bluuebunny/crossref_metadata_2025_split huggingface dataset:
NLRP3 and AIM2 inflammasomes exacerbate the pathogenic Th17 cell response to eggs of the helminthSchistosoma mansoni
Authors: Suresh Kumar Meena Kumari Madhusoodhanan , Liu Pengyu , Jump Kaile , Morales Yoelkys , Miller Emily A , Shecter Ilana , Stadecker Miguel J. , Kalantari Parisa 
Published: March 2024

AbstractInfection with the helminthSchistosoma mansonican cause exacerbated morbidity and mortality via a pathogenic host CD4 T cell-mediated immune response directed against parasite egg antigens, with T helper (Th) 17 cells playing a major role in the development of severe granulomatous hepatic immunopathology. The role of inflammasomes in intensifying disease has been reported; however, neither the types of caspases and inflammasomes involved, nor their impact on the Th17 response are known. Here we show that enhanced egg-induced IL-1β secretion and pyroptotic cell death required both caspase-1 and caspase-8 as well as NLRP3 and AIM2 inflammasome activation. Schistosome genomic DNA activated AIM2, whereas reactive oxygen species, potassium efflux and cathepsin B, were the major activators of NLRP3. NLRP3 and AIM2 deficiency led to a significant reduction in pathogenic Th17 responses, suggesting their crucial and non-redundant role in promoting inflammation. Additionally, we show that NLRP3- and AIM2-induced IL-1β suppressed IL-4 and protective Type I IFN (IFN-I) production, which further enhanced inflammation. IFN-I signaling also curbed inflammasome-mediated IL-1β production suggesting that these two antagonistic pathways shape the severity of disease. Lastly, Gasdermin D (Gsdmd) deficiency resulted in a marked decrease in egg-induced granulomatous inflammation. Our findings establish NLRP3/AIM2-Gsdmd axis as a central inducer of pathogenic Th17 responses which is counteracted by IFN-I pathway in schistosomiasis.SummarySchistosomiasis is a major tropical parasitic disease caused by trematode worms of the genus Schistosoma. Morbidity and mortality in infection with the speciesSchistosoma mansoniare due to a pathogenic CD4 T cell-mediated immune response directed against parasite eggs, resulting in granulomatous inflammation. In severe cases of schistosomiasis, there is liver fibrosis, hepatosplenomegaly, portal hypertension, gastro-intestinal hemorrhage and death. Here we describe the role of two proteins, the NLRP3 and AIM2 inflammasomes, in intensifying disease. We found that upstream proteins which activate these inflammasomes are caspase-1 and caspase 8; these in turn lead to the activation of another protein, Gasdermin D (Gsdmd), which facilitates the release of the proinflammatory cytokine IL-1β. Importantly, we observed that mice deficient in Gsdmd exhibit diminished pathology. Finally, we discovered that the protective Type I Interferon (IFN-I) pathway counteracts the caspase/inflammasome/Gsdmd axis thereby controlling egg mediated inflammation. These results give us a deeper understanding of the functional features of the crosstalk between inflammasome and IFN-I pathway, which may lead to the identification of novel targets for therapeutic intervention.
Age-specificity in territory quality and spatial structure in a wild bird population
Authors: Woodman Joe P. , Cole Ella F. , Firth Josh A. , Sheldon Ben C. 
Published: March 2024

AbstractAge influences behaviour, survival, and reproduction; hence variation in population age structure can affect population-level processes. The extent of spatial age structure may be important in driving spatially-variable demography, particularly when space-use is linked to reproduction, yet it is not well understood. We use long-term data from a wild bird population to examine spatial age structure and quantify covariance between territory quality and age. We find associations between age and aspects of territory quality, but little evidence for spatial age structure compared to territory quality and reproductive structure. We also report little between-year repeatability of spatial age structure compared to structure in reproductive output. We suggest that high breeding site fidelity and frequent territory turnover by younger breeders, driven by high mortality and immigration rates, limits the association between age and territory quality and weakens overall spatial age structure. Greater spatial structure and repeatability in reproductive output compared to age suggests that habitat quality may be more important in driving spatially-variable demography than age in this system. We suggest that the framework developed here can be used in other taxa to assess spatial age structure, particularly in longer-lived species where we predict from our findings there may be greater structure.
The genomic trajectory of ovarian high grade serous carcinoma is determined in STIC lesions
Authors: Cheng Z. , Ennis D.P. , Lu B. , Mirza H.B. , Sokota C. , Kaur B. , Singh N. , Le Saux O. , Russo G. , Giannone G. , Tookman L.A. , Krell J. , Barnes C. , McDermott J. , McNeish I.A. 
Published: March 2024

AbstractOvarian high-grade serous carcinoma (HGSC) originates in the fallopian tube, with secretory cells carrying aTP53mutation, known as ‘p53 signatures’, identified as potential precursors. p53 signatures evolve into serous tubal intraepithelial carcinomas (STIC) lesions, which, in turn, progress into invasive HGSC that readily spread to the ovary and disseminate around the peritoneal cavity. We recently investigated the genomic landscape of early- and late-stage HGSC and found higher ploidy in late-stage (median 3.1) than early-stage (median 2.0) samples. Here, to explore whether the high ploidy and possible whole genome duplication observed in late-stage disease are determined early in the evolution of HGSC, we analysed archival formalin-fixed paraffin-embedded samples (FFPE) from five HGSC patients. p53 signatures and STIC lesions were laser-capture microdissected and sequenced using shallow whole genome sequencing (sWGS), while invasive ovarian/fallopian tube and metastatic carcinoma samples underwent macrodissection and were profiled using both sWGS and targeted next generation sequencing. Results showed highly similar patterns of global copy number change between STIC lesions and invasive carcinoma samples within each patient. Ploidy changes were evident in STIC lesions, but not p53 signatures, and there was strong correlation between ploidy in STIC lesions and invasive ovarian/fallopian tube and metastatic samples in each patient. The reconstruction of sample phylogeny for each patient from relative copy number indicated that high ploidy, when present, occurred early in the evolution of HGSC, which was further validated by copy number signatures in ovarian and metastatic tumours. These findings suggest that aberrant ploidy, suggestive of whole genome duplication, arises early in HGSC, and is detected in STIC lesions, implying that the trajectory of HGSC may be determined at the earliest stages of tumour development.
Analysis of higher order interactions quantifies co-ordination in the epigenome and reveals novel biological relationships in Kabuki syndrome
Authors: Cuvertino Sara , Garner Terence , Martirosian Evgenii , Walusimbi Bridgious , Kimber Susan J. , Banka Siddharth , Stevens Adam 
Published: March 2024

ABSTRACTComplex direct and indirect relationships between multiple variables are a characteristic of all natural systems and are defined as higher order interactions (HOIs). Traditional differential and network analyses fail to account for the richness of omic datasets and miss HOIs. We investigated genome-wide peripheral blood DNA methylation data from Kabuki syndrome type 1 (KS1) and control individuals, identified 2,002 differentially methylated points (DMPs), and inferred 17 differentially methylated regions, which represent only 189 DMPs. We followed these results with quantification of HOIs by applying hypergraph network models on all the CpGs in the two datasets and revealed differences in co-ordination of the DMPs along with lower entropy and higher co-ordination of the peripheral epigenome in KS1 implying reduced network complexity. We demonstrate that the hypergraph approach captures substantially more information, enables factoring trans-relationships, and identifies biologically relevant pathways that escape the standard analyses. These findings construct the basis of a suitable model that is not computationally intensive for the analysis of the organisation of the epigenome in rare diseases. This approach can be applied to other types of omic datasets, and to other fields of science and medicine to investigate mechanism in big data.
Use of Mucosally Administered Outer Membrane Vesicles Derived fromBordetella pertussisto Diminish Nasal Bacterial Colonization
Authors: Rudi E. , Gaillard E. , Bottero D , Hozbor D 
Published: March 2024

AbstractBackgroundWe previously identifiedBordetella pertussis-derived outer membrane vesicles (OMVs) as a promising immunogen for improving pertussis vaccines. In this study, we evaluated the efficacy of our vaccine prototype in immunization strategies aimed at reducing disease transmission by targeting colonization in the upper airways while maintaining protection against severe disease by reducing colonization in the lower respiratory tract.MethodsWe assessed different mucosal administration strategies in a murine model, including homologous 2-dose schedules and heterologous prime-boost strategies combining intramuscular (IM) systemic immunization with mucosal routes (intranasal (IN) or sublingual (SL)). We utilized mucosal c-di-AMP and/or systemic alum adjuvants to formulate the OMV vaccine prototype. A homologous IM immunization schedule and commercial vaccines were used for comparison.ResultsAll tested heterologous schemes induced higher levels of specific IgG with significant avidity, as well as high levels of IgG1 and IgG2 compared, to corresponding homologous 2-dose schemes via mucosal routes (OMVIN-INor OMVSL-SL). High IgA levels were observed post-B. pertussischallenge following OMVIN-INtreatments and heterologous treatments where the second dose was administered via a mucosal route. Furthermore, schemes involving the intranasal route, whether in a homologous or heterologous scheme, induced the highest levels of IL-17 and IFN-γ. Accordingly, these schemes showed superior efficacy against nasal colonization than the commercial vaccines. Specifically, homologous intranasal immunization exhibited the highest protective capacity against nasal colonization while maintaining an excellent level of protection in the lower respiratory tract. To enhance the protective capacity against nasal colonization further, we conducted a comparative analysis of formulations containing different adjuvants (c-di-AMP, alum, or a combination of both) administered via homologous intranasal routes. These assays revealed that the use of alum, either alone or in combination with c-di-AMP, did not enhance the immune protective capacity.ConclusionsAll the experiments presented here highlight that the use of OMVs, regardless of the scheme utilized, with the exception of OMVSL-SL, outperformed acellular pertussis (aP) vaccines, achieving a greater reduction in bacterial colonization in the upper respiratory tract (p<0.001).
Sequence composition and conservation predict the phenotypic relevance of transposable elements
Authors: Cerruti Yari , Fusco Daniela , Jahanbin Mahdis , Marnetto Davide , Provero Paolo 
Published: March 2024

AbstractTransposable elements (TEs) are powerful drivers of genome evolution, in part through their ability to rapidly rewire the host regulatory network by creating transcription factor binding sites that can potentially be turned to the host’s advantage in a process called exaptation. However, the effects on the host phenotype vary widely among different TEs. Here, we classify TEs based on their contribution to the human host phenotypes at both molecular and macroscopic scales. TE contributions to chromatin accessibility, gene expression, and the heritability of complex traits are strongly correlated to each other, confirming that the main mechanism through which TEs affect the host phenotype is through the rewiring of the regulatory network. TE sequence and evolutionary features are able to explain a large fraction of the variance in phenotypic relevance, and in particular more than 50% of the variance of their contribution to the heritability of complex traits. A conspicuous exception to this pattern is represented by TEs of the ERV1 family, whose phenotypic impact cannot be explained by our model: In particular, this family includes a set of relatively young TEs whose phenotypic relevance is much larger than would be expected based on their sequence and evolutionary parameters. These TEs are involved in fast-evolving biological processes related to the interaction of the organism with its environment. In conclusion, our results confirm quantitatively that TE insertions affect the host phenotype mostly through the rewiring of its regulatory network; identify a signature of phenotypic relevance based on sequence and conservation properties; and highlight several TEs as promising candidates for functional studies.
miRNA circuit modules for precise, tunable control of gene expression
Authors: Du Rongrong , Flynn Michael J. , Honsa Monique , Jungmann Ralf , Elowitz Michael B. 
Published: March 2024

AbstractThe ability to express transgenes at specified levels is critical for understanding cellular behaviors, and for applications in gene and cell therapy. Transfection, viral vectors, and other gene delivery methods produce varying protein expression levels, with limited quantitative control, while targeted knock-in and stable selection are inefficient and slow. Active compensation mechanisms can improve precision, but the need for additional proteins or lack of tunability have prevented their widespread use. Here, we introduce a toolkit of compact, synthetic miRNA-based circuit modules that provide precise, tunable control of transgenes across diverse cell types. These circuits, termed DIMMERs (Dosage-Invariant miRNA-Mediated Expression Regulators) use multivalent miRNA regulatory interactions within an incoherent feed-forward loop architecture to achieve nearly uniform protein expression over more than two orders of magnitude variation in underlying gene dosages or transcription rates. They also allow coarse and fine control of expression, and are portable, functioning across diverse cell types. In addition, a heuristic miRNA design algorithm enables the creation of orthogonal circuit variants that independently control multiple genes in the same cell. These circuits allowed dramatically improved CRISPR imaging, and super-resolution imaging of EGFR receptors with transient transfections. The toolbox provided here should allow precise, tunable, dosage-invariant expression for research, gene therapy, and other biotechnology applications.One sentence descriptionCompact synthetic miRNA-based regulatory circuits enable tunable, orthogonal, and generalizable dosage-invariant gene expression control for research and biotechnology.
HemaCisDB: An Interactive Database for Analyzing Cis-Regulatory Elements Across Hematopoietic Malignancies
Authors: Cai Xinping , Zhang Qianru , Liu Bolin , Sun Lu , Liu Yuxuan 
Published: March 2024

AbstractNoncoding cis-regulatory elements (CREs), such as transcriptional enhancers, are key regulators of gene expression programs. Accessible chromatin and H3K27ac are well-recognized markers for CREs associated with their biological function. Deregulation of CREs is commonly found in hematopoietic malignancies yet the extent to which CRE dysfunction contributes to pathophysiology remains incompletely understood. Here, we developed HemaCisDB, an interactive, comprehensive, and centralized online resource for CRE characterization across hematopoietic malignancies, serving as a useful resource for investigating the pathological roles of CREs in blood disorders. Currently, we collected 922 ATAC-seq, 190 DNase-seq, and 531 H3K27ac ChIP-seq datasets from patient samples and cell lines across different myeloid and lymphoid neoplasms. HemaCisDB provides comprehensive quality control metrics to assess ATAC-seq, DNase-seq, and H3K27ac ChIP-seq data quality. The analytic modules in HemaCisDB include transcription factor (TF) footprinting inference, super-enhancer identification, and core transcriptional regulatory circuitry analysis. Moreover, HemaCisDB also enables the study of TF binding dynamics by comparing TF footprints across different disease types or conditions via web-based interactive analysis. Together, HemaCisDB provides an interactive platform for CRE characterization to facilitate mechanistic studies of transcriptional regulation in hematopoietic malignancies. HemaCisDB is available athttps://hemacisdb.chinablood.com.cn/.
Katanin, kinesin-13 and ataxin-2 inhibit premature interaction between maternal and paternal genomes inC. eleganszygotes
Authors: Beath Elizabeth A. , Bailey Cynthia , Magadum Meghana Mahantesh , Qiu Shuyan , McNally Karen L. , McNally Francis J. 
Published: March 2024

AbstractFertilization occurs before completion of oocyte meiosis in the majority of animal species and sperm contents move long distances within zygotes of mouse andC. elegans. If incorporated into the meiotic spindle, paternal chromosomes could be expelled into a polar body resulting in lethal monosomy. Through live imaging of fertilization inC. elegans, we found that the microtubule disassembling enzymes, katanin and kinesin-13 limit long range movement of sperm contents and that maternal ataxin-2 maintains paternal DNA and paternal mitochondria as a cohesive unit that moves together. Depletion of katanin or double depletion of kinesin-13 and ataxin-2 resulted in capture of the sperm contents by the meiotic spindle. Thus limiting movement of sperm contents and maintaining cohesion of sperm contents within the zygote both contribute to preventing premature interaction between maternal and paternal genomes.
Phosphoproteomic analysis reveals the diversity of signaling behind ErbB inhibitor-induced phenotypes
Authors: Vaparanta Katri , Jokilammi Anne , Merilahti Johannes , Örling Johanna , Virtanen Noora , Sahlgren Cecilia , Elenius Klaus , Paatero Ilkka 
Published: March 2024

AbstractThe impact of kinase inhibitors on the phosphoproteome has been rarely investigated at a whole organism level. Here we performed a phosphoproteomic analysis in embryonic zebrafish to identify the signaling pathways perturbed by ErbB receptor tyrosine kinase inhibitors at the organism level. The phosphorylation of proteins associated with the PI3K/Akt, p38 MAPK, Notch, Hippo/Yap and β-catenin signaling pathways were differentially regulated by the ErbB inhibitors. Gene set enrichment analyses indicated differential neurological and myocardial phenotypes of different ErbB inhibitors. To assess the neurological and myocardial effects, motility and ventricle growth assays were performed on zebrafish embryos treated with the ErbB and downstream signaling pathway inhibitors. The treatment with the inhibitors targeting the PI3K/Akt, p38 MAPK, and Notch signaling pathways along with the ErbB inhibitors AG1478 and Lapatinib perturbed the overall movement and ventricle wall growth of zebrafish embryos. Taken together, these results indicate that inhibitors with the same primary targets can affect different signaling pathways while eliciting similar physiological phenotypes.
Initial Learning in the Brain: From Rules to Action
Authors: Fregni Sofia , Wolfensteller Uta , Ruge Hannes 
Published: March 2024

AbstractWe used fMRI to investigate the neural changes and representational dynamics associated with different learning modes during initial learning and subsequent implementation of previously acquired stimulus-response (S-R) associations. We compared instruction-based learning (INS) and trial-and-error learning (TE) via a third observation-based learning (OBS) condition. This was yoked to the TE condition and shared features with both, the INS and TE conditions. During learning, neural changes were observed in the Frontoparietal and Default Mode Networks across learning modes, consistent with a general decrease in cognitive control demand as learning progresses. INS and TE exhibited condition-specific signal changes, which we interpreted in the context of covert motor preparation during INS, and intentional action and increased cognitive control demand during early TE trials, respectively. Multivariate pattern analysis revealed individual rule information in bilateral prefrontal, premotor, and parietal cortices across learning modes. Most regions revealed consistent representations of individual S-R rules between the learning stage and subsequent implementation stage, regardless of the learning mode. This suggests that initially formed S-R rule representations guide task performance during S-R rule implementation, irrespective of how they are acquired. Finally, within the primary motor cortex, individual S-R rules were decodable during the learning stage not only when motor responses were overtly executed, as in TE, but also in the absence of overt motor execution, as in INS. This finding substantiates previous claims of covert motor preparatory mechanisms during INS.
Cdonis required for organ Left-Right patterning via regulating DFCs migration and the sequential ciliogenesis
Authors: Deng Zhilin , Chang Wenqi , Li Chengni , Li Botong , Huang Shuying , Huang Jingtong , Zhang Ke , Li Yuanyuan , Liu Xingdong , Ran Qin , Guo Zhenhua , Huang Sizhou 
Published: March 2024

AbstractCdonandbocare members of the cell adhesion molecule subfamily III Ig/fibronectin. Although they were reported to be involved in muscle and neural development at late developmental stage, while their early roles in embryonic development are unknown. Here we discovered that zebrafishcdonbut notbocwas expressed in dorsal forerunner cells (DFCs) and epitheliums of Kupffer’s vesicle (KV), implying the possible role ofcdonin organ LR patterning. Further data showed that the liver and heart LR patterning was disturbed incdonmorphants andcdonmutants. Mechanically, we found thatcdonloss of function led to dispersed DFCs migration, smaller KV and defective ciliogenesis, which resulting in randomizedNodal/spawsignaling and the sequential organ LR patterning defect. Finally, predominant distribution of acdonMO in DFCs led to defects in DFCs migration, KV morphogenesis/ciliogenesis,Nodal/spawsignaling and organ LR asymmetry, being similar to those incdonmorphants andcdon-/-embryos, indicating a cell-autonomous role ofcdonin regulating KV formation and ciliogenesis during LR patterning. In conclusion, our data demonstrated that, during gastrulation stage and early somitogenesis stage,cdonis required for proper DFCs migration, KV formation and ciliogenesis, thus playing an important role in setting up organ LR asymmetry.