, L. lactis could secrete enteroendocrine hormone according to optical signals. As an example, optogenetic L. lactis could secrete glucagon-like peptide-1(GLP-1) under the control of the wearable optogenetic device. To improve the half-life of GLP-1 in vivo, the Fc domain from immunoglobulin was fused. Treated with this strategy, blood glucose, weight and other features were relatively well controlled in rats and mice models. Furthermore, up-conversion microcapsules were introduced to increase the excitation wavelength of the optogenetic system for better penetrability. This strategy has biomedical potential in metabolic diseases therapy by mimicking enteroendocrine.