Search Results (4,376)

Manganese ions (Mn²⁺) are an essential trace element within organisms spanning the entire tree of life. It has reported that Mn²⁺ exerts strong immunocompetence effects and exhibits antiviral effects against various human and animal viruses, including DNA and RNA viruses. Recently, Mn²⁺ has been found to be involved in the activation of the innate immune DNA-sensing cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) pathway and subsequent antiviral function. However, the antiviral mechanism of Mn²⁺ remains unclear. In the current study, the results suggest that the cGAS-STING pathway is essential for Mn²⁺ to promote interferon (IFN) signaling, but it is not essential for triggering antiviral functions. After knocking out the STING or interferon regulatory factor 3 (IRF3) gene, Mn²⁺ still retains its antiviral activity against herpes simplex virus type 1 (HSV-1) and vesicular stomatitis virus (VSV). Furthermore, the results from transcriptomic analysis indicate that Mn²⁺ can induce a significant change in the apoptotic process in STING⁻/⁻ 3D4/21 cells. Mn²⁺ can induce cell apoptosis through the oxidative stress pathway, and inhibiting the apoptotic signal could suppress Mn²⁺-mediated antiviral activity in STING⁻/⁻ 3D4/21 cells. Additionally, dual knockout of IRF3 and caspase3, resulting in concurrent loss of IFN and apoptotic signals, eliminates the antiviral effects of Mn²⁺. In summary, the current study suggests that Mn²⁺ could exert antiviral effects not only through the cGAS-STING-IFN pathway but also via the reactive oxygen species (ROS)-apoptosis pathway. Full article

Investigation of deposystems, sediment routing, and basin architecture during Gondwana breakup refines understanding of Permian–Cretaceous landscape evolution in the central Andes. New chronostratigraphic and provenance constraints from the Eastern Cordillera and Subandean Zone of Bolivia (19–22°S) are based on U-Pb geochronology of detrital and volcanic zircons and ⁴⁰Ar/³⁹Ar dating of interbedded basalts. A discontinuous <2 km-thick Permian–Cretaceous succession records deposition in fluvial, lacustrine, alluvial fan, eolian, and shallow marine environments. Stratigraphic correlations indicate alternations between isolated half-graben subbasins and regional, non-compartmentalized basins. Detrital zircon age spectra from 18 sandstones document sediment recycling from western orogenic and magmatic arc sources and eastern cratonic basement. Synextensional successions of Early Triassic, Early Jurassic, and mid-Cretaceous age were sourced mainly from the west, including Carboniferous and Devonian rocks, while post-extensional fluvial and eolian systems were derived chiefly from the eastern craton. Variations in thickness, facies, and mafic magmatism reflect alternating extensional and neutral tectonic regimes, with localized synextensional subsidence potentially linked to extensional collapse, mantle plume activity, and South Atlantic opening. Comparison with Andean regions in Peru and Argentina indicates that episodic extension and post-extensional thermal subsidence accompanied subduction along the western margin of South America during Gondwana-Pangea breakup. Full article

The rapid global spread of antimicrobial resistance among pathogenic microorganisms poses a serious challenge to both human and animal health, underscoring the urgent need for new strategies to combat resistance. Antimicrobial peptides (AMPs), key components of the innate immune system, are promising candidates because they disrupt the membranes of bacteria, fungi, and viruses, thereby reducing the risk of resistance development. Lactoferrin (LF), a multifunctional iron-binding glycoprotein abundant in mammalian milk, is a rich source of AMPs. Cationic peptide fragments such as lactoferricin and lactoferrampin exhibit more potent direct antimicrobial activity than the intact protein. Our previous studies have shown that peptides derived from Equine milk lactoferrin exhibit antihypertensive, anti-inflammatory, and anti-oncogenic activity in silico, highlighting their multifunctional bioactive potential. Building on these results, the present study aims to investigate the antimicrobial properties of these peptides. We used an integrated approach combining computer modeling and in vitro studies to identify and validate novel antimicrobial peptides from equine milk lactoferrin. Bioinformatics tools, including AMPScanner and CAMP, were used to predict antimicrobial domains, followed by experimental testing against Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. The results showed that equine milk lactoferrin peptides possess potent and selective antimicrobial activity, with efficacy varying across bacterial species. These data expand the functional profile of lactoferrin-derived peptides, demonstrating their multifunctionality, and suggest that equine milk lactoferrin represents a promising natural source of antimicrobial agents, supporting alternative strategies to reduce antibiotic use in human and veterinary medicine. Full article

This study examines the current account implications of sustainable rural tourism in Türkiye by measuring rural tourism intensity through tourist arrivals in locally embedded and small-scale accommodation structures—including mountain lodges, camping sites, hostels, pensions, motels, village houses, and boutique hotels—collectively referred to as the LESS variable. Using monthly time series data over the period 2000–2025, the trade deficit is modeled as a function of rural accommodation intensity and the real effective exchange rate. The empirical framework employs Johansen cointegration analysis evaluated through the Pantula principle, Vector Error Correction Model-based Granger causality tests, full-sample bootstrap causality tests, and rolling window bootstrap causality analysis to capture time-varying causal dynamics. The findings confirm a long-run cointegration relationship among the variables and reveal that rural tourism intensity exerts a statistically significant causal effect on the trade deficit, with the relationship intensifying during crisis periods such as the 2008 global financial crisis and the COVID-19 shock. Specifically, increases in rural accommodation intensity are found to exert a negative and significant effect on the trade deficit, indicating that locally embedded tourism structures enhance net foreign exchange retention through lower import leakage. These results suggest that tourism structures characterized by stronger local embeddedness and lower import intensity enhance net foreign exchange retention and contribute to external balance stability. Full article

Type 2 diabetes mellitus (T2DM) is frequently complicated by dyslipidemia, which accelerates insulin resistance and the progression of cardiovascular and hepatic diseases. While exercise intervention is a cornerstone of T2DM management, a systems-level understanding of its underlying molecular mechanisms remains incomplete. This article summarizes current evidence to propose that exercise functions as a signaling network regulator, concurrently modulating critical lipid metabolism-related signaling pathways: cyclic adenosine monophosphate (cAMP), phosphatidylinositol 3-kinase–protein kinase B (PI3K–AKT), forkhead box O (FOXO), and mitogen-activated protein kinase (MAPK) signaling pathways. We delineate how dysregulation of these signaling pathways contributes to lipid disorders in T2DM, highlighting their tissue-specific and often bidirectional roles. Subsequently, we detail the molecular adaptations induced by various exercise modalities—from aerobic training to high-intensity intervals—that restore homeostasis of this signaling network. By integrating these findings, we present a novel framework for precision exercise—defined as the tailoring of exercise modality, intensity, and volume based on an individual’s predominant signaling pathway disturbance, assessed via circulating or tissue-specific biomarkers. This framework advocates for future exercise prescriptions to be guided by molecular profiling alongside traditional physiological indicators. This mechanistic insight not only deepens our comprehension of exercise physiology but also paves the way for more effective, personalized strategies to combat T2DM and its metabolic complications. Full article

Background/Objectives: The emergence of antimicrobial-resistant (AMR) pathogens in aquaculture ecosystems poses a significant risk to both food security and human health. Shewanella species are recognized as significant AMR reservoirs, yet their prevalence and resistance mechanisms within a shrimp-related ecosystem remain poorly characterized. This study aimed to perform a genotypic and phenotypic characterization of S. algae VK101, isolated from wild-caught black tiger shrimp (Penaeus monodon) broodstock. Methods: A complete 5.21 Mb genome was generated using a hybrid Illumina and Oxford Nanopore sequencing approach. Antimicrobial susceptibility was evaluated for 21 antibiotics via Minimum Inhibitory Concentration (MIC) testing. Comparative pangenomics and genome-wide association studies (GWAS) across 125 S. algae genomes were conducted to identify novel resistance determinants. Results: MIC analysis revealed that VK101 was resistant to ampicillin (>16 µg/mL) and colistin (8 µg/mL), while showing intermediate susceptibility to imipenem and ciprofloxacin. In silico analysis identified 205 antimicrobial resistance genes (ARGs), including a perfect hit for the fluoroquinolone resistance gene qnrA3. Notably, no mcr genes were detected. Although VK101 exhibited moderate resistance (8 µg/mL), GWAS across the broader S. algae population linked a specific lptA mutation (K140N) to high-level resistance (64 µg/mL). Other GWAS-identified genes (e.g., czcA, ampC, and oprM) likely represent indirect associations driven by genetic linkage or clade-specific markers rather than direct causal factors. Conclusions: These findings highlighted the presence of multidrug-resistant S. algae in wild-caught P. monodon broodstock, reflecting the occurrence of antimicrobial resistance in aquatic environments. Colistin resistance in these isolates was primarily mediated by chromosomal variants rather than mobile mcr elements, indicating the need for integrated genomic surveillance within the aquaculture value chain. Full article

Background/Objectives: The Saker Falcon (Falco cherrug) is an endangered raptor species of ecological and conservation relevance. Despite its status, data regarding its microbiota and the prevalence of antimicrobial resistance (AMR) remain scarce, especially in Eastern Europe. This single-facility study aims to investigate the phenotypic and genotypic AMR profiles of Gram-negative bacteria isolated from captive Saker Falcons in Western Romania. Methods: Freshly voided fecal droppings were collected non-invasively from 40 clinically healthy Saker Falcons. Bacterial identification was performed using selective media and the VITEK^® 2 system. Antimicrobial susceptibility testing (AST) was conducted on a representative subset of 12 isolates. Selected resistance-associated genes were screened by conventional PCR. Results: Escherichia coli was the most prevalent 60% (n = 24/40), followed by Hafnia alvei 10% (n = 4/40) and Pseudomonas spp. 10% (n = 4/40). AST revealed phenotypic resistance among Enterobacteriaceae primarily to ampicillin 20% (n = 2/10), tetracycline 20% (n = 2/10), fluoroquinolones and sulfonamides 10% (n = 1/10), while susceptibility to imipenem 90% (n = 9/10) and gentamicin 90% (n = 9/10) remained high. The targeted resistance-associated genes were detected in selected phenotypically resistant isolates. PCR screening detected blaZ and ampC in 62.5% (n = 5/8) of tested isolates, blaOXA-61 in 37.5% (n = 3/8), blaOXA-51 in 25% (n = 2/8), tetK in 37.5% (n = 3/8), and gyrA in 12.5% (n = 1/8). The isolate used as the negative control, pansusceptible in AST, was confirmed negative for all targeted genes. Conclusions: This single-facility study provides baseline data on AMR traits in Gram-negative bacteria associated with Saker Falcons in Western Romania. Given the limited scale and isolate-based design of the study, the findings should be interpreted cautiously, but they support further investigation of wildlife-associated AMR within a One Health context. Full article

Heterotopic ossification (HO), the pathological formation of mature bone in non-skeletal soft tissues (e.g., muscles, tendons), severely impairs patient mobility and quality of life. Despite decades of research, systematic analysis of signaling networks across HO subtypes (acquired traumatic HO, hereditary Fibrodysplasia Ossificans Progressiva (FOP), Progressive Osseous Heteroplasia (POH)) remains insufficient, and clinical therapies suffer from high recurrence and severe side effects. This review synthesizes recent advances in HO pathogenesis: FOP involves gain-of-function activin A receptor type I (ACVR1) mutations (mostly R206H), disrupting bone morphogenetic protein (BMP)/Activin A signaling; POH arises from paternal guanine nucleotide-binding protein, alpha-stimulating activity polypeptide (GNAS) loss-of-function mutations, derepressing Hedgehog signaling via reduced cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) activity; tHO features trauma-induced inflammation/hypoxia activating BMP/transforming growth factor–beta (TGF-β) pathways. Key signaling crosstalk (e.g., BMP-Yes-associated protein (YAP)-Indian hedgehog (IHH)) is integrated, and novel therapies (ACVR1 inhibitors, Activin A antibodies, retinoic acid receptor gamma (RARγ) agonists, adeno-associated virus (AAV)-mediated ACVR1 silencing) are highlighted, with emphasis on subtype-specific efficacy. A stratified, mechanism-based HO management framework is proposed, aiming to accelerate precision therapy development and advance understanding of aberrant tissue regeneration. Full article

Natural products represent an important reservoir for GPCR ligand discovery. In this study, we established an integrated workflow combining virtual screening, biophysical validation, functional signaling assays, and transcriptomic profiling to identify reticuline, a dopamine-derived intermediate from the genus of Stephania, as a potential agonist of dopamine D5 receptor (D5R). Molecular docking revealed that most dopamine-derived compounds along the BIA synthetic pathway exhibit predicted binding affinities for the D5R that are lower than that of dopamine. As expected, the reticuline–D5R complex has a favorable predicted binding affinity of −7.9 kcal/mol. As for binding validation, direct interaction between reticuline and D5R was experimentally confirmed using cell membrane chromatography (CMC) and bio-layer interferometry (BLI), yielding a dissociation constant of 1.07 μM. cAMP assay demonstrated that reticuline activates D5R-mediated Gs-cAMP increasement in a concentration-responsive manner, which exhibits agonist-like activity with an EC₅₀ value of 0.07 μM. The transcriptomic profiling further revealed that reticuline treatment induces transcriptional reprogramming in D5R-overexpressing cells, with enrichment of pathways related to ribosome biogenesis, mitochondrial oxidative phosphorylation, and neurodegenerative diseases. In summary, this study demonstrates that reticuline acts as a potential D5R agonist and highlights a systematic natural product-GPCR discovery strategy integrating computational prediction, experimental validation, and transcriptome-level mechanistic exploration. Full article

The cyclic AMP receptor protein (CRP) is a highly conserved global transcriptional regulator that integrates carbon metabolism and environmental adaptation in bacteria. However, its systematic role in the regulation of virulence in K. pneumoniae remains poorly understood; In this study, we constructed a crp deletion mutant (Δcrp) and a complemented strain (c-Δcrp) and employed a combination of in vitro virulence assays, in vivo infection models, transcriptomic profiling, and functional metabolic analyses to dissect the CRP-mediated metabolism–virulence regulatory axis; We show that crp deficiency does not significantly alter susceptibility to clinically relevant antibiotics but markedly impairs biofilm formation, motility, and host cell adhesion and invasion. In murine infection models, the Δcrp strain exhibits significantly reduced pulmonary colonization and lethality. Transcriptomic analysis reveals broad downregulation of phosphotransferase system (PTS)-associated genes, including srlA/srlB/srlE, mtlA and malX. Functional assays further demonstrate that crp loss severely compromises growth on multiple host-relevant carbon sources and is accompanied by aberrant accumulation of intracellular ATP and NADH, indicative of disrupted metabolic homeostasis; Collectively, these findings identify crp as an important regulator associated with PTS-mediated carbon metabolic balance, and virulence-related phenotypes in K. pneumoniae. Accordingly, targeting the CRP–PTS axis may offer a theoretical basis for metabolism-oriented anti-virulence interventions against K. pneumoniae by attenuating pathogenicity. Full article

Glucose deprivation is a major metabolic stress that requires coordinated adaptive responses to maintain cellular homeostasis and survival, yet the role of tripartite motif-containing 24 (TRIM24) in this process remains unclear. To address this question, we generated CRISPR-Cas9-mediated TRIM24-knockout MCF-7 and HEK293 cell lines, performed targeted metabolomic profiling and aspartate assays, used 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), aminooxyacetic acid (AOA), aspartate supplementation, and glutamic-oxaloacetic transaminase 2 (GOT2) knockdown to probe AMPK signaling and aspartate metabolism, and examined starvation responses in constitutive Trim24 knockout mice on a C57BL/6 background. Loss of TRIM24 sensitized cells to glucose deprivation. Re-expression of TRIM24 partially restored cell viability under glucose deprivation in both MCF-7 and HEK293 cells. Under glucose-free conditions, TRIM24 deficiency was associated with impaired AMP-activated protein kinase (AMPK) pathway activation, increased intracellular aspartate accumulation, and altered ATP/AMP levels. Pharmacological reactivation of AMPK by AICAR improved the survival of TRIM24-deficient cells under glucose deprivation. Reducing intracellular aspartate by AOA treatment or GOT2 knockdown restored AMPK pathway activation and improved adaptation to glucose deprivation, whereas exogenous aspartate suppressed AMPK signaling and increased ATP/AMP levels. In vivo, starvation of Trim24-deficient mice was associated with reduced AMPK pathway activation and increased aspartate levels. Together, these findings support a model in which TRIM24 contributes to adaptation to glucose deprivation and in which abnormal aspartate accumulation contributes to impaired AMPK pathway activation in TRIM24-deficient cells. Full article

Background/Objectives: Carbohydrate-restricted diets (CHRs) are increasingly employed in the treatment of obesity. We aimed to investigate the effects of a CHR on hepatic lipid anabolism and its association with changes in the proinflammatory environment and insulin signaling. Methods: Forty-eight C57BL/6J female mice were used in this study. We aimed to analyze the impact of a CHR on the hepatic proinflammatory profile and its relationship with changes in insulin signaling and fatty acid anabolism in obese female mice after two months on a high-fat diet. We also examined the impact of a one-month chow diet after CHR. Blood samples were collected, and the liver was processed during all-time study periods for analyses of biochemical, hormonal, and inflammatory markers, as well as possible changes in leptin and insulin signaling pathways. Results: Compared with chow-fed mice, CHR mice showed increased interleukin (IL)-1β and IL-2 levels, as well as leptin-related signaling in the liver. There was also a decrease in the expression of fatty acid synthase and the phosphorylation of ATP-citrate lyase, which was associated with a reduction in the activation of the insulin receptor, Akt, the mammalian target of rapamycin, cAMP-response element-binding protein, and glycogen synthase kinase 3β. The subsequent reintroduction of a chow diet after CHR resulted in lower hepatic free fatty acid and triglyceride levels than in obese mice without previous CH restriction. Conclusions: This study suggests that CHR inhibits de novo hepatic lipogenesis in obese mice by attenuating insulin signaling in a low-grade proinflammatory state. Full article

Purinergic signaling plays a critical role in several inflammatory diseases, including acute lung injury, inflammatory bowel disease, coronary artery diseases, and various cancers. Purine and its derivatives, specifically adenosine and ATP, exhibit a critical regulatory axis that bridges platelet activation, vascular thrombosis, and sterile inflammation. Myocardial infarction (MI) initiates a complex pathophysiological cascade characterized by profound hypoxia, inflammation response, reduced coronary blood flow, and increased oxidative stress, which leads to myocardial cell death and apoptosis. Reperfusion therapy remains a primary strategy for restoring coronary blood flow and maximally limiting infarct size; increased infarct size further exacerbates ischemic injury, making it myocardial ischemic/reperfusion injury (MIRI). In this review, we delineate the mechanistic “triad axis”, comprising adenosine signaling, hypoxia-inducible factor (HIF) stabilization, and reactive oxygen species (ROS) homeostasis; this axis serves as a pivotal determinant of cardiomyocyte death during MIRI. We further examine the cell-specific roles of adenosine signaling in modulating immune cell infiltration and function within the ischemic milieu. Finally, we highlight the emerging role of mitochondrial ROS (mtROS) and HIF-dependent signaling in circadian regulation, suggesting that the chronotherapeutic approaches targeting these pathways may offer transformative opportunities for the treatment of ischemic heart disease (IHD). Full article

Alzheimer’s disease (AD) is characterized by amyloid-β deposition, neuroinflammation, and mitochondrial dysfunction. Phosphodiesterase 4 (PDE4), a key regulator of cyclic nucleotides in neurons, represents a promising therapeutic target for AD. In this study, we performed a PDE4 inhibition-guided screen of an in-house marine natural product library derived from marine fungi, leading to the identification of a sesterterpenoid variecolactone (VLT) as a potent PDE4 inhibitor. VLT exhibited selective PDE4D inhibition (IC₅₀ = 2.302 μM) with minimal activity against other PDE subtypes. Further mechanical investigation revealed that VLT treatment elevated cAMP and p-CREB levels, reduced amyloid-β (Aβ) accumulation, promoted synaptic function, and ameliorated mitochondrial fragmentation, along with mtDNA homeostasis in the AD cell model. Moreover, under conditions of mtDNA depletion or Drp1 overexpression, VLT exerted neuroprotective effects and maintained mtDNA homeostasis via the cAMP-PKA-CREB signaling pathway. These results demonstrate that PDE4 inhibition by VLT represents a promising therapeutic strategy for AD and related neurodegenerative disorders. Full article

Background/Objectives: Infantile cardiomyopathy is a rare but often life-threatening condition in which monogenic causes are particularly relevant, especially when cardiac disease is preceded by hypotonia or multisystem involvement. Among sarcomeric genes, MYL2, encoding the ventricular regulatory myosin light chain, plays a critical role in myocardial contractility. However, biallelic MYL2-associated disease remains exceptionally rare, and its clinical spectrum is not fully defined. This study aims to describe a novel case and further delineate the phenotype of recessive MYL2-related cardiomyopathy. Methods: We report a male infant with congenital hypotonia and delayed motor development who underwent extensive metabolic, neuromuscular, and neuroimaging evaluation. Trio-based whole-exome sequencing was performed to identify a potential genetic etiology, followed by variant interpretation using standard bioinformatic and ACMG/AMP criteria. Results: The patient developed acute decompensated heart failure at approximately 10 months of age, with severe left ventricular systolic dysfunction and multiorgan failure, and died at 12 months despite maximal intensive care support. Whole-exome sequencing identified a homozygous MYL2 c.413T>A (p.Met138Lys) missense variant. The variant is absent or extremely rare in population databases, affects a highly conserved residue, is predicted to be deleterious by multiple in silico tools, and is compatible with autosomal recessive inheritance, with both parents confirmed as heterozygous carriers. In the context of a phenotype consistent with recessive MYL2-associated disease, these findings support a likely pathogenic interpretation. Conclusions: This case expands the allelic and phenotypic spectrum of recessive MYL2-associated cardiomyopathy and highlights the value of early genomic testing in infants with unexplained hypotonia and rapidly progressive cardiac dysfunction. Molecular diagnosis may aid in prognosis, clinical decision-making, and genetic counseling. Full article