bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gut microbial and human genetic signatures of inflammatory bowel disease increase risk of comorbid mental disorders
Authors: Lee Junho , Oh Shin Ju , Ha Eunji , Shin Ga Young , Kim Hyo Jong , Kim Kwangwoo , Lee Chang Kyun 
Published: December 2023

AbstractThe high prevalence of comorbid mental disorders (CMDs), such as anxiety and depression, in patients with inflammatory bowel disease (IBD) is well documented. The reported bidirectional relationship between the two conditions suggests a crucial role of a gut-brain axis in CMD development in patients with IBD. This study aimed to investigate a complex interplay between gut microbiota and host genetic variants relevant to the development of CMDs in IBD. Genome-wide variant data, gut metagenomic data, and/or anxiety/depression estimates were obtained from 507 patients with IBD and 75 healthy controls. A series of integrative analyses were performed, profiling gut microbial diversity, microbial abundance, polygenic risk score, microbial quantitative trait locus (mbQTL), and microbial IBD-risk score. Patients with IBD had significantly lower gut microbial alpha diversity than controls, particularly those with CMD. Beta diversity revealed that a large fraction of IBD-associated taxa contributing to the top principal component were potentially associated with CMD risk. We identified 146 significantly differentially abundant taxa (DATs) between IBD patients and controls, and 48 DATs between CMD-free and CMD-affected IBD patients, with the majority showing consistent changes in abundance between IBD and CMD. Microbial IBD-risk scores, developed to estimate the degree of microbial IBD-specific burden in each individual, supported a significant enrichment of IBD-risk signatures in CMD-affected patients. Additionally, we found an IBD-risk mbQTL for an IBD/CMD-associated DAT, implicating an interplay between IBD-risk variants and gut dysbiosis in the development of both IBD and CMD. Collectively, IBD-associated gut dysbiosis predominantly confers risk of CMD in IBD patients partially through genetic variant-mediated regulation.
The curvilinear relationships between grand parity and incidence of hormone-dependent cancers; follow-up of postmenopausal women in the Norwegian 1960 Census
Authors: Lund Eiliv , Busund Lill-Tove Rasmussen , Holden Lars 
Published: December 2023

AbstractBreast, ovarian and endometrial cancers are named hormone dependent cancers (HDC) because of the effects of endogenous hormones, including parity, on the incidence rates. Here, we will test the hypothesis that each additional child has the same relative preventive effect on the risk of each of the three cancer sites and with similar shapes of the incidence curves over the extended exposure range, 1 - 18 children in postmenopausal women.The study is based on parity information from the Norwegian 1960 Census for women aged 45-89 years. A total of 385 816 married women answered the question of number of children in present marriage to a civil servant. Follow-up continued until the first of any of the HDC diagnosis, death, or end of follow-up 2005 through linkages based on the unique Norwegian birth number. Included were 16 905 breast cancers, 3 827 ovarian cancers and 3 834 endometrial cancers. Based on person-years (PY), the percentage change in incidence rates of the three cancer sites for each additional child was calculated using a logit regression model including models with higher order terms. A new statistical method for analyses of collinearity between parity and age at first birth has been developed. Age at marriage was used as a proxy for age at first birth.Parity had strong linear effects on the incidence rates for all three cancer sites (p<2e-16). The percentage decrease for each of the cancer diagnosis for an additional child were for breast cancer 10.5% (95% CI; 9.6-11.4), ovarian cancer 13.2% (11.2-15.3) and endometrial cancer 10.9% (8.9-12.8) with similar curvilinear relationship. Models with higher order terms gave slightly better fit to the data with a stronger protective effect for increasing parity on ovarian cancers, while for breast cancer age became more important. Combining the incidence of all three cancers gave a percentage decrease for each additional child of 11.0% (10.1-11.8). The risk for HDC cancer was reduced with earlier age at marriage (first birth) for women with 1-2 children for breast cancer and ovarian cancer and 1 child for endometrial cancer, but the effect was smaller than one additional child. Age of the women at marriage was not significant for the sum of the three cancers.The study demonstrated the strong, regular protective effect of each additional child or full-term pregnancy on the incidence rates of the hormone-dependent cancers throughout the exposure range and with similar curvilinear relations. Reduced fertility is a common, strong etiological factor for the three hormone-dependent cancers in postmenopausal women. These findings support a hypothesis that similar immunological changes during each pregnancy could be the biological explanation.
A novel human model to deconvolve cell-intrinsic phenotypes of genetically dysregulated pathways in lung squamous cell carcinoma
Authors: Ogden Julia , Sellers Robert , Sahoo Sudhakar , Oojageer Anthony , Chaturvedi Anshuman , Dive Caroline , Lopez-Garcia Carlos 
Published: December 2023

ABSTRACTTractable, patient relevant models are needed to investigate cancer progression and heterogeneity. Here, we report an alternative and unique in vitro model of lung squamous cell carcinoma (LUSC) using primary human bronchial epithelial cells (hBECs) from three healthy donors. The co-operation of ubiquitous alterations (TP53andCDKN2Aloss) and components of commonly deregulated pathways including squamous differentiation (SOX2), PI3K signalling (PTEN) and the oxidative stress response (KEAP1) was investigated by generating hBECs harbouring cumulative alterations. Our analyses confirmed thatSOX2-overexpression initiates early preinvasive LUSC stages, and co-operation with the oxidative stress response and PI3K pathways to drive more aggressive phenotypes, with expansion of cells expressing LUSC biomarkers and invasive properties. This cooperation was consistent with the classical LUSC subtype. Importantly, we connected pathway dysregulation with gene expression changes associated with cell-intrinsic processes and immunomodulation. Our approach constitutes a powerful system to model LUSC and unravel genotype-phenotype causations of clinical relevance.
A Comparative Analysis of Imaging-Based Spatial Transcriptomics Platforms
Authors: Cook David P. , Jensen Kirk B. , Wise Kellie , Roach Michael J. , Dezem Felipe Segato , Ryan Natalie K. , Zamojski Michel , Vlachos Ioannis S. , Knott Simon R. V. , Butler Lisa M. , Wrana Jeffrey L. , Banovich Nicholas E. , Plummer Jasmine T. , Martelotto Luciano G. 
Published: December 2023

AbstractSpatial transcriptomics is a rapidly evolving field, overwhelmed by a multitude of technologies. This study aims to offer a comparative analysis of datasets generated from leadingin situimaging platforms. We have generated spatial transcriptomics data from serial sections of prostate adenocarcinoma using the 10x Genomics Xenium and NanoString CosMx SMI platforms. Additionally, orthogonal single-nucleus RNA sequencing (snRNA-seq) was performed on the same FFPE tissue to establish a reference for the tumor’s transcriptional profiles. We assessed various technical aspects, such as reproducibility, sensitivity, dynamic range, cell segmentation, cell type annotation, and congruence with single-cell profiling. The practicality of assessing cellular organization and biomarker localization was evaluated. Although fewer genes are measured (CosMx: 960, Xenium: 377, with an overlap of 125), Xenium consistently demonstrates higher sensitivity, a broader dynamic range, and better alignment with single-cell reference profiles. Conversely, CosMx’s out-of-the-box segmentation outperformed Xenium’s, resulting in noticeable transcript misassignment in Xenium within certain tissue areas. However, the impact of this on the cells’ transcriptional profile was minimal. Together, this comprehensive comparison of two leading commercial platforms for spatial transcriptomics provides essential metrics for assessing their performance, offering invaluable insights for future research and technological advancements in this dynamic field.
Analysis of clinicalCandida parapsilosisisolates reveals copy number variation in key fluconazole resistance genes
Authors: Bergin Sean , Doorley Laura A. , Rybak Jeffrey M. , Wolfe Kenneth H. , Butler Geraldine , Cuomo Christina A. , Rogers P. David 
Published: December 2023

AbstractWe used whole-genome sequencing to analyse a collection of 35 fluconazole resistant and 7 susceptibleCandida parapsilosisisolates together with coverage analysis and GWAS techniques to identify new mechanisms of fluconazole resistance. Phylogenetic analysis shows that although the collection is diverse, two probable outbreak groups were identified. We identified copy number variation of two genes,ERG11andCDR1B, in resistant isolates. Two strains have a CNV at theERG11locus; the entire ORF is amplified in one, and only the promoter region is amplified in the other. We show the annotated telomeric geneCDR1Bis actually an artefactualin silicofusion of two highly similar neighbouringCDRgenes due to an assembly error in theC. parapsilosisCDC317 reference genome. We report highly variable copy numbers of theCDR1Bregion across the collection. Several strains have increased expansion of the two genes into a tandem array of new chimeric genes. Other strains have experienced a deletion between the two genes creating a single gene with a reciprocal chimerism. We find translocations, duplications, and gene conversion across theCDRgene family in theC. parapsilosisspecies complex, showing that it is a highly dynamic family.
Peroxiredoxinylation buffers the redox state of the proteome upon cellular stress
Authors: Seisenbacher Gerhard , Raguz Nakic Zrinka , Borràs Eva , Sabidó Eduard , Sauer Uwe , de Nadal Eulalia , Posas Francesc 
Published: December 2023

AbstractThe redox state of proteins is essential for their function and guarantees cell fitness. Peroxiredoxins protect cells against oxidative stress, maintain redox homeostasis, act as chaperones and transmit hydrogen peroxide signals to redox regulators. Despite the profound structural and functional knowledge of peroxiredoxins action, information on how the different functions are concerted is still scare. Using global proteomic analyses, we show here that the yeast peroxiredoxin Tsa1 binds hundreds of proteins of essential biological processes, including protein turnover and carbohydrate metabolism. Several of these interactions are of covalent nature and failure of this peroxiredoxinylation leads to global changes in the metabolome and reduced stress resistance. Thioredoxins directly remove TSA1-formed mixed disulfide intermediates, thus expanding the role of the thioredoxin-peroxiredoxin redox cycle pair to buffer the redox state of proteins in an unprecedented way.
Massively parallel base editing screens to map variant effects on anti-tumor hallmarks of primary human T cells
Authors: Walsh Zachary H. , Shah Parin , Kothapalli Neeharika , Nikolenyi Gergo , Shah Shivem B. , Leuzzi Giuseppe , Mu Michael , Ho Patricia , Abuzaid Sinan , Brodtman Zack D. , Vasan Neil , AlQuraishi Mohammed , Milner Joshua D. , Ciccia Alberto , Melms Johannes C. , Izar Benjamin 
Published: December 2023

ABSTRACTBase editing enables generation of single nucleotide variants, but large-scale screening in primary human T cells is limited due to low editing efficiency, among other challenges1. Here, we developed a high-throughput approach for high-efficiency and massively parallel adenine and cytosine base-editor screening in primary human T cells. We performed multiple large-scale screens editing 102 genes with central functions in T cells and full-length tiling mutagenesis of selected genes, and read out variant effects on hallmarks of T cell anti-tumor immunity, including activation, proliferation, and cytokine production. We discovered a broad landscape of gain- and loss-of-function mutations, including inPIK3CDand its regulatory subunit encoded byPIK3R1, LCK,AKT1, CTLA-4andJAK1. We identified variants that affected several (e.g.,PIK3CDC416R) or only selected (e.g.LCKY505C) hallmarks of T cell activity, and functionally validated several hits by probing downstream signaling nodes and testing their impact on T cell polyfunctionality and proliferation. Using primary human T cells in which we engineered a T cell receptor (TCR) specific to a commonly presented tumor testis antigen as a model for cellular immunotherapy, we demonstrate that base edits identified in our screens can tune specific or broad T cell functions and ultimately improve tumor elimination while exerting minimal off-target activity. In summary, we present the first large-scale base editing screen in primary human T cells and provide a framework for scalable and targeted base editing at high efficiency. Coupled with multi-modal phenotypic mapping, we accurately nominate variants that produce a desirable T cell state and leverage these synthetic proteins to improve models of cellular cancer immunotherapies.
Recombine and succeed: a story of Cry toxins to expand the host range
Authors: Shikov Anton E. , Alagov Ruslan O. , Nizhnikov Anton A. , Belousova Maria E. , Antonets Kirill S. 
Published: December 2023

AbstractBackgroundCry toxins are the most widely used sources of bioinsecticides in agriculture; therefore, improving their functionality requires a deep understanding of natural evolution. It is thought that Cry toxins emerge via domain III swapping, yet the underlying mechanism remains unclear.ResultsWe detected 50 recombination events using a dataset of 368 clusters representing a known diversity of Cry toxins using a computational analysis. Not only do domain swaps engage all the domains, but they also occur continuously with approximately 70% of toxins participating in domain exchanges. Once they happen, hybrid toxins face purifying selection pressure reflecting the advantageous nature of receiving novel domains. When these domain exchanges occur, their host specificity changes dramatically. Strains housing these loci are enriched withcrygenes and can kill a broader spectrum of hosts, thus implying that recombination allows them to occupy novel niches. The respective recombination-affectedcrygenes are flanked with insertions and harbor highly conservative blocks between the domains’ borders suggesting that the genomic context governs the intra-domain recombination.ConclusionsOur study expands the established views of the role of recombination in the emergence of Cry toxins. Here, we demonstrate that the domain exchanges shape both Cry sequences, the composition of toxins in bacterial strains, and the sets of hosts affected. The collected data allowed us to propose a mechanism for how these toxins originate. Overall, the results suggest that domain exchanges have a profound impact on Cry toxins being a major evolutionary driver.
New avenues for potentially seeking microbial responses to climate change beneath Antarctic ice shelves
Authors: Vicedo Aitana Llorenç , Gomez Monica Lluesma , Zeising Ole , Kleiner Thomas , Freitag Johannes , Martínez-Hernández Francisco J. , Wilhelms Frank , Martínez-García Manuel 
Published: December 2023

AbstractThe signs of climate change are undeniable, and the impact of these changes on ecosystem function heavily depends on the response of microbes that underpin the food web. Antarctic ice shelf is a massive mass of floating ice that extends from the continent into the ocean, exerting a profound influence on global carbon cycles. Beneath Antarctic ice shelves, marine ice stores valuable genetic information, where marine microbial communities before the industrial revolution are archived. Here, in this proof-of-concept, by employing a combination of single-cell genomics and metagenomics, we have been able to sequence frozen microbial DNA (≍300 years old) stored in the marine ice core B15 collected from the Filchnner-Ronne Ice Shelf. Metagenomic data indicated thatProteobacteriaandThaumarchaeota(e.g.Nitrosopumilus spp.) followed byActinobacteria(e.g. Actinomarinales) were abundant. Remarkably, our data allow us to ‘travel to the past’ and calibrate genomic and genetic evolutionary changes for ecologically relevant microbes and functions, such asNitrosopumilusspp., preserved in the marine ice (≍300 years old) with those collected recently in seawater under an ice shelf (year 2017). The evolutionary divergence for the ammonia monooxygenase geneamoAinvolved in chemolithoautotrophy was about 0.88 amino acid and 2.8 nucleotide substitution rate per 100 sites in a century, while the accumulated rate of genomic SNPs was 2,467 per 1 Mb of genome and 100 years. Whether these evolutionary changes remained constant over the last 300 years or accelerated during post-industrial periods remains an open question that will be further elucidated.ImportanceSeveral efforts have been undertaken to predict the response of microbes under climate change, mainly based on short-term microcosm experiments under forced conditions. A common concern is that manipulative experiments cannot properly simulate the response of microbes to climate change, which is a long-term evolutionary process. In this proof-of-concept study with a limited sample size, we demonstrate a novel approach yet to be fully explored in science for accessing genetic information from putative past marine microbes preserved under Antarctic Ice shelves before Industrial revolution. This potentially allow us estimating evolutionary changes as exemplified in our study. We advocate for gathering a more comprehensive Antarctic marine ice core datasets across various periods and sites. Such a dataset would enable the establishment of a robust baseline, facilitating a better assessment of the potential effects of climate change on key genetic signatures of microbes.
Persistence of backtracking by human RNA polymerase II
Authors: Yang Kevin B , Rasouly Aviram , Epshtein Vitaly , Martinez Criseyda , Nguyen Thao , Shamovsky Ilya , Nudler Evgeny 
Published: December 2023

SummaryRNA polymerase II (pol II) can backtrack during transcription elongation, exposing the 3’ end of nascent RNA. Nascent RNA sequencing can approximate the location of backtracking events that are quickly resolved; however, the extent and genome wide distribution of more persistent backtracking is unknown. Consequently, we developed a novel method to directly sequence the extruded, “backtracked” 3’ RNA. Our data shows that pol II slides backwards more than 20 nucleotides in human cells and can persist in this backtracked state. Persistent backtracking mainly occurs where pol II pauses near promoters and intron-exon junctions, and is enriched in genes involved in translation, replication, and development, where gene expression is decreased if these events are unresolved. Histone genes are highly prone to persistent backtracking, and the resolution of such events is likely required for timely expression during cell division. These results demonstrate that persistent backtracking has the potential to affect diverse gene expression programs.
Structure-Infused Protein Language Models
Authors: Peñaherrera Daniel , Koes David Ryan 
Published: December 2023

AbstractEmbeddings from protein language models (PLM’s) capture intricate patterns for protein sequences, enabling more accurate and efficient prediction of protein properties. Incorporating protein structure information as direct input into PLMs results in an improvement on the predictive ability of protein embeddings on downstream tasks. In this work we demonstrate that indirectly infusing structure information into PLMs also leads to performance gains on structure related tasks. The key difference between this framework and others is that atinference timethe model does not require access to structure to produce its embeddings.
Host E3 ubiquitin ligase ITCH mediatesToxoplasma gondiieffector GRA35-triggered NLRP1 inflammasome activation and cell-autonomous immunity
Authors: Wang Yifan , Hollingsworth L. Robert , Sangaré Lamba Omar , Paredes-Santos Tatiana C. , Krishnamurthy Shruthi , Penn Bennett H. , Wu Hao , Saeij Jeroen P. J. 
Published: December 2023

ABSTRACTToxoplasma gondiiis an intracellular parasite that can activate the NLRP1 inflammasome leading to macrophage pyroptosis in Lewis rats, but the underlying mechanism is not well understood. In this study, we performed a genome-wide CRISPR screen and identified the dense granule proteins GRA35, GRA42, and GRA43 as theToxoplasmaeffectors mediating cell death in Lewis rat macrophages. GRA35 localizes on the parasitophorous vacuole membrane, where it interacts with the host E3 ubiquitin ligase ITCH. Inhibition of proteasome activity or ITCH knockout prevented pyroptosis inToxoplasma-infected Lewis rat macrophages, consistent with the “NLRP1 functional degradation model”. However, there was no evidence that ITCH directly ubiquitinates or interacts with rat NLRP1. We also found that GRA35-ITCH interaction affectedToxoplasmafitness in IFNγ-activated human fibroblasts, likely due to ITCH’s role in recruiting ubiquitin and the parasite-restriction factor RNF213 to the parasitophorous vacuole membrane. These findings identify a new role of host E3 ubiquitin ligase ITCH in mediating effector-triggered immunity, a critical concept that involves recognizing intracellular pathogens and initiating host innate immune responses.IMPORTANCEEffector-triggered immunity represents an innate immune defense mechanism that plays a crucial role in sensing and controlling intracellular pathogen infection. The NLRP1 inflammasome in the Lewis rats can detectToxoplasmainfection, which triggers proptosis in infected macrophages and eliminates the parasite’s replication niche. The work reported here revealed that host E3 ubiquitin ligase ITCH is able to recognize and interact withToxoplasmaeffector protein GRA35 localized on the parasite-host interface, leading to NLRP1 inflammasome activation in Lewis rat macrophages. Furthermore, ITCH-GRA35 interaction contributes to the restriction ofToxoplasmain human fibroblasts stimulated by IFNγ. Thus, this research provides valuable insights into understanding pathogen recognition and restriction mediated by host E3 ubiquitin ligase.