Unmasking metabolic endotoxemia: Proteinase K-enhanced detection of free and protein-associated endotoxin in human serum.

Transgenic overexpression of miR-486 and sAnk1.5 does not alter glucose handling in mice.

On diffusion-controlled Li-trapping in high energy Li-ion cells under fast discharge and freezing conditions

With the increasing integration of distributed energy resources and the growing variability of multiple loads, distribution networks face significant uncertainties in measurement data, line parameters, and topology. Traditional state estimation methods, such as weighted least squares, rely on accurate network parameters and are therefore highly sensitive to measurement noise and topology variations. To address these challenges, this work proposes a comprehensive data-driven framework for ADN state estimation that features a novel integration of an improved deep residual network (i-ResNet) and transfer learning. An improved deep residual network (i-ResNet) is developed to enable fast and robust state estimation without dependence on online parameters, even under uncertain data conditions. Furthermore, a transfer learning–based model is introduced to accommodate topology changes by leveraging historical data from multiple network configurations. Experimental studies on the IEEE 33-bus and 118-bus test systems are conducted to evaluate the performance of the proposed approach. The results demonstrate that the proposed method achieves higher accuracy and faster convergence than conventional techniques, with voltage magnitude errors consistently maintained below 1%.

Wave–wind energy conversion systems integrated have become an interesting alternative for enhancing the reliability of renewable power generation, mainly at maritime/coastal sites with severe resourcevariation. However, the interconnection of two very fluctuating energy sources impose great power quality challenges, dynamic stability and coordinated control. In this study, a new hybrid wave–wind system aimed at real time energy management and MPPT has been developed based on Fuzzy Logic –MPC driven MOPSO optimization algorithm is proposed. The proposed structure combines: (i) a Fuzzy Logic Controller (FLC) for adaptive MPPT control in non-linear and fast changing sea states; (ii) a Model Predictive Controller (MPC) for short-horizon optimisation of active/reactive power flows and converter dynamics; and, (iii), a MOPSO supervisory layer that continuouslymonitors the efficiency, power smoothness and mechanical stress system-wide.Numerical results indicate that the proposed FLC–MPC control is truly responsive to fast variations of wave height and wind turbulence, up to 22% improvement in MPPT tracking accuracy with respect to conventional approaches being reported. By allowing the system to adjust the number of optimal control parameters off grid the MOPSO algorithm achieves a 17% decrease in power oscillations, 28% improved energy capture ratio as well as significant decreases on turbine and point absorber mechanical loading. Moreover, the hierarchical mode guarantees that both the storage use and grid-connected operation are implemented in a coordinated manner, such that with complex ocean–wind disturbances, the voltage and frequency can be stably regulated.In conclusion, it can be noted that the multi-layer intelligent control approach satisfied energy capture maximum effort and system reliability, as well as improved power quality for in integrated wave–wind energy systems. This work provides a scalable platform for the next-generation marine renewable hybridization and enables the transition to sustainable offshore energy infrastructure and secure coastal microgrids.

Background/Objectives: Both HIV infection and antiretroviral therapy contribute to dyslipidemia and abnormal body fat distribution in people living with HIV (PLWH). Exercise training is an effective intervention to protect against these metabolic changes. However, little is known about the mechanisms underlying the impact of exercise training on lipid metabolism in PLWH. This study aimed to comparatively evaluate the effect of high-intensity functional circuit training on the plasma lipidome of PLWH and HIV-negative subjects (control). Methods: PLWH (n = 13) and control (n = 14) were submitted to 8 weeks of exercise training. Body composition, anthropometric, and biochemical parameters were measured. Plasma was obtained in a fasting state for lipidomic analysis. Results: Anthropometric and biochemical parameters revealed lower levels of leptin, HDL-C, body fat %, and BMI combined with elevated aspartate transaminase (AST) and Homeostasis Model Assessment of β-cell function (HOMA_beta) in PLWH when compared to control subjects that persisted from baseline to post-exercise training. Nonetheless, contrasting levels of adiponectin, fasting insulin, and phosphatidylcholine-containing lipids observed at baseline were equalized after training in PLWH. In control subjects, significant reductions in concentrations of triglycerides alongside phosphatidylinositol and glycosylated ceramides were observed post-exercise training. By contrast, PWLH displayed an increase in diglycerides, acylcarnitines, and free cholesterol levels after exercise training, together with decreased concentrations of free fatty acids, cholesteryl esters, and glycosylated ceramides. Conclusions: In addition to specific lipidome alterations in each group, particularly driven by improved insulin resistance in PLWH, this study showed concomitant modulation of several glycerophospholipids and sphingolipids, suggesting health-promoting effects of short-term exercise training. Collectively, these modulated lipid species represent interesting targets for future lipidomic-based studies evaluating not only the effects of exercise training but also the molecular mechanisms resulting in a healthier plasma lipidome profile.

Summary Background\Objectives Glucose-dependent insulinotropic polypeptide (GIP) is secreted by enteroendocrine K cells in response to nutrient ingestion. The aims of this study are: 1) to evaluate the cross-sectional associations between plasma GIP change in response to an oral glucose challenge (as a surrogate of GIP secretion) with obesity-related anthropometric measurements, fasting inflammatory biomarkers, and fasting circulating adipokines. 2) to evaluate the feasibility of using postprandial plasma GIP as a biomarker of adiposity-related phenotypes in response to starch-based meals. Methods Fifty normoglycemic women without obesity (19-32 years) were evaluated with an oral glucose tolerance test (OGTT). A feasibility study was conducted in a subset of eight women to estimate responses to starch-based meals (25 g of starch). Postprandial glycemic-related changes in plasma hormones/metabolites were assessed, as well as circulating adipokines and inflammatory biomarkers in fasting conditions. Results The Incremental-GIP change after 2-hour OGTT was significantly associated with waist circumference (rho=0.34; P=0.02), fasting plasma TNF-α (rho=0.54; P=0.0002), and white blood cell count (rho=0.39; P=0.008), but not with MCP-1, total adiponectin, leptin, or the free leptin index. A strong inverse association was found between incremental-GIP change and fasting plasma High-Molecular-Weight (HMW) Adiponectin (rho = -0.50; P = 0.0004), which remained significant after adjusting for age and body mass index. Conclusion An inverse association was found between postprandial GIP levels and circulating HMW-adiponectin levels in humans. This research highlights the suitability of using postprandial plasma GIP as a biomarker for metabolic disturbances of increased adiposity, even in the absence of obesity.

Levothyroxine (LT4) is recommended for intake in a fasting state to optimize absorption. However, fasting intake is often burdensome and may reduce adherence. In a previous questionnaire study, we observed a strong patient preference for taking LT4 with breakfast. Therefore, we conducted a randomized controlled trial to evaluate whether non-fasting LT4 intake ─accompanied by a 15% dose increase─ could maintain thyroid-stimulating hormone (TSH) stability compared to fasting LT4 intake. Adults with well-controlled hypothyroidism were randomized to fasting or dose-adjusted, breakfast LT4 intake. TSH, free T4 (FT4), and total T3 (TT3) were measured every six weeks, followed by LT4 dose adjustment if needed. The primary outcome was TSH stability, defined as two consecutive values within reference range and a maximum ±1 mIU/L change from baseline. Patients were followed until TSH stability was reached, with a maximum of 24 weeks. After the initial study period, patients in the fasting group were invited to cross over to non-fasting intake, with similar follow-up. Eighty-eight patients (80.7% female, median age 62y [IQR:49-69]) were randomized to fasting (n=43) or breakfast intake (n=45). TSH stability was comparable between groups: 74.4% (95%CI:61.0%-88.0%) in the fasting vs. 73.3% (95%CI:60.0%-87.0%) in the breakfast group (p=NS). Similar findings were observed in the crossover group. The breakfast group reported greater improvement in self-reported well-being (33.3% vs. 16.3%, p=0.07) and a stronger preference for non-fasting intake (76.2% vs. 44.2%, p<0.001). By the end of the study, 88.9% chose to continue non-fasting intake. LT4 ingestion with breakfast with a 15% dose increase, maintained TSH stability and improved patient well-being. Given the strong patient preference, this patient-centered approach may offer a viable alternative to fasting administration.

Typically, parent drug is measured for bioequivalence (BE) assessment because it's more sensitive to detect formulation differences, compared to its metabolite(s). For simvastatin immediate release (IR) tablets, current product-specific guidance (PSG) recommends measuring both parent and metabolite but taking metabolite as supportive data. This study aims to utilize physiologically based pharmacokinetic (PBPK) modeling and virtual BE (VBE) simulation to evaluate the sensitivity of parent vs metabolite as analyte on BE assessment, using simvastatin case and explore relevant mechanism. PBPK model was developed to describe drug exposures of parent drug simvastatin (SV) and metabolite simvastatin acid (SVA) in healthy individuals administered with 20-80mg IR tablets under fasting condition. VBE simulations were conducted to evaluate the sensitivity of SV and SVA as analytes to assess BE between test product and reference listed drug. PBPK model incorporating enzyme- and transporter-mediated kinetics reasonably captures fasting PK profiles for SV and SVA. VBE simulations indicate that parent drug, in general, is more sensitive to demonstrate BE as compared to metabolite. However, this study highlighted the importance of conducting BE analysis using PK data for both SV and SVA when the test product contains certain excipients in the formulation that may impact transporter activity for changing clearance and subsequent drug exposure of metabolite. The VBE simulation results further implied that in some cases, SVA as analyte is more sensitive to show drug exposure differences and may enhance the assessment of formulation effect, as compared to SV. This aligns with current PSG recommendations.

Alzheimer's disease (AD) blood biomarkers (BBMs) are increasingly used in clinical trials and clinical practice. However, widespread adoption of BBMs requires further understanding of factors that might influence the interpretation of these biomarkers which would allow for the development of standardized sample collection protocols. For example, studies of the effect of fasting on AD BBM concentrations have yielded inconsistent findings. In this study, we evaluated plasma concentrations of amyloid-beta(Aβ) 42, Aβ40, phosphorylated Tau (p-tau) 181, p-tau217, and neurofilament light chain (NfL) in cognitively normal individuals under fasting and non-fasting conditions. EDTA-plasma was collected from healthy donors (n=14; age >55yrs old) two weeks apart, at the same time of day. The first sample collection was under fasting conditions in which donors did not eat or drink (except water) for at least 12 hours prior to collection. The second sample collection was under non-fasting conditions in which donors were instructed to eat a meal in the morning, approximately half an hour prior to collection. Plasma Aβ42, Aβ40, p-tau181, p-tau217, and NfL concentrations were measured on the Fujirebio Lumipulse G1200 analyzer. Wilcoxon signed-rank test was used to compare values between the fasting and non-fasting results. Spearman's rank correlation was used to assess biomarker correlation between fasting status. Moderate to strong correlation was observed between the fasting and non-fasting measurements: p-tau217 (rs: 0.86), p-tau181 (rs: 0.89), NfL (rs: 0.94), p-tau217/Aβ42 (rs: 0.80), Aβ42/40 (rs: 0.66), Aβ42 (rs: 0.77), and Aβ40 (rs: 0.92). Average percent difference between the 2 conditions was: p-tau217 27%, p-tau181 6%, NfL 9%, p-tau217/ Aβ42 25%, Aβ42/40 4%, Aβ42 2%, and Aβ40 -6%. Statistically significant differences (p≤0.05) between fasting and non-fasting measurements were observed for p-tau217, NfL, p-tau217/Aβ42, Aβ42/Aβ40, and Aβ42; but not for Aβ40 or p-tau181. This data suggests that for some AD BBMs, there may be statistically significant differences in concentrations of samples collected in fasting versus non-fasting conditions. However, further studies are needed to determine if the observed differences may affect the clinical interpretation of these BBMs in individuals with amyloid related pathology.

ABSTRACTTo investigate if a newly developed tadalafil oral soluble film (OSF) was bioequivalent to the approved tadalafil tablets, a clinical study was conducted in healthy Chinese male volunteers under fasting conditions. In this study, 36 volunteers were randomized into three groups and received one tadalafil tablet, one tadalafil OSF with water, or one OSF without water in each period. The dosages were all 10 mg. Blood samples were collected and centrifuged. Plasma concentrations of tadalafil were determined by liquid chromatography tandem mass spectrometry. Pharmacokinetic (PK) parameters including maximum plasma concentration (Cmax), area under the concentration versus time curve (AUC) from dosing to the last sampling time (AUC0–t), AUC from administration to infinity (AUC0–∞), time to Cmax, half‐life and terminal elimination rate constant were calculated. Primary PK parameters including Cmax, AUC0–t, and AUC0–∞ were logarithmically transformed and an analysis of variance was applied to determine the bioequivalence between the reference and test formulation, as well as bioequivalence between tadalafil OSF administered with or without water. Safety was assessed by adverse events (AEs), serious adverse events (SAEs) and results of laboratory tests and examinations. The 90% confidence intervals of geometric mean ratios of primary PK parameters were all within the bioequivalence range of 80.00%–125.00%. AEs were mild or moderate and no SAEs were reported. Under fasting conditions, the test OSF formulation was bioequivalent to the reference tablets, and the test OSF administered with water was bioequivalent to that without water. All investigational formulations were well tolerated in the study.Trial Registration: chinadrugtrials.org.cn (CTR20181044).

Reassessing anhedonia in Genetic Absence Epilepsy: Sucrose preference unaltered by spike-wave discharges in WAG/Rij rats.

Combination of two Na+ channel-inhibiting anticonvulsants lacosamide and phenytoin: An additive, synergistic, or antagonistic effect?

Tamsulosin is a highly selective α1A adrenergic receptor antagonist that can relax smooth muscles in the urethra, bladder neck, and prostate and improve urinary disorders. It is therefore widely used to treat lower urinary tract symptoms caused by benign prostatic hyperplasia. The aim of this study is to evaluate the pharmacokinetic (PK) characteristics and bioequivalence of 2 different formulations (tamsulosin sustained-release tablets and tamsulosin sustained-release capsules) in healthy Chinese subjects. This study was a single-center, randomized, open label, 2-formulation, single-administration, 2-cycle, double-crossover fasting/postprandial bioequivalence trial that included 56 healthy volunteers (28 fasting and 28 postprandial). Blood samples were collected from volunteers after oral administration, plasma concentrations of tamsulosin were determined by liquid chromatography-tandem mass spectrometry for PK analysis, and the safety and tolerability of the drug were monitored. Under fasting and postprandial conditions, the 90% confidence intervals for maximum observed concentration (Cmax) and area under the plasma concentration-time curve from time 0 to the last sampling time (AUC0-t) of the test and reference formulations were within an acceptable range (80%-125%). All adverse events (AEs) were mild and no serious AEs were observed in the study. The subject formulation of tamsulosin extended-release tablets was safe and well tolerated in healthy Chinese Volunteers.

Volatile organic compounds (VOCs) in urine have shown increasing promise as non-invasive biomarkers for the early detection and monitoring of diseases. However, their volatile nature may make them highly susceptible to pre-analytical factors, presenting significant challenges for consistent biomarker discovery and reproducibility within metabolomic workflows. This study aimed to assess the impact of four critical pre-analytical variables, including fasting state, centrifugation procedures, room temperature (RT) stability, and freeze-thaw (FT) cycles, as well as intra- and inter-individual variability on the profiles of urinary VOC in general and volatile carbonyl compounds (VCC), in particular. Urine samples were analysed using headspace solid-phase microextraction coupled with gas chromatography-mass spectrometry (HS-SPME/GC-MS). Our findings demonstrate that, although multivariate analysis did not discriminate between fasting and non-fasting states, univariate analysis revealed that the levels of distinct VOCs and VCCs significantly differed between both states. The urinary VOC or VCC profiles were very similar under both standard centrifugation and sequential mild pre-centrifugation followed by ultracentrifugation. These findings suggest that supernatants obtained from assays involving ultracentrifugation are suitable for volatilome analysis. RT stability studies demonstrated that VOC profiles remain stable for up to 21h at RT, whereas VCC profiles showed alterations after 14h. Compound-specific variations were also observed following repeated FT cycles, with several VOCs disclosing significant changes after two cycles, while VCC profiles remained stable, with no significant alterations detected. Both intra- and inter-individual variability were high, as evidenced by relative standard deviations exceeding 30% for most compounds and intraclass correlation coefficients below 0.4, indicating limited temporal reliability over a 2.5-month period with eight timepoint collections. These findings underscore the essential role of pre-analytical standardization in urinary volatile analysis and support the implementation of rigorous protocols to enhance data reproducibility and biomarker discovery in metabolomics.

Peripheral renin-angiotensin system and cognitive decline in Parkinson's disease patients without co-morbidities.

This study evaluated the safety, tolerability, and pharmacokinetics of JBD0131, a novel nitroimidazooxazole antitubercular agent, in healthy adults. We previously reported JBD0131, a novel nitroimidazooxazole antitubercular agent, which overcomes drug resistance and bioavailability limitations of existing anti-tuberculosis therapies. The clinical trial was structured into three parts: an initial single ascending dose (SAD) phase under fasting conditions, a food-effect assessment, and a final multiple ascending dose (MAD) phase conducted after meals. Among 95 enrolled participants, JBD0131 demonstrated favorable safety and tolerability across all regimens. No serious adverse events (AEs) or treatment discontinuations occurred. Treatment-emergent AE incidence was comparable to placebo without dose-dependent trends. Pharmacokinetic (PK) analysis showed that systemic exposure for JBD0131, measured by maximum plasma concentration (C max) and area under the plasma concentration-time curve (AUC), increased proportionally with the dose. The presence of food significantly enhanced the bioavailability and delayed the median time to reach peak concentration (T max) by approximately 2 h. These findings collectively demonstrate that JBD0131 has an acceptable safety profile and predictable, linear pharmacokinetics in healthy adults. The observed food effect, which boosts systemic exposure, along with the drug's linear accumulation, supports the need for further investigation to define optimal treatment regimens for future clinical development.

This study assessed the pharmacokinetics (PK) and bioequivalence (BE) of valsartan and amlodipine (80/5mg) tablets in healthy Chinese subjects under fasting and fed conditions. A randomized, open-label, four-period crossover trial was conducted, with participants receiving test (T) or reference (R) formulations in cycles separated by a 14-day washout. Plasma concentrations of valsartan and amlodipine were measured using high-performance liquid chromatography-tandem mass spectrometry. PK parameters were analyzed noncompartmentally, and BE was evaluated using reference-scaled average bioequivalence (RSABE) for high-variability parameters (CVW ≥ 30%) and average bioequivalence (ABE) for low-variability parameters (CVW < 30%). Under fasting conditions, the maximum concentration of drug in blood plasma (Cmax) of valsartan was assessed using RSABE methodology and demonstrated bioequivalence. For amlodipine, bioequivalence was established through conventional ABE analysis, with the 90% confidence intervals (CIs) for the geometric mean ratios (GMRs) of Cmax, AUC0-t, and AUC0-∞ all residing within the predefined equivalence boundaries. Under postprandial conditions, both drugs met BE criteria using ABE, with 90% CIs of GMRs within the acceptable range. Importantly, postprandial administration resulted in a significant reduction of approximately 30% in systemic exposure of valsartan for both test and reference formulations. All adverse events were mild and transient. The T and R formulations demonstrated bioequivalence and were well tolerated, supporting their interchangeability.

Beyond phototoxicity: The dark side of new methylene blue on mitochondrial and cellular bioenergetics.

Abstract Quantum state transfer is investigated beyond the nearest-neighbour coupling scheme in long spin-1/2 linear chains. Exploiting the properties of the next-nearest neighbour Hamiltonian's dispersion relation, it is shown that with minimal engineering, i.e., an on-site magnetic field on the two end sites and only a few symmetrically-modified end inter-site couplings, an average transfer fidelity above 99% can be achieved. To leading order, the required time scales linearly with the length of the chain. Such a fast, high-quality quantum state transfer is based on the ballistic propagation of the wave packet centred in the linear region of the dispersion relation by means of the on-site magnetic field. At the same time, the wave packet width, modulated by the inter-site couplings at the chain ends, whose values are found via a carefully designed genetic algorithm, is constrained mostly in the linear region of the dispersion relation. Our coupling scheme is shown to hold for arbitrary values of the next-nearest inter-site coupling and can be straightforwardly applied to longer-range coupling schemes.