bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative Chloroplast Genome Study of Zingiber in China Sheds Light on Plastome Characterization and Phylogenetic Relationships
Authors: Xia Maoqin , Jiang Dongzhu , Xu Wuqin , Liu Xia , Zhu Shanshan , Xing Haitao , Zhang Wenlin , Zou Yong , Li Hong-Lei
Published: November 2024

Background: Zingiber Mill., a morphologically diverse herbaceous perennial genus of Zingiberaceae, is distributed mainly in tropical to warm-temperate Asia. In China, species of Zingiber have crucial medicinal, edible, and horticultural values; however, their phylogenetic relationships remain unclear. Methods: To address this issue, the complete plastomes of the 29 Zingiber accessions were assembled and characterized. Comparative plastome analysis and phylogenetic analysis were conducted to develop genomic resources and elucidate the intraspecific phylogeny of Zingiber. Results: The newly reported plastomes ranged from 161,495 to 163,880 bp in length with highly conserved structure. Results of comparative analysis suggested that IR expansions/contractions and changes of repeats were the main reasons that influenced the genome size of the Zingiber plastome. A large number of SSRs and six highly variable regions (rpl20, clpP, ycf1, petA-psbJ, rbcL-accD, and rpl32-trnL) have been identified, which could serve as potential DNA markers for future population genetics or phylogeographic studies on this genus. The well-resolved plastome phylogeny suggested that Zingiber could be divided into three clades, corresponding to sect. Pleuranthesis (sect. Zingiber + sect. Dymczewiczia) and sect. Cryptanthium. Conclusions: Overall, this study provided a robust phylogeny of Zingiber plants in China, and the newly reported plastome data and plastome-derived markers will be of great significance for the accurate identification, protection, and agricultural management of Zingiber resources in the future.
SNP Polymorphisms Are Associated with Environmental Factors in Sockeye Salmon Populations Across the Northwest Pacific: Insights from Redundancy Analysis
Authors: Khrustaleva Anastasia M.
Published: November 2024

The SNP variation in sockeye salmon across the Asian part of its range was studied in 23 samples from 16 lake–river systems of the West Pacific Coast to improve understanding of genetic adaptation in response to spawning watersheds conditions. Identification of candidate SNPs and environmental factors that can contribute to local adaptations in sockeye salmon populations was carried out using redundancy analysis (RDA), a powerful tool for landscape genetics proven to be effective in genotype–environment association studies. Climatic and hydrographic indices (7 indices in total), reflecting abiotic conditions in freshwater habitats of sockeye salmon and characterizing the temperature regime in the river basin, its variability during the year, the amount of precipitation, as well as the height of the maximum tide in the estuary, were used as predictor factors. Among the 45 analyzed SNPs, several loci (ALDOB-135, HGFA, and RAG3-93) correlated with predictors gradients along the northwest Pacific coast were identified. The putative candidate loci localized in genes involved in the immune and inflammatory responses, as well as genes encoding temperature-sensitive enzymes and some hormones regulating ion homeostasis in fish during the anadromous migration and smoltification, were potentially associated with environmental conditions in natal rivers. The findings could have implications for aquaculture, conservation, and resource management in the context of global climate change.
The Association Between Cadmium Exposure and Prostate Cancer: An Updated Systematic Review and Meta-Analysis
Authors: Firmani Giorgio , Chiavarini Manuela , Dolcini Jacopo , Quarta Stefano , D’Errico Marcello Mario , Barbadoro Pamela
Published: November 2024

Prostate cancer (PCa) is a common cancer among men, and it has a multifactorial etiology. Cadmium (Cd), a toxic heavy metal classified as a carcinogen by the IARC, can cause various acute and chronic effects. This systematic review and meta-analysis aims to update previous findings on the association between Cd exposure and PCa. We carried out a literature search in PubMed, Web of Science, and Scopus up to May 2024, identifying eight new articles. The effect size from the highest and lowest exposure categories were extracted and analyzed using a random-effects model. Heterogeneity was assessed with the I2 test, and publication bias was evaluated using funnel plot asymmetry. Overall, the effect size for PCa associated with Cd exposure, combining previous and new articles, was 1.11 (95% CI 0.85–1.45). Heterogeneity was high, but no significant publication bias was detected. For studies from Europe, the effect size was 1.47 (95% CI 1.00–2.17). Notably, 11 articles from the previous systematic review and meta-analysis highlighted that higher Cd exposure is significantly associated with more aggressive histopathological types of PCa (OR 1.50, 95% CI 1.08–2.07). These findings suggest a potential public health concern, indicating the need for further research to clarify the risk associated with Cd exposure.
Application of Machine Learning and Deep Neural Visual Features for Predicting Adult Obesity Prevalence in Missouri
Authors: Dahu Butros M. , Martinez-Villar Carlos I. , Toubal Imad Eddine , Alshehri Mariam , Ouadou Anes , Khan Solaiman , Sheets Lincoln R. , Scott Grant J.
Published: November 2024

This research study investigates and predicts the obesity prevalence in Missouri, utilizing deep neural visual features extracted from medium-resolution satellite imagery (Sentinel-2). By applying a deep convolutional neural network (DCNN), the study aims to predict the obesity rate of census tracts based on visual features in the satellite imagery that covers each tract. The study utilizes Sentinel-2 satellite images, processed using the ResNet-50 DCNN, to extract deep neural visual features (DNVF). Obesity prevalence data, sourced from the CDC’s 2022 estimates, is analyzed at the census tract level. The datasets were integrated to apply a machine learning model to predict the obesity rates in 1052 different census tracts in Missouri. The analysis reveals significant associations between DNVF and obesity prevalence. The predictive models show moderate success in estimating and predicting obesity rates in various census tracts within Missouri. The study emphasizes the potential of using satellite imagery and advanced machine learning in public health research. It points to environmental factors as significant determinants of obesity, suggesting the need for targeted health interventions. Employing DNVF to explore and predict obesity rates offers valuable insights for public health strategies and calls for expanded research in diverse geographical contexts.
Geographically-Informed Modeling and Analysis of Platform Attitude Jitter in GF-7 Sub-Meter Stereo Mapping Satellite
Authors: Xia Haoran , Tang Xinming , Mo Fan , Xie Junfeng , Li Xiang
Published: November 2024

The GF-7 satellite, China’s inaugural sub-meter-level stereoscopic mapping satellite, has been deployed for a wide range of applications, including natural resource investigation, environmental monitoring, fundamental surveying, and the development of global geospatial information resources. The satellite’s stable platform and reliable imaging systems are crucial for achieving high-quality imaging and precise attitude measurements. However, the satellite’s operation is affected by both internal and external factors, which induce vibrations in the satellite platform, thereby affecting image quality and mapping accuracy. To address this challenge, this paper proposes a novel method for constructing a satellite platform vibration model based on geographic location information. The model is developed by integrating composite data from star sensors and gyroscopes (gyro) with subsatellite point location data. The experimental methodology involves the composite processing of gyro data and star sensor optical axis angles, integration of the processed data through time-matching and normalization, and denoising of the integrated data, followed by trigonometric fitting to capture the periodic characteristics of platform vibrations. The positions of the satellite substellar points are determined from the satellite orbit data. A rigorous geometric imaging model is then used to construct a vibration model with geographic location correlation in combination with the satellite subsatellite point positions. The experimental results demonstrate the following: (1) Over the same temporal range, there is a significant convergence in the waveform similarities between the gyro data and the star sensor optical axis angles, indicating a strong correlation in the jitter information; (2) The platform vibration exhibits a robust correlation with the satellite’s geographic location along its orbit. Specifically, the model reveals that the GF-7 satellite experiences the maximum vibration amplitude between 5° S and 20° S latitude during its ascending phase, and the minimum vibration amplitude between 5° N and 20° N latitude during the descending phase. The model established in this study offers theoretical support for optimizing satellite attitude and mitigating platform vibrations.
Deciphering the Genetic and Biochemical Drivers of Fruit Cracking in Akebia trifoliata
Authors: Nazir Mian Faisal , Jia Tianjiao , Zhang Yi , Dai Longyu , Xu Jie , Zhao Yafang , Zou Shuaiyu
Published: November 2024

This study investigates the molecular mechanisms underlying fruit cracking in Akebia trifoliata, a phenomenon that significantly impacts fruit quality and marketability. Through comprehensive physiological, biochemical, and transcriptomic analyses, we identified key changes in cell wall components and enzymatic activities during fruit ripening. Our results revealed that ventral suture tissues exhibit significantly elevated activities of polygalacturonase (PG) and β-galactosidase compared to dorsoventral line tissues, indicating their crucial roles in cell wall degradation and structural weakening. The cellulose content in VS tissues peaked early and declined during ripening, while DL tissues maintained relatively stable cellulose levels, highlighting the importance of cellulose dynamics in fruit cracking susceptibility. Transcriptomic analysis revealed differentially expressed genes (DEGs) associated with pectin biosynthesis and catabolism, cell wall organization, and oxidoreductase activities, indicating significant transcriptional regulation. Key genes like AKT032945 (pectinesterase) and AKT045678 (polygalacturonase) were identified as crucial for cell wall loosening and pericarp dehiscence. Additionally, expansin-related genes AKT017642, AKT017643, and AKT021517 were expressed during critical stages, promoting cell wall loosening. Genes involved in auxin-activated signaling and oxidoreductase activities, such as AKT022903 (auxin response factor) and AKT054321 (peroxidase), were also differentially expressed, suggesting roles in regulating cell wall rigidity. Moreover, weighted gene co-expression network analysis (WGCNA) identified key gene modules correlated with traits like pectin lyase activity and soluble pectin content, pinpointing potential targets for genetic manipulation. Our findings offer valuable insights into the molecular basis of fruit cracking in A. trifoliata, laying a foundation for breeding programs aimed at developing crack-resistant varieties to enhance fruit quality and commercial viability.
Role of Balanced Involvement of the ICOS/ICOSL/Osteopontin Network in Cutaneous Wound Healing
Authors: Christaki Foteini , Ghasemi Amirabbas , Pantham Deepika , Abouali Reza , Provera Alessia , Vecchio Cristina , Sheferaw Anteneh Nigussie , Dianzani Chiara , Sutti Salvatore , Rolla Roberta , Sacchetti Sara , Giacomini Luca , Dianzani Umberto , Stoppa Ian
Published: November 2024

Inducible T-cell costimulator (ICOS, CD278) is a costimulatory receptor primarily expressed by activated T cells. It binds to ICOS ligand (ICOSL, CD275), which is expressed by various immune and non-immune cell types, particularly in inflamed tissues. ICOSL can also bind to osteopontin (OPN), a protein that functions both as a component of the extracellular matrix and as a soluble pro-inflammatory cytokine. Previous studies, including ours, have shown that ICOS and ICOSL play a role in skin wound healing, as mice deficient in either ICOS or ICOSL exhibit delayed healing. The aim of this study was to investigate the involvement of the ICOS/ICOSL/OPN network in skin wound healing by analyzing mice that are single knockouts for ICOS, ICOSL, or OPN, or double knockouts for ICOS/OPN or ICOSL/OPN. Our results showed that wound healing is impaired in all single knockout strains, but not in the two double knockout strains. Cellular and molecular analyses of the wound healing sites revealed that the healing defect in the single knockout strains is associated with reduced neutrophil infiltration and decreased expression of α-SMA (a marker of myofibroblasts), IL-6, TNFα, and VEGF. In contrast, the normalization of wound closure observed in the double knockout strains was primarily linked to increased vessel formation. A local treatment with recombinant ICOS-Fc improved healing in all mouse strains expressing ICOSL, but not in those lacking ICOSL, and led to a local increase in vessel formation and macrophage recruitment, predominantly of the M2 type.
Structure of Full-Length Src Kinase and Its Key Phosphorylated States: Molecular Dynamics Study
Authors: Strelkova Maria A. , Tolstova Anna P. , Mitkevich Vladimir A. , Petrushanko Irina Yu. , Makarov Alexander A.
Published: November 2024

Src kinase is one of the key regulators of cellular metabolism and is dysregulated in numerous diseases, including cancer, neurodegenerative diseases, and particularly Alzheimer’s disease. Despite its therapeutic importance, its full-length structure has never been obtained before, as it contains an intrinsically disordered regulatory region, SH4UD. The SH4UD region is crucial for Src activation, functional dimerization, and regulation by other kinases. In this study, we used the replica exchange molecular dynamics approach with a hybrid temperature and Hamiltonian tempering to obtain the conformational ensemble of full-length Src kinase in its non-phosphorylated state and in the presence of its two key regulatory phosphorylations: pY419 and pY530. The representative structures and simulation trajectories of non-phosphorylated pY419 and pY530 Src are available in open access. We demonstrate that pY419 phosphorylation, which is associated with Src activation, enhances its motility, whereas inhibited pY530 Src preserves relatively compact conformation. This study also provides insights into how SH4UD contributes to Src substrate binding, dimerization, and autophosphorylation, highlighting the putative role of 14-RRR-16 in this process.
Photocleavable Guide crRNAs for a Light-Controllable CRISPR/Cas9 System
Authors: Sakovina Lubov , Vokhtantsev Ivan , Akhmetova Elizaveta , Vorobyeva Mariya , Vorobjev Pavel , Zharkov Dmitry O. , Novopashina Darya
Published: November 2024

The design of controllable and precise RNA-targeted CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats) systems is an important problem of modern molecular biology and genetic technology. Herein, we have designed a series of photocleavable guide CRISPR RNAs (crRNA) and their 2′-modified (2′-fluoro and locked nucleic acid) analogs containing one or two 1-(2-nitrophenyl)-1,2-ethanediol photolabile linkers (PL). We have demonstrated that these crRNAs can be destroyed by relatively mild UVA irradiation with the rate constants 0.24–0.77 min−1 and that the photocleavage markedly slows down the action of Cas9 nuclease in the model in vitro system. Two PLs provide more rapid crRNA destruction than a single linker. PLs in the crRNA structure improve the specificity of DNA cleavage by Cas9 nuclease for the fully complementary target. The application of photocleavable crRNA in CRISPR/Cas9 genome editing permits the system to be switched off in a spatiotemporally controlled manner, thus alleviating its off-target effects.
Rabbit and Human Angiotensin-Converting Enzyme-2: Structure and Electric Properties
Authors: Hristova Svetlana H. , Popov Trifon T. , Zhivkov Alexandar M.
Published: November 2024

The angiotensin-converting enzyme-2 (ACE2) is a transmembrane glycoprotein, consisting of two segments: a large carboxypeptidase catalytic domain and a small transmembrane collectrin-like segment. This protein plays an essential role in blood pressure regulation, transforming the peptides angiotensin-I and angiotensin-II (vasoconstrictors) into angiotensin-1-9 and angiotensin-1-7 (vasodilators). During the COVID-19 pandemic, ACE2 became best known as the receptor of the S-protein of SARS-CoV-2 coronavirus. The purpose of the following research is to reconstruct the 3D structure of the catalytic domain of the rabbit enzyme rACE2 using its primary amino acid sequence, and then to compare it with the human analog hACE2. For this purpose, we have calculated the electric properties and thermodynamic stability of the two protein globules employing computer programs for protein electrostatics. The analysis of the amino acid content and sequence demonstrates an 85% identity between the two polypeptide chains. The 3D alignment of the catalytic domains of the two enzymes shows coincidence of the α-helix segments, and a small difference in two unstructured segments of the chain. The electric charge of the catalytic domain of rACE2, determined by 70 positively chargeable amino acid residues, 114 negatively chargeable ones, and two positive charges of the Zn2+ atom in the active center exceeds that of hACE2 by one positively and four negatively chargeable groups; however, in 3D conformation, their isoelectric points pI 5.21 coincide. The surface electrostatic potential is similarly distributed on the surface of the two catalytic globules, but it strongly depends on the pH of the extracellular medium: it is almost positive at pH 5.0 but strongly negative at pH 7.4. The pH dependence of the electrostatic component of the free energy discloses that the 3D structure of the two enzymes is maximally stable at pH 6.5. The high similarity in the 3D structure, as well as in the electrostatic and thermodynamic properties, suggests that rabbit can be successfully used as an animal model to study blood pressure regulation and coronavirus infection, and the results can be extrapolated to humans.
Interplay Between Ocular Ischemia and Glaucoma: An Update
Authors: Coviltir Valeria , Burcel Miruna Gabriela , Baltă George , Marinescu Maria Cristina
Published: November 2024

Glaucoma is a main cause of irreversible blindness worldwide, with a high impact on productivity and quality of life. The mechanical and ischemic theories are currently the most recognized pathophysiological pathways that explain the neurodegeneration of retinal nerve fibers in glaucoma. In this narrative review, aspects of ischemia in glaucoma are discussed, including vascular dysregulation, retinal ischemia signaling pathways, roles of vascular endothelial growth factors, and future research and therapeutic directions. In conclusion, a better understanding of the ischemic processes in glaucoma may lead to innovative treatment options and improved management and follow-up of our patients.
Insights into Medication-Induced Osteonecrosis of the Jaw Through the Application of Salivary Proteomics and Bioinformatics
Authors: Schwartzová Vladimíra , Laputková Galina , Talian Ivan , Marcin Miroslav , Schwartzová Zuzana , Glaba Dominik
Published: November 2024

Long-term treatment with bisphosphonates is accompanied by an increased risk of medication-related osteonecrosis of the jaw (MRONJ). Currently, no clinically useful biomarkers for the predictive diagnosis of MRONJ are available. To investigate the potential key proteins involved in the pathogenesis of MRONJ, a proteomic LC-MS/MS analysis of saliva was performed. Differentially expressed proteins (DEPs) were analyzed using BiNGO, ClueGO, cytoHubba, MCODE, KEGG, and ReactomeFI software packages using Cytoscape platforms. In total, 1545 DEPs were identified, including 43 up- and 11 down-regulated with a 1.5-fold cut-off value and adj. p-value < 0.05. The analysis provided a panel of hub genes, including APOA2, APOB, APOC2, APOC3, APOE, APOM, C4B, C4BPA, C9, FGG, GC, HP, HRG, LPA, SAA2-SAA4, and SERPIND1. The most prevalent terms in GO of the biological process were macromolecular complex remodeling, protein–lipid complex remodeling, and plasma lipoprotein particle remodeling. DEPs were mainly involved in signaling pathways associated with lipoproteins, the innate immune system, complement, and coagulation cascades. The current investigation advanced our knowledge of the molecular mechanisms underlying MRONJ. In particular, the research identified the principal salivary proteins that are implicated in the onset and progression of this condition.
Gla Rich Protein (GRP) Mediates Vascular Smooth Muscle Cell (VSMC) Osteogenic Differentiation, Extracellular Vesicle (EV) Calcification Propensity, and Immunomodulatory Properties
Authors: Viegas Carla , Carreira Joana , Maia Teresa M. , Macedo Anjos L. , Matos António P. , Neves José , Simes Dina
Published: November 2024

Vascular calcification (VC) is a complex process involving vascular smooth muscle cell (VSMC) osteogenic differentiation, inflammation, and extracellular vesicle (EV) calcification and communication networks. Gla rich protein (GRP) is a calcification inhibitor involved in most of these processes. However, the molecular mechanism of GRP in VC and the specific characteristics, cargo, and functionality of calcifying EVs require further elucidation. Here, we use a combination of human ex vivo aortic fragments and primary vascular smooth muscle cell (VSMC) models to obtain new information on GRP function in VC and EVs released by VSMCs. We demonstrate that GRP inhibits VSMC osteogenic differentiation through downregulation of bone-related proteins and upregulation of mineralization inhibitors, with decreased mineral crystallinity in EVs deposited into the tissue extracellular matrix (ECM). EVs isolated by ultracentrifugation at 30K and 100K from the cell media (CM) and deposited in the ECM from control (CTR) and mineralizing (MM) VSMCs were biochemically, physically, and proteomically characterized. Four different EV populations were identified with shared markers commonly present in all EVs but with unique protein cargo and specific molecular profiles. Comparative proteomics identified several regulated proteins specifically loaded into MM EV populations associated with multiple processes involved in VC. Functional analysis demonstrated that 30K and 100K ECM-MM EVs with higher calcium and lower GRP levels induced macrophage inflammation. Our findings reinforce the functional relevance of GRP in multiple VC processes and suggest that ECM EVs released under calcification stress function as a new signaling axis on the calcification–inflammation cycle.
Targeted Chiral Metabolomics of D-Amino Acids: Their Emerging Role as Potential Biomarkers in Neurological Diseases with a Focus on Their Liquid Chromatography–Mass Spectrometry Analysis upon Chiral Derivatization
Authors: Lella Cinzia , Nestor Liam , De Bundel Dimitri , Vander Heyden Yvan , Van Eeckhaut Ann
Published: November 2024

In neuroscience research, chiral metabolomics is an emerging field, in which D-amino acids play an important role as potential biomarkers for neurological diseases. The targeted chiral analysis of the brain metabolome, employing liquid chromatography (LC) coupled to mass spectrometry (MS), is a pivotal approach for the identification of biomarkers for neurological diseases. This review provides an overview of D-amino acids in neurological diseases and of the state-of-the-art strategies for the enantioselective analysis of chiral amino acids (AAs) in biological samples to investigate their putative role as biomarkers for neurological diseases. Fluctuations in D-amino acids (D-AAs) levels can be related to the pathology of neurological diseases, for example, through their role in the modulation of N-methyl-D-aspartate receptors and neurotransmission. Because of the trace presence of these biomolecules in mammals and the complex nature of biological matrices, highly sensitive and selective analytical methods are essential. Derivatization strategies with chiral reagents are highlighted as critical tools for enhancing detection capabilities. The latest advances in chiral derivatization reactions, coupled to LC-MS/MS analysis, have improved the enantioselective quantification of these AAs and allow the separation of several chiral metabolites in a single analytical run. The enhanced performances of these methods can provide an accurate correlation between specific D-AA profiles and disease states, allowing for a better understanding of neurological diseases and drug effects on the brain.
SMN Deficiency Induces an Early Non-Atrophic Myopathy with Alterations in the Contractile and Excitatory Coupling Machinery of Skeletal Myofibers in the SMN∆7 Mouse Model of Spinal Muscular Atrophy
Authors: Berciano María T. , Gatius Alaó , Puente-Bedia Alba , Rufino-Gómez Alexis , Tarabal Olga , Rodríguez-Rey José C. , Calderó Jordi , Lafarga Miguel , Tapia Olga
Published: November 2024

Spinal muscular atrophy (SMA) is caused by a deficiency of the ubiquitously expressed survival motor neuron (SMN) protein. The main pathological hallmark of SMA is the degeneration of lower motor neurons (MNs) with subsequent denervation and atrophy of skeletal muscle. However, increasing evidence indicates that low SMN levels not only are detrimental to the central nervous system (CNS) but also directly affect other peripheral tissues and organs, including skeletal muscle. To better understand the potential primary impact of SMN deficiency in muscle, we explored the cellular, ultrastructural, and molecular basis of SMA myopathy in the SMNΔ7 mouse model of severe SMA at an early postnatal period (P0-7) prior to muscle denervation and MN loss (preneurodegenerative [PND] stage). This period contrasts with the neurodegenerative (ND) stage (P8-14), in which MN loss and muscle atrophy occur. At the PND stage, we found that SMN∆7 mice displayed early signs of motor dysfunction with overt myofiber alterations in the absence of atrophy. We provide essential new ultrastructural data on focal and segmental lesions in the myofibrillar contractile apparatus. These lesions were observed in association with specific myonuclear domains and included abnormal accumulations of actin-thin myofilaments, sarcomere disruption, and the formation of minisarcomeres. The sarcoplasmic reticulum and triads also exhibited ultrastructural alterations, suggesting decoupling during the excitation–contraction process. Finally, changes in intermyofibrillar mitochondrial organization and dynamics, indicative of mitochondrial biogenesis overactivation, were also found. Overall, our results demonstrated that SMN deficiency induces early and MN loss-independent alterations in myofibers that essentially contribute to SMA myopathy. This strongly supports the growing body of evidence indicating the existence of intrinsic alterations in the skeletal muscle in SMA and further reinforces the relevance of this peripheral tissue as a key therapeutic target for the disease.
Resistance Exercise Improves Glycolipid Metabolism and Mitochondrial Biogenesis in Skeletal Muscle of T2DM Mice via miR-30d-5p/SIRT1/PGC-1α Axis
Authors: Zheng Lifang , Rao Zhijian , Wu Jiabin , Ma Xiaojie , Jiang Ziming , Xiao Weihua
Published: November 2024

Exercise is a recognized non-pharmacological treatment for improving glucose homeostasis in type 2 diabetes (T2DM), with resistance exercise (RE) showing promising results. However, the mechanism of RE improving T2DM has not been clarified. This study aims to investigate the effects of RE on glucose and lipid metabolism, insulin signaling, and mitochondrial function in T2DM mice, with a focus on the regulatory role of miR-30d-5p. Our results confirmed that RE significantly improved fasting blood glucose, IPGTT, and ITT in T2DM mice. Enhanced expression of IRS-1, p-PI3K, and p-Akt indicated improved insulin signaling. RE improved glycolipid metabolism, as well as mitochondrial biogenesis and dynamics in skeletal muscle of T2DM mice. We also found that miR-30d-5p was upregulated in T2DM, and was downregulated after RE. Additionally, in vitro, over-expression of miR-30d-5p significantly increased lipid deposition, and reduced glucose uptake and mitochondrial biogenesis. These observations were reversed after transfection with the miR-30d-5p inhibitor. Mechanistically, miR-30d-5p regulates glycolipid metabolism in skeletal muscle by directly targeting SIRT1, which affects the expression of PGC-1α, thereby influencing mitochondrial function and glycolipid metabolism. Taken together, RE effectively improves glucose and lipid metabolism and mitochondrial function in T2DM mice, partly through regulating the miR-30d-5p/SIRT1/PGC-1α axis. miR-30d-5p could serve as a potential therapeutic target for T2DM management.
POLD3 as Controller of Replicative DNA Repair
Authors: Alli Nabilah , Lou-Hing Anna , Bolt Edward L. , He Liu
Published: November 2024

Multiple modes of DNA repair need DNA synthesis by DNA polymerase enzymes. The eukaryotic B-family DNA polymerase complexes delta (Polδ) and zeta (Polζ) help to repair DNA strand breaks when primed by homologous recombination or single-strand DNA annealing. DNA synthesis by Polδ and Polζ is mutagenic, but is needed for the survival of cells in the presence of DNA strand breaks. The POLD3 subunit of Polδ and Polζ is at the heart of DNA repair by recombination, by modulating polymerase functions and interacting with other DNA repair proteins. We provide the background to POLD3 discovery, investigate its structure, as well as function in cells. We highlight unexplored structural aspects of POLD3 and new biochemical data that will help to understand the pivotal role of POLD3 in DNA repair and mutagenesis in eukaryotes, and its impact on human health.
Explainable Machine Learning Models Using Robust Cancer Biomarkers Identification from Paired Differential Gene Expression
Authors: Díaz de la Guardia-Bolívar Elisa , Martínez Manjón Juan Emilio , Pérez-Filgueiras David , Zwir Igor , del Val Coral
Published: November 2024

In oncology, there is a critical need for robust biomarkers that can be easily translated into the clinic. We introduce a novel approach using paired differential gene expression analysis for biological feature selection in machine learning models, enhancing robustness and interpretability while accounting for patient variability. This method compares primary tumor tissue with the same patient’s healthy tissue, improving gene selection by eliminating individual-specific artifacts. A focus on carcinoma was selected due to its prevalence and the availability of the data; we aim to identify biomarkers involved in general carcinoma progression, including less-researched types. Our findings identified 27 pivotal genes that can distinguish between healthy and carcinoma tissue, even in unseen carcinoma types. Additionally, the panel could precisely identify the tissue-of-origin in the eight carcinoma types used in the discovery phase. Notably, in a proof of concept, the model accurately identified the primary tissue origin in metastatic samples despite limited sample availability. Functional annotation reveals these genes’ involvement in cancer hallmarks, detecting subtle variations across carcinoma types. We propose paired differential gene expression analysis as a reference method for the discovering of robust biomarkers.
T-Type Voltage-Gated Calcium Channels: Potential Regulators of Smooth Muscle Contractility
Authors: Tomida Shota , Ishima Tamaki , Nagai Ryozo , Aizawa Kenichi
Published: November 2024

Emerging evidence has indicated a possible link between attenuation of contractility in aortic smooth muscle cells and pathogenesis of aortic dissection, as revealed through comprehensive, multi-omic analyses of familial thoracic aortic aneurysm and dissection models. While L-type voltage-gated calcium channels have been extensively investigated for their roles in smooth muscle contraction, more recent investigations have suggested that downregulation of T-type voltage-gated calcium channels, rather than their L-type counterparts, may be more closely associated with impaired contractility observed in vascular smooth muscle cells. This review provides a detailed examination of T-type voltage-gated calcium channels, highlighting their structure, electrophysiology, biophysics, expression patterns, functional roles, and potential mechanisms through which their downregulation may contribute to reduced contractile function. Furthermore, the application of multi-omic approaches in investigating calcium channels is discussed.
Biological Importance of Complex Sphingolipids and Their Structural Diversity in Budding Yeast Saccharomyces cerevisiae
Authors: Tani Motohiro
Published: November 2024

Complex sphingolipids are components of eukaryotic biomembranes and are involved in various physiological functions. In addition, their synthetic intermediates and metabolites, such as ceramide, sphingoid long-chain base, and sphingoid long-chain base 1-phosphate, play important roles as signaling molecules that regulate intracellular signal transduction systems. Complex sphingolipids have a large number of structural variations, and this structural diversity is considered an important molecular basis for their various physiological functions. The budding yeast Saccharomyces cerevisiae has simpler structural variations in complex sphingolipids compared to mammals and is, therefore, a useful model organism for elucidating the physiological significance of this structural diversity. In this review, we focus on the structure and function of complex sphingolipids in S. cerevisiae and summarize the response mechanisms of S. cerevisiae to metabolic abnormalities in complex sphingolipids.
Molecular Communication of Microbial Plant Biostimulants in the Rhizosphere Under Abiotic Stress Conditions
Authors: Ali Sajid , Akhtar Muhammad Saeed , Siraj Muhammad , Zaman Wajid
Published: November 2024

Microbial plant biostimulants offer a promising, sustainable solution for enhancing plant growth and resilience, particularly under abiotic stress conditions such as drought, salinity, extreme temperatures, and heavy metal toxicity. These biostimulants, including plant growth-promoting rhizobacteria, mycorrhizal fungi, and nitrogen-fixing bacteria, enhance plant tolerance through mechanisms such as phytohormone production, nutrient solubilization, osmotic adjustment, and antioxidant enzyme activation. Advances in genomics, metagenomics, transcriptomics, and proteomics have significantly expanded our understanding of plant–microbe molecular communication in the rhizosphere, revealing mechanisms underlying these interactions that promote stress resilience. However, challenges such as inconsistent field performance, knowledge gaps in stress-related molecular signaling, and regulatory hurdles continue to limit broader biostimulant adoption. Despite these challenges, microbial biostimulants hold significant potential for advancing agricultural sustainability, particularly amid climate change-induced stresses. Future studies and innovation, including Clustered Regularly Interspaced Short Palindromic Repeats and other molecular editing tools, should optimize biostimulant formulations and their application for diverse agro-ecological systems. This review aims to underscore current advances, challenges, and future directions in the field, advocating for a multidisciplinary approach to fully harness the potential of biostimulants in modern agriculture.
Mediastinal Teratoma with Nephroblastomatous Elements: Case Report, Literature Review, and Comparison with Maturing Fetal Glomerulogenic Zone/Definitive Zone Ratio and Nephrogenic Rests
Authors: Alfawaz Bader , Koujok Khaldoun , Eamer Gilgamesh , Sergi Consolato M.
Published: November 2024

Extrarenal teratoid Wilms’ tumor (TWT) is a variant of Wilms’ tumor with fewer than 30 cases reported in the literature. It comprises more than 50% heterologous tissue and presents a significant diagnostic challenge due to its complex histology. We report an unusual case of mediastinal teratoma with nephroblastomatous elements in an 8-year-old female. The patient presented with respiratory distress, fever, weight loss, and a large anterior mediastinal mass. Imaging revealed a heterogeneous tumor containing fat, fluid, and calcification, suggestive of a teratoma. Surgical resection confirmed a mature cystic teratoma with foci of nephroblastoma. Pathological analysis demonstrated a mixture of ectodermal, mesodermal, and endodermal tissues alongside nephroblastomatous components. Immunohistochemistry was positive for Wilms Tumor 1 and other relevant markers, confirming the diagnosis. The patient had an uneventful postoperative course and was discharged after three days. This case adds to the growing body of research on extrarenal TWT, particularly its occurrence in the mediastinum, a rare site for such tumors. A literature review highlighted that extrarenal TWT often affects children, typically presenting in the retroperitoneum or sacrococcygeal regions, with varying recurrence rates and long-term outcomes. This case underscores the importance of histopathological and immunohistochemical analysis in diagnosing TWT and differentiating it from other mediastinal tumors to ensure appropriate treatment planning, emphasizing the need for long-term follow-up due to the potential for recurrence or metastasis. This paper also provides an in-depth look at nephron development and nephrogenic rests, highlighting the structural and functional aspects of nephrogenesis and the factors that disrupt it in fetal kidneys.
The Molecular Characterization and Antioxidant Defense of a Novel Nrf2 from the Pacific Abalone Haliotis discus hannai Ino
Authors: Qiao Kun , Huang Qiongmei , Chen Bei , Xu Min , Hao Hua , Su Yongchang , Liu Shuji , Pan Nan , Liu Zhiyu
Published: November 2024

The Nrf2/ARE pathway is considered the most important endogenous antioxidant signaling pathway in mammals, playing a crucial role in defending against external damage. This study investigated the functional characteristics of Nrf2 in the abalone, Haliotis discus hannai. The full-length cDNA sequence of the HdhNrf2 gene was cloned using rapid amplification of cDNA ends (RACE) technology and consists of 4568 base pairs encoding a protein of 694 amino acids. The predicted theoretical molecular weight was 77 kDa, with an isoelectric point of 4.72. Multiple sequence alignment analysis revealed the relative conservation of the HdhNrf2 amino acid sequence in H. discus hannai. The tissue expression pattern of the HdhNrf2 gene was analyzed using real-time fluorescence quantitative PCR, which showed the highest expression in the gills, followed by hemocytes, with the lowest levels in the foot and mantle. The inducible expression of HdhNrf2 and antioxidant genes in abalone under H2O2 stress was investigated at various time points. Furthermore, an expression vector, pET-28a(+)-rHdhNrf2, was constructed, and the recombinant protein rHdhNrf2 was obtained through induced expression and purification. These findings indicated that HdhNrf2 plays a crucial role in the defense of abalones against oxidative stress.
The Quenching of Long-Wavelength Fluorescence by the Closed Reaction Center in Photosystem I in Thermostichus vulcanus at 77 K
Authors: Akhtar Parveen , van Stokkum Ivo H. M. , Lambrev Petar H.
Published: November 2024

Photosystem I in most organisms contains long-wavelength or “Red” chlorophylls (Chls) absorbing light beyond 700 nm. At cryogenic temperatures, the Red Chls become quasi-traps for excitations as uphill energy transfer is blocked. One pathway for de-excitation of the Red Chls is via transfer to the oxidized RC (P700+), which has broad absorption in the near-infrared region. This study investigates the excitation dynamics of Red Chls in Photosystem I from the cyanobacterium Thermostichus vulcanus at cryogenic temperatures (77 K) and examines the role of the oxidized RC in modulating their fluorescence kinetics. Using time-resolved fluorescence spectroscopy, the kinetics of Red Chls were recorded for samples with open (neutral P700) and closed (P700+) RCs. We found that emission lifetimes in the range of 710–720 nm remained unaffected by the RC state, while more red-shifted emissions (>730 nm) decayed significantly faster when the RC was closed. A kinetic model describing the quenching by the oxidized RC was constructed based on simultaneous fitting to the recorded fluorescence emission in Photosystem I with open and closed RCs. The analysis resolved multiple Red Chl forms and variable quenching efficiencies correlated with their spectral properties. Only the most red-shifted Chls, with emission beyond 730 nm, are efficiently quenched by P700+, with rate constants of up to 6 ns−1. The modeling results support the notion that structural and energetic disorder in Photosystem I can have a comparable or larger effect on the excitation dynamics than the geometric arrangement of Chls.
Impact of Rab27 on Melanoma Cell Invasion and sEV Secretion
Authors: Horodecka Katarzyna , Czernek Liliana , Pęczek Łukasz , Gadzinowski Mariusz , Klink Magdalena
Published: November 2024

The migratory and invasive capabilities of melanoma cells contribute to metastasis. Therefore, targeting the genes driving these processes can support melanoma therapy. Rab27A and Rab27B contribute to tumor formation progression in many types of cancer through various mechanisms, including the secretion of small extracellular vesicles (sEVs). We explored the role of these GTPases in melanoma cell functioning in three RAB27A knockout (KO) cell lines (A375, DMBC12, and SkMel28) and a double RAB27A/B KO A375 cell line. The loss of RAB27A impaired the migration and invasion of DMBC12 and SkMel28 cells; however, the behavior of highly aggressive A375 cells was unaffected. The RAB27A/B double knockout moderately decreased the migratory capacity of A375 cells without disturbing their invasiveness. Additionally, the silencing of RAB27A did not affect the number and mean size of the sEVs, despite some alterations in the protein content of the vesicles. Both Rab27 isoforms can, at least partially, act independently. The potential role of Rab27A in the functioning of melanoma cells depends on the individual character of the cell line, but not on its basal expression, and seems to be unrelated to the secretion of sEVs.
Beneficial Effects of Xanthohumol on Metabolic Syndrome: Evidence from In Vitro and Animal Model Studies
Authors: Gómez-Zorita Saioa , Proença Carina , Fernández-Quintela Alfredo , Moreno-Indias Isabel , Portillo María P.
Published: November 2024

Metabolic syndrome refers to the simultaneous occurrence of several disorders that have been associated with other co-morbidities, such as a pro-inflammatory state and non-alcoholic fatty liver disease. Nowadays, it is a growing public health problem that contributes to the development of non-communicable diseases, such as type 2 diabetes, cardiovascular disease, and cognitive deficits among others. Its incidence has been related to modifiable lifestyle factors, mainly dietary patterns and physical activity. In addition, numerous studies have observed the potential beneficial effects of polyphenols in the prevention and treatment of metabolic syndrome components in both animals and humans. In this line, the aim of this review is to present the scientific evidence available about the beneficial effects of the phenolic compound xanthohumol in the prevention and/or treatment of obesity, dyslipidemia, insulin resistance, and fatty liver, which are important components of metabolic syndrome. All the potential beneficial effects described in this manuscript have been observed in vitro and in animal models, there are no published clinical trials in this context yet.
Caspase-1 Variants and Plasma IL-1β in Patients with Leishmania guyanensis Cutaneous Leishmaniasis in the Amazonas
Authors: de Souza Josué Lacerda , de Farias Guerra Marcus Vinitius , de Mesquita Tirza Gabrielle Ramos , Junior José do Espírito Santo , Sequera Hector David Graterol , da Silva Lener Santos , da Silva Larissa Almeida , Moura Filipe Menezes , Menescal Lizandra Stephanny Fernandes , da Costa Torres Júlia , Pinheiro Suzana Kanawati , Kerr Herllon Karllos Athaydes , Ogusku Mauricio Morishi , de Souza Mara Lúcia Gomes , de Moura Neto Jose Pereira , Sadahiro Aya , Ramasawmy Rajendranath
Published: November 2024

Leishmaniasis, a disease caused by protozoan Leishmania spp., exhibits a broad range of clinical manifestations. Host resistance or susceptibility to infections is often influenced by the genetic make-up associated with natural immunity. Caspase-1, a key component of the NLRP3 inflammasome, is critical for processing pro-IL-1β into its active form, IL-1β, while CARD8 functions as an NLRP3 inflammasome inhibitor. We conducted a case–control study comparing L. guyanensis-cutaneous leishmaniasis (Lg-CL) patients with healthy individuals (HCs) by analyzing the CASP1 genetic variants rs530537A>G, rs531542C>T, rs531604A>T and rs560880G>T. Additionally, a combined analysis of CARD8rs2043211A>T with CASP1rs530537 was performed. The genotype distribution for the four variants showed no significant differences between Lg-CL patients and HCs. However, the haplotype analysis of the four CASP1 variants identified the GTTT haplotype as associated with a 19% decreased likelihood of Lg-CL development, suggesting a protective effect against disease progression. The combined analysis of CARD8 with CASP1 variants indicated that individuals homozygous for both variants (GG/TT) exhibited a 38% reduced risk of developing Lg-CL (OR = 0.62 [95%CI:0.46–0.83]) in comparison to individuals with other genotype combinations. No correlation was found between the CASP1 variant genotypes and plasma IL-1β levels. CASP1 may act as a genetic modifier in Lg-CL.
ICOSLG Is Associated with Anti-PD-1 and Concomitant Antihistamine Treatment Response in Advanced Melanoma
Authors: Mallardo Domenico , Fordellone Mario , Ottaviano Margaret , Marano Giuseppina , Vitale Maria Grazia , Mallardo Mario , Capasso Mariagrazia , De Cristofaro Teresa , Capone Mariaelena , Meinardi Teresa , Paone Miriam , Sabatelli Patrizia , De Filippi Rosaria , Cesano Alessandra , Cavalcanti Ernesta , Caracò Corrado , Warren Sarah , Budillon Alfredo , Simeone Ester , Ascierto Paolo Antonio
Published: November 2024

We previously demonstrated that patients with metastatic unresectable stage IIIb–IV melanoma receiving cetirizine (a second-generation H1 antagonist antihistamine) premedication with immunotherapy had better outcomes than those not receiving cetirizine. In this retrospective study, we searched for a gene signature potentially predictive of the response to the addition of cetirizine to checkpoint inhibition (nivolumab or pembrolizumab with or without previous ipilimumab). Transcriptomic analysis showed that inducible T cell costimulator ligand (ICOSLG) expression directly correlated with the disease control rate (DCR) when detected with a loading value > 0.3. A multivariable logistic regression model showed a positive association between the DCR and ICOSLG expression for progression-free survival and overall survival. ICOSLG expression was associated with CD64, a specific marker of M1 macrophages, at baseline in the patient samples who received cetirizine concomitantly with checkpoint inhibitors, but this association was not present in subjects who had not received cetirizine. In conclusion, our results show that the clinical advantage of concomitant treatment with cetirizine during checkpoint inhibition in patients with malignant melanoma is associated with high ICOSLG expression, which could predict the response to immune checkpoint inhibitor blockade.