The application of synthetic insecticides is the primary means of controlling Aedes mosquitoes in Malaysia, but the efficacy of this method is undermined by the evolution of resistance. Aedes albopictus as one of the dominant and competent arboviral vectors has an elusive insecticide resistance status in different geographical regions of Northern Peninsular Malaysia. This underscores the importance of assessing the diverse types of insecticides used and their association with target-site resistance mechanism in this species, which forms the basis of the present study. WHO bioassays were performed on Ae. albopictus larvae and adults from four localities (Penang and Perlis), towards 0.034 ppm temephos, 0.25% permethrin, 0.03% deltamethrin, 0.25% pirimiphos-methyl, and 0.1% propoxur. The partial voltage-gated sodium channel (vgsc) gene domain (DIIS6, DIIIS6, and DIVS6) of pyrethroid-exposed samples were subsequently genotyped through direct sequencing for single-nucleotide mutations, together with genetic variations and haplotype networks analysis. The predicted protein structures for the mutated regions and their binding affinities to pyrethroids were also evaluated using in silico docking. Varying degrees of resistance were observed in all Penang and Perlis strains to all tested insecticides. Moreover, the detection of the F1534L mutation and newly discovered non-synonymous mutations (A1022S/P, E1041K, P1585R, and F1695L) suggest the progression of resistance alleles dissemination in these strains. The analysis of genetic variations, resistance allele distribution patterns, and haplotype networks showed evidence for multiple origins of these mutations. Data also revealed the discovered mutations affect the affinity of vgsc-binding proteins to pyrethroids. This study highlights the genotype-phenotype associations in Ae. albopictus and their genetic links to pyrethroid resistance, offering insights to strengthen vector control strategies in Malaysia.
Children and adolescents with overweight or obesity commonly exhibit impaired glucose metabolism and insulin resistance, increasing their future metabolic risk. Although combined aerobic and resistance exercise is a promising non-pharmacological strategy for pediatric obesity management, its effects on glucose metabolism and insulin resistance remain inconclusive. This systematic review and meta-analysis evaluated randomized controlled trials of combined aerobic and resistance exercise in children and adolescents aged 18 years or younger with overweight or obesity. PubMed, Cochrane Library, Web of Science, and Embase were searched from inception to March 1, 2026. Risk of bias was assessed using RoB 2, and certainty of evidence using GRADE. Eighteen trials involving 682 participants were included. Compared with control conditions, combined aerobic and resistance exercise significantly reduced fasting plasma glucose and fasting insulin, and may be associated with reductions in HOMA-IR. Subgroup and meta-regression analyses suggested that effects varied by sex, session duration, age, and continent. Evidence certainty was low for fasting plasma glucose and fasting insulin and very low for HOMA-IR. Combined aerobic and resistance exercise may improve glucose metabolism and alleviate insulin resistance in this population, although the findings for HOMA-IR should be interpreted cautiously because of the very low certainty of evidence.
Persons with depression are disproportionately at risk for developing insulin resistance. Replicated evidence indicates that insulin resistance blunts acute antidepressant response; however, some antidepressants exacerbate insulin resistance risk. Herein, we aim to comprehensively evaluate previous literature reporting on the effects of antidepressants on measures of insulin resistance with the view to disaggregate class- and drug-specific effects. A systematic search on PubMed, Ovid and Scopus (inception-July 2025) was conducted, with a manual search of Google Scholar and reference lists. Two reviewers (S.W. and G.H.L.) independently screened studies. Clinical trials investigating FDA-approved antidepressants on a validated measure of insulin resistance were included. Studies were assessed using the National Institute of Health quality assessment tools. Select tricyclic antidepressants (i.e., nortriptyline, amitriptyline, imipramine) were associated with acute and long-term disruptions in insulin sensitivity. SSRIs were not associated with acute alterations in insulin sensitivity. Preliminary evidence suggests agomelatine and bupropion are metabolically neutral and may improve insulin resistance in persons with diabetes mellitus. SNRIs do not adversely affect glucose-insulin signaling in the long-term. There was a paucity of studies reporting the effects of other antidepressant classes and agents. The effect of antidepressants on mechanisms mediating insulin sensitivity is mixed, with a relatively limited body of evidence currently available. While select SSRIs and tricyclic antidepressants may adversely affect glucose-insulin homeostasis, conclusions remain preliminary. The development of novel antidepressants may provide an opportunity to optimize psychiatric and metabolic outcomes. Identifying mechanisms contributing to insulin resistance could inform future discovery and development of antidepressants.
Colorectal cancer (CRC) ranks among the most prevalent malignancies globally, and radiotherapy remains a critical treatment modality. However, its efficacy is frequently compromised by acquired radioresistance. The endoplasmic reticulum chaperone protein BIP plays a pivotal role in regulating radioresistance by coordinating the balance between protective autophagy and apoptosis, though the regulatory roles of circular RNAs (circRNAs) in this process remain poorly understood. Differentially expressed circRAB5A (hsa-circ-0123297) was identified from the GSE186940 dataset. Its expression was validated in radioresistant CRC clinical samples and cell lines. Mechanistic investigations involved ADAR1 binding assays, circRAB5A gain/loss-of-function studies, autophagy-apoptosis profiling, ubiquitination analysis, TRIM21-mediated degradation assays, and in vivo xenograft models. CircRAB5A was significantly downregulated in radioresistant CRC clinical samples and cell lines. This downregulation was driven by ADAR1, which suppressed circRAB5A biogenesis by binding to Alu Jo/Jr elements. Functional assays showed circRAB5A depletion conferred radioresistance in CRC cells by promoting protective autophagy and inhibiting apoptosis. Mechanistically, circRAB5A destabilized BIP by enhancing TRIM21-mediated ubiquitination. The circRAB5A/BIP axis further modulates the autophagy-apoptosis balance through the p-Akt/Beclin1 signaling pathway, thereby influencing radiosensitivity. In vivo xenograft experiments demonstrated that stable knockdown of circRAB5A attenuated the anti-tumor effects of radiation, whereas knockdown of BIP sensitized CRC cells to radiotherapy even at low doses. Collectively, the ADAR1/circRAB5A/BIP molecular circuitry governs CRC radioresistance by regulating the autophagy-apoptosis balance. Our findings highlight that low circRAB5A expression may serve as a potential biomarker for radioresistance, and that targeting this axis, particularly BIP, represents a promising strategy for overcoming radioresistance in CRC.
Antibiotic-resistant bloodstream infections are a major public health concern, particularly in children under five years of age. The objective of this study was to determine the prevalence of bloodstream infections and assess the antimicrobial resistance profiles and their associated factors among febrile children under five years of age in Bahir Dar, northwest Ethiopia. A cross-sectional study was conducted from November to December 2025 among 281 children under five years of age who attended the pediatric clinic of Felege Hiwot Comprehensive Specialized Hospital in Bahir Dar. Sociodemographic and clinical data were collected using a structured questionnaire through face-to-face interviews with the parents or guardians. Approximately 3 mL of venous blood was aseptically collected and cultured using standard microbiological techniques. Bacterial identification was performed based on colony characteristics and biochemical tests. Antimicrobial susceptibility testing was performed using the Kirby-Bauer disk diffusion method. Data were entered into EpiData version 3.1 and analyzed using SPSS version 26. Logistic regression analysis was used to identify factors associated with bloodstream infections, and statistical significance was set at p < 0.05. The prevalence of bloodstream infection was 19.2% (54/281; 95% CI: 14.0%-24.4%). The most common isolate was Klebsiella pneumoniae (31%), followed by Enterobacter cloacae (11%), Escherichia coli (9%), and Acinetobacter baumannii (9) %. Gram-negative bacteria accounted for 80% of the isolates. Antimicrobial susceptibility testing revealed high resistance rates to commonly used antibiotics, particularly ampicillin (87.0%, 40/46), trimethoprim-sulfamethoxazole (86.3%, 44/51), and cefepime 42/54 (77.8). Resistance was also high to ciprofloxacin (68.5%, 37/54), tobramycin (68.6%, 35/51), amoxicillin-clavulanic acid (66.0%, 31/47), gentamicin (63.3%, 31/49), tetracycline (61.1%, 33/54), and chloramphenicol (60.5%, 26/43). In contrast, lower resistance rates were observed for cefotaxime (37.0%, 20/54) and meropenem (20.4%, 11/54). Significant associated factors of blood stream infections included age < 1 year (AOR = 2.11; 95% CI: 1.46-2.86), fever duration > 7 days (AOR = 2.74; 95% CI: 1.22-6.15), partially immunized children (AOR = 3.21; 95% CI: 1.08-9.51; p = 0.036), and non-immunized children (AOR = 9.87; 95% CI: 3.61-26.9; p < 0.001). The prevalence of bloodstream infections among febrile children under five years of age was high. Younger age, fever duration > 7 days, and partially immunization and non-immunization were significant predictors of bloodstream infection. Strengthening antimicrobial stewardship, improving immunization coverage, and enhancing early diagnosis are essential to reduce the burden of bloodstream infections and combat antimicrobial resistance.
MdWRKY61 enhances jasmonic acid signal transduction by inhibiting the expression of MdJAZ1, a negative regulator in the jasmonic acid signaling pathway, thereby increasing apple resistance to Colletotrichum fructicola. Glomerella leaf spot (GLS), a fungal disease caused by Colletotrichum species, poses a significant threat to the global apple industry. The WRKY transcription factor family plays a crucial role in plant defense responses; however, their specific functions and the mechanisms underlying resistance to GLS remain poorly understood. In this study, MdWRKY61 overexpression lines and wild-type (WT) plants were inoculated with Colletotrichum fructicola to assess GLS resistance. At 4 days post-inoculation, overexpression lines exhibited a 45.4% ~ 50.0% lower disease incidence and a 22.0 ~ 29.3 reduction in disease index compared to WT. Physiological assays showed decreased hydrogen peroxide and superoxide anion levels, alongside elevated superoxide dismutase and peroxidase activities in overexpression lines. These findings indicate that overexpression of MdWRKY61 enhances resistance to C. fructicola in apple and alleviates oxidative damage induced by pathogen infection. Hormone analyses revealed that the overexpression of MdWRKY61 enhanced the accumulation of jasmonic acid (JA), and in vitro tests confirmed that JA treatment significantly suppressed C. fructicola mycelial growth. Molecular biological experiments revealed that MdWRKY61 directly binds to the W-box element (TTGACT) in the promoter region of MdJAZ1, a negative regulator in the JA signaling pathway, thereby inhibiting its transcriptional expression. Collectively, these findings suggest that MdWRKY61 enhances JA signal transduction by downregulating MdJAZ1, thereby increasing apple resistance to GLS. These results highlight MdWRKY61 as a promising candidate for genetic engineering to develop novel disease-resistant apple cultivars.
Current adjuvant strategies to combat antimicrobial resistance such as β-lactamase inhibitors and efflux pump blockers prevent antibiotic degradation or export. We introduce a fundamentally different approach: exploiting bacterial nutrient sensing to drive antibiotic influx and overwhelm resistance. Fosfomycin is transported into bacterial cytoplasm via the glucose-6-phosphate (G6P) channel UhpT, which is activated by G6P. We demonstrate that fluorinated glucose-6-phosphate analogues showed superior activation of UhpT, leading to higher fosfomycin influx. In Escherichia coli, 3-fluoro-D-glucopyranosyl-6-phosphate showed 128-fold potentiation of fosfomycin, reversed fosA-mediated fosfomycin resistance, and displayed profound suppression of resistance evolution. In Staphylococcus aureus, 4-fluoro-D-glucopyranosyl-6-phosphate achieved 32-fold potentiation and broke fosB-mediated resistance. Furthermore, co-administration of these analogues improved Galleria mellonella survival (75-80%) versus fosfomycin monotherapy (30-40%). We demonstrate this high potentiation effect is combination of metabolic stability, persistent extracellular presence and favorable binding to the sensor protein. This influx-targeting strategy establishes a new paradigm to revive legacy antibiotics against multidrug-resistant pathogens.
Temozolomide (TMZ) resistance presents a serious challenge in glioma treatment. It has been revealed that high expression of ADP-ribosylation factor-like GTPase 13B (ARL13B) is an important risk factor for glioma patients and is strongly related to RHO GTPase. Here, we presented a unique mechanism by which ARL13B induces TMZ resistance. The TCGA and CGGA datasets were used to conduct survival analysis. Metascape was utilized to perform pathway enrichment analysis. Western blot (WB), nanoparticle tracking analysis (NTA), and liquid chromatography-mass spectrometry (LC-MS) were used to explore the mechanisms of drug vesicular exocytosis that leads to ARL13B-mediated TMZ resistance. WB, qRT-PCR, and ChIP were used to validate the extracellular-regulated kinase (ERK)/P90 transcriptional regulatory signaling pathways. The expression of ARL13B increased ectosome efflux and decreased intracellular drug concentration. Besides, the ERK/P90 pathway could transcriptionally regulate ARL13B with C/EBPβ being one of the transcription factors of ARL13B. Inhibiting the ERK/P90 pathway could enhance the efficacy of TMZ. ARL13B was regulated by the ERK/P90 pathway and might impair the efficacy of TMZ by increasing drug efflux through ectosomes. Therefore, our study provided a novel mechanism of TMZ resistance and identifies a new target for glioma therapy.
Unilateral limb immobilization leads to rapid declines in muscle strength and function. Cross-education has been proposed as a strategy to mitigate disuse-related strength loss, although current evidence remains largely indirect. Although widely studied in the lower limb, evidence specific to the upper limb has not been systematically synthesized. To determine the effects of unilateral resistance training on contralateral strength and muscle thickness in the upper limb and to explore the potential influence of contralateral limb immobilization on the magnitude of cross-education. A systematic review and meta-analysis of randomized controlled trials was conducted. Searches were performed in PubMed, PEDro, Cochrane Library, Web of Science, and Scopus from inception to January 2026. Eligible studies included healthy adults performing unilateral upper-limb resistance training compared with a non-exercise control group. Outcomes were contralateral strength and muscle thickness. Random-effects meta-analyses were performed using standardized mean differences (SMD) with 95% confidence intervals (CI). Risk of bias was assessed using the Cochrane RoB 2 tool and certainty of evidence using GRADE approach. Thirty-one studies involving 1,214 participants were included. Unilateral resistance training produced small but significant improvements in contralateral maximal voluntary isometric contraction (SMD = 0.42; 95% CI 0.12-0.72) and one-repetition maximum strength (SMD = 0.36; 95% CI 0.04-0.69). Subgroup analyses suggested potentially larger effects in studies involving partial or total immobilization of the contralateral limb, although based on few heterogeneous studies. No significant effects were observed for muscle thickness (SMD = 0.14; 95% CI -0.23-0.51). Certainty of evidence ranged from low to very low. Unilateral resistance training elicits small but significant improvements in contralateral upper-limb strength without detectable hypertrophic adaptations. These findings support a predominantly neural mechanism underlying cross-education and suggest potential relevance for strength preservation strategies during periods of upper-limb disuse, although evidence is indirect.
With the global population aged 65 years and older projected to exceed 1.5 billion by 2050, sarcopenia-driven insulin resistance is emerging as an urgent yet still under-recognised contributor to the diabetes burden in older adults, underscoring the timeliness of a focused molecular synthesis of this entity for guiding both diagnostic recognition and therapeutic prioritisation. Molecularly different, age-driven insulin resistance promotes skeletal muscle ageing, mitochondrial bioenergetic collapse, and prolonged neuroendocrine metaflammation in type-4 diabetes (T4DM). In ageing myocytes, poor IRS-1/PI3K/Akt signalling, GLUT4 trafficking anomalies, AMPK suppression, ROS-mediated mtDNA instability, and decreased OXPHOS capacity induce T4DM. Senescent muscle cells generate IL-6, TNF-α, and MCP-1 when p16INK4a/p21 checkpoints activate, forming a self-reinforcing inflammatory cycle. Myostatin overactivation, irisin decrease, and FGF21 imbalance influence glucose homeostasis. Metabolism declines due to hypothalamic insulin resistance, microglial inflammation, gut dysbiosis-driven TLR4/NF-κB signalling, and epigenetic remodelling via miR-29, miR-34a, and l Using precision biomarkers like GDF-15, β2-microglobulin, and p16INK4a with multi-omics phenotyping may change diagnosis. Senolytics, NAD⁺ replenishment, SIRT1 activators, mitophagy inducers, anti-myostatin medicines, and exosome-based therapies shift metabolic care towards senescence. T4DM's molecular architecture and precision geriatric endocrinology translational targets are reviewed here.
Methyl jasmonate (MeJA) plays a key role in enhancing plant resistance to a wide range of diseases. However, the specific defense responses it induced and the underlying molecular mechanisms remain incompletely understood in many plant-pathogen systems. This study aimed to determine whether exogenous MeJA enhances resistance to leaf spot disease caused by Alternaria tenuissima in peony (Paeonia lactiflora) and to elucidate the associated molecular and biochemical mechanisms through integrated transcriptomic and biochemical analyses. Compared with the control (CK), pretreatment with 25-75 µmol L- 1 MeJA significantly reduced disease severity, with 75 µmol L- 1 identified as the optimal concentration. Peony leaves pretreated with this concentration exhibited a stronger hypersensitive response than the CK, with initial differentiation observed at 24 h after inoculation. Transcriptome sequencing analysis identified 1,017 differentially expressed genes between the MeJA-pretreated and CK groups, primarily associated with cell wall organization, phenylpropanoid biosynthesis, terpenoid backbone biosynthesis, and flavonoid biosynthesis pathways. MeJA pretreatment up-regulated the genes involved in phenylpropanoid and lignin biosynthesis, including peroxidase 27 (POD27) and caffeic acid 3-O-methyltransferase (COMT), as well as flavonoid-related genes such as chalcone isomerase (CHI). Genes regulating pectin methylesterification, including pectin methylesterase (PME) and PME inhibitor (PMEI), were also modulated. In addition, transcription factors such as basic leucine zipper (bZIP) and heat shock transcription factor (HSF) were activated. Biochemical analyses confirmed increased levels of major cell wall components (lignin, cellulose, hemicellulose, and pectin) and total flavonoids were significantly higher in MeJA-pretreated plants compared with CK plants. A putative model of MeJA-induced defense responses against A. tenuissima was proposed. Exogenous MeJA pretreatment enhances resistance to leaf spot disease caused by A. tenuissima in peony by promoting cell wall reinforcement and flavonoid accumulation. These findings highlight the potential of MeJA as a strategy for managing leaf spot disease in peony cultivation.
Enzalutamide (ENZA) is a second-generation antiandrogen therapy that provides overall survival (OS) benefit for prostate cancer (PC) patients. However, many patients have baseline or develop resistance to ENZA. Currently, no biomarkers are used in clinical decision making to predict the efficacy of ENZA therapy. We aimed to identify cell-free DNA (cfDNA) biomarkers for metastatic castration-resistant prostate cancer (mCRPC) predictive to ENZA response. Comparative whole-exome and transcriptome sequencing was performed on three ENZA-resistant and parental ENZA-sensitive PC cell line pairs. Bioinformatic analysis identified UCA1, ORM1, and androgen receptor (AR) as candidate markers for serum cfDNA testing. Digital droplet PCR was used to analyze UCA1, ORM1 and AR in cfDNA from serum samples of mCRPC patients who underwent ENZA (n = 20), abiraterone (ABI; n = 20) and 40 docetaxel (DOC; n = 40) treatment. UCA1 copy number gain was significantly associated with reduced OS in ENZA-treated patients (p = 0.030). AR gain correlated with poorer OS in ABI-treated patients (p = 0.039), whereas no association was observed in DOC-treated patients. Normal AR and UCA1 levels were associated with significantly better OS in ENZA and ABI-treated patients. These findings suggest that UCA1 gain may predict reduced efficacy of ENZA treatment, while AR gain indicates decreased effectiveness of ABI but not ENZA and DOC therapies. These results may help support therapeutic decisions in the clinical settings.
Cardiovascular-kidney-metabolic (CKM) syndrome stage 3 represents a critical, yet highly insidious, window of subclinical target organ damage. We aimed to comprehensively compare nine baseline non-insulin-based surrogate indices of insulin resistance to predict progression to CKM stage 3 and determine their scenario-specific clinical utility. This longitudinal study included 2958 adults initially at CKM stages 0-2 from the China Health and Retirement Longitudinal Study. Independent associations were assessed using multivariable logistic regression and restricted cubic splines. Discriminative ability was evaluated using the area under the receiver operating characteristic curve (AUC). Incremental predictive values over a basic clinical model were quantified via continuous net reclassification improvement (NRI) and integrated discrimination improvement (IDI). The net clinical benefit was further evaluated through decision curve analysis (DCA). During follow-up, 497 (16.8%) participants progressed to CKM stage 3. After adjusting for comprehensive covariates, all nine indices were independently associated with the outcome. Notably, composite indices coupling systemic glucolipotoxicity with central adiposity exhibited preferable predictive superiority. Triglyceride-glucose index combined with waist-to-height ratio (TyG-WHtR) and triglyceride-glucose index combined with waist circumference (TyG-WC) yielded the highest odds ratios per 1-SD increment (1.86 and 1.82, respectively). Incorporating them into the basic model significantly increased the AUC and provided the most substantial improvements in patient reclassification (NRI: 0.524 and 0.512, respectively; both P < 0.001) and discrimination (IDI). Furthermore, DCA confirmed that models augmented with TyG-WC or TyG-WHtR provided the highest net clinical benefit across varying threshold probabilities. This prognostic dominance remained robust across four stringent sensitivity analyses. TyG-WC and TyG-WHtR are the most robust, independent predictors of incident CKM stage 3. They offer a highly actionable, scenario-adaptable screening strategy: TyG-WC serves as an ultra-accessible "first-pass" filter for large-scale public health triage, while TyG-WHtR provides a calibrated prognostic anchor for high-threshold, individualized clinical decision-making.
While the role of resistance training-induced muscle hypertrophy on early strength gains is still debated, it is unclear whether the specificity of training, such as high-load (H) training for increasing strength, results in different motor unit (MU) adaptations than combined high- and low-load (H + L) training for increasing strength and hypertrophy. Therefore, this study examined the effects of six weeks of either H- or H + L-training on leg press 1-repetition maximum (1-RM), isometric knee extensor strength via maximal voluntary contraction (MVC), and muscle cross-sectional area (mCSA) and MU behavior of the vastus lateralis (VL) in untrained males that were pseudorandomized into a H (n = 18), H + L (n = 17), or a control group (n = 11). Surface electromyographic (sEMG) signals for a 40% MVC were recorded from the VL and decomposed for analysis of MU: recruitment thresholds (RTs), action potential amplitudes (MUAPAMPs), and mean firing rates (MFRs). Normalized EMG amplitude (N-EMGRMS) at 40% MVC was also calculated. Despite a 21% increase in mCSA for H + L compared to 4% for H, both training groups had similar increases for 1-RM and MVC. Additionally, H + L exhibited hypertrophied muscle fibers for MUs with RTs ≥ 20% MVC, decreased MFR of those MUs, and lower N-EMGRMS at 40% MVC, whereas H increased MFRs of the lower-threshold MUs with no change in MU size or N-EMGRMS. The findings of this study provide support that early changes in MU behavior are sensitive to specificity of training and/or changes in muscle morphology, whereas early strength gains are not necessarily driven by increases in mCSA.
Insulin resistance (IR) is thought to be a major metabolic driver of both metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiometabolic diseases (CMD). Although several IR-related indices have been linked to individual CMD, their associations with cardiometabolic multimorbidity (CMM) and stage-specific disease progression in individuals with MASLD remain unclear. A total of 109,604 UK Biobank participants with MASLD who were free of CMD at baseline were included in this study. The analysis covered nine IR-related metrics, including the triglyceride-glucose (TyG) index, TyG-body mass index (TyG-BMI), TyG-waist circumference (TyG-WC), TyG-waist-to-height ratio (TyG-WHtR), TyG-body roundness index (TyG-BRI), TyG-a body shape index (TyG-ABSI), TyG-visceral adiposity index (TyG-VAI), TyG-weight-adjusted waist index (TyG-WWI), and the triglyceride-to-high-density lipoprotein cholesterol ratio (TG/HDL-C). Associations with incident CMM were estimated using Cox models. Multi-state models were applied to evaluate stage-specific transitions. Incremental predictive performance was evaluated using time-dependent ROC analyses, C-index, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Exploratory mediation analyses were further performed to explore possible biological pathways. Over a median follow-up of 15.9 years, 4944 participants developed CMM. Higher levels of all IR-related indices were linked to a greater risk of CMM. In the fully adjusted model, the strongest associations were observed for TyG-WHtR, TyG-BMI, and TyG-WC, with HRs (95% CIs) of 2.70 (2.45-2.97), 2.36 (2.16-2.58), and 2.33 (2.12-2.56), respectively, for the highest versus lowest quartile. Multistate analyses indicated that these indices showed stage-specific associations across the CMM trajectory. For transitions from a CMD-free state to single CMDs, the strongest associations were observed for T2D. Transitions from CHD or stroke were more likely to progress to CMM when exposed to higher IR-related indices. All indices modestly improved CMM prediction beyond conventional risk factors (all P < 0.001), with TyG-WHtR showing the best performance. Exploratory mediation analyses suggested that inflammatory, hepatic, and renal biomarkers jointly accounted for 11-23% of the associations. Among individuals with MASLD, IR-related indices were significantly associated with the incidence and progression of CMM. Indices incorporating central adiposity, especially TyG-WHtR, provided the most informative risk estimates and modest incremental predictive value.
Agricultural productivity is compromised by drought events. We investigate how small-sized molybdenum nanodots (MNDs) can increase maize (Zea mays L.) seedling shoot fresh and dry weights under drought stress. Because the oxygen vacancies endow MNDs with excellent reactive oxygen species (ROS) scavenging ability, MNDs protect photosynthesis via scavenging efficacies against superoxide anions (O2•-) by 23.6% and hydrogen peroxide (H2O2) by 22.8%, improving the net photosynthetic rate (Pn, +53.9%) and maximum photosynthetic efficiency (+13.1%). This drives the carbon-nitrogen metabolic network and secondary metabolism in leaves and increases levels of proline (+36.2%) and malic acid (+50.0%) to maintain osmotic and redox homeostasis. MNDs also affect the phyllosphere, fostering conditions that favor drought tolerance (e.g., increased dissolved organic carbon leads to greater dominance of Bacteroidota and Proteobacteria, and restoration of nutrient cycles through enhanced nitrogen fixation, cellulose degradation, and phosphate solubilization). MNDs improve maize seedling survival through dual-directional empowerment under drought stress. This reveals the potential of nanomaterial-mediated resilience to address climate change and food shortage.
Ureteral stents are widely used in the management of renal obstruction and are prone to colonization by biofilm-forming Pseudomonas aeruginosa, a pathogen capable of causing persistent infections. It is crucial to elucidate the molecular determinants of virulence and resistance for the effective management of ureteral stent associated infections. This study was conducted to explore the resistance and virulence determinants of Pseudomonas aeruginosa colonizing ureteral stents. Among 86, P. aeruginosa was found in 79 (91.8%) of patients. Colonization was significantly associated with higher grades of sent encrustation (p <0.001). Biofilm formation was observed in 65(85.5%) isolates. Significant association was found between virulence factors and antibiotic resistance (p<0.001). Virulence genes, algD and ureC were detected in 59.2% and 97.3% of isolates, respectively. β-lactamase genes were highly prevalent, with blaTEM (77.6%) and blaOXA-1 (73.6%) predominating, followed by blaCTXM-3 (47.3%), blaSHV (30.2%), and ampC (57.8%). The emerging carbapenemase blaFIM-1 was identified in 13.1% of the isolates. Efflux pump and porin-associated genes (mexB, oprD, mexA, oprM) were detected in 73.7%, 69.7%, 52.6%, and 47.4% of isolates, respectively. Among non-β-lactam resistance genes, Sul1 (72.3%), dfr (68.4%), and tetB (59.2%) were most prevalent. The high prevalence of biofilm formation and coexistence of multiple resistance and virulence genes suggest that P. aeruginosa possess characteristics that may contribute to persistence on ureteral stents. The detection of the emerging blaFIM-1 carbapenemase gene underscores evolving resistance that might compromise therapeutic strategies. Regular monitoring of stent-associated colonization is essential to prevent infection, stent failure, and increased clinical burden.
Irisin is an exercise-induced myokine that has been proposed to exert beneficial effects on metabolic health. However, its response to different exercise training modalities in individuals with overweight or obesity remains inconsistent. This systematic review and meta-analysis primarily aimed to evaluate the effects of various exercise interventions on circulating irisin levels as the primary outcome in overweight and obese adults. Additionally, we assessed changes in other selected myokines and metabolic markers as secondary outcomes to provide a better understanding of exercise induced physiological adaptations. A systematic search was conducted in Web of Science, EMBASE, Cochrane Library, PubMed, SCOPUS, and Google Scholar (up to 22 April 2025) to identify randomized controlled trials (RCTs) evaluating the effects of different exercise training protocols (aerobic, resistance, concurrent, and high-intensity interval training) on circulating irisin levels in adults with overweight or obesity. The primary eligibility criterion to include studies was the measurement of circulating irisin. Within the RCTs meeting this criterion, we additionally extracted data on selected myokines (follistatin, myostatin, and FGF21) and metabolic markers (glycemic control and lipid profiles) when reported. These secondary outcomes were analyzed to contextualize irisin responses within broader metabolic adaptations, but no separate systematic search was performed for these variables. Pooled effect sizes were calculated using random-effects models and expressed as standardized mean differences (SMDs) with 95% confidence intervals (CIs). Using the median split technique, subgroup analyses were computed according to exercise training modality. A total of 50 studies comprising 1780 participants (1104 in exercise groups and 676 in passive control groups) were included. For the primary outcome, exercise training was associated with a significant increase in circulating irisin (SMD 0.62, 95% CI 0.39-0.85, p < 0.001, n = 76 arms, 1721 subjects) compared with passive controls. Among the secondary outcomes, training was also associated with increases in high-density lipoprotein cholesterol (SMD 0.25, 95% CI 0.03-0.47, p = 0.030], n = 18 arms, 420 subjects), follistatin (SMD 0.89, 95% CI 0.37-1.41, p = 0.008, n = 7 arms, 141 subjects), and fibroblast growth factor 21 (FGF-21; SMD 1.00, 95% CI 0.10-1.91, p = 0.003, n = 13 arms, 280 subjects). In contrast, exercise training did not significantly affect myostatin levels (SMD - 0.45, 95% CI - 1.07 to 0.18, p = 0.160, n = 11 arms, 283 subjects). Additionally, exercise training significantly reduced fasting blood glucose (SMD - 0.61, 95% CI - 0.89 to - 0.33, p < 0.001, n = 28 arms, 696 subjects), insulin (SMD - 0.80, 95% CI - 1.11 to - 0.50, p < 0.001, n = 24 arms, 566 subjects), homeostatic model assessment for insulin resistance (SMD - 0.75, 95% CI - 1.08 to - 0.43, p < 0.001, n = 28 arms, 609 subjects), hemoglobin A1C (HbA1C) (SMD - 0.96, 95% CI - 1.23 to - 0.70, p < 0.001, n = 12 arms, 275 subjects), and low-density lipoprotein cholesterol (SMD - 0.38, 95% CI - 0.74 to - 0.02, p = 0.040, n = 18 arms, 443 subjects). Exploratory subgroup analysis showed significant increases in irisin following resistance training (SMD 0.88 [95% CI, 0.44 to 1.33], [p = 0.001], n = 21 arms, 537 subjects, I2 = 79% [p = 0.001]), high-intensity interval training (SMD 0.61 [95% CI, 0.13 to 1.09], [p = 0.001], n = 17 arms, 346 subjects, I2 = 75% [p = 0.001]), and concurrent training (SMD 0.42 [95% CI, 0.16 to 0.68], [p = 0.002], n = 18 arms, 356 subjects, I2 = 21% [p = 0.20]). Although resistance training demonstrated numerically larger effects, differences between exercise modalities were not statistically significant (p > 0.05). Regular exercise is an effective intervention for increasing circulating irisin levels and favorably modulating other myokines such as follistatin and FGF-21 in adults with overweight or obesity. Resistance training showed larger numerical effects, but the differences between exercise types were not statistically significant. These adaptations, alongside improvements in metabolic markers, support the role of structured exercise as part of a comprehensive strategy for improving metabolic health in this population. PROSPERO CRD42025637476.
This study aimed to develop and evaluate hybrid composites of ultra-high molecular weight polyethylene (UHMWPE) reinforced with hydroxyapatite (HAP) and titanium dioxide (TiO2) for synthetic cartilage applications in joint prostheses. Three composite formulations were prepared using a solvent dispersing method followed by hot pressing, and their mechanical, tribological, and antibacterial properties were analyzed. Transmission electron microscopy (TEM) and X-ray diffraction (XRD) were employed to assess the dispersion quality of the fillers. TiO2 content was varied (1, 3, 5, and 10 wt%) while HAP content was fixed at 20 wt%. In the UHMWPE matrix, HAP served as a bone osteo-inductive agent and TiO2 as an anti-wear additive. Wear testing against Ti6Al4V alloy using dry sliding and simulated body fluid (SBF) revealed that 3 wt% TiO2 enhanced wear resistance due to the formation of a dense lubricant film. The Agar Well Diffusion method confirmed significant antibacterial activity in the composites. Furthermore, fatigue tests conducted at frequencies of 1 Hz and 3 Hz demonstrated improved fatigue life and maximum stress for the P-H-3T composite (3 wt% TiO2). This improvement was attributed to the homogeneous dispersion of the nanoparticles, which facilitated better stress transfer and delayed crack initiation. Excessive TiO2 led to particle agglomeration, reducing fatigue resistance. The results highlight that 3 wt% TiO2 provides an optimal balance between strength, wear resistance, and fatigue life for biomedical applications.