bluuebunny/crossref_metadata_2025_split huggingface dataset:
DISTINCT PATTERNS OF ENDOTHELIAL CELL ACTIVATION PRODUCED BY EXTRACELLULAR HISTONES AND BACTERIAL LIPOPOLYSACCHARIDE
Authors: Piffard Sophia H. , Hennig Grant W. , Sackheim Adrian M. , Howard Abigail J. , Lambert Aaron , Majumdar Devdoot , Nelson Mark T. , Freeman Kalev 
Published: August 2024

ABSTRACT

Objective: Vascular endothelial cells (ECs) sense and respond to both trauma factors (histone proteins) and sepsis signals (bacterial lipopolysaccharide, LPS) with elevations in calcium (Ca2+), but it is not clear if the patterns of activation are similar or different. We hypothesized that within seconds of exposure, histones but not LPS would produce a large EC Ca2+ response. We also hypothesized that histones would produce different spatio-temporal patterns of Ca2+ events in veins than in arteries. Methods: We studied cultured ECs (EA.hy926) and native endothelial cells from surgically opened murine blood vessels. High-speed live cell imaging of Ca2+ events were acquired for 5 min before and after stimulation of cultured ECs with histones or LPS alone or in combination. Histone-induced EC Ca2+ events were also compared in native endothelial cells from resistance-sized arteries and veins. Ca2+ activity was quantified as “Ca2+ prevalence” using custom spatiotemporal analysis. Additionally, cultured ECs were collected after 6 h of exposure to histones or LPS for RNA sequencing. Results: ECs—both in culture and in blood vessels—rapidly increased Ca2+ activity within seconds of histone exposure. In contrast, LPS exposure produced only a slight increase in Ca2+ activity in cultured ECs and no effect on blood vessels over 5-min recording periods. Histones evoked large aberrant Ca2+ events (>30 s in duration) in both veins and arteries, but with different spatio-temporal patterns. Ca2+ activity in arterial ECs often appeared as “rosettes”, with Ca2+ events that propagated from one cell to all adjacent surrounding cells. In veins, ECs responded individually without spreading. Surprisingly, exposure of cultured ECs to LPS for 5 min before histones potentiated EC Ca2+ activity by an order of magnitude. Exposure of ECs to histones or LPS both increased gene expression, but different mRNAs were induced. Conclusions: LPS and histones activate ECs through mechanisms that are distinct and additive; only histones produce large aberrant Ca2+ events. ECs in arteries and veins display different patterns of Ca2+ responses to histones.
USP31 PROMOTES THE INFLAMMATORY RESPONSE OF HUMAN LUNG ORGANOIDS TO LIPOPOLYSACCHARIDE TREATMENT
Authors: Xiao Wenbiao , Lin Bingwen , Wang Ying , Huang Peng , Lin Jiandong , Xiao Xiongjian 
Published: August 2024

ABSTRACT

Background: Acute lung injury (ALI) is a severe condition characterized by a high mortality rate, driven by an uncontrolled inflammatory response. Emerging evidence has underscored the crucial role of the ubiquitin system in ALI. However, because of their vast number, the specific functions of individual ubiquitination regulators remain unclear. Materials and methods: In this study, we established human lung organoids (HLOs) derived from human embryonic stem cells and subjected them to lipopolysaccharide (LPS) treatment to induce an inflammatory response, mimicking ALI. Subsequently, we detected the expression of inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interleukin 6, interleukin 18 (IL-18), and interleukin-1β (IL-1β), by quantitative polymerase chain reaction experiments. We also detected changes in the mRNA expression of several USPs before and after HLOs treatment and thus screened for USPs that had significant changes in HLOs after LPS stimulation. After screening for USP, we silenced the USP in HLOs and then subjected them to LPS treatment, and TNF-α, IL-6, IL-18, and IL-1β expressions were detected using quantitative polymerase chain reaction assays. Meanwhile, western blot was used to detect changes in NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) and apoptosis-associated Speck-like protein containing a CARD (ASC) protein level in HLOs. Results: Through screening the expression of 40 ubiquitin-specific proteases (USPs), which are responsible for removing ubiquitination, we identified several USPs that exhibited differential expression in LPS-treated HLOs compared to untreated HLOs. Notably, USP31 emerged as the most significantly upregulated USP, and the knockdown of USP31 markedly attenuated the inflammatory response of HLOs to LPS treatment. Conclusions: USP31 may play a facilitating role in the inflammatory response during ALI.
PLASMA PROTEOME, METABOLOME MENDELIAN RANDOMIZATION IDENTIFIES SEPSIS THERAPEUTIC TARGETS
Authors: Deng Ruiming , Huang Guiming , Zhou Juan , Zeng Kai 
Published: August 2024

ABSTRACT

Background: The interrelation between the plasma proteome and plasma metabolome with sepsis presents a multifaceted dynamic that necessitates further research to elucidate the underlying causal mechanisms. Methods: Our investigation used public genome-wide association study data to explore the relationships among the plasma proteome, metabolome, and sepsis, considering different sepsis subgroup. Initially, two-sample Mendelian randomization established causal connections between the plasma proteome and metabolome with sepsis. Subsequently, multivariate and iterative Mendelian randomization analyses were performed to understand the complex interactions in plasma during sepsis. The validity of these findings was supported by thorough sensitivity analyses. Result: The study identified 25 plasma proteins that enhance risk and 34 that act as protective agents in sepsis. After P value adjustment (0.05/1306), ICAM5 emerged with a positive correlation to sepsis susceptibility (P value = 2.14E-05, OR = 1.10, 95% CI = 1.05–1.15), with this significance preserved across three sepsis subgroup examined. Additionally, 29 plasma metabolites were recognized as risk factors, and 15 as protective factors for sepsis outcomes. After P value adjustment (0.05/997), elevated levels of 1,2,3-benzenetriol sulfate (2) was significantly associated with increased sepsis risk (P value = 3.37E-05, OR = 1.18, 95% CI = 1.09–1.28). Further scrutiny revealed that this plasma metabolite notably augments the abundance of ICAM5 protein (P value = 3.52E-04, OR = 1.11, 95% CI = 1.04–1.17), devoid of any detected heterogeneity, pleiotropy, or reverse causality. Mediated Mendelian randomization revealed ICAM5 mediated 11.9% of 1,2,3-benzenetriol sulfate (2)’s total effect on sepsis progression. Conclusion: This study details the causal link between the plasma proteome and metabolome with sepsis, highlighting the roles of ICAM5 and 1,2,3-benzenetriol sulfate (2) in sepsis progression, both independently and through crosstalk.
MedSegBench: A Comprehensive Benchmark for Medical Image Segmentation in Diverse Data Modalities
Authors: Aydin Musa , Kuş Zeki 
Published: August 2024

ABSTRACTMedSegBench is a comprehensive benchmark designed to evaluate deep learning models for medical image segmentation across a wide range of modalities.. This benchmark includes 35 datasets with over 60,000 images, covering modalities such as ultrasound, MRI, and X-ray. It addresses challenges in medical imaging, such as variability in image quality and dataset imbalances, by providing standardized datasets with train/validation/test splits. The benchmark supports binary and multi-class segmentation tasks with up to 19 classes. Evaluations are conducted using the U-Net architecture with various encoder/decoder networks, including ResNets, EfficientNet, and DenseNet, to evaluate model performance. MedSegBench serves as a valuable resource for developing robust and flexible segmentation algorithms. It allows for fair comparisons across different models and promotes the development of universal models for medical tasks. The datasets and source code are publicly available, encouraging further research and development in medical image analysis.
IRF5 mediates adaptive immunity via altered glutamine metabolism, mTORC1 signaling and post-transcriptional regulation following T cell receptor activation
Authors: Brune Zarina , Lu Ailing , Moss Matthew , Brune Leianna , Huang Amanda , Matta Bharati , Barnes Betsy J 
Published: August 2024

ABSTRACTAlthough dynamic alterations in transcriptional, translational, and metabolic programs have been described in T cells, the factors and pathways guiding these molecular shifts are poorly understood, with recent studies revealing a disassociation between transcriptional responses and protein expression following T cell receptor (TCR) stimulation. Previous studies identified interferon regulatory factor 5 (IRF5) in the transcriptional regulation of cytokines, chemotactic molecules and T effector transcription factors following TCR signaling. In this study, we identified T cell intrinsic IRF5 regulation of mTORC1 activity as a key modulator of CD40L protein expression. We further demonstrated a global shift in T cell metabolism, with alterations in glutamine metabolism accompanied by shifts in T cell populations at the single cell level due to loss ofIrf5. T cell conditionalIrf5knockout mice in a murine model of experimental autoimmune encephalomyelitis (EAE) demonstrated protection from clinical disease with conserved defects in mTORC1 activity and glutamine regulation. Together, these findings expand our mechanistic understanding of IRF5 as an intrinsic regulator of T effector function(s) and support the therapeutic targeting of IRF5 in multiple sclerosis.Sentence SummaryFindings provide new insight into the mechanisms by which T cell intrinsic IRF5 regulates the adaptive immune response via modulation of mTORC1 signaling, glutamine metabolism, and protein translation.
Transplantation of bioengineered lung using decellularized mouse lungs and primary human endothelial cells
Authors: Suzuki Takaya , Watanabe Tatsuaki , Tomiyama Fumiko , Ito Takayasu , Okada Yoshinori 
Published: August 2024

ABSTRACTLung transplantation is a critical treatment for patients with end-stage lung diseases like idiopathic pulmonary fibrosis, but challenges such as donor shortages and post-transplant complications persist. Bioengineered lungs, integrating patient-specific cells into decellularized animal scaffolds, present a promising alternative. Despite progress in using bioengineered lungs in animal models, functionality and structure remain immature. This protocol addresses a critical barrier in organ bioengineering: the need for a cost-effective experimental platform. By using mouse models instead of larger animals like rats or swine, researchers can significantly reduce the resources required for each experiment, accelerating research progress. The protocol outlines a detailed procedure for lung bioengineering using mouse heart-lung blocks and human primary cells, focusing on isolation strategy for the mouse heart-lung block, decellularization, bioreactor setup, perfusion-based organ culture, and orthotopic transplantation of bioengineered lungs. This mouse-scale platform not only reduces experimental costs but also provides a viable framework for optimizing cell types and numbers for recellularization, testing different cell types using histological and molecular methods, and ensuring blood flow post-transplantation. The method holds potential for broad applications, including studying cell interactions in three-dimensional culture conditions, cell-matrix interactions, and ex vivo cancer modeling, thereby advancing the field of organ bioengineering.SUMMARYThis paper describes how to create bioengineered mouse lungs using the decellularization and recellularization methods. It also describes subsequent orthotopic lung transplantation in detail.
Multiple factors regulate i-motif and G-quadruplex structuresin vitro: analysis of repeated and non-repeated polyG/polyC clusters by circular dichroism
Authors: Diggins Levi , Ross Daniel , Bhanot Sundeep , Corallo Rebecca , Daley Rachel , Patel Krishna , Lewis Olivia , Donahue Shane , Thaddeus Jacob , Hiers Lauren , Syed Christopher , Eagerton David , Mohanty Bidyut K. 
Published: August 2024

ABSTRACTThe B-form of DNA in the genome contains thousands of sequences that can form various noncanonical structures. Of particular interest are two structures namely G-quadruplex (G4), formed by two or more stacks of four guanine residues in a plane, and intercalating-motif (i-motif, iM) formed by alternately arranged C-C+pairs. Circular dichroism (CD) spectroscopy is a fast biophysical technique to analyze G4s and iMs. We conducted a CD analysis of two types of DNA sequences, one containing tandem repeats and one without, for the generation of G4s and iMs under various environmental conditions, which include pH, buffer composition, boiling, with flanking sequences, complimentary DNA strands, and single-stranded DNA binding protein (SSB). Changes in pH and boiling caused drastic variations in the CD spectra of DNA containing tandem repeats of GGGGCC and GGCCCC from the C9ORF72 gene, although some changes in G4/iM-forming DNA from promoter-proximal regions of several oncogenes also occur. An increase in the number of hexanucleotide repeats generated complex CD patterns at specific pH due to the presence of both G and C bases. The presence of flanking sequences affects CD pattern of a mixture of G4- and iM-forming sequences of the c-MYC promoter-proximal region. SSB disassembled G4 and iMs of all sequences suggesting anin vivorole for SSBs in disassembly of G4s and iMs during various DNA transactions.
High glycaemic variability in individuals with type 1 diabetes is associated with a reduced proportion of CD8+TNF+cells in response to influenza A virus
Authors: Zhen Wei Marcus Tong , Hulme Katina D. , Law Soi Cheng , Noye Ellesandra , Dorey Emily S. , Chew Keng Yih , Rowntree Louise C. , van de Sandt Carolien E. , Kedzierska Katherine , Goeijenbier Marco , Ronacher Katharina , Alzaid Fawaz , Julla Jean-Baptiste , Riveline Jean-Pierre , Lineburg Katie , Smith Corey , Grant Emma J. , Gras Stephanie , Gallo Linda A. , Barett Helen L. , Short Kirsty R. 
Published: August 2024

ABSTRACTObjectiveDiabetes mellitus significantly increases the risk of severe respiratory virus disease like influenza and COVID-19. Early evidence suggests that this susceptibility to respiratory viral disease is driven by glycaemic variability, rather than average blood glucose levels. In healthy individuals, blood glucose levels remain relatively stable throughout the day. However, in individuals living with diabetes, blood glucose spikes are more frequent and higher in magnitude. Continuous glucose monitoring (CGM) provides a unique opportunity to detect these hyper and hypoglycaemic events, even in the presence of an in range HbA1c.Research design and methodsHere, we use blood samples and CGM data obtained from people living with Type 1 diabetes (T1D) to determine the effects of glycaemic variability on the T-cell response to influenza virus. Low glycaemic variability was defined as a coefficient of variation (CV) <33% (n = 13) whilst high glycaemic variability was defined as a CV >33% (n = 19).ResultsWe show that high glycaemic variability in participants living with T1D is associated with a reduced proportion of CD8+CD107α-IFNγ-MIP1β-TNF+T-cells in response to stimulation with influenza virus and an influenza peptide pool. High glycaemic variability in this patient population is primarily driven by hypoglycaemic events and was also associated with an increase in the proportion of naïve CD8+T cells and a decrease in terminally differentiated CD8+T cells (TEMRA).ConclusionsTogether, this study provides the first evidence that glycaemic variability affects the T- cell response to respiratory viruses. These data suggest that monitoring glycaemic variability may have important implications in understanding the antiviral immune response in people with diabetes.
Immunological profiles in Lynch syndrome colorectal cancers are not specific to mismatch repair gene defects
Authors: Helderman Noah C. , IJsselsteijn Marieke E. , Cabuta Madalina , van der Ploeg Manon , van Wezel Tom , Ahadova Aysel , Kloor Matthias , Morreau Hans , Nielsen Maartje , de Miranda Noel F.C.C. 
Published: August 2024

AbstractBackground and aimsColorectal carcinomas (CRCs) in patients with Lynch syndrome (LS) exhibit heightened immunogenicity due to mismatch repair deficiency (MMR-d), often resulting in favorable responses to T cell immune checkpoint therapies. Recent studies indicate that the phenotype and genotype of LS-associated CRCs vary depending on the specific MMR gene mutated. Here, we investigated whether the immune profiles of LS-associated CRCs differ based on the MMR gene defects.MethodsTissue material from 18MLH1-,16MSH2-,40MSH6-, and23PMS2-mutated CRCs and 35 sporadic MMR-d CRCs were included in the study. Imaging mass cytometry (IMC) analysis, along with targeted multiplex immunofluorescence imaging (mIF) and immunohistochemistry, were applied to examine the tumor immune microenvironment, including Human Leukocyte Antigen (HLA) class I and programmed death-ligand 1 (PD-L1) expression.ResultsUnsupervised hierarchical clustering of cell phenotypes identified by IMC, followed by mIF validation, revealed comparable lymphoid and myeloid cell infiltration levels across CRCs from all MMR groups. Infiltrating T cell levels negatively correlated with the number of mutations at coding microsatellite sequences, particularly inMLH1-mutated CRCs. HLA class I defects were observed in 76% of all CRCs. These defects were more frequently accompanied by β2M defects in hereditary MMR-d CRCs (67%) compared to sporadic MMR-d CRCs (37%), and did not associate with the number of γδ T cells, which were present in CRCs from all MMR groups. PD-L1 expression in tumor cells was only detected in 8% of all CRCs.ConclusionOur findings illustrate that, from an immunological perspective, there is no evidence of differing immunogenic features across MMR defects. This is important to consider when developing preventive vaccine strategies and evaluating immunotherapy for LS patients and those with MMR-d CRCs.
Epidemiological Analysis of HIV and HPgV Co-infection in a Brazilian Population
Authors: de Barros Campelo Júnior Evônio , Passos de Castilho Ana Maria , Santos de Morais Viviane Martha , de Oliveira Mendes Cahú Georgea Gertrudes , Cunha Gabriel Galindo , de Araújo Oliveira Vitoria Maria , de Arraes Alencar Ximenes Ricardo , Cunha Duarte Coêlho Maria Rosângela 
Published: August 2024

ABSTRACTObjectivesThis study aimed to determine the prevalence of Human Pegivirus 1 infection among people living with HIV (PLWHIV) in Northeast Brazil and identify associated risk factors, given the potential impact of HPgV on HIV disease progressionMethodsWe conducted a cross-sectional analysis of 249 PLWHIV receiving care at a tertiary hospital in Northeast Brazil. Bivariate and multivariate logistic regression models were used to assess the association between sociodemographic characteristics, risk behaviors, healthcare access, and HPgV infection.ResultsThe prevalence of HPgV infection among the study population was 23.3%. Inhaled drug use emerged as a significant risk factor for HPgV infection in the multivariate analysis.ConclusionsA concerning prevalence of HPgV infection exists among PLWHIV in Northeast Brazil. The identification of inhaled drug use as a risk factor suggests potential transmission routes beyond traditional modes. These findings highlight the need for targeted public health interventions and harm reduction strategies to address this significant public health concern.
GlycoRNA-L and glycoRNA-S mediate human monocyte adhesion via binding to Siglec-5
Authors: Fu Mingui , Qian Yisong , Huang Evan , Schwarz Zain , Tai Hannah , Tillock Katherine , Lei Tianhua 
Published: August 2024

SUMMARYIt was recently reported that RNAs can be glycosylated, and a majority of such glycosylated RNAs (referred to as glycoRNAs) are located on the outer cell surface. We here reported that there are two forms of glycoRNAs, named as glycoRNA-L and glycoRNA-S, robustly expressed in human monocytes. Both of glycoRNA-L and glycoRNA-S contributed to the interaction of human monocytes and endothelial cells via directly binding to Siglec-5. GlycoRNA-L predominantly expressed in most of tissues and cell lines. GlycoRNA-S only expressed in some cell lines and tissues. Siglec-5 preferentially binds to glycoRNA-L than glycoRNA-S. The composition of glycan chains in glycoRNA-L and glycoRNA-S is different. GlycoRNA-L contains more sialic acid, whereas glycoRNA-S contains more GlcNAc. Together, these results demonstrate that two forms of glycoRNAs exist, which may play significant role in controlling the interaction of human monocytes and endothelial cells and contribute to the pathogenesis of inflammatory diseases.
Auditory perception and neural representation of temporal fine structure are impaired by age but not by cochlear synaptopathy
Authors: Steenken Friederike , Beutelmann Rainer , Oetjen Henning , Köppl Christine , Klump Georg M. 
Published: August 2024

AbstractAge-related hearing loss is a complex phenomenon. The earliest-onset degenerative event is the gradual loss of neural connections between cochlea and auditory brainstem. To probe for perceptual deficits that might arise from this loss, cochlear synaptopathy was induced pharmacologically in young-adult gerbils which were then tested in a challenging listening task for the perception of temporal fine structure. Treated gerbils behaved no differently than normal-hearing, young-adult animals. In contrast, old gerbils, which typically express many cochlear and central-neural pathologies, showed impaired perception. To probe for the underlying mechanisms, single-unit responses were obtained from the auditory nerve to the same test stimuli. Responses from old gerbils showed no impairment in temporal locking to the stimulus fine structure. However, responses were significantly more driven by slower temporal fluctuations of the stimulus envelope, suggesting that the central auditory system may be unable to extract the relevant information for discrimination from such altered inputs.
Recapitulation of clinical features in a patient-derived xenograft mouse model of VEXAS Syndrome
Authors: Arede Liliana , Coutinho Rita , Duarte Tiago L , Lopes Marta , Simões Rui V , Silva Susana , Baptista Pedro , Lopes José Manuel , Faria Raquel , Duarte Delfim 
Published: August 2024

AbstractPatient-derived xenografts (PDX) are valuable tools to model human disease and test new therapies. Here, we report, for the first time, a PDX model recapitulating the unique characteristics of a VEXAS patient (unique patient number UPN1).