Search Results (23,395)

Time-fractional diffusion equations describe subdiffusive transport in heterogeneous media, but their numerical treatment is complicated by the nonlocal Caputo derivative and by the weak singularity that the solution develops at the initial time. We study a global-in-time discretization that combines spectral collocation in time—on the fractional power basis ${\left\{t^{\mathsf{\ell }\alpha }\right\}}_{\mathsf{\ell }=0}^N$, evaluated at Chebyshev–Gauss–Lobatto nodes, which reproduces the leading terms of the singular expansion of the solution—with a second-order conservative finite-difference stencil in space that uses harmonic averaging of the diffusivity at the cell faces and therefore remains accurate across discontinuous media. The resulting fully discrete problem is a large, nonsymmetric, dense-in-time linear system whose two-norm condition number grows like the inverse square of the spatial mesh size, so that Krylov subspace iteration without preconditioning stalls under refinement. Exploiting the Kronecker sum structure of the discrete operator, we build a preconditioner by fast diagonalization of the spatial factor through the discrete sine transform. For constant diffusivity the preconditioner reproduces the operator exactly and yields a direct solver; for variable diffusivity it is spectrally equivalent to the operator, and we prove that the eigenvalues of the preconditioned system cluster in a disk centered at one whose radius depends only on the coefficient contrast, and not on the mesh, the number of temporal degrees of freedom, or the fractional order. Numerical experiments in one and two space dimensions confirm second-order spatial accuracy and a preconditioned iteration count that stays flat—twelve iterations from $M=32$ up to $M=1024$ in one dimension and eleven up to $M=256$ per direction in two—while the unpreconditioned count grows by more than two orders of magnitude. In time, the accuracy is spectral until round-off in the ill-conditioned Vandermonde matrix of the power basis takes over: the barrier is reached at $N=9,10,13$ for $\alpha =0.3,0.5,0.7$, where the attainable error is about ${10}^{-6}$. A benchmark against the L1 scheme on uniform and graded meshes, the Alikhanov L2-$1_{\sigma }$ scheme and Grünwald–Letnikov convolution quadrature quantifies when the global approach pays: on forced problems and on modes with $\kappa \lambda T^{\alpha }\lesssim 2$ it reaches a prescribed accuracy one to two orders of magnitude faster and with several times less memory, while for strongly damped modes the fractional power basis converges only algebraically and graded time marching is preferable below a relative error of ${10}^{-2}$. Full article

Existing piston–cylinder lubrication studies often simplify the pressure boundary as a constant load or a single field, making it difficult to capture pump-level pressure excitation, local oil-film response, and non-concentric posture under variable loading. This paper establishes a thermo–fluid–solid coupling framework integrating an AMESim full-pump model, a Fluent transient oil-film model, and a Transient Structural model; UDF transfer of periodic pressure, dynamic meshes, and a calibrated Roelands law were used to analyze parallel-offset and center-tilted postures. As the load pressure increased from 10 to 30 MPa, the maximum discharge–half-cycle temperature rose from 28.39 to 36.95 °C, and the average positive leakage during the third-cycle high-pressure stage increased from 0.0201 to 0.1026 L/min; increasing speed from 1000 to 3000 r/min reduced cycle-averaged leakage by 8.93%. At 500 r/min and 30 MPa, the parallel-offset case reached 46.34 °C, 41 kPa, and 0.0990 L/min in maximum temperature, maximum shear stress, and average leakage, whereas the center-tilted case produced a peak resultant force of 3537.12 N, a cylinder inner-wall high-stress band of 76.96 MPa, and a maximum piston deformation and equivalent stress of 4.31 μm and 83.16 MPa. These results clarify the distinct lubrication behavior and potential uneven-wear risk associated with the two representative non-concentric postures, and provide a basis for clearance design and posture-sensitive condition assessment of axial piston pumps. Full article

This paper explores methods to eliminate high-voltage spikes during dead time ($t_{dt}$) in high-frequency inverters for Wireless Power Transfer (WPT) systems, focusing on the transition from traditional Silicon IGBTs to enhancement-mode Gallium Nitride (GaN) HEMTs. At elevated switching frequencies, dead-time parameters strongly govern system efficiency and signal integrity. While IGBTs suffer from reverse-recovery charge ($Q_{rr}$) in antiparallel freewheeling diodes that generates severe voltage spikes, hard-switching GaN systems require precise dead-time minimization to prevent shoot-through while limiting third-quadrant conduction losses. Unlike prior WPT studies bounded by specific hardware setups, this paper presents a baseline technology benchmark that explicitly decouples intrinsic semiconductor commutation physics, specifically $Q_{rr}=0$ versus third-quadrant conduction, from macro-system parameters ($f_{sw}$, power level, and resonant topology). Experimental evaluation of a 130 kHz L-S-tuned GaN full-bridge inverter confirms that primary current commutates via third-quadrant conduction during dead time, completely eliminating reverse-recovery voltage spikes ($I_{rr}=0$). Ultimately, this work demonstrates that GaN’s spike-free operation is an intrinsic device-level property, reframing the dead-time optimization objective from transient overvoltage suppression to third-quadrant conduction loss minimization in next-generation WPT systems. Full article

Background/Objectives: Allergic rhinoconjunctivitis (AR) induced by house dust mites (HDMs) is a common condition that impairs quality of life, and allergen immunotherapy is the only treatment accepted to modify its natural course. However, real-world evidence on polymerized HDM subcutaneous immunotherapy (SCIT) remains limited. We evaluated the up to 24-month effectiveness of polymerized HDM SCIT and examined how baseline symptom burden affects the measured response. Methods: In a retrospective, single-arm, real-world cohort, 353 patients (mean age 15.9 (12.3) years) with HDM-induced AR with/without asthma (asthma subpopulation, n = 112) initiated polymerized SCIT (ALXOID^®, Inmunotek S.L., Spain) with an extract of house dust mites (Dermatophagoides pteronyssinus, D. farinae, Blomia tropicalis). Patients were followed for up to 24 months; 139 contributed an observation at month 12 and 67 at month 24. The primary outcome was the Rhinoconjunctivitis Combined Symptom–Medication Score (RCSMS); secondary outcomes were a visual analog scale (VAS) and the ESPRINT-15 quality-of-life questionnaire. Effectiveness was estimated using mixed models for repeated measures. The pre-specified primary-analysis population was restricted to a baseline RCSMS ≥ 2 to avoid floor effects and regression to the mean at low baseline scores. Results: At month 24, the RCSMS decreased by 0.938 points (−35.3%) in the full cohort and by 48.3% in the baseline RCSMS ≥ 2 population; in the full cohort, the VAS and ESPRINT-15 improved by 50.6% and 69.7%, respectively (all p < 0.001; within-subject effect sizes were small for the full-cohort RCSMS and medium for all other outcomes). The shape of the improvement trajectory did not differ by age group, and all age groups exceeded the minimal clinically important difference; the age analysis was exploratory. Patients with baseline RCSMS < 2 showed continued improvement in VAS and ESPRINT-15 scores. In contrast, the RCSMS increased, a pattern consistent with a statistical floor effect, suggesting limited responsiveness of the score at low baseline values. Conclusions: Up to 24 months, polymerized HDM SCIT was associated with clinically meaningful improvements in symptoms, medication use, and quality of life, most clearly in patients with a baseline RCSMS ≥ 2. Baseline symptom severity should be considered when interpreting combined symptom–medication outcomes in allergen immunotherapy. The single-arm design precludes causal inference. Full article

Objective: This study aimed to investigate the combined associations of food insecurity and Mediterranean diet adherence with glycemic control and to determine whether gut-derived metabolites differ according to food insecurity and macrovascular complication status in adults with type 2 diabetes mellitus (T2DM). Methods: In this cross-sectional study, food insecurity was assessed using the Food Insecurity Experience Scale, and Mediterranean diet adherence was evaluated with the 14-item Mediterranean Diet Adherence (MDA) Scale. Serum trimethylamine N-oxide (TMAO) and L-carnitine concentrations were quantified using enzyme-linked immunosorbent assay (ELISA). Multinomial logistic regression was used as the primary analysis of data-derived HbA1c tertiles, and separate binary logistic regression models were performed as sensitivity analyses. ANCOVA was used for adjusted comparisons of continuous outcomes. Results: In the primary multinomial analysis, none of the combined food insecurity–MDA patterns were significantly associated with the intermediate or highest HbA1c tertiles after multivariable adjustment. However, point estimates suggested higher odds of the intermediate HbA1c tertile among participants with food insecurity and high MDA adherence (AOR = 3.41, 95% CI: 0.76–15.25) and of the highest HbA1c tertile among those with food insecurity and low MDA adherence (AOR = 4.74, 95% CI: 0.66–34.16); these estimates were imprecise. Sensitivity analyses using separate binary logistic regression models yielded stronger associations, but these findings should also be interpreted cautiously. Participants with macrovascular complications exhibited significantly higher serum TMAO and L-carnitine concentrations (p = 0.026 and p = 0.039, respectively), whereas food-insecure participants had significantly lower concentrations of both metabolites (p = 0.009 and p = 0.018, respectively). Higher dietary fiber and plant protein intakes were cross-sectionally associated with lower TMAO concentrations, while L-carnitine concentrations were positively associated with dietary fiber intake and inversely associated with plant protein intake. Conclusions: Combined food insecurity–MDA patterns showed suggestive but imprecise differences in HbA1c category membership that require confirmation in larger prospective studies. Serum TMAO and L-carnitine concentrations differed according to food insecurity and macrovascular complication status and were associated with selected dietary components. These findings should be interpreted as exploratory cross-sectional associations rather than evidence of causal or mechanistic effects. Full article

The high mortality associated with largemouth bass ranavirus (LMBRaV) disease requires rapid and sensitive diagnosis methods to prevent virus spread and subsequent outbreak. The recombinase polymerase amplification combined with the CRISPR/Cas12a system (RPA-CRISPR/Cas12a) assay and RPA-CRISPR/Cas12a, coupled with lateral flow dipstick (RPA-CRISPR/Cas12a-LFD) assay for LMBRaV, were established in this study for low viral load surveillance. The major capsid protein (mcp) gene is highly conserved and is widely used as the target sequence in LMBRaV detection. First, based on the mcp gene sequence of LMBRaV, three candidate crRNAs were designed. Among them, the crRNA-2, which exhibited the highest cleavage activity, was selected through dual evaluation of fluorescence signal intensity and LFD color development. Then, the key reaction conditions for both assays were optimized as follows: LbCas12a protein concentration of 150 nM, crRNA-2 concentration of 200 nM, and ssDNA reporters’ concentration of 200 nM. Moreover, specificity evaluation showed that both combined assays specifically recognized LMBRaV, with no cross-reactivity detected against other aquatic pathogens, such as CyHV-2, GSIV, ISKNV, WSSV, GCRV II or CrERV. The detection limit was 1 copy/μL of DNA sample for both RPA-CRISPR/Cas12a and RPA-CRISPR/Cas12a-LFD assays. Finally, validation using 24 clinical samples (16 positive, eight negative) showed that both LMBRaV RPA-CRISPR/Cas12a assays achieved 100% detection rate, whereas conventional PCR detected 13 positive samples (detection rate 81.26%). ddPCR served as the reference method for clinical validation. Therefore, the LMBRaV RPA-CRISPR/Cas12a assay and the RPA-CRISPR/Cas12a-LFD assay provide sensitive, specific, and easy-to-operate methods for the rapid detection of LMBRaV. Full article

Objective: To compare the cardiometabolic characteristics of patients with mild autonomous cortisol secretion (MACS) and nonfunctioning adrenal incidentalomas (NFAI), with particular emphasis on their biochemical and echocardiographic profiles. Methods: This retrospective study included 67 patients with adrenal incidentalomas, classified as NFAI (n = 32) or MACS (n = 35) according to the post-1-mg dexamethasone suppression test (DST) cortisol concentration. Clinical characteristics, hormonal profiles, metabolic parameters, conventional echocardiographic measurements, and global longitudinal strain (GLS) were compared between the groups. Associations between GLS and biochemical parameters were evaluated using correlation analyses, with Benjamini–Hochberg false discovery rate correction applied for multiple testing. Results: Compared with the NFAI group, patients with MACS had lower adrenocorticotropic hormone (ACTH) (13.0 ± 7.1 vs. 18.6 ± 9.7 pg/mL, p = 0.008) and dehydroepiandrosterone sulfate (DHEA-S) concentrations (46.4 ± 31.6 vs. 82.8 ± 48.0 µg/dL, p < 0.001), as well as higher post-1-mg DST cortisol concentrations (3.4 ± 1.3 vs. 1.2 ± 0.5 µg/dL, p < 0.001). Triglyceride concentrations were also higher in the MACS group (165.3 ± 70 vs. 129.4 ± 90.2 m g/dL, p = 0.004). Most conventional echocardiographic parameters were comparable between the groups. GLS did not differ significantly between NFAI and MACS patients (21.92 ± 2.2 vs. 21.94 ± 1.9, respectively; mean difference: 0.0, 95% CI: −1.0 to 1.0, p = 0.846). Nominal correlations between GLS and selected biochemical parameters did not remain statistically significant after false discovery rate correction. Conclusions: MACS was associated with distinct endocrine and metabolic characteristics compared with NFAI; however, no significant between-group difference in GLS was observed. These cross-sectional findings do not establish myocardial dysfunction or a temporal relationship between cortisol autonomy and cardiovascular alterations. Larger prospective longitudinal studies are required to clarify the cardiovascular implications of MACS. Full article

Background/Objectives: Anti-PD-(L)1 immune checkpoint inhibitors (ICIs) provide durable responses in nearly 50% of patients with advanced Merkel cell carcinoma (MCC). However, for those progressing on first-line ICI therapy, optimal subsequent therapy remains unclear. Although presumed to have limited benefit, the efficacy of re-exposure with anti-PD-(L)1 alone has not been formally reported. We assessed real-world outcomes of patients within a Seattle-based MCC repository who received this salvage approach. Methods: Among 106 patients who received salvage therapy after first-line ICI progression, 16 underwent single-agent anti-PD-(L)1 monotherapy re-exposure during salvage. Patients progressing >3 months after their last immunotherapy dose were excluded. Outcomes included progression-free survival (PFS), disease-specific survival (DSS), and objective response rate (ORR). Results: The median time from end of first-line ICI therapy to anti-PD-(L)1 re-exposure was 51 days (IQR 22–92). Most patients switched between PD-1 and PD-L1 inhibitors (n = 9), while others were re-exposed with the same agent (n = 5) or a different PD-1 inhibitor (n = 2). One of 16 patients experienced a partial response with the same PD-1 inhibitor (ORR 6%; 95% CI: 0.2–30%) at 3 months after re-exposure, followed by progression 10 months after re-exposure. Median PFS was 2.2 months (95% CI: 1.3–5.1 months), and median DSS was 14.7 months (95% CI: 10.4–NR). Conclusions: These data suggest that re-exposure with anti-PD-(L)1 monotherapy confers minimal and short-lived benefit in ICI-refractory MCC, reinforcing the need to develop alternative salvage strategies. Future trials for ICI-refractory MCC mandating an ICI monotherapy arm are unlikely to be appealing to patients or physicians based on a low chance of clinical benefit for this approach. Full article

Background: Suicide is a leading cause of preventable death, yet machine learning (ML) analyses of forensic (medico-legal) suicide data are scarce and, to our knowledge, absent for Romania. Population-based forensic registries offer exhaustive, autopsy-confirmed coverage that is structurally distinct from clinical or civil death-registration data. We applied supervised and unsupervised ML to a complete regional medico-legal suicide registry to profile the method of death and to identify latent victim subgroups of preventive relevance. Methods: We analysed 395 consecutive suicide deaths (Galați and Brăila counties, ≈750,000 inhabitants; 2018–2024). Two supervised classifiers—L2-regularised logistic regression (LR) and random forest (RF, 200 trees)—were trained to discriminate hanging from other methods, using eleven sociodemographic and clinical predictors, and evaluated by 10-fold stratified cross-validation. Given severe class imbalance, the area under the ROC curve (AUC) was the primary metric. Model hyperparameters were fixed a priori, and no class-imbalance correction was applied; both decisions are pre-specified and justified in the Methods. Robustness was assessed by stratified non-parametric bootstrap confidence intervals for the odds ratios, a tipping-point sensitivity analysis for the undocumented clinical fields, and Ward-linkage hierarchical clustering as an independent partitioning check. Predictor importance was quantified by out-of-bag (OOB) permutation importance and Spearman correlations. Unsupervised structure was assessed by K-means clustering (k = 2–7), with the optimal solution selected by the average silhouette coefficient and the elbow (WCSS) criterion. Reporting followed TRIPOD+AI and STROBE. Results: The study population was predominantly male (87.1%) and rural (73.2%), with a mean age of 54.1 years; hanging accounted for 94.2% of deaths—far above the European average (≈50%). RF achieved AUC = 0.865 ± 0.181 and LR AUC = 0.847 ± 0.192, both within the “excellent” discrimination band; sensitivity was very high (0.995–0.997) and specificity was limited (0.233–0.367), an expected consequence of imbalance. Prior suicide attempts (OOB importance 0.959; Spearman ρ = −0.549, p < 0.001; OR = 0.496, 95% CI 0.25–0.72) and the presence of a suicide note (importance 0.575; ρ = −0.439, p < 0.001; OR = 0.549, 95% CI 0.34–0.76) were the dominant predictors. K-means identified two well-separated clusters (silhouette = 0.707), and the partition was reproduced exactly by Ward-linkage hierarchical clustering (adjusted Rand index = 1.000). Cluster 2 (n = 19; 4.8%) was a clinically distinct, younger subgroup (42.4 vs. 54.7 years) characterised by prior attempts (57.9% vs. 0%), suicide notes (68.4% vs. 0%), higher psychiatric comorbidity (52.6% vs. 30.9%) and lower hanging proportion (36.8% vs. 97.1%)—an exploratory, hypothesis-generating profile of recurrent suicidal behaviour with documented prior contact with the medical or medico-legal system. The principal findings were stable across all plausible degrees of clinical under-documentation in the tipping-point sensitivity analysis. Conclusions: ML applied to a complete forensic suicide registry reproduced known regional epidemiology and, beyond classical statistics, isolated an exploratory but clinically coherent high-risk subgroup of direct relevance to the audit of structured post-attempt follow-up. This is, to our knowledge, the first ML study of Romanian forensic suicide data and supports integrating ML into medico-legal research and into the regional targeting and audit of existing post-attempt follow-up provision. Full article

Background and Objectives: Pulsed field ablation (PFA) and cryoballoon ablation (CRYO) are established approaches for pulmonary vein isolation in atrial fibrillation (AF). Given emerging concerns regarding hemolysis following PFA, this pilot study aims to directly compare outcomes between these modalities. This study aims to evaluate differences in laboratory parameters potentially compatible with hemolysis and procedural safety between PFA and CRYO among AF patients. Materials and Methods: In this retrospective single-center analysis, 33 symptomatic AF patients underwent either PFA (n = 17) or CRYO (n = 16). Hemoglobin, hematocrit, platelet count, total bilirubin and renal function were measured at all three pre-specified time points: baseline, immediately after ablation and on day 1. Group × time interactions were tested with linear mixed-effects models, and changes are reported with 95% confidence intervals (CIs). Acute kidney injury (AKI) was defined by KDIGO serum creatinine criteria and assessed individually; sensitivity analyses were restricted to pulmonary-vein-isolation (PVI)-only procedures. Additionally, procedural metrics and complication frequencies were analyzed between groups. Results: The baseline demographics and clinical characteristics did not differ significantly between both groups. Both ablation techniques led to substantial reductions in hemoglobin following the procedure, with no between-group difference (day-1 change −1.84 vs. −1.57 g/dL; difference −0.27, 95% CI −1.01 to +0.47; group × time p = 0.192). Notably, total bilirubin increased to a greater extent with PFA (day-1 change +0.48 vs. +0.15 mg/dL; difference +0.33, 95% CI +0.06 to +0.59; group × time p = 0.003), with the largest separation immediately after ablation (1.43 ± 0.36 vs. 0.99 ± 0.35 mg/dL, p = 0.001). No patient in either group met KDIGO criteria for AKI of any stage; the largest post-procedural rise in creatinine was +0.10 mg/dL in both groups. Conclusions: Both PFA and CRYO caused acute declines in hemoglobin, and total bilirubin rose more after PFA, with no accompanying change in renal function. Further studies involving larger cohorts and direct hemolysis biomarkers are necessary to corroborate these findings. Full article

Background/Objectives: The emergence of plasmid-mediated mcr genes has enabled horizontal dissemination of resistance to colistin, a last-resort antibiotic against multidrug-resistant Enterobacterales. In Tunisia, genomic data on mcr-positive Escherichia coli are still limited. This study reports the genomic characterization of human clinical mcr-positive E. coli isolates from the Military Hospital of Tunis. Methods: Between August 2023 and March 2025, seven E. coli isolates with low-level colistin-resistance (MIC = 4–8 µg/mL) were collected from six patients. They were characterized by antibiotic susceptibility testing and WGS to determine resistome, MLST, genetic relatedness, and plasmid content. Results: The E. coli isolates belonged to diverse sequence types (STs), except for two isolates collected from the same patient 2.5 months apart, which were highly related. Overall, this pattern is consistent with a polyclonal spread. The mcr-1.1 gene was located on IncI2 (n = 5) or IncX4 (n = 2) plasmids, which exhibited high similarity both among themselves and in comparison with plasmids previously reported in human and livestock isolates. Most isolates were multidrug-resistant, harboring acquired resistance genes to multiple antibiotic classes, and chromosomal mutations conferring fluoroquinolone resistance. Three isolates additionally carried chromosomal insertions of the bla_CTX-M-55 gene. Resistance to cefiderocol was observed in one isolate and was associated with CirA and Fiu truncation. Conclusions: These findings highlight ongoing dissemination of mcr-1.1-positive E. coli isolates in Tunisia, primarily driven by plasmid transfer. Continuous genomic surveillance and One Health-oriented antibiotic stewardship are essential to limit the spread of colistin-resistance and the emergence of resistance to newer agents such as cefiderocol. Full article

Background: Patients with end-stage kidney disease commonly develop hyperparathyroidism, which may impair muscle strength and physical function. Elevated parathyroid hormone (PTH) levels have been associated with weakness and poor Timed Up and Go (TUG) test performance. We hypothesized that elevated PTH at kidney transplantation would correlate with worse TUG performance and poorer post-transplant outcomes. Methods: We performed a retrospective cohort study of 226 kidney transplant recipients (2015–2023) at a single transplant center with documented TUG testing and PTH levels. Patients were divided into normal PTH (≤600 pg/mL, nPTH) and high PTH (>600 pg/mL, hPTH) groups. Demographics, clinical characteristics, and transplant outcomes, including graft and patient survival, were analyzed. Results: The hPTH group (n = 16) was younger than the nPTH group (41.8 vs. 55.4 years, p < 0.001) and more likely to have English as a second language (62.5% vs. 35.6%, p = 0.032). They also had lower estimated post-transplant survival scores (29.3 vs. 52.0, p = 0.003) and higher rates of hyperphosphatemia (18.8% vs. 4.3%, p = 0.044). TUG pass rates, acute rejection, delayed graft function, and patient survival were similar between groups. However, the hPTH group demonstrated shorter mean graft survival (6.6 vs. 7.7 years, p = 0.022). On multivariable Cox regression, elevated PTH at transplantation remained independently associated with graft failure (adjusted hazard ratio 20.6, 95% CI 1.91–222). Conclusions: Elevated PTH at transplant was associated with poorer graft survival despite similar rejection rates and patient survival. Although not directly measured in this study, high PTH may reflect increased medical complexity or adherence-related challenges. Full article

Background/Objectives: Vonoprazan is a potassium-competitive acid blocker with potential for the treatment of equine gastric ulcer syndrome. Vonoprazan metabolic pathways in horses have not been characterized. This study aimed to identify vonoprazan metabolites following oral administration and to determine the metabolic enzymes responsible for their metabolism using in vitro models. Methods: Six healthy adult Thoroughbred horses received vonoprazan (0.5 and 1 mg/kg PO) in a randomized crossover design. Plasma concentrations of vonoprazan-N-oxide (M-I) and vonoprazan-nitrone (M-III) were quantified using a validated liquid chromatography-tandem mass spectrometry method, and a non-compartmental pharmacokinetic analysis was performed. In vitro metabolism was evaluated using equine liver microsomes (ELMs) and equine recombinant CYP450 (eq-rCYP) enzymes. Enzyme kinetics were characterized using nonlinear regression modeling. Results: Both metabolites were detected in plasma after oral administration. Systemic exposure to M-I was markedly greater than M-III at both doses. At 1 mg/kg, mean ± SD C_max values were 39.2 ± 28.3 ng/mL for M-I and 1.67 ± 1.66 ng/mL for M-III. AUC_0–∞ increased dose-proportionally for both metabolites. In ELMs, M-I formation followed substrate inhibition kinetics, whereas M-III formation followed Michaelis–Menten kinetics. Among recombinant enzymes, CYP2D50 and CYP3A94 were the primary contributors to metabolite formation, exhibiting metabolite-specific kinetic profiles. Conclusions: These findings demonstrate that vonoprazan undergoes hepatic oxidative metabolism in horses, with M-I as the predominant circulating metabolite. Equine recombinants CYP2D50 and CYP3A94 appear to play central roles in equine vonoprazan metabolism, providing foundation for future evaluation of drug–drug interaction potential and clinical use in this species. Full article

SARS-CoV-2 relies on a virus-encoded RNA capping pathway to produce 5′ cap structures that are essential for mRNA stability, efficient translation, and evasion of host innate immune surveillance. Within this pathway, nonstructural protein 14 (nsp14) catalyzes N7 methylation of the guanine cap, a key step that converts the cap core into a functional Cap-0 structure and enables subsequent maturation. Owing to its essential role in viral replication and its high conservation across coronaviruses, nsp14 has emerged as an attractive antiviral target. Recent structural and biochemical studies have elucidated the architecture of the nsp14 N7-methyltransferase domain, revealing an S-adenosyl-L-methionine (SAM)-dependent fold with a defined cofactor-binding site and an adjacent cap-binding pocket that orients the RNA substrate for methyl transfer. These insights have guided the development of diverse inhibitor classes, including SAM-competitive analogs, bisubstrate-like compounds, and non-nucleoside inhibitors identified through screening approaches. While early SAM-like inhibitors demonstrated target tractability, their therapeutic potential has been limited by challenges in selectivity and cellular permeability. More recent inhibitors that target the cap-binding pocket or exploit product-assisted ternary complex mechanisms highlight alternative strategies for achieving improved potency and specificity. Despite these advances, current structural models rely on truncated RNA substrates and isolated protein constructs, which may not fully capture the native catalytic environment. Future efforts to resolve nsp14 within the replication–transcription complex and develop novel inhibition strategies will be critical for advancing mechanistic understanding and antiviral development. Full article

Oaxaca is one of the most biocultural diverse regions in Mexico. Although the white-nosed coati (Nasua narica L.; Procyonidae, Mammalia) is widely used by Indigenous and rural communities throughout the Neotropics, its role within subsistence hunting, traditional food systems, and local management practices in Oaxaca has remained undocumented. This study analyzes the biocultural significance of N. narica hunting and consumption among four Indigenous groups in northern Oaxaca. Data were collected through ethnographic techniques, i.e., semi-structured interviews with locals, ethnozoological field trips, and participatory workshops conducted with Zoque, Zapotec, Chinantec, and Mazatec communities. In addition, an extensive literature review was carried out to contextualize and compare the field data. N. narica hunting is predominantly diurnal and collective, frequently involving dogs (Canis lupus familiaris) and horses (Equus ferus caballus), and fulfills at least three functions, including food provisioning, crop protection, and limited wild meat trade. N. narica meat is incorporated into traditional diet and prepared in at least five culturally distinct culinary forms. The use of N. narica reflects complex ethnoecological knowledge and long-term human–fauna interactions embedded within Indigenous livelihoods. These findings underscore the relevance of a biocultural ethnoecological approach for understanding subsistence hunting, wild meat use, and rural livelihoods in Mesoamerica. Full article