bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing the Impact and Cost-Effectiveness of Exposome Interventions on Alzheimer’s Disease: A Review of Agent-Based Modeling and Other Data Science Methods for Causal Inference
Authors: Liu Shelley H. , Weber Ellerie S. , Manz Katherine E. , McCarthy Katharine J. , Chen Yitong , Schüffler Peter J. , Zhu Carolyn W. , Tracy Melissa
Published: November 2024

Background: The exposome (e.g., totality of environmental exposures) and its role in Alzheimer’s Disease and Alzheimer’s Disease and Related Dementias (AD/ADRD) are increasingly critical areas of study. However, little is known about how interventions on the exposome, including personal behavioral modification or policy-level interventions, may impact AD/ADRD disease burden at the population level in real-world settings and the cost-effectiveness of interventions. Methods: We performed a critical review to discuss the challenges in modeling exposome interventions on population-level AD/ADRD burden and the potential of using agent-based modeling (ABM) and other advanced data science methods for causal inference to achieve this. Results: We describe how ABM can be used for empirical causal inference modeling and provide a virtual laboratory for simulating the impacts of personal and policy-level interventions. These hypothetical experiments can provide insight into the optimal timing, targeting, and duration of interventions, identifying optimal combinations of interventions, and can be augmented with economic analyses to evaluate the cost-effectiveness of interventions. We also discuss other data science methods, including structural equation modeling and Mendelian randomization. Lastly, we discuss challenges in modeling the complex exposome, including high dimensional and sparse data, the need to account for dynamic changes over time and over the life course, and the role of exposome burden scores developed using item response theory models and artificial intelligence to address these challenges. Conclusions: This critical review highlights opportunities and challenges in modeling exposome interventions on population-level AD/ADRD disease burden while considering the cost-effectiveness of different interventions, which can be used to aid data-driven policy decisions.
A Review on Uranium Mineralization Related to Na-Metasomatism: Indian and International Examples
Authors: Mishra Priyanka , Sati Manju , Krishnamurthi Rajagopal
Published: November 2024

Uranium mineralization related to Na-metasomatism is known as Na-metasomatite or albitite-type. They represent the fourth-largest uranium resource globally and constitute fifty thousand tons of U resources. The present work gives details about well-known Na-metasomatic uranium occurrences worldwide in terms of structures, metasomatic stages, geochemical characteristics, fluid inclusions, and compositions of stable isotopes. The host rocks are granite, granitoid, and metamorphosed volcano-sedimentary rocks, and these rocks experienced two/three deformational stages. U mineralization is mainly confined to faults and characterized by granitic intrusive, cataclasis, mylonitization, and albitization. The albitized rocks exhibit two to three metasomatic and late hydrothermal stages. The first stage is marked by the replacement of pre-existing host minerals during a ductile shear regime. The second stage is related to U mineralization contemporaneous with the brittle deformation. The albitized rocks exhibit depletion in Si, K, Ba, and heavy rare-earth elements relative to the host rocks and enrichments in Na, Ca, U, Zr, P, V, Sr, and light rare-earth elements. U-enrichment is positively correlated with Na, Mo, Cu, and high-field strength elements. The pressure–temperature (P-T) conditions of U mineralization are considered to be epithermal and mesothermal. Fluid inclusion studies indicate that the mineralizing fluids were rich in Na+, Mg2+, Cl−, CO2, H2O, F−, and PO43− and meteoric–magmatic derived. The geological processes responsible for the genesis of Na-metasomatic U deposits of the North Delhi Fold Belt (India) are comparable with some international examples, i.e., Australia, Ukraine, Cameroon, Brazil, Guyana, China, and the USA.
Measuring Eco-Anxiety with the Polish Version of the 13-Item Hogg Eco-Anxiety Scale (HEAS-13): Latent Structure, Correlates, and Psychometric Performance
Authors: Larionow Paweł , Mackiewicz Julia , Mudło-Głagolska Karolina , Michalak Maciej , Mazur Monika , Gawrych Magdalena , Komorowska Kamilla , Preece David A.
Published: November 2024

Background/Objectives: The Hogg Eco-Anxiety Scale (HEAS-13) is a thirteen-item measure of eco-anxiety, with four dimensions: (1) affective symptoms, (2) rumination, (3) behavioural symptoms, and (4) anxiety about personal impact. Being a recently developed questionnaire, data on its psychometrics are limited. The aim of this study was to introduce a Polish version of the HEAS-13 and examine its psychometric properties. Methods: Our sample consisted of 634 Polish-speaking adults, with ages ranging from 18 to 67 years. We assessed the HEAS-13’s factor structure, internal consistency, test–retest reliabilities, and its concurrent validity via relationships with climate-related variables, psychopathology symptoms, and well-being. We put emphasis on examining the discriminant validity of the HEAS-13 against general psychological distress. Results: As expected, the Polish HEAS-13 demonstrated strong factorial validity with an intended four-factor structure. The internal consistency and test–retest reliabilities of the scale were good and moderate, respectively. Higher levels of eco-anxiety were associated with higher environmental concerns, the experience of climate change (i.e., one’s perception of being affected by climate change), pro-environmental behavioural engagement, climate change worry, anxiety, and depressive symptoms, as well as lower levels of well-being. We empirically supported the strong discriminant validity of the HEAS-13, demonstrating that eco-anxiety was separable from general psychological distress. We also noted that females, younger people, and those with lower educational levels experienced higher eco-anxiety. To facilitate the use of this measure, we propose a potential screening cut-off value for the HEAS-13, which can indicate meaningfully elevated levels of eco-anxiety. Conclusions: Overall, the Polish version of the HEAS-13 has strong psychometric properties, usefully enabling the examination of climate-related anxiety. Our findings highlight its potential in cross-cultural research and healthcare practice.
Integrating Deep Learning and Energy Management Standards for Enhanced Solar–Hydrogen Systems: A Study Using MobileNetV2, InceptionV3, and ISO 50001:2018
Authors: Joshua Salaki Reynaldo , Junghyun Yang , Park Sanguk , Kwon Kihyeon
Published: November 2024

This study addresses the growing need for effective energy management solutions in university settings, with particular emphasis on solar–hydrogen systems. The study’s purpose is to explore the integration of deep learning models, specifically MobileNetV2 and InceptionV3, in enhancing fault detection capabilities in AIoT-based environments, while also customizing ISO 50001:2018 standards to align with the unique energy management needs of academic institutions. Our research employs comparative analysis of the two deep learning models in terms of their performance in detecting solar panel defects and assessing accuracy, loss values, and computational efficiency. The findings reveal that MobileNetV2 achieves 80% accuracy, making it suitable for resource-constrained environments, while InceptionV3 demonstrates superior accuracy of 90% but requires more computational resources. The study concludes that both models offer distinct advantages based on application scenarios, emphasizing the importance of balancing accuracy and efficiency when selecting appropriate models for solar–hydrogen system management. This research highlights the critical role of continuous improvement and leadership commitment in the successful implementation of energy management standards in universities.
A Simple Neural Network for Estimating Fine Sediment Sources Using XRF and XRD
Authors: Mutiso Selline , Nakayama Keisuke , Komai Katsuaki
Published: November 2024

Suspended sediment (SS) has a wide range of negative effects such as increased water turbidity, altered habitat structures, sedimentation, and effects on hydraulic systems and environmental engineering projects. Nevertheless, the methods for accurately determining SS sources on a basin-scale are poorly understood. Herein, we used a simplified neural network analysis (NNA) model to identify the sources of SS in Japan’s Oromushi River Catchment Basin. Fine soil samples were collected from different locations of the catchment basin, processed, and separately analysed using X-ray fluorescence (XRF) and X-ray diffraction (XRD). The sampling stations were grouped according to the type of soil cover, vegetation type and land-use pattern. The geochemical components of each group were fed into the same neural network layer, and a series of equations were applied to estimate the sediment contribution from each group to the downstream side of the river. Samples from the same sampling locations were also analysed by XRD, and the obtained peak intensity values were used as the input in the NNA model. SS mainly originated from agricultural fields, with regions where the ground is covered with volcanic ash identified as the key sources through XRF and XRD analysis, respectively. Therefore, based on the nature of the surface soil cover and the land use pattern in the catchment basin, NNA was found to be a reliable data analytical technique. Moreover, XRD analysis does not incorporate carbon, and also provides detailed information on crystalline phases. The results obtained in this study, therefore, do not depend on seasonal uncertainty due to organic matter.
Beliefs and Violent Behavior in Interpersonal Relationships of Young Adults: A Systematic Review
Authors: Araújo Eduardo , Santos Anita , Oliveira Claúdia , Cruz Olga Souza , Moreira Diana
Published: November 2024

Beliefs are information-processing structures formed along an individual’s developmental pathway. Beliefs can legitimize involvement in inappropriate or violent behaviors, particularly when they crystallize into cognitive schemas. While beliefs aid individuals in interpreting the surrounding world, overly rigid and inflexible beliefs can constrain the individual’s ability to process available information. This Systematic Review, carried out according to the PRISMA norms and guidelines, aims to understand the most prevalent beliefs regarding relationships among young adults and to examine their associations with violent or deviant behaviors. Articles included in this review were retrieved from the EBSCO, PubMed, and Web of Science databases in July 2022, resulting in a total of 594 studies, which were subsequently screened by two independent reviewers. A total of 51 studies were then selected for full reading, but 36 were excluded based on pre-defined eligibility criteria, leaving a final sample of 18 studies published between 2014 and 2022. The main objectives, country of origin, instruments used, sample composition and age, main results and conclusions were extracted from each study. Findings point toward the presence of related and legitimate beliefs about violence in intimate relationships, domestic violence, sexual violence, acceptance of the rape myth, or consent to engage in sexual activities.
Spatiotemporal Dynamics of Water Quality: Long-Term Assessment Using Water Quality Indices and GIS
Authors: Balla Dániel , Kiss Emőke , Zichar Marianna , Mester Tamás
Published: November 2024

The severe contamination of groundwater supplies in rural areas is a global problem that requires strict environmental measures. Related to this, one of the most important challenges at present is the elimination of local sources of pollution. Therefore, this research examined the local water quality changes following the construction of the sewerage network, under the framework of long-term monitoring (2011–2022) in Báránd, Hungary, using water quality indices and GIS (Geographic Information System) techniques. In order to understand the purification processes and spatial and temporal changes, three periods were determined: the pre-sewerage period (2011–2014), the transitional period (2015–2018), and the post-sewerage period (2019–2022). Forty monitoring wells were included in the study, ensuring complete coverage of the municipality. The results revealed a high level of pollution in the area in the pre-sewerage period. Based on the calculated indices, an average of 80% of the wells were ranked in categories 4–5, indicating poor water quality, while less than 8% were classified in categories 1–2, indicating good water quality. No significant purification process was detected in the transitional period. However, marked changes were observed in the post-sewerage period as a result of the elimination of local sources of pollution. In the post-sewerage period, the number of monitoring wells ranked as excellent and good increased significantly. Additionally, the number of wells assigned to category 5 decreased markedly, compared to the reference period. The significant difference between the three periods was confirmed by the Wilcoxon test as well (p < 0.05). Based on interpolated maps, it was found that, in the post-sewerage period, an increasing section of the settlement had good or excellent water quality. In addition to an assessment of long-term tendencies, the annual fluctuations in the water quality of the wells were also examined. This showed that the purification processes do not occur in a linear pattern but are influenced by various factors (e.g., precipitation). Our results highlight the importance of protecting and improving groundwater resources in municipal areas and the relevance of long-term monitoring of water adequate management policy.
Discovery of Potent Benzothiazole Inhibitors of Oxidoreductase NQO2, a Target for Inflammation and Cancer
Authors: Belgath Asma A. , Emam Aya M. , Taujanskas Joshua , Bryce Richard A. , Freeman Sally , Stratford Ian J.
Published: November 2024

Inhibitors of NQO2 (NRH: quinone oxidoreductase) have potential application in several areas of medicine and pharmacology, including cancer, neurodegeneration (PD and AD), stroke, and diabetes. Here, resveratrol, a known inhibitor of NQO2, was used as the lead by replacing the double bond in resveratrol with a benzothiazole scaffold. Fifty-five benzothiazoles were designed as NQO2 inhibitors and synthesized, comprising five benzothiazole series with 3,5-dimethoxy, 2,4-dimethoxy, 2,5-dimethoxy, 3,4-dimethoxy, and 3,4,5-trimethoxy substituents, the key synthetic step being a Jacobson cyclisation with the appropriate thiobenzamide. All compounds were evaluated in an NQO2 enzyme inhibition assay, with four compounds having IC50 values of <100 nM. The most active (IC50 25 nM) was 6-hydroxy-2-(3’,5’-dihydroxyphenyl)benzo[d]thiazole (15), a good mimetic of resveratrol. Three of the 3’,4’,5’-trimethoxybenzothiazole analogues, with 6-methoxy (40, IC50 51 nM), 6-amino (48, IC50 79 nM), and 6-acetamide (49, IC50 31 nM) substituents, were also potent inhibitors of NQO2. Computational modelling indicated the most active compounds exhibited good shape complementarity and polar interactions with the NQO2 active site. Through the inhibition of NQO2, benzothiazole-based compounds may have the potential to enhance the efficiency of cancer therapies or minimise oxidative damage in neuroinflammation.
Complete Mitogenome Assembly and Comparative Analysis of Vaccinium bracteatum (Ericaceae), a Rich Source of Health-Promoting Molecules
Authors: Zhou Peng , Li Fei , Zhang Qiang , Zhang Min
Published: November 2024

Vaccinium bracteatum is a valuable plant used both as food and medicine in China, but low production limits the development of its industry. As such, it is important to develop genetic resources for the high-value species for preservation of wild populations and utilization. The complete chloroplast and nuclear genomes have already been available; however, its mitogenome has not yet been characterized. Here, the V. bracteatum mitogenome was assembled using HiFi reads, and a comparative analysis was conducted. The mitogenome was a circular sequence of 708,384 bp with a GC content of 45.28%, in which 67 genes were annotated, including 36 protein-coding genes, 26 tRNA genes, 3 rRNA genes, and 2 pseudogenes. Overall, 370 dispersed repeats, 161 simple repeats, and 42 tandem repeats were identified, and 360 RNA editing sites were predicted. There was extensive DNA migration among the three genomes. In addition, most of the protein-coding genes underwent purifying selection throughout evolution, and the nucleotide diversity was highly variable. In addition, comparative analysis indicated that the sizes, structures, and gene contents of the mitogenomes differed significantly, but the GC contents and functional genes were relatively conserved among the Ericales species. Mitogenome-based phylogenetic analysis indicated the precise. evolutionary and taxonomic status of V. bracteatum. The complete mitogenome represents the last link of the reference genome of V. bracteatum and lays the foundation for effective utilization and molecular breeding of this plant.
The Interplay Between the MYC Oncogene and Ribosomal Proteins in Osteosarcoma Onset and Progression: Potential Mechanisms and Indication of Candidate Therapeutic Targets
Authors: Guerrieri Ania Naila , Hattinger Claudia Maria , Marchesini Federica , Melloni Martina , Serra Massimo , Ibrahim Toni , Penzo Marianna
Published: November 2024

High-grade osteosarcoma (OS) is the most common primary bone tumor mainly affecting children and young adults. First-line treatment consists of neo-adjuvant chemotherapy with doxorubicin, cisplatin, and methotrexate and surgery. The mean long-term survival rate for localized disease at diagnosis is 65–70%, dropping down to 20% when metastases are present at diagnosis. Therefore, curing OS is a clinical challenge, particularly for patients that do not respond to standard treatments. MYC has frequently been reported to be involved in the pathogenesis of OS and its high expression may be associated with drug resistance and patients’ worse prognosis. Moreover, MYC is a master regulator of ribosomal proteins (RPs) synthesis and ribosome biogenesis (RiBi), which is often up-regulated in human tumors. In recent years, RPs have been recognized not only for their traditional role in ribosome assembly but also for their extra-ribosomal functions, many of which are linked to the onset and progression of cancer. In this review we focus on the role and possible interplay of MYC and RPs expression in association with drug resistance and worse prognosis in OS and discuss therapeutic options that target de-regulated MYC, RiBi, or RPs, which are already clinically available or under evaluation in clinical trials.
Protective Effects of Ambroxol on Aβ and α-Synuclein-Induced Neurotoxicity Through Glucocerebrosidase Activation in HT-22 Hippocampal Neuronal Cells
Authors: Lin Sheng-Chieh , Chang Ching-Chi , Tsou Sing-Hua , Chiu Pai-Yi , Cheng Ju-Fang , Hung Hui-Chih , Chen Wei-Jen , Ho Ying-Jui , Lin Chih-Li
Published: November 2024

Dementia with Lewy bodies (DLB) is a progressive neurodegenerative disorder marked by the accumulation of α-synuclein (αSyn), often co-existing with amyloid β (Aβ) pathology. Current treatments are largely symptomatic, highlighting a critical need for disease-modifying therapies. Evidence suggests that αSyn aggregates contribute to neuronal death in DLB, particularly when exacerbated by Aβ. Given the role of autophagy in clearing misfolded proteins, exploring agents that promote this pathway is essential for developing effective treatments. Ambroxol (AMBX), a mucolytic drug, has demonstrated potential in activating glucocerebrosidase (GCase), an enzyme that enhances lysosomal function and facilitates the autophagic clearance of toxic protein aggregates, including αSyn. This study aims to evaluate AMBX’s neuroprotective effects in a cellular model of DLB, with the goal of identifying new therapeutic agents that target the underlying pathology of DLB. In this study, HT-22 hippocampal neuronal cells were exposed to αSyn and Aβ, followed by AMBX treatment. Our results showed that AMBX significantly improved cell viability and reduced apoptosis in cells co-treated with αSyn and Aβ. Additionally, AMBX restored GCase activity, promoted autophagy, and reduced oxidative stress, which in turn mitigated αSyn aggregation and phosphorylation. These findings suggest that by activating GCase and enhancing autophagy, AMBX may help alleviate DLB-associated neurodegeneration. This study underscores the potential of AMBX as a therapeutic agent for DLB and supports further investigation in animal models and clinical trials to validate its efficacy in neurodegenerative disease contexts.
The Gene Cluster Cj0423–Cj0425 Negatively Regulates Biofilm Formation in Campylobacter jejuni
Authors: Wang Zhi , Wu Yuwei , Liu Ming , Chen Ling , Xiao Kaishan , Huang Zhenying , Zhao Yibing , Wang Huixian , Ding Yu , Lin Xiuhua , Zeng Jiahui , Peng Feiting , Zhang Jumei , Wang Juan , Wu Qingping
Published: November 2024

Abstract: Campylobacter jejuni (C. jejuni) is a zoonotic foodborne pathogen that is widely distributed worldwide. Its optimal growth environment is microaerophilic conditions (5% O2, 10% CO2), but it can spread widely in the atmospheric environment. Biofilms are thought to play an important role in this process. However, there are currently relatively few research works on the regulatory mechanisms of C. jejuni biofilm formation. In this study, a pan-genome analysis, combined with the analysis of biofilm phenotypic information, revealed that the gene cluster Cj0423–Cj0425 is associated with the negative regulation of biofilm formation in C. jejuni. Through gene knockout experiments, it was observed that the Cj0423–Cj0425 mutant strain significantly increased biofilm formation and enhanced flagella formation. Furthermore, pull-down assay revealed that Cj0424 interacts with 93 proteins involved in pathways such as fatty acid synthesis and amino acid metabolism, and it also contains the quorum sensing-related gene luxS. This suggests that Cj0423–Cj0425 affects fatty acid synthesis and amino acid metabolism, influencing quorum sensing and strain motility, ultimately inhibiting biofilm formation.
Autophagy Involvement in Non-Neoplastic and Neoplastic Endometrial Pathology: The State of the Art with a Focus on Carcinoma
Authors: Pizzimenti Cristina , Fiorentino Vincenzo , Ruggeri Chiara , Franchina Mariausilia , Ercoli Alfredo , Tuccari Giovanni , Ieni Antonio
Published: November 2024

Autophagy is a cellular process crucial for maintaining homeostasis by degrading damaged proteins and organelles. It is stimulated in response to stress, recycling nutrients and generating energy for cell survival. In normal endometrium, it suppresses tumorigenesis by preventing toxic accumulation and maintaining cellular homeostasis. It is involved in the cyclic remodelling of the endometrium during the menstrual cycle and contributes to decidualisation for successful pregnancy. Such a process is regulated by various signalling pathways, including PI3K/AKT/mTOR, AMPK/mTOR, and p53. Dysregulation of autophagy has been associated with benign conditions like endometriosis and endometrial hyperplasia but also with malignant neoplasms such as endometrial carcinoma. In fact, it has emerged as a crucial player in endometrial carcinoma biology, exhibiting a dual role in both tumour suppression and tumour promotion, providing nutrients during metabolic stress and allowing cancer cell survival. It also regulates cancer stem cells, metastasis and therapy resistance. Targeting autophagy is therefore a promising therapeutic strategy in endometrial carcinoma and potential for overcoming resistance to standard treatments. The aim of this review is to delve into the intricate details of autophagy’s role in endometrial pathology, exploring its mechanisms, signalling pathways and potential therapeutic implications.
Influence of Secondary Metabolites According to Maturation of Perilla (Perilla frutescens) on Respiratory Protective Effect in Fine Particulate Matter (PM2.5)-Induced Human Nasal Cell
Authors: Kim Min-Young , Kim Jung-In , Kim Sang-Woo , Kim Sungup , Oh Eunyoung , Lee Jeongeun , Lee Eunsoo , An Yeon-Ju , Han Chae-Yeon , Lee Heungsu , Lee Myoung-Hee
Published: November 2024

Fine particulate matter (PM2.5) exposure worsens chronic respiratory diseases through oxidative stress and inflammation. Perilla frutescens (L.) has potential respiratory protective properties, but the impact of growth stages on its beneficial metabolites is unclear. We aimed to evaluate how different growth stages affect phenolic acids, flavonoids, and polycosanols in perilla seeds and flowers and their efficacy in countering PM2.5-induced damage. Perilla seeds and flowers from five varieties at 10, 20, 30, and 40 days post-flowering were analyzed for metabolite content. Their antioxidant, anti-inflammatory, and respiratory protective effects were tested in RPMI 2650 cells. Our findings indicated that perilla flowers contained higher levels of functional components than seeds and exhibited significant variation with maturation. Phenolic acids of perilla flowers were highest at the early stages of maturation after flowering. However, individual flavones of perilla flowers were the highest at the late maturation stages after flowering. Extracts from perilla flowers harvested 20 days after flowering exhibited significant respiratory protection, effectively inhibiting inflammatory cytokines, mucus secretion, and oxidative stress markers. In conclusion, the flower parts of perilla, particularly those harvested 20 days after flowering, are useful materials for obtaining phenolic compounds, including rosmarinic acid, with high antioxidant and respiratory enhancement effects.
Raloxifene Protects Oxygen-Glucose-Deprived Astrocyte Cells Used to Mimic Hypoxic-Ischemic Brain Injury
Authors: Toro-Urrego Nicolás , Luaces Juan P. , Kobiec Tamara , Udovin Lucas , Bordet Sofía , Otero-Losada Matilde , Capani Francisco
Published: November 2024

Perinatal asphyxia (PA) is a clinical condition characterized by oxygen supply suspension before, during, or immediately after birth, and it is an important risk factor for neurodevelopmental damage. Its estimated 1/1000 live births incidence in developed countries rises to 5–10-fold in developing countries. Schizophrenia, cerebral palsy, mental retardation, epilepsy, blindness, and others are among the highly disabling chronic pathologies associated with PA. However, so far, there is no effective therapy to neutralize or reduce PA-induced harm. Selective regulators of estrogen activity in tissues and selective estrogen receptor modulators like raloxifene have shown neuroprotective activity in different pathological scenarios. Their effect on PA is yet unknown. The purpose of this paper is to examine whether raloxifene showed neuroprotection in an oxygen–glucose deprivation/reoxygenation astrocyte cell model. To study this issue, T98G cells in culture were treated with a glucose-free DMEM medium and incubated at 37 °C in a hypoxia chamber with 1% O2 for 3, 6, 12, and 24 h. Cultures were supplemented with raloxifene 10, and 100 nM during both glucose and oxygen deprivation and reoxygenation periods. Raloxifene 100 nM and 10 nM improved cell survival—65.34% and 70.56%, respectively, compared with the control cell groups. Mitochondrial membrane potential was preserved by 58.9% 10 nM raloxifene and 81.57% 100 nM raloxifene cotreatment. Raloxifene co-treatment reduced superoxide production by 72.72% and peroxide production by 57%. Mitochondrial mass was preserved by 47.4%, 75.5%, and 89% in T98G cells exposed to 6-h oxygen–glucose deprivation followed by 3, 6, and 9 h of reoxygenation, respectively. Therefore, raloxifene improved cell survival and mitochondrial membrane potential and reduced lipid peroxidation and reactive oxygen species (ROS) production, suggesting a direct effect on mitochondria. In this study, raloxifene protected oxygen–glucose-deprived astrocyte cells, used to mimic hypoxic–ischemic brain injury. Two examiners performed the qualitative assessment in a double-blind fashion.
Effects of Melatonin Pre- and Post-Drought Treatment on Oxidative Stress Markers and Expression of Proline-Related Transcripts in Young Wheat Plants
Authors: Katerova Zornitsa , Todorova Dessislava , Vaseva Irina I. , Shopova Elena , Petrakova Margarita , Iliev Martin , Sergiev Iskren
Published: November 2024

Wheat can tolerate a mild water deficit, but prolonged drought causes a number of detrimental physiological changes resulting in a substantial decrease in productivity. The present study evaluates the potential of the natural plant growth regulator melatonin to alleviate the negative effects of moderate drought in two Bulgarian winter wheat cultivars at the early vegetative stage. Melatonin doses of 75 µM were root-supplemented 24 h before or after the stress period. The levels of several biometric parameters, osmolyte content and stress indicators as well as the expression of genes coding for key enzymes of the proline biosynthesis pathway were analyzed in leaves at the end of the drought stress and after two and four days of recovery. Applied alone, melatonin did not exert significant effects on most of the monitored parameters. Water deprivation negatively affected seedlings’ fresh weight and water content and increased the stress markers and osmolyte levels. These were accompanied by a high accumulation of TaP5CS and TaP5CR transcripts coding for the enzymes Δ-pyrroline-5-carboxylate synthase and Δ-pyrroline-5-carboxylate reductase, respectively. The effect of melatonin in reducing drought stress was similar whether applied before or after exposure, though slightly more effective when used as a pre-treatment.
Transcriptomic Changes During the Replicative Senescence of Human Articular Chondrocytes
Authors: Atasoy-Zeybek Aysegul , Hawse Gresin P. , Nagelli Christopher V. , Lopez De Padilla Consuelo M. , Abdel Matthew P. , Evans Christopher H.
Published: November 2024

Aging is a major risk factor for osteoarthritis (OA), but the specific mechanisms connecting aging and OA remain unclear. Although chondrocytes rarely divide in adult articular cartilage, they undergo replicative senescence in vitro, offering a model to study aging-related changes under controlled conditions. OA cartilage was obtained from an 80-year-old male and a 72-year-old female, while normal cartilage was sourced from a 26-year-old male. Chondrocyte cultures were established and sub-cultured to their Hayflick limit. Bulk RNA sequencing on early- and late-passage human articular chondrocytes identified transcriptomic changes associated with cellular aging. Early-passage OA chondrocytes already showed senescent phenotypes, unlike normal chondrocytes. All three cultures underwent 30 population doublings before replicative exhaustion, at which point all cells displayed senescence. During this process, cells lost their ability to form cartilaginous pellets. Differential gene expression analysis revealed distinct transcriptomic profiles between early- and late-passage chondrocytes and between normal and OA-derived cells. Genes related to matrix synthesis, degradation, inflammation, and the senescence-associated secretory phenotype (SASP) showed significant expression changes. Despite being a small pilot study, these findings suggest that further research into the molecular and metabolic changes during chondrocyte senescence could provide valuable insights into OA pathobiology.
Heparin Immobilization Enhances Hemocompatibility, Re-Endothelization, and Angiogenesis of Decellularized Liver Scaffolds
Authors: Yadav Chandra Jit , Yadav Usha , Afrin Sadia , Lee Jun-Yeong , Kamel Jihad , Park Kyung-Mee
Published: November 2024

Bioengineered livers are currently an acceptable alternative to orthotopic liver transplants to overcome the scarcity of donors. However, the challenge of using a bioengineered liver is the lack of an intact endothelial layer in the vascular network leading to thrombosis. Heparin-modified surfaces have been demonstrated to decrease thrombogenicity in earlier research. However, in our study, we aimed to apply heparin immobilization to enhance the hemocompatibility, endothelial cell (EC) adhesion, and angiogenesis of rat decellularized liver scaffolds (DLS). Heparin was immobilized on the DLS by the end-point attachment technique. The scaffold’s hemocompatibility was assessed using ex vivo blood perfusion and platelet adhesion studies. The heparinized scaffold (HEP-DLS) showed a significantly reduced thrombogenicity and platelet aggregation. HEP-DLS was recellularized with EA.hy926 cells via the portal vein and maintained in the bioreactor for 7 days, showing increased EC adhesion and coverage within the blood vessels. The Resazurin reduction assay confirmed the presence of actively proliferating cells in the HEP-DLS. The scaffolds were implanted subcutaneously into the dorsum of mice for 21 days to evaluate cell migration and angiogenesis. The results showed significant increases in the number of blood vessels in the HEP-DLS group. Our results demonstrated that heparin immobilization reduces thrombosis, promotes re-endothelialization, and enhances angiogenesis in DLS. The research provides insight into the potential use of heparin in the formation of a functioning vasculature.
Aquaporins in Biliary Function: Pathophysiological Implications and Therapeutic Targeting
Authors: Khalil Mohamad , Gena Patrizia , Di Ciaula Agostino , Portincasa Piero , Calamita Giuseppe
Published: November 2024

Aquaporins (AQPs) are transmembrane proteins permeable to water and a series of small solutes. AQPs play a key role in pathways of hepatobiliary secretion at the level of the liver, bile ducts, and gallbladder. AQP8 and -9 are pivotal in facilitating the osmotic water movement of hepatic bile, which is composed of 95% water. In the biliary tract, AQP1 and -4 are involved in the rearrangement of bile composition by mechanisms of reabsorption/secretion of water. In the gallbladder, AQP1 and -8 are also involved in trans-epithelial bidirectional water flow with the ultimate goal of bile concentration. Pathophysiologically, AQPs have been indicated as players in several hepatobiliary disorders, including cholestatic diseases and cholesterol cholelithiasis. Research on AQP function and the modulation of AQP expression is in progress, with the identification of potent and homolog-specific compounds modulating the expression or inhibiting these membrane channels with promising pharmacological developments. This review summarizes the contribution of AQPs in physiological and pathophysiological stages related to hepatobiliary function.
Insights into Reproductive Immunology and Placental Pathology
Authors: Szukiewicz Dariusz
Published: November 2024

The formation of a daughter organism as a result of the fusion of an egg and a sperm cell, followed by the implantation of the embryo, the formation of the placenta, and the further growth of the embryo and then fetus until delivery, poses particular challenges for the immune system [...]
Molecular Dynamics Simulations of Nucleosomes Containing Histone Variant H2A.J
Authors: Kosarim Nikita A. , Fedulova Anastasiia S. , Shariafetdinova Aleksandra S. , Armeev Grigoriy A. , Shaytan Alexey K.
Published: November 2024

Histone proteins form the building blocks of chromatin—nucleosomes. Incorporation of alternative histone variants instead of the major (canonical) histones into nucleosomes is a key mechanism enabling epigenetic regulation of genome functioning. In humans, H2A.J is a constitutively expressed histone variant whose accumulation is associated with cell senescence, inflammatory gene expression, and certain cancers. It is sequence-wise very similar to the canonical H2A histones, and its effects on the nucleosome structure and dynamics remain elusive. This study employed all-atom molecular dynamics simulations to reveal atomistic mechanisms of structural and dynamical effects conferred by the incorporation of H2A.J into nucleosomes. We showed that the H2A.J C-terminal tail and its phosphorylated form have unique dynamics and interaction patterns with the DNA, which should affect DNA unwrapping and the availability of nucleosomes for interactions with other chromatin effectors. The dynamics of the L1-loop and the hydrogen bonding patterns inside the histone octamer were shown to be sensitive to single amino acid substitutions, potentially explaining the higher thermal stability of H2A.J nucleosomes. Taken together, our study demonstrated unique dynamical features of H2A.J-containing nucleosomes, which contribute to further understanding of the molecular mechanisms employed by H2A.J in regulating genome functioning.
Adipose Tissues Have Been Overlooked as Players in Prostate Cancer Progression
Authors: Liermann-Wooldrik Kia T. , Kosmacek Elizabeth A. , Oberley-Deegan Rebecca E.
Published: November 2024

Obesity is a common risk factor in multiple tumor types, including prostate cancer. Obesity has been associated with driving metastasis, therapeutic resistance, and increased mortality. The effect of adipose tissue on the tumor microenvironment is still poorly understood. This review aims to highlight the work conducted in the field of obesity and prostate cancer and bring attention to areas where more research is needed. In this review, we have described key differences between healthy adipose tissues and obese adipose tissues, as they relate to the tumor microenvironment, focusing on mechanisms related to metabolic changes, abnormal adipokine secretion, altered immune cell presence, and heightened oxidative stress as drivers of prostate cancer formation and progression. Interestingly, common treatment options for prostate cancer ignore the adipose tissue located near the site of the tumor. Because of this, we have outlined how excess adipose tissue potentially affects therapeutics’ efficacy, such as androgen deprivation, chemotherapy, and radiation treatment, and identified possible drug targets to increase prostate cancer responsiveness to clinical treatments. Understanding how obesity affects the tumor microenvironment will pave the way for understanding why some prostate cancers become metastatic or treatment-resistant, and why patients experience recurrence.
Gene Expression Profiling of the Peritumoral Immune Cell Infiltrate of Penile Squamous Cell Carcinomas
Authors: Winkelmann Ria , Becker Nina , Leichner Regina , Wild Peter J. , Demes Melanie , Banek Severine , Döring Claudia , Bein Julia
Published: November 2024

Penile carcinomas are rare tumors in Europe and need further investigations due to their inferior prognosis in late tumor stages. The presence of disparate immune cell infiltrates was observed in these tumors, which were subsequently demonstrated to give rise to divergent tumor prognoses. The objective was to further characterize this immune cell infiltrate with the use of immunohistochemistry and RNA expression. A total of twelve well-characterized cases of penile squamous cell carcinomas with known infection status by human papillomavirus (HPV) and p16 status were assessed. The cases were classified according to their morphological characteristics, including those exhibiting a pronounced peritumoral immune cell infiltrate and those with less peritumoral immune cell infiltration. The generation of RNA expression data was conducted using the nCounter® PanCancer Immune Profiling Panel. Computational models were employed to calculate the proportions of immune cells. To corroborate the findings, an immunohistochemical analysis was conducted using antibodies against CD20, CD3, CD4, CD8, MUM1, CD68, and CD117. Our cases were clustered according to the immune cell infiltrate detected via histology in a group with less immune cell infiltrate density and in a group with increased immune cell infiltrate density. Generally, all immune cells showed an increased amount in the group with pronounced immune cell infiltrate density. The clusters were found to relate to cell functions, the complement system, cytotoxicity, pathogen defense, regulation, and T-cell functions. In cases exhibiting a pronounced immune cell infiltrate, the top three genes that exhibited the greatest upregulation were GZMA, MICB, and GNLY. No relationship to HPV infection status was demonstrated. Immunohistochemistry validated the data gained via RNA expression and showed a correlation with EPIC and Cibersort. The clustering of cases based on immune cell infiltrate density revealed significant distinctions between groups with lower and higher immune cell infiltrate density. The group with increased immune cel infiltrate density showed a greater abundance of immune cells, aligning with key functions like cytotoxicity, pathogen defense, and T-cell regulation. Among these cases, the genes GZMA, MICB, and GNLY were significantly upregulated, suggesting their involvement in an increased immune response. The role of HPV infection status in our cases with regard to the peritumoral immune cell infiltrate remains inconclusive.
Effect of Combination of Blue and Red Light with Terbinafine on Cell Viability and Reactive Oxygen Species in Human Keratinocytes: Potential Implications for Cutaneous Mycosis
Authors: Pérez González Luis Alfonso , Martínez-Pascual María Antonia , Toledano-Macías Elena , Jara-Laguna Rosa Cristina , Fernández-Guarino Montserrat , Hernández-Bule María Luisa
Published: November 2024

Cutaneous mycoses are common infections whose treatment has become more complex due to increasing antifungal resistance and the need for prolonged therapies, hindering patient adherence and increasing the incidence of adverse effects. Consequently, the use of physical therapies, especially photodynamic therapy (PDT), has increased for the treatment of onychomycosis due to its antimicrobial capacity being mediated by the production of reactive oxygen species. This study investigates the in vitro effect of applying blue light (448 nm) or red light (645 nm), alone or together with terbinafine, on the viability of human keratinocytes and the production of reactive oxygen species. The combination of terbinafine and blue light significantly increases ROS production and caspase-3 expression, while red light together with terbinafine increases catalase, superoxide dismutase (SOD) and PPARγ expression, which reduces the amount of ROS in the cultures. The effect of both treatments could be useful in clinical practice to improve the response of cutaneous mycoses to pharmacological treatment, reduce their toxicity and shorten their duration.
Correction: Giunta et al. Ameliorative Effects of PACAP against Cartilage Degeneration. Morphological, Immunohistochemical and Biochemical Evidence from in Vivo and in Vitro Models of Rat Osteoarthritis. Int. J. Mol. Sci. 2015, 16, 5922–5944
Authors: Giunta Salvatore , Castorina Alessandro , Marzagalli Rubina , Szychlinska Marta Anna , Pichler Karin , Mobasheri Ali , Musumeci Giuseppe
Published: November 2024

In the original publication [...]
Radial Data Visualization-Based Step-by-Step Eliminative Algorithm to Predict Colorectal Cancer Patients’ Response to FOLFOX Therapy
Authors: Kryczka Jakub , Bachorz Rafał Adam , Kryczka Jolanta , Boncela Joanna
Published: November 2024

Application of the FOLFOX scheme to colorectal cancer (CRC) patients often results in the development of chemo-resistance, leading to therapy failure. This study aimed to develop a functional and easy-to-use algorithm to predict patients’ response to FOLFOX treatment. Transcriptomic data of CRC patient’s samples treated with FOLFOX were downloaded from the Gene Expression Omnibus database (GSE83129, GSE28702, GSE69657, GSE19860 and GSE41568). Comparing the expression of top up- and downregulated genes in FOLFOX responder and non-responder patients’ groups, we selected 30 potential markers that were used to create a step-by-step eliminative procedure based on modified radial data visualization, which depicts the interplay between the expression level of chosen attributes (genes) to locate data points in low-dimensional space. Our analysis proved that FOLFOX-resistant CRC samples are predominantly characterized by upregulated expression levels of TMEM182 and MCM9 and downregulated LRRFIP1. Additionally, the procedure developed based on expression levels of TMEM182, MCM9, LRRFIP1, LAMP1, FAM161A, KLHL36, ETV5, RNF168, SRSF11, NCKAP5, CRTAP, VAMP2, ZBTB49 and RIMBP2 proved to be capable in predicting FOLFOX therapy response. In conclusion, our approach can give a unique insight into clinical decision-making regarding therapy scheme administration, potentially increasing patients’ survival and, consequently, medical futility due to incorrect therapy application.
OsbHLH5 Synergically Regulates Phenolamide and Diterpenoid Phytoalexins Involved in the Defense of Rice Against Pathogens
Authors: Zhou Shen , Zhang Ran , Wang Qiming , Zhu Jinjin , Zhou Junjie , Sun Yangyang , Shen Shuangqian , Luo Jie
Published: November 2024

Rice (Oryza sativa) produces phenolamides and diterpenoids as major phytoalexins. Although the biosynthetic pathways of phenolamides and diterpenoids in plants have been revealed, knowledge of their accumulation regulatory mechanisms remains limited, and, in particular, no co-regulatory factor has been identified to date. Here, using a combined co-expression and evolutionary analysis, we identified the basic helix–loop–helix (bHLH) transcription factor OsbHLH5 as a positive bifunctional regulator of phenolamide and diterpenoid biosynthesis in rice. Metabolomic analysis revealed that OsbHLH5 significantly increased the content of phenolamides (such as feruloyl tryptamine (Fer-Trm) and p-coumaroyl tyramine (Cou-Tyr)) and diterpenoid phytoalexins (such as momilactones A, momilactones B) in the overexpression lines, while their content was reduced in the OsbHLH5 knockout lines. Gene expression and dual-luciferase assays revealed that OsbHLH5 activates phenolamide biosynthetic genes (including putrescine hydroxycinnamoyltransferase 3 (OsPHT3), tyramine hydroxycinnamoyltransferases 1/2 (OsTHT1/2), and tryptamine benzoyltransferase 2 (OsTBT2)) as well as diterpenoid biosynthetic genes (including copalyl diphosphate synthase 4 (OsCPS4) and kaurene synthase-like 4/7/10/11 (OsKSL4/7/10/11)). Furthermore, we have demonstrated that OsbHLH5 is induced by jasmonic acid (JA), while pathogen inoculation assays indicated that the overexpression of OsbHLH5 in transgenic rice plants leads to enhanced resistance to Xanthomonas oryzae pv. oryzae (Xoo). Overall, we have identified a positive regulator of phenolamide and diterpenoid biosynthesis and have demonstrated that biotic stress induces phytoalexin accumulation partly in an OsbHLH5-dependent manner, providing new insights into the metabolic interactions involved in pathogen response and offering valuable gene resources for the development, through genetic improvement, of new rice varieties that are resistant to diseases.