bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcript profiling ofplastid ferrochelatase twomutants reveals that chloroplast singlet oxygen signals lead to global changes in RNA profiles and are mediated by Plant U-Box 4
Authors: Rai Snigdha , Lemke Matthew D. , Arias Anika M. , Mendez Maria F. Gomez , Dehesh Katayoon , Woodson Jesse D. 
Published: May 2024

AbstractBackgroundIn response to environmental stresses, chloroplasts generate reactive oxygen species, including singlet oxygen (1O2), an excited state of oxygen that regulates chloroplast-to-nucleus (retrograde) signaling, chloroplast turnover, and programmed cell death (PCD). Yet, the central signaling mechanisms and downstream responses remain poorly understood. TheArabidopsis thaliana plastid ferrochelatase two(fc2) mutant conditionally accumulates1O2and Plant U-Box 4 (PUB4), a cytoplasmic E3 ubiquitin ligase, is involved in propagating1O2signals for chloroplast turnover and cellular degradation. Thus, thefc2andfc2 pub4mutants are useful genetic tools to elucidate these signaling pathways. Previous studies have focused on the role of1O2in promoting cellular degradation infc2mutants, but its impact on retrograde signaling from mature chloroplasts (the major site of1O2production) is poorly understood.ResultsTo gain mechanistic insights into1O2signaling pathways, we compared transcriptomes of adult wt,fc2, andfc2 pub4plants. The accumulation of1O2infc2plants broadly repressed genes involved in chloroplast function and photosynthesis, while inducing genes and transcription factors involved in abiotic and biotic stress, the biosynthesis of jasmonic acid (JA) and salicylic acid (SA), microautophagy, and senescence. Elevated JA and SA levels were observed in1O2-stressedfc2plants.pub4reversed most of this1O2-induced gene expression and reduced the JA content infc2plants. Thepub4mutation also blocked JA-induced senescence pathways in the dark. However, fc2 pub4 plantsmaintained constitutively elevated levels of SA even in the absence of bulk1O2accumulation.ConclusionsTogether, this work demonstrates that infc2plants,1O2leads to a robust retrograde signal that may protect cells by downregulating photosynthesis and ROS production while simultaneously mounting a stress response involving SA and JA. The induction of microautophagy and senescence pathways indicate that1O2-induced cellular degradation is a genetic response to this stress, and the bulk of this transcriptional response is modulated by the PUB4 protein. However, the effect ofpub4on hormone synthesis and signaling is complex and indicates that an intricate interplay of SA and JA are involved in promoting stress responses and programmed cell death during photo-oxidative damage.
Deep phenotyping of the prostate tumor microenvironment reveals molecular stratifiers of relapse linked to inflammatory chemokine expression and aberrant metabolism
Authors: Krossa Sebastian , Andersen Maria K. , Midtbust Elise , Wess Maximilian , Kiviaho Antti , Sharma Abhibhav , Viset Trond , Størkersen Øystein , Giskeødegård Guro F. , Nykter Matti , Urbanucci Alfonso , Rye Morten B. , Tessem May-Britt 
Published: May 2024

AbstractUnderstanding the molecular characteristics and changes of the tumor microenvironment (TME) associated with aggressive prostate cancer (PCa) is essential for precise diagnosis and treatment. We interrogated spatially resolved integrated transcriptomics and metabolomics data to build molecular strafiers discriminating patients with aggressive, potentially relapsing, and metastasizing PCa. We report a relapse associated (RA) gene expression signature characterized by upregulated immune response related gene expression scoring high in cancer, stroma, and glandular tissue of relapsing patients. Further, we identified a signature specific to a distinct sub-group of morphologically non-cancerous glands in prostate tissue from patients with relapsing cancer. This signature, named chemokine-enriched-gland (CEG) signature, was characterized by upregulated gene expression of pro-inflammatory chemokines. Glands with a high CEG score were enriched for club-like cells and surrounding stroma was infiltrated by immune cells. Tissue regions scoring high for both CEG and RA signatures were associated with reduced levels of citrate and zinc and loss of normal prostate secretory gland functions via reduced expression of genes necessary for citrate secretion. In summary we report that aggressive PCa is associated with an increased inflammatory status linked to chemokine production and club-like cell enrichment in potentially pre-cancerous prostate glands displaying an aberrant metabolism.
Spike-in enhanced phosphoproteomics uncovers synergistic signaling responses to MEK inhibition in colon cancer cells
Authors: van Bentum Mirjam , Klinger Bertram , Sieber Anja , Lehmann Nadine , Naghiloo Sheyda , Haji Mohamed , Niquet Sylvia , Mertins Philipp , Blüthgen Nils , Selbach Matthias 
Published: May 2024

AbstractTargeted kinase inhibitors are a cornerstone of cancer therapy, but their success is often hindered by the complexity of cellular signaling networks that can lead to resistance. Overcoming this challenge necessitates a deep understanding of cellular signaling responses. While standard global phosphoproteomics offers extensive insights, lengthy processing times, the complexity of data interpretation, and frequent omission of crucial phosphorylation sites limit its utility. Here, we combine data-independent acquisition (DIA) with spike-in of synthetic heavy stable isotope-labeled phosphopeptides to facilitate the targeted detection of particularly informative phosphorylation sites. Our spike-in enhanced detection in DIA (SPIED-DIA) approach integrates the improved sensitivity of spike-in-based targeted detection with the discovery potential of global phosphoproteomics into a simple workflow. We employed this method to investigate synergistic signaling responses in colorectal cancer cell lines following MEK inhibition. Our findings highlight that combining MEK inhibition with growth factor stimulation synergistically activates JNK signaling in HCT116 cells. This synergy emphasizes the therapeutic potential of concurrently targeting MEK and JNK pathways, as evidenced by the significantly impaired growth of HCT116 cells when treated with both inhibitors. Our results demonstrate that SPIED-DIA effectively identifies synergistic signaling responses in colorectal cancer cells, presenting a valuable tool for uncovering new therapeutic targets and strategies in cancer treatment.
Fundamental transport mechanism of mucin-2 ER-to-Golgi trafficking identifies source of ER stress in inflammatory bowel disease
Authors: Morsink Margaretha A.J. , Koch Lena S. , Hu Shixian , Weersma Rinse K. , van Goor Harry , Bourgonje Arno R. , Broersen Kerensa 
Published: May 2024

AbstractThe intestinal mucous layer relies on mucin-2 secretion. While the mucin-2 secretory pathway has been studied, endoplasmic reticulum (ER) to Golgi apparatus (Golgi) trafficking remains poorly understood. The size of mucin-2 exceeds the capacity of regular coat protein complex II (COPII) vesicles, responsible for ER-to-Golgi transport. After confirming conventional secretion of mucin-2, we showed that COPII vesicle enlargement is facilitated by TANGO1 and cTAGE5, and promoted by KLHL12. Inflammatory bowel disease (IBD) is characterized by a compromised mucous layer, altered activity of Transforming Growth Factor β (TGF-β), and increased ER stress. Using a cell culture, we showed that TGF-β inhibition induces TANGO1-mediated ER stress. Mucosal gene expression analysis in IBD patients confirmed elevated ER stress and validated concomitantly altered mRNA levels of TGF-β with mucin-2 and transport proteins TANGO1 and cTAGE5. In conclusion, we propose that the unsuccessful formation of enlarged COPII vesicles could be a source of ER stress in IBD, because of lowered TANGO1 protein expression, subsequently leading to decreased mucin-2 secretion.
CellAgent: An LLM-driven Multi-Agent Framework for Automated Single-cell Data Analysis
Authors: Xiao Yihang , Liu Jinyi , Zheng Yan , Xie Xiaohan , Hao Jianye , Li Mingzhi , Wang Ruitao , Ni Fei , Li Yuxiao , Luo Jintian , Jiao Shaoqing , Peng Jiajie 
Published: May 2024

AbstractSingle-cell RNA sequencing (scRNA-seq) data analysis is crucial for biological research, as it enables the precise characterization of cellular heterogeneity. However, manual manipulation of various tools to achieve desired outcomes can be labor-intensive for researchers. To address this, we introduce CellAgent (http://cell.agent4science.cn/), an LLM-driven multi-agent framework, specifically designed for the automatic processing and execution of scRNA-seq data analysis tasks, providing high-quality results with no human intervention. Firstly, to adapt general LLMs to the biological field, CellAgent constructs LLM-driven biological expert roles—planner, executor, and evaluator—each with specific responsibilities. Then, CellAgent introduces a hierarchical decision-making mechanism to coordinate these biological experts, effectively driving the planning and step-by-step execution of complex data analysis tasks. Furthermore, we propose a self-iterative optimization mechanism, enabling CellAgent to autonomously evaluate and optimize solutions, thereby guaranteeing output quality. We evaluate CellAgent on a comprehensive benchmark dataset encompassing dozens of tissues and hundreds of distinct cell types. Evaluation results consistently show that CellAgent effectively identifies the most suitable tools and hyperparameters for single-cell analysis tasks, achieving optimal performance. This automated framework dramatically reduces the workload for science data analyses, bringing us into the “Agent for Science” era.
Liver kinase B1 (LKB1) regulates the epigenetic landscape of mouse pancreatic beta cells
Authors: Haberman Nejc , Cheung Rebecca , Pizza Grazia , Cvetesic Nevena , Nagy Dorka , Maude Hannah , Blazquez Lorea , Lenhard Boris , Cebola Inês , Rutter Guy A. , Martinez-Sanchez Aida 
Published: May 2024

ABSTRACTLiver kinase B1 (LKB1/STK11) is an important regulator of pancreatic β-cell identity and function. Elimination ofLkb1from the β-cell results in improved glucose-stimulated insulin secretion and is accompanied by profound changes in gene expression, including the upregulation of several neuronal genes. The mechanisms through which LKB1 controls gene expression are, at present, poorly understood. Here, we explore the impact of β cell- selective deletion ofLkb1on chromatin accessibility in mouse pancreatic islets. To characterize the role of LKB1 in the regulation of gene expression at the transcriptional level, we combine these data with a map of islet active transcription start sites and histone marks. We demonstrate that LKB1 elimination from β-cells results in widespread changes in chromatin accessibility, correlating with changes in transcript levels. Changes occurred in hundreds of promoter and enhancer regions, many of which were close to neuronal genes. We reveal that dysregulated enhancers are enriched in binding motifs for transcription factors important for β-cell identity, such as FOXA, MAFA or RFX6 and we identify microRNAs (miRNAs) that are regulated by LKB1 at the transcriptional level. Overall, our study provides important new insights into the epigenetic mechanisms by which LKB1 regulates β-cell identity and function.
A Novel Mutation in LXRα Uncovers a Role for Cholesterol Sensing in Limiting Metabolic Dysfunction-Associated Steatohepatitis (MASH)
Authors: Clark Alexis T. , Russo-Savage Lillian , Ashton Luke A. , Haghshenas Niki , Schulman Ira G. 
Published: May 2024

AbstractLiver x receptor alpha (LXRα, Nr1h3) functions as an important intracellular cholesterol sensor that regulates fat and cholesterol metabolism at the transcriptional level in response to the direct binding of cholesterol derivatives. We have generated mice with a mutation in LXRα that reduces activity in response to endogenous cholesterol derived LXR ligands while still allowing transcriptional activation by synthetic agonists. The mutant LXRα functions as a dominant negative that shuts down cholesterol sensing. When fed a high fat, high cholesterol diet LXRα mutant mice rapidly develop pathologies associated with Metabolic Dysfunction-Associated Steatohepatitis (MASH) including ballooning hepatocytes, liver inflammation, and fibrosis. Strikingly LXRα mutant mice have decreased liver triglycerides but increased liver cholesterol. Therefore, MASH-like phenotypes can arise in the absence of large increases in triglycerides. Reengaging LXR signaling by treatment with synthetic agonist reverses MASH suggesting that LXRα normally functions to impede the development of liver disease.
Unveiling Conserved Allosteric Hot Spots in Protein Domains from Sequences
Authors: Hacisuleyman Aysima , Fasshauer Dirk 
Published: May 2024

AbstractThe amino acid sequence determines the structure, function, and dynamics of a protein. In recent years, enormous progress has been made in translating sequence information into 3D structural information using artificial intelligence. However, because of the underlying methodology, it is an immense computational challenge to extract this information from the ever-increasing number of sequences. In the present study, we show that it is possible to create 2D contact maps from sequences, for which only a few exemplary structures are available on a laptop without the need for GPUs. This is achieved by using a pattern-matching approach. The resulting contact maps largely reflect the interactions in the 3D structures and contain information about its function and dynamics. This approach was used to explore the evolutionarily conserved allosteric mechanisms and identify the source– sink (driver-driven) relationships by using an established method that combines Schreiber’s concept of entropy transfer with a simple Gaussian network model. The validity of our method was tested on the DHFR, PDZ, SH3, and S100 domains, with our predictions consistently aligning with the experimental findings.
Brain-specificGata4downregulation inGreywickfemale mice models the metabolic subtype of polycystic ovary syndrome
Authors: Nawaito Sherin A. , Esmael Mostafa , Souchkova Ouliana , Cardinal Tatiana , Bernas Guillaume , Bergeron Karl-F. , Gayda Fanny , Bergeron Francis , Bouchard Marie-France , Zhou Xiang , Ongaro Luisina , Bernard Daniel J. , Short Jacob , Wray Susan , Viger Robert S. , Mounier Catherine , Pilon Nicolas 
Published: May 2024

ABSTRACTPolycystic ovary syndrome (PCOS) is a heterogenous disorder characterized by reproductive and metabolic abnormalities. PCOS etiology remains poorly understood, although the hypothalamus is suspected to play a central role in many cases. Human genetic studies have also shown an association with the transcription factor-coding geneGATA4, but without providing a functional link. Here, we show that adultGreywickfemale mice may bridge this gap. These mice phenocopy PCOS with partial penetrance, due to serendipitous insertion of aGata4promoter-driven transgene in a strong enhancer region. Resulting robust transgene expression in subsets of hypothalamic neurons and glia impairs endogenousGata4expression, resulting in misexpression of genes linked to the control of fertility and food intake. We also show that this previously overlooked role of GATA4 in the hypothalamus can be replicated by conditional knockout approaches. Overall, this study sheds light not only on PCOS etiology but also on the role played by GATA4 in the central control of reproduction.
The role of mu-opioid receptors in pancreatic islet alpha cells
Authors: Kong Chen , Castro Daniel C. , Lee Jeongmin , Piston David W. 
Published: May 2024

ABSTRACT30% of people in the United States have diabetes or pre-diabetes. Many of these individuals will develop diabetic neuropathy as a comorbidity, which is often treated with exogenous opioids like morphine, oxycodone, or tramadol. Although these opioids are effective analgesics, growing evidence indicates that they may directly impact the endocrine pancreas function in human and preclinical models. One common feature of these exogenous opioid ligands is their preference for the mu opioid receptor (MOPR), so we aimed to determine if endogenous MOPRs directly regulate pancreatic islet metabolism and hormone secretion. We show that pharmacological antagonism of MOPRs enhances glucagon secretion, but not insulin secretion, from human islets under high glucose conditions. This increased secretion is accompanied by increased cAMP signaling. mRNA expression of MOPRs is enriched in human islet α-cells, but downregulated in T2D islet donors, suggesting a link between metabolism and MOPR expression. Conditional genetic knockout of MOPRs in murine α-cells increases glucagon secretion in high glucose conditions without increasing glucagon content. Consistent with downregulation of MOPRs during metabolic disease, conditional MOPR knockout mice treated with a high fat diet show impaired glucose tolerance, increased glucagon secretion, increased insulin content, and increased islet size. Finally, we show that MOPR-mediated changes in glucagon secretion are driven, in part, by KATPchannel activity. Together, these results demonstrate a direct mechanism of action for endogenous opioid regulation of endocrine pancreas.
Multi-omics phenotyping characterizes molecular divergence underlying different clinical scenarios of inflammatory bowel disease
Authors: Tien Nguyen Tran Nam , Choi Eun Jeong , Thu Nguyen Quang , Yu Seung Jung , Nguyen Duc Ninh , Kim Dong Hyun , Long Nguyen Phuoc , Lee Hong Sub 
Published: May 2024

ABSTRACTClinically heterogeneous spectrum and molecular phenotypes of inflammatory bowel disease (IBD) remain to be comprehensively elucidated. This study set out to explore the serum molecular profiles (I) of IBD subtypes; in association with (II) elevated fecal calprotectin and (III) disease activity states; (IV) upon treatment escalation; and (V) in patients who needed treatment escalation. The serum proteome, metabolome, and lipidome of 75 treated IBD patients were profiled. Single- and multi-omic data analysis was performed to determine differential analytes and integrative biosignatures. (I) Chronic inflammation, and phosphatidylcholine and bile acid homeostasis disturbances underlined the differences between Crohn’s disease (CD) and ulcerative colitis. (II) Elevated calprotectin was associated with higher levels of inflammatory proteins and sphingomyelins (SM) and lower levels of bile acids, amino acids, and triacylglycerols (TG). Relative to patient remission, active disease state (III) was characterized by decreased SMs and increased inflammatory proteins and TGs. (IV) Treatment escalation was associated with augmented levels of inflammatory response-related proteins and reduced levels of amino acids. Most TG species increased in the post-treatment escalation. Moreover, needed-treatment-escalation patients had significantly lower levels of TGs (V). They also showed increased SMs and decreased signaling receptor binding proteins. Multi-omics analysis revealed biosignatures that captured the differences between groups of each scenario. Eight analytes, including NFASC, ANGPTL4, and chenodeoxycholate, were found in at least three biosignatures. Collectively, disturbances in immune response, bile acid homeostasis, amino acids, and lipids alteration potentially underlie the clinically heterogeneous spectrum of IBD.
A Postdoctoral Training Program in Bioimage Analysis
Authors: Cimini Beth A , Tromans-Coia Callum , Stirling David , Sivagurunathan Suganya , Senft Rebecca , Ryder Pearl , Miglietta Esteban , Llanos Paula , Jamali Nasim , Diaz-Rohrer Barbara , Dasgupta Shatavisha , Cruz Mario , Weisbart Erin , Carpenter Anne E 
Published: May 2024

AbstractWe herein describe a postdoctoral training program designed to train biologists with microscopy experience in bioimage analysis. We detail the rationale behind the program, the various components of the training program, and outcomes in terms of works produced and the career effects on past participants. We analyze the results of an anonymous survey distributed to past and present participants, indicating overall high value of all 12 rated aspects of the program, but significant heterogeneity in which aspects were most important to each participant. Finally, we propose this model as a template for other programs which may want to train experts in professional skill sets, and discuss the important considerations when running such a program. We believe that such programs can have extremely positive impact for both the trainees themselves and the broader scientific community.
Magnetically Steered Cell Therapy For Functional Restoration Of Intraocular Pressure Control In Open-Angle Glaucoma
Authors: Fard M. Reza Bahrani , Chan Jessica , Read A. Thomas , Li Guorong , Cheng Lin , Safa Babak N. , Siadat Seyed Mohammad , Jhunjhunwala Anamik , Grossniklaus Hans E. , Emelianov Stanislav Y. , Stamer W. Daniel , Kuehn Markus H. , Ethier C. Ross 
Published: May 2024

AbstractTrabecular meshwork (TM) cell therapy has been proposed as a next-generation treatment for elevated intraocular pressure (IOP) in glaucoma, the most common cause of irreversible blindness. Using a magnetic cell steering technique with excellent efficiency and tissue-specific targeting, we delivered two types of cells into a mouse model of glaucoma: either human adipose-derived mesenchymal stem cells (hAMSCs) or induced pluripotent cell derivatives (iPSC-TM cells). We observed a 4.5 [3.1, 6.0] mmHg or 27% reduction in intraocular pressure (IOP) for nine months after a single dose of only 1500 magnetically-steered hAMSCs, associated with restoration of function to the conventional outflow pathway, as judged by increased outflow facility and TM cellularity. iPSC-TM cells were also effective, but less so, showing only a 1.9 [0.4, 3.3] mmHg or 13% IOP reduction and increased risk of tumorigenicity. In both cases, injected cells remained detectable in the iridocorneal angle three weeks post-transplantation. Based on the locations of the delivered cells, the mechanism of IOP lowering is most likely paracrine signaling. We conclude that magnetically-steered hAMSC cell therapy has potential for long-term treatment of ocular hypertension in glaucoma.One Sentence SummaryA novel magnetic cell therapy provided effective intraocular pressure control in a mouse model of glaucoma, motivating future translational studies.