bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stat3-mediated Atg7 expression enhances anti-tumor immunity in melanoma
Authors: Zimmerman Sarah M. , Suh Erin , Smith Sofia R. , Souroullas George P. 
Published: June 2024

ABSTRACTEpigenetic modifications to DNA and chromatin control oncogenic and tumor suppressive mechanisms in melanoma. EZH2, the catalytic component of the Polycomb repressive complex 2 (PRC2), which mediates methylation of lysine 27 on histone 3 (H3K27me3), can regulate both melanoma initiation and progression. We previously found that mutantEzh2Y641Finteracts with the immune regulator Stat3 and together they affect anti-tumor immunity. However, given the numerous downstream targets and pathways affected by EZH2, many mechanisms that determine its oncogenic activity remain largely unexplored. Using genetically engineered mouse models we further investigated the role of pathways downstream of EZH2 in melanoma carcinogenesis and identified significant enrichment in several autophagy signatures, along with increased expression of autophagy regulators, such as Atg7. In this study, we investigated the effect of Atg7 on melanoma growth and tumor immunity within the context of anEzh2Y641Fepigenetic state. We found that expression of Atg7 is largely dependent on Stat3 expression and that deletion of Atg7 slows down melanoma cell growthin vivo, but notin vitro. Atg7 deletion also results in increased CD8+ T cells and reduced myelosuppressive cell infiltration in the tumor microenvironment, suggesting a strong immune system contribution in the role of Atg7 in melanoma progression. These findings highlight the complex interplay between genetic mutations, epigenetic regulators, and autophagy in shaping tumor immunity in melanoma.
Steady-state, therapeutic, and helminth-induced IL-4 compromise protective CD8 T cell bystander activation
Authors: Maurice Nicholas J , Dalzell Talia S , Jarjour Nicholas N , DePauw Taylor A , Jameson Stephen C 
Published: June 2024

AbstractMemory CD8 T cells (Tmem) can be activated into innate-like killers by cytokines like IL-12, IL-15, and/or IL-18; but mechanisms regulating this phenomenon (termed bystander activation) are not fully resolved. We found strain-intrinsic deficiencies in bystander activation using specific pathogen-free mice, whereby basal IL-4 signals antagonize IL-18 sensing. We show that therapeutic and helminth-induced IL-4 impairs protective bystander-mediated responses against pathogens. However, this IL-4/IL-18 axis does not completely abolish bystander activation but rather tunes the expression of direct versus indirect mediators of cytotoxicity (granzymes and interferon-γ, respectively). We show that antigen-experience overrides strain-specific deficiencies in bystander activation, leading to uniform IL-18 receptor expression and enhanced capacity for bystander activation/cytotoxicity. Our data highlight that bystander activation is not a binary process but tuned/deregulated by other cytokines that are elevated by contemporaneous infections. Further, our findings underscore the importance of antigen-experienced Tmemto dissect the contributions of bystander Tmemin health and disease.
Multimodal Phasor Approach to study breast cancer cells invasion in 3D spheroid model
Authors: Tedeschi Giulia , Palomba Francesco , Scipioni Lorenzo , Digman Michelle A. 
Published: June 2024

AbstractWe implemented a multimodal set of functional imaging techniques optimized for deep-tissue imaging to investigate how cancer cells invade surrounding tissues and how their physiological properties change in the process. As a model for cancer invasion of the extracellular matrix, we created 3D spheroids from triple-negative breast cancer cells (MDA-MB-231) and non-tumorigenic breast epithelial cells (MCF-10A). We analyzed multiple hallmarks of cancer within the same spheroid by combining a number of imaging techniques, such as metabolic imaging of NADH by Fluorescence Lifetime Imaging Microscopy (NADH-FLIM), hyperspectral imaging of a solvatochromic lipophilic dye (Nile Red) and extracellular matrix imaging by Second Harmonic Generation (SHG). We included phasor-based bioimage analysis of spheroids at three different time points, tracking both morphological and biological properties, including cellular metabolism, fatty acids storage, and collagen organization. Employing this multimodal deep-imaging framework, we observed and quantified cancer cell plasticity in response to changes in the environment composition.
Functional Changes to Achilles Tendon and Enthesis in a Mouse Model of an Adolescent Masculine Gender-Affirming Hormone Treatment
Authors: Hold LeeAnn A. , Phillips Tessa , Cordts Paige , Steltzer Steph , Bae Seung-Ho , Henry Brandon , Migotsky Nicole , Grossman Sydney , Cruz Cynthia Dela , Padmanabhan Vasantha , Moravek Molly , Shikanov Ariella , Abraham Adam C. , Killian Megan L. 
Published: June 2024

AbstractMany transgender youth seek gender affirming care, such as puberty suppression, to prolong decision-making and to align their physical sex characteristics with their gender identity. During peripubertal growth, connective tissues such as tendon rapidly adapt to applied mechanical loads (e.g., exercise) yet if and how tendon adaptation is influenced by sex and gender affirming hormone therapy during growth remains unknown. The goal of this study was to understand the how pubertal suppression influences the structural and functional properties of the Achilles tendon using an established mouse model of transmasculine gender affirming hormone therapy. C57BL/6N female-born mice were assigned to experimental groups to mimic gender-affirming hormone therapy in human adolescents, and treatment was initiated prior to the onset of puberty (at postnatal day 26, P26). Experimental groups included controls and mice serially treated with gonadotropin release hormone analogue (GnRHa), delayed Testosterone (T), or GnRHa followed by T. We found that puberty suppression using GnRHa, with and without T, improved the overall tendon load capacity in female-born mice. Treatment with T resulted in an increase in the maximum load that tendon can withstand before failure. Additionally, we found that GnRHa, but not T, treatment resulted in a significant increase in cell density at the Achilles enthesis.NEW & NOTEWORTHYThese findings demonstrate that puberty suppression or testosterone does not negatively influence tendon structural or functional properties in a mouse model of transmasculine gender affirming care. In all treatment groups, the ability of the tendon to withstand load was significantly increased. Puberty suppression with GnRHa significantly increased enthesis cell density, suggesting an extended growth phase. These findings elucidate the effects of gender affirming care on the structural and functional properties of the tendon and enthesis.
HDI-STARR-seq: Condition-specific enhancer discovery in mouse liver in vivo
Authors: Chang Ting-Ya , Waxman David J 
Published: June 2024

AbstractSTARR-seq and other massively-parallel reporter assays are widely used to discover functional enhancers in transfected cell models, which can be confounded by plasmid vector-induced type-I interferon immune responses and lack the multicellular environment and endogenous chromatin state of complex mammalian tissues. Here, we describe HDI-STARR-seq, which combines STARR-seq plasmid library delivery to the liver, by hydrodynamic tail vein injection (HDI), with reporter RNA transcriptional initiation driven by a minimalAlbuminpromoter, which we show is essential for mouse liver STARR-seq enhancer activity assayed 7 days after HDI. Importantly, little or no vector-induced innate type-I interferon responses were observed. Comparisons of HDI-STARR-seq activity between male and female mouse livers and in livers from males treated with an activating ligand of the transcription factor CAR (Nr1i3) identified many condition-dependent enhancers linked to condition-specific gene expression. Further, thousands of active liver enhancers were identified using a high complexity STARR-seq library comprised of ∼50,000 genomic regions released by DNase-I digestion of mouse liver nuclei. When compared to stringently inactive library sequences, the active enhancer sequences identified were highly enriched for liver open chromatin regions with activating histone marks (H3K27ac, H3K4me1, H3K4me3), were significantly closer to gene transcriptional start sites, and were significantly depleted of repressive (H3K27me3, H3K9me3) and transcribed region histone marks (H3K36me3). HDI-STARR-seq offers substantial improvements over current methodologies for large scale, functional profiling of enhancers, including condition-dependent enhancers, in liver tissue in vivo, and can be adapted to characterize enhancer activities in a variety of species and tissues by selecting suitable tissue- and species-specific promoter sequences.
Suppression of T cell function by phosphoethanolamine, a metabolite enriched in tumor interstitial fluid
Authors: Wang Yupeng , Wilfahrt Drew , Cai Chufan , Lontos Konstantinos , Cameron Benjamin , Xie Bingxian , Peralta Ronal M. , AminiTabrizi Roya , Shah Hardik , Rivadeneira Dayana B. , Muir Alexander , Delgoffe Greg M. 
Published: June 2024

AbstractNutrient stress represents a significant barrier for antitumor immunity, and tumor interstitial fluid (TIF) often contains metabolites that hinder immune function. However, it is difficult to isolate the effects of tumor nutrient stress from other suppressive factors. Thus, we employed a chemically-defined cell culture medium based on the metabolomic profile of TIF: Tumor Interstitial Fluid Medium (TIFM). Culture of CD8+T cells in TIFM limited cell expansion and impaired CD8+T cell effector functions upon restimulation, suggesting tumor nutrient stress alone is sufficient to drive T cell dysfunction. We identified phosphoethanolamine (pEtn), a phospholipid intermediate, as a driver of T cell dysfunction. pEtn dampened TCR signaling by depleting T cells of diacylglycerol required for TCR signal transduction. Reduction of pEtn accumulation in tumors improved intratumoral T cell function and tumor control, suggesting pEtn accumulation plays a dominant role in TME immunosuppression.
Metabolomic Profiling and Characterization of a Novel 3D Culture System for Studying Chondrocyte Mechanotransduction
Authors: Brahmachary Priyanka P. , Erdogan Ayten E. , Myers Erik P. , June Ronald K. 
Published: June 2024

AbstractBackground/ObjectiveArticular chondrocytes synthesize and maintain the avascular and aneural articular cartilage.In vivothese cells are surrounded by a 3D pericellular matrix (PCM) containing predominantly collagen VI. The PCM protects chondrocytes and facilitates mechanotransduction. PCM stiffness is critical in transmitting biomechanical signals to chondrocytes. Various culture systems with different hydrogels are used to encapsulate chondrocytes for 3D culture, but many lack either the PCM or thein vivostiffness of the cartilage matrix. This study aimed at establishing a culture system to investigate a) if chondrocytes cultured in alginate will develop a PCM and b) study mechanotransduction via metabolic changes induced in 3D agarose-embedded chondrocytes upon mechanical stimulation.MethodsWe cultured primary human and bovine chondrocytes in monolayers or as alginate encapsulated cells in media containing sodium L-ascorbate. PCM expression was analyzed by immunofluorescence and western blots. We further characterized the response of chondrocytes embedded in physiologically stiff agarose to dynamic compression through metabolomic profiling.ResultsWe found that primary human and bovine chondrocytes, when cultured in alginate beads with addition of sodium L-ascorbate for 7 days, had a pronounced PCM, retained their phenotype, and synthesized both collagens VI and II. This novel culture system enables alginate-encapsulated chondrocytes to develop a robust PCM thereby creating a model system to study mechanotransduction in the presence of an endogenous PCM. We also observed distinct compression-induced changes in metabolomic profiles between the monolayer-agarose and alginate-released agarose-embedded chondrocytes indicating physiological changes in cell metabolism.Conclusion/SignificanceThese data show that 3D preculture of chondrocytes in alginate before encapsulation in physiologically stiff agarose leads to pronounced development of pericellular matrix that is sustained in the presence of ascorbate. This model can be useful in studying the mechanism by which chondrocytes respond to cyclical compression and other types of loading simulatingin vivophysiological conditions.
Chromosome-level genome assemblies for two quinoa inbred lines from northern and southern highlands of Altiplano where quinoa originated
Authors: Kobayashi Yasufumi , Hirakawa Hideki , Shirasawa Kenta , Nishimura Kazusa , Fujii Kenichiro , Oros Rolando , Almanza Giovanna R. , Nagatoshi Yukari , Yasui Yasuo , Fujita Yasunari 
Published: June 2024

SummaryQuinoa, an annual allotetraploid plant native to the Andean highlands of South America, is emerging as an important seed crop for global food and nutrition security due to its ability to grow in marginal environments and its excellent nutritional properties. Because quinoa is partially allogamous, we have developed quinoa inbred lines necessary for molecular genetic analysis. Our comprehensive genomic analysis showed that the quinoa inbred lines fall into three genetic subpopulations: northern highland, southern highland, and lowland. Lowland and highland quinoa are the same species, but have very different genotypes and phenotypes. Lowland quinoa has relatively small grains and a darker grain color, and is widely tested and grown around the world. In contrast, the white, large-grained highland quinoa is grown in the Andean highlands, including the region where quinoa originated, and is exported worldwide as high-quality quinoa. Recently, we have shown that viral vectors can be used to regulate endogenous genes in quinoa, paving the way for functional genomics of quinoa. However, although a high-quality assembly has recently been reported for a lowland quinoa line, genomic resources of the quality required for functional genomics are not available for highland quinoa lines. Here we present high-quality chromosome-level genome assemblies for two highland inbred quinoa lines, J075 representing the northern highland line and J100 representing the southern highland line, using PacBio HiFi sequencing and dpMIG-seq. The assembled genome sizes of J075 and J100 are 1.29 and 1.32 Gb, with contigs N50 of 66.3 and 12.6 Mb, and scaffold N50 of 71.2 and 70.6 Mb, respectively, comprising 18 pseudochromosomes. The repetitive sequences of J075 and J100 represent 72.6% and 71.5% of the genome, the majority of which are long terminal repeats (GypsyandCopia), representing 44.0% and 42.7% of the genome, respectively. Thede novoassembled genomes of J075 and J100 were predicted to contain 64,945 and 65,303 protein-coding genes, respectively. The high quality genomes of these highland quinoa lines will facilitate quinoa functional genomics research on quinoa and contribute to the identification of key genes involved in environmental adaptation and quinoa domestication.
VaxOptiML: Leveraging Machine Learning for Accurate Prediction of MHC-I & II Epitopes for Optimized Cancer Immunotherapy
Authors: T Dhanushkumar , B G Sunila , Hebbar Sripad Rama , Selvam Prasanna Kumar , Vasudevan Karthick 
Published: June 2024

AbstractIn the realm of cancer immunotherapy, the ability to accurately predict epitopes is crucial for advancing vaccine development. Here, we introduce VaxOptiML (available athttps://vaxoptiml.streamlit.app/), an integrated pipeline designed to enhance epitope prediction and prioritization. Utilizing a curated dataset of experimentally validated epitopes and sophisticated machine learning techniques, VaxOptiML features three distinct models that predict epitopes from target sequences, pair them with personalized HLA types, and prioritize them based on immunogenicity scores. Our rigorous process of data cleaning, feature extraction, and model building has resulted in a tool that demonstrates exceptional accuracy, sensitivity, specificity, and F1-score, surpassing existing prediction methods. The robustness and efficacy of VaxOptiML are further illustrated through comprehensive visual representations, underscoring its potential to significantly expedite epitope discovery and vaccine design in cancer immunotherapy, Additionally, we have deployed the trained ML model using Streamlit for public usage, enhancing accessibility and usability for researchers and clinician.
Vasoactive Intestinal Peptide Amphiphile Micelle Material Properties Influence Their Cell Association and Internalization
Authors: Wang Xiaofei , Barcellona Agustin T. , Nowruzi Fateme , Brandt Kambrie , Schulte Megan C. , Kruse Luke E. , Dong Eric , Ulery Bret D. 
Published: June 2024

AbstractVasoactive intestinal peptide (VIP) is a promising anti-inflammatory peptide therapeutic that is known to induce biological effects by interacting with its cognate receptor (i.e., VPAC) on the surface of antigen presenting cells (APCs). For VIP-based drug delivery technologies like nano- and microparticles, little is known about the effect VPAC targeting has on APC behavior. This is further influenced by the fact that particulate material properties including chemistry, shape, and size are all known to influence APC behavior. In this study, peptide amphiphile micelles (PAMs) were employed as a modifiable platform to study the impact VPAC targeting and physical particle properties have on their association with macrophages. VIP amphiphile micelles (VIPAMs) and their scrambled peptide amphiphile micelle analogs (SVIPAMs) were fabricated from various chemistries yielding particle batches that were comprised of spheres (10 - 20 nm in diameter) and/or cylinders of varying lengths (i.e., 20 - 9000 nm). Micelle surface attachment to and internalization by macrophages were observed using confocal microscopy and their association was characterized by flow cytometry. The enclosed work provides strong evidence that macrophages rapidly bind VPAC specific micelles independent of physical properties though micelle shape and size as well as receptor-specificity all influence their long-term macrophage association. Specifically, a mixture of spherical and short cylindrical VIPAMs were able to achieve the greatest cell association which may correlate to their capacity to fully bind the VPAC receptors available on the surface of macrophages. These results provide the foundation of how nano- and microparticle physical properties and targeting capacity synergistically influence their capacity to associate with APCs.
A tool for mapping medical narratives into medical ontologies in low resource settings: A case study for German
Authors: Mustafa Faizan E , Diaz Ochoa Juan G. 
Published: June 2024

AbstractNamed Entity Recognition (NER) is extremely relevant in the clinical field since it allows the extraction of information, such as diagnoses or medical procedures, from non-structured data (doctor’s letters, vignettes, etc.) and coding them based on international classification systems. As a result, language models should be trained to recognize and classify these items accurately. While Large Language Models (LLMs) like ChatGPT are capable of recognizing medical entities in texts, they are not reliable at performing this task. Unlike English, where there are a variety of resources to assist with this task, other languages, such as German, lack appropriate language models. This study presents a methodology for the generation of high-quality full-synthetic datasets and the implementation of a workflow for the identification and classification of diseases, co-diseases, and medical procedures for clinical narratives in oncology.
Differential Results of Polygenic Risk Scoring for Multiple Sclerosis in European and African American Populations
Authors: Rivier Cyprien A. , Payabvash Seyedmehdi , Zhao Hongyu , Hafler David A. , Falcone Guido J. , Longbrake Erin E. 
Published: June 2024

AbstractImportanceThe risk of multiple sclerosis (MS) is significantly influenced by polygenic inheritance. Polygenic risk scores (PRS) for MS can help identify high-risk individuals and stratify populations for clinical trials. However, most genome-wide association studies (GWAS) have been conducted in populations of European ancestry, raising questions about the accuracy of these PRS in other ancestries.ObjectiveTo determine whether a PRS for MS can effectively stratify individuals of non-European ancestries.Design, setting and participantsThis cross-sectional study utilized prospectively collected data from the All of Us Research Program (2018-2023). It included participants who had both whole genome sequencing and electronic health record (EHR) data.Exposure(s)A PRS comprising 282 independent single nucleotide variants for MS, divided into quintiles.Main Outcome(s) and Measure(s)Prevalence of multiple sclerosis ascertained through ICD-10 or SNOMED codes.ResultsIn this study population, MS cases comprised 1.0% (327 cases) of the European population, 0.56% (183 cases) of the African population, and 0.46% (150 cases) of the Latino/admixed American population. In analyses adjusting for age, sex, and genetic principal components, the PRS associates with MS risk in the European population, with a 141% increase in the risk of MS for individuals in the highest compared to the lowest PRS quintile (OR: 2.41 [1.69-3.50], test-for-trend p<0.001). Similarly, the PRS appropriately partitions the Latino/admixed population into increasing MS risk groups (OR: 2.56 [1.45-4.78], test-for-trend p-value <0.001). However, it did not significantly stratify the African population into distinct MS risk categories (OR: 1.45 [0.95-2.25], test-for-trend p=0.10).Conclusions and RelevanceA PRS for MS effectively stratified individuals of European and Latino/admixed ancestries but not African ancestry. This highlights the need for ancestry-specific PRS development to ensure accurate risk prediction across diverse populations, emphasizing the importance of including non-European groups in MS genetic research.