bluuebunny/crossref_metadata_2025_split huggingface dataset:
Current infectious disease research practices with forcibly displaced people in the top ten low- and middle-income host countries: A Systematic Review
Authors: Gross Neila , Tarnas Maia C. , Sayeeda Rashmina J. , Ching Carly , Flynn David , Zaman Muhammad H 
Published: September 2024

ABSTRACTInfectious disease research is essential for disease prevention and management within refugee camps and informal settlements. We aim to assess the state of infectious disease research with displaced communities in the top ten refugee-hosting low- and middle-income countries. We searched three journal databases for primary research that explicitly included refugees or was conducted in a refugee camp, informal settlement, or displaced people-serving hospital and focused directly on an infectious disease following PRISMA guidelines. Forty studies (out of 1,179) met the inclusion criteria. Common research challenges included population mobility, limited external validity, and low recruitment. No studies included the community in the initial study conception or investigated the research impact on the community. Community involvement was often through community health workers (45%). Of the 18 studies that studied a resource-based intervention, 20% explicitly noted that the intervention was unsustainable. Such context-specific considerations are vital in research with displaced communities.
Avian interferon regulatory factor (IRF) family reunion: IRF3 and IRF9 found
Authors: Ungrová Lenka , Geryk Josef , Kohn Marina , Kučerová Dana , Krchlíková Veronika , Hron Tomáš , Pečenka Vladimír , Pajer Petr , Gáliková Eliška , Pecnová Ľubomíra , Kaspers Bernd , Hejnar Jiří , Nehyba Jiří , Elleder Daniel 
Published: September 2024

ABSTRACTInterferon regulatory factors (IRFs) are a family of transcription factors in jawed vertebrates with important functions in immunity and many other key cellular processes. The genomes of most vertebrates encode ten IRF genes (IRF1 to IRF10). IRF3 and IRF9 have key roles in the interferon (IFN) induction and signaling. Most of our knowledge about the IFN pathways originates from the study of the mammalian IFN system, and the description of the corresponding avian components is not as complete. Both IRF3 and IRF9 were considered missing from the chicken genome and also from the genomes of all other avian species. Here we describe multiple avian IRF3 and IRF9 genes, all with difficult GC-rich sequence context which prevented their earlier characterization. IRF3 orthologs are more narrowly distributed and are present in the avian infraclass Palaeognathae residing in a syntenic genomic locus shared with other vertebrates. In contrast, IRF9 orthologs were found in most avian species with the notable exception of the order Galliformes. In about half of the avian orders analyzed, IRF9 was located in noncanonical chromosomal positions indicating past evolutionary translocations. Importantly, phylogenetic analysis confirmed the correct orthology of all newly described avian IRFs. We performed a series of experiments using duck (Anas platyrhynchos) IRF9, confirming its key role in the IFN signaling pathway. Knockout of IRF9 in duck embryonal fibroblasts decreases the induction of IFN-stimulated genes (ISGs). Full induction of ISGs in duck cells requires both intact IRF9 and canonical IFN-stimulated response element (ISRE). Lastly, intact IRF9 is needed for IFN-mediated protection of duck cells against vesicular stomatitis virus (VSV)-induced cytopathic effect. The identification of avian IRFs fills an important gap in our understanding of avian immunology and brings new questions related to the evolution of the IRF family.
Slit3 Fragments Orchestrate Neurovascular Expansion and Thermogenesis in Brown Adipose Tissue
Authors: Duarte Afonso Serdan Tamires , Cervantes Heidi , Frank Benjamin , Tian Qiyu , Choi Chan Hee J. , Hoffmann Anne , Cohen Paul , Blüher Matthias , Schwartz Gary J , Shamsi Farnaz 
Published: September 2024

AbstractBrown adipose tissue (BAT) represents an evolutionary innovation enabling placental mammals to regulate body temperature through adaptive thermogenesis. Brown adipocytes are surrounded by a dense network of blood vessels and sympathetic nerves that support their development and thermogenic function. Cold exposure stimulates BAT thermogenesis through the coordinated induction of brown adipogenesis, angiogenesis, and sympathetic innervation. However, how these distinct processes are coordinated remains unclear. Here, we identify Slit guidance ligand 3 (Slit3) as a new niche factor that mediates the crosstalk among adipocyte progenitors, endothelial cells, and sympathetic nerves. We show that adipocyte progenitors secrete Slit3 which regulates both angiogenesis and sympathetic innervation in BAT and is essential for BAT thermogenesis in vivo. Proteolytic cleavage of Slit3 generates secreted Slit3-N and Slit3-C fragments, which activate distinct receptors to stimulate angiogenesis and sympathetic innervation, respectively. Moreover, we introduce bone morphogenetic protein-1 (Bmp1) as the first Slit protease identified in vertebrates. In summary, this study underscores the essential role of Slit3-mediated neurovascular network expansion in enabling cold-induced BAT adaptation. The co-regulation of neurovascular expansion by Slit3 fragments provides a bifurcated yet harmonized approach to ensure a synchronized response of BAT to environmental challenges. This study presents the first evidence that adipocyte progenitors regulate tissue innervation, revealing a previously unrecognized dimension of cellular interaction within adipose tissue.
Cryo-EM structures of human GPR155 elucidate its regulatory and transport mechanisms
Authors: Sharma Mansi , Jaijyan Dabbu K. , Nanda Sristi , Samso Montserrat , Hu Wenhui , Singh Shikha , Singh Appu K. 
Published: September 2024

AbstractGPR155 is a polymodal lysosomal membrane “transceptor” comprising both a transporter domain and a GPCR domain, predominantly expressed in brain. GPR155 facilitates cholesterol-dependent mTORC1 signaling and is implicated in neurological disorders like Huntington’s disease. The GPCR domain likely does not bind extracellular ligands canonically, and the functional relationship between GPR155 domains remains unclear. Here, we report the first structures of monomeric human GPR155 and two distinct dimers, revealing an inward-open transporter domain and an inactivated GPCR domain with a unique luminal loop 7 conformation occupying orthosteric pocket. The dimeric assembly is cholesterol-sensitive: at low cholesterol, the transporter domain resembles plant PIN transporters and transports auxin molecules; at high cholesterol, it forms a unique dimer stabilized by cholesterol. Altogether, these findings have implications for uncovering new lysosomal signaling pathways.
Assessing the role ofAtGRP7 arginine 141, a target of dimethylation by PRMT5, in flowering time control
Authors: Steffen Alexander , Dombert Katarzyna , Iglesias María José , Nolte Christine , de Leone María José , Yanovsky Marcelo J. , Mateos Julieta L. , Staiger Dorothee 
Published: September 2024

AbstractArginine (R) methylation, catalyzed by PROTEIN ARGININE METHYLTRANSFERASES (PRMTs), is critical for regulation of gene expression at the transcriptional and post-transcriptional level. Among nine PRMT genes in Arabidopsis, PRMT5 catalyzing symmetric R dimethylation of its targets is best characterized. PRMT5 mutants are late flowering and show altered responses to environmental stress. Among PRMT5 targets areArabidopsis thalianaGLYCINE RICH RNA BINDING PROTEIN 7 (AtGRP7) andAtGRP8 that promote the transition to flowering.AtGRP7 R141 has been shown to be modified by PRMT5. Here, we tested whether this symmetric dimethylation of R141 is important forAtGRP7’s physiological role in flowering time control. We constructedAtGRP7 mutant variants with non-methylable R141 (R141A, R141K). Genomic clones containing these variants complemented the late flowering phenotype of thegrp7-1mutant to the same extend as wild-typeAtGRP7. Furthermore, overexpression ofAtGRP7 R141A or R141K promoted flowering similar to overexpression of the wild-type protein. Thus, flowering time does not depend on R141 and its modification. However,AtGRP7 R141 contributes to the activity of GRP7 in response to abscisic. Immunoprecipitation ofAtGRP7-GFP in theprmt5background revealed that antibodies against dimethylated arginine still recognizedAtGRP7, suggesting that additional methyltransferases may be responsible for modification ofAtGRP7.
A Graph-Informed Modeling Framework Empowering Gene Pathway Discovery
Authors: Wang Yihao , Wang Yue , Jin Jin 
Published: September 2024

AbstractThis study introduces a novel graph-informed modeling framework for improving the statistical analysis of gene expression data, particularly in the context of identifying differentially expressed gene pathways and gene expression-assisted disease classification in a high-dimensional data setting. By integrating gene regulatory network information into hypothesis testing for the difference between mean vectors and linear discriminant analysis, we aim to effectively capture and utilize previously validated external gene interaction information. Our method leverages a block-coordinate descent approach which enables us to incorporate mixed graph information into linear structural equation modeling, accommodating directed/undirected edges and potential cycles in gene regulatory networks. Extensive simulations under various data scenarios have demonstrated the effectiveness of our approach with improved power for gene pathway tests and disease classification over existing methods. An application to a lung cancer dataset from the Cancer Genome Atlas Program (TCGA) further exemplifies the potential of our graph-informed approach in empowering the detection of differentially expressed gene pathways and gene expression-based classification of different lung cancer stages. Our findings underscore the potential utility of incorporating gene regulatory network information in gene pathway analysis, setting the stage for future advancements in gene pathway discovery, disease diagnosis, and treatment strategies.
Recognition of phylogenetically diverse pathogens through enzymatically amplified recruitment of RNF213
Authors: Casado Ana Crespillo , Pothukuchi Prathyush , Naydenova Katerina , Yip Matthew C. J. , Young Janet M. , Boulanger Jerome , Dharamdasani Vimisha , Harper Ceara , Hammoudi Pierre-Mehdi , Otten Elsje G. , Boyle Keith , Gogoi Mayuri , Malik Harmit S. , Randow Felix 
Published: September 2024

AbstractInnate immunity senses microbial ligands known as pathogen-associated molecular patterns (PAMPs). Except for nucleic acids, PAMPs are exceedingly taxa-specific, thus enabling pattern recognition receptors to detect cognate pathogens while ignoring others. How the E3 ubiquitin ligase RNF213 can respond to phylogenetically distant pathogens, including Gram-negativeSalmonella, Gram-positiveListeria,and eukaryoticToxoplasma, remains unknown. Here we report that the evolutionary history of RNF213 is indicative of repeated adaptation to diverse pathogen target structures, especially in and around its newly identified CBM20 carbohydrate-binding domain, which we have resolved by cryo-EM. We find that RNF213 forms coats on phylogenetically distant pathogens. ATP hydrolysis by RNF213’s dynein-like domain is essential for coat formation on all three pathogens studied as is RZ finger-mediated E3 ligase activity for bacteria. Coat formation is not diffusion-limited but instead relies on rate-limiting initiation events and subsequent cooperative incorporation of further RNF213 molecules. We conclude that RNF213 responds to evolutionarily distant pathogens through enzymatically amplified cooperative recruitment.
The wheat VIH2-3B, a functional PPIP5K controls the localization of fasciclin-like arabinogalactan protein
Authors: Shukla Anuj , Tanwar Rahul , Agrwal Kanupriya , Ghosh Riya , Jessen Henning Jacob , Laha Debabrata , Pandey Ajay K 
Published: September 2024

AbstractInositol pyrophosphates (PP[InsPs) are important signalling molecules, that participate in multiple physiological processes across a wide range of eukaryotes. Metabolic pathway kinases (VIP1/VIHs) leading to the production of PP-InsPs are now well characterized in yeast and plants. Previously, the wheat inositol pyrophosphate kinase (TaVIH2) was shown to encode a catalytic active kinase domain. Heterologousexpression ofTaVIH2inArabidopsis thalianashowed enhanced drought tolerance by modulating the cell composition. In this study, we attempted to identify the interacting protein targets of wheat VIH2-3B using a yeast two-hybrid (Y2H) cDNA library screen, identifying 52 putative interactors that are primarily involved in cell wall-related functions. Notably, fasciclin-like arabinogalactan protein (FLA7), a glycosylphosphatidylinositol (GPI)-anchored protein emerged as the most frequently interacting partner in the screen. Further analysis using pull-down assays validated the interaction between TaVIH2-3B and TaFLA7in vivo. Using the reporter fusion studies, we observed the localization of TaFLA7 to be a plasma membrane. We also observed that this localization of the FLA7 was perturbed in the yeastvip1Δ strain. The expression of TaVIH2-3B bearing PP-InsP5K enzymatic activity in yeast mutants rescued the localisation of the FLA7 to the membrane. Expression analysis ofTaFLA7showed differential expression response under drought in wheat shoot tissues.TaFLA7was also found to be highly expressed during grain development, particularly in the endosperm and seed coat during grain maturation. Taken together, these findings highlight the potential role of TaVIH2 in cell wall remodelling and stress response pathways, offering new insights into the functional roles of VIH proteins in plants.Key word:Inositol pyrophosphates, kinases, cell wall maintenance.
Cgasdeficiency promotes tumor growth by supporting B cell persistence and angiogenesis
Authors: Chantawichitwong Papasara , Kumpunya Sarinya , Wongtangprasert Tossapon , Visitchanakun Peerapat , Pisitkun Trairak , Pisitkun Prapaporn 
Published: September 2024

AbstractThe cGAS sensor activates STING/IFN signaling, which is crucial for immune defense against pathogens and triggers inflammation in autoimmune diseases and antitumor responses. This study investigated the cGAS-mediated immune response in tumorigenesis using the MC-38 tumor model.Cgas-/-mice exhibited significantly larger tumors and lower survival rates than wild-type (WT) mice. Tumors inCgas-/-mice showed increased fibrosis and neovascularity. WT mice mounted a more robust T-cell-mediated antitumor response, with higher levels of NK and effector T cells, whileCgas-/-mice showed an expansion of B cells, including regulatory B cells producing IL-10. B cells from tumor-bearingCgas-/-mice survived better in the tumor- conditioned medium than those from WT mice. B cell depletion significantly reduced tumor size in WT mice but had minimal effect inCgas-/-mice, where fibrosis and tumor vasculature persisted. Despite B cell depletion, B cells remained in the tumors ofCgas-/-mice, in contrast to WT mice, where their reduction correlated with an increase in CD8+infiltrating cells. Expression ofTlr7andTlr9remained elevated and unaffected by B cell depletion inCgas-/-tumors, whileBaffexpression was higher and further increased after B cell depletion.Cgas-/-B cells promoted angiogenesis, as indicated by enhanced endothelial tube formation. In summary, cGAS deficiency fosters a tumor microenvironment that supports B cell survival, promotes a pro-tumor immune environment, and enhances angiogenesis, contributing to tumor progression.
AUK3 is required for faithful nuclear segregation in the bloodstream form ofTrypanosoma brucei
Authors: Black J.A. , Poulton B.C. , Gonzaga B.S. , Iskantar A. , Tosi L.R.O. , McCulloch R 
Published: September 2024

ABSTRACTEukaryotic chromosomes segregate faithfully prior to nuclear division to ensure genome stability. If segregation becomes defective, the chromosome copy number of the cell may alter leading to aneuploidy and/or polyploidy, both common hallmarks of cancers. In eukaryotes, aurora kinases regulate chromosome segregation during mitosis and meiosis, but their functions in the divergent, single-celled eukaryotic pathogenTrypanosoma bruceiare less understood. Here, we focused on one of three aurora kinases in these parasites, TbAUK3, a homologue of the human aurora kinase AURKC, whose functions are primarily restricted to meiosis. We show that RNAi targeted depletion of TbAUK3 correlates with nuclear segregation defects, reduced proliferation, and decreased DNA synthesis, suggestive of a role for TbAUK3 during mitotic, not meiotic, chromosome segregation. Moreover, we uncover a putative role for TbAUK3 during the parasite’s response to DNA damage since we show that depletion of TbAUK3 enhances DNA instability and sensitivity to genotoxic agents.HIGHLIGHTSThe C-terminus of TbAUK3 is disorderedTbAUK3 depletion coincides with nuclear segregation defectsDepletion of TbAUK3 enhances DNA instability
Turning the tables: Loss of adaptive immunity reverses sex differences in tuberculosis
Authors: Hertz David , Eggers Lars , von Borstel Linda , Goldmann Torsten , Lotter Hannelore , Schneider Bianca E. 
Published: September 2024

AbstractSex-based differences in innate immunity may play a crucial role in susceptibility to and progression of tuberculosis (TB), a disease that disproportionately affects men. This study aimed to examine whether early host-pathogen interactions contribute to the heightened vulnerability of males toMycobacterium tuberculosis(Mtb) infection. Using recombination activating gene knockout (RAG KO) mice, which lack adaptive immunity, we were able to isolate and analyze innate immune responses toMtbwithout the influence of T and B cells. Surprisingly, and in stark contrast to wild-type mice that reflect the male bias as observed in humans, female RAG KO mice were more susceptible toMtbthan their male counterparts. Increased lung CFU in females was accompanied by a significant rise in inflammation, indicated by elevated levels of inflammatory cytokines and chemokines, as well as a massive influx of neutrophils into the lungs. In contrast, male mice exhibited higher levels of IFN-γ and CCL5, along with a greater presence of NK cells in their lungs, suggesting that, in the absence of adaptive immunity, males benefit from a more robust NK cell response, potentially offering greater protection by better controlling inflammation and slowing disease progression.
Engineering Human ARMMs as Therapeutic Non-Viral Vehicles forin vivoDelivery of Genome Editing Payloads
Authors: Wang Qiyu , Liu Shu-Lin , Zhao Wen-Ning , von Kleeck Ryan , Thomas Michael , Luther Kristin , Vahramian Zahra , Sun Yumei , Vyas Komal , Moharil Pearl , Chatzinakos Chris , Semple Carson O. , Badji Jennifer A. , Gens Leah , Bryant Alysia , Greenway Steve , Chang Chou-Wei , Francoeur Adam , Valkov Nedyalka , O’Brien Killian , Nabhan Joseph F. 
Published: September 2024

AbstractThe ability to edit the human genome to treat previously incurable diseases or to modify previously undruggable targets has the potential to transform the lives of patients. However, delivery of genome editing machineriesin vivo, and in a transient manner, continues to be a major challenge. We engineered human cell-derived ARRDC1-mediated microvesicles (ARMMs) as non-viral vehicles that mediate intracellular delivery of proteins, including DNA-modifying enzymes such as Cre recombinase and Cas9/guide RNA ribonucleoproteins (RNPs). ARMMs packaged multiple payloads per vesicle in our production system, yielding dose-dependent functional delivery of Cre or Cas9/gRNA RNP to a variety of cell types, including primary mouse and human cells. Oropharyngeal aspiration of ARMMs loaded with Cre led to biodistribution to alveolar macrophages (AMs), whereas intravenous administration predominantly to Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs), and splenocytes. Suprisingly, one administration of ARMMs loaded with Cas9 RNPs by oropharyngeal aspiration or intravenously resulted in efficient knockout of multiple genes in AMs or KCs, suggesting potential therapeutic utility. Through intravenous administration of ARMMs loaded with Cas9/NLRP3 gRNA we showed amelioration of drug-induced liver injury in a mouse model, supporting the use of ARMMs as human cell-derived therapeutic vehicles for genome editor deliveryin vivo.
Characterization of non-coding variants associated with transcription factor binding through ATAC-seq-defined footprint QTLs in liver
Authors: Dudek Max F. , Wenz Brandon M. , Brown Christopher D. , Voight Benjamin F. , Almasy Laura , Grant Struan F.A. 
Published: September 2024

AbstractNon-coding variants discovered by genome-wide association studies (GWAS) are enriched in regulatory elements harboring transcription factor (TF) binding motifs, strongly suggesting a connection between disease association and the disruption of cis-regulatory sequences. Occupancy of a TF inside a region of open chromatin can be detected in ATAC-seq where bound TFs block the transposase Tn5, leaving a pattern of relatively depleted Tn5 insertions known as a “footprint”. Here, we sought to identify variants associated with TF-binding, or “footprint quantitative trait loci” (fpQTLs) in ATAC-seq data generated from 170 human liver samples. We used computational tools to scan the ATAC-seq reads to quantify TF binding likelihood as “footprint scores” at variants derived from whole genome sequencing generated in the same samples. We tested for association between genotype and footprint score and observed 693 fpQTLs associated with footprint-inferred TF binding (FDR < 5%). Given that Tn5 insertion sites are measured with base-pair resolution, we show that fpQTLs can aid GWAS and QTL fine-mapping by precisely pinpointing TF activity within broad trait-associated loci where the underlying causal variant is unknown. Liver fpQTLs were strongly enriched across ChIP-seq peaks, liver expression QTLs (eQTLs), and liver-related GWAS loci, and their inferred effect on TF binding was concordant with their effect on underlying sequence motifs in 80% of cases. We conclude that fpQTLs can reveal causal GWAS variants, define the role of TF binding site disruption in disease and provide functional insights into non-coding variants, ultimately informing novel treatments for common diseases.Graphical AbstractWe leverage footprinting methods to infer transcription factor binding likelihood genome-wide across 170 liver ATAC-seq samples and implicate 693 SNPs with a genetic influence on binding. Unlike other comparable approaches, this analytical method is not limited in resolution by the constraints of linkage disequilibrium, and can prioritize likely causal variants at GWAS loci for subsequent experimental validation.