bluuebunny/crossref_metadata_2025 huggingface dataset:
STAT4 Gene Variant rs7574865 Is Associated with Rheumatoid Arthritis Activity and Anti-CCP Levels in the Western but Not in the Southern Population of Mexico
Authors: Bravo-Villagra Karla Mayela , Muñoz-Valle José Francisco , Baños-Hernández Christian Johana , Cerpa-Cruz Sergio , Navarro-Zarza José Eduardo , Parra-Rojas Isela , Aguilar-Velázquez José Alonso , García-Arellano Samuel , López-Quintero Andres
Published: February 2024

Rheumatoid Arthritis (RA) is a multifactorial autoimmune disease. Currently, several genes play an important role in the development of the disease. The objective was to evaluate the association of the STAT4 rs7574865 and rs897200 gene variants with RA susceptibility, DAS28, RF, and anti-CCP in Western and Southern Mexico populations. Genotyping was performed on 476 samples (cases = 240; controls = 236) using the Taqman® system and qPCR probes. Disease activity was assessed using DAS28 and HAQ DI. CRP, ESR, RF, and anti-CCP were determined for clinical assessment. Our study showed there is a statistically significant association with susceptibility to RA for the rs7574865 variant in the Western population for the GT and TT genotypes. The same genotypes also showed a moderate-to-high activity according to DAS28 and positive anti-CCP compared to the control group. This association was not found in the Southern population. This work confirms the association of the rs7574865 variant with RA, as well as a moderate-to-high activity and positive anti-CCP in the Western population but not in the Southern population. No association of the rs897200 variant was found in any of the studied populations.
A Low-Cost Early Warning Method for Infectious Diseases with Asymptomatic Carriers
Authors: Gaspari Mauro
Published: February 2024

At the beginning of 2023, the Italian former prime minister, the former health minister and 17 others including the current president of the Lombardy region were placed under investigation on suspicion of aggravated culpable epidemic in connection with the government’s response at the start of the COVID-19 pandemic. The charges revolve around the failure by authorities to take adequate measures to prevent the spread of the virus in the Bergamo area, which experienced a significant excess of deaths during the initial outbreak. The aim of this paper is to analyse the pandemic data of Italy and the Lombardy region in the first 10 days of the pandemic, spanning from the 24th of February 2020 to the 4th of March 2020. The objective is to determine whether the use of early warning indicators could have facilitated the identification of a critical increase in infections. This identification, in turn, would have enabled the timely formulation of strategies for pandemic containment, thereby reducing the number of deaths. In conclusion, to translate our findings into practical guidelines, we propose a low-cost early warning method for infectious respiratory diseases with asymptomatic carriers.
Reducing Post-Operative Hospital Length of Stay following Uncomplicated Appendectomy in Pediatric Patients: A Prospective Clinical Study
Authors: Jeski Michelle A. , Stanger Jennifer D. , Schafer Melissa S. , Osten Andrew W. , Conners Gregory P.
Published: February 2024

An uncomplicated appendectomy in children is common. Safely minimizing the post-operative length of stay is desirable from hospital, patient, and parent perspectives. In response to an overly long mean length of stay following uncomplicated appendectomies in children of 2.5 days, we developed clinical pathways with the goal of safely reducing this time to 2.0 or fewer days. The project was conducted in an urban, academic children’s hospital. The pathways emphasized the use of oral, non-narcotic pain medications; the education of parents and caregivers about expectations regarding pain control, oral food intake, and mobility; and the avoidance of routine post-operative antibiotic use. A convenience sample of 46 patients aged 3–16 years old was included to evaluate the safety and efficacy of the intervention. The mean post-operative length of stay was successfully reduced by 80% to 0.5 days without appreciable complications associated with earlier discharge. The hospital length of stay following an uncomplicated appendectomy in children may be successfully and safely reduced through the use of carefully devised, well-defined, well-disseminated clinical pathways.
Fear of COVID-19 and PTSD: The Protective Function of Problem-Solving Appraisals in Mental Health
Authors: Padmanabhanunni Anita , Pretorius Tyrone Brian
Published: February 2024

The COVID-19 pandemic was experienced by many people as a major traumatic event, and it contributed to high levels of fear, anxiety, and PTSD. Negative cognitive appraisals have been consistently implicated in the onset and maintenance of psychological distress, but there is far less research on the protective role of adaptive appraisals in mental health outcomes. The current study aimed to address this gap by investigating the role of problem-solving appraisals in the relationship between fear of COVID-19 and PTSD. Participants were students (n = 322) who completed the Fear of COVID-19 Scale, the Problem-Solving Inventory, the PTSD Checklist for DSM-5, and the five-item short version of the trait scale of the State–Trait Anxiety Inventory. Participants had a mean age of 26 years (±10.2; range 17–63). The results revealed that problem-solving appraisal mediated the effects of fear of COVID-19 on all the dimensions of PTSD. However, moderated mediation analysis demonstrated that the mediation effect was moderated by anxiety. In this regard, the indirect effects of fear of COVID-19 on PTSD were only significant for respondents with low anxiety levels. Our findings suggest that intervention efforts need to focus on identifying and actively targeting maladaptive appraisals of the problem-solving ability as well as addressing anxiety-related symptoms that may impede coping.
Culture of Safety and Preparedness: Benefits of Applying a Daily Mitigation Mindset in the Hospital Setting
Authors: Griffin Anne Reid , Dobalian Aram , Langan Joanne C. , Shipman Sallie J.
Published: February 2024

Aim: Utilizing the subjective experience of nurse executives who have supervised nurses during a major disaster in a hospital setting, this study aims to describe the subjective experience of nurse executives (NE) who have supervised nurses’ responses to major disasters. This paper will focus on strategies to support nursing response to disasters, specifically to strengthen resiliency and the ability to maintain function despite the shock of a disaster, including those caused by climate change. Methods: Semi-structured interviews were conducted with 11 hospital-based nurse executives who supervised nurses during some of the worst natural and human-made disasters in different regions of the United States. A phenomenological approach was used to analyze and describe emerging themes from the qualitative data. Results: Three nurse executives demonstrated theme saturation for mitigation steps to augment traditional disaster readiness activities: (1) Assessment of human infrastructure: daily skills needed during disaster response; (2) Identification and study of failure points and metrics; (3) Strengthening human infrastructure: rectifying deficiencies; and (4) Monitoring metrics and making corrections during conventional periods. Conclusion: Mitigation steps may improve outcomes in hospital function during conventional times; therefore, these steps may improve resiliency and the ability to maintain functions during major disasters, including climate change.
Uterine Fibroid Prevalence in a Predominantly Black, Chicago-Based Cohort
Authors: Ndebele Sithembinkosi , Turner Tecora , Liao Chuanhong , Aschebrook-Kilfoy Briseis , Randorf Nina , Ahsan Habibul , Odunsi Kunle , Madueke-Laveaux Obianuju Sandra
Published: February 2024

(1) Objectives: To investigate the effect of individual-level, neighborhood, and environmental variables on uterine fibroid (UF) prevalence in a Chicago-based cohort. (2) Methods: Data from the Chicago Multiethnic Prevention and Surveillance Study (COMPASS) were analyzed. Individual-level variables were obtained from questionnaires, neighborhood variables from the Chicago Health Atlas, and environmental variables from NASA satellite ambient air exposure levels. The Shapiro–Wilk test, logistic regression models, and Spearman’s correlations were used to evaluate the association of variables to UF diagnosis. (3) Results: We analyzed 602 participants (mean age: 50.3 ± 12.3) who responded to a question about UF diagnosis. More Black than White participants had a UF diagnosis (OR, 1.32; 95% CI, 0.62–2.79). We observed non-significant trends between individual-level and neighborhood variables and UF diagnosis. Ambient air pollutants, PM2.5, and DSLPM were protective against UF diagnosis (OR 0.20, CI: 0.04–0.97: OR 0.33, CI: 0.13–0.87). (4) Conclusions: Associations observed within a sample in a specific geographic area may not be generalizable and must be interpreted cautiously.
Exploring the Link between Altitude of Residence and Smoking Patterns in the United States
Authors: Boxer Danielle Jeanne-Marie , Sung Young-Hoon , Nunez Nicolas A. , Fitzgerald Colleen Elizabeth , Renshaw Perry Franklin , Kondo Douglas Gavin
Published: February 2024

Introduction: Smoking-related diseases affect 16 million Americans, causing approximately 480,000 deaths annually. The prevalence of cigarette smoking varies regionally across the United States, and previous research indicates that regional rates of smoking-related diseases demonstrate a negative association with altitude. The purpose of this study was to determine the relationship between altitude and the prevalence of cigarette smoking by county (N = 3106) in the United States. We hypothesized that smoking prevalence among adults would be negatively associated with mean county altitude. Methods: A multivariate linear regression was performed to examine the relationship between county-level mean altitude and county smoking rate. Covariates were individually correlated with 2020 smoking data, and significant associations were included in the final model. Results: The multivariate linear regression indicated that the county-level smoking rates are significantly reduced at high altitudes (p < 0.001). The model accounted for 89.5% of the variance in smoking prevalence, and for each 1000-foot increase in altitude above sea level, smoking rates decreased by 0.143%. Based on multivariate linear regression, the following variables remained independently and significantly associated: race, sex, educational attainment, socioeconomic status, unemployment, physical inactivity, drinking behavior, mental distress, and tobacco taxation. Conclusions: Our results indicate that smoking rates are negatively associated with altitude, which may suggest that altitude affects the pharmacokinetics, pharmacodynamics, and mechanistic pathways involved in cigarette use. Further research is needed to explore the relationship between altitude and smoking and how altitude may serve as a protective factor in the acquisition and maintenance of tobacco use disorders.
Board Expertise Background and Firm Performance
Authors: Lee Chiou-Yann , Wen Chun-Ru , Thi-Thanh-Nguyen Binh
Published: February 2024

This study presents a novel financial performance forecasting method that combines the threshold technique with Artificial Neural Networks (ANN). It applies the threshold regression method to identify the factors within the board of directors that influence the financial performance of traditional industries in Taiwan. The findings indicate that the ANN method effectively predicts financial performance by using relevant board structure data. Furthermore, the empirical results suggest that boards with more members demonstrate increased profitability. Additionally, a more significant presence of board members with accounting expertise contributes to more consistent profits. In contrast, an increased presence of members with financial expertise has a more pronounced impact on profitability.
Autocrine Regulation of Interleukin-6 via the Activation of STAT3 and Akt in Cardiac Myxoma Cells
Authors: Jougasaki Michihisa , Takenoshita Yoko , Umebashi Katsuyuki , Yamamoto Masayoshi , Sudou Ku , Nakashima Hitoshi , Sonoda Masahiro , Kinjo Tamahiro
Published: February 2024

Plasma concentrations of a pleiotropic cytokine, interleukin (IL)-6, are increased in patients with cardiac myxoma. We investigated the regulation of IL-6 in cardiac myxoma. Immunohistochemical staining and reverse transcription-polymerase chain reaction (RT-PCR) revealed that IL-6 and its receptors, IL-6 receptor (IL-6R) and gp130, co-existed in the myxoma cells. Myxoma cells were cultured, and an antibody array assay showed that a conditioned medium derived from the cultured myxoma cells contained increased amounts of IL-6. Signal transducer and activator of transcription (STAT) 3 and Akt were constitutively phosphorylated in the myxoma cells. An enzyme-linked immunosorbent assay (ELISA) showed that the myxoma cells spontaneously secreted IL-6 into the culture medium. Real-time PCR revealed that stimulation with IL-6 + soluble IL-6R (sIL6R) significantly increased IL-6 mRNA in the myxoma cells. Pharmacological inhibitors of STAT3 and Akt inhibited the IL-6 + sIL-6R-induced gene expression of IL-6 and the spontaneous secretion of IL-6. In addition, IL-6 + sIL-6R-induced translocation of phosphorylated STAT3 to the nucleus was also blocked by STAT3 inhibitors. This study has demonstrated that IL-6 increases its own production via STAT3 and Akt pathways in cardiac myxoma cells. Autocrine regulation of IL-6 may play an important role in the pathophysiology of patients with cardiac myxoma.
Multiple Sclerosis: Roles of miRNA, lcnRNA, and circRNA and Their Implications in Cellular Pathways
Authors: Cipriano Giovanni Luca , Schepici Giovanni , Mazzon Emanuela , Anchesi Ivan
Published: February 2024

Multiple sclerosis (MS) is a degenerative condition characterized by axonal damage and demyelination induced by autoreactive immune cells that occur in the Central Nervous System (CNS). The interaction between epigenetic changes and genetic factors can be widely involved in the onset, development, and progression of the disease. Although numerous efforts were made to discover new therapies able to prevent and improve the course of MS, definitive curative treatments have not been found yet. However, in recent years, it has been reported that non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), acting as gene expression regulators, could be used as potential therapeutic targets or biomarkers to diagnose and fight MS. In this review, we discussed the role of miRNAs, lncRNAs, and circRNAs, as well as their expression level changes and signaling pathways that are related to preclinical and human MS studies. Hence, the investigation of ncRNAs could be important to provide additional information regarding MS pathogenesis as well as promote the discovery of new therapeutic strategies or biomarkers.
Application of Advanced Molecular Methods to Study Early-Onset Neonatal Sepsis
Authors: Kosmeri Chrysoula , Giapros Vasileios , Serbis Anastasios , Baltogianni Maria
Published: February 2024

Early-onset sepsis (EOS) is a global health issue, considered one of the primary causes of neonatal mortality. Diagnosis of EOS is challenging because its clinical signs are nonspecific, and blood culture, which is the current gold-standard diagnostic tool, has low sensitivity. Commonly used biomarkers for sepsis diagnosis, including C-reactive protein, procalcitonin, and interleukin-6, lack specificity for infection. Due to the disadvantages of blood culture and other common biomarkers, ongoing efforts are directed towards identifying innovative molecular approaches to diagnose neonates at risk of sepsis. This review aims to gather knowledge and recent research on these emerging molecular methods. PCR-based techniques and unrestricted techniques based on 16S rRNA sequencing and 16S–23S rRNA gene interspace region sequencing offer several advantages. Despite their potential, these approaches are not able to replace blood cultures due to several limitations; however, they may prove valuable as complementary tests in neonatal sepsis diagnosis. Several microRNAs have been evaluated and have been proposed as diagnostic biomarkers in EOS. T2 magnetic resonance and bioinformatic analysis have proposed potential biomarkers of neonatal sepsis, though further studies are essential to validate these findings.
Autoimmunity and Autoinflammation: Relapsing Polychondritis and VEXAS Syndrome Challenge
Authors: Cardoneanu Anca , Rezus Ioana Irina , Burlui Alexandra Maria , Richter Patricia , Bratoiu Ioana , Mihai Ioana Ruxandra , Macovei Luana Andreea , Rezus Elena
Published: February 2024

Relapsing polychondritis is a chronic autoimmune inflammatory condition characterized by recurrent episodes of inflammation at the level of cartilaginous structures and tissues rich in proteoglycans. The pathogenesis of the disease is complex and still incompletely elucidated. The data support the important role of a particular genetic predisposition, with HLA-DR4 being considered an allele that confers a major risk of disease occurrence. Environmental factors, mechanical, chemical or infectious, act as triggers in the development of clinical manifestations, causing the degradation of proteins and the release of cryptic cartilage antigens. Both humoral and cellular immunity play essential roles in the occurrence and perpetuation of autoimmunity and inflammation. Autoantibodies anti-type II, IX and XI collagens, anti-matrilin-1 and anti-COMPs (cartilage oligomeric matrix proteins) have been highlighted in increased titers, being correlated with disease activity and considered prognostic factors. Innate immunity cells, neutrophils, monocytes, macrophages, natural killer lymphocytes and eosinophils have been found in the perichondrium and cartilage, together with activated antigen-presenting cells, C3 deposits and immunoglobulins. Also, T cells play a decisive role in the pathogenesis of the disease, with relapsing polychondritis being considered a TH1-mediated condition. Thus, increased secretions of interferon γ, interleukin (IL)-12 and IL-2 have been highlighted. The “inflammatory storm” formed by a complex network of pro-inflammatory cytokines and chemokines actively modulates the recruitment and infiltration of various cells, with cartilage being a source of antigens. Along with RP, VEXAS syndrome, another systemic autoimmune disease with genetic determinism, has an etiopathogenesis that is still incompletely known, and it involves the activation of the innate immune system through different pathways and the appearance of the cytokine storm. The clinical manifestations of VEXAS syndrome include an inflammatory phenotype often similar to that of RP, which raises diagnostic problems. The management of RP and VEXAS syndrome includes common immunosuppressive therapies whose main goal is to control systemic inflammatory manifestations. The objective of this paper is to detail the main etiopathogenetic mechanisms of a rare disease, summarizing the latest data and presenting the distinct features of these mechanisms.
Iron–Imine Cocktail in Drug Development: A Contemporary Update
Authors: Anane Judith , Owusu Esther , Rivera Gildardo , Bandyopadhyay Debasish
Published: February 2024

Organometallic drug development is still in its early stage, but recent studies show that organometallics having iron as the central atom have the possibility of becoming good drug candidates because iron is an important micro-nutrient, and it is compatible with many biological systems, including the human body. Being an eco-friendly Lewis acid, iron can accept the lone pair of electrons from imino(sp2)-nitrogen, and the resultant iron–imine complexes with iron as a central atom have the possibility of interacting with several proteins and enzymes in humans. Iron–imine complexes have demonstrated significant potential with anticancer, bactericidal, fungicidal, and other medicinal activities in recent years. This article systematically discusses major synthetic methods and pharmacological potentials of iron–imine complexes having in vitro activity to significant clinical performance from 2016 to date. In a nutshell, this manuscript offers a simplistic view of iron complexes in medicinal inorganic chemistry: for instance, iron is presented as an “eco-friendly non-toxic” metal (as opposed to platinum) that will lead to non-toxic pharmaceuticals. The abundant literature on iron chelators shows that many iron complexes, particularly if redox-active in cells, can be quite cytotoxic, which can be beneficial for future targeted therapies. While we made every effort to include all the related papers, any omission is purely unintentional.
Genomic Insights into High-Altitude Adaptation: A Comparative Analysis of Roscoea alpina and R. purpurea in the Himalayas
Authors: Wang Ya-Li , Li Li , Paudel Babu Ram , Zhao Jian-Li
Published: February 2024

Environmental stress at high altitudes drives the development of distinct adaptive mechanisms in plants. However, studies exploring the genetic adaptive mechanisms of high-altitude plant species are scarce. In the present study, we explored the high-altitude adaptive mechanisms of plants in the Himalayas through whole-genome resequencing. We studied two widespread members of the Himalayan endemic alpine genus Roscoea (Zingiberaceae): R. alpina (a selfing species) and R. purpurea (an outcrossing species). These species are distributed widely in the Himalayas with distinct non-overlapping altitude distributions; R. alpina is distributed at higher elevations, and R. purpurea occurs at lower elevations. Compared to R. purpurea, R. alpina exhibited higher levels of linkage disequilibrium, Tajima’s D, and inbreeding coefficient, as well as lower recombination rates and genetic diversity. Approximately 96.3% of the genes in the reference genome underwent significant genetic divergence (FST ≥ 0.25). We reported 58 completely divergent genes (FST = 1), of which only 17 genes were annotated with specific functions. The functions of these genes were primarily related to adapting to the specific characteristics of high-altitude environments. Our findings provide novel insights into how evolutionary innovations promote the adaptation of mountain alpine species to high altitudes and harsh habitats.
Sustained Effectiveness and Safety of Therapeutic miR-10a/b in Alleviating Diabetes and Gastrointestinal Dysmotility without Inducing Cancer or Inflammation in Murine Liver and Colon
Authors: Singh Rajan , Ha Se Eun , Park Han Sung , Debnath Sushmita , Cho Hayeong , Baek Gain , Yu Tae Yang , Ro Seungil
Published: February 2024

microRNAs (miRNAs) are key regulators of both physiological and pathophysiological mechanisms in diabetes and gastrointestinal (GI) dysmotility. Our previous studies have demonstrated the therapeutic potential of miR-10a-5p mimic and miR-10b-5p mimic (miR-10a/b mimics) in rescuing diabetes and GI dysmotility in murine models of diabetes. In this study, we elucidated the safety profile of a long-term treatment with miR-10a/b mimics in diabetic mice. Male C57BL/6 mice were fed a high-fat, high-sucrose diet (HFHSD) to induce diabetes and treated by five subcutaneous injections of miR-10a/b mimics for a 5 month period. We examined the long-term effects of the miRNA mimics on diabetes and GI dysmotility, including an assessment of potential risks for cancer and inflammation in the liver and colon using biomarkers. HFHSD-induced diabetic mice subcutaneously injected with miR-10a/b mimics on a monthly basis for 5 consecutive months exhibited a marked reduction in fasting blood glucose levels with restoration of insulin and significant weight loss, improved glucose and insulin intolerance, and restored GI transit time. In addition, the miR-10a/b mimic-treated diabetic mice showed no indication of risk for cancer development or inflammation induction in the liver, colon, and blood for 5 months post-injections. This longitudinal study demonstrates that miR-10a/b mimics, when subcutaneously administered in diabetic mice, effectively alleviate diabetes and GI dysmotility for 5 months with no discernible risk for cancer or inflammation in the liver and colon. The sustained efficacy and favorable safety profiles position miR-10a/b mimics as promising candidates in miRNA-based therapeutics for diabetes and GI dysmotility.
Deciphering Molecular Mechanisms Involved in the Modulation of Human Aquaporins’ Water Permeability by Zinc Cations: A Molecular Dynamics Approach
Authors: Mom Robin , Réty Stéphane , Mocquet Vincent , Auguin Daniel
Published: February 2024

Aquaporins (AQPs) constitute a wide family of water channels implicated in all kind of physiological processes. Zinc is the second most abundant trace element in the human body and a few studies have highlighted regulation of AQP0 and AQP4 by zinc. In the present work, we addressed the putative regulation of AQPs by zinc cations in silico through molecular dynamics simulations of human AQP0, AQP2, AQP4, and AQP5. Our results align with other scales of study and several in vitro techniques, hence strengthening the reliability of this regulation by zinc. We also described two distinct putative molecular mechanisms associated with the increase or decrease in AQPs’ water permeability after zinc binding. In association with other studies, our work will help deciphering the interaction networks existing between zinc and channel proteins.
Long Non-Coding RNAs: New Insights in Neurodegenerative Diseases
Authors: Anilkumar Adithya K. , Vij Puneet , Lopez Samantha , Leslie Sophia M. , Doxtater Kyle , Khan Mohammad Moshahid , Yallapu Murali M. , Chauhan Subhash C. , Maestre Gladys E. , Tripathi Manish K.
Published: February 2024

Neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), are gradually becoming a burden to society. The adverse effects and mortality/morbidity rates associated with these NDDs are a cause of many healthcare concerns. The pathologic alterations of NDDs are related to mitochondrial dysfunction, oxidative stress, and inflammation, which further stimulate the progression of NDDs. Recently, long non-coding RNAs (lncRNAs) have attracted ample attention as critical mediators in the pathology of NDDs. However, there is a significant gap in understanding the biological function, molecular mechanisms, and potential importance of lncRNAs in NDDs. This review documents the current research on lncRNAs and their implications in NDDs. We further summarize the potential implication of lncRNAs to serve as novel therapeutic targets and biomarkers for patients with NDDs.
The Protein Kinase A Inhibitor KT5720 Prevents Endothelial Dysfunctions Induced by High-Dose Irradiation
Authors: Boittin François-Xavier , Guitard Nathalie , Toth Maeliss , Riccobono Diane , Théry Hélène , Bobe Régis
Published: February 2024

High-dose irradiation can trigger numerous endothelial dysfunctions, including apoptosis, the overexpression of adhesion molecules, and alteration of adherens junctions. Altogether, these endothelial dysfunctions contribute to the development of tissue inflammation and organ damage. The development of endothelial dysfunctions may depend on protein phosphorylation by various protein kinases, but the possible role of protein kinase A (PKA) has not been investigated so far, and efficient compounds able to protect the endothelium from irradiation effects are needed. Here we report the beneficial effects of the PKA inhibitor KT5720 on a panel of irradiation-induced endothelial dysfunctions in human pulmonary microvascular endothelial cells (HPMECs). High-dose X-irradiation (15 Gy) triggered the late apoptosis of HPMECs independent of the ceramide/P38 MAP kinase pathway or p53. In contrast, the treatment of HPMECs with KT5720 completely prevented irradiation-induced apoptosis, whether applied before or after cell irradiation. Immunostainings of irradiated monolayers revealed that KT5720 treatment preserved the overall integrity of endothelial monolayers and adherens junctions linking endothelial cells. Real-time impedance measurements performed in HPMEC monolayers confirmed the overall protective role of KT5720 against irradiation. Treatment with KT5720 before or after irradiation also reduced irradiation-induced ICAM-1 overexpression. Finally, the possible role for PKA in the development of endothelial dysfunctions is discussed, but the potency of KT5720 to inhibit the development of a panel of irradiation-induced endothelial dysfunctions, whether applied before or after irradiation, suggests that this compound could be of great interest for both the prevention and treatment of vascular damages in the event of exposure to a high dose of radiation.
CHST4 Gene as a Potential Predictor of Clinical Outcome in Malignant Pleural Mesothelioma
Authors: Okado Shoji , Kato Taketo , Hanamatsu Yuki , Emoto Ryo , Imamura Yoshito , Watanabe Hiroki , Kawasumi Yuta , Kadomatsu Yuka , Ueno Harushi , Nakamura Shota , Mizuno Tetsuya , Takeuchi Tamotsu , Matsui Shigeyuki , Chen-Yoshikawa Toyofumi Fengshi
Published: February 2024

Malignant pleural mesothelioma (MPM) develops primarily from asbestos exposures and has a poor prognosis. In this study, The Cancer Genome Atlas was used to perform a comprehensive survival analysis, which identified the CHST4 gene as a potential predictor of favorable overall survival for patients with MPM. An enrichment analysis of favorable prognostic genes, including CHST4, showed immune-related ontological terms, whereas an analysis of unfavorable prognostic genes indicated cell-cycle-related terms. CHST4 mRNA expression in MPM was significantly correlated with Bindea immune-gene signatures. To validate the relationship between CHST4 expression and prognosis, we performed an immunohistochemical analysis of CHST4 protein expression in 23 surgical specimens from surgically treated patients with MPM who achieved macroscopic complete resection. The score calculated from the proportion and intensity staining was used to compare the intensity of CHST4 gene expression, which showed that CHST4 expression was stronger in patients with a better postoperative prognosis. The median overall postoperative survival was 107.8 months in the high-expression-score group and 38.0 months in the low-score group (p = 0.044, log-rank test). Survival after recurrence was also significantly improved by CHST4 expression. These results suggest that CHST4 is useful as a prognostic biomarker in MPM.
Genome-Wide Identification and Characterization of Tomato Fatty Acid β-Oxidase Family Genes KAT and MFP
Authors: Li Long , Liu Zesheng , Pan Xuejuan , Yao Kangding , Wang Yuanhui , Yang Tingyue , Huang Guohong , Liao Weibiao , Wang Chunlei
Published: February 2024

Fatty acids and their derivatives play a variety of roles in living organisms. Fatty acids not only store energy but also comprise membrane lipids and act as signaling molecules. There are three main proteins involved in the fatty acid β-oxidation pathway in plant peroxisomes, including acyl-CoA oxidase (ACX), multifunctional protein (MFP), and 3-ketolipoyl-CoA thiolase (KAT). However, genome-scale analysis of KAT and MFP has not been systemically investigated in tomatoes. Here, we conducted a bioinformatics analysis of KAT and MFP genes in tomatoes. Their physicochemical properties, protein secondary structure, subcellular localization, gene structure, phylogeny, and collinearity were also analyzed. In addition, a conserved motif analysis, an evolutionary pressure selection analysis, a cis-acting element analysis, tissue expression profiling, and a qRT-PCR analysis were conducted within tomato KAT and MFP family members. There are five KAT and four MFP family members in tomatoes, which are randomly distributed on four chromosomes. By analyzing the conserved motifs of tomato KAT and MFP family members, we found that both KAT and MFP members are highly conserved. In addition, the results of the evolutionary pressure selection analysis indicate that the KAT and MFP family members have evolved mainly from purifying selection, which makes them more structurally stable. The results of the cis-acting element analysis show that SlKAT and SlMFP with respect may respond to light, hormones, and adversity stresses. The tissue expression analysis showed that KAT and MFP family members have important roles in regulating the development of floral organs as well as fruit ripening. The qRT-PCR analysis revealed that the expressions of SlKAT and SlMFP genes can be regulated by ABA, MeJA, darkness, NaCl, PEG, UV, cold, heat, and H2O2 treatments. These results provide a basis for the involvement of the SlKAT and SlMFP genes in tomato floral organ development and abiotic stress response, which lay a foundation for future functional study of SlKAT and SlMFP in tomatoes.
Pathological Interplay between Inflammation and Mitochondria Aggravates Glutamate Toxicity
Authors: Vaglio-Garro Annette , Kozlov Andrey V. , Smirnova Yuliya D. , Weidinger Adelheid
Published: February 2024

Mitochondrial dysfunction and glutamate toxicity are associated with neural disorders, including brain trauma. A review of the literature suggests that toxic and transmission actions of neuronal glutamate are spatially and functionally separated. The transmission pathway utilizes synaptic GluN2A receptors, rapidly released pool of glutamate, evoked release of glutamate mediated by Synaptotagmin 1 and the amount of extracellular glutamate regulated by astrocytes. The toxic pathway utilizes extrasynaptic GluN2B receptors and a cytoplasmic pool of glutamate, which results from the spontaneous release of glutamate mediated by Synaptotagmin 7 and the neuronal 2-oxoglutarate dehydrogenase complex (OGDHC), a tricarboxylic acid (TCA) cycle enzyme. Additionally, the inhibition of OGDHC observed upon neuro-inflammation is due to an excessive release of reactive oxygen/nitrogen species by immune cells. The loss of OGDHC inhibits uptake of glutamate by mitochondria, thus facilitating its extracellular accumulation and stimulating toxic glutamate pathway without affecting transmission. High levels of extracellular glutamate lead to dysregulation of intracellular redox homeostasis and cause ferroptosis, excitotoxicity, and mitochondrial dysfunction. The latter affects the transmission pathway demanding high-energy supply and leading to cell death. Mitochondria aggravate glutamate toxicity due to impairments in the TCA cycle and become a victim of glutamate toxicity, which disrupts oxidative phosphorylation. Thus, therapies targeting the TCA cycle in neurological disorders may be more efficient than attempting to preserve mitochondrial oxidative phosphorylation.
The Impact of 90 Parkinson’s Disease-Risk Single Nucleotide Polymorphisms on Urinary Bis(monoacylglycerol)phosphate Levels in the Prodromal and PD Cohorts
Authors: Fang Shuai , Lee Priscilla Ann Hweek , Wang Zejian , Zhao Bo
Published: February 2024

Parkinson’s disease (PD) is a common neurodegenerative disorder with a prolonged prodromal phase. Higher urinary bis(monoacylglycerol)phosphate (BMP) levels associate with LRRK2 (leucine-rich repeat kinase 2) and GBA1 (glucocerebrosidase) mutations, and are considered as potential noninvasive biomarkers for predicting those mutations and PD progression. However, their reliability has been questioned, with inadequately investigated genetics, cohorts, and population. In this study, multiple statistical hypothesis tests were employed on urinary BMP levels and sequences of 90 PD-risk single nucleotide polymorphisms (SNPs) from Parkinson’s Progression Markers Institution (PPMI) participants. Those SNPs were categorized into four groups based on their impact on BMP levels in various cohorts. Variants rs34637584 G/A and rs34637584 A/A (LRRK2 G2019S) were identified as the most relevant on increasing urinary BMP levels in the PD cohort. Meanwhile, rs76763715 T/T (GBA1) was the primary factor elevating BMP levels in the prodromal cohort compared to its T/C and C/C variants (N370S) and the PD cohort. Proteomics analysis indicated the changed transport pathways may be the reasons for elevated BMP levels in prodromal patients. Our findings demonstrated that higher urinary BMP levels alone were not reliable biomarkers for PD progression or gene mutations but might serve as supplementary indicators for early diagnosis and treatment.
Transcriptomic Analysis of Mineralized Adipose-Derived Stem Cell Tissues for Calcific Valve Disease Modelling
Authors: Brodeur Alyssa , Roy Vincent , Touzel-Deschênes Lydia , Bianco Stéphanie , Droit Arnaud , Fradette Julie , Ruel Jean , Gros-Louis François
Published: February 2024

Calcific aortic valve disease (CAVD) is characterized by the fibrosis and mineralization of the aortic valve, which leads to aortic stenosis and heart failure. At the cellular level, this is due to the osteoblastic-like differentiation of valve interstitial cells (VICs), resulting in the calcification of the tissue. Unfortunately, human VICs are not readily available to study CAVD pathogenesis and the implicated mechanisms in vitro; however, adipose-derived stromal/stem cells (ASCs), carrying the patient’s specific genomic features, have emerged as a promising cell source to model cardiovascular diseases due to their multipotent nature, availability, and patient-specific characteristics. In this study, we describe a comprehensive transcriptomic analysis of tissue-engineered, scaffold-free, ASC-embedded mineralized tissue sheets using bulk RNA sequencing. Bioinformatic and gene set enrichment analyses revealed the up-regulation of genes associated with the organization of the extracellular matrix (ECM), suggesting that the ECM could play a vital role in the enhanced mineralization observed in these tissue-engineered ASC-embedded sheets. Upon comparison with publicly available gene expression datasets from CAVD patients, striking similarities emerged regarding cardiovascular diseases and ECM functions, suggesting a potential link between ECM gene expression and CAVDs pathogenesis. A matrisome-related sub-analysis revealed the ECM microenvironment promotes the transcriptional activation of the master gene runt-related transcription factor 2 (RUNX2), which is essential in CAVD development. Tissue-engineered ASC-embedded sheets with enhanced mineralization could be a valuable tool for research and a promising avenue for the identification of more effective aortic valve replacement therapies.
Identification of the Reference Genes for Relative qRT-PCR Assay in Two Experimental Models of Rabbit and Horse Subcutaneous ASCs
Authors: Ivanova Zhenya , Petrova Valeria , Grigorova Natalia , Vachkova Ekaterina
Published: February 2024

Obtaining accurate and reliable gene expression results in real-time RT-PCR (qRT-PCR) data analysis requires appropriate normalization by carefully selected reference genes, either a single or a combination of multiple housekeeping genes (HKGs). The optimal reference gene/s for normalization should demonstrate stable expression across varying conditions to diminish potential influences on the results. Despite the extensive database available, research data are lacking regarding the most appropriate HKGs for qRT-PCR data analysis in rabbit and horse adipose-derived stem cells (ASCs). Therefore, in our study, we comprehensively assessed and compared the suitability of some widely used HKGs, employing RefFinder and NormFinder, two extensively acknowledged algorithms for robust data interpretation. The rabbit and horse ASCs were obtained from subcutaneous stromal vascular fraction. ASCs were induced into tri-lineage differentiation, followed by the eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) treatment of the adipose-differentiated rabbit ASCs, while horse experimental groups were formed based on adipogenic, osteogenic, and chondrogenic differentiation. At the end of the experiment, the total mRNA was obtained and used for the gene expression evaluation of the observed factors. According to our findings, glyceraldehyde 3-phosphate dehydrogenase was identified as the most appropriate endogenous control gene for rabbit ASCs, while hypoxanthine phosphoribosyltransferase was deemed most suitable for horse ASCs. The obtained results underscore that these housekeeping genes exhibit robust stability across diverse experimental conditions, remaining unaltered by the treatments. In conclusion, the current research can serve as a valuable baseline reference for experiments evaluating gene expression in rabbit and horse ASCs. It highlights the critical consideration of housekeeping gene abundance and stability in qPCR experiments, emphasizing the need for an individualized approach tailored to the specific requirements of the study.
A New Algorithm Framework for the Influence Maximization Problem Using Graph Clustering
Authors: Agra Agostinho , Samuco Jose Maria
Published: February 2024

Given a social network modelled by a graph, the goal of the influence maximization problem is to find k vertices that maximize the number of active vertices through a process of diffusion. For this diffusion, the linear threshold model is considered. A new algorithm, called ClusterGreedy, is proposed to solve the influence maximization problem. The ClusterGreedy algorithm creates a partition of the original set of nodes into small subsets (the clusters), applies the SimpleGreedy algorithm to the subgraphs induced by each subset of nodes, and obtains the seed set from a combination of the seed set of each cluster by solving an integer linear program. This algorithm is further improved by exploring the submodularity property of the diffusion function. Experimental results show that the ClusterGreedy algorithm provides, on average, higher influence spread and lower running times than the SimpleGreedy algorithm on Watts–Strogatz random graphs.
Contribution to Rail System Revitalization, Development, and Integration Projects Evaluation: A Case Study of the Zadar Urban Area
Authors: Ahac Maja , Ahac Saša , Majstorović Igor , Stepan Željko
Published: February 2024

This paper aims to contribute to the process of evaluating urban rail infrastructure projects through the presentation of the methodology and the results of a preliminary feasibility study concerning the revitalization, development, and (re)integration of the rail with road, maritime, and air transportation in the Zadar urban area. The analysis included the identification and evaluation of rail infrastructure alignment variants that would ensure the revitalization of the existing railway infrastructure, relocation of freight rail traffic from the narrow and densely developed suburban coastal area, promotion of intermodal passenger and freight transportation, improvement of urban and regional accessibility and connectivity, increase of traffic safety, reduction of travel time and operating costs, and decrease of traffic impacts on the environment. By consulting legal frameworks, spatial planning documentation, and analyzing the socio-economic context and existing transportation infrastructure function, six variants for the (re)development of the rail infrastructure were designed. As their design approached the area’s transportation issues from different angles and could contribute differently to the area’s economic, social, and territorial issues, a multi-criteria analysis supplemented with a partial cost–benefit analysis was conducted to select the most suitable variant. The evaluation was based on seven weighted criteria quantified by the normalization of 32 indicator values, scored from 1 to 5, where a score of 5 was considered the highest. Weighting the scores according to the ratios determined through a consultation process with stakeholders resulted in ranking the best variant with a total score of 3.7 and the worst one with a total score of 2.6. To avoid potential objections that the set of criteria weights used was subjective and the result biased, a sensitivity analysis was carried out by systematically varying the weights among criteria. The results showed that the best-ranked variant was also the least sensitive to applied weight shifts, with a score range of 0.2.
Characterization of a Large Area Hybrid Pixel Detector of Timepix3 Technology for Space Applications
Authors: Farkas Martin , Bergmann Benedikt , Broulim Pavel , Burian Petr , Ambrosi Giovanni , Azzarello Philipp , Pušman Lukáš , Sitarz Mateusz , Smolyanskiy Petr , Sukhonos Daniil , Wu Xin
Published: February 2024

We present the characterization of a highly segmented “large area” hybrid pixel detector (Timepix3, 512 × 512 pixels, pixel pitch 55 µm) for application in space experiments. We demonstrate that the nominal power consumption of 6 W can be reduced by changing the settings of the Timepix3 analog front-end and reducing the matrix clock frequency (from the nominal 40 MHz to 5 MHz) to 2 W (in the best case). We then present a comprehensive study of the impact of these changes on the particle tracking performance, the energy resolution and time stamping precision by utilizing data measured at the Super-Proton-Synchrotron (SPS) at CERN and at the Danish Center for Particle Therapy (DCPT). While the impact of the slower sampling frequency on energy measurement can be mitigated by prolongation of the falling edge of the analog signal, we find a reduction of the time resolution from 1.8 ns (in standard settings) to 5.6 ns (in analog low-power), which is further reduced utilizing a lower sampling clock (e.g., 5 MHz, in digital low-power operation) to 73.5 ns. We have studied the temperature dependence of the energy measurement for ambient temperatures between −20 °C and 50 °C separately for the different settings.
Management and Outcome of Women with Placenta Accreta Spectrum and Treatment with Uterine Artery Embolization
Authors: Neef Vanessa , Flinspach Armin N. , Eichler Katrin , Woebbecke Tirza R. , Noone Stephanie , Kloka Jan A. , Jennewein Lukas , Louwen Frank , Zacharowski Kai , Raimann Florian J.
Published: February 2024

Background: Placenta accreta spectrum (PAS) disorders are a continuum of placental pathologies with increased risk for hemorrhage, blood transfusion and maternal morbidity. Uterine artery embolization (UAE) is a safe approach to the standardization of complex PAS cases. The aim of this study is to analyze anemia and transfusion rate, outcome and anesthesiological management of women who underwent caesarean delivery with subsequent UAE for the management of PAS. Material and Methods: This retrospective observational study included all pregnant women admitted to the University Hospital Frankfurt between January 2012 and September 2023, with a diagnosis of PAS who underwent a two-step surgical approach for delivery and placenta removal. Primary procedure included cesarean delivery with subsequent UAE, secondary procedure included placenta removal after a minim of five weeks via curettage or HE. Maternal characteristics, anesthesiological management, complications, anemia rate, blood loss and administration of blood products were analyzed. Results: In total, 17 women with PAS were included in this study. Of these, 5.9% had placenta increta and 94.1% had placenta percreta. Median blood loss was 300 (200–600) mL during primary procedure and 3600 (450–5500) mL during secondary procedure. In total, 11.8% and 62.5% of women received red blood cell transfusion during the primary and secondary procedures, respectively. After primary procedure, postpartum anemia rate was 76.5%. The HE rate was 64.7%. Regional anesthesia was used in 88.2% during primary procedure. Conclusion: The embolization of the uterine artery for women diagnosed with PAS is safe. Anemia management and the implementation of blood conservation strategies are crucial in women undergoing UAE for the management of PAS.