bluuebunny/crossref_metadata_2025 huggingface dataset:
Auditory Neuropathy Caused by a Structural Variation in the OTOF Gene, Identified Using Oxford Nanopore Adaptive Sampling
Authors: Kumai Takumi , Nishio Shin-ya , Moteki Hideaki , Katada Akihiro , Usami Shin-ichi
Published: January 2025

Background/Objectives: The OTOF gene is reported to be the causative gene for non-syndromic recessive sensorineural hearing loss and auditory neuropathy spectrum disorder. About 300 variants have been reported, but there have been no reports to date on copy gain variants. Methods: We identified a copy gain variant in the OTOF gene through short-read next-generation sequencing analysis from one patient with auditory neuropathy. We also performed long-read next-generation sequencing analysis using the Oxford Nanopore Technologies adaptive sampling procedure. Results: The four-year-old male carried a duplication of chr2: 26,477,852 to 26,483,106 (a 5254-base duplication including exon 14 to exon 18 of the OTOF gene NM_001287489) and a c.5385C>A single nucleotide variant. We also confirmed that these two variants were located in the trans configuration based on haplotype phasing results using the long-read next-generation sequencing data. Conclusions: This is the first report of an auditory neuropathy patient with a large duplication variant in the OTOF gene. The identified variants were novel, but based on the clinical phenotype of the patient, these variants seem to be the genetic cause of this patient’s phenotype. Oxford Nanopore Technologies adaptive sampling is a powerful tool for the analysis of structural variants (particularly for determining the breakpoint and direction) and haplotype phasing.
Effects of Trunk Covering and Airflow Treatment on Sap Flux and Bud Burst During the Dormant Stage in ‘Fuji’ Apples
Authors: Choi Young-Min , Choi Dong-Geun
Published: January 2025

The effects of recent climate change, including warm winters and repeated temperature fluctuations during dormancy, can lead to freezing injuries that result in significant economic losses in the fruit industry. This study aimed to examine the physiological responses of ‘Fuji’/M9 apple trees to trunk covering and continuous airflow treatments over 30 days, providing insights into mitigating freezing damage. The temperature difference between the sunlit and shaded sides of the trunk was lower in the whitewashed and foam insulation-covered treatments compared to those covered with newspaper, rice straw, or left uncovered. Under airflow treatment, the temperature difference in the uncovered control was 2.2 °C lower than in the non-airflow group, while no significant difference was observed in the whitewash treatment. Sap flow initiation was observed the earliest in the foam insulation-covered treatment and the latest in the whitewashed treatment. The timing of bud burst followed the order of foam insulation, rice straw, whitewash, newspaper, and the uncovered control. Furthermore, sap flow initiation and the bud burst period were delayed under airflow treatment compared to non-airflow conditions. This study provides fundamental insights into the effects of covering materials and airflow on apple tree physiology during dormancy, offering valuable information to guide future research in this field.
Resveratrol in Grapevine Components, Products and By-Products—A Review
Authors: Căpruciu Ramona
Published: January 2025

Resveratrol, a valuable compound found in grapevines, is found in significant amounts in grapes and wine, but also in other parts of the plant (leaves, roots, shoots) and derived products (juice, raisins, powders, grape pomace). Synthesis factors considerably influence the resveratrol content, and research aims to optimise these factors to maximise yield, with applications in agriculture, food, cosmetics, and medicine. This literature survey aims to review and synthesise existing knowledge on aspects of resveratrol’s chemical structure and isomers, biological properties, and the factors influencing resveratrol synthesis and content in grapevine and sources of resveratrol in grapevine components, products, and by-products. Current research is focusing on methods to stabilise resveratrol to increase the functionality of food products and the bioavailability of the compound in the colon, thereby contributing to human health, which reflects the interdisciplinary interest in the use of resveratrol as an ingredient with nutraceutical properties.
Evaluating Cartographic Communication in Croatian National Parks: User Perceptions of Pictograms
Authors: Cibilić Iva , Poslončec-Petrić Vesna
Published: January 2025

This study examines the understanding of tourist maps in Croatian national parks, emphasizing a user-centered approach to enhancing cartographic design, the tourist experience, and map readability. Although tourist maps are widely used, there is limited research evaluating these cartographic products, particularly in terms of their comprehensibility and effectiveness in communicating spatial information. To address this gap, we examined existing cartographic materials published by Croatian national park authorities in line with recognized cartographic standards. An online questionnaire, completed by 132 participants of varying ages and educational backgrounds, was used to evaluate the understanding of Point of Interest (POI) pictograms. The results obtained within both gap analysis and needs assessment underscore the need for user-centered improvements in cartographic communication and provide a foundation for the development of more effective map designs tailored to user needs.
A Senescent Cluster in Aged Human Hematopoietic Stem Cell Compartment as Target for Senotherapy
Authors: Poisa-Beiro Laura , Landry Jonathan J. M. , Yan Bowen , Kardorff Michael , Eckstein Volker , Villacorta Laura , Krammer Peter H. , Zaugg Judith , Gavin Anne-Claude , Benes Vladimir , Zhou Daohong , Raffel Simon , Ho Anthony D.
Published: January 2025

To identify the differences between aged and young human hematopoiesis, we performed a direct comparison of aged and young human hematopoietic stem and progenitor cells (HSPCs). Alterations in transcriptome profiles upon aging between humans and mice were then compared. Human specimens consist of CD34+ cells from bone marrow, and mouse specimens of hematopoietic stem cells (HSCs; Lin− Kit+ Sca1+ CD150+). Single-cell transcriptomic studies, functional clustering, and developmental trajectory analyses were performed. A significant increase in multipotent progenitor 2A (MPP2A) cluster is found in the early HSC trajectory in old human subjects. This cluster is enriched in senescence signatures (increased telomere attrition, DNA damage, activation of P53 pathway). In mouse models, the accumulation of an analogous subset was confirmed in the aged LT-HSC population. Elimination of this subset has been shown to rejuvenate hematopoiesis in mice. A significant activation of the P53–P21WAF1/CIP1 pathway was found in the MPP2A population in humans. In contrast, the senescent HSCs in mice are characterized by activation of the p16Ink4a pathway. Aging in the human HSC compartment is mainly caused by the clonal evolution and accumulation of a senescent cell cluster. A population with a similar senescence signature in the aged LT-HSCs was confirmed in the murine aging model. Clearance of this senescent population with senotherapy in humans is feasible and potentially beneficial.
Etoposide as a Key Therapeutic Agent in Lung Cancer: Mechanisms, Efficacy, and Emerging Strategies
Authors: Jang Jung Yoon , Kim Donghwan , Im Eunok , Kim Nam Deuk
Published: January 2025

Topoisomerase II inhibitors, particularly etoposide, have long been integral to the treatment of lung cancer, especially small cell lung cancer. This review comprehensively examines the mechanisms of action of etoposide, its clinical efficacy, and its role in current lung cancer treatment regimens. Etoposide exerts its anticancer effects by inducing DNA strand breaks through the inhibition of topoisomerase II, leading to cancer cell apoptosis. Despite their widespread use, challenges such as drug resistance, toxicity, and limited efficacy in non-small cell lung cancer have spurred ongoing research on combination therapies and novel drug formulations. Emerging therapeutic strategies include the integration of etoposide with immunotherapy, targeted therapies, and novel drug delivery systems aimed at enhancing the therapeutic window and overcoming drug resistance. This article aims to inform the development of more effective treatment strategies by providing a critical overview of the clinical applications of etoposide and exploring future directions for lung cancer therapy.
Re-Sensitization of Resistant Ovarian Cancer SKOV3/CDDP Cells to Cisplatin by Curcumin Pre-Treatment
Authors: Hasan Aseel Ali , Kalinina Elena , Zhdanov Dmitry , Volodina Yulia , Tatarskiy Victor
Published: January 2025

A major challenging problem facing effective ovarian cancer therapy is cisplatin resistance. Re-sensitization of cisplatin-resistant ovarian cancer cells to cisplatin (CDDP) has become a critical issue. Curcumin (CUR), the most abundant dietary polyphenolic curcuminoids derived from turmeric (Curcuma longa), has achieved previously significant anti-cancer effects against human ovarian adenocarcinoma SKOV-3/CDDP cisplatin-resistant cells by inhibition the gene expression of the antioxidant enzymes (SOD1, SOD2, GPX1, CAT and HO1), transcription factor NFE2L2 and signaling pathway (PIK3CA/AKT1/MTOR). However, the detailed mechanisms of curcumin-mediated re-sensitization to cisplatin in SKOV-3/CDDP cells still need further exploration. Here, a suggested curcumin pre-treatment therapeutic strategy has been evaluated to effectively overcome cisplatin-resistant ovarian cancer SKOV-3/CDDP and to improve our understanding of the mechanisms behind cisplatin resistance. The findings of the present study suggest that the curcumin pre-treatment significantly exhibited cytotoxic effects and inhibited the proliferation of the SKOV-3/CDDP cell line compared to the simultaneous addition of drugs. Precisely, apoptosis induced by curcumin pre-treatment in SKOV-3/CDDP cells is mediated by mitochondrial apoptotic pathway (cleaved caspases 9, 3 and cleaved PARP) activation as well as by inhibition of thioredoxin reductase (TRXR1) and mTOR/STAT3 signaling pathway. This current study could deepen our understanding of the anticancer mechanism of CUR pre-treatment, which not only facilitates the re-sensitization of ovarian cancer cells to cisplatin but may lead to the development of targeted and effective therapeutics to eradicate SKOV-3/CDDP cancer cells.
The Role of Nutrition, Oxidative Stress, and Trace Elements in the Pathophysiology of Autism Spectrum Disorders
Authors: Długosz Anna , Wróblewski Marcin , Błaszak Błażej , Szulc Joanna
Published: January 2025

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and interaction, alongside repetitive behaviors, and atypical sensory-motor patterns. The growing prevalence of ASD has driven substantial advancements in research aimed at understanding its etiology, preventing its onset, and mitigating its impact. This ongoing effort necessitates continuous updates to the body of knowledge and the identification of previously unexplored factors. The present study addresses this need by examining the roles of nutrition, oxidative stress, and trace elements in the pathophysiology of ASD. In this review, an overview is provided of the key dietary recommendations for individuals with ASD, including gluten-free and casein-free (GFCF) diets, ketogenic diets (KDs), and other nutritional interventions. Furthermore, it explores the involvement of oxidative stress in ASD and highlights the significance of trace elements in maintaining neuropsychiatric health. The impact of these factors on molecular and cellular mechanisms was discussed, alongside therapeutic strategies and their efficacy in managing ASD.
A Novel Large Duplication on the X Chromosome as a Cause of Familial Generalized Dystonia: A Case Report
Authors: Costa António , Pereira Diogo , Malaquias Maria João , Brandão Ana Filipa , Oliveira Jorge , Magalhães Marina
Published: January 2025

Chromosomal aberrations are rare but known causes of movement disorders, presenting with broad phenotypes in which dystonia may be predominant. During the investigation of such cases, chromosomal studies are not often considered as a first approach. In this article, the authors describe a family affected by a generalized form of dystonia, evolving from a focal phenotype, for which a new X chromosome large duplication was found to be the likely causative, therefore highlighting the role of such studies when facing complex movement disorders.
Subacute PM2.5 Exposure Induces Hepatic Insulin Resistance Through Inflammation and Oxidative Stress
Authors: Lu Yao , Qiu Wenke , Liao Ruiwei , Cao Wenjuan , Huang Feifei , Wang Xinyuan , Li Ming , Li Yan
Published: January 2025

Epidemiological studies prove that type II diabetes, characterized by insulin resistance (IR), may be caused by fine particulate matter 2.5 (PM2.5). However, underlying mechanisms whereby PM2.5, particularly during short-term exposure, induces liver dysfunction leading to IR remains poorly understood. In the present study, HepG2 cells and the BALB/c mouse model were used to explore how PM2.5 affects insulin sensitivity. The effects of subacute PM2.5 exposure on glucose metabolism were examined using commercial kits. Oxidative stress and inflammation were detected by fluorescent staining and RT-qPCR. The phosphorylation of PI3K/AKT was examined by Western blot. Subacute PM2.5 exposure induced IR, as reflected by increased glucose levels in cell supernatants, elevated insulin levels, and the impaired intraperitoneal glucose tolerance test in mice. PM2.5 induced oxidative stress, as evidenced by increased reactive oxygen species, cytochrome P450 2E1, and malondialdehyde, along with reduced superoxide dismutase 1/2 and silent information regulator 1. IL-6 and TNF-α were found to be upregulated using RT-qPCR. Western blot showed that PM2.5 inhibited the PI3K-AKT signaling pathway, indicated by the decreased phosphorylation of PI3K/AKT in HepG2 cells. Additionally, H&E staining showed only mild hepatic injury in mice liver. These results firmly suggest that subacute PM2.5 exposure induces insulin resistance through oxidative stress, inflammation, and the inhibition of the PI3K-AKT signaling pathway.
Genome-Wide Characterization of Extrachromosomal Circular DNA in the Midgut of BmCPV-Infected Silkworms and Its Potential Role in Antiviral Responses
Authors: Tong Xinyu , Lei Chao , Liu Yilin , Yin Mei , Peng Huan , Qiu Qunnan , Feng Yongjie , Hu Xiaolong , Gong Chengliang , Zhu Min
Published: January 2025

Extrachromosomal circular DNAs (eccDNAs) has been found to be widespread and functional in various organisms. However, comparative analyses of pre- and post-infection of virus are rarely known. Herein, we investigated the changes in expression patterns of eccDNA following infection with Bombyx mori cytoplasmic polyhedrosis virus (BmCPV) and explore the role of eccDNA in viral infection. Circle-seq was used to analyze eccDNAs in the midgut of BmCPV-infected and BmCPV-uninfected silkworms. A total of 5508 eccDNAs were identified, with sizes varying from 72 bp to 17 kb. Most of eccDNAs are between 100 to 1000 bp in size. EccDNA abundance in BmCPV-infected silkworms was significantly higher than in BmCPV-uninfected silkworms. GO and KEGG analysis of genes carried by eccDNAs reveals that most are involved in microtubule motor activity, phosphatidic acid binding, cAMP signaling pathway, and pancreatic secretion signaling pathways. Several eccDNAs contain sequences of the transcription factor SOX6, sem-2, sp8b, or Foxa2. Association analysis of eccDNA-mRNA/miRNA/circRNA revealed that some highly expressed genes are transcribed from relevant sequences of eccDNA and the transcription of protein coding genes influenced the frequency of eccDNA. BmCPV infection resulted in changes in the expression levels of six miRNAs, but no known miRNAs with altered expression levels due to changes in eccDNA abundance were identified. Moreover, it was found that 1287 and 924 sequences representing back-spliced junctions of circRNAs were shared by the junctions of eccDNAs in the BmCPV-infected and uninfected silkworms, respectively, and some eccDNAs loci were shared by circRNAs on Chromosomes 2, 7, 11, 14, and 24, suggesting some eccDNAs may exert its function by being transcribed into circRNAs. These findings suggest that BmCPV infection alter the expression pattern of eccDNAs, leading to changes in RNA transcription levels, which may play roles in regulating BmCPV replication. In the future, further experiments are needed to verify the association between eccDNA-mRNA/miRNA/circRNA and its function in BmCPV infection.
Two-Step Cell Death Induction by the New 2-Arachidonoyl Glycerol Analog and Its Modulation by Lysophosphatidylinositol in Human Breast Cancer Cells
Authors: Akimov Mikhail G. , Gretskaya Natalia M. , Gorbacheva Evgenia I. , Khadour Nisreen , Sherstyanykh Galina D. , Bezuglov Vladimir V.
Published: January 2025

2-arachnadoyl glycerol (2-AG) is one of the most common endocannabinoid molecules with anti-proliferative, cytotoxic, and pro-proliferative effects on different types of tumors. Typically, it induces cell death via cannabinoid receptor 1/2 (CB1/CB2)-linked ceramide production. In breast cancer, ceramide is counterbalanced by the sphingosine-1-phosphate, and thus the mechanisms of 2-AG influence on proliferation are poorly understood. We evaluated the mechanism of the anti-proliferative action by 2-AG and the influence of lysophaosphatidylinositol (LPI) on it in six human breast cancer cell lines of different tumor degree (MCF-10A, MCF-7, BT-474, BT-20, SK-BR-3, and MDA-MB-231) using resazurin test, inhibitor, blocker, and anti-oxidant analysis, and siRNA interference. To avoid acyl migration in 2-AG, we replaced it with the analog 2-arachidonoyl-1,3-difluoropropanol (2-ADFP) newly synthesized by us. Using a molecular docking approach, we showed that at the CB2 receptor, 2-ADFP and 2-AG were very close to each other. However, 2-ADFP demonstrated a stronger affinity towards CB1 in the antagonist-bound conformation. 2-ADFP was anti-proliferative in all the cell lines tested. The toxicity of 2-ADFP was enhanced by LPI. 2-ADFP activity was reduced or prevented by the CB2 and vanilloid receptor 1 (TRPV1) blockers, inositol triphosphate receptor, CREB, and cyclooxygenase 2 inhibitor, and by anti-oxidant addition. Together with the literature data, these results indicate CB2- and TRPV1-dependent COX-2 induction with concomitant cell death induction by the oxidized molecule’s metabolites.
Comparative Analysis of Iodine Levels, Biochemical Responses, and Thyroid Gene Expression in Rats Fed Diets with Kale Biofortified with 5,7-Diiodo-8-Quinolinol
Authors: Waśniowska Justyna , Piątkowska Ewa , Pawlicki Piotr , Smoleń Sylwester , Kopeć Aneta , Dyląg Agnieszka , Krzemińska Joanna , Koronowicz Aneta
Published: January 2025

Iodine is a key micronutrient essential for the synthesis of thyroid hormone, which regulates metabolic processes and maintains overall health. Despite its importance, iodine deficiency is a global health issue, leading to disorders such as goiter, hypothyroidism, and developmental abnormalities. Biofortification of crops with iodine is a promising strategy to enhance the dietary iodine intake, providing an alternative to iodized salt. Curly kale (Brassica oleracea var. sabellica) is a nutrient-rich vegetable high in vitamins A, C, K; minerals; fiber; and bioactive compounds with antioxidant, anti-inflammatory, and detoxifying properties. This study evaluates the effects of diets containing iodine-biofortified curly kale (‘Oldenbor F1’ and ‘Redbor F1’) on iodine content, tissue iodine levels, and various biochemical parameters in laboratory rats. The biofortified curly kale was enriched with 5,7-diiodo-8-quinolinol. The iodine content in the AIN-93G (control) diet and the non-biofortified curly kale diets did not differ significantly. However, diets with 5,7-diiodo-8-quinolinol biofortified kale showed significantly higher iodine levels compared with the control diets. Tissue analysis revealed the highest iodine concentrations in the liver and kidneys of rats fed diets with biofortified curly kale, indicating better iodine bioavailability. Biochemical analysis showed that rats fed the biofortified kale diet had lower total cholesterol (TC) and triglyceride (TG) levels compared with rats fed the control diet. Additionally, the biofortified diet improved the liver function markers (ALAT, ASAT) and reduced oxidative stress markers (TBARS). The study also investigated the expression of thyroid-related genes (Slc5A5, Tpo, Dio1, Dio2) in response to diets containing biofortified kale. The results demonstrated significant changes in gene expression, indicating adaptive mechanisms to dietary iodine levels and the presence of bioactive compounds in the biofortified kale. The study also observed variations in uric acid levels, with lower concentrations in rats fed a diet with biofortified curly kale. Biofortified curly kale supports thyroid function and improves liver and kidney health by reducing oxidative stress and modulating key biochemical and genetic markers. These findings suggest that biofortified curly kale can effectively increase dietary iodine intake as a nutritional intervention to address iodine deficiency and promote overall health.
Lidocaine Enhanced Antitumor Efficacy and Relieved Chemotherapy-Induced Hyperalgesia in Mice with Metastatic Gastric Cancer
Authors: Gao Peiwen , Peng Fei , Liu Jing , Wu Weiwei , Zhao Guoyan , Liu Congyan , Cao Hangxue , Li Yuncheng , Qiu Feng , Zhang Wensheng
Published: January 2025

With the widespread use of lidocaine for pain control in cancer therapy, its antitumor activity has attracted considerable attention in recent years. This paper provides a simple strategy of combining lidocaine with chemotherapy drugs for cancer therapy, aiming to relieve chemotherapy-induced pain and achieve stronger antitumor efficacy. However, there is still a lack of substantial pre-clinical evidence for the efficacy and related mechanisms of such combinations, obstructing their potential clinical application. In this study, we propose intraperitoneal chemotherapy (IPC) against gastric cancer (GC) as an ideal scenario to evaluate the efficacy of a lidocaine/paclitaxel combination. Firstly, we used human GC cells MKN-45-luc to investigate the antitumor activity and related mechanisms of the lidocaine/paclitaxel combination in vitro. Then, we used C57BL/6 mice with intraperitoneal drug suffusion to evaluate the efficacy of lidocaine to suppress paclitaxel-induced hyperalgesia and related mechanisms. Lastly, in BALB/c tumor-bearing nude mice we evaluated the synergistic antitumor activity and pain-relieving effect of the lidocaine/paclitaxel combination. Our results showed enhanced antitumor activity for the lidocaine/paclitaxel combination, which induced apoptosis, inhibited migration, and the invasion of GC cells in a synergistic manner. In animal models, the lidocaine/paclitaxel combination effectively inhibited growth and peritoneal metastasis of the tumor, resulting in prolonged survival time. Meanwhile, lidocaine showed considerable anti-inflammatory activity alongside its anesthetic effect, which, in combination, effectively relieved hyperalgesia induced by paclitaxel. These results suggested that intraperitoneal suffusion with lidocaine/paclitaxel could be a pain-free IPC formulation with enhanced antitumor activity, which could provide a promising treatment for GC with peritoneal metastasis.
Understanding Deep Endometriosis: From Molecular to Neuropsychiatry Dimension
Authors: Pszczołowska Magdalena , Walczak Kamil , Kołodziejczyk Weronika , Kozłowska Magdalena , Kozłowski Gracjan , Gachowska Martyna , Leszek Jerzy
Published: January 2025

Endometriosis is a widely spread disease that affects about 8% of the world’s female population. This condition may be described as a spread of endometrial tissue apart from the uterine cavity, but this process’s pathomechanism is still unsure. Apart from classic endometriosis symptoms, which are pelvic pain, infertility, and bleeding problems, there are neuropsychiatric comorbidities that are usually difficult to diagnose. In our review, we attempted to summarize some of them. Conditions like migraine, anxiety, and depression occur more often in women with endometriosis and have a significant impact on life quality and pain perception. Interestingly, 77% of endometriosis patients with depression also have anxiety. Neuroimaging gives an image of the so-called endometriosis brain, which means alternations in pain processing and cognition, self-regulation, and reward. Genetic factors, including mutations in KRAS, PTEN, and ARID1A, influence cellular proliferation, differentiation, and chromatin remodeling, potentially exacerbating lesion severity and complicating treatment. In this review, we focused on the aspects of sciatic and obturator nerve endometriosis, the emotional well-being of endometriosis-affected patients, and the potential influence of endometriosis on dementia, also focusing on prolonged diagnosis. Addressing endometriosis requires a multidisciplinary approach, encompassing molecular insights, innovative therapies, and attention to its psychological and systemic effects.
Ellagic Acid: A Green Multi-Target Weapon That Reduces Oxidative Stress and Inflammation to Prevent and Improve the Condition of Alzheimer’s Disease
Authors: Alfei Silvana , Zuccari Guendalina
Published: January 2025

Oxidative stress (OS), generated by the overrun of reactive species of oxygen and nitrogen (RONS), is the key cause of several human diseases. With inflammation, OS is responsible for the onset and development of clinical signs and the pathological hallmarks of Alzheimer’s disease (AD). AD is a multifactorial chronic neurodegenerative syndrome indicated by a form of progressive dementia associated with aging. While one-target drugs only soften its symptoms while generating drug resistance, multi-target polyphenols from fruits and vegetables, such as ellagitannins (ETs), ellagic acid (EA), and urolithins (UROs), having potent antioxidant and radical scavenging effects capable of counteracting OS, could be new green options to treat human degenerative diseases, thus representing hopeful alternatives and/or adjuvants to one-target drugs to ameliorate AD. Unfortunately, in vivo ETs are not absorbed, while providing mainly ellagic acid (EA), which, due to its trivial water-solubility and first-pass effect, metabolizes in the intestine to yield UROs, or irreversible binding to cellular DNA and proteins, which have very low bioavailability, thus failing as a therapeutic in vivo. Currently, only UROs have confirmed the beneficial effect demonstrated in vitro by reaching tissues to the extent necessary for therapeutic outcomes. Unfortunately, upon the administration of food rich in ETs or ETs and EA, URO formation is affected by extreme interindividual variability that renders them unreliable as novel clinically usable drugs. Significant attention has therefore been paid specifically to multitarget EA, which is incessantly investigated as such or nanotechnologically manipulated to be a potential “lead compound” with protective action toward AD. An overview of the multi-factorial and multi-target aspects that characterize AD and polyphenol activity, respectively, as well as the traditional and/or innovative clinical treatments available to treat AD, constitutes the opening of this work. Upon focus on the pathophysiology of OS and on EA’s chemical features and mechanisms leading to its antioxidant activity, an all-around updated analysis of the current EA-rich foods and EA involvement in the field of AD is provided. The possible clinical usage of EA to treat AD is discussed, reporting results of its applications in vitro, in vivo, and during clinical trials. A critical view of the need for more extensive use of the most rapid diagnostic methods to detect AD from its early symptoms is also included in this work.
Proteins and DNA Sequences Interacting with Tanshinones and Tanshinone Derivatives
Authors: Szymczyk Piotr , Majewska Małgorzata , Nowak Jadwiga
Published: January 2025

Tanshinones, biologically active diterpene compounds derived from Salvia miltiorrhiza, interact with specific proteins and DNA sequences, influencing signaling pathways in animals and humans. This study highlights tanshinone–protein interactions observed at concentrations achievable in vivo, ensuring greater physiological relevance compared to in vitro studies that often employ supraphysiological ligand levels. Experimental data suggest that while tanshinones interact with multiple proteomic targets, only a few enzymes are significantly affected at biologically relevant concentrations. This apparent paradox may be resolved by tanshinones’ ability to bind DNA and influence enzymes involved in gene expression or mRNA stability, such as RNA polymerase II and human antigen R protein. These interactions trigger secondary, widespread changes in gene expression, leading to complex proteomic alterations. Although the current understanding of tanshinone–protein interactions remains incomplete, this study provides a foundation for deciphering the molecular mechanisms underlying the therapeutic effects of S. miltiorrhiza diterpenes. Additionally, numerous tanshinone derivatives have been developed to enhance pharmacokinetic properties and biological activity. However, their safety profiles remain poorly characterized, limiting comprehensive insights into their medicinal potential. Further investigation is essential to fully elucidate the therapeutic and toxicological properties of both native and modified tanshinones.
Involvement of miR775 in the Post-Transcriptional Regulation of Fructose-1,6-Bisphosphate Aldolase in Maize (Zea mays L.) Leaves Under Hypoxia
Authors: Fedorin Dmitry N. , Khomutova Anna E. , Eprintsev Alexander T. , Igamberdiev Abir U.
Published: January 2025

Different types of microRNA participate in the post-transcriptional regulation of target genes. The content of several hypoxia-dependent miRNAs in plant cells, including miR775, increases in the conditions of oxygen deficiency. Electrophoretic studies of total RNA samples from the leaves of flooded seedlings of maize (Zea mays L.) revealed the presence of two interfering complexes with miR775 at 12 h of hypoxic incubation. A nucleotide sequence analysis of a sample containing the interfering complex of miR775 with mRNA from maize leaves showed a high degree of homology with the ICL/PEPM_KPHMT lyase family domain. It corresponded to a fragment of fructose-1,6-bisphosphate aldolase mRNA. By real-time PCR, we established the dynamics of the content of transcripts of aldolase isoenzyme genes under hypoxia in maize leaves. A decrease in the transcriptional activity of the aldolase 1 gene (Aldo1) correlated with a high content of miR775 in maize leaf cells. The fraction of extracellular vesicles sedimented at 100,000× g, was enriched with miR775. The accumulation of aldolase 2 (Aldo2) mRNA transcripts under hypoxic conditions indicates its participation in maintaining glycolysis when Aldo1 expression is inhibited. We conclude that an increase in the total content of free miR775 and its participation in the suppression of the Aldo1 gene represents an important mechanism in developing the adaptive reaction of cellular metabolism in response to hypoxia.
Restoring Homeostasis: Treating Amyotrophic Lateral Sclerosis by Resolving Dynamic Regulatory Instability
Authors: Lee Albert J. B. , Bi Sarah , Ridgeway Eleanor , Al-Hussaini Irfan , Deshpande Sakshi , Krueger Adam , Khatri Ahad , Tsui Dennis , Deng Jennifer , Mitchell Cassie S.
Published: January 2025

Amyotrophic lateral sclerosis (ALS) has an interactive, multifactorial etiology that makes treatment success elusive. This study evaluates how regulatory dynamics impact disease progression and treatment. Computational models of wild-type (WT) and transgenic SOD1-G93A mouse physiology dynamics were built using the first-principles-based first-order feedback framework of dynamic meta-analysis with parameter optimization. Two in silico models were developed: a WT mouse model to simulate normal homeostasis and a SOD1-G93A ALS model to simulate ALS pathology dynamics and their response to in silico treatments. The model simulates functional molecular mechanisms for apoptosis, metal chelation, energetics, excitotoxicity, inflammation, oxidative stress, and proteomics using curated data from published SOD1-G93A mouse experiments. Temporal disease progression measures (rotarod, grip strength, body weight) were used for validation. Results illustrate that untreated SOD1-G93A ALS dynamics cannot maintain homeostasis due to a mathematical oscillating instability as determined by eigenvalue analysis. The onset and magnitude of homeostatic instability corresponded to disease onset and progression. Oscillations were associated with high feedback gain due to hypervigilant regulation. Multiple combination treatments stabilized the SOD1-G93A ALS mouse dynamics to near-normal WT homeostasis. However, treatment timing and effect size were critical to stabilization corresponding to therapeutic success. The dynamics-based approach redefines therapeutic strategies by emphasizing the restoration of homeostasis through precisely timed and stabilizing combination therapies, presenting a promising framework for application to other multifactorial neurodegenerative diseases.
1,3,5-Triazine: A Promising Molecular Scaffold for Novel Agents for the Treatment of Alzheimer’s Disease
Authors: Silva Carlos F. M. , Guerrinha Ana P. D. de M. S. , Carvalho Sofia , Pinto Diana C. G. A. , Silva Artur M. S.
Published: January 2025

Currently, Alzheimer’s disease (AD) is one of the most frequent forms of dementia. From a molecular perspective, the molecular characteristics that better define this disease consist of abnormal protein deposits between neuronal cells, namely senile plaques (SPs) and neurofibrillary tangles (NFTs), consisting of protein aggregates of amyloid-β and hyperphosphorylated tau protein, respectively. In addition to these protein aggregates, a third molecular hallmark of AD consists of depleted neurotransmitter acetylcholine levels. To date, the treatments developed for this disease are mostly focused on the use of AChE inhibitors, presenting only a symptomatic approach against the disease instead of a cure. Triazines are nitrogen-containing heterocyclic compounds that, throughout the years, have attracted a lot of curiosity from medicinal chemists for presenting numerous biological properties and being widely present in nature. In particular, this class of compounds has been associated with inhibiting several biological targets, emerging as a promising class for developing new pharmacological agents. However, there is still a scarcity of knowledge regarding the potential of this type of compound against any of the hallmarks of AD. For this reason, this paper intends to fulfill this absence by highlighting the potential of a subclass of triazines, 1,3,5-triazines (sym-triazines), as promising molecules for developing novel AD treatments. Thus, an in-depth analysis of 1,3,5-triazine derivatives is performed regarding its inhibitory activity against AChE (cholinergic hypothesis) and its capability to inhibit amyloid-β formation and aggregation (amyloid hypothesis). Through this analysis, it is possible to indicate some structural features optimal for each described activity, a compilation that we believe to be essential for the scientific community in this never-ending pursuit.
Influence of Simulated Altitude Exposure (2500 m) on Patients with Fontan Palliation Based on Circulating Hypoxia-Associated Factors
Authors: Müller Nicole , Hart Christopher , Härtel Julian Alexander , Jordan Jens , Tank Jens , Breuer Johannes , Grau Marijke , Frede Stilla , Splettstoesser Frank , Kratz Tobias
Published: January 2025

Patients with a univentricular heart live with chronic hypoxia (75–85%) in their first years of life, which could affect adaptation to altitude or other hypoxic insults later in life. To test this hypothesis, we exposed 18 patients with Fontan circulation (age: 24.5 [16.3–38.8] years; f/m 9/9) to simulated altitude using normobaric hypoxia (15.2% oxygen, equivalent to 2500 masl) for 24 h. In blood samples obtained in normoxia (T1, 21% oxygen) and after 24 h hypoxia after a submaximal stress test, we measured hypoxia-regulated molecules involved in angiogenesis and tissue homeostasis. A significant increase was displayed for IL-10 (p = 0.001), CCL2 (p = 0.006), ANG-1 (p = 0.001), ANG-2 (p = 0.029), FGF-1 (p = 0.001) and FGF-2 (p = 0.024). E-Selectin (p < 0.001) and NRG-1 were significantly different at p = 0.026 at T2 compared to baseline. However, OPN and OSF-1 did not exhibit significant changes (p = 0.348; p = 0.065). Fontan patients show hypoxia-related protein patterns similar to healthy individuals despite intermittent hypoxemia, but their response to standardised hypoxia was described here for the first time, requiring further study.
The Evolution of Digital Security by Design Using Temporal Network Analysis
Authors: Williams Lowri , Khan Hamza , Burnap Pete
Published: January 2025

Digital Security by Design (DSbD) is an initiative supported by the UK government aimed at transforming digital technology to deliver necessary digital resilience and prosperity across the UK. As emerging challenges in the field of digital security evolve, it becomes essential to explore how entities involved in DSbD interact and change over time. Understanding these dynamic relationships can provide crucial insights for the development and improvement of security practices. This paper presents a data-driven analysis of the evolving landscape of DSbD from 2019 to 2024, gathering insights from textual documents referencing DSbD. Using a combination of text mining techniques and network analysis, a large corpus of textual documents was examined to identify key entities, including organisations, individuals, and the relationships between them. A network was then visualised to analyse the structural connections between these entities, revealing how key concepts and actors have evolved. The results and discussion demonstrate that the network analysis offers a unique advantage in tracking and visualising these evolving relationships, providing insights into shifts in focus, emerging trends, and changes in technological adoption over time. For example, a notable finding from the analysis is the substantial increase in node relationships associated with Artificial Intelligence (AI). We hypothesise that this surge reflects the growing integration of AI into digital security strategies, driven by the need for more adaptive and autonomous solutions to tackle evolving cyber threats, as well as the rapid introduction of new AI tools to the market and their swift adoption across various industries. By mapping such connections, such results are useful, helping practitioners and researchers recognise new security demands and adjust strategies to better respond to the evolving landscape of DSbD.
Transforming Children’s Attitudes Toward Insects Through In-School Encounters
Authors: Miller Kathleen M. , Beegle Dana K. , Blevins Wycoff Stephanie , Frank Daniel L.
Published: January 2025

Each year, the Department of Entomology at Virginia Tech hosts an entomology-themed outreach event known as Hokie BugFest. This on-campus, festival-sized experience aims to educate the public about insects and other arthropods through hands-on activities, games, displays, and live arthropods. In 2021, due to the COVID-19 pandemic, Hokie BugFest and similar large public events were cancelled. In response, the department launched Hokie BugFest on the Go, which offered smaller-scale, in-person learning opportunities during these closures. Instead of hosting the community on campus, Virginia Tech’s Department of Entomology brought live arthropods, university experts, and the exciting science of entomology directly into schools, fostering small-group, hands-on learning experiences. In 2022, a playful assessment was added to the traveling outreach program to measure changes in student attitudes and perceptions of insects and other arthropods before and after the program. The assessment also gauged students’ favorite arthropods after seeing, and in some cases handling, them live during the program. Assessment results revealed valuable insights into how hands-on, applied learning experiences can shift children’s attitudes toward arthropods. Results showed that even after expressing trepidation and fears, students’ knowledge and comfort levels with insects and other arthropods increased as they interacted and learned throughout the program. These findings underscore the value of using engaging, hands-on, small-group approaches when designing entomology-themed outreach events for young audiences and offer guidance for future programs.
Long-Term Exposure to Lambda-Cyhalothrin Reveals Novel Genes Potentially Involved in Aedes aegypti Insecticide Resistance
Authors: Mejía Alejandro , Mejía-Jaramillo Ana María , Fernandez Geysson Javier , Granada Yurany , Lowenberger Carl , Triana-Chávez Omar
Published: January 2025

Insecticide resistance in Aedes aegypti populations hinders vector control programs. Many studies have focused on the classical mechanisms, kdr mutations, and metabolic enzymes to understand the development of insecticide resistance. In this study, we subjected a strain of Ae. aegypti to selective pressure for 13 consecutive generations to understand the development and extent of insecticide resistance. We delved into the transcriptomics of this pressured strain to gain insights into the molecular changes underlying insecticide resistance in Ae. aegypti. Our data suggest mosquito resistance is influenced by additional mechanisms that are difficult to explain using only classical mechanisms. The response by mosquitoes varies depending on the exposure time. Initially, when mosquitoes are in contact with insecticides, they modulate the expression of metabolic enzymes and gain some point mutations in the sodium channel genes. After long-term exposure, the mosquitoes respond to insecticides by expressing different proteins involved in the cuticle, energetic metabolism, and synthesis of proteases. We propose a model that includes these novel mechanisms found after prolonged insecticide exposure, which work in conjunction with established mechanisms (kdr and metabolic resistance) but have a different timeline in terms of expression and appearance.
The Trans-Axillary Vein Approach for the Ablation of Anterior–Septal, Anterior, and Anterior–Lateral Accessory Pathways in Children: More than an Alternative to the Femoral Vein
Authors: Ferrari Paola , Malanchini Giovanni , Limonta Raul , Ferrari Gabriele , Leidi Cristina , De Filippo Paolo
Published: January 2025

Background: Catheter ablation of right anterior, anterior–lateral, and anterior–septal accessory pathways is still challenging in children, even after seminal improvements in mapping and catheter design over the last years. The trans-jugular approach was described as an alternative to the femoral vein recently. As a direct comparison between the femoral approach and the superior approach using the axillary vein was lacking, we conducted the present study. Methods: Twenty-two pediatric patients were enrolled in this retrospective study. Patients with prior ablation attempts were excluded. Another 22 consecutive patients with the same AP localizations were selected as a control group and treated with ablation through the femoral vein. Left axillary vein cannulation was performed advancing an 18-gauge needle using fluoroscopic landmarks (the first rib below the inferior border of the clavicle). All mapping and ablations of accessory pathways were performed with a 7 F deflectable radiofrequency ablation catheter. The main outcome of this study was ablation success at 1 year. Recurrences were defined as a relapse of preexcitation on a 12-lead electrocardiogram and/or documented supraventricular tachycardia. Results: There were no significant differences in sex, age, or weight between groups. No complications occurred acutely or during follow-up. There were no significant differences in acute success rates between the two groups (19/22 vs. 22/22; p = 0.56) at 24 h ECG recordings. At the 1-year follow-up the total recurrence rate was 15.9% (7/44 patients); there was a significantly lower recurrence rate among patients in the trans-jugular group (27.2% vs. 4.5%; p = 0.039). Conclusions: The present study suggests that the trans-axillary vein approach is a safe and effective alternative to the classical femoral approach in pediatric patients.
On-Line Survey About Autonomic Dysreflexia in Individuals with Spinal Cord Injury in Croatia
Authors: Markić Dean , Minić Željka , Šimičić Josip , Kuljanić Karin , Strčić Josip , Bonifačić David , Sušanj Ivan Marin , Jakšić Ante , Sveško Visentin Helena , Ehrman Robert , Marinović Marin
Published: January 2025

Background/Objectives: Autonomic dysreflexia (AD) is a clinical syndrome affecting persons with spinal cord injury (SCI). The aim of the study was to present the experience of individuals with SCI and AD in Croatia. Single-center questionnaire study. Setting: Faculty of Medicine, University of Rijeka, Rijeka, Croatia. Persons with SCI were divided into those with an SCI at T6 and above (n = 41) and those with an SCI at T7 and below (n = 29). Based on anamnestic data, patients with an SCI at T6 and above were further divided into those with and without self-reported clinical symptoms of AD (respectively: n = 33 and n = 8). Methods: The online survey included 23 questions of various types. It consisted of a general (demographic) section, section with specific questions about AD, and a section on self-assessment and quality of life. Based on the answers, the experience and knowledge of AD among individuals with an SCI in Croatia was assessed. Results: A total of 70 individuals with an SCI completed the whole survey. The average age was 40.6 years. The patients were predominantly male (72.9%) and mostly with a traumatic SCI (84.3%). Of the 70 individuals with an SCI, 35 (50%) reported they were familiar with AD, with the majority indicating that the internet was their primary source of information. Among those with an SCI who were unaware of AD, most (34/35 = 97.1%) wanted to learn about AD. The self-assessed quality of life was insignificantly better in patients with an SCI below T6 than in those with higher lesions. Patients with AD reported different symptoms and the most frequently reported symptom was a headache (70%). In 64% of participants, the primary trigger of AD were issues with the urinary bladder. In most individuals (55%), symptoms were not recognized by the healthcare providers. The individuals with AD were dissatisfied with the information about AD they received from doctors or nurses. Overall, 61% of all participants with AD rated their quality of life as good. Conclusions: Persons with an SCI are not adequately informed about AD. In most persons with AD, their symptoms are not properly recognized by healthcare providers. Our results suggest the need for more education of healthcare professionals about AD.