bluuebunny/crossref_metadata_2025_split huggingface dataset:
Jasmonic acid and methyl jasmonate attenuate neuroinflammation via crosstalk with the prostaglandin E2/receptor EP2 signaling axis
Authors: Ward Emily L , Chen Philip E , Hussien-Ali Alaa 
Published: November 2023

AbstractThe jasmonates are a class of oxylipin phytohormones known to exhibit anti-inflammatory, antioxidant, and anti-cancer effects in mammalian cells. We investigated the ability of three jasmonate compounds (jasmonic acid, methyl jasmonate, and 12-OPDA) and two structurally distinct jasmonate precursors (alpha-linolenic acid and palmitic acid) to attenuate inflammation in anin vitromodel of neurodegenerative disease, for which the mechanisms of action have not been well identified. The study modeled chronic neuroinflammation in SH-SY5Y neuroblastoma cells using exogenous prostaglandin E2(PGE2) treatment. Prostaglandin E2caused concentration-dependent levels of inflammation and SH-SY5Y cell death, which were attenuated by the jasmonates and their precursors. To this end, structural similarities between the jasmonates and PGE2were correlated with increased potency of their anti-inflammatory effects. Downstream biomarkers of signaling through the pro-inflammatory E prostanoid receptor subtype 2 (EP2) were then quantified using enzyme-linked immunosorbent assay methods. Of the compounds tested, only jasmonic acid and methyl jasmonate attenuated inflammation in the SH-SY5Y cells via crosstalk with the PGE2/EP2 signaling axis. Additionally, structural models and molecular binding simulations serve as evidence for our hypothesis that JA and MeJA achieve this crosstalk through competitive inhibition of the receptor EP2. This novel finding has implications in the study of neurodegenerative diseases for which the disease pathology is related to chronic neuroinflammation, including Alzheimer’s Disease (AD), Parkinson’s Disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). In addition, these findings add to the understanding of the relationship between pro-inflammatory prostaglandin E2signaling and disease severity.
Integrating cellular graph embeddings with tumor morphological features to predict in-silico spatial transcriptomics from H&E images
Authors: Prabhakar Vignesh , Warner Elisa , Liu Kai 
Published: November 2023

AbstractSpatial transcriptomics allows precise RNA abundance measurement at high spatial resolution, linking cellular morphology with gene expression. We present a novel deep learning algorithm predicting local gene expression from histopathology images. Our approach employs a graph isomorphism neural network capturing cell-to-cell interactions in the tumor microenvironment and a Vision Transformer (CTransPath) for obtaining the tumor morphological features. Using a dataset of 30,612 spatially resolved gene expression profiles matched with histopathology images from 23 breast cancer patients, we identify 250 genes, including established breast cancer biomarkers, at a 100 µm resolution. Additionally, we co-train our algorithm on spatial spot-level transcriptomics from 10x Visium breast cancer data along with another variant of our algorithm on TCGA-BRCA bulk RNA Seq. data, yielding mutual benefits and enhancing predictive accuracy on both these datasets. This work enables image-based screening for molecular biomarkers with spatial variation, promising breakthroughs in cancer research and diagnostics.
A Cre-dependent reporter mouse for quantitative real-time imaging of Protein Kinase A activity dynamics
Authors: Tilden Elizabeth I. , Maduskar Aditi , Oldenborg Anna , Sabatini Bernardo L. , Chen Yao 
Published: November 2023

AbstractIntracellular signaling dynamics play a crucial role in cell function. Protein kinase A (PKA) is a key signaling molecule that has diverse functions, from regulating metabolism and brain activity to guiding development and cancer progression. We previously developed an optical reporter, FLIM-AKAR, that allows for quantitative imaging of PKA activity via fluorescence lifetime imaging microscopy and photometry. However, using viral infection or electroporation for the delivery of FLIM-AKAR is invasive, cannot easily target sparse or hard-to-transfect/infect cell types, and results in variable expression. Here, we developed a reporter mouse,FL-AK, which expresses FLIM-AKAR in aCre-dependent manner from theROSA26locus.FL-AKprovides robust and consistent expression of FLIM-AKAR over time. Functionally, the mouse line reports an increase in PKA activity in response to activation of both Gαsand Gαq-coupled receptors in brain slices.In vivo, FL-AKreports PKA phosphorylation in response to neuromodulator receptor activation. Thus,FL-AKprovides a quantitative, robust, and flexible method to reveal the dynamics of PKA activity in diverse cell types.
VLIB: Unveiling insights through Visual and Linguistic Integration of Biorxiv data relevant to cancer via Multimodal Large Language Model
Authors: Prabhakar Vignesh , Liu Kai 
Published: November 2023

AbstractThe field of cancer research has greatly benefited from the wealth of new knowledge provided by research articles and preprints on platforms like Biorxiv. This study investigates the role of scientific figures and their accompanying captions in enhancing our comprehension of cancer. Leveraging the capabilities of Multimodal Large Language Models (MLLMs), we conduct a comprehensive analysis of both visual and linguistic data in biomedical literature. Our work introduces VLIB, a substantial scientific figure-caption dataset generated from cancer biology papers on Biorxiv. After thorough preprocessing, which includes figure-caption pair extraction, sub-figure identification, and text normalization, VLIB comprises over 500,000 figures from more than 70,000 papers, each accompanied by relevant captions. We fine-tune baseline MLLMs using our VLIB dataset for downstream vision-language tasks, such as image captioning and visual question answering (VQA), to assess their performance. Our experimental results underscore the vital role played by scientific figures, including molecular structures, histological images, and data visualizations, in conjunction with their captions, in facilitating knowledge translation through MLLMs. Specifically, we achieved a ROUGE score of 0.66 for VQA and 0.68 for image captioning, as well as a BLEU score of 0.72 for VQA and 0.70 for image captioning. Furthermore, our investigation highlights the potential of MLLMs to bridge the gap between artificial intelligence and domain experts in the field of cancer biology.
Large Language Model-Driven Evaluation of Medical Records Using MedCheckLLM
Authors: Schubert Marc Cicero , Wick Wolfgang , Venkataramani Varun 
Published: November 2023

AbstractLarge Language Models (LLMs) offer potential in healthcare, especially in the evaluation of medical documents. This research introduces MedCheckLLM, a multi-step framework designed for the systematic assessment of medical records against established evidence-based guidelines, a process termed ‘guideline-in-the-loop’. By keeping the guidelines separate from the LLM’s training data, this approach emphasizes validity, flexibility, and interpretability. Suggested evidence-based guidelines are externally accessed and fed back into the LLM for a evaluation. The method enables implementation of guideline updates and personalized protocols for specific patient groups without retraining. We applied MedCheckLLM to expert-validated simulated medical reports, focusing on headache diagnoses following International Headache Society guidelines. Findings revealed MedCheckLLM correctly extracted diagnoses, suggested appropriate guidelines, and accurately evaluated 87% of checklist items, with its evaluations aligning significantly with expert opinions. The system not only enhances healthcare quality assurance but also introduces a transparent and efficient means of applying LLMs in clinical settings. Future considerations must address privacy and ethical concerns in actual clinical scenarios.
Acute myeloid leukemia with mixed phenotype is characterized byRUNX1mutations, stemness features and limited lineage plasticity
Authors: Galera Pallavi , Dilip Deepika , Derkach Andriy , Chan Alexander , Zhang Yanming , Persuad Sonali , Mishera Tanmay , Liu Ying , Famulare Christopher , Gao Qi , Mata Douglas A. , Arcila Maria , Geyer Mark B. , Stein Eytan , Dogan Ahmet , Levine Ross L. , Roshal Mikhail , Glass Jacob , Xiao Wenbin 
Published: November 2023

ABSTRACTMixed phenotype (MP) in acute leukemias poses unique classification and management dilemmas and can be seen in entities other than de novo mixed phenotype acute leukemia (MPAL). Although WHO classification empirically recommends excluding AML with myelodysplasia related changes (AML-MRC) and therapy related AML (t-AML) with mixed phenotype (referred to as “AML-MP”) from MPAL, there is lack of studies investigating the clinical, genetic, and biologic features of AML-MP. We report the first cohort of AML-MP integrating their clinical, immunophenotypic, genomic and transcriptomic features with comparison to MPAL and AML without MP. Patients with AML-MP share similar clinical and genetic features to its AML counterpart but differs from MPAL. AML-MP harbors more frequentRUNX1mutations than AML without MP and MPAL.RUNX1mutations or complex karyotypes did not impact the survival of MPAL patients. Unsupervised hierarchal clustering based on immunophenotype identified biologically distinct clusters with phenotype/genotype correlation and outcome differences. Furthermore, transcriptomic analysis showed an enrichment for stemness signature in AML-MP and AML without MP as compared to MPAL. Lastly, MPAL but not AML-MP often switched to lymphoid only immunophenotype after treatment. Expression of transcription factors critical for lymphoid differentiation were upregulated only in MPAL, but not in AML-MP. Our study for the first time demonstrates that AML- MP clinically and biologically resembles its AML counterpart without MP and differs from MPAL, supporting the recommendation to exclude these patients from the diagnosis of MPAL. Future studies are needed to elucidate the molecular mechanism of mixed phenotype in AML.Key pointsAML-MP clinically and biologically differs from MPAL but resembles AML.AML-MP showsRUNX1mutations, stemness and limited lineage plasticity.
Role of ablation therapy in conjunction with surgical resection for neuroendocrine tumors (NETs): Risks and benefits of multimodality surgical treatment for NETs involving liver
Authors: Ostapenko Alexander , Stroever Stephanie , Eyasu Lud , Kim Minha , Aploks Krist , Dong Xiang , Seshadri Ramanathan 
Published: November 2023

AbstractBackgroundResection of hepatic metastasis from neuroendocrine tumors (NETs) improves quality of life and prolongs 5-year survival. Ablation can be utilized with surgery to achieve complete resection. Although several studies report long-term outcomes for patients undergoing ablation, none have explored perioperative effects of ablation in patients with metastatic NETs. Our goal was to determine if intra-operative ablation during hepatectomy increases risk of adverse outcomes such as surgical site infections (SSIs), bleeding, and bile leak.MethodsA retrospective analysis of the hepatectomy NSQIP database from 2015-2019 was performed to determine the odds of SSIs, bile leaks, or bleeding in patients undergoing intraoperative ablation when compared to hepatectomy alone.ResultsOf the 966 patients included in the study, 298(30.9%) underwent ablation during hepatectomy. There were 78(11.7%) patients with SSIs in the hepatectomy alone group and 39(13.1%) patients with a SSIs in the hepatectomy with ablation group. Bile leak occurred in 41(6.2%) and 14(4.8%) patients in the two groups, respectively; bleeding occurred in 117(17.5%) and 33(11.1%), respectively. After controlling for confounding variables, ablation did not increase risk of SSI (p=0.63), bile leak (p=0.34) or bleeding (p=0.07) when compared to patients undergoing resection alone on multivariate analysis.ConclusionsIntraoperative ablation with hepatic resection for NETs is safe in the perioperative period without significant increased risk of infection, bleeding, or bile leak. Surgeons should utilize this modality when appropriate to achieve optimal disease control and outcomes.
AMEBIASIS: AN ANALYSIS OF ITS DISTINCTIVE PRESENTATION IN THE CONTEXT OF JORDANIAN CASES
Authors: Al-khlifeh Enas , Hasanat Ahmad B. 
Published: November 2023

ABSTRACTAmebiasis is a serious health problem, particularly in economically disadvantaged countries. However, unresolved questions remain regarding the clinical symptoms and laboratory results of amebiasis in Jordan, a developing country. Therefore, we assessed the prevalence and severity of amebiasis in a sizable population in the center of Jordan in relation to potential risk variables such as environment, age and sex of the patients, collecting data from the medical records of the patients treated at the Al-Hussein Hospital in Al-Salt city between 2020 and 2022. Clinical manifestations and laboratory findings, including fecal red blood cell and leukocyte counts, total and differential leukocyte counts by age, and other information were included in this report. This study showed that amebiasis is a common problem in Al-Salt city, accounting for 16.8% of all gastroenteritis cases. Amebiasis affects individuals of all sexes and ages. When comparing males of different ages to females of similar ages, both age and male sex showed an increased risk of amebiasis (P=0.014). Infants and toddlers accounted for more than one-quarter of the cases, with more than half of them diagnosed with watery diarrhea. Numerous patients of all age groups displayed age-related neutrophilic leukocytosis and atypical WBC counts. The findings of this study suggest that amebiasis is highly prevalent, affects a significant proportion of infants and toddlers, and causes severe clinical symptoms. This is the first study on Al-Salt city population with respect to multiple variables and demographic factors. These data are crucial for the decision-making of medical professionals. The epidemiology of amebiasis in Jordan must be determined, and preventive measures must be developed, especially for childcare at educational facilities.
Pathological claustrum activity drives aberrant cognitive network processing in human chronic pain
Authors: Stewart Brent W. , Keaser Michael L. , Lee Hwiyoung , Margerison Sarah M. , Cormie Matthew A. , Moayedi Massieh , Lindquist Martin A. , Chen Shuo , Mathur Brian N. , Seminowicz David A. 
Published: November 2023

SummaryAberrant cognitive network activity and cognitive deficits are established features of chronic pain. However, the nature of cognitive network alterations associated with chronic pain and their underlying mechanisms require elucidation. Here, we report that the claustrum, a subcortical nucleus implicated in cognitive network modulation, is activated by acute painful stimulation and pain-predictive cues in healthy participants. Moreover, we discover pathological activity of the claustrum and a lateral aspect of the right dorsolateral prefrontal cortex (latDLPFC) in migraine patients. Dynamic causal modeling suggests a directional influence of the claustrum on activity in this latDLPFC region, and diffusion weighted imaging (DWI) verifies their structural connectivity. These findings advance understanding of claustrum function during acute pain and provide evidence of a possible circuit mechanism driving cognitive impairments in chronic pain.
Development of a high throughput system to screen compounds that revert the activated hepatic stellate cells to a quiescent-like state
Authors: Nakano Yasuhiro , Itoh Tohru , Tanaka Minoru , Miyajima Atsushi , Kido Taketomo 
Published: November 2023

AbstractChronic liver injury induces fibrosis that often proceeds to cirrhosis and hepatocellular carcinoma, indicating that prevention and/or resolution of fibrosis is a promising therapeutic target. Hepatic stellate cells (HSCs) are the major driver of fibrosis by expressing extracellular matrices (ECM). HSCs, in the normal liver, are quiescent and activated by liver injury to become myofibroblasts that proliferate and produce ECM. It has been shown that activated HSCs (aHSCs) become a “quiescent-like” state by removal of liver insults. Therefore, deactivation agents can be a therapeutic drug for advanced liver fibrosis. Using aHSCs prepared from human induced pluripotent stem cells, we found that aHSCs were reverted to a quiescent-like state by a combination of chemical compounds that either inhibit or activate a signaling pathway, Lanifibranor, SB431542, Dorsomorphin, retinoic acid, palmitic acid and Y27632,in vitro. Based on these results, we established a high throughput system to screen agents that induce deactivation and demonstrate that a single chemical compound can induce deactivation.
DeLoop: a deep learning model for chromatin loop prediction from sparse ATAC-seq data
Authors: Luo Yihai , Zhang Zhihua 
Published: November 2023

AbstractDeciphering gene regulation and understanding the functional implications of disease-associated non-coding variants require the identification of cell-type-specific 3D chromatin interactions. Current chromosome conformation capture technologies fall short in resolution when handling limited cell inputs. To address this limitation, we introduce DeLoop, a deep learning model designed to predict CTCF-mediated chromatin loops from sparse ATAC-seq data by leveraging multitask learning techniques and attention mechanisms. Our model utilizes ATAC-seq data and DNA sequence features, showcasing superior performance compared to existing state-of-the-art models, particularly under low read depth conditions, enabling accurate chromatin loop inference when sufficient cells are infeasible. In addition, generalizing across cell types, DeLoop proves effective in de novo prediction tasks and its potential for predicting functional interactions.
Reinstatement ofRIG-Iin chickens via genetic modification reveals new insights into the dynamic evolution of avian immune sensors
Authors: Sid Hicham , von Heyl Theresa , Schleibinger Sabrina , Klinger Romina , Guabiraba Rodrigo , Guillory Vanaique , Schade Benjamin , Elleder Daniel , Sives Samantha , Vervelde Lonneke , Trapp Sascha , Schusser Benjamin 
Published: November 2023

AbstractRetinoic acid-inducible gene I(RIG-I) activates mitochondrial antiviral signaling proteins, initiating the antiviral response.RIG-IandRNF135, a ubiquitin ligase regulator, are missing in domestic chickens but conserved in mallard ducks. It was long believed that chickens’RIG-Iloss was linked to increased avian influenza susceptibility. We reinstated both genes in chickens and examined their susceptibility to the avian influenza virus H7N1. UninfectedRIG-I-expressing chickens exhibited shifts in T and B cells, while the H7N1 infection led to severe disease, persistent weight loss, and increased viral replication. Conversely, the co-expression ofRIG-IandRNF135reduced the viral replication and was associated with high inflammatory response. Our data indicate that the loss ofRIG-Iin chickens likely evolved to counteract deleterious inflammation caused by viral infection. We highlight the effects of restoring evolutionary lost genes in birds and suggest a new immunological approach to reduce viral replication and prevent infection.Graphical abstract
Cultivation, chemistry, and genome ofPsilocybe zapotecorum
Authors: Miller Dusty Rose , Jacobs Jordan Taylor , Rockefeller Alan , Singer Harte , Bollinger Ian M. , Conway James , Slot Jason C. , Cliffel David E. 
Published: November 2023

AbstractPsilocybe zapotecorumis a strongly blue-bruising psilocybin mushroom used by indigenous groups in southeastern Mexico and beyond. While this species has a rich history of ceremonial use, research into its chemistry and genetics have been limited. Herein, we detail mushroom morphology and report on cultivation parameters, chemical profile, and the full genome sequence ofP. zapotecorum. First, growth and cloning methods are detailed that are simple, and reproducible. In combination with high resolution microscopic analysis, the strain was barcoded, confirming species-level identification. Full genome sequencing reveals the architecture of the psilocybin gene cluster inP. zapotecorum,and can serve as a reference genome for Psilocybe Clade I. Characterization of the tryptamine profile revealed a psilocybin concentration of 17.9±1.7 mg/g, with a range of 10.6-25.7 mg/g (n=7), and similar tryptamines (psilocin, baeocystin, norbaeocystin, norpsilocin, aeruginascin, 4-HO-tryptamine, and tryptamine) in lesser concentrations for a combined tryptamine concentration of 22.5±3.2 mg/g. These results showP. zapotecorumto be a potent – and variable –Psilocybemushroom. Chemical profiling, genetic analysis, and cultivation assist in demystifying these mushrooms. As clinical studies with psilocybin gain traction, understanding the diversity of psilocybin mushrooms will assure that psilocybin therapy does not become synonymous with psilocybin mushrooms.
Immunosuppressive tumor microenvironment of osteosarcoma
Authors: Taylor Aaron Michael , Sheng Jianting , Ng Patrick Kwok Shing , Harder Jeffrey M. , Kumar Parveen , Ahn Ju Young , Cao Yuliang , Dzis Alissa M. , Jillette Nathaniel L. , Goodspeed Andrew , Bodlak Avery , Wu Qian , Isakoff Michael S. , George Joshy , Grassmann Jessica D.S. , Luo Diane , Flynn William F. , Courtois Elise T. , Robson Paul , Hayashi Masanori , Paolillo Alini Trujillo , Petrilli Antonio Sergio , de Toledo Silvia Regina Caminada , Balarezo Fabiola Sara , Lindsay Adam D. , Hoang Bang , Wong Stephen T.C. , Lau Ching C. 
Published: November 2023

AbstractOsteosarcoma is the most common malignant bone tumor in children, characterized by a high degree of genomic instability, resulting in copy-number alterations and genomic rearrangements without disease-defining recurrent mutations. Clinical trials based on molecular characterization have failed to find new effective therapies or improve outcomes over the last 40 years. To better understand the immune microenvironment of osteosarcoma, we performed single-cell RNA sequencing on six tumor biopsy samples, combined with a previously-published cohort of six samples. Additional osteosarcoma samples were profiled using spatial transcriptomics for validation of discovered subtypes and to add spatial context. Analysis revealed immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs), regulatory and exhausted T-cells, and LAMP3+ dendritic cells. Using cell-cell communication modeling, we identified robust interactions between MDSCs and other cells, leading to NF-κB upregulation and an immunosuppressive microenvironment, as well as interactions involving regulatory T-cells and osteosarcoma cells that promoted tumor progression and a proangiogenic niche.Statement of SignificanceOsteosarcoma patient survival has remained stagnant for several decades due to lack of successful therapy for high-risk patients, including those with metastatic disease. Identifying novel therapeutics including immunotherapies is of great clinical importance. Our study highlights several important immunosuppressive mechanisms within osteosarcoma that should be considered when developing future immunotherapies.