bluuebunny/crossref_metadata_2025_split huggingface dataset:
Untangling the mechanisms of pulmonary hypertension-induced right ventricular stiffening in a large animal model
Authors: Kakaletsis Sotirios , Malinowski Marcin , Mathur Mrudang , Sugerman Gabriella P. , Lucy Jeff J. , Snider Caleb , Jazwiec Tomasz , Bersi Matthew , Timek Tomasz A. , Rausch Manuel K. 
Published: April 2023

ABSTRACTBackgroundPulmonary arterial hypertension (PHT) is a devastating disease with low survival rates. In PHT, chronic pressure overload leads to right ventricle (RV) remodeling and stiffening; thus, impeding diastolic filling and ventricular function. Multiple mechanisms contribute to RV stiffening, including wall thickening, microstructural disorganization, and myocardial stiffening. The relative importance of each mechanism is unclear. Our objective is to use a large animal model as well as imaging, experimental, and computational approaches to untangle these mechanisms.MethodsWe induced PHT in eight sheep via pulmonary artery banding. After eight weeks, the hearts underwent anatomic and diffusion tensor MRI to characterize wall thickening and microstructural disorganization. Additionally, myocardial samples underwent histological and gene expression analyses to quantify compositional changes and mechanical testing to quantify myocardial stiffening. All findings were compared to 12 control animals. Finally, we used computational modeling to disentangle the relative importance of each stiffening mechanism.ResultsFirst, we found that the RVs of PHT animals thickened most at the base and the free wall. Additionally, we found that PHT induced excessive collagen synthesis and microstructural disorganization, consistent with increased expression of fibrotic genes. We also found that the myocardium itself stiffened significantly. Importantly, myocardial stiffening correlated significantly with excess collagen synthesis. Finally, our model of normalized RV pressure-volume relationships predicted that myocardial stiffness contributes to RV stiffening significantly more than other mechanisms.ConclusionsIn summary, we found that PHT induces wall thickening, microstructural disorganization, and myocardial stiffening. These remodeling mechanisms were both spatially and directionally dependent. Using modeling, we show that myocardial stiffness is the primary contributor to RV stiffening. Thus, myocardial stiffening may be an important predictor for PHT progression. Given the significant correlation between myocardial stiffness and collagen synthesis, collagen-sensitive imaging modalities may be useful for non-invasively estimating myocardial stiffness and predicting PHT outcomes.
Resolvin D2-GPR18 Signaling on Myeloid Cells Limits Plaque Necrosis
Authors: Lipscomb Masharh , Walis Sean , Marinello Michael , Mena Hebe Agustina , Spite Matthew , Fredman Gabrielle 
Published: April 2023

AbstractIntroduction/ObjectiveDysregulated inflammation-resolution programs are associated with atherosclerosis progression. Inflammation-resolution is in part mediated by Resolvins, including Resolvin D2 (RvD2). RvD2, which activates a G-protein coupled receptor (GPCR) called GPR18, limits plaque progression. Cellular targets of RvD2 are not known.Approach and ResultsHere we developed humanized GPR18 floxed (“fl/fl”) and a myeloid (Lysozyme M Cre) GPR18 knockout (mKO) mouse. We functionally validated this model by assessing efferocytosis in bone marrow derived macrophages (BMDMs) and found that RvD2 enhanced efferocytosis in the fl/fl, but not in the mKO BMDMs. We employed two different models to evaluate the role of GPR18 in atherosclerosis. We first used the PCSK9-gain of function approach and found increased necrosis in the plaques of the mKO mice compared with fl/fl mice. Next, we performed a bone marrow transfer of fl/fl or mKO bone marrow intoLdlr-/-recipients. For these experiments, we treated each genotype with either Veh or RvD2 (25 ng/mouse, 3 times/week for 3 weeks). Myeloid loss of GPR18 resulted in significantly more necrosis and cleaved caspase-3+cells compared with fl/fl transplanted mice. RvD2 treatment decreased plaques necrosis and cleaved caspase-3+cells in fl/fl, but not in the mKO transplanted mice.ConclusionsThese results are the first to suggest a causative role for endogenous RvD2 signaling on myeloid cells in limiting plaque necrosis. Moreover, these results provide a mechanistic basis for RvD2 as a therapy limiting plaque necrosis.
Assessment of the normal cell contamination impact on tumour sample analysed with SNP arrays: The signal confusion nightmare
Authors: Poulet Christophe B. , Swingland James T. , Botta Vincent , Robe Pierre , Herens Christian , Turkheimer Federico , Bours Vincent 
Published: April 2023

AbstractRecent advances in high-throughput technologies enable a more comprehensive interpretation of the tumour evolution through the study of the intra-tumour heterogeneity. Several algorithms, however, often relies on the use of models that described the top of the iceberg regarding the stromal contamination of the samples, making diagnosis difficult to assess. Indeed, such as radio wave receivers, tools to analyse high-throughput technologies data, are used to enable the discrimination between multiple signals differing in frequencies. However, such tools often look at the average frequency more than distinct signals, leading to analyse a confused signal. This confusion could dramatically lead to a mis–interpretation of the real data, especially during the diagnosis as it relies on the choice of a unique scenario among many others. Here, we describe how this signal confusion occurs in the most classical DNA microarray analysis of tumours and we provide statistics to determine how many other possible scenario can lead the same signals, in order to improve the robustness of pigeon hole logic based analysis. Based on simulations, where a unique tumour population was diluted by an increasing gradient of normal cells, we underline the causes and consequences of such signal confusion for up to five allelic copies. Despite the removal of all technical biaises and background noise, we show how the signal confusion remains systematically present in the commonly used DNA microarray analysis, especially for the genotypes AAAAB, AAAB and AAB for copy numbers 5, 4 and 3 respectively, as well as their symmetric combinations for the B allele.
PPIAT: Target Mass Spectrometry-based Protein-Protein Interaction Analytics Tool
Authors: Park Jongham , Son Ahrum , Kim Hyunsoo 
Published: April 2023

AbstractMotivationThe formation of protein networking is critical for understanding the biological functions of proteins and the underlying mechanisms of disease. To gain insights into target proteins that interact with a particular disease, we need to profiling all the proteins involved in the disease beforehand. However, the profiling results may not necessarily match with an experimental target protein. Therefore, it is necessary to identify physical protein-protein interactions (PPIs) using various methods. The cross-linking mass spectrometry (XL-MS) method is a representative approach to identify physical interactions between proteins, but there are many challenges in calculating theoretical mass values for application to target mass spectrometry.ResultsThe research team developed PPIAT, which integrates information on reviewed human proteins, protein-protein interactions, cross-linkers, enzymes, and modifications. All functions are available for free on the web application.Availability and implementationThe PPIAT is available atwww.ppiat.cnu.ac.krContactkimlab@cnu.ac.kr
Spatial analysis of human lung cancer reveals organized immune hubs enriched for stem-like CD8 T cells and associated with immunotherapy response
Authors: Chen Jonathan H. , Nieman Linda T. , Spurrell Maxwell , Jorgji Vjola , Richieri Peter , Xu Katherine H. , Madhu Roopa , Parikh Milan , Zamora Izabella , Mehta Arnav , Nabel Christopher S. , Freeman Samuel S. , Pirl Joshua D. , Lu Chenyue , Meador Catherine B. , Barth Jaimie L. , Sakhi Mustafa , Tang Alexander L. , Sarkizova Siranush , Price Colles , Fernandez Nicolas F. , Emanuel George , He Jiang , Raay Katrina Van , Reeves Jason W. , Yizhak Keren , Hofree Matan , Shih Angela , Sade-Feldman Moshe , Boland Genevieve M. , Pelka Karin , Aryee Martin , Korsunsky Ilya , Mino-Kenudson Mari , Gainor Justin F. , Hacohen Nir 
Published: April 2023

ABSTRACTThe organization of immune cells in human tumors is not well understood. Immunogenic tumors harbor spatially-localized multicellular ‘immunity hubs’ defined by expression of the T cell-attracting chemokinesCXCL10/CXCL11and abundant T cells. Here, we examined immunity hubs in human pre-immunotherapy lung cancer specimens, and found that they were associated with beneficial responses to PD-1-blockade. Immunity hubs were enriched for many interferon-stimulated genes, T cells in multiple differentiation states, andCXCL9/10/11+ macrophages that preferentially interact with CD8 T cells. Critically, we discovered the stem-immunity hub, a subtype of immunity hub strongly associated with favorable PD-1-blockade outcomes, distinct from mature tertiary lymphoid structures, and enriched for stem-like TCF7+PD-1+ CD8 T cells and activatedCCR7+LAMP3+ dendritic cells, as well as chemokines that organize these cells. These results elucidate the spatial organization of the human intratumoral immune response and its relevance to patient immunotherapy outcomes.
Quartets enable statistically consistent estimation of cell lineage trees under an unbiased error and missingness model
Authors: Han Yunheng , Molloy Erin K. 
Published: April 2023

AbstractCancer progression and treatment can be informed by reconstructing its evolutionary history from tumor cells. However, traditional methods assume the input data are error-free and the output tree is fully resolved. These assumptions are challenged in tumor phylogenetics because single-cell sequencing produces sparse, error-ridden data and because tumors evolve clonally. Here, we find that methods based on quartets (four-leaf, unrooted trees) withstand these barriers. We consider a popular tumor phylogenetics model, in which mutations arise on a (highly unresolved) tree and then (unbiased) errors and missing values are introduced. Quartets are implied by mutations present in two cells and absent from two cells. Our main result is that the most probable quartet identifies the unrooted model tree on four cells. This motivates seeking a tree such that the number of quartets shared between it and the input mutations is maximized. We prove an optimal solution is a consistent estimator of the unrooted cell lineage tree; this guarantee includes the case where the model tree is highly unresolved, with error defined as the number of false negative branches. Lastly, we outline how quartet-based methods might be employed when there are copy number aberrations and other challenges specific to tumor phylogenetics.
tauFisher accurately predicts circadian time from a single sample of bulk and single-cell transcriptomic data
Authors: Duan Junyan , Ngo Michelle N. , Karri Satya Swaroop , Tsoi Lam C. , Gudjonsson Johann E. , Shahbaba Babak , Lowengrub John , Andersen Bogi 
Published: April 2023

AbstractAs the circadian clock regulates fundamental biological processes, disrupted clocks are often observed in patients and diseased tissues. Determining the circadian time of the patient or the tissue of focus is essential in circadian medicine and research. Here we present tau-Fisher, a computational pipeline that accurately predicts circadian time from a single transcriptomic sample by finding correlations between rhythmic genes within the sample. We demonstrate tauFisher’s out-standing performance in both bulk and single-cell transcriptomic data collected from multiple tissue types and experimental settings. Application of tauFisher at a cell-type level in a single-cell RNA-seq dataset collected from mouse dermal skin implies that greater circadian phase heterogeneity may explain the dampened rhythm of collective core clock gene expression in dermal immune cells compared to dermal fibroblasts. Given its robustness and generalizability across assay platforms, experimental setups, and tissue types, as well as its potential application in single-cell RNA-seq data analysis, tauFisher is a promising tool that facilitates circadian medicine and research.
A photoreceptor-based hydrogel with red light-responsive reversible sol-gel transition as transient cellular matrix
Authors: Hörner Maximilian , Becker Jan , Bohnert Rebecca , Baños Miguel , Jerez-Longres Carolina , Mühlhäuser Vanessa , Härrer Daniel , Wong Tin Wang , Meier Matthias , Weber Wilfried 
Published: April 2023

AbstractHydrogels with adjustable mechanical properties have been engineered as matrices for mammalian cells and allow the dynamic, mechano-responsive manipulation of cell fate and function. Recent research yielded hydrogels, where biological photoreceptors translated optical signals into a reversible and adjustable change in hydrogel mechanics. While their initial application provided important insights into mechanobiology, broader implementation is limited by a small dynamic range of addressable stiffness. Here, we overcome this limitation by developing a photoreceptor-based hydrogel with reversibly adjustable stiffness from 800 Pa to the sol state. The hydrogel is based on star-shaped polyethylene glycol, functionalized with the red/far-red light photoreceptor phytochrome B (PhyB), or phytochrome-interacting factor 6 (PIF6). Upon illumination with red light, PhyB heterodimerizes with PIF6, thus crosslinking the polymers and resulting in gelation. However, upon illumination with far-red light, the proteins dissociate and trigger a complete gel-to-sol transition. We comprehensively characterize the hydrogel’s light-responsive mechanical properties and apply it as reversible extracellular matrix for the spatiotemporally controlled deposition of mammalian cells within a microfluidic chip. We anticipate that this technology will open new avenues for the site- and time-specific positioning of cells and will contribute to overcome spatial restrictions.
Dolphin social phenotypes vary in response to food availability but not the North Atlantic Oscillation index
Authors: Fisher David N. , Cheney Barbara J. 
Published: April 2023

AbstractSocial behaviours can allow individuals to flexibly respond to environmental change, potentially buffering adverse effects. However, individuals may respond differently to the same environmental stimulus, complicating predictions for population-level response to environmental change. Here we show that bottlenose dolphins (Tursiops truncatus) alter their social behaviour at yearly and monthly scales in response to a proxy for food availability (salmon abundance) but do not respond to variation in a proxy for climate (the North Atlantic Oscillation index). There was also individual variation in plasticity for gregariousness and connectedness to distant parts of the social network, although these traits showed limited repeatability. In contrast, individuals showed consistent differences in clustering with their immediate social environment at the yearly scale but no individual variation in plasticity for this trait at either time scale. These results indicate that social behaviour in free-ranging cetaceans can be highly resource dependent with individuals increasing their connectedness over short timescales but possibly reducing their wider range of connection at longer timescales. Some social traits showed more individual variation in plasticity or mean behaviour than others, highlighting how predictions for the responses of populations to environmental variation must consider the type of individual variation present in the population.
Targeting Myeloma Essential Genes using NOT Gated CAR- T Cells, a computational approach
Authors: Walker Ieuan G , Roy James , Anderson Georgina , Lopez Jose Guerrereo , Chapman Michael A 
Published: April 2023

AbstractSensitive cell surface proteomics studies have shown that the number of completely tumour-specific targets for adoptive cellular immunotherapy is extremely low. Even approved CAR T-cell targets appear to have expression in the central nervous system, leading to long-term neurological complications. We propose that this toxicity could be significantly improved by adoption of NOT-gates, which have been shown to limit CAR T-cell activity against healthy tissue expressing a second target that is absent on the tumour. Furthermore, the approach could also target essential, but non-specific proteins on tumour cells. The use of a NOT gate confers the specificity, whilst targeting the essential protein limits antigen escape. Here we explore the feasibility of such an approach for CAR T-cell targeting of primary myeloma. We show that none of the 45 most essential proteins are unique to the myeloma cell. However, whilst widely expressed, one of the most important proteins for myeloma cell survival, the transferrin receptor, could safely be targeted by a NOT-gate approach. Exploring co-expression patterns demonstrate 26 proteins that are not expressed on myeloma cells, but which are coexpressed with the transferrin receptor in all healthy tissues. We also describe a web app, NOTATER, which can be used by scientists with no bioinformatic capabilities to explore potential NOT-gate combinations in myeloma.
Inhibition of miR-214 expression by small molecules alleviates head and neck cancer metastasis by targeting ALCAM/TFAP2 signaling
Authors: Agarwal Anshu , Kansal Vikash , Farooqi Humaira , Prasad Ram , Singh Vijay Kumar 
Published: April 2023

AbstractPredominantly, head and neck cancer (HNC) is considered a regional disease and develops in the nasal cavity, oral cavity, tongue, pharynx, and larynx. In the advanced stage, the HNC spread into distant organs. By the time head and neck cancer diagnosed, the estimated metastasis is occurred in 10-40% cases. The most important vital organs affected by distant metastasis are the lungs, bones, and liver. Despite several advancements in chemotherapies, no significant changes are observed as 5-year survival rate remains the same. Therefore, it is crucial to decipher molecular mechanisms contributing to the metastatic dissemination of head and neck cancer. Here, we tested a novel ALCAM/TFAP2 signaling by targeting multidisciplinary miR-214 expression in head and cancer cells. Our results revealed that HNC cell lines (CAL27, SCC-9, SCC-4, and SCC-25) exhibit higher expression of miR-214 compared with normal human bronchial epithelial (NHBE) cells. Higher expression of miR-214 drives the invasive potential of these cell lines. Down-regulation of miR-214 in CAL27 and SCC-9 cells either using an anti-miR-214 inhibitor (50nM) or a small molecule of green tea (EGCG) inhibited cell invasion. Treating CAL27 and SCC-9 cells with EGCG also reduces ALCAM expression, a key activated leukocyte cell adhesion molecule, potentially blocking mesenchymal phenotype. Dietary administration of EGCG significantly inhibits distant metastasis of SCC-9 cells into the lungs, liver, and kidneys. Our results also demonstrate that the reduction of miR-214 expression influences in vitro cell movement and extravasation, as evident by reduced CD31 expression, a neovascularization marker. Together, these studies suggest that identifying bioactive molecules that can inhibit distant metastasis regulated by the miRNAs may provide potent interventional approaches and a better understanding of the complex functions of miRNAs and their therapeutic targets for clinical application.
Hepatocyte Dedifferentiation Profiling In Alcohol-Related Liver Disease Identifies CXCR4 As A Driver Of Cell Reprogramming
Authors: Aguilar-Bravo Beatriz , Ariño Silvia , Blaya Delia , Pose Elisa , Martinez García de la Torre Raquel A. , Latasa María U , Martínez-Sánchez Celia , Zanatto Laura , Sererols-Viñas Laura , Cantallops Paula , Affo Silvia , Coll Mar , Thillen Xavier , Dubuquoy Laurent , Avila Matías A , Argemi Josep Maria , Paz Arantza Lamas , Nevzorova Yulia A. , Cubero Javier , Bataller Ramon , Lozano Juan José , Ginès Pere , Mathurin Philippe , Sancho-Bru Pau 
Published: April 2023

ABSTRACTBackground and AimsLoss of hepatocyte identity is associated with impaired liver function in alcohol-related hepatitis (AH). In this context, hepatocyte dedifferentiation gives rise to cells with a hepatobiliary (HB) phenotype expressing biliary and hepatocytes markers and showing immature features. However, the mechanisms and the impact of hepatocyte dedifferentiation in liver disease are poorly understood.MethodsHB cells and ductular reaction (DR) cells were quantified and microdissected from liver biopsies from patients with alcohol-related liver disease (ALD). Hepatocyte- specific overexpression or deletion of CXCR4, and CXCR4 pharmacological inhibition were assessed in mouse liver injury. Patient-derived and mouse organoids were generated to assess plasticity.ResultsHere we show that HB and DR cells are increased in patients with decompensated cirrhosis and AH, but only HB cells correlate with poor liver function and patients’ outcome. Transcriptomic profiling of HB cells revealed the expression of biliary-specific genes and a mild reduction of hepatocyte metabolism. Functional analysis identified pathways involved in hepatocyte reprogramming, inflammation, stemness and cancer gene programs. CXCR4 pathway was highly enriched in HB cells, and correlated with disease severity and hepatocyte dedifferentiation.In vitro, CXCR4 was associated with biliary phenotype and loss of hepatocyte features. Liver overexpression of CXCR4 in chronic liver injury decreased hepatocyte specific gene expression profile and promoted liver injury. CXCR4 deletion or its pharmacological inhibition ameliorated hepatocyte dedifferentiation and reduced DR and fibrosis progression.ConclusionsThis study shows the association of hepatocyte dedifferentiation with disease progression and poor outcome in AH. Moreover, the transcriptomic profiling of HB cells revealed CXCR4 as a new driver of hepatocyte-to-biliary reprogramming and as a potential therapeutic target to halt hepatocyte dedifferentiation in AH.Lay summaryHere we describe that hepatocyte dedifferentiation is associated with disease severity and a reduced synthetic capacity of the liver. Moreover, we identify the CXCR4 pathway as a driver of hepatocyte dedifferentiation and as a therapeutic target in alcohol-related hepatitis.
Hydramorphogenesis as phase-transition dynamics
Authors: Agam Oded , Braun Erez 
Published: April 2023

ABSTRACTWe utilize whole-bodyHydraregeneration from a small tissue segment to develop a physics framework for animal morphogenesis. Introducing experimental controls over this process, an external electric field and a drug that blocks gap junctions, allows us to characterize the essential step in the morphological transition - from a spherical shape to an elongated spheroid. We find that spatial fluctuations of the Ca2+distribution in theHydra’stissue drive this transition and construct a field-theoretic model that explains the morphological transition as a first-order-like phase transition resulting from the coupling of the Ca2+field and the tissue’s local curvature. Various predictions of this model are verified experimentally.