bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mapping atherogenesis mechanisms in smooth muscle cells by targeting genes linked to coronary artery disease
Authors: Albarrán-Juárez Julián , Markov Anton , Jensen Anne Louise , Møller Peter Loof , Uryga Anna K. , Djordjevic Djordje , Hansen Jakob , Jensen Lise Filt , Sharysh Diana , Pyke Charles , Moreno Jaime , Borghetti Giulia , Bachmann Julian , Herum Kate , Røge Lisa Maria , Traylor Matthew , Nyberg Michael , Nyegaard Mette , Bentzon Jacob Fog 
Published: November 2024

AbstractRecent genome-wide association studies (GWAS) have identified multiple vascular cell-expressed genes linked to coronary artery disease (CAD), suggesting that smooth muscle cells (SMCs) and SMC-derived metaplastic cells are promising targets for novel antiatherosclerosis therapies. However, the disease-promoting pathways of most GWAS-identified genes are unknown, hindering their translation into therapeutic targets. This study integrated public GWAS data for CAD and single-cell RNA sequencing (scRNA-seq) analyses of human atherosclerotic plaques to identify 20 GWAS risk genes with a putative mechanism of action in SMCs or SMC-derived cells.Gene perturbation experiments in SMCs coaxed to plaque-relevant phenotypes revealed that the selected risk genes, despite encoding very different types of proteins, regulated shared sets of genes associated with contractile functions, cell cycle pathways, NFκB, and type I interferon signaling. By integrating information about GWAS gene effect direction and a deep analysis of cholesterol- and stretch-induced gene modules in SMCs, we find evidence that cholesterol-induced signaling is a pro-atherogenic disease mechanism in SMCs that is upregulated by detrimental and downregulated by protective GWAS genes.Overall, our study identifies a set of candidate disease mechanisms in SMCs that are regulated by multiple GWAS genes across several SMC assays. Furthermore, it provides proof-of-concept for using GWAS gene effect directionality to predict the pathogenic effect of candidate disease mechanisms that can be extended to other GWAS genes and cell types in the future.
Deciphering Memory Patterns in Eco-Epidemiological systems through the lens of BaFOMS: A Bayesian Fractional Order Model Selection Method
Authors: Mestry Dipali Vasudev , Singh Pratik , Rocklöv Joacim , Bhowmick Amiya Ranjan 
Published: November 2024

AbstractThe evolution of eco-epidemiological systems is significantly influenced by the memory or previous history of the system. These non-Markovian dynamics are effectively modelled using fractional derivatives (FDs), incorporating memory kernels that reflect long-term or short-term memory characteristics in corresponding nonlinear fractional differential evolution equations. We introduce BaFOMS, a framework for identifying and selecting the optimal FD model for eco-epidemiological processes based on historical data. Specifically, we evaluate a class of fractional logistic growth models defined by their time correlation functions and determine the optimal model through Bayesian inference, selecting the one with the highest posterior probability. We also demonstrated BaFOMS efficiency in parameter estimation and forecasting, producing reliable results with quantified uncertainties. The method is shown to be robust across a range of eco-epidemiological datasets, offering computational efficiency and reliable inference about the evolution dynamics.
Maternal exercise alters placental proteome in an exercise mode-specific manner
Authors: Jevtovic Filip , Wisseman Breanna , Jahan Fahmida , Claiborne Alex , Collier David N. , DeVente James E. , Mouro Steven , Zeczycki Tonya , Goodyear Laurie J. , May Linda E. 
Published: November 2024

AbstractMaternal exercise is a widely recommended and safe intervention associated with the improvement of maternal gestational and infant metabolic health. While various modes of exercise are deemed safe during pregnancy, the effects of supervised maternal aerobic, resistance, and combination (aerobic+resistance) exercise remain understudied. Specifically, it remains unknown how different modes of maternal exercise affect the placenta, an organ central to maternal-fetal communication and successful pregnancy outcomes. This study aimed to characterize the placental proteomic changes in response to controlled and supervised maternal exercise during gestation. Results showed that the placental proteomic landscape changes in an maternal exercise mode-specific way. Additionally, proteomics revealed that ∼20% of the identified placental proteins were associated with maternal exercise volume during gestation. These results highlight the differential effect maternal exercise modes have on the placental proteome and further implicate the placenta in mediating the effects of maternal exercise on maternal and infant health.
The adaptive landscapes of three globalEscherichia colitranscriptional regulators
Authors: Antunes Westmann Cauã , Goldbach Leander , Wagner Andreas 
Published: November 2024

AbstractThe evolution of new gene regulation is an important source of evolutionary adaptations and innovations, especially when organisms encounter new environments. At its heart is the process by which new and strong DNA binding sites of transcription factors (TFs) originate in evolution. Here we study the potential of Darwinian evolution to create strong binding sites for the threeEscherichia coliglobal transcription factors CRP, Fis, and IHF. Using a massively parallel reporter assay, we measure for each TF the ability of more than 30,000 binding sites to regulate gene expression. We use the resulting data to map the adaptive landscape of each TF. We find that all three landscapes are rugged, epistatic, and harbor multiple peaks. The highest peaks are widely scattered throughout the landscape, indicating that strong regulation can be achieved by very different binding sites. Landscape ruggedness does not prevent the evolution of strong regulation, because more than 10% of evolving populations can attain one of the highest peaks. Adaptive evolution starting from the same DNA sequence can attain more than one high peak, and some high peaks are more likely to be reached than others. Our experiments show that de novo adaptive evolution of new gene regulation is feasible. It is also subject to a blend of chance, historical contingency, and evolutionary biases that favor some peaks and evolutionary paths over others.
Opposing Regulation of TNF Responses and IL-1β+ Macrophages by PGE2-cAMP and IFN-γ Signaling
Authors: Sokhi Upneet K. , Mishra Bikash , Yuan Ruoxi , Chinenov Yuri , Singaraju Anvita , Chan Karmela K. , Bass Anne R. , Donlin Laura , Ivashkiv Lionel B. 
Published: November 2024

AbstractIL-1β-expressing macrophages have been described in rheumatoid arthritis (RA), immune checkpoint inhibitor-induced inflammatory arthritis (ICI-arthritis), and pancreatic cancer and proposed to be pathogenic. In RA and pancreatic cancer IL-1β+ macrophages express a TNF+PGE2 (TP) gene expression signature induced by cooperation between PGE2 and TNF signaling, but mechanisms that induce these cells and the extent to which they contribute to arthritic phenotypes are not known. In this study we used an integrated transcriptomic and epigenomic analysis in primary human monocytes to study PGE2-TNF crosstalk, and how it is regulated by IFN-γ, as occurs in RA synovial macrophages. We identified a (TNF + PGE2)- induced gene expression signature that is enriched in an IL1β+ RA macrophage subset defined by scRNAseq and includes genes in pathogenic IL-1, Notch and neutrophil chemokine pathways. A similar gene expression signature was apparent in an IL-1β+ macrophage subset newly identified by scRNAseq in ICI-arthritis. TP signature genes are distinct from canonical inflammatory NF-κB target genes such asTNF,IL6andIL12Band are activated by cooperation of PGE2-induced AP-1, CEBP and NR4A family transcription factors with TNF-induced NF-κB activity. Unexpectedly, IFN-γ suppressed induction of AP-1, CEBP and NR4A activity to ablate induction of IL-1, Notch and neutrophil chemokine genes, while promoting expression of distinct inflammatory genes such asTNFand T cell chemokines like CXCL10. These results reveal the basis for synergistic induction of inflammatory genes by PGE2 and TNF, and a novel regulatory axis whereby IFN-γ and PGE2 oppose each other to determine the balance between two distinct TNF-induced inflammatory gene expression programs relevant for RA and ICI-arthritis.
Surface remodeling and inversion of cell-matrix interactions underlies community recognition and dispersal inVibrio choleraebiofilms
Authors: Moreau Alexis , Nguyen Danh T. , Hinbest Alex , Zamora Anthony , Weerasekera Ranjuna , Matej Katherine , Zhou Xuening , Sanchez Sandra , Brenes Ignacio Rodriguez , Tai Jung-Shen Benny , Nadell Carey D. , Ng Wai-Leung , Gordon Vernita , Komarova Natalia L. , Olson Rich , Li Ying , Yan Jing 
Published: November 2024

ABSTRACTBiofilms are ubiquitous surface-associated bacterial communities embedded in an extracellular matrix. While it is commonly assumed that biofilm-dwelling cells are glued together by the matrix, how the cell-matrix interaction depends on the specific biochemistry of the matrix components and how this interaction varies during biofilm growth remains unclear. Here, we investigated cell-matrix interactions inVibrio cholerae(Vc), the causative agent of cholera. We combine genetics, microscopy, simulation, and biochemical tools to show thatVccells are not attractive toVibriopolysaccharide (VPS), the main matrix component, but they can be bridged with each other and to the VPS network through crosslinking by Bap1. Downregulation of VPS and surface trimming by the polysaccharide lyase RbmB cause surface remodeling as biofilms age, shifting the nature of cell-matrix interactions from attractive to repulsive and facilitating cell dispersal as aggregated groups. Our results suggest a new conceptual model in understanding the intricate cell-matrix interaction as the major driver for biofilm development, which is potentially generalizable to certain other biofilm-forming species and exopolysaccharides.
Mutant RIT1 cooperates with YAP to drive an EMT-like lung cancer state
Authors: Rominger Mary C. , Gupta Saksham , Moorthi Sitapriya , McSharry Maria , Kamlapurkar Shriya , O’Brien Siobhan , Waldum Annie , Lo April , Duke Fujiko , Lowe Amy R. , Cromwell Elizabeth , Glabman Raisa , Koehne Amanda , Berger Alice H. 
Published: November 2024

ABSTRACTThe discovery of oncogene addiction in cancer has led to the development of over a dozen FDA-approved biomarker-driven therapies in lung adenocarcinoma. Somatic mutations of the “Ras-like in all tissues” (RIT1) gene are non-canonical driver events in lung cancer, occurring in ∼2% of lung adenocarcinomas in a mutually exclusive fashion withKRASandEGFRmutations. Patients withRIT1-mutant lung cancer lack targeted therapy treatment options, and a lack of pre-clinical models has hindered the development of therapeutic strategies forRIT1-mutant lung cancer. Here we report a new mouse model of RIT1-driven lung cancer in which the human RIT1M90Ivariant can be induced in a Cre-regulated manner. We show that autochthonous expression of RIT1M90Iin the lung weakly promotes cancer alone or in combination with loss of thep53tumor suppressor. However, potent synergy between RIT1M90Iand inactivation ofNf2drives an aggressive epithelial-to-mesenchymal (EMT) lung cancer with 100% penetrance and short latency. We show this oncogenic cooperation is driven by synergistic activation of cJUN, a component of the AP-1 complex. Therapeutic inhibition of MEK and YAP/TEAD suppressed RIT1-driven lung cancer in vivo. These data identify YAP/TEAD as an important mediator of RIT1’s oncogenic potential and nominate TEAD as an important drug target inRIT1-mutant lung cancer.HIGHLIGHTSWe report a new RIT1M90I-mutant autochthonous lung tumor modelThe most common oncogenic variant of RIT1, RIT1M90I, weakly promotes lung tumor developmentRIT1M90Idrives the formation of lethal lung tumors in cooperation withp53andNf2tumor suppressor gene lossRIT1M90Iand YAP cooperatively regulate cJUN expressionTherapeutic MEK and TEAD targeting suppresses RIT1M90I-driven tumorigenesis
Improving the Capstone Biochemistry Lab and Evolution to a Course-Based Undergraduate Research Experience: Lessons Learned from the COVID-19 Online Modality
Authors: Rascón Alberto A. 
Published: November 2024

ABSTRACTThe restructuring of an upper division biochemistry lab capstone course intended for biochemistry students with a range of laboratory experience was explored. A goal of the course was to give students practice with necessary skills in biochemical and biological techniques, especially for an entry level general position in biotechnology. The immediate impact of the online capstone course mandated by the COVID-19 pandemic limited students on learning essential hands-on research skills but evolved during the transition back to in-person instruction to include more elements of in-person practice. This article highlights the evolution of the capstone biochemistry lab to an in-person CURE capstone lab, with lessons learned and resources successfully used during the COVID-19 remote course. These include changes in the way information was disseminated, access to online resources, and modifications in student assessments. This article documents how course evolution resulted in a shift in pedagogical strategies leading to building a community of biochemistry learners that could be used to help college faculty in developing a CURE capstone lab.
Lysosomes cell autonomously regulate myeloid cell states and immune responses
Authors: Tejwani Leon , Balak Christopher , Skuja Lukas L. , Tatarakis David , Rana Anil , Fitzgerald Gabriel A. , Ha Connie , Lunkes de Melo Gabrielly , Sun Elizabeth W. , Heffner Catherine M. , Simon Matthew J. , Dugas Jason C. , Sarrafha Lily , Liang Eric , Sandmann Thomas , Glass Christopher K. , Di Paolo Gilbert 
Published: November 2024

ABSTRACTMyeloid cells maintain tissue homeostasis via the recognition, engulfment, and lysosomal clearance of dying cells and cellular debris, which is often accompanied by changes from homeostatic to reactive states. While a role for phagocytic receptors in gating these transitions has been described1,2, less is known about if and how lysosomes can contribute to transcriptional and functional plasticity. To determine how lysosomal health impacts myeloid cell states, we evaluated microglia and macrophages deficient for progranulin (encoded byGrn), a lysosomal protein with pleiotropic functions whose loss is associated with several neurodegenerative diseases3–8. Single-cell RNA-sequencing of the aged mouse brain identified aGrnknockout (KO)-specific microglial subpopulation marked by high GPNMB expression that displays hallmarks of lysosomal dysfunction, including lipofuscin accumulation. Epigenetic analysis of aged microglia revealed MITF/TFE transcription factors as key mediators of the transcriptional states associated withGrndeficiency. In addition to identifying a core myeloid cell transcriptional response to diverse lysosomal stressors, targeted perturbations of various lysosomal propertiesin vitrouncovered a cell autonomous, TREM2- independent, response to lysosomal deacidification (via v-ATPase or VPS34 loss of function) that overlaps withGrnKO microglia phenotypes, including the induction of a lysosomal gene program, increased proliferation, and secretion of pro-inflammatory cytokines. Compound loss-of-function approaches established GPNMB upregulation upon lysosomal stress is required for the compensatory response to enhance lysosomal function via promoting acidification. Finally, pharmacological endolysosomal reacidification through sodium/proton exchanger inhibition partially rescuedGrnKO microglia phenotypes. Overall, these data establish a fundamental link between lysosomal health and myeloid cell epigenetic, transcriptional, and functional states observed in neurodegeneration models.
Investigating Protein Degradability through Site-Specific Ubiquitin Ligase Recruitment
Authors: Shade Olivia , Ryan Amy , Belsito Gabriella , Deiters Alexander 
Published: November 2024

AbstractWe report targeted protein degradation through the site-specific recruitment of native ubiquitin ligases to a protein of interest via conjugation of E3 ligase ligands. Direct comparison of degradation ability of proteins displaying the corresponding bioconjugation handle at different regions of protein surfaces was explored. We demonstrate the benefit of proximal lysine residues and investigate flexibility in linker length for the design of optimal degraders. Two proteins without known small molecule ligands, EGFP and DUSP6, were differentially degraded when modified at different locations on their protein surfaces. Further, the cereblon-mediated degradation of the known PROTAC target ERRα was improved through the recruitment of the E3 ligase to regions different from the known ligand binding site. This new methodology will provide insight into overall protein degradability, even in the absence of a known small molecule ligand and inform the process of new ligand and PROTAC development to achieve optimal protein degradation. Furthermore, this approach represents a new, small molecule-based conditional OFF switch of protein function with complete genetic specificity. Importantly, the protein of interest is only modified with a minimal surface modification (< 200 Da) and does not require any protein domain fusions.
Factors affecting antenatal corticosteroid use in low- and middle-income countries: facility characteristics, structural readiness, and past performance of CEmONC signal functions
Authors: Yang Wen-Chien , Arsenault Catherine , Fan Victoria Y. , Ali Nazia Binte , Alwy Al-beity Fadhlun Mohamed , Smith Emily R. 
Published: November 2024

ABSTRACTBackgroundAntenatal corticosteroids (ACS) utilization is disproportionately limited in low- and middle-income countries where most global preterm newborns who could benefit from this intervention are born. Understanding the factors affecting ACS use is crucial for improving its uptake. This study aimed to investigate facility-level factors associated with ACS use in low-resource countries.MethodsWe used data from ten Service Provision Assessment surveys across nine countries. We restricted the sample to facilities that provided delivery services. Our primary outcome was recent ACS use, defined as having administered ACS within the past three months before the survey. We conducted mixed-effect log binomial regressions, with country as a fixed effect and sub-national regions as random intercepts, to explore the association between recent ACS use and facility characteristics, injectable corticosteroids and ultrasound availability, facility structural readiness, and past performance of nine Comprehensive Emergency Obstetric and Newborn Care (CEmONC) signal functions.ResultsThis study included 6183 facilities from nine countries. Across eight countries with nationally representative data, only 22.7% (median, range 4.0% to 27.4%) of facilities that provided delivery services had used ACS recently. Urban facilities had a 21% higher likelihood of recent ACS use (95% CI 6%–38%) than rural facilities. Corticosteroid availability was associated with a 14% higher likelihood of recent ACS use (95% CI 1%–29%). Facilities in the highest readiness tertile were more likely to have recent ACS use than those in the lowest (RR 1.91, 95% CI 1.58–2.30). Each CEmONC signal function, except for assisted vaginal deliveries, was significantly associated with recent ACS use, with neonatal resuscitation having the largest effect (RR 2.62, 95% CI 1.93–3.55).ConclusionFacilities that had performed CEmONC services were more likely to administer ACS, highlighting the importance of provider knowledge, skills, and competence in managing obstetric and newborn emergencies for effective ACS provision.
Targeted pre-conditioning and cell transplantation in the murine lower respiratory tract
Authors: Kohn Anat , Herriges Michael J. , Basak Payel , Ma Liang , Thapa Bibek R. , Kotton Darrell N. , Hawkins Finn J. 
Published: November 2024

AbstractTransplantation of airway basal stem cells could achieve a durable cure for genetic diseases of the airway, such as cystic fibrosis and primary ciliary dyskinesia. Recent work demonstrated the potential of primary- and pluripotent stem cell (PSC)-derived basal cells to efficiently engrai into the mouse trachea aier injury. However, there are many hurdles to overcome in translating these approaches to humans including developing safe and efficient methods for delivery in larger animal models. We propose a model which targets preconditioning and cell-delivery to the intrapulmonary airways utilizing a micro- bronchoscope for delivery. The detergent polidocanol was adapted for distal lung pre-conditioning, inducing intrapulmonary airway epithelial denudation by 5 and 24-hours post-delivery. While initial re- epithelialization of airways occurred later than tracheas, complete repair was observed within 7-days. Both PSC-derived and primary basal cells delivered via micro-bronchoscope post-polidocanol injury engraied in tracheas and intrapulmonary airways, respectively. Transplanted cells differentiated into ciliated and secretory lineages while maintaining a population of basal cells. These findings demonstrate the utility of bronchoscopically targeted pre-conditioning and cell delivery to the conducting intra- pulmonary airways, providing an important framework for pre-clinical translation of approaches for engineered airway epithelial regeneration.
Single nucleotide switches confer bacteriophage resistance toPseudomonas protegens
Authors: Vacheron Jordan , Heiman Clara M. , Keel Christoph 
Published: November 2024

AbstractPhage therapy offers a promising strategy against bacterial pathogens in medicine and agriculture, but the rise of phage-resistant bacteria presents a significant challenge to its sustainability. Here, we used an environmental model bacterium,Pseudomonas protegensCHA0, to investigate phage resistance mechanisms in laboratory conditions through genomic analysis of four phage-resistant variants (C2, C4, C17, C18). Whole-genome sequencing revealed frequent deletions, insertions, and single nucleotide substitutions, particularly in genes encoding enzymes involved in cell surface modifications. The T428P mutation in AlgC, a phosphoglucomutase, and the P229T substitution in YkcC, a glycosyltransferase, each conferred resistance by potentially altering phage receptor accessibility while preserving bacterial fitness. These findings suggest that subtle mutations in surface-modifying enzymes enable phage resistance by modifying phage-receptor accessibility while maintaining bacterial growth, highlighting adaptive mechanisms in bacterial phage interactions. Further structural analysis is needed to fully understand these mutation-driven resistance mechanisms.