bluuebunny/crossref_metadata_2025 huggingface dataset:
Chronic and Acute Pain and Adverse Economic Outcomes in a 9/11-Exposed Cohort
Authors: Brite Jennifer , Maqsood Junaid , Yu Shengchao , Alper Howard E. , Cone James E.
Published: November 2024

The objective of this study was to determine the association between acute and chronic pain and various economic and quality-of-life outcomes. The study sample was drawn from the World Trade Center Health Registry. Both acute and chronic pain were measured in 2020–2021. Logistic regression models were constructed to determine the odds of several economic and quality-of-life variables: early retirement, low household income, decline in household income, quality of life, and not working due to health. Those who had extreme pain in the last four weeks that interfered with normal work had 3.12 (95% confidence interval (CI): 2.36, 4.39) times the odds of early retirement, 5.34 (95% CI: 3.47, 8.21) times the odds of having a household income below USD 50,000, 2.56 (95% CI: 1.51, 4.33) times the odds of having an income decrease, and 14.4 (95% CI: 11.3, 18.3) times the rate of poor health days compared to those with no pain. Similar results were found for chronic pain. The detrimental effects of pain may influence multiple facets of a patient’s life, and both financial and overall well-being may diminish even several years after a pain diagnosis.
Mortality from Hypertrophic Cardiomyopathy in Brazil—Historical Series
Authors: Santos Emerson de Santana , Castro Pedro Henrique Gomes , Lima Laís Prado Smith , Pimentel João Victor Andrade , Kuhn Gabriel da Costa , Sousa Antônio Carlos Sobral , Oliveira Joselina Luzia Menezes
Published: November 2024

Hypertrophic cardiomyopathy (HCM) is a relatively prevalent disease, primarily of a genetic etiology, affecting both sexes and characterized by left ventricular hypertrophy. However, limitations within healthcare systems, socioracial factors, and the issue of underdiagnosis hinder accurate mortality assessments in our region. This study, therefore, aimed to assess the mortality trends associated with HCM in Brazil from 2010 to 2020, with a focus on socioracial factors and healthcare disparities. This ecological, time-series study employed a quantitative approach based on secondary data from the Mortality System (SIM) developed by the Brazilian Ministry of Health. Mortality incidence and trend analyses were conducted using the average annual percent change (AAPC) and the annual percent change (APC). The results indicated a predominance of HCM-related deaths among white males aged 40 years and older. Additionally, an increasing trend in HCM-related mortality was observed among white and brown males and females aged 40 years and above from 2010 to 2018. Throughout the entire period covered in the study, the incidence of deaths due to HCM increased by 18.3% and 69.8% in the northeastern and southeastern regions. The findings suggest that health system managers should consider addressing the factors influencing HCM mortality and encourage the development and implementation of clinical protocols across healthcare institutions nationwide. Such protocols are recommended to facilitate early diagnosis and establish effective treatment strategies, ultimately aiming to improve the survival rates and quality of life for individuals affected by HCM.
Large Language Model-Driven Structured Output: A Comprehensive Benchmark and Spatial Data Generation Framework
Authors: Li Diya , Zhao Yue , Wang Zhifang , Jung Calvin , Zhang Zhe
Published: November 2024

Large language models (LLMs) have demonstrated remarkable capabilities in document processing, data analysis, and code generation. However, the generation of spatial information in a structured and unified format remains a challenge, limiting their integration into production environments. In this paper, we introduce a benchmark for generating structured and formatted spatial outputs from LLMs with a focus on enhancing spatial information generation. We present a multi-step workflow designed to improve the accuracy and efficiency of spatial data generation. The steps include generating spatial data (e.g., GeoJSON) and implementing a novel method for indexing R-tree structures. In addition, we explore and compare a series of methods commonly used by developers and researchers to enable LLMs to produce structured outputs, including fine-tuning, prompt engineering, and retrieval-augmented generation (RAG). We propose new metrics and datasets along with a new method for evaluating the quality and consistency of these outputs. Our findings offer valuable insights into the strengths and limitations of each approach, guiding practitioners in selecting the most suitable method for their specific use cases. This work advances the field of LLM-based structured spatial data output generation and supports the seamless integration of LLMs into real-world applications.
Identification and Causes of Neighborhood Commercial Areas: Focusing on the Development of Daily Life Circles in Urban Built Environments
Authors: Feng Tianyi , Zhou Ying
Published: November 2024

Urban planning in China is shifting from an administrative unit-based approach to community life circle planning, aiming to align planning units with residents’ actual activity ranges. As the most fundamental life circle, daily life circle (DLC) planning must adopt a bottom-up approach. However, the widely applicable methods for delineating DLCs remain lacking. This study presents a strategy for delineating DLCs centered on neighborhood commercial areas that aggregate essential daily life services. Correspondingly, a method is proposed for identifying neighborhood commercial areas based on residents’ actual usage of facilities. The method was applied in Qinhuai District, Nanjing, where neighborhood commercial areas were identified and the factors influencing their formation and types were quantitatively analyzed. The results indicate the following: (1) the proposed method accurately identifies neighborhood commercial areas that can serve as DLC central areas; (2) commercial diversity, public transportation stops, and parking spots are the three most influential factors in neighborhood commercial area formation, exhibiting non-linear and threshold effects; and (3) the type of neighborhood commercial areas varies by population density, housing prices, and street betweenness, with betweenness being the most significant factor. These findings provide methods and indicators for DLC delineation and planning, contributing to the realization of the DLC construction concept.
Are Δ9-Tetrahydrocannabinol and Its Major Metabolites Substrates or Inhibitors of Placental or Human Hepatic Drug Solute-Carrier Transporters?
Authors: Chen Xin , Gáborik Zsuzsanna , Mao Qingcheng , Unadkat Jashvant D.
Published: November 2024

Δ9-Tetrahydrocannabinol (THC) is the primary psychoactive component of cannabis which is being increasingly consumed by pregnant people. In humans, THC is sequentially metabolized in the liver to its circulating metabolites 11-hydroxy-THC (11-OH-THC, psychoactive) and 11-nor-9-carboxy-THC (THC-COOH, non-psychoactive). Human and macaque data show that fetal exposure to THC is considerably lower than the corresponding maternal exposure. Through perfused human placenta studies, we showed that this is due to the active efflux of THC (fetal-to-maternal) by a placental transporter(s) other than P-glycoprotein or breast cancer resistance protein. The identity of this placental transporter(s) as well as whether THC or its metabolites are substrates or inhibitors of hepatic solute carrier transporters is unknown. Therefore, we investigated whether 5 μM THC, 0.3 μM 11-OH-THC, and 2.5 μM THC-COOH are substrates and/or inhibitors of placental or hepatic solute carrier transporters at their pharmacologically relevant concentrations. Using HEK cells overexpressing human OATP1B1, OATP1B3, OATP2B1, OCT1, OCT3, OAT2, OAT4, or NTCP, and prototypic substrates/inhibitors of these transporters, we found that THC and THC-COOH were substrates but not inhibitors of OCT1. THC-COOH was a weak substrate of OCT3 and a weak inhibitor of OAT4. THC, 11-OH-THC, and THC-COOH were found not to be substrates/inhibitors of the remaining transporters investigated.
Predicting and Monitoring Immune Checkpoint Inhibitor Therapy Using Artificial Intelligence in Pancreatic Cancer
Authors: Yu Guangbo , Zhang Zigeng , Eresen Aydin , Hou Qiaoming , Amirrad Farideh , Webster Sha , Nauli Surya , Yaghmai Vahid , Zhang Zhuoli
Published: November 2024

Pancreatic cancer remains one of the most lethal cancers, primarily due to its late diagnosis and limited treatment options. This review examines the challenges and potential of using immunotherapy to treat pancreatic cancer, highlighting the role of artificial intelligence (AI) as a promising tool to enhance early detection and monitor the effectiveness of these therapies. By synthesizing recent advancements and identifying gaps in the current research, this review aims to provide a comprehensive overview of how AI and immunotherapy can be integrated to develop more personalized and effective treatment strategies. The insights from this review may guide future research efforts and contribute to improving patient outcomes in pancreatic cancer management.
Artificial Gravity Attenuates the Transcriptomic Response to Spaceflight in the Optic Nerve and Retina
Authors: Kremsky Isaac , Pergerson Reyna , Justinen Stephen , Stanbouly Seta , Willey Jeffrey , Fuller Charles A. , Takahashi Satoru , Vitaterna Martha Hotz , Bouxsein Mary , Mao Xiaowen
Published: November 2024

The development of eye pathology is a serious concern for astronauts who spend time in deep space. Microgravity is a major component of the spaceflight environment which could have adverse effects on ocular health. The use of centrifugation to exert forces that partially or fully mimic Earth-level gravity in space is a possible countermeasure to mitigate the effects of microgravity on the eye. Therefore, we subjected mice on the International Space Station (ISS) to microgravity (0 G) or artificial gravity by centrifugation at 0.33 G, 0.67 G, and 1 G, and then performed RNA sequencing (RNA-seq) on optic nerve and retinal tissue after returning them to Earth alive. We find that the microgravity environment induces transcriptomic changes in the optic nerve and retina consistent with an increased oxidative stress load, inflammation, apoptosis, and lipid metabolic stress. We also find that adding artificial gravity on board the ISS attenuates the transcriptomic response to microgravity in a dose-dependent manner. Such attenuation may effectively protect from and mitigate spaceflight-induced detrimental effects on ocular tissue.
Train and Reprogram Your Brain: Effects of Physical Exercise at Different Stages of Life on Brain Functions Saved in Epigenetic Modifications
Authors: Kukla-Bartoszek Magdalena , Głombik Katarzyna
Published: November 2024

Multiple studies have demonstrated the significant effects of physical exercise on brain plasticity, the enhancement of memory and cognition, and mood improvement. Although the beneficial impact of exercise on brain functions and mental health is well established, the exact mechanisms underlying this phenomenon are currently under thorough investigation. Several hypotheses have emerged suggesting various possible mechanisms, including the effects of hormones, neurotrophins, neurotransmitters, and more recently also other compounds such as lactate or irisin, which are released under the exercise circumstances and act both locally or/and on distant tissues, triggering systemic body reactions. Nevertheless, none of these actually explain the long-lasting effect of exercise, which can persist for years or even be passed on to subsequent generations. It is believed that these long-lasting effects are mediated through epigenetic modifications, influencing the expression of particular genes and the translation and modification of specific proteins. This review explores the impact of regular physical exercise on brain function and brain plasticity and the associated occurrence of epigenetic modifications. It examines how these changes contribute to the prevention and treatment of neuropsychiatric and neurological disorders, as well as their influence on the natural aging process and mental health.
FAAH Inhibition Counteracts Neuroinflammation via Autophagy Recovery in AD Models
Authors: Armeli Federica , Coccurello Roberto , Giacovazzo Giacomo , Mengoni Beatrice , Paoletti Ilaria , Oddi Sergio , Maccarrone Mauro , Businaro Rita
Published: November 2024

Endocannabinoids have attracted great interest for their ability to counteract the neuroinflammation underlying Alzheimer’s disease (AD). Our study aimed at evaluating whether this activity was also due to a rebalance of autophagic mechanisms in cellular and animal models of AD. We supplied URB597, an inhibitor of Fatty-Acid Amide Hydrolase (FAAH), the degradation enzyme of anandamide, to microglial cultures treated with Aβ25-35, and to Tg2576 transgenic mice, thus increasing the endocannabinoid tone. The addition of URB597 did not alter cell viability and induced microglia polarization toward an anti-inflammatory phenotype, as shown by the modulation of pro- and anti-inflammatory cytokines, as well as M1 and M2 markers; moreover microglia, after URB597 treatment released higher levels of Bdnf and Nrf2, confirming the protective role underlying endocannabinoids increase, as shown by RT-PCR and immunofluorescence experiments. We assessed the number and area of amyloid plaques in animals administered with URB597 compared to untreated animals and the expression of autophagy key markers in the hippocampus and prefrontal cortex from both groups of mice, via immunohistochemistry and ELISA. After URB597 supply, we detected a reduction in the number and areas of amyloid plaques, as detected by Congo Red staining and a reshaping of microglia activation as shown by M1 and M2 markers’ modulation. URB597 administration restored autophagy in Tg2576 mice via an increase in BECN1 (Beclin1), ATG7 (Autophagy Related 7), LC3 (light chain 3) and SQSTM1/p62 (sequestrome 1) as well as via the activation of the ULK1 (Unc-51 Like Autophagy Activating Kinase 1) signaling pathway, suggesting that it targets mTOR/ULK1-dependent autophagy pathway. The potential of endocannabinoids to rebalance autophagy machinery may be considered as a new perspective for therapeutic intervention in AD.
The Role of Oxytocin and Vasopressin in People with Borderline Personality Disorder: A Closer Look at Adolescents
Authors: Uzar Magdalena , Dmitrzak-Węglarz Monika , Słopień Agnieszka
Published: November 2024

Borderline personality disorder constitutes a significant medical challenge. Despite the fact that its occurrence among adolescents is currently attracting increasing interest from both clinicians and researchers, there is still insufficient data on this phenomenon. The etiology and maintenance of borderline personality disorder are not yet fully comprehended. Neuropeptides, including oxytocin and vasopressin, are considered to be involved in the development of this condition. The mechanism behind the actions of these neurohormones requires further investigation. Our work aims to collect and analyze the available research and existing hypotheses on the role of oxytocin and vasopressin in people with borderline personality disorder, with special attention drawn to adolescents suffering from this condition.
Characterization and Experimental Use of Multiple Myeloma Bone Marrow Endothelial Cells and Progenitors
Authors: Garbicz Filip , Kaszkowiak Marcin , Dudkiewicz-Garbicz Julia , Dorfman David M. , Ostrowska Julia , Barankiewicz Joanna , Salomon-Perzyński Aleksander , Lech-Marańda Ewa , Nguyen Tuyet , Juszczyński Przemyslaw , Carrasco Ruben D. , Misiewicz-Krzeminska Irena
Published: November 2024

Multiple myeloma (MM) is a plasma cell malignancy that resides within the bone marrow microenvironment, relying heavily on interactions with its cellular components. Among these, endothelial cells (ECs) play a pivotal role in MM progression and the development of therapeutic resistance. In this study, we analyzed publicly available single-cell RNA sequencing data to identify unique pathway activations distinguishing ECs from MM patients and healthy donors. We developed a novel protocol to isolate and culture endothelial progenitor cells (EPCs) and ECs directly from MM patient bone marrow, demonstrating their ability to promote myeloma cell proliferation. Validation studies confirmed that these MM-derived ECs exhibit angiogenic potential as well as the expression of characteristic endothelial lineage markers. These findings underscore the critical role of bone marrow ECs in the MM tumor microenvironment and highlight potential new therapeutic targets to disrupt MM progression.
Bioinformatic Multi-Strategy Profiling of Congenital Heart Defects for Molecular Mechanism Recognition
Authors: de Oliveira Fabyanne Guimarães , Foletto João Vitor Pacheco , Medeiros Yasmin Chaves Scimczak , Schuler-Faccini Lavínia , Kowalski Thayne Woycinck
Published: November 2024

Congenital heart defects (CHDs) rank among the most common birth defects, presenting diverse phenotypes. Genetic and environmental factors are critical in molding the process of cardiogenesis. However, these factors’ interactions are not fully comprehended. Hence, this study aimed to identify and characterize differentially expressed genes involved in CHD development through bioinformatics pipelines. We analyzed experimental datasets available in genomic databases, using transcriptome, gene enrichment, and systems biology strategies. Network analysis based on genetic and phenotypic ontologies revealed that EP300, CALM3, and EGFR genes facilitate rapid information flow, while NOTCH1, TNNI3, and SMAD4 genes are significant mediators within the network. Differential gene expression (DGE) analysis identified 2513 genes across three study types, (1) Tetralogy of Fallot (ToF); (2) Hypoplastic Left Heart Syndrome (HLHS); and (3) Trisomy 21/CHD, with LYVE1, PLA2G2A, and SDR42E1 genes found in three of the six studies. Interaction networks between genes from ontology searches and the DGE analysis were evaluated, revealing interactions in ToF and HLHS groups, but none in Trisomy 21/CHD. Through enrichment analysis, we identified immune response and energy generation as some of the relevant ontologies. This integrative approach revealed genes not previously associated with CHD, along with their interactions and underlying biological processes.
Tuning the Electronic Properties of CumAgn Bimetallic Clusters for Enhanced CO2 Activation
Authors: Alotaibi Turki , Alotaibi Moteb , Alhawiti Fatimah , Aldosari Nawir , Alsunaid Majd , Aldawas Lama , Qahtan Talal F. , Ismael Ali K.
Published: November 2024

The urgent demand for efficient CO2 reduction technologies has driven enormous studies into the enhancement of advanced catalysts. Here, we investigate the electronic properties and CO2 adsorption properties of CumAgn bimetallic clusters, particularly Cu4Ag1, Cu1Ag4, Cu3Ag2, and Cu2Ag3, using generalized gradient approximation (GGA)/density functional theory (DFT). Our results show that the atomic arrangement within these clusters drastically affects their stability, charge transfer, and catalytic performance. The Cu4Ag1 bimetallic cluster emerges as the most stable structure, revealing superior charge transfer and effective chemisorption of CO2, which promotes effective activation of the CO2 molecule. In contrast, the Cu1Ag4 bimetallic cluster, in spite of comparable adsorption energy, indicates insignificant charge transfer, resulting in less pronounced CO2 activation. The Cu3Ag2 and Cu2Ag3 bimetallic clusters also display high adsorption energies with remarkable charge transfer mechanisms, emphasizing the crucial role of metal composition in tuning catalytic characteristics. This thorough examination provides constructive insights into the design of bimetallic clusters for boosted CO2 reduction. These findings could pave the way for the development of cost-effective and efficient catalysts for industrial CO2 reduction, contributing to global efforts in carbon management and climate change mitigation.
Development of High-Production Bacterial Biomimetic Vesicles for Inducing Mucosal Immunity Against Avian Pathogenic Escherichia coli
Authors: Li Yue , Quan Yuji , Chen Peng , Zhuge Xiangkai , Qin Tao , Chen Sujuan , Peng Daxin , Liu Xiufan
Published: November 2024

To evaluate the immunoprotective effect of bacterial biomimetic vesicles (BBVs) against avian pathogenic Escherichia coli (APEC), a ΔtolA J11 mutant strain was generated by deleting the tolA gene in the low pathogenic O78 serotype J11 strain. The total protein content of outer membrane vesicles (OMVs) derived from the ΔtolA J11 strain exhibited a sevenfold increase compared to the wild-type strain. Additionally, high-pressure homogenization technology was employed to produce BBVs, resulting in a sixfold increase in total protein content compared to spontaneously secreted OMVs from ΔtolA J11. The immunogenicity of both OMVs and BBVs was assessed through intranasal or intramuscular immunization in specific pathogen-free (SPF) chickens. Results demonstrated that intranasal immunization with OMVs or BBVs in chickens elicited specific IgY antibodies against APEC outer membrane proteins and specific sIgA antibodies in the nasal cavity and trachea, as well as a significant increase in the proliferation response of chicken peripheral blood lymphocytes. The bacterial load in the blood and various organs of the challenged chickens were significantly reduced, resulting in a 66.67% and 58.30% survival rate against a high pathogenic serotype O78 strain challenge, while the control group exhibited only a 16.67% survival rate. The intramuscular immunization with OMVs or BBVs in chickens only induced specific IgY antibodies, with a survival rate of only 33.33% for challenged chickens during the same period. Therefore, intranasal vaccination of the highly productive BBVs is capable of eliciting an immune response similar to that of OMVs and providing protection against APEC infection, thus offering innovative insights for the advancement of APEC vaccines.
Novel Gene Variants in a Nationwide Cohort of Patients with Pheochromocytoma and Paraganglioma
Authors: Martínez de Lapiscina Idoia , Diego Estrella , Baquero Candela , Fernández Elsa , Menendez Edelmiro , Moure Maria Dolores , Ruiz de Azua Teresa , Castaño Luis , Valdés Nuria ,   on behalf of the Collaborative Working Group
Published: November 2024

Pheochromocytomas (PCCs) and paragangliomas (PGLs), denoted PPGLs, are rare neuroendocrine tumours and are highly heterogeneous. The phenotype–genotype correlation is poor; therefore, additional studies are needed to understand their pathogenesis. We describe the clinical characteristics of 63 patients with PPGLs and perform a genetic study. Genetic screening was performed via a targeted gene panel, and clinical variables were compared among patients with a positive molecular diagnosis and negative ones in both PCC and PGL cohorts. The mean age of patients with PCC was 50.0, and the mean age of those with PGL was 54.0. Disease-causing germline variants were identified in 16 individuals (25.4%), twelve and five patients with PCC and PGL, respectively. Genetically positive patients were younger at diagnosis in both cohorts. Variants in genes associated with either isolated PPGLs or syndromic forms of the disease were detected in a cohort of PPGLs. We have identified novel variants in known genes and set the importance of genetic screening to every patient with PPGLs, with a special focus on the young. A longer follow up of patients with variants in genes associated with syndromic forms is of clinical value.
Genome-Wide Identification of Basic Helix–Loop–Helix (bHLH) Family in Peanut: Potential Regulatory Roles in Iron Homeostasis
Authors: Shi Gangrong , Zhang Zheng , Li Jinxiu
Published: November 2024

The basic helix–loop–helix (bHLH) superfamily is the second-largest transcription factor family that participates in a wide range of biological processes in plants, including iron homeostasis. Although the family has been studied in several plant species, a comprehensive investigation is still needed for peanut (Arachis hypogaea). Here, a genome-wide analysis identified 373 AhbHLH genes in peanut, which were divided into 14 groups or subfamilies according to phylogenetic analysis. Clustered members generally share similar gene/protein structures, supporting the evolutionary relationships among AhbHLH proteins. Most AhbHLHs experienced whole-genome or segmental duplication. The majority of AhbHLH proteins had a typical bHLH domain, while several phylogenetic groups, including Group VI, X, XIII, and XIV, had the HLH domain. The expression of several AhbHLH genes, including AhbHLH001.3, AhbHLH029.1/.2, AhbHLH047.1/.2, AhbHLH115.1/.2, AhbHLH097.1/.2, AhbHLH109.4, and AhbHLH135.1, was induced by Fe deficiency for both cultivars, or at least in Silihong, suggesting an important role in the Fe deficiency response in peanut. Nine genes (AhbHLH001.3, AhbHLH029.1/.2, AhbHLH047.1/.2, AhbHLH097.1/.2, and AhbHLH115.1/.2) were specifically induced by Fe deficiency in Silihong, and their expression was higher in Silihong than that in Fenghua 1. These genes might be responsible for higher tolerance to Fe deficiency in Silihong. Our findings provide comprehensive information for further elucidating the regulatory mechanism of Fe homeostasis in peanut.
Unveiling Biomarkers in Head and Neck Squamous Cell Carcinoma through Bioinformatics: The Role of SPP1 and KRT78
Authors: Cheon Jaehwan , Kim Byoungjae , Park Jaehyung , Shin Jaemin , Kim Tae Hoon
Published: November 2024

Head and neck squamous cell carcinoma (HNSCC) is the most common form of head and neck cancer, ranking sixth in global cancer incidence. Identifying molecular drivers of tumorigenesis and metastasis is essential for early detection and treatment. This study analyzed gene expression profiles from three datasets (GSE6791, GSE29330, and GSE58911) to identify differentially expressed genes (DEGs) in HNSCC. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were employed to functionally annotate these DEGs. A protein–protein interaction (PPI) network was constructed for selecting hub genes using the STRING database. Finally, hub gene and protein expression levels were evaluated in patients with HNSCC, along with their association with overall survival. Our analysis identified twenty-eight co-DEGs comprising eight up-regulated and twenty down-regulated genes, primarily involved in extracellular matrix (ECM) organization, proteolysis, ECM disassembly, and keratinization processes. Furthermore, the PPI network revealed eight hub genes based on their high degree of connectivity. Notably, SPP1 demonstrated up-regulation, while KRT78 was down-regulated in HNSCC. Remarkably, the expression levels of these hub genes correlated with tumor grade, clinical cancer stage, and poor prognosis in HNSCC. Our findings hold significant clinical potential for early diagnosis and the development of novel therapeutic targets for patients with HNSCC.
Inert Gas Mild Pressure Action on Healthy Humans: The “IPA” Study
Authors: Balestra Costantino , Leveque Clément , Mrakic-Sposta Simona , Coulon Mathias , Tumbarello Romain , Vezzoli Alessandra , Bosco Gerardo , Imtiyaz Zuha , Thom Stephen R.
Published: November 2024

The goal of this study was to evaluate inflammatory and oxidative stress responses in human subjects (9 females and 15 males) (age [29.6 ± 11.5 years old (mean ± SD)], height [172.0 ± 10.05 cm], and weight [67.8 ± 12.4 kg]) exposed to 1.45 ATA of helium (He) or nitrogen (N2) without concurrent hyperoxia. We hypothesized that elevated gas pressures would elicit an inflammatory response concurrent with oxidative stress. Consistent with ex vivo studies, both gasses elicited neutrophil activation, small elevations in microparticles (MPs) and increases in intra-MP interleukin (IL)-1β and inflammatory nitric oxide synthase, and an increase in urinary IL-6 concurrent with a marked reduction in plasma gelsolin. Mixed responses indictive of oxidative stress, with some biomarker elevations but little change in others and a decrease in some, were observed. Overall, these results demonstrate that exposure to typical diving gasses at a mildly elevated partial pressure will initiate inflammatory responses, which may play a significant role in decompression sickness (DCS). The complex pattern of oxidative stress responses may be indicative of competing systemic reactions and sampling different body fluids.
Immune Response and Transcriptome Analysis of the Head Kidney to Different Concentrations of Aeromonas veronii in Common Carp (Cyprinus carpio)
Authors: Zhang Jin , Ding Ning , Qi Yingjie , Jiang Na , Xing Wei , Li Tieliang , Ma Zhihong , Cao Yiming , Zhang Yan , Li Jiongtang
Published: November 2024

The common carp (Cyprinus carpio), a major economic freshwater fish, is suffering from a variety of bacterial infectious diseases because of its high-density, factory and intensive farming patterns. Aeromonas veronii is the causative agent of high mortality in common carp, causing severe economic losses in aquaculture. However, the regulatory mechanisms involved in the response of common carp to this bacterial infection remain poorly understood. In this study, we compared mortality, blood serum LZM (Lysozyme) and IgM (Immunoglobulin M) levels and transcriptome patterns of head kidney tissues after infection with different concentrations of Aeromonas veronii. We observed that mortality increased progressively with an increasing pathogen concentration. The concentrations of blood serum LZM and IgM significantly increased after infection. A total of 13 and 925 differentially expressed genes (DEGs) were identified after infection with low (T4) and high (T9) concentrations of bacterial suspension, respectively. KEGG and GO analyses of the DEGs highlighted multiple immune-related signaling pathways. Weighted gene co-expression network analysis (WGCNA) revealed that 136 and 83 hub genes were related to blood serum LZM and IgM, respectively. Finally, the gene expression in the head kidney was validated via RT–qPCR to be consistent with the transcriptome. These results provide insights into the mechanisms of the immune response to infection with different concentrations of Aeromonas veronii and offer useful information for further studies on immune defense mechanisms in common carp.
Fusarium sacchari Effector FsMEP1 Contributes to Virulence by Disturbing Localization of Thiamine Thiazole Synthase ScTHI2 from Sugarcane
Authors: Wang Lulu , Wu Deng , Hong Tianshu , Ren Qianqian , Wang Shichao , Bao Yixue , Yao Wei , Zhang Muqing , Hu Qin
Published: November 2024

Fusarium sacchari is a significant pathogenic fungus that causes sugarcane Pokkah Boeng. Proteins secreted by pathogenic fungi can be delivered into hosts to suppress plant immunity and establish infection. However, there is still much to be discovered regarding F. sacchari’s secreted effectors in overcoming plant immunity. In this paper, we characterize a novel effector called FsMEP1, which is essential for the virulence of F. sacchari. FsMEP1 contains a conserved zinc-binding motif sequence, HEXXH, and is highly expressed during host infection. Using the Agrobacterium tumefaciens-mediated transient expression system, it was confirmed that FsMEP1 could suppress Bcl-2-associated X protein (BAX)-triggered cell death, callose deposition, and ROS explosion in Nicotiana benthamiana. Furthermore, the deletion of FsMEP1 demonstrated its requirement for contributing to the pathogenicity of F. sacchari in sugarcane. Further analysis revealed that FsMEP1 could interact with the sugarcane thiamine thiazole synthase ScTHI2 and disrupt its normal localization, thereby inhibiting the synthesis of thiamine and the defense responses mediated by ScTHI2. Based on these findings, we propose that ScTHI2 represents a potential molecular target for improving sugarcane resistance to Pokkah Boeng disease.
Innate Immunity and Synovitis: Key Players in Osteoarthritis Progression
Authors: Panichi Veronica , Costantini Silvia , Grasso Merimma , Arciola Carla Renata , Dolzani Paolo
Published: November 2024

Osteoarthritis (OA) is a chronic progressive disease of the joint. Although representing the most frequent cause of disability in the elderly, OA remains partly obscure in its pathogenic mechanisms and is still the orphan of resolutive therapies. The concept of what was once considered a “wear and tear” of articular cartilage is now that of an inflammation-related disease that affects over time the whole joint. The attention is increasingly focused on the synovium. Even from the earliest clinical stages, synovial inflammation (or synovitis) is a crucial factor involved in OA progression and a major player in pain onset. The release of inflammatory molecules in the synovium mediates disease progression and worsening of clinical features. The activation of synovial tissue-resident cells recalls innate immunity cells from the bloodstream, creating a proinflammatory milieu that fuels and maintains a damaging condition of low-grade inflammation in the joint. In such a context, cellular and molecular inflammatory behaviors in the synovium could be the primum movens of the structural and functional alterations of the whole joint. This paper focuses on and discusses the involvement of innate immunity cells in synovitis and their role in the progression of OA.
The Expression of HPV-16 E5 Oncoprotein Impacts the Transcript Profiles of FGFR2 and EMT-Related Genes in Preneoplastic Anal Epithelium Lesions
Authors: Raffa Salvatore , Mancini Vanessa , French Deborah , Rollo Francesca , Benevolo Maria , Giuliani Eugenia , Donà Maria Gabriella , Ranieri Danilo , Belleudi Francesca
Published: November 2024

Anal Squamous Cell Carcinoma (SCCA) is a rare Human Papillomavirus type 16 (HPV16)-associated carcinoma whose pathogenesis is still poorly understood. Recent studies based on biopsy and Next Generation Sequencing (NGS) approaches have linked the viral episomal status to aggressive SCCA phenotypes, suggesting a potential role of the 16E5 oncoprotein in tumor development. Our previous findings indicated that 16E5 induces Fibroblast Growth Factor Receptor 2 (FGFR2) isoform switching, aberrant mesenchymal FGFR2c expression, Epithelial Mesenchymal Transition (EMT), and cell invasion in various in vitro human keratinocyte models, as well as in the in vivo context of cervical Low-grade Squamous Intraepithelial Lesions (LSILs). To further explore the role of 16E5 in epithelial carcinogenesis, this study aims to investigate the molecular profile in HPV-related anal lesions. The results showed a significant positive correlation between 16E5 and FGFR2c, as well as 16E5 or FGFR2c and key EMT-related transcription factors, particularly in the group of HPV16 positive anal samples not containing without high grade lesions. Additionally, by coupling the molecular analysis with an interactome investigation, we hypothesized a potential functional interplay between the Ca2+ channel Transient Receptor Potential Ankyrin 1 (TRPA1) and FGFR2c, mediated by 16E5 during the establishment of the oncogenic signaling. These findings will help to elucidate the actual relevance of 16E5 in the early progression of anal lesions and contribute to determine its potential as target for future preventive approaches for HPV16-positive SCCA.
Overexpression of LAR1 Suppresses Anthocyanin Biosynthesis by Enhancing Catechin Competition Leading to Promotion of Proanthocyanidin Pathway in Spine Grape (Vitis davidii) Cells
Authors: Lin Junxuan , Lai Gongti , Guo Aolin , He Liyuan , Yang Fangxue , Huang Yuji , Che Jianmei , Lai Chengchun
Published: November 2024

Proanthocyanidins (PAs) are a class of polyphenolic compounds recognized for their potent antioxidant, anti-cancer, anti-inflammatory, and cardioprotective properties. However, the production of PAs from natural sources is often limited by high costs, resource wastage, and environmental damage. In this study, we investigated the overexpression of VdLAR1, along with phenotypic observation, metabolite determination, light quality treatment, and RT-qPCR analysis, in spine grape cells. The results demonstrated a significant increase in the contents of proanthocyanidins and flavonoids in pVdLAR1-overexpressing transgenic cell lines, while anthocyanin levels showed a decreasing trend. Furthermore, the treatment with white and blue light on the T5 cell line resulted in enhanced accumulation of proanthocyanidins, catechins, and flavonoids, whereas anthocyanins and epicatechins exhibited a declining pattern. Thus, short-wavelength light promoted the accumulation of metabolites, with the proanthocyanidin content in the T5 transformed cell line reaching 2512.0 μg/g (FW) during blue light incubation. RT-qPCR analysis revealed that the key genes involved in the biosynthesis of proanthocyanidin and anthocyanin were upregulated in the transgenic spine grape cell lines, with VdLAR1 expression increasing by several hundredfold, far surpassing the expression levels of LDOX and ANR. The VdLAR1 overexpression markedly improved substrate competitiveness within the metabolic pathway, promoting catechin biosynthesis while inhibiting the production of epicatechins and anthocyanins. This finding provides compelling evidence that LAR1 is a crucial gene for catechin biosynthesis. This research establishes both theoretical and practical foundations for the regulation and development of natural proanthocyanidins, addressing issues related to high costs, safety concerns, resource wastage, and environmental damage associated with their production.
The Effects of Different Respiratory Viruses on the Oxidative Stress Marker Levels in an In Vitro Model: A Pilot Study
Authors: Bażanów Barbara , Michalczyk Katarzyna , Kafel Alina , Chełmecka Elżbieta , Skrzep-Poloczek Bronisława , Chwirot Aleksandra , Nikiel Kamil , Olejnik Aleksander , Suchocka Alicja , Kukla Michał , Bogielski Bartosz , Jochem Jerzy , Stygar Dominika
Published: November 2024

Respiratory viruses are among the most common causes of human infections. Examining pathological processes linked to respiratory viral infections is essential for diagnosis, treatment strategies, and developing novel therapeutics. Alterations in oxidative stress levels and homeostasis are significant processes associated with respiratory viral infections. The study aimed to compare selected oxidative stress markers: total oxidative status (TOS), total antioxidant capacity (TAC), and the oxidative stress index (OSI) levels and glutathione peroxidase (GPx) and glutathione reductase (GR) activities in normal (MRC5 cell line) and tumor (A549 cell line) lung cells infected with human coronaviruses (HCoV) OC43 and 229E, human adenovirus type 5 (HAdV5), or human rhinovirus A (HRV A). We observed that a respiratory viral infection more significantly affected non-enzymatic oxidative stress markers in a lung adenocarcinoma model (A549 cells), while human lung fibroblasts (MRC-5 cell line) presented changes in enzymatic and non-enzymatic oxidative stress markers. We suggest that further detailed research is required to analyze this phenomenon.
A Systematic Review: Quercetin—Secondary Metabolite of the Flavonol Class, with Multiple Health Benefits and Low Bioavailability
Authors: Frenț Olimpia-Daniela , Stefan Liana , Morgovan Claudia Mona , Duteanu Narcis , Dejeu Ioana Lavinia , Marian Eleonora , Vicaș Laura , Manole Felicia
Published: November 2024

The main goal of this systematic review on the flavonol class secondary metabolite quercetin is to evaluate and summarize the existing research on quercetin’s potential health benefits, therapeutic properties, and effectiveness in disease prevention and treatment. In addition to evaluating quercetin’s potential for drug development with fewer side effects and lower toxicity, this type of review attempts to collect scientific evidence addressing quercetin’s roles as an antioxidant, anti-inflammatory, antibacterial, and anticancer agent. In the first part, we analyze various flavonoid compounds, focusing on their chemical structure, classification, and natural sources. We highlight their most recent biological activities as reported in the literature. Among these compounds, we pay special attention to quercetin, detailing its chemical structure, physicochemical properties, and process of biosynthesis in plants. We also present natural sources of quercetin and emphasize its health benefits, such as its antioxidant and anti-inflammatory effects. Additionally, we discuss methods to enhance its bioavailability, analyzing the latest and most effective delivery systems based on quercetin.
Establishment and Use of Primary Cultured Astrocytes from Alexander Disease Model Mice
Authors: Kubota Yuto , Shigetomi Eiji , Saito Kozo , Shinozaki Youichi , Kobayashi Kenji , Tanaka Masayoshi , Parajuli Bijay , Tanaka Kenji F. , Koizumi Schuichi
Published: November 2024

Alexander disease (AxD) is an intractable neurodegenerative disease caused by mutations in glial fibrillary acidic protein (GFAP), which is predominantly expressed in astrocytes. Thus, AxD is a primary astrocyte disease. However, it remains unclear how GFAP mutations affect astrocytes and cause AxD pathology. Three features are characteristic of AxD astrocytes in vivo: (1) Rosenthal fibers (RFs), the hallmark of AxD; (2) aberrant Ca2+ signals (AxCa); and (3) upregulation of disease-associated genes (AxGen). We established a primary culture system for astrocytes from an AxD transgenic mouse model, and used it to analyze the above features of AxD pathogenesis in astrocytes in vitro. We observed the formation of RFs in AxD primary cultures. The abundance of RFs was greater in AxD-transgene-homozygous compared with -hemizygous astrocytes, indicating a gene dosage effect, and this abundance increased with time in culture, indicating a developmental process effect. However, cultured AxD astrocytes did not exhibit changes in either AxCa or AxGen. We therefore conclude that RFs in astrocytes form via a cell-autonomous mechanism, whereas AxCa and AxGen are likely to occur via a non-cell-autonomous mechanism through interactions with other cells, such as neurons, microglia, and vascular cells. Although primary cultured AxD astrocytes are suitable for elucidating the mechanisms of RFs formation and for intervention studies, it should be noted that they cannot reflect the pathophysiology of non-cell-autonomous events in astrocytes.
Hedgehog Pathway Is a Regulator of Stemness in HER2-Positive Trastuzumab-Resistant Breast Cancer
Authors: Er Idris , Boz Er Asiye Busra
Published: November 2024

HER2 overexpression occurs in 20–30% of breast cancers and is associated with poor prognosis. Trastuzumab is a standard treatment for HER2-positive breast cancer; however, resistance develops in approximately 50% of patients within a year. The Hedgehog (Hh) signalling pathway, known for its role in maintaining stemness in various cancers, may contribute to trastuzumab resistance in HER2-positive breast cancer. This study aimed to investigate the role of Hedgehog signalling in maintaining stemness and contributing to trastuzumab resistance in HER2-positive breast cancer cell lines. Trastuzumab-resistant HER2-positive breast cancer cell lines, SKBR3 and HCC1954, were developed through continuous trastuzumab exposure. Cells were treated with GANT61 (Hh inhibitor, IC50:10 µM) or SAG21K (Hh activator, IC50:100 nM) for 24 h to evaluate the Hedgehog signalling response. Stemness marker expression (Nanog, Sox2, Bmi1, Oct4) was measured using qRT-PCR. The combination index (CI) of GANT61 with trastuzumab was calculated using CompuSyn software (version 1.0) to identify synergistic doses (CI < 1). The synergistic concentrations’ impact on stemness markers was assessed. Data were analysed using two-way ANOVA and Tukey’s post hoc test (p < 0.05). Trastuzumab-resistant cells exhibited increased Hedgehog signalling activity. Treatment with GANT61 significantly downregulated stemness marker expression, while SAG21K treatment led to their upregulation in both SKBR3-R and HCC1954-R cells. The combination of GANT61 and trastuzumab demonstrated a synergistic effect, markedly reducing the expression of stemness markers. These findings indicate that Hedgehog signalling plays a pivotal role in maintaining stemness in trastuzumab-resistant cells, and that the inhibition of this pathway may prevent tumour progression. Hedgehog signalling is crucial in regulating stemness in trastuzumab-resistant HER2-positive breast cancer. Targeting this pathway could overcome resistance and enhance trastuzumab efficacy. Further studies should explore the clinical potential of Hedgehog inhibitors in combination therapies.
Thrombosis in Paroxysmal Nocturnal Hemoglobinuria (PNH): From Pathogenesis to Treatment
Authors: Kokoris Styliani , Polyviou Antri , Evangelidis Paschalis , Grouzi Elisavet , Valsami Serena , Tragiannidis Konstantinos , Gialeraki Argyri , Tsakiris Dimitrios A. , Gavriilaki Eleni
Published: November 2024

Paroxysmal Nocturnal Hemoglobinuria (PNH) constitutes a rare bone marrow failure syndrome characterized by hemolytic anemia, thrombotic events (TEs), and bone marrow aplasia of variable degrees. Thrombosis is one of the major clinical manifestations of the disease, affecting up to 40% of individuals with PNH. Venous thrombosis is more prevalent, affecting mainly unusual sites, such as intrabdominal and hepatic veins. TEs might be the first clinical manifestation of PNH. Complement activation, endothelial dysfunction, hemolysis, impaired bioavailability of nitric oxide, and activation of platelets and neutrophils are implicated in the pathogenesis of TEs in PNH patients. Moreover, a vicious cycle involving the coagulation cascade, complement system, and inflammation cytokines, such as interleukin-6, is established. Complement inhibitors, such as eculizumab and ravulizumab (C5 inhibitors), have revolutionized the care of patients with PNH. C5 inhibitors should be initiated in patients with PNH and thrombosis, while they constitute a great prophylactic measure for TEs in those individuals. Anticoagulants, such as warfarin and low-molecular-weight heparin, and, in selected cases, direct oral anticoagulants (DOACs) should be used in combination with C5 inhibitors in patients who develop TEs. Novel complement inhibitors are considered an alternative treatment option, especially for those who develop extravascular or breakthrough hemolysis when terminal inhibitors are administered.
Plasma Glutaminyl-Peptide Cyclotransferase Mediates Glucosamine-Metabolism-Driven Protection Against Hypertension: A Mendelian Randomization Study
Authors: Ge Fei , Sun Yu , Han Cong-Cong , Wei Zi-Liang , Guan Xin , Guo Si-Wan , Quan Shui , Zhou Jia-Guo , Pang Rui-Ping
Published: November 2024

Hypertension is one of the major risk factors for morbidity and mortality worldwide. In this study, Mendelian randomization was utilized to investigate how dietary supplement intake can impact hypertension based on circulating plasma metabolite genome-wide association study (GWAS) datasets, protein quantitative trait loci (pQTLs) of plasma proteins, and multiple public summary-level GWAS data. Pathway enrichment analysis combined with the results of inverse variance weighted Mendelian randomization revealed that a lower risk of hypertension was associated with the dietary intake of glucosamine, an anti-inflammatory supplement: odds ratio (OR) (95% CI): 0.888 (0.824–0.958). Additionally, glucosamine 6-phosphate N-acetyltransferase was identified as a protective factor against hypertension, OR (95% CI): 0.995 (0.992–0.998), shedding light on the potential protective mechanism of glucosamine. Mediation Mendelian randomization indicated that the protective effect of glucosamine metabolism was mediated by glutaminyl-peptide cyclotransferase, with a mediation proportion of 12.1% (5.9–18.2%), p < 0.05. This study offers new insights into preventive strategies for individuals with hypertension risk.