bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blood and tissue correlates of steroid non-response in checkpoint inhibition-induced immune-related adverse events
Authors: van Eijs Mick J.M. , van der Wal M. Marlot , Klotškova Hedi-Britt , Dautzenberg Noël M.M. , Schuiveling Mark , Verheijden Rik J. , van Schaik Fiona D.M. , Oldenburg Bas , Nierkens Stefan ,   the UNICIT Consortium, Suijkerbuijk Karijn P.M. , van Wijk Femke 
Published: December 2024

AbstractHigh-dose steroids constitute the cornerstone of first-line treatment for immune-related adverse events (irAEs) associated with immune checkpoint inhibitors, but compromise antitumor immunity. A deeper understanding of irAEs and their response to steroids can contribute to more targeted irAE management regimens. We took a multi-omics approach to identify blood- and tissue-based predictors of steroid response and to explore underlying mechanisms of steroid non-response in irAEs. In the blood, steroid non-response correlated with trends for elevated Tc1/Tc17 CD8+T cells and serum interleukin (IL)-17, IL-6, IL-12 and IL-23 prior to initiation of steroids, along with persistent (CD8+) T cell proliferation and activation after start of steroids. A remarkably fast decrease in inflammatory gene signatures and lymphocyte infiltration was observed in colitis tissue of steroid responders obtained within 24h after initiation of steroids. Peripheral T cell PD-1 receptor occupancy was not associated with steroid response. Colitis tissue of steroid non-responders was enriched for activated CD4+memory T cells and a pronounced type 1/17 immune response. Together, our findings suggest rapid immunological effects of steroids in circulating cells and irAE-affected tissue and support that an enhanced type 1/type 17 response is associated with steroid non-response in irAEs.
Understanding and overcoming innate and acquired MAPK-inhibition resistance in anaplastic thyroid cancer
Authors: Zeng Peter YF , Meens Jalna , Pan Harrison , Cecchini Matthew J. , Jarycki Laura , Ryan Sarah B. , Dawson Alice E. , Karimi Amir , Shaikh Mushfiq H. , Palma David A. , Winquist Eric , Gunaratnam Laksman , Mymryk Joe S. , Barrett John W. , Boutros Paul C. , Ailles Laurie , Nichols Anthony C. 
Published: December 2024

AbstractAnaplastic thyroid cancer (ATC) is one of the most lethal human cancers, with some patients succumbing to the disease within weeks of diagnosis. Although a subset of patients with ATC with BRAFV600Emutation respond to the monomeric type I RAF inhibitor (RAFi) dabrafenib in combination with MEK inhibitor (MEKi) trametinib, most rapidly develop adaptive or acquired resistance. These patients, along with those who do not harbor the BRAFV600Ealteration, have limited treatment options. To understand the mechanism of resistance to dabrafenib and trametinib, we utilized multi-region whole genome, high-coverage whole exome and single nuclei RNA-sequencing of ATC patient tumours to unravel genomic, transcriptomic, and microenvironmental evolution during type I RAFi and MEKi therapy. Single-cell nuclei RNA sequencing of matched primary and resistant ATC patient tumours identified reactivation of the MAPK-pathway, along with immunosuppressive macrophage proliferation, underlying the development of acquired resistance. Our translational genomics led us that hypothesize that type II RAFi, which inhibit both RAF monomers and dimers, can be efficacious in overcoming treatment resistance. Screening of a panel of type II RAFi revealed that ATC cell lines are exquisitely sensitive to the type II RAFi, naporafenib, by inhibiting EphA2-mediated MAPK-signaling. We further demonstrated that naporafenib, in combination with the MEKi trametinib, can durably and robustly overcome both innate and acquired treatment resistance to dabrafenib and trametinib using ATC cell lines and patient-derived xenograft models. Finally, we describe a novel mechanism of acquired resistance to type II RAFi and MEKi through compensatory mutations inMAST1. Taken together, our work using translational and functional genomics has unraveled the differential mechanisms of treatment resistance to type I and type II RAFi in combination with trametinib and rationalizes the clinical investigation of type II RAFi in the setting of thyroid cancer.
Effects of contrast-medium and vertebral measurement level on computed tomography-based body composition parameters of skeletal muscle and adipose tissue
Authors: Akamatsu Nobuhiko , Gonoi Wataru , Hanaoka Shouhei , Inui Shohei , Kurokawa Mariko , Taguchi Satoru , Sugawara Kotaro , Kume Haruki , Abe Osamu 
Published: December 2024

AbstractObjectiveTo comprehensively evaluate the effects of contrast-medium administration and measurement level (L3 and L1) on computed tomography (CT) derived body composition parameters, promising prognostic factors for various diseases.Methods203 dynamic contrast-enhanced CT examinations, including unenhanced (phase 0) and early arterial, late arterial, portal, and equilibrium phases (phases 1-4, respectively), were retrospectively enrolled in the study. Areas and mean densities of skeletal muscle (SMA and MSMD), subcutaneous adipose tissue (SATA and MSATD), and visceral adipose tissue (VATA and MVATD) were measured at L3 and L1 levels across five phases (phase 0–4). Measurement changes among phases and levels were assessed statistically.ResultsThe rates of SMA, SATA, and VATA on phase 1/2/3/4 compared to those on phase 0 were as follows: L3 SMA +1.1%/+2.1%/+2.8%/+3.5%; L1 SMA, +2.0%/+2.7%/+3.0%/+3.7%; L3 SATA −0.4%/−1.9%/−2.9%/−4.7%; L1 SATA −0.3%/−2.2%/−3.5%/−6.1%; L3 VATA −7.5%/−17.8%/−20.0%/−22.2%; L1 VATA −8.5%/−20.1%/−22.6%/−23.7%. Differences of MSMD, MSATD, and MVATD on phase 1/2/3/4 between those on phase 0 were as follows (Hounsfield Units): L3 MSMD, +2.1/+5.8/+7.8/+9.6; L1 MSMD, +2.9/+7.7/+9.1/+9.8; L3 MSATD, +1.2/+3.7/+4.8/+6.2; L1 MSATD, +1.2/+3.8/+4.7/+5.6; L3 MVATD, +1.5/+4.1/+5.2/+6.1; L1 MVATD, +1.9/+4.9/+5.8/+6.3. The values between L3 and L1 showed a linear solid correlation (coefficient of determination, 0.950–0.999), suggesting interchangeability.ConclusionChanges in body composition parameters measured in various contrast phases and two dominant body levels were comprehensively elucidated, promoting the interchangeability of cohorts with mixed CT conditions.
Genome-wide Machine Learning Analysis of Anosmia and Ageusia with COVID-19
Authors: Pietan Lucas , Phillippi Elizabeth , Melo Marcelo , El-Shanti Hatem , Smith Brian J , Darbro Benjamin , Braun Terry , Casavant Thomas 
Published: December 2024

ABSTRACTThe COVID-19 pandemic has caused substantial worldwide disruptions in health, economy, and society, manifesting symptoms such as loss of smell (anosmia) and loss of taste (ageusia), that can result in prolonged sensory impairment. Establishing the host genetic etiology of anosmia and ageusia in COVID-19 will aid in the overall understanding of the sensorineural aspect of the disease and contribute to possible treatments or cures. By using human genome sequencing data from the University of Iowa (UI) COVID-19 cohort (N=187) and the National Institute of Health All of Us (AoU) Research Program COVID-19 cohort (N=947), we investigated the genetics of anosmia and/or ageusia by employing feature selection techniques to construct a novel variant and gene prioritization pipeline, utilizing machine learning methods for the classification of patients. Models were assessed using a permutation-based variable importance (PVI) strategy for final prioritization of candidate variants and genes. The highest held-out test set area under the receiver operating characteristic (AUROC) curve for models and datasets from the UI cohort was 0.735 and 0.798 for the variant and gene analysis respectively and for the AoU cohort was 0.687 for the variant analysis. Our analysis prioritized several novel and known candidate host genetic factors involved in immune response, neuronal signaling, and calcium signaling supporting previously proposed hypotheses for anosmia/ageusia in COVID-19.
GWAS highlights the neuronal contribution to multiple sclerosis susceptibility
Authors: Zeng Lu , Atlas Khan , Lama Tsering ,   the International Multiple Sclerosis Genetics Consortium, Chitnis Tanuja , Weiner Howard , Wang Gao , Fujita Masashi , Zipp Frauke , Taga Mariko , Kiryluk Krzysztof , De Jager Philip L. 
Published: December 2024

AbstractMultiple Sclerosis (MS) is a chronic inflammatory and neurodegenerative disease affecting the brain and spinal cord. Genetic studies have identified many risk loci, that were thought to primarily impact immune cells and microglia. Here, we performed a multi-ancestry genome- wide association study with 20,831 MS and 729,220 control participants, identifying 236 susceptibility variants outside the Major Histocompatibility Complex, including four novel loci. We derived a polygenic score for MS and, optimized for European ancestry, it is informative for African-American and Latino participants. Integrating single-cell data from blood and brain tissue, we identified 76 genes affected by MS risk variants. Notably, while T cells showed the strongest enrichment, inhibitory neurons emerged as a key cell type, highlighting the importance of neuronal and glial dysfunction in MS susceptibility.
Ubiquitin Ligase ITCH Regulates Life Cycle of SARS-CoV-2 Virus
Authors: Xiang Qiwang , Wouters Camille , Chang Peixi , Lu Yu-Ning , Liu Mingming , Wang Haocheng , Yang Junqin , Pekosz Andrew , Zhang Yanjin , Wang Jiou 
Published: December 2024

AbstractSARS-CoV-2 infection poses a major threat to public health, and understanding the mechanism of viral replication and virion release would help identify therapeutic targets and effective drugs for combating the virus. Herein, we identified E3 ubiquitin-protein ligase Itchy homolog (ITCH) as a central regulator of SARS-CoV-2 at multiple steps and processes. ITCH enhances the ubiquitination of viral envelope and membrane proteins and mutual interactions of structural proteins, thereby aiding in virion assembly. ITCH-mediated ubiquitination also enhances the interaction of viral proteins to the autophagosome receptor p62, promoting their autophagosome-dependent secretion. Additionally, ITCH disrupts the trafficking of the protease furin and the maturation of cathepsin L, thereby suppressing their activities in cleaving and destabilizing the viral spike protein. Furthermore, ITCH exhibits robust activation during the SARS-CoV-2 replication stage, and SARS-CoV-2 replication is significantly decreased by genetic or pharmacological inhibition of ITCH. These findings provide new insights into the mechanisms of the SARS-CoV-2 life cycle and identify a potential target for developing treatments for the virus-related diseases.
Cryo-EM reveals that cardiac IGLV6-derived AL fibrils can be polymorphic
Authors: Bassett Parker , Nguyen Binh A. , Singh Virender , Garrett Patrick T. , Moresco James J. , Kaur Gurbakhash , Afrin Shumaila , Pękała Maja , Saelices Lorena 
Published: December 2024

ABSTRACTAL amyloidosis is a systemic disease caused by the aggregation of free antibody light chains (LC) secreted by aberrant plasma cell clones into the bloodstream. These LC aggregates form amyloid fibrils that deposit in multiple organs, leading to organ failure and, ultimately, death. Investigating the structural basis of LC aggregation is a critical avenue for understanding the biopathology of AL amyloidosis. Structural insights into AL fibril formation may reveal mechanisms driving amyloid deposition and inspire novel therapeutic strategies. Previous studies using cryo-electron microscopy have uncovered diverse AL fibril structures extracted from multiple patients, highlighting variability in fibril architecture. Here, we present a novel cryo-EM structure of AL cardiac fibrils from a patient with AL amyloidosis. This structure reveals a unique fibril fold and the coexistence of multiple morphologies, including single- and double-protofilament forms. Notably, some of these double-protofilament fibrils exhibit an uncommon rotational symmetry, raising intriguing questions about the mechanisms governing fibril formation and evolution over time.
High-Throughput Epigenetic Profiling Immunoassays for Accelerated Disease Research and Clinical Development
Authors: Van den Ackerveken Priscilla , Hannart Clotilde , Pamart Dorian , Varsebroucq Robin , Wargnies Marion , Thiry Olivia , Lurkin Marie , Vincent Séverine , Chapelier Muriel , Rommelaere Guillaume , Herzog Marielle 
Published: December 2024

AbstractEpigenetics which examines the regulation of genes without modification of the DNA sequence, plays a crucial role in various biological processes and disease mechanisms. Among the different forms of epigenetic modifications, histone post-translational modifications (PTMs) are important for modulating chromatin structure and gene expression. Aberrant levels of histone PTMs are implicated in a wide range of diseases, including cancer, making them promising targets for biomarker discovery and therapeutic intervention. In this context, blood, tissues, or cells serve as valuable resources for epigenetic research and analysis. Traditional methods such as mass spectrometry and western blotting are widely used to study histone PTMs, providing qualitative and (semi)quantitative information. However, these techniques often face limitations that could include throughput and scalability, particularly when applied to clinical samples. To overcome these challenges, we developed and validated 13 Nu.Q® immunoassays to detect and quantify specific histone PTM-nucleosomes from K2EDTA plasma samples. Then, we tested these assays on other types of samples, including chromatin extracts from frozen tissues, as well as cell lines and white blood cells Our findings demonstrate that the Nu.Q®assays offer high specificity, sensitivity, precision and linearity, making them effective tools for epigenetic profiling. A comparative analysis of HeLa cells using mass spectrometry, Western blot, and Nu.Q®immunoassays revealed a consistent histone PTMs signature, further validating the effectiveness of these assays. Additionally, we successfully applied Nu.Q®assays across various biological samples, including human tissues from different organs and specific white blood cell subtypes, highlighting their versatility and applicability in diverse biological contexts.
Molecular cloning and host range analysis of three cytomegaloviruses fromMastomys natalensis
Authors: Staliunaite Laura , Puhach Olha , Ostermann Eleonore , Rosenke Kyle , Nichols Jenna , Oestereich Lisa , Feldmann Heinz , Davison Andrew J. , Jarvis Michael A. , Brune Wolfram 
Published: December 2024

AbstractHerpesvirus-based vectors are attractive for use as conventional or transmissible vaccines against emerging zoonoses in inaccessible animal populations. In both cases, cytomegaloviruses as members of the subfamilyBetaherpesvirinaeare particularly suitable for vaccine development as they are highly specific for their natural host species, infect a large proportion of their host population, and cause mild infections in healthy individuals. The Natal multimammate mouse (Mastomys natalensis) is the natural reservoir of Lassa virus, which causes deadly hemorrhagic fever in humans.M. natalensiswas recently reported to harbor at least three different cytomegaloviruses (MnatCMV1, MnatCMV2 and MnatCMV3). Herein, we report the molecular cloning of three complete MnatCMV genomes in a yeast and bacterial artificial chromosome (YAC-BAC) hybrid vector. Purified viral genomes were cloned in yeast by single-step transformation-associated recombination (STAR cloning) and subsequently transferred toEscherichia colifor further genetic manipulation. Integrity of the complete cloned viral genomes was verified by sequencing, and replication fitness of viruses reconstituted from these clones was analyzed by replication kinetics inM. natalensisfibroblasts and kidney epithelial cells. We also found that neither parental nor cloned MnatCMVs replicated in mouse and rat fibroblasts, nor did they show sustained replication in baby hamster kidney cells, consistent with the expected narrow host range for these viruses. We further demonstrated that an exogenous sequence can be inserted by BAC-based mutagenesis between open reading frames M25 and m25.1 of MnatCMV2 without affecting replication fitnessin vitro, identifying this site as potentially suitable for the insertion of vaccine target antigen genes.ImportanceCytomegaloviruses recently discovered in the Natal multimammate mouse (Mastomys natalensis) are widespread within theM. natalensispopulation. Since these rodents also serve as natural hosts of the human pathogen Lassa virus (LASV), we investigated the potential suitability ofM. natalensisCMVs (MnatCMVs) as vaccine vectors. We describe the cloning of three different MnatCMV genomes as bacterial artificial chromosomes (BACs). Replicative capacity and species specificity of these BAC-derived MnatCMVs were analyzed in multiple cell types. We also identified a transgene insertion site within one of the MnatCMV genomes suitable for the incorporation of vaccine target antigens. Together, this study provides a foundation for the development of MnatCMVs as transmissible MnatCMV-based LASV vaccines to reduce LASV prevalence in hard-to-reachM. natalensispopulations and thereby zoonotic transmission to humans.
E-box independent chromatin recruitment turns MYOD into a transcriptional repressor
Authors: Nicoletti Chiara , Massenet Jimmy , Pintado-Urbanc Andreas P. , Connor Leah J. , Nicolau Monica , Sundar Swetha , Xu Mingzhi , Schmitt Anthony , Zhang Wenxin , Fang Zesen , Chan Tsz Ching Indigo , Tapscott Stephen J. , Cheung Tom H. , Simon Matthew D. , Caputo Luca , Puri Pier Lorenzo 
Published: December 2024

AbstractMYOD is an E-box sequence-specific basic Helix-Loop-Helix (bHLH) transcriptional activator that, when expressed in non-muscle cells, induces nuclear reprogramming toward skeletal myogenesis by promoting chromatin accessibility at previously silent loci. Here, we report on the identification of a previously unrecognized property of MYOD as repressor of gene expression, via E-box-independent chromatin binding within accessible genomic elements, which invariably leads to reduced chromatin accessibility. MYOD-mediated repression requires the integrity of functional domains previously implicated in MYOD-mediated activation of gene expression. Repression of mitogen-and growth factor-responsive genes occurs through promoter binding and requires a highly conserved domain within the first helix. Repression of cell-of-origin/alternative lineage genes occurs via binding and decommissioning of distal regulatory elements, such as super-enhancers (SE), which requires the N-terminal activation domain as well as two chromatin-remodeling domains and leads to reduced strength of CTCF-mediated chromatin interactions. Surprisingly, MYOD-mediated chromatin compaction and repression of transcription do not associate with reduction of H3K27ac, the conventional histone mark of enhancer or promoter activation, but with reduced levels of the recently discovered histone H4 acetyl-methyl lysine modification (Kacme). These results extend MYOD biological properties beyond the current dogma that restricts MYOD function to a monotone transcriptional activator and reveal a previously unrecognized functional versatility arising from an alternative chromatin recruitment through E-box or non-E-box sequences. The E-box independent repression of gene expression by MYOD might provide a promiscuous mechanism to reduce chromatin accessibility and repress cell-of-origin/alternative lineage and growth factor/mitogen-responsive genes to safeguard the integrity of cell identity during muscle progenitor commitment toward the myogenic lineage.
The capsule and genetic background, rather than specific loci, strongly influence pneumococcal growth kinetics
Authors: Chaguza Chrispin , Arends Daan W. , Lo Stephanie W. , Putri Indri Hapsari , York Anna , Lees John A. , Wyllie Anne L. , Weinberger Daniel M. , Bentley Stephen D. , de Jonge Marien I. , Cremers Amelieke J.H. 
Published: December 2024

AbstractBacterial growth characteristics intrinsic to each strain can impact and influence gene expression, antibiotic susceptibility, and disease pathogenesis. However, little is known about specific genomic variations that influence these bacterial growth features. Here, we investigate the impact ofStreptococcus pneumoniaegenetics on itsin vitro growth features to shed light on genes that may be important targets in the development of vaccines and therapeutics. We use statistical models to estimate growth features and show that they varied significantly across capsular serotypes and lineages, strongly correlated with the phylogeny, and were highly heritable, highlighting a strong genetic basis. Despite this, genome-wide association studies revealed no specific genomic loci statistically associated with the growth features independently of the genetic background, including those in the capsular polysaccharide synthesis locus. Our findings show that the serotype and lineage, and possibly a combination of genomic loci, influence intrinsic pneumococcal growth kinetics, which may have implications on pneumococcal disease pathogenesis.
Genetic Analysis of Flagellar-Mediated Surface Sensing byPseudomonas aeruginosaPA14
Authors: Kuchma Sherry , Geiger C.J. , Webster Shanice , Fu Yu , Montoya Robert , O’Toole G.A. 
Published: December 2024

AbstractSurface sensing is a key aspect of the early stage of biofilm formation. ForP. aeruginosa, the type IV pili (TFP), the TFP alignment complex and PilY1 were shown to play a key role in c-di-GMP signaling upon surface contact. The role of the flagellar machinery in surface sensing is less well understood inP. aeruginosa. Here we show, consistent with findings from other groups, that a mutation in the gene encoding the flagellar hook protein (ΔflgK) or flagellin (ΔfliC) results in a strain that overproduces the Pel exopolysaccharide (EPS) with a concomitant increase in c-di-GMP levels. We use a candidate gene approach and genetic screens, combined with phenotypic assays, to identify key roles for the MotAB and MotCD stators and the FliG protein, a component of the flagellar switch complex, in stimulating the surface-dependent, increased c-di-GMP level noted for these flagellar mutants. These findings are consistent with previous studies showing a role for the stators in surface sensing. We also show that mutations in the genes coding for the diguanylate cyclases SadC and RoeA as well as SadB, a protein involved in early surface colonization, abrogate the increased c-d-GMP-related phenotypes of the ΔflgKmutant. Together, these data indicate that bacteria monitor the status of flagellar synthesis and/or function during surface sensing as a means to trigger the biofilm program.ImportanceUnderstanding how the flagellum contributes to surface sensing byP. aeruginosais key to elucidating the mechanisms of biofilm initiation by this important opportunistic pathogen. Here we take advantage of the observation that mutations in the flagellar hook protein or flagellin enhance surface sensing. We exploit this phenotype to identify key players in this signaling pathway, a critical first step in understanding the mechanistic basis of flagellar-mediated surface sensing. Our findings establish a framework for the future study of flagellar-based surface sensing.