Role In Modulation Research Articles

A Computational Approach to Characterize the Protein S-Mer Tyrosine Kinase (PROS1-MERTK) Protein-Protein Interaction Dynamics

AbstractProtein S (PROS1) has recently been identified as a ligand for the TAM receptor MERTK, influencing immune response and cell survival. The PROS1–MERTK interaction plays a role in cancer progression, promoting immune evasion and metastasis in multiple cancers by fostering a tumor-supportive microenvironment. Despite its importance, limited structural insights into this interaction underscore the need for computational studies to explore their binding dynamics, potentially guiding targeted therapies. In this study, we investigated the PROS1–MERTK interaction using advanced computational analyses to support immunotherapy research. High-resolution structural models from ColabFold, an AlphaFold2 adaptation, provided a baseline structure, allowing us to examine the PROS1–MERTK interface with ChimeraX and map residue interactions through Van der Waals criteria. Molecular dynamics (MD) simulations were conducted in GROMACS over 100 ns to assess stability and conformational changes using RMSD, RMSF, and radius of gyration (Rg). The PROS1–MERTK interface was predicted to contain a heterogeneous mix of amino acid contacts, with lysine and leucine as frequent participants. MD simulations demonstrated prominent early structural shifts, stabilizing after approximately 50 ns with small conformational shifts occurring as the simulation completed. In addition, there are various regions in each protein that are predicted to have greater conformational fluctuations as compared to others, which may represent attractive areas to target to halt the progression of the interaction. These insights deepen our understanding of the PROS1–MERTK interaction role in immune modulation and tumor progression, unveiling potential targets for cancer immunotherapy.

Anti-diabetic effects of marine natural products through redox modulation via Nrf2/HO-1 cytoprotective pathways

Diabetes mellitus (DM), a major global health concern, is a chronic metabolic disorder. Bioactive compounds sourced from numerous marine natural products recently have drawn attention as novel therapeutic approaches. Considering these chemicals and their role in cellular redox modulation by involving the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway, the current study attempts to highlight their anti-diabetic effects and the molecular mechanisms involved. Reactive oxygen species (ROS)-mediated oxidative stress, inflammation, and cellular damage are linked to most human pathologies specifically DM. The Nrf2/HO-1 pathway is a key defense mechanism developed by the cells to combat ROS burst. Marine natural compounds have strong pharmacological potential in triggering cellular antioxidant defense mechanisms by declining oxidative damage and inflammation linked to DM. How marine natural products potentially alleviate DM specifically type 2 diabetes (T2D) and its related issues is especially focused on. The literature was thoroughly analyzed to open a discussion about specific marine compounds and their well-established anti-diabetic effects to elucidate possible therapeutic applications. Furthermore, opportunities and the pros and cons of using these marine bioactive compounds as complementary treatment for DM are also discussed. The diverse characteristics of marine natural products, specifically with regard to redox control, offer promising opportunities for drug discovery and therapeutic interventions in clinical trials.

Electron‐Penetrating in Heterointerface Engineering for Oxygen Evolution Reaction in Seawater Splitting

AbstractThe interfacial electric field (IEF) between heterogeneous units plays an important role in the electronic modulation of active centers during oxygen evolution reaction (OER). However, the weak electronic coupling between spatially separated IEFs limits the deep activation of metal sites on the surface of the catalyst. Herein, a proof‐of‐concept strategy is provided that imbed MS2 (M = Ni3Fe) species with high spin Fe orbits into heterogeneous units to promote the electron penetrating between IEFs. By designing a Fe2O3@MS/MS2@MOy model catalyst, the electronic interaction between adjacent IEFs is effectively enhanced for the deep oxidation of bimetals on the surface, breaking the competing relationship between adsorbed evolution mechanism (AEM) and lattice oxygen mechanism (LOM) of catalysts during OER. As a result, the onset overpotential of the synthesized electrode is only 171 mV, and it maintains excellent stability for more than 2300 h at a current density of 10 mA cm−2 in 1 M KOH + 0.5 M NaCl electrolyte.

Dual-Steric Hindrance Modulation of Interface Electrochemistry for Potassium-Ion Batteries.

Electrolyte chemistry regulation is a feasible and effective approach to achieving a stable electrode-electrolyte interface. How to realize such regulation and establish the relationship between the liquid-phase electrolyte environment and solid-phase electrode remains a significant challenge, especially in solid electrolyte interphase (SEI) for metal-ion batteries. In this work, solvent/anion steric hindrance is regarded as an essential factor in exploring the electrolyte chemistry regulation on forming ether-based K+-dominated SEI interface through the cross-combination strategy. Theoretical calculation and experimental evidence have successfully indicated a general principle that the combination of increasing solvent steric hindrance with decreasing anion steric hindrance indeed prompts the construction of an ideal anion-rich sheath solvation structure and guarantees the cycling stability of antimony-based alloy electrode (Sb@3DC, Sb nanoparticles anchored in three-dimensional carbon). These confirm the critical role of electrolyte modulation based on molecular design in the formation of stable solid-liquid interfaces, particularly in electrochemical energy storage systems.

Immune System Modulation by Extracellular Vesicles: Implications for Disease Treatment

Extracellular vesicles (EVs), including exosomes and microvesicles, have emerged as crucial mediators of intercellular communication, playing a significant role in immune system modulation. These nanosized vesicles transfer bioactive molecules such as proteins, lipids, and nucleic acids, influencing immune responses and contributing to various disease processes, including cancer, autoimmune disorders, and infections. The dual functionality of EVs capable of either activating or suppressing immune responses depending on their origin and cargo highlights their therapeutic potential. This review explores the mechanisms through which EVs modulate immune functions, their implications in disease pathogenesis, and their innovative applications in therapeutic strategies. In oncology, tumor-derived EVs can promote immune evasion, while engineered EVs show promise as vehicles for targeted drug delivery and cancer immunotherapy. In autoimmune diseases, EVs can either exacerbate inflammation or facilitate tolerance, offering new avenues for treatment. Furthermore, EVs hold potential as biomarkers for disease diagnosis and monitoring due to their stability in bodily fluids and ability to reflect cellular states. However, challenges remain in standardizing EV isolation, characterization, and clinical application. Future advancements in bioengineering, along with improved understanding of EV biology, are crucial for harnessing their therapeutic potential. This review emphasizes the importance of EVs in immune modulation and their promising implications for innovative disease treatment strategies. Keywords: Extracellular vesicles, immune modulation, cancer therapy, autoimmune diseases, biomarkers

Prolactin Role in COVID-19 and Its Association with the Underlying Inflammatory Response

The COVID-19 pandemic has prompted interest in identifying reliable biomarkers to predict disease severity and guide clinical decisions. Prolactin (PRL), a hormone traditionally associated with lactation, has gained attention for its role in immune modulation. This study aimed to assess PRL as a biomarker for disease severity in COVID-19. A prospective cohort of 142 patients with moderate to severe COVID-19, defined as a WHO-CPS 5 or 6, was recruited from the University General Hospital of Patras. Baseline PRL levels were measured using an electrochemiluminescence immunoassay, and serum cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-12p70, and TNF-α, were quantified through flow cytometry. Clinical outcomes, including mortality and the need for invasive mechanical ventilation (IMV), were recorded. Results indicated that PRL levels were significantly higher in female patients (12.95 ng/mL vs. 9.40 ng/mL, p < 0.001) but they did not correlate with key severity indices such as CCI, SOFA score upon admission or inflammatory markers. No significant associations between baseline PRL levels, cytokine concentrations, and clinical outcomes in COVID-19 were noted. Our findings suggest that PRL may lack prognostic reliability for disease severity compared to more established predictive markers and that its role in the immune response remains uncertain.

Effect of Melatonin on the Production Performance, Blood Biochemical Parameters, Nutrient Digestibility, and Gastrointestinal Microbiome of Liaoning Cashmere Goats

Melatonin’s capacity to improve cashmere production and quality in goats is well established, but its underlying mechanisms, particularly those concerning the gastrointestinal microbiome, remain inadequately understood. This study aims to elucidate the effects of melatonin implantation on the production performance, blood biochemical parameters, nutrient digestibility, and gastrointestinal microbiome of Liaoning cashmere goats. Thirty newborn Liaoning cashmere goat lambs were selected and randomly assigned to control and melatonin groups using a paired test design. The melatonin group received three melatonin implantations at 15, 75, and 135 days of age, respectively, with a dosage of 2 mg/kg body weight, while the control group received no treatment. Digestive metabolism tests were conducted at 150 and 300 days of age; prior to these tests, blood, rumen fluid, and rectal feces were collected. Apparent nutrient digestibility and blood biochemical indexes were determined, and rumen fluid and rectal feces were analyzed using microbial 16S rRNA sequencing. The results indicated that melatonin significantly reduced daily weight gain and body weight at 60 days (p < 0.05) while significantly increasing daily weight gain at 300 days (p < 0.05). Additionally, it significantly increased cashmere length and reduced its fineness (p < 0.05). Melatonin significantly enhanced nitrogen deposition (p < 0.05), elevated plasma levels of T-AOC, CAT, GSH-PX, and BUN (p < 0.05), and reduced plasma levels of MDA, GOT, GPT, and AKP (p < 0.05). Moreover, melatonin significantly elevated the microbial Ace and Chao1 indices in rectal feces (p < 0.05), increasing genera beneficial for feed digestion and absorption, including Prevotella, Lachnospiraceae, Ruminococcus, and Synergistaceae (p < 0.05); the abundance of these beneficial genera were positively correlated with improved cashmere production performance, antioxidant activity, and liver and kidney function. In conclusion, melatonin enhances cashmere production by modulating gastrointestinal microbiota, antioxidant activity, liver and kidney function, and nitrogen metabolism in cashmere goats. This study provides a theoretical foundation for melatonin’s role in microbiota modulation, which is essential for promoting high-quality and sustainable development in the cashmere goat industry.

Enhancing Security in Low-power Wide-area (LPWA) IoT Environments: The Role of HSM, Tamper-proof Technology, and Quantum Cryptography

Low-power wide-area (LPWA) networks are integral to expanding Internet of Things (IoT) applications, offering extensive coverage with low power consumption. However, these networks face significant security challenges due to their widespread deployment and inherent constraints. In order to provide secure services in an LPWA IoT environment, important information stored in IoT devices (encryption keys, device unique numbers, etc.) must be safely protected from external hacking or theft by physical access, and it is necessary to develop tamper-proof technology to enhance physical security. Meanwhile, with so many ruggedized IoT devices processing and transmitting sensitive information, security systems are essential to protect the integrity and privacy of IoT data. This paper explores the critical role of hardware security modules (HSMs), tamper-proof technology, and quantum cryptography in enhancing the physical, network, and data security of LPWA IoT environments. We propose operational strategies for HSMs, tamper-proof technology in ruggedized LPWA IoT settings, and a quantum key distribution (QKD)-based IPsec solution for robust network and data security.

Flavonoids from Rhododendron nivale Hook. f ameliorate alcohol-associated liver disease via activating the PPARα signaling pathway

Background: Flavonoids are increasingly recognized for their potent antioxidant properties and potential therapeutic roles in the management of alcohol-associated liver disease (ALD). Extracts derived from Rhododendron nivale Hook. f. (FRN) have been shown to influence glutathione metabolism in aging animal models, exhibiting notable antioxidant effects. However, the specific impact of FRN on ALD remains insufficiently explored. Hypothesis/PurposeThis study seeks to elucidate the efficacy of FRN in alleviating the pathology associated with ALD, delving into the underlying molecular mechanisms that facilitate its protective effects. Study Design: We employed network pharmacology to predict the functional roles and pathway enrichments associated with FRN targets. Both a murine model of ALD and in vitro cellular models were utilized to clarify the mechanistic basis by which FRN mitigates ALD. Methods: FRN was extracted and characterized according to well-established methodologies outlined in our previous studies. Potential functions and pathways implicated by FRN were predicted through network pharmacology analyses. A combination of liver transcriptomics, targeted lipidomics, molecular biology techniques, and antagonists of relevant targets were employed to investigate the mechanisms through which FRN exerts its protective effects in ALD. Results: Network pharmacology identified multiple target genes modulated by FRN, particularly those within critical ALD-related signaling pathways, such as PPARα signaling and fatty acids (FAs) degradation. Notably, treatment with FRN in the ALD murine model led to a significant attenuation of hepatic lipid accumulation and a restoration of serum AST and ALT to baseline ranges. Subsequent validation through liver transcriptomics and molecular biology techniques revealed an upregulation of PPARα expression concomitant with a downregulation of ACSL1 in FRN-treated ALD mice. Targeted lipidomic and bioinformatic analyses from cellular assays demonstrated that FRN substantially reduced the accumulation of long-chain fatty acids in hepatocytes. Importantly, the reversal of FRN's protective effects on lipid accumulation through the PPARα antagonist GW6471 provides compelling evidence for the critical role of PPARα signaling modulation in mediating the beneficial impact of FRN on ALD. Conclusion: Our research highlights FRN's capacity to alleviate ALD through PPARα pathway activation, paving the way for innovative treatment strategies. This underscores the significance of natural compounds in pharmacotherapy, suggesting that FRN may provide an effective alternative for managing ALD.

Fingolimod, a sphingosine-1-phosphate receptor modulator, prevents neonatal bronchopulmonary dysplasia and subsequent airway remodeling in a murine model.

Neonatal bronchopulmonary dysplasia (BPD) is associated with alveolar simplification and airway remodeling. Airway remodeling leads to deformation of airways characterized by peribronchial collagen deposition and hypertrophy of airway smooth muscle, which contribute to the narrowing of airways. Poorly developed lungs contribute to reduced lung function that deteriorates with the passage of time. We have earlier shown that sphingosine kinase 1 (SPHK 1)/sphingosine-1-phosphate (S1P)/S1P receptor1 (S1PR1) signaling plays a role in the pathogenesis of BPD. In this study, we investigated the role of fingolimod or FTY720, a known S1PR1 modulator approved for the treatment of multiple sclerosis in the treatment of BPD. Fingolimod promotes the degradation of S1PR1 by preventing its recycling, thus serving as the equivalent of an inhibitor. Exposure of neonatal mice to hyperoxia enhanced the expression of S1PR1 in both airways and alveoli as compared with normoxia. This increased expression of S1PR1 in the airways persisted into adulthood, accompanied by airway remodeling and airway hyperreactivity (AHR) after neonatal hyperoxia. Intranasal fingolimod at a much lower dose compared with the intraperitoneal route of administration during neonatal hyperoxia improved alveolarization in neonates and reduced airway remodeling and AHR in adult mice associated with improved lung function. The intranasal route was not associated with the lymphopenia seen with the intraperitoneal route of administration of the drug. An increase in S1PR1 expression in the airways was associated with an increase in the expression of enzyme lysyl oxidase (LOX) in the airways following hyperoxia, which was suppressed by fingolimod. This association warrants further investigation.NEW & NOTEWORTHY The role of the S1P receptor1 modulator, fingolimod, as an FDA-approved drug in preventing the recurrence of multiple sclerosis is established. Fingolimod prevented bronchopulmonary dysplasia (BPD) and its sequela of airway remodeling in a neonatal murine model. This protection was associated with the downregulation of lysyl oxidase signaling pathway. Fingolimod could be repurposed for the therapy of BPD.

Exploration of New Drug Candidate Derived from Antioxidants of Korean Native Halophytes: Control of Acinetobacter baumannii with Antipathogenic Activity

The rise of antibiotic-resistant bacteria poses a significant challenge to the treatment of bacterial infections, necessitating the development of novel antibiotics or strategies to preserve the efficacy of existing ones. This study investigates the role of oxidative stress modulation in the pathogenicity of multidrug-resistant (MDR) bacterial strains, aiming to identify potential avenues for new drug design. Specifically, the anti-biofilm effects of crude extracts and fractions from seven halophyte species native to Jeju Island, South Korea, were evaluated against Acinetobacter baumannii ATCC 17978. Notably, the 85% aqueous methanol fraction of Peucedanum japonicum Thunb. (Pj) and the n-hexane fraction of Lysimachia mauritiana Lam. (Lm) demonstrated significant anti-biofilm activity. Further assessments revealed that these fractions also exhibited notable antioxidant and anti-inflammatory properties, with the Pj fraction showing a lifespan extension effect in the Caenorhabditis elegans model. These findings suggest that Pj and Lm hold promise as potential candidates for the development of new therapeutic agents targeting MDR bacteria.

Development of a PD-L1 Overexpression System in HEK293T Cells: A Platform for Studying Immune Evasion Mechanisms

Programmed death-ligand 1 (PD-L1) is a key immune checkpoint protein that facilitates tumor immune evasion by interacting with PD-1 receptors on T cells, making the PD-1/PD-L1 axis a critical target in cancer immunotherapy. However, resistance to these therapies remains a challenge, necessitating further exploration of PD-L1’s functions and regulatory mechanisms. In this study, we amplified the PD-L1 coding sequence (CDS) from human cDNA, cloned it into a pcDNA3.1 vector, and transfected it into HEK293T cells to establish a robust in vitro PD-L1 overexpression system. Quantitative RT-qPCR demonstrated a 300-400 fold increase in PD-L1 mRNA expression compared to controls. These results confirm the successful construction of the PD-L1 overexpression plasmid and validate its application as a tool for studying PD-L1’s role in immune modulation and its potential implications in overcoming resistance to immunotherapy. This system provides a valuable platform for future investigations into PD-L1-mediated mechanisms of immune evasion and cancer progression.

Evaluation of a probiotic blend on psychosocial health and biomarkers of inflammatory, immune and stress response in adults with subthreshold depression: a double-blind, randomised, placebo-controlled trial.

This study examined the efficacy of a probiotic in reducing depressive symptom severity in people with subthreshold depression. In a double-blind, randomised, placebo-controlled trial, a probiotic (1 × 10^9 live cells per strain: Limosilactobacillus fermentum LF16 (DSM26956), Lacticaseibacillus rhamnosus LR06 (DSM21981), Lactiplantibacillus plantarum LP01 (LMG P-21021) and Bifidobacterium longum 04 (DSM23233)) or placebo was taken daily for 12 weeks. Data were collected at baseline, 6 and 12 weeks including psychological symptom severity (Beck Depression Inventory, BDI; Patient Health Questionnaire, PHQ; Hospital Anxiety Depression Scale, HADS; and Depression Anxiety and Stress Scale, DASS). Biomarkers of glycaemia, inflammation (high-sensitivity C-reactive protein, hs-CRP), antioxidant status (total glutathione (GSH)) and stress (cortisol awakening response, CAR) were also measured. Thirty-nine participants (nineteen probiotic;twenty placebo) were enrolled. There were no significant between-group differences in the examined psychological symptom severity scores, despite certain significant within-group changes observed in both groups from baseline to 6 and/or 12 weeks of follow-up. Regarding biomarkers, the probiotic group showed reduced hs-CRP (-1520; 95 % CI -273·7, -2766·2 ng/dl) and CAR (-0·28; 95 % CI -0·05, -0·51 μg/dl) at 12 weeks, but increased total GSH (3·9; 95 % CI 0·1, 7·5 ng/dl) at 6 weeks, compared with the placebo. The current study reported favourable decreases in depressive symptoms in both groups. Although the within-group changes observed in the probiotic group were supported by favourable inflammatory, antioxidant status and stress biomarker changes compared with the placebo, further research is required to shed more light on the role of gut microbiota modulation on emotional regulation.

Anti-fibrotic effects of the sirt6-activator mdl-800 in cardiac stromal cells

Abstract Background Epigenetic changes are among the molecular substrates of cellular stress responses and tissue remodeling in heart failure progression. The sirtuin family of NAD+-dependent histone and non-histone protein deacetylases exert a protective anti-fibrotic role by negatively modulating the inflammatory response and by positive regulation of autophagy-related genes. Sirtuin6 (SIRT6) stands out as a key cardiac protector that can mitigate aging-induced cardiomyocyte senescence and cardiac hypertrophy. Cardiac stromal cells (CSCs) play a pivotal role in fibrosis and remodeling, regulating the composition and stiffness of the extracellular matrix (ECM). Autophagy enhancement has anti-fibrotic effects in CSCs, but the specific role of SIRT6 modulation in CSCs remains unexplored. Purpose To investigate the biological effects of MDL-800, a synthetic allosteric SIRT6 activator, on the stress response and fibrotic activation of CSCs. Methods CSCs were isolated from 4-week-old C57Bl6J mice by explant culture and stimulated with 10ng/ml of TGF-beta1 (TGFb1) up to 72h to induce fibrotic activation. CSCs were treated with MDL-800 up to 10µM and up to 72h, analyzed for cell viability, gene and protein expression levels. Results TGFb1 treatment led to a 0.64-fold reduction in SIRT6 gene expression after 24h. The MTS assay was used to assess a viability dose-response to MDL-800 up to 72h of treatment. The non-toxic concentrations of 2.5µM and 5µM were selected for further experiments (2.5µM vs CTR 0.97-fold and 5µM vs CTR 0.92-fold, normalized OD vs t0). Co-treatment of 5µM MDL-800 with TGFb1 for 72h resulted in a dose-dependent decrease in the expression of TGFb1-induced fibroblast activation markers, as confirmed by immunofluorescence staining for aSMA (TGFb1 vs CTR 2.21-fold, p<0.05; 5µM vs TGFb1 0.46-fold, p<0.05, N=4; mean fluorescence intensity). The anti-fibrotic effect mediated by MDL-800 was further validated by real-time PCR indicating a reduction in the mRNA expression of multiple fibrotic markers, including ACTA2 (TGFb1 vs CTR 1.67-fold, 5µM vs TGFB 0.29-fold; N=2), COL1a1 (TGFb1 vs CTR 1.32-fold, 5µM vs TGFb1 0.87-fold; N=2) COL3a1 (TGFb1 vs CTR 1.06-fold, 5µM vs TGFb1 0.43-fold; N=2) and POSTN (TGFb1 vs CTR 6.37-fold, 5µM vs TGFb1 0.23-fold; N=2). Treatment with 5µM MDL-800 demonstrated an increase in SIRT6 gene expression, suggesting a transcriptional modulation (TGFb1 vs CTR 0.95-fold, 5µM vs TGFb1 1.68-fold; N=2). Western Blot analyses showed an increase in protein levels of the autophagosome marker LC3-II following treatment with 5µM MDL-800 (TGFb1 vs CTR 0.95-fold; 5µM vs TGFb1 3.01-fold), suggesting that autophagy enhancement may be a potential mechanism for the observed anti-fibrotic effects. Conclusion MDL-800 treatment in CSCs is associated with a dose-dependent reduction of TGFb1-induced fibrotic markers and to increased levels of the autophagy marker, suggesting its potential use as an anti-fibrotic molecule for the heart.

Single-cell omics and machine learning integration to develop a polyamine metabolism-based risk score model in breast cancer patients

BackgroundBreast cancer remains the leading malignant neoplasm among women globally, posing significant challenges in terms of treatment and prognostic evaluation. The metabolic pathway of polyamines is crucial in breast cancer progression, with a strong association to the increased capabilities of tumor cells for proliferation, invasion, and metastasis.MethodsWe used a multi-omics approach combining bulk RNA sequencing and single-cell RNA sequencing (scRNA-seq) to study polyamine metabolism. Data from The Cancer Genome Atlas, Gene Expression Omnibus, and Genotype-Tissue Expression identified 286 differentially expressed genes linked to polyamine pathways in breast cancer. These genes were analyzed using univariate COX and machine learning algorithms to develop a prognostic scoring algorithm. Single-cell RNA sequencing validated the model by examining gene expression heterogeneity at the cellular level.ResultsOur single-cell analyses revealed distinct subpopulations with different expressions of genes related to polyamine metabolism, highlighting the heterogeneity of the tumor microenvironment. The SuperPC model (a constructed risk score) demonstrated high accuracy when predicting patient outcomes. The immune profiling and functional enrichment analyses revealed that the genes identified play a crucial role in cell cycle control and immune modulation. Single-cell validation confirmed that polyamine metabolism genes were present in specific cell clusters. This highlights their potential as therapeutic targets.ConclusionsThis study integrates single cell omics with machine-learning to develop a robust scoring model for breast cancer based on polyamine metabolic pathways. Our findings offer new insights into tumor heterogeneity, and a novel framework to personalize prognosis. Single-cell technologies are being used in this context to enhance our understanding of the complex molecular terrain of breast cancer and support more effective clinical management.

Host cytokine genetic polymorphisms in a selected population of persons living with hepatitis B virus infection in the central region of Ghana.

Hepatitis B virus (HBV) infection is a public health concern in resource limited settings like Ghana. Over the past decades, it is noted that the natural course of HBV in persons infected are taking a worse turn leading to liver cirrhosis and cancer. The outcome of HBV infection is influenced by viral and host factors including genetics. Cytokine variations affect virus survival and progression and may even influence associated complications. Cytokines such as tumor necrosis factor alpha (TNF-α), interleukins (IL-4, IL-6, IL-8, IL-10, IL-18), interferon gamma (IFN)-γ, and tumor growth factor-beta (TGF-β) have key roles in HBV infection and modulation. In this study, polymorphisms occurring in five cytokines were analysed to understand how they can influence prognosis of HBV infection. The study is a single centre cross-sectional study involving 227 participants made up of HBV infected participants and HBV-negative controls. Recruitment was from March 2021 to April 2022. Blood samples were taken for full blood count, HBV antigen profile, liver function tests, HBV DNA quantification and cytokine genotyping. FIB score was calculated using available tools. Statistical analysis was undertaken with p < 0.05 set as statistically significant. The 20-39-year-old group formed majority of the HBV infected participants with 60% of all participants being classified as healthy HBsAg carriers. IL2 rs1479920 GG carriers ((1258.93; 0.00-5011.87) IU/mL had reduced HBV DNA in comparison to IL2 rs1479920 AA ((5011.87; 2113.49-5956.62) /AG (3548.13; 0.00-6309.57) IU/mL carriers. TNF-α rs1800629 AA carriers (1258.93; 0.00-3981.07) IU/mL had a reduction in HBV DNA levels in comparison to TNF-α rs1800629 GG carriers (1584.89; 0.00-5011.87) IU/mL. The results of univariate (OR = 0.08, 0.00-0.93; p = 0.043) and multivariate (OR = 0.02, 0.00-0.67; p = 0.029) analysis, showed that carrying TNF-α rs1800629 AA genotype reduce susceptibility to high FIB score compared with GG genotypes. In univariate analysis, subjects aged 20-39years (OR = 5.00, 1.13-6.10; p = 0.034) and 40-59years (OR = 41.99, 3.74-47.21; p = 0.0002) were more susceptible to high FIB score compared to subjects aged 1-19years. Being female (OR = 2.42, 1.03-5.71; p = 0.043) in the univariate models showed higher odds of having high levels of HBV DNA in the multivariate model. There was a reduced likelihood of herbal medicine usage influencing HBV DNA levels significantly (OR = 0.29, 0.10-0.86; p = 0.025). In conclusion, variations in IL2 rs1479920 GG and IL2 rs1479921 AA could offer protective effects by reducing HBV DNA. TNF-α rs179924CT may also cause elevation in HBV DNA levels whiles TNF-α -308A/G, showed a potential protective effect on liver scarring in HBV infected participants. It is therefore important to take a further look at such variations for understanding of HBV modulation in the Ghanaian population.

Genomic identification, characterization, and stress-induced expression profiling of glyoxalase and D-lactate dehydrogenase gene families in Capsicum annuum

BackgroundCapsicum annuum, a significant agricultural and nutritional crop, faces production challenges due to its sensitivity to various abiotic stresses. Glyoxalase (GLY) and D-lactate dehydrogenase (D-LDH) enzymes play vital roles in mitigating these stresses by detoxifying the stress-induced cytotoxin, methylglyoxal (MG).MethodsA genome-wide study was conducted to identify and characterize glyoxalase I (GLYI), glyoxalase II (GLYII), unique glyoxalase III or DJ-1 (GLYIII), and D-LDH gene candidates in Capsicum annuum. The identified members were evaluated based on their evolutionary relationships with known orthologues, as well as their gene and protein features. Their expression patterns were examined in various tissues, developmental stages, and in response to abiotic stress conditions using RNA-seq data and qRT-PCR.ResultsA total of 19 GLYI, 9 GLYII, 3 DJ-1, and 11 D-LDH members were identified, each featuring characteristic domains: glyoxalase, metallo-β-lactamase, DJ-1_PfpI, and FAD_binding_4, respectively. Phylogenetic analysis revealed distinct clades depending on functional diversification. Expression profiling demonstrated significant variability under stress conditions, underscoring their potential roles in stress modulation. Notably, gene-specific responses were observed with CaGLYI-2, CaGLYI-7, CaGLYII-6, CaDJ-1 A, and CaDLDH-1 showed upregulation under salinity, drought, oxidative, heat, and cold stresses, while downregulation were shown for CaGLYI-3, CaGLYII-1, CaDJ-1B, and CaDJ-1 C. Remarkably, CaGLYI-1 presented a unique expression pattern, upregulated against drought and salinity but downregulated under oxidative, heat, and cold stress.ConclusionThe identified GLY and D-LDH gene families in Capsicum annuum exhibited differential expression patterns under different abiotic stresses. Specifically, CaGLYI-2, CaGLYI-7, CaGLYII-6, CaDJ-1 A, and CaDLDH-1 were upregulated in response to all five analyzed abiotic stressors, highlighting their critical role in stress modulation amidst climate change. This study enhances our understanding of plant stress physiology and opens new avenues for developing stress-resilient crop varieties, crucial for sustainable agriculture.

Hypoxia-inducible Factor-1α Pathway in Cerebral Ischemia: From Molecular Mechanisms to Therapeutic Targets.

Ischemic injury to the brain can result in a variety of life-threatening conditions, mortality, or varying degrees of disability. Hypoxia-inducible factor 1α (HIF 1α), an oxygen- sensitive transcription factor that controls the adaptive metabolic response to hypoxia, is a critical constituent of cerebral ischemia. It participates in numerous processes, such as metabolism, proliferation, and angiogenesis, and plays a major role in cerebral ischemia. Through the use of a number of different search engines like Scopus, PubMed, Bentham, and Elsevier databases, a literature review was carried out for investigating the pharmacological modulation of HIF-1α pathways for the treatment of cerebral ischemia. Various signalling pathways, such as Mitogen-activated protein kinase (MAPK), Janus kinase/ signal transducers and activators (JAK/STAT), Phosphoinositide-3-kinase (PI3-K), and cAMPresponse element binding protein (CREB) play a vital role in modulation of HIF-1α pathway, which helps in preventing the pathogenesis of cerebral ischemia. The pharmacological modulation of the HIF-1α pathway via various molecular signalling pathways, such as PI3-K, MAPK, CREB, and JAK/STAT activators, offer a promising prospect for future interventions and treatment for cerebral ischemia.

TG-PGAT: An AIS Data-Driven Dynamic Spatiotemporal Prediction Model for Ship Traffic Flow in the Port

Accurate prediction of ship traffic flow is essential for developing intelligent maritime transportation systems. To address the complexity of ship traffic flow data in the port and the challenges of capturing its dynamic spatiotemporal dependencies, a dynamic spatiotemporal model called Temporal convolutional network-bidirectional Gated recurrent unit-Pearson correlation coefficient-Graph Attention Network (TG-PGAT) is proposed for predicting traffic flow in port waters. This model extracts spatial features of traffic flow by combining the adjacency matrix and spatial dynamic coefficient correlation matrix within the Graph Attention Network (GAT) and captures temporal features through the concatenation of the Temporal Convolutional Network (TCN) and Bidirectional Gated Recurrent Unit (BiGRU). The proposed TG-PGAT model demonstrates higher prediction accuracy and stability than other classic traffic flow prediction methods. The experimental results from multiple angles, such as ablation experiments and robustness tests, further validate the critical role and strong noise resistance of different modules in the TG-PGAT model. The experimental results of visualization demonstrate that this model not only exhibits significant predictive advantages in densely trafficked areas of the port but also outperforms other models in surrounding areas with sparse traffic flow data.

Hypoxic glioma-derived exosomal miR-25-3p promotes macrophage M2 polarization by activating the PI3K-AKT-mTOR signaling pathway

BackgroundExosomes (EXO) play crucial roles in intercellular communication and glioma microenvironment modulation. Tumor-associated macrophages are more likely to become M2-like type macrophages in the immunosuppressive microenvironment. Here, we aimed to investigate the effects and molecular mechanisms of hypoxic glioma-derived exosomes mediated M2-like macrophage polarization.MethodsHighly expressed miRNAs in exosomes derived from glioma cells cultured under hypoxia condition compared to normoxic condition were identified through microRNA sequencing. The polarization status of macrophages was determined using qRT-PCR, Western blotting, flow cytometry, and immunohistochemistry. By using RNA-seq, we aimed to identify the downstream target genes regulated by miR-25-3p in macrophages and investigate the mechanistic pathways through which it exerts its effects. The proliferation and migration capabilities of glioma cells were assessed through EdU, Transwell assays, and in vivo experiments.ResultsWe found that miR-25-3p was upregulated in the exosomes derived from hypoxic glioma cells and can be transferred to the macrophage. In macrophages, miR-25-3p downregulates the expression of PHLPP2, thereby activating the PI3K-AKT-mTOR signaling pathway, ultimately leading to macrophage M2 polarization. As part of a feedback loop, M2-polarized macrophages can, in turn, promote malignant glioma progression.ConclusionOur study reveals that miR-25-3p from hypoxic glioma cells is delivered to macrophages via exosomes as a mediator, promoting M2 polarization of macrophages through the miR-25-3p/PHLPP2/PI3K-AKT signaling pathway. This study suggests that targeted interventions to modulate miR-25-3p expression, transmission, or inhibition of PI3K-AKT pathway activation can disrupt the immune-suppressive microenvironment, providing a novel approach for immunotherapy in gliomas.Graphical