Search Results (11,023)

Interferon Regulatory Factor 5 plays an important role in the regulation of innate immune responses by amplifying the Nuclear Factor κB response, which is critical in gout inflammation. Furthermore, the rs4728141 polymorphism C allele was associated with both increased IRF5 expression and susceptibility to gout. We examine the association between rs4728141 and cytokine production in response to various Toll-Like Receptor ligands and describe the transcriptomic and proteomic changes observed in patients with gout and controls in relation to this polymorphism. We examine the transcriptome of freshly isolated peripheral blood mononuclear cells (PBMCs) from 93 normouricemic donors and 63 gout patients as well as serum inflammatory proteome in 197 control and 195 gout samples. Stimulation experiments of freshly isolated human PBMCs were performed over 24 h, followed by RNA-sequencing in gout patients and cytokine production measurement by ELISA in normouricemic donors and gout patients. The rs4728141 C allele was associated with increased IL-1β expression in unstimulated PBMCs of controls, but not in gout. No association between the polymorphism and serum inflammatory proteome was found. As expected, an increased IRF5 expression was observed in stimulated PBMCs of rs4728141 C allele carriers in response to several stimulations. Interestingly, IL-1β production was specifically enhanced in association to the rs4728141 C allele when cells were stimulated with palmitate with or without monosodium urate crystals. This pattern of cytokine production shows a functional impact of rs4728141 in gout through altered IL-1β production. Full article

There is a need to develop rapid, in situ methods that require less sample preparation and lower limits of detection for the detection of High Explosives (HEs). Considering that human hair is one of the primary attributes of the human body, its presence can be used to identify possible traces of hair evidence for forensic screenings. Using non-invasive in situ approaches coupled with multivariate analysis (MVA) can enable rapid detection, thereby decreasing analysis time and reducing the cognitive load on analysts, with response times as low as milliseconds or lower. This preliminary study demonstrates the detection of 2,4,6-trinitrotoluene (TNT), 1,3,5-trinitroperhydro-1,3,5-triazine (RDX), and pentaerythritol tetranitrate (PETN) on black, bleached, and natural gray human hair coupled with principal component analysis (PCA). It was possible to discriminate the HE signals from those of the substrates (hair types) on black, gray, and bleached hair by monitoring characteristic peaks for the nitro group’s vibrations of the explosives. Gray hair presented good discrimination for the explosives due to the absence of melanin. The best modes for discriminating HEs from all three hair types were identified using PCA, with data pretreatment based on the first and second derivatives of the algorithms. The classifications were based on the more substantial variation in the NO₂ symmetric vibration for each HE. Full article

Lymphocyte-activation gene 3 (LAG3) is an immune checkpoint receptor and inhibitory regulator of T-cells. Here, we analyzed the prevalence of LAG3 rs870849 in B-cell lymphoma patients and the treatment outcomes according to the LAG3 genetic background and discovered that LAG3 germline variants may affect the risk of developing lymphoma and also affect the treatment outcome of DLBCL patients in the current CD19 CAR-T cell therapies. The LAG3 rs870849 was prevalent at high frequency in DLBCL patients. Significant differences in treatment outcomes to CAR-T cell therapy emerged in LAG3 I455hom versus I455Thet and T455hom carriers. The overall and complete response rates to CAR-T cell therapy were lower in the I455hom genetic subgroup with median PFS in the I455hom of 2 versus 20 months in the T455hom and I455Thet subgroups (p = 0.025). Median OS was 6 months in the LAG3 I455hom versus 41 months in the T455hom and I455Thet subgroups (p = 0.007). LAG3 rs870849 may affect treatment outcome in CAR-T cell therapy, with favorable outcomes in T455 carriers. Specific combinations of CTLA4 and LAG3 germline variants may cooperate to affect the response to CAR-T cell therapy. Full article

In response to escalating global concerns about waste generation throughout the product life cycle, the Circular Economy (CE) has emerged as a central alternative to the dominant linear economic model. The integration of CE principles into supply chain management is manifested in Circular Supply Chain Management (CSCM), offering a novel perspective on supply chain sustainability. Despite the growing research interest in developing CSCM to enhance supply chain sustainability, assessment approaches of this concept are notably absent in the literature. This study addresses this gap by focusing on the assessment and performance measurement of circular practices in the context of supply chains. At first, the research presents a bibliometric analysis to delve into the performance and science mapping of CSCM assessment, providing a comprehensive view of the scientific landscape. Subsequently, a content analysis is then used to identify current assessment approaches, focusing on frameworks, methodologies, barriers, enablers, and CE strategies. The study proposes a conceptual model based on the SCOR framework, including core categories such as enablers (business model, technology, collaboration, design) and results (material, water, energy flows) represented by the Rs strategies. This model contributes to bridging theoretical gaps and guiding practitioners and policymakers in the design, evaluation, and implementation of circular supply chains. Full article

MicroRNA-22 (miR-22) is a negative regulator of mitochondrial biogenesis, as well as lipid and glucose metabolism, in metabolically active tissues. Silencing miR-22 holds promise as a potential treatment of obesity and metabolic syndrome, as it restores metabolic capacity—enhancing oxidative metabolism—and reduces ectopic fat accumulation in chronic obesity, a driver of impaired metabolic flexibility and muscle mass loss. Intramuscular adipose accumulation and defective mitochondrial function are features associated with obese-mediated muscle atrophy and hallmarks of neuromuscular disorders such as Duchenne muscular dystrophy. Therefore, miR-22 could represent a compelling molecular target to improve muscle health across various muscle-wasting conditions. This study describes a pharmacological strategy for the inhibition of miR-22 in skeletal muscle by employing a mixmer antisense oligonucleotide (ASO, anti-miR-22). Administration of the ASO in a mouse model of obesity positively modulated myogenesis while protecting dystrophic mice from muscle function decline, enhancing fatigue resistance, and limiting pathological fibrotic remodeling. Mechanistically, we show that anti-miR-22 treatment promotes derepression of genes involved in mitochondrial homeostasis, favoring oxidative fiber content regardless of the disease model, thus promoting a more resilient phenotype. Furthermore, we suggest that miR-22 inhibition increases autophagy by transcriptional activation of multiple negative regulators of mammalian target of rapamycin (mTOR) signaling to decrease immune infiltration and fibrosis. These findings position miR-22 as a promising therapeutic target for muscle atrophy and support its potential to restore muscle health. Full article

Atmospheric nitrogen input has been a severe challenge worldwide. The influences of N deposition on carbon cycling, loss, and storage have been recognized as a critical issue. This study aimed to assess the immediate responses of soil respiration to different N deposition treatments in radiata pine (Pinus radiata D. Don) and chestnut-leaved oak (Quercus castaneifolia C. A. Mey) plantations within 12 months. N treatments were performed monthly at levels of 0, 50, 100, and 150 kg N ha⁻¹ year⁻¹ from October 2017 to September 2018. Litterfall was collected and analyzed seasonally for its mass and C content. Within the 0–10 cm depth of mineral soil in both plantations, parameters such as total nitrogen, pH, microbial biomass carbon (MBC), organic carbon (OC), and fine root biomass were measured seasonally. Soil respiration (Rs) was determined through monthly measurements of CO₂ concentration in the field using a portable, closed chamber technique. The control plots exhibited the highest Rs during spring (2.96, 2.85 μmol CO₂ m⁻² s⁻¹) and summer (2.92, 3.1 μmol CO₂ m⁻² s⁻¹) seasons in oak and pine plantations, respectively. However, the introduction of nitrogen significantly diminished Rs in both plantations. Moreover, N treatments caused a notable reduction of soil MBC and fine root biomass. Soil microbial entropy and the C/N ratio were also significantly decreased by nitrogen treatments in both plantations, with the most prominent effects observed in summer. The observed decline in Rs in N-treated plots can be attributed to the decrease in MBC and fine root biomass, potentially with distinct contributions of these components in the pine and oak plantations. Our findings suggested that N-induced alteration in soil carbon dynamics was more pronounced in the oak plantation, which resulted in more SOC accumulation with increasing N inputs, while the pine plantation showed no significant changes in SOC. Full article

Background/Objectives: Bitter Taste Receptors (encoded by TAS2R genes) are expressed in mucosal and bronchial epithelia, as well as in immune cells, contributing to defense against airborne pathogens such as SARS-CoV-2. Data on single-nucleotide polymorphisms (SNPs) in TAS2R genes or pseudogenes in COVID-19 are limited. This study examined the association between TAS2R SNPs and COVID-19 infection and seroconversion in European individuals participating in the Canadian Longitudinal Study on Aging. Methods: Data from the Genome-wide Genetic Data, Comprehensive Baseline (version 7.0), Follow-up 2 (version 1.1), COVID-19 Questionnaire Study (4-2020 to 12-2020), and COVID-19 Seroprevalence (Antibody) Study (11-2020 to 7-2021) datasets were accessed. Associations of TAS2R SNPS with COVID-19 infection or seroconversion were determined using logistic regression adjusted for sociodemographics, genetic principal components, smoking, vaccine doses, and chronic medical conditions (diabetes, immune-mediated inflammatory diseases (IMIDs), respiratory disease, and cardiovascular disease). Results: In the COVID-19 Questionnaire Study (N = 14,073), the rs117458236 (C) variant in TAS2R20 showed a trend toward an association with COVID-19 infection (OR = 1.95; 95% Confidence Interval (CI): 0.98, 3.51). In the COVID-19 Antibody Study (N = 8313), the rs2234235(G) variant in TAS2R1 was associated with anti-nucleocapsid (OR = 1.55; CI: 1.06, 2.20) and anti-spike response (OR = 0.74; CI: 0.57, 0.98); the rs2234010(A) variant in TAS2R5 was associated with anti-nucleocapsid (OR = 1.56; CI: 1.08, 2.19); and the rs34039200(A) variant in TAS2R62P was associated with anti-spike (OR = 0.86; CI: 0.77, 0.97). In a subgroup analysis, the rs2234235(G) variant in TAS2R1 was associated with a decreased anti-spike response to infection or vaccination in individuals with IMIDs or respiratory disease and an increased risk of SARS-CoV-2 infection. Conclusions: TAS2R variants are associated with COVID-19 infection and vaccine response. These data may inform personalized management and vaccination strategies. Full article

This study addresses the challenges encountered in mechanized agricultural fields, particularly the soil disruption associated with conventional horizontal rotary straw cleaning equipment. To mitigate the inefficiency of straw cleaning observed in the current vertical rotary apparatus, this study introduces a vertical rotary fixed-angle straw cleaning device. The essential conditions for establishing the cutter tooth angle were identified through theoretical analysis. Analyzing the kinematics of the cutter tooth to direct the movement of the straw, we determined that the deflection angle of the cutter tooth group (DA) is a critical parameter for enhancing the effectiveness of straw cleaning. A multiphase interaction model encompassing soil, straw, and machinery components was developed utilizing a coupled simulation approach with RecurDyn and EDEM software. The Box–Behnken response surface methodology was employed to systematically investigate the interaction effects of three critical parameters on both the straw cleaning rate and the soil disturbance rate: operation speed (OS), rotation speed of the straw cleaning rotary table (RS), and the DA. For optimization experiments where the OS is set to 2.4 m/s, RS is 400 r/min, and DA is 48°, the straw cleaning rate reaches 94.1% and the soil disturbance rate is 27.2%. This device can efficiently create a localized clean seeding belt for no-till planters without significantly damaging the soil structure, providing an innovative solution for the development of low-disturbance, high-efficiency conservation tillage equipment. Full article

Background/Objectives: We aimed to investigate the association between VDR gene variants and vitamin D levels in elite male power athletes of Kazakhstan. Methods: We recruited 92 elite male power athletes of Kazakhstan. Concentrations of serum 25(OH)D were measured with the Access 25(OH) Vitamin D Total Assay on the Unicel Dxl 800 Access Immunoassay System. Gene polymorphisms were determined by a real-time polymerase chain reaction (RT-PCR) allelic discrimination assay using TaqMan™ probes. Results: Vitamin D insufficiency was registered in 63% of athletes. Age (χ² = 6.83, p < 0.01), BMI (χ² = 6.83, p < 0.01), and sport experience (χ² = 4.44, p < 0.04) showed a statistically significant association with vitamin D insufficiency and deficiency (age, χ² = 7.93, p < 0.01; BMI, χ² = 5.11, p < 0.03; sport experience, χ² = 6.19, p = 0.01). The A/A genotype of the VDR FokI polymorphism (rs2228570) showed a strong correlation with vitamin D insufficiency (G/G-G/A vs. A/A, OR = 9.25, 95% CI = 2.01–42.51, p < 0.01) but not deficiency. Conclusions: Our study reveals a significant prevalence of vitamin D insufficiency and deficiency among elite male power athletes of Kazakhstan. Age, BMI, and sport experience are essential factors in developing personalized strategies to address vitamin D insufficiency. The A/A genotype of the VDR FokI polymorphism can be used as a potential biomarker for vitamin D inadequacy in elite male power athletes of Kazakhstan. Full article

Diabetes mellitus (DM) is a complex chronic disease, with a prevalence that has reached alarming proportions in recent decades. In this study, we aimed to analyze the association of type 2 diabetes mellitus (T2DM) with certain insulin resistance (IR) indicators, according to the gender of the participants enrolled in the PREDATORR study. Biomarkers such as the triglyceride–glucose (TyG) index and its derivates, triglyceride-to-high-density lipoprotein cholesterol (TG/HDL-c), and metabolic score for insulin resistance (METS-IR), as well as recent indicators, like cholesterol, HDL, the glucose (CHG) index and its derivates, CHG–body mass index (CHG-BMI), and CHG–waist circumference (CHG-WC), as well as its newly proposed derivates, such as CHG–waist-to-height ratio (CHG-WHtR), CHG–neck circumference (CHG-NC), and CHG–neck-to-height ratio (NHtRs were analyzed in 2080 subjects, divided into two groups, according to gender). Univariate and multivariate logistic regression was used to identify the relationships between IR indicators and T2DM. Regardless of gender, all the analyzed indicators presented statistically significantly higher values in T2DM (+) compared to T2DM (−). For both studied groups, CHG–WHtR had the largest AUROC curve: in males, the AUROC curve was 0.809, the cut-off value being 3.22, with a 70.7% sensitivity and 75.3% specificity; in females, the AUROC curve was 0.840, the cut-off value was 3.20, with a 79.3% sensitivity and 75.5% specificity, respectively. Regardless of gender, the age-adjusted model for multivariate logistic regression analysis demonstrated that TyG and CHG were predictive factors for T2DM. Full article

The regionalization of input–output tables enables a granular understanding of economic systems, allowing for interregional and interindustry analysis for goods and services in a local economy. This paper details the construction of an intermunicipal IO matrix for the state of Rio Grande do Sul (Brazil), a region marked by both economic diversification and significant territorial disparities. Using the 16-sector state IO matrix (base year 2019) provided by the state-level treasury (SEFAZ-RS) as a starting point, we adapt the Interregional Input–Output Adjustment System (IIOAS), integrating gravity-based trade modelling and RAS balancing, to produce a disaggregated structure for 497 municipalities. The regionalization follows three main steps: (i) generation of an initial matrix assuming proportional municipal shares in sectoral supply and demand; (ii) iterative RAS-based adjustments to align with municipal and state-level constraints; and (iii) incorporation of complementary municipal data—including employment, GDP, household consumption, and exports—to refine final demand and value-added allocations. The results demonstrate the feasibility of deriving spatially intermunicipal IO structures from limited data. The results show that, while industrial and service activities are concentrated around the Porto Alegre metropolitan area, rural subregions remain specialized in low value-added primary sectors. Full article

Intracellular emetic signals involved in the cannabinoid CB₁ receptor inverse agonist/antagonist SR141716A were investigated. SR141716A (20 mg/kg, i.p.)-evoked vomiting occurred via both the central and peripheral mechanisms. This was accompanied by robust emesis-associated increases in the following: (i) c-fos- and phospho-glycogen synthase kinase-3α/β (p-GSK-3αβ)-expression in the shrew’s dorsal vagal complex (DVC), (ii) phospho-extracellular signal-regulated kinase1/2 (p-ERK_1/2) expression in both the DVC and jejunal enteric nervous system, and (iii) time-dependent upregulation of cAMP levels and phosphorylation of protein kinase A (PKA), protein kinase B (Akt), GSK-3α/β, ERK_1/2, and protein kinase C αβII (PKCαβII) in the brainstem. SR141716A-evoked emetic parameters were attenuated by diverse inhibitors of the following: PKA, ERK_1/2, GSK-3, phosphatidylinositol 3-kinase (PI3K)-Akt pathway, phospholipase C (PLC), PKC, Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), L-type Ca²⁺ channel (LTCC), store-operated Ca²⁺ entry (SOCE), inositol trisphosphate receptor (IP3R), ryanodine receptor (RyRs), both 5-HT₃-, and D_2/3-receptor antagonists, and the transient receptor potential vanilloid 1 receptor (TRPV1R) agonist. SR141716A appears to evoke vomiting via inverse agonist activity involving emesis-associated kinases, including cAMP/PKA, ERK_1/2, PI3K/Akt/GSK-3, PLC/PKCαβII, and CaMKII, which depend upon Ca²⁺ mobilization linking extracellular Ca²⁺ entry via plasma membrane Ca²⁺ channels (LTCC, SOCE, TRIPV1R) and intracellular Ca²⁺ release via IP3Rs and RyRs. The 5-HT₃, NK₁, and D_2/3 receptors also contribute to SR141716A-mediated vomiting. Full article

Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with a fivefold increase in stroke risk. Direct oral anticoagulants (DOACs), including apixaban, are now the preferred therapy for stroke prevention in patients with non-valvular AF (NVAF). However, interindividual variability in drug response and safety remains a major challenge, particularly in elderly patients with comorbidities and polypharmacy. Genetic polymorphisms in drug-metabolizing enzymes and transporters may contribute to variability in apixaban exposure and bleeding risk. This study aimed to evaluate the association of polymorphisms in ABCB1, CYP3A4, and CYP3A5 with steady-state plasma concentrations of apixaban (Cssmin) and hemorrhagic complications in elderly patients with NVAF. Methods: This cross-sectional study included 197 patients (mean age 83 ± 8 years; 67% women) with NVAF treated with apixaban (5 mg twice daily). Genotyping of ABCB1 (rs1045642, rs2032582, rs1128503), CYP3A4*22 (rs35599367), and CYP3A5*3 (rs776746) was performed using allele-specific real-time PCR. Cssmin of apixaban was determined by high-performance liquid chromatography coupled with tandem mass spectrometry. Associations with bleeding events were evaluated. Results: Bleeding events were recorded in 40 patients (20.3%). An association signal was observed for ABCB1 rs1045642, where carriers of the CC genotype had a higher risk of bleeding compared with alternative alleles (OR = 2.805; 95% CI: 1.326–5.935; p = 0.006). After correction for multiple testing, the association remained significant only under the log-additive model (OR = 1.93 per C allele; 95% CI: 1.17–3.20; q = 0.0275; p_adj = 0.044), while recessive and codominant effects did not withstand Bonferroni adjustment. No significant associations were observed for rs2032582, rs1128503, CYP3A4*22, or CYP3A5*3. None of the studied polymorphisms, including rs1045642, significantly affected Cssmin. Concomitant therapy, particularly with antiarrhythmic drugs and statins (rosuvastatin), also increased bleeding risk. Conclusions: The findings highlight the potential contribution of ABCB1 rs1045642 and specific drug–drug interactions to the risk of hemorrhagic complications in elderly NVAF patients receiving apixaban. Full article

Uveal melanoma (UM) is the most common primary intraocular tumor in adults. Because of its high potential for spreading and its limited response to treatment, UM remains a clinical challenge. Previous studies suggest that clinical adrenergic receptor (AR) antagonists might be effective in the treatment of UM. This study reports the antitumor activity of α-blocker in UM spheroids generated from α_1A- and α_2A-AR-positive UM cell lines. These cell lines were derived from primary tumors or hepatic metastases and differed in their genetic risk status for metastasis. Drug screening with UM spheroids revealed that prazosin and doxazosin dose-dependently reduced viability, whereas terazosin, alfuzosin, silodosin, tamsulosin, and phenoxybenzamine were found to be inefficient. Prazosin induced apoptosis, resulting in the disintegration of UM spheroid morphology and growth inhibition. Additionally, prazosin prevented UM spheroid cell outgrowth and long-term survival, indicating potential for tumor control. Like the selective α_1A-AR antagonist RS17053, prazosin inhibited the formation and growth of UM spheroids stimulated by the α_1-agonist phenylephrine. This suggests a tumor-preventive effect through the blockade of α_1A-AR. The present study highlights the responses of UM spheroids to α-AR antagonists and demonstrates that prazosin, doxazosin, or RS17053 may be a treatment option for preventing UM tumor recurrence or metastasis. Full article

Background: Metabolic syndrome, a cardiovascular risk cluster, is recognized as a global health priority influenced by gene–diet interactions. The rs2794720 polymorphism has not been previously reported in relation to metabolic syndrome. This study examined the associations between dietary iron, SNP rs2794720, and metabolic syndrome in Chinese metropolitan population, with a focus on sex-specific and genotype-specific effects. Methods: A community-based cross-sectional study enrolled 2639 adults (1254 males, 1385 females) from Shanghai, China. Anthropometric measurements, laboratory analyses, and genotyping for the participants were performed. Dietary assessment utilized the 3-day 24 h dietary recall method. Metabolic syndrome was identified by the presence of at least three out of five metabolic abnormalities according to the NCEP—ATP III criteria. Results: After adjusting for confounders, in males, metabolic syndrome risk was associated with dietary iron (p = 0.002) but not with rs2794720 (p = 0.731). In females, metabolic syndrome risk was associated with rs2794720 (p = 0.014) and dietary iron (p = 0.016), with a significant interaction observed between rs2794720 and dietary iron (p = 0.047). Stratified by rs2794720, among females lacking the C allele, there was a linear trend between dietary iron and metabolic syndrome risk (p = 0.048). Compared to the reference group (lowest-intake GG homozygotes), the Q2–Q4 Ors (95% CI) were 5.31 (1.08, 39.52), 5.50 (1.16, 40.28), and 8.40 (1.80, 41.44)), while the major allele carriers did not show this trend (p = 0.704); compared to the reference group, the Q1–Q4 ORs(95% CI) were 6.13 (1.68, 39.66), 7.53 (2.06, 48.86), 8.10 (2.20, 52.60), and 7.84 (2.07, 51.70)). Conclusions: Our study first identified rs2794720 as a novel SNP associated with metabolic syndrome in Chinese females. The association between dietary iron and metabolic syndrome risk was unique to GG homozygotes (the minority), whereas CC/CG genotypes (the majority) showed no such association. Full article