Search Results (450)

Background: Migraine is a disabling neurological disorder in which neuropeptides, particularly pituitary adenylate cyclase-activating polypeptide (PACAP), play pathogenic roles. The kynurenine pathway (KP) is increasingly implicated in migraine-related glutamatergic and neuroinflammatory mechanisms. Previously, we showed that the neuroprotective metabolite kynurenic acid attenuates PACAP overexpression following trigeminovascular activation. This study investigated the effects of kynurenine aminotransferase II (KAT-II) inhibition on PACAP expression and KP metabolites during trigeminal sensitization. Methods: Rats received Complete Freund’s Adjuvant (CFA) or saline injection into the right whisker pad. KAT-II inhibitor PF-04859989 (16 and 32 mg/kg) or saline was administered intraperitoneally 72 h later. Blood samples and nucleus trigeminus caudalis (TNC) were collected for PACAP and KP quantification. Results: CFA treatment induced significant PACAP overexpression in the TNC and altered peripheral KP metabolite levels. PF-04859989 further increased PACAP expression, reaching significance at the 16 mg/kg dose, whereas no significant additional effect was observed at 32 mg/kg. In parallel, treatment with PF-04859989 altered peripheral KP metabolite concentrations in the peripheral inflammatory model, predominantly at the lower dose. Conclusions: This study demonstrates that KAT-II inhibition by PF-04859989 modulates PACAP signaling and KP metabolism under trigeminal inflammatory conditions. These findings support KP–PACAP interactions and may identify novel migraine-related therapeutic targets. Full article

Antimicrobial resistance in mycobacteria arises from a complex interplay of intrinsic and acquired mechanisms that collectively limit the efficacy of current therapeutic options. Intrinsic resistance is largely driven by the low permeability of the mycobacterial cell envelope, the activity of efflux pumps, and the presence of drug-modifying enzymes, which together restrict intracellular drug accumulation and contribute to broad baseline tolerance. This review integrates resistance mechanisms of both M. tuberculosis and M. abscessus, two clinically relevant mycobacteria that share core molecular pathways while exhibiting species-specific determinants that complicate treatment. Additional intrinsic factors, including biofilm formation and stress-induced adaptive responses, further enhance persistence and reduce susceptibility to multiple drug classes. Acquired resistance predominantly results from chromosomal mutations affecting drug targets or prodrug activation pathways, such as katG, inhA, rpoB, gyrA, and pncA in Mycobacterium tuberculosis, leading to high rates of multidrug-resistant and extensively drug-resistant disease. In nontuberculous mycobacteria, species-specific determinants—including inducible macrolide resistance mediated by erm(41) in M. abscessus, plasmid-mediated erm (55) variants, rrl and rrs mutations, diverse enzymatic inactivation systems, and regulatory alterations in the MarR family that result in inducible resistance to drugs such as ethionamide —generate highly variable resistance profiles that complicate treatment. Recent advances in molecular diagnostics, including PCR-based assays, whole-genome sequencing, CRISPR-based diagnostic platforms, AI-assisted diagnostics, and emerging multi-omics approaches, have improved the detection of resistance-associated mutations and enhanced understanding of mycobacterial pathophysiology. In parallel, new therapeutic agents and optimized regimens offer promising avenues to overcome resistance, although emerging resistance to novel drugs underscores the need for continued surveillance. This review synthesizes current knowledge on the molecular basis of resistance in M. tuberculosis and NTM, highlighting implications for diagnosis, treatment, and future research. Full article

Here we report the draft genome sequences of three Enterococcus faecalis strains, LAB1, LAB10, and LAB11, isolated from the pond water of a tilapia (Oreochromis niloticus) aquaculture farm at the University Nangui Abrogoua, Abidjan, Ivory Coast. These strains were previously characterised for their probiotic, plant growth-promoting (PGP), and nitrifying properties. All three strains were assigned to sequence type ST19 by multilocus sequence typing (MLST). The draft genomes of LAB1, LAB10, and LAB11 consist of 34, 35, and 34 contigs, totalling 2.94 Mb each (GC content 37.40%). Prokka annotation predicted 2872, 2873, and 2875 protein-coding sequences (CDS) for LAB1, LAB10, and LAB11, respectively. Genomic screening revealed no vancomycin resistance genes; however, tet(M) and lsa(A) resistance determinants were identified in all three strains, located on a repUS43-type plasmid replicon. Fourteen virulence factor homologs conserved in the E. faecalis reference strain V583 were detected, including Ebp pili, gelatinase (gelE), Fsr quorum-sensing system, and capsule biosynthesis genes, but no cytolysin operon was identified. Genes associated with stress tolerance (katA, sodA), bile salt hydrolysis (cbh), siderophore transport (fepC, fhuD), and ethanolamine nitrogen metabolism (eutB/eutC) were identified in all three genomes. Pan-genome analysis with the E. faecalis reference strain revealed 551 core gene clusters and 279 gene clusters exclusive to the three aquaculture isolates. Despite their high genomic similarity, we report the three genomes as distinct isolates due to observed differences in their expressed phenotypic properties. These sequences provide a genomic resource supporting the development of multifunctional probiotic consortia for integrated aquaponic systems. Full article

Digital financial inclusion (DFI) has become a central topic in financial inclusion research because digital payments, mobile money, internet banking, and platform-based finance can reduce access barriers and expand formal financial participation. Prior studies have documented the development relevance of financial inclusion and have constructed multidimensional financial inclusion and DFI indices, often using PCA and related composite-indicator methods. A remaining measurement gap concerns the equal observability of different digital-finance architectures within a common cross-country indicator set. This study addresses that gap by analyzing an existing PCA-based DFI score for 40 Organisation of Islamic Cooperation (OIC) countries over 2015–2024 through a channel-observability framework. The objective is to examine whether the observed DFI ranking is captured more directly through mobile-money indicators than through the available infrastructure-based representation of bank-led digital finance. The analysis decomposes the six available indicators into a bank-led visibility proxy, based on internet penetration and ATM density, and a mobile-money visibility proxy, based on mobile agents, mobile accounts, mobile transaction volume, and transaction value relative to GDP. The OIC-wide mean DFI score increased from 11.31 in 2015 to 31.24 in 2024, while dispersion widened and the 2015 and 2024 top-ten country groups had zero overlap. The channel diagnostics show that the highest observed DFI scores are concentrated among countries whose digital-finance activity is directly recorded through mobile-money indicators, whereas several financially advanced economies are visible mainly through the bank-led infrastructure proxy. Zero-coded mobile-money observations are interpreted as indicator-visibility signals for the standalone mobile-money channel and considered separately from broader digital-finance activity. The Random Forest analysis functions as a bounded internal sensitivity audit of the existing six-indicator score and shows that mobile-money transaction variables carry the largest within-score explanatory weight. The theoretical contribution is to frame DFI measurement as an architecture-dependent observability problem rather than only as a weighting problem. The practical implication is that cross-country DFI rankings should be interpreted together with channel diagnostics, especially when bank-led digital services such as mobile banking, card payments, POS transactions, QR payments, and instant-payment systems are outside the balanced indicator set. Full article

Service-Based Architectures (SBAs) in 5G core and cloud-native deployments require differentiated treatment for service classes with heterogeneous latency, reliability, and throughput expectations. Although HTTP/3 over QUIC is an important evolution of the HTTP ecosystem, HTTP/2 remains operationally relevant in SBA environments where TCP/TLS-based infrastructures and 3GPP service-based interfaces continue to rely on HTTP/2 communication. This paper therefore focuses on HTTP/2 priority signaling and the problem of translating application-level Service Level Agreement (SLA) policies into protocol-level priority metadata. To address this problem, the paper presents an SLA-aware priority management system built around the RFC 9218 extensible prioritization scheme, specifically its urgency and incremental parameters. The system integrates three coordinated subsystems: a rule-based Priority Classification Engine (PCE), a feedback-driven Dynamic Priority Mapping Algorithm (DPMA), and a runtime priority-update manager that applies bounded priority adjustments under changing network and load conditions. The revised evaluation reports a 7200-observation baseline campaign covering four operating modes, ten service classes, nine network profiles, and twenty repetitions per service–profile–mode combination, together with a 14,880-observation scalability and overhead campaign across increasing concurrent-stream levels. Compared with the unmanaged HTTP/2 baseline, DPMA reduced mean latency by 24.8%, P95 latency by 35.1%, P99 latency by 38.0%, and SLA violations by 19.9 percentage points. Compared with the legacy RFC 7540 baseline, DPMA reduced mean latency by 39.0%, P95 latency by 49.3%, P99 latency by 49.9%, and SLA violations by 21.1 percentage points. Compared with the static RFC 9218 baseline, DPMA reduced mean latency by 38.7%, P95 latency by 48.1%, P99 latency by 50.6%, and SLA violations by 21.4 percentage points. The scalability analysis shows that DPMA maintained P95 latency between 126.8 ms and 128.2 ms over the tested 1–100 concurrent-stream range, with priority-update decision overhead below 0.004 ms per request. The results indicate that SLA-aware use of RFC 9218 priority metadata can improve latency and SLA-compliance behavior in controlled SBA-like HTTP/2 environments while preserving a transparent and auditable prioritization policy. Full article

Pulmonary arterial hypertension (PAH) is a progressive and life-threatening condition characterized by elevated pulmonary vascular resistance eventually causing right ventricular failure and premature death. Despite advances in targeted therapies, morbidity and mortality levels remain high, highlighting the need for additional treatment strategies that address the disease’s multifactorial pathophysiology. Attention has recently centred on two pharmacological groups with proven roles in other cardiovascular settings: sodium–glucose cotransporter 2 inhibitors (SGLT2i) and mineralocorticoid receptor antagonists (MRAs). SGLT2 inhibitors have demonstrated robust clinical benefits in heart failure (HF), type 2 diabetes mellitus (T2DM), and chronic kidney disease (CKD), extending survival and reducing hospitalizations. Although their primary actions involve renal glucose and sodium handling, accumulating evidence suggests they may also exert favourable effects on the pulmonary vasculature, endothelial function, and right ventricular performance. In parallel, elevated aldosterone levels have been implicated in vascular remodelling, inflammation, and fibrosis in PAH, suggesting a potential therapeutic role for MRAs. However, the strength and clinical significance of these associations remain under investigation. The aim of this review is to synthesize and critically appraise the current evidence regarding the potential role of SGLT2 inhibitors and MRAs in the treatment of pulmonary arterial hypertension, exploring their mechanistic rationale, preclinical findings, and available clinical data to determine whether these agents may offer additional therapeutic benefit in PAH management. Full article

Understory mosses modify near-surface soil conditions, but how elevation regulates their influence on active and mineral-associated soil organic carbon (SOC) remains unclear. We compared independently selected moss-covered and non-moss-covered soils across a 3200–3500 m elevational gradient and integrated soil physicochemical measurements, microbial biomass (MB), dissolved organic matter (DOM), microbial necromass carbon (MNC), particulate organic carbon (POC), mineral-associated organic carbon (MAOC), metagenomic profiling, and piecewise structural equation modeling. Moss-covered soils consistently contained higher SOC and MAOC, but lower DOM, MB, and generally lower POC, than non-moss-covered soils. MNC showed an elevation-dependent reversal, with higher values under moss cover at 3200 m but lower values under moss cover at 3300–3500 m. Elevation was not a significant uniform driver of MB, DOM, MNC, POC, or MAOC; instead, its influence was mainly reflected in interactions with surface cover and in elevation-related changes in moss-layer structure, diversity, and hydrothermal conditions. Core carbon-fixation and degradation functions remained broadly stable, whereas specific functional modules shifted within moss-covered soils: acetate and acetyl-CoA metabolism genes (ackA and abfD) were relatively abundant at 3300–3400 m, while the polysaccharide-reprocessing gene SGA1 and oxidative-transformation gene katG increased toward higher elevations, and pmoC/amoC rebounded at 3500 m. Structural equation models linked the microbial functional gene system more strongly to POC, whereas MNC was positively associated with MAOC, and the direct POC-to-MAOC pathway was not significant. These findings indicate that moss cover is associated with contrasting SOC allocation patterns and stronger microbial necromass–MAOC coupling, while elevation modulates these relationships indirectly through changes in moss communities, soil microenvironment, and microbial functional potential. Full article

Background: Coarctation of the aorta (CoA) is a congenital narrowing of the aortic isthmus near the ductus arteriosus or ligamentum arteriosum. Despite successful anatomical repair, patients remain at risk of recoarctation, arterial hypertension, and diffuse aortopathy, suggesting intrinsic vessel-wall abnormalities beyond localized obstruction. The developmental and molecular basis of these persistent vascular features remains incompletely understood. Methods: Human aortic tissue samples were obtained from 8 male infants with CoA and 6 age- and sex-matched controls aged <1 year. Total RNA was isolated, and gene expression profiling was performed using whole human genome oligo microarrays (Agilent). Differentially expressed transcripts were subjected to pathway, network, and upstream regulator analyses using Ingenuity Pathway Analysis (IPA, Qiagen). Selected candidate genes were evaluated by RT-qPCR in independent verification sets. Results: Transcriptomic profiling identified 402 analysis-ready transcripts distinguishing CoA from control tissue. Exploratory pathway analyses suggested extracellular matrix remodeling characterized by collagen turnover, integrin-mediated cell–matrix interactions, wound-healing signaling, and fibrosis-associated programs. In addition, enrichment analyses identified developmental annotations involving retinoic acid (RA)/RAR/RXR signaling, HOX-associated developmental programs, and a shared HOX/MEIS-associated signature. Network and upstream regulator analyses further suggested associations with cytoskeletal, muscle-associated, and epigenetic regulatory pathways, including KAT6A, KAT6B, retinoic acid/RAR/RXR signaling, DNMT3B, KMT2A, and ARID1A. RT-qPCR independently confirmed increased expression of EDN1, AGTR2, IRS4, and TFAP2B.Conclusions: Infantile CoA tissue exhibited molecular signatures consistent with vessel-wall remodeling accompanied by developmental, vascular signaling, and smooth muscle/cytoskeletal regulatory programs. These findings support the hypothesis that developmental patterning signals and postnatal extracellular matrix remodeling coexist within CoA tissue and may contribute to persistent vascular abnormalities beyond anatomical repair. Given the exploratory nature of the study, these observations should be considered hypothesis-generating and require validation in independent cohorts. Full article

Seaweed-derived biostimulants are increasingly used to improve seed germination and early seedling development in horticultural crops. This study evaluated the effects of five commercially available seaweed extract (SWE) formulations (ASCO, AQUA, KAT, SAGA, and BIO) applied at 2 mL L⁻¹ on germination, seedling growth, biomass accumulation, moisture-related traits, and biomass allocation indices of Capsicum annuum L. under controlled conditions. A 10-day in vitro Petri dish bioassay was conducted using five experimental replicates for each treatment. Significant differences among the treatments were observed for several germination, growth, biomass, and moisture-related parameters. KAT exhibited the highest final germination percentage, whereas SAGA exhibited the fastest germination response and the highest seedling vigor index. SAGA was associated with higher root length and total dry weight, whereas AQUA exhibited among the highest root biomass values. BIO recorded the highest moisture content, leaf length, and shoot-to-root ratio. Correlation analysis identified significant relationships among growth and biomass traits, whereas principal component analysis revealed distinct multivariate response patterns among the evaluated formulations. Overall, the commercial SWE formulations showed different response profiles during the early seedling development of C. annuum under the conditions of present study. Further studies are required to evaluate the consistency of these responses across different concentrations, cultivars, and growing environments. Full article

Many rhizobia use quorum sensing (QS) systems to detect their population density and modify their symbiotic behavior with the legume host. There are three LuxRI-type QS systems in Rhizobium etli CFN42, and CinR plays a key role in symbiotic performance. However, the details of how CinR regulates the symbiotic process remain unknown. In this study, we employed the RNA-Seq method to screen differentially expressed genes between the wild-type strain and the ΔcinR mutant of R. etli CFN42. We found that most of the genes related to reactive oxygen species (ROS) were expressed at lower levels in the ΔcinR mutant than in CFN42. We also found that the ΔcinR mutant was more sensitive to H₂O₂ than to CFN42. We then showed that CinR positively regulated katG expression and possessed an affinity to bind the katG promoter in the absence of the AHL ligand. The addition of AHLs promoted CinR binding to the katG promoter and enhanced katG expression. Accumulation of H₂O₂ and O₂^•− was observed in root nodules formed by the ΔcinR mutant. Crucially, katG overexpression rescued the H₂O₂-sensitive phenotype in vitro and partially restored defective symbiotic performance in nodules formed by the ΔcinR mutant on the common bean. These results suggest that CinR globally regulates ROS scavenging gene expression in order to balance oxidative stress within root nodules, promoting nitrogenase activity of R. etli CFN42. Full article

Introduction: Stenotrophomonas maltophilia (S. maltophilia) has emerged as an important opportunistic pathogen. It is resistant to most available antibiotics due to its intrinsic resistance, leaving only some antibacterial agents as possible therapeutic options, which is further complicated by acquired mechanisms of antimicrobial resistance. This study aimed to provide a comprehensive genomic characterization of clinical S. maltophilia complex (Smc) isolates, focusing on molecular characterization of its resistance and virulence, since studies tackling this are scarce in Oman. Methods: This study is a prospective cross-sectional study, in which a total of 21 clinical isolates of Smc were collected from different clinical samples and further characterized using Whole Genome Sequencing. Results: Besides S. maltophilia, the isolates included S. hibiscicola, S. pavanii, and S. muris for the first time in Oman. All isolates were found to be susceptible to cefiderocol, levofloxacin, and minocycline. Sequence types (STs) were diverse among the isolates, with more than half of the isolates showing new STs with novel alleles. Additionally, blaOXA-2, sul1, and the recently described aac(6′)-Iap and aph(9)-Ic were detected among the isolates. Moreover, virulence-associated genes (smf-1, pilT, pilQ, gpmA, rmlA, spgM, stmPr1, plcN, clpP, and katE) were highly conserved across all isolates. Mobile genetic elements were detected in most of the isolates (76.20%). Conclusions: The collected isolates showed high ST diversity and showed no specific pattern in terms of antibiotic susceptibility and resistance genes. More studies are needed to establish relationships between the different members of the Smc and the different molecular resistome and virulome. Full article

(1) Background and Objectives: Parkinson’s disease’s (PD) underlying pathophysiology still remains incompletely understood, with Braak’s hypothesis of ASyn pathology propagation being the most widely accepted. Recently, a novel model has been introduced, proposing two distinct ASyn propagation pathways: a bottom-up trajectory termed Body-first PD, and a central nervous system (CNS)-initiated pathway termed Brain-first PD. This distinction introduces new perspectives in the PD literature landscape regarding diagnosis, prognostic factors and patient management. This study set out to systematically synthesize the current literature comparing Brain-first and Body-first PD, with a focus on clinical characteristics and disease progression, diagnostic biomarkers, and management approaches. (2) Materials and Methods: A systematic literature search was conducted in March 2025 using PubMed, Cochrane Library, DOAJ and Google Scholar. Human observational, diagnostic, and interventional studies published between 2019 and March 2025, including patients with de novo or early PD, were eligible. Pre-motor REM sleep behavioral disorder (RBD) was used as the primary differentiation criterion. Risk of bias was evaluated using the Joanna Briggs Institute (JBI) critical appraisal checklists. Results were synthesized using a narrative approach. (3) Results: Sixteen studies comprising 2107 PD patients met the inclusion criteria. Body-first PD was associated with a higher non-motor symptom (NMS) burden, faster disease progression, and a higher prevalence of cognitive impairment. Additionally, Body-first PD patients exhibited more widespread and symmetrical neurodegeneration, along with electrophysiological and metabolic differences. Distinct biomarker and microbiome profiles were also observed between subtypes. No eligible studies addressing management approaches were identified. (4) Conclusions: In conclusion, the available evidence suggests that Brain-first and Body-first PD may represent two distinct pathophysiological entities, a proposal with great significance for the diagnosis, prognosis and management of PD patients. However, the predominantly cross-sectional nature of the current literature limits causal inference. Future longitudinal and interventional studies are required to clarify the potential clinical implications of this subtype classification theory. Full article

Background/Objectives: Breast cancer remains a leading cause of cancer-related mortality among women worldwide. This study presents a systematically justified multi-modal breast cancer classification pipeline that combines established, physically motivated preprocessing operations, modality-specific deep learning models, late-fusion inference, and a deployment-aware federated learning evaluation. Rather than introducing new image restoration or federated optimization algorithms, this work formalizes how standard preprocessing methods can be organized according to the dominant degradation characteristics of ultrasound, MRI, and mammography, and evaluates their contribution under centralized and simulated federated learning settings. Methods: Patient-wise stratified five-fold cross-validation was applied across ultrasound (BUSI, $n=780$), dynamic contrast-enhanced MRI (DUKE, $n=922$), and mammography (CBIS-DDSM, $n=400$). A five-algorithm federated learning comparison, including FedAvg, FedProx, SCAFFOLD, FedNova, and FP16-FedAvg, was conducted under IID and non-IID conditions using a Dirichlet distribution with $\alpha =0.5$. The evaluation reports diagnostic performance together with per-round training time, communication time, latency-related measurements, and cumulative bandwidth. Ablation experiments, McNemar’s test, Cohen’s h effect sizes, and confidence intervals were used to support the analysis. Results: Per-modality models achieved 92.50 ± 1.2%, 90.63 ± 1.5%, and 92.00 ± 1.3% accuracy for ultrasound, MRI, and mammography, respectively, with statistically significant improvements over the corresponding baselines according to McNemar’s test ($p<0.05$). Weighted late fusion achieved 93.10 ± 1.1% accuracy and improved performance compared with the best individual modality ($p=0.031$). FP16 transmission reduced cumulative bandwidth from 8.14 GB to 1.23 GB ($-84.9\%$) without a statistically significant performance difference compared with FP32 transmission ($p=0.74$), while SCAFFOLD achieved the highest non-IID accuracy (90.50%). Conclusions: The findings demonstrate internal technical validity and deployment-relevant trade-offs, but they should be interpreted cautiously because the federated evaluation is simulation-based, key-slice extraction may require annotation-assisted assumptions, and external multi-center validation remains necessary before clinical deployment. Reported improvements are statistically significant in several comparisons, but corresponding Cohen’s h effect sizes are small, and clinical meaningfulness requires independent validation rather than inference from p-values alone. Full article

The concepts of anthromes and human appropriation of net primary production (HANPP) are both valuable in understanding our human-dominated planet, yet they have never been integrated theoretically or empirically. Here we utilize an extensive county-level dataset on HANPP and its product-level components to derive, through cluster analysis, ten contemporary US anthromes. From highest to lowest density of harvested HANPP, the anthromes are: rainfed corn–soy, dairy fodder, spring wheat–small grain, dryland winter wheat, subtropical soy–cotton, commercial timber, mixed hardwood and pasture, recovered eastern forest, prairie–sagebrush rangeland, and arid and alpine sparse grazing. Expanding to thirteen anthromes maintains these, while bifurcating the commercial timber (softwood, hardwood), rainfed corn–soy (core, fringe) and mixed hardwood and pasture anthromes. Trend analysis shows the expansion of the high-HANPP rainfed corn–soy and the low-HANPP recovered eastern forest anthromes between 2002 and 2017, while some other anthromes with moderate HANNP_harvest are contracting. The methods described here can be applied to any country where data on HANPP can be obtained. Full article

Cyclin-dependent kinase 1 (CDK1) is frequently upregulated in multiple cancers and plays a central role in cell cycle progression and tumorigenesis. However, whether CDK1 directly regulates the histone acetyltransferase KAT8 (also known as MOF) in non-small cell lung cancer (NSCLC) remains unclear. Here, we identify CDK1 as a kinase that directly interacts with and phosphorylates KAT8 at serine 348 (S348) and threonine 418 (T418). Mechanistically, CDK1-mediated phosphorylation, particularly at S348, enhances the interaction between KAT8 and MSL1, thereby stabilizing the MSL complex and promoting KAT8-dependent acetylation of histone H4 at lysine 16 (H4K16). Functionally, the phosphorylation-deficient mutant KAT8-S348A exhibits impaired MSL complex assembly, reduced H4K16 acetylation, and decreased NSCLC cell proliferation both in vitro and in vivo. Pharmacological inhibition of CDK1 using RO-3306 suppresses KAT8 phosphorylation and H4K16 acetylation, leading to significant tumor growth inhibition. Notably, this effect is partially rescued by re-expression of wild-type KAT8 but not by the S348A mutant, supporting a phosphorylation-dependent mechanism. Collectively, these findings define a CDK1–KAT8 signaling axis that promotes NSCLC proliferation through epigenetic regulation and suggest that targeting CDK1-dependent KAT8 phosphorylation may represent a potential therapeutic strategy for lung cancer. Full article