bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thrifty wide-context models of B cell receptor somatic hypermutation
Authors: Sung Kevin , Johnson Mackenzie M. , Dumm Will , Simon Noah , Haddox Hugh , Fukuyama Julia , Matsen Frederick A 
Published: December 2024

AbstractSomatic hypermutation (SHM) is the diversity-generating process in antibody affinity maturation. Probabilistic models of SHM are needed for analyzing rare mutations, for understanding the selective forces guiding affinity maturation, and for understanding the underlying biochemical process. High throughput data offers the potential to develop and fit models of SHM on relevant data sets. In this paper we model SHM using modern frameworks. We are motivated by recent work suggesting the importance of a wider context for SHM, however, assigning an independent rate to each k-mer leads to an exponential proliferation of parameters. Thus, using convolutions on 3-mer embeddings, we develop “thrifty” models of SHM that have fewer free parameters than a 5-mer model and yet have a significantly wider context. These offer a slight performance improvement over a 5-mer model. We also find that a per-site effect is not necessary to explain SHM patterns given nucleotide context. Also, the two current methods for fitting an SHM model — on out-of-frame sequence data and on synonymous mutations — produce significantly different results, and augmenting out-of-frame data with synonymous mutations does not aid out-of-sample performance.
MultiPopPred: A Trans-Ethnic Disease Risk Prediction Method, and its Application to the South Asian Population
Authors: Kamal Ritwiz , Narayanan Manikandan 
Published: December 2024

AbstractGenome-wide association studies (GWAS) aimed at estimating the disease risk of genetic factors have long been focusing on homogeneous Caucasian populations, at the expense of other understudied non-Caucasian populations. Therefore, active efforts are underway to understand the differences and commonalities in exhibited disease risk across different populations or ethnicities. There is, consequently, a pressing need for computational methods that efficiently exploit these population specific vs. shared aspects of the genotype-phenotype relation. We propose MultiPopPred, a novel trans-ethnic polygenic risk score (PRS) estimation method, that taps into the shared genetic risk across populations and transfers information learned from multiple well-studied auxiliary populations to a less-studied target population. MultiPopPred employs a specially designed Nesterov-smoothed penalized shrinkage model and a L-BFGS optimization routine. We present three variants of MultiPopPred based on the availability of individual-level vs. summary-level data and the weightage of each auxiliary population. Extensive comparative analyses performed on simulated genotype-phenotype data reveal that MultiPopPred improves PRS prediction in the South Asian population by 65% on settings with low target sample sizes and by 21% overall across all simulation settings, when compared to state-of-the-art trans-ethnic PRS estimation methods. This performance trend is promising and encourages application and further assessment of MultiPopPred under other simulation and real-world settings.
Implementation of aClostridium luticellariigenome-scale model for upgrading syngas fermentations
Authors: Scott William T. , Rockx Siemen , Mariën Quinten , Regueira López Alberte , Candry Pieter , Ganigué Ramon , Koehorst Jasper J. , Schaap Peter J. 
Published: December 2024

ABSTRACTSyngas fermentation is a powerful platform for converting waste streams into sustainable carboxylic acid precursors for value-added biochemicals. Steel mills produce significant syngas, yet industrial microbial syngas valorization remains unrealized. The most promising syngas-converting biocat-alysts consist ofClostridiaspecies, such asClostridium kluyveri, Clostridium autoethanogenum, andClostridium ljungdahlii. Clostridium luticellarii, a recently discovered species, shares close phylogenetic ties with these organisms. Preliminary metabolic studies suggest its potential for syngas acetogenesis as well as chain elongation. In this study, we createiSJ444, a constraint-based metabolic model ofC. luticellariiusingiHN637of a close relativeC. ljungdahliias a starting point. Model predictions support hypothesized methanol and syngas pathways from the metabolic characterization studies; however, the use of propionate could not be accurately predicted. Thermodynamic Flux Analysis (TFA) reveals thatC. luticellariimaintains stable energy dissipation across most reactions when exposed to varying pH, with significant increases observed in reactions associated with the Wood-Ljungdahl pathway (WLP), such as the HACD1 reaction, at higher pH (6.5), suggesting an adaptive role in energy management under neutral conditions. Flux sampling simulations exploring metabolic flux distributions show thatC. luticellariimight fit into syngas fermenting platforms. In both cases, high hydrogen-to-carbon source ratios result in better production of (iso)butyrate and caproate. We present a minimal genome-scale metabolic model ofC. luticellariias a foundation for further exploration and optimization. Although our predictions of its metabolic behavior await experimental validation, they underscore the potential ofC. luticellariito enhance syngas fermentation platforms.HighlightsiSJ444modelsC. luticellariimetabolism for syngas fermentation and chain elongation.Thermodynamic flux analysis (TFA) reveals adaptive energy balancing in pathways.Simulations highlightC. luticellariias a producer of value-added biochemicals like butyrate, isobutyrate, and caproateMetabolic insights fromiSJ444suggest efficient syngas conversion using varied substrates for industrial use.
TheMUC5Bpromoter variant results in proteomic changes in the non-fibrotic lung
Authors: Herrera Jeremy A. , Maslanka Mark , Blumhagen Rachel Z. , Blomberg Rachel , Lwin Nyan Ye , Brancato Janna , Cool Carlyne D. , Huber Jonathan P. , Kurche Jonathan S. , Magin Chelsea M. , Hansen Kirk C. , Yang Ivana V. , Schwartz David A. 
Published: December 2024

AbstractThe gain-of-functionMUC5Bpromoter variant is the dominant risk factor for the development of idiopathic pulmonary fibrosis (IPF). However, its impact on protein expression in both non-fibrotic control and IPF lung specimens have not been well characterized. Utilizing laser capture microdissection coupled to mass spectrometry (LCM-MS), we investigated the proteomic profiles of airway and alveolar epithelium in non-fibrotic controls (n = 12) and IPF specimens (n = 12), stratified by the presence of theMUC5Bpromoter variant. Through qualitative and quantitative analyses, as well as pathway analysis and immunohistological validation, we have identified a distinct MUC5B-associated protein profile. Notably, the non-fibrotic control alveoli exhibited substantial MUC5B-associated protein changes, with an increase of IL-3 signaling. Additionally, we found that the epithelial cells overlying IPF fibroblastic foci cluster closely to alveolar epithelia and express proteins associated with cellular stress pathways. In conclusion, our findings suggest that theMUC5Bpromoter variant leads to protein changes in alveolar and airway epithelium that appears to be associated with the initiation and progression of lung fibrosis.
Temporal dynamics of fluorescence and photoacoustic signals of a Cetuximab-IRDye800 conjugate in EGFR-overexpressing tumors
Authors: Saad Mohammad A. , Allen Derek , Sweeney Allison , Xavierselvan Marvin , Mallidi Srivalleesha , Hasan Tayyaba 
Published: December 2024

AbstractMolecular fluorescence-guided surgery has shown promise for tumor margin delineation but is limited by its depth profiling capability. Interestingly, most fluorophores, either clinically approved or in clinical trials, can also be used as photoacoustic contrast agents, yet their use is limited due to the low light fluence permitted for clinical use and the limited sensitivity of current photoacoustic imaging systems. There is therefore an urgent unmet need to establish methods for enhancing contrast in molecular targeted PA imaging which could potentially complement and overcome limitations in molecular fluorescence guided therapies. In this study, we compare the photoacoustic (PA) and fluorescence imaging capabilities of a cetuximab-IRDye800 conjugate in a subcutaneous tumor xenograft model. We demonstrate that while the fluorescence signal increases steadily over time after administration of cetuximab-IRDye800, PA signal peaks early (∼2 fold higher at 6-hour as compared to pre-injection controls) and then decreases (∼1.3 fold higher at 24-hour as compared to pre-injection controls). This pattern aligns with previous findings using other antibody-conjugated PA contrast agents. Mechanistically, we demonstrate that the formation of H-aggregates upon antibody conjugation enhances PA contrast of the IRDye800. The disruption of these H-aggregates, as the antibody-dye conjugate is degraded post receptor-mediated endocytosis, decreases PA signal intensity. The timeframe of maximum PA signal and decrease thereafter is consistent with the time frame of receptor-mediated endocytosis of cetuximab-IRDye800. Our data suggests that tumor cell surface binding results in peak PA signal while lysosomal localization and degradation results in a significant drop in PA signal. Our study sheds light on the distinct temporal dynamics of PA and fluorescence signals of Cetuximab-IRDye800 conjugate and we propose that optimizing IRDye800 conjugation to antibodies can further enhance PA signal intensity when timed to precisely to capture IRDye800 in an H-aggregate form.
A multi-level formalism to capture the characteristics of hybrid phenotypes in Epithelial-Mesenchymal Plasticity
Authors: Hari Kishore , Tripathi Shubham , Anand Vaibhav , Jolly Mohit Kumar , Levine Herbert 
Published: December 2024

AbstractEpithelial-mesenchymal plasticity (EMP) is a cell-fate switching program that enables cells to adopt a spectrum of phenotypes ranging from epithelial (E) to mesenchymal (M) and hybrid E/M states. Hybrid E/M phenotypes are considered optimal for cancer metastasis due to their association with metastatic initiation and traits such as stemness, drug resistance, and collective migration. Boolean models of gene regulatory networks (GRNs) underlying EMP have provided valuable insights into the dynamics of E and M phenotypes. However, these models fail to capture hybrid phenotypes effectively, as Boolean frameworks allow only binary gene expression, while hybrid E/M cells exhibit partial expression of both E and M genes. To address this limitation, we modified a threshold-based Boolean formalism to incorporate intermediate gene expression levels. The resulting multilevel model reveals new hybrid steady states with partial expression of both E and M genes, expanding the phenotypic landscape beyond that captured by traditional Boolean models. These hybrid states exhibit lower frustration and higher abundance, indicating enhanced stability. By resolving degeneracy in the dynamics, we further demonstrate that hybrid states identified by the multilevel model are more stable. These findings suggest that adding minimal complexity to Boolean models can uncover previously hidden qualitative features of phenotypic landscapes governed by GRNs.
Integration of spatial multiplexed protein imaging and transcriptomics in the human kidney tracks the regenerative potential timeline of proximal tubules
Authors: Asghari Mahla , Sabo Angela R. , Barwinska Daria , Ferreira Ricardo Melo , Ferkowicz Michael , Bowen William S. , Cheng Ying-Hua , Gisch Debora L. , Gulbronson Connor , Phillips Carrie L , Kelly Katherine J. , Sutton Timothy A. , Williams James C , Vazquez Miguel , O’Toole John , Palevsky Paul , Rosas Sylvia E. , Waikar Sushrut S. , Kiryluk Krzysztof , Parikh Chirag , Hodgins Jeff , Sarder Pinaki , De Boer Ian H. , Himmelfarb Jonathan , Kretzler Matthias ,   Kidney Precision Medicine Project, Jain Sanjay , Eadon Michael T. , Winfree Seth , El-Achkar Tarek M. , Dagher Pierre C 
Published: December 2024

AbstractThe organizational principles of nephronal segments are based on longstanding anatomical and physiological attributes that are closely linked to the homeostatic functions of the kidney. Novel molecular approaches have recently uncovered layers of deeper signatures and states in tubular cells that arise at various timepoints on the spectrum between health and disease. For example, a dedifferentiated state of proximal tubular cells with mesenchymal stemness markers is frequently seen after injury. The persistence of such a state is associated with failed repair. Here, we introduce a novel analytical pipeline applied to highly multiplexed spatial protein imaging to characterize proximal tubular subpopulations and neighborhoods in reference and disease human kidney tissue. The results were validated and extended through integration with spatial and single cell transcriptomics. We demonstrate that, in reference tissue, a large proportion of S1 and S2 proximal tubular epithelial cells express THY1, a mesenchymal stromal and stem cell marker that regulates differentiation. Kidney disease is associated with loss of THY1 and transition towards expression of PROM1, another stem cell marker shown recently to be linked to failed repair. We demonstrate that the trajectory of proximal tubular cells to THY1 expression is clearly distinct from that of PROM1, and that a state with PROM1 expression is associated with niches of inflammation. Our data support a model in which the interplay between THY1 and PROM1 expression in proximal tubules associates with their regenerative potential and marks the timeline of disease progression.
Epigenetic Regulation of Inflammatory NF-κB Target Genes by IFN-γ via IRF1
Authors: Mishra Bikash , Wingert Claire , Bachu Mahesh , Ivashkiv Lionel B. 
Published: December 2024

AbstractThe regulation of inflammatory gene expression involves complex interactions between transcription factors (TFs), signaling pathways and epigenetic chromatin-mediated mechanisms. This study investigated mechanisms by which by IFN-γ-mediated priming augments TLR-induced expression of NF-κB target genes in primary human monocytes. IFN-γ priming enhanced the expression of signature inflammatory genes such asIL6,TNF,IL1B, andCXCL10when monocytes were exposed to various TLR agonists. RNA-seq analysis identified genes synergistically activated by IFN-γ and LPS, which were enriched in inflammatory pathways. Similar synergistic activation was observed with the TLR1/2 agonist PAM3CYS, suggesting a shared regulatory mechanism. ATAC-seq analysis revealed that TLR ligands induce IRF1 TF activity independently of IFN-γ. JAK1/2 inhibitor (iJAK) treatment reduced IRF1 expression and protein levels, especially in IFN-γ-treated monocytes, but not in LPS-stimulated monocytes, suggesting LPS-induced IRF1 may compensate for loss of IFN-γ-induced IRF1. We applied CRISPR-Cas9 to knock out IRF1 in primary human monocytes and found loss of IRF1 abrogates synergistic activation of key inflammatory genes, suggesting a pivotal role for IRF1. This genetic data was corroborated by IRF1 CUT&RUN data showing resistance of IRF1 binding to JAK inhibition under (IFN-γ + LPS) costimulated conditions, and co-occupancy of IRF1 binding sites by NF-κB. This study enhances our understanding of inflammatory gene regulation, highlighting IRF1 as a key player and a potential therapeutic target for inflammatory diseases.
Cell type-SpecificIn VivoProteomes with a Multi-copy Mutant Methionyl t-RNA Synthetase Mouse Line
Authors: Alvarez-Pardo Rodrigo , tom Dieck Susanne , Desch Kristina , Nassim Assir Belquis , Olmedo Salinas Cristina , Sivakumar Riya S. , Langer Julian D. , Alvarez-Castelao Beatriz , Schuman Erin M. 
Published: December 2024

AbstractThe functional diversity of cells is driven by the different proteins they express. While improvements in protein labeling techniques have allowed for the measurement of proteomes with increased sensitivity, measuring cell type-specific proteomesin vivoremains challenging. One of the most useful pipelines is bioorthogonal non-canonical amino acid tagging (BONCAT) with the MetRS* system, consisting of a transgenic mouse line expressing a mutant methionyl-tRNA synthetase (MetRS*) controlled by Cre recombinase expression. This system allows for cell type-specific labeling of proteins with a non-canonical amino acid (azidonorleucine, ANL), which can be subsequently conjugated to affinity or fluorescent tags using click chemistry. Click-modified proteins can then be visualized, purified and identified. The reduction in sample complexity allows for the detection of small changes in protein composition. Here we describe a multicopy MetRS* mouse line (3xMetRS* mouse line), which exhibits markedly enhanced ANL protein labeling, boosting the sensitivity and temporal resolution of the system and eliminating the need for working under methionine depletion conditions. Cell type-specificin vivolabeling is possible even in heterozygous animals, thus offering an enormous advantage for crossing the line into mutation and disease-specific backgrounds. Using the 3xMetRS* line we identified thein vivoproteome of a sparse cell population - the dopaminergic neurons of the olfactory bulb and furthermore determined newly synthesized proteins after short labeling durations following a single intraperitoneal ANL injection.
Birth weight discordance, gene expression, and DNA methylation: A review of epigenetic twin studies
Authors: Wadji Dany Laure , Nemoda Zsofia , Martin-Soelch Chantal , Wicky Chantal 
Published: December 2024

AbstractBackgroundBirth weight is considered as an important indicator of environmental conditions during prenatal development. Molecular mechanisms, including epigenetic modifications play an important role in the body’s adaptation to ever changing environmental conditions. As twin design can be used to identify the role of environmental contributions while controlling for genetic variations, numerous monozygotic twin studies have shown how adverse prenatal environment can lead to birth weight discordance (BWD).ObjectiveAn overview of the literature about epigenetic modifications associated with BWD in twins.MethodWe searched PubMed and Ovid MEDLINE(R) databases and included 34 papers that studied associations between BWD and DNA (hydroxy)methylation or gene expression in easily accessible samples of twin pregnancies or peripheral tissues of twins later in life.ResultsResearchers and clinicians still lack consensus on BWD thresholds, which vary between 15-30% depending on the type of placentation and gestational age. The gene expression twin studies measured mostly metabolism-related candidate genes in placental tissues. Only small-scale twin studies measured BWD associated gene expression patterns on genome-wide level using neonatal cells. Most DNA methylation twin studies used epigenome-level analyses, but the analysed tissue and age of sampling varied widely (blood from adults, saliva samples from children, placenta at delivery). Importantly, a handful of growth-related genes (e.g.,IGF2,LEPROT, ADRB3,GLUT3) were associated with BWD.ConclusionTranscriptional changes of genes coding for placental glucose transporters and hypoxia-induced proteins possibly reflect compensatory processes in twin pregnancies. Epigenetic regulation of growth-related genes in the offspring offer a relevant mechanism to counterbalance adverse prenatal environment.Graphical abstractGraphical abstract/Figure 1.(Created inhttps://BioRender.com)Although monozygotic twins have almost the same DNA sequence (see double stranded DNA helix in the middle), there are many molecular regulatory processes differentially affected by certainin uteroenvironmental factors (such as unequal blood supply). Therefore, in a proportion of twin pregnancies, the intrauterine growth of the developing embryos is uneven, resulting in substantial birth weight difference. The underlying epigenetic alterations, such as DNA methylation changes can be long-lasting, measurable after birth and may serve as biomarkers reflecting risk for later health problems. An important technical feature is that the DNA molecule is quite stable and the methyl groups are attached covalently (shown as Me), hence methylation analyses are wide-spread in medical studies.
Inflammatory signature and restriction of adaptive immunity are associated with unfavorable outcomes on immune checkpoint blockade in patients with advanced head and neck squamous cell carcinoma
Authors: Paschold Lisa , Schultheiss Christoph , Schmidt-Barbo Paul , Klinghammer Konrad , Hahn Dennis , Tometten Mareike , Schafhausen Philippe , Blaurock Markus , Brandt Anna , Westgaard Ingunn , Kowoll Simone , Stein Alexander , Hinke Axel , Binder Mascha 
Published: December 2024

ABSTRACTBackgroundIn most patients with relapsed or metastatic head and neck squamous cell carcinoma (rmHNSCC), immunotherapy with PD-1 targeting antibodies does not yield durable responses. PD-L1 tissue expression - the most commonly assessed marker for checkpoint inhibiting antibodies - is an insufficient predictor of treatment outcome.MethodsWe evaluated various blood and tissue-based biomarkers in the context of immune checkpoint blockade-based treatment to find suitable response biomarkers in a clinical trial cohort of patients with rmHNSCC.ResultsThe PD-L1 expression level in tumor or tumor microenvironment was not associated with treatment benefit. In contrast, inflammation-related markers such as IL-6, high peripheral neutrophils and high levels of cell-free DNA, as well as markers related to adaptive immune dysfunction such as altered T cell dynamics and secretion of immune checkpoint molecules, were associated with poor clinical outcomes. Patients lacking these high-risk markers performed remarkably well on inhibition of immune checkpoints with pembrolizumab.ConclusionsBiomarker-guided patient selection for pembrolizumab monotherapy or novel combinatorial approaches - potentially including anti-inflammatory agents – for patients with immune-impaired, inflammatory profiles may be the next step in personalizing immunotherapy for these hard-to-treat patients.
Investigating Nutritional Interventions for Managing Irritable-Bowel Syndrome: A Bibliometric Analysis
Authors: Mal Madho , Arshad Faraz , Iftikhar Sadaf , Tummala Nayanika , Waqas Saad Ahmed , Kamal Usama Hussain , Noor Rizwana , Afridi Muhammad Khalid , Ali Abraish 
Published: December 2024

AbstractBackgroundThe bibliometric analysis provides a structured approach for providers and researchers to access clinically relevant information to improve patient care.MethodsWe used SCOPUS as our database and made a list of the top 50 most-cited articles from 2002 to 2022. Variables analyzed included citation count, annual citations, publication year, journal with impact factor, author details, country, institution, and funding.ResultsCitations for 50 articles varied from 67 to 919, with a median of 129 and an IQR of 210. Most of the articles (n = 34) were published between 2013 and 2018. The number of authors per article ranged from 3 to 18. Munir J.G. coauthored the most significant number of articles (n = 7). The top countries of origin for the articles were the UK (n = 15), the USA (n = 10), and Australia (n = 7). The dietary interventions discussed in our list included low FODMAP (n = 27), probiotics (n = 6), GFD (n = 4), an Ig4 exclusion diet (n = 3), and other interventions (n = 10). Female authors were the first authors in 30 articles and senior authors in 19 articles, compared to their male counterparts.ConclusionsAn analysis of the top 50 cited articles on nutritional interventions in IBS highlights interest and impact trends, aiding policymakers in funding decisions. The predominance of a low-FODMAP diet underscores the focus on efficacy, potentially guiding standardized dietary guidelines.