Search Results (2,296)

Wireless power transfer (WPT) systems for autonomous underwater vehicles (AUVs) are gaining traction in marine exploration due to their operational convenience, safety, and flexibility. Nevertheless, disturbances from ocean currents and marine organisms frequently induce rotational, axial, and air-gap misalignments, significantly degrading the output power stability. To mitigate this issue, this paper proposes a novel reconfigurable WPT system utilizing coaxial antipodal dual DD (CAD-DD) coils, which strategically switches between a detuned S-LCC topology and a detuned S-S topology at a fixed operating frequency. By characterizing the output power versus the coupling coefficient (P-k) profiles under both reconfiguration modes, a parameter design methodology is developed to ensure stable power delivery across wide coupling variations. Experimental validation using a 1.2 kW AUV charging prototype demonstrates remarkable tolerance to misalignment: ±30° rotation, ±120 mm axial displacement, and 20–50 mm air-gap variation. Within this range, the output power fluctuation is confined to within 5%, while the system efficiency exceeds 85% consistently, peaking at 91.56%. Full article

Ceftazidime–avibactam (CAZ-AVI) is a second-generation intravenous β-lactam/β-lactamase inhibitor combination. In recent years, substantial evidence has emerged regarding the efficacy and safety of CAZ-AVI. However, data on its use in critically ill patients remain limited. Background/Objectives: This multicenter, retrospective, observational cohort study was conducted across four Intensive Care Units (ICUs) in three hospitals in the Marche region of Italy. The primary objective was to evaluate the 30-day clinical outcomes and identify risk factors associated with 30-day clinical failure—defined as death, microbiological recurrence, or persistence within 30 days after discontinuation of therapy—in critically ill patients treated with CAZ-AVI. Methods: The study included all adult critically ill patients admitted to the participating ICUs between January 2020 and September 2023 who received CAZ-AVI for at least 72 h for the treatment of a confirmed or suspected Gram-negative bacterial (GNB) infection. Results: Among the 161 patients included in the study, CAZ-AVI treatment resulted in a positive clinical outcome (i.e., clinical improvement and 30-day survival) in 58% of cases (n = 93/161), while the overall mortality rate was 24% (n = 38/161). Relapse or persistent infection occurred in a substantial proportion of patients (25%, n = 41/161). Notably, acquired resistance to CAZ-AVI was observed in 26% of these cases, likely due to suboptimal use of the drug in relation to its pharmacokinetic/pharmacodynamic (PK/PD) properties in critically ill patients. Furthermore, treatment failure was more frequent among immunosuppressed individuals, particularly liver transplant recipients. Conclusions: This study demonstrates that the mortality rate among ICU patients treated with this novel antimicrobial combination is consistent with findings from other studies involving heterogeneous populations. However, the rapid emergence of resistance underscores the need for vigilant surveillance and the implementation of robust antimicrobial stewardship strategies. Full article

Porcine circovirus type 2 (PCV2) is a globally prevalent swine pathogen that induces immunosuppression, predisposing pigs to subclinical infections. In intensive farming systems, PCV2 persistently impairs growth performance and vaccine efficacy, leading to substantial economic losses in the swine industry. Emerging evidence suggests that certain viruses exploit Suppressor of Cytokine Signaling 3 (SOCS3), a key immune checkpoint protein, to subvert host innate immunity by suppressing cytokine signaling. While SOCS3 has been implicated in various viral infections, its regulatory role in PCV2 replication remains undefined. This study aims to elucidate the mechanisms underlying the interplay between SOCS3 and PCV2 during viral pathogenesis. Porcine SOCS3 was amplified using RT-PCR and stably overexpressed in PK-15 cells through lentiviral delivery. Bioinformatics analysis facilitated the design of three siRNA candidates targeting SOCS3. We systematically investigated the effects of SOCS3 overexpression and knockdown on PCV2 replication kinetics and host antiviral responses by quantifying the viral DNA load and the mRNA levels of cytokines. PCV2 infection upregulated SOCS3 expression at both transcriptional and translational levels in PK-15 cells. Functional studies revealed that SOCS3 overexpression markedly enhanced viral replication, whereas its knockdown suppressed viral proliferation. Intriguingly, SOCS3-mediated immune modulation exhibited a divergent regulation of antiviral cytokines: PCV2-infected SOCS3-overexpressing cells showed elevated IFN-β but suppressed TNF-α expressions, whereas SOCS3 silencing conversely downregulated IFN-β while amplifying TNF-α responses. This study unveils a dual role of SOCS3 during subclinical porcine circovirus type 2 (PCV2) infection: it functions as a host-derived pro-viral factor that facilitates viral replication while simultaneously reshaping the cytokine milieu to suppress overt inflammatory responses. These findings provide novel insights into the mechanisms underlying PCV2 immune evasion and persistence and establish a theoretical framework for the development of host-targeted control strategies. Although our results identify SOCS3 as a key host determinant of PCV2 persistence, the precise molecular pathways involved require rigorous experimental validation. Full article

Background/Objectives: Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and currently is the second-leading cause of cancer-related mortality globally. Current front-line systemic therapies for advanced HCC offer only modest improvements in patient overall survival. HCC is a sexually dimorphic disease, and cancer progression is driven in part by AR activity. Here, we present novel niclosamide pro-drugs for use in advanced HCC based upon niclosamide’s known anti-AR activity and additional anti-cancer pathway efficacy. Methods: Niclosamide analogs were evaluated for their impacts on the AR protein in two HCC cell lines with different AR phenotypes. Amino acid conjugates of niclosamide were developed, and pharmacokinetic (PK) analyses were conducted to determine improvements in clearance and oral exposure. Finally, niclosamide analogs and amino acid conjugates were evaluated in an in vivo model of HCC. Results: Niclosamide analogs maintained anti-AR properties in HCC. Valine-conjugated niclosamide showed improved oral exposure, positioning it as a potential therapeutic in advanced HCC. Conclusions: Valine–niclosamide improves upon niclosamide’s poor solubility and oral bioavailability, increasing its utility for a variety of therapeutic uses. Further study of valine–niclosamide in advanced HCC and in other cancers or diseases is warranted. Full article

Icariin (ICA) is widely recognized for its health benefits. In this work, we examined the intermolecular interactions between ICA and proteinase K (PK) via multi-spectroscopic techniques and molecular simulations. The experimental findings revealed that ICA quenched the fluorescence emission of PK by forming a noncovalent complex. Both hydrogen bonding and van der Waals interactions are essential for the complex’s formation. Then Förster resonance energy transfer (FRET), competitive experiments, and synchronous fluorescence spectroscopy were adopted to verify the formation of the complex. Molecular docking studies demonstrated that ICA could spontaneously bind to PK by hydrogen bonding and hydrophobic interactions, which is consistent with the spectroscopic results. The PK-ICA complex’s dynamic stability was evaluated using a 50 ns molecular dynamics (MD) simulation. The simulation results revealed no significant structural deformation or positional changes throughout the entire simulation period. The complex appears to be rather stable, as seen by the average root-mean-square deviation (RMSD) fluctuations for the host protein in the PK-ICA complex of 1.08 Å and 3.09 Å. These outcomes of molecular simulations suggest that ICA interacts spontaneously and tightly with PK, consistent with the spectroscopic findings. The approach employed in this research presents a pragmatic and advantageous method for examining protein–ligand interactions, as evidenced by the concordance between empirical and theoretical findings. Full article

Background/Objectives: Current dosing recommendations for piperacillin/tazobactam suggest adjustments only for patients with creatinine clearance (CrCl) below 40 mL/min, potentially neglecting the variability in drug exposure among patients with a CrCl greater than 40 mL/min. This study aimed to develop a population pharmacokinetic (PK) model for piperacillin/tazobactam and explore optimal dosage regimens tailored by renal function and pathogen susceptibility. Methods: Twelve healthy adults received a single intravenous dose of piperacillin/tazobactam (4 g/0.5 g). Population PK models were developed using nonlinear mixed-effects modeling. Monte Carlo simulations were conducted to identify optimal dosing regimens across various renal functions and MIC levels, guided by pharmacodynamic targets defined as the percentage of time that free drug concentrations exceed the minimum inhibitory concentration (fT_>MIC). Results: PK profiles of both drugs were best described by two-compartment models. Estimated glomerular filtration rate (eGFR) adjusted by body surface area and body weight were identified as significant covariates influencing drug clearance and peripheral volume of distribution. Simulations showed that the standard dosing regimen (4/0.5 g q6h with 30 min infusion) achieved a 90% probability of target attainment (PTA) for 50%fT_>MIC at MIC values up to 4 mg/L in patients with normal renal function. However, this regimen often did not achieve a 90% PTA for stringent targets (100%fT_>MIC, 100%fT_>4MIC) or higher MICs, particularly in patients with eGFR ≥ 130 mL/min. Conclusions: These findings suggest current dosing regimens may be inadequate and highlight the potential of alternative strategies, such as extended or continuous infusion, which warrant further investigation in clinical populations to optimize therapeutic outcomes. Full article

The recent identification of early-onset mutational signatures with geographic variations by Diaz-Gay et al. is a significant finding, since early-onset colorectal cancer has emerged as an alarming public health challenge in the past two decades, and the pathomechanism remains unclear. Environmental risk factors, including lifestyle and diet, are highly suspected. The identification of colibactin from Escherichia coli as a potential pathogenic source is a major step forward in addressing this public health challenge. Therefore, the following opinion manuscript aims to outline the likely onset of the pathomechanism and the critical role of acquired Piezo2 channelopathy in early-onset colorectal cancer, which skews proton availability and proton motive force regulation toward E. coli within the microbiota–host symbiotic relationship. In addition, the colibactin produced by the pks island of E. coli induces host DNA damage, which likely interacts at the level of Wnt signaling with Piezo2 channelopathy-induced pathological remodeling. This transcriptional dysregulation eventually leads to tumorigenesis of colorectal cancer. Mechanotransduction converts external physical cues to inner chemical and biological ones. Correspondingly, the proposed quantum mechanical free-energy-stimulated ultrafast proton-coupled tunneling, initiated by Piezo2, seems to be the principal and essential underlying novel oscillatory signaling that could be lost in colorectal cancer onset. Hence, Piezo2 channelopathy not only contributes to cancer initiation and impaired circadian regulation, including the proposed hippocampal ultradian clock, but also to proliferation and metastasis. Full article

Infections caused by extended-spectrum β-lactamase-producing Enterobacterales (ESBL-Es) pose a significant global threat with notable increases in prevalence worldwide. Carbapenems are often used as the first line of treatment. However, their overuse accelerates resistance development, highlighting the urgent need for clinically viable carbapenem-sparing strategies. Cefmetazole (CMZ) and flomoxef (FMOX) are parenteral antibiotics that are widely used in Japan and have emerged as potential carbapenem alternatives. Repositioning these agents effectively addresses the clinical need for carbapenem-sparing strategies and outpatient ESBL-E management. This review aims to reposition CMZ and FMOX for real-world clinical practice by synthesizing basic research, clinical studies, and pharmacokinetics/pharmacodynamics (PKs/PDs) analyses, which suggest that these agents may be effective in treating ESBL-E infections—particularly urinary tract infections, as evidenced by their minimum inhibitory concentration (MIC) values. The clinical outcomes of these interventions have been comparable to those of carbapenems, which support their role in antimicrobial stewardship. Their PK/PD characteristics emphasize the importance of dose optimization to ensure therapeutic efficacy, whereas recent insights into resistance mechanisms provide a foundation for appropriate use. As novel antibiotic development takes substantial time, revisiting existing options is increasingly important. Notably, the Infectious Diseases Society of America’s 2024 guidance on antimicrobial resistance has omitted CMZ and FMOX, owing to which clinicians have limited guidance on their use, particularly in regions like Japan where these antibiotics are widely employed. By addressing this knowledge gap, the present review offers a comprehensive evaluation of these drugs and highlights their potential as intravenous agents in ESBL-E management. Furthermore, it highlights the ongoing challenge of ensuring effective oral step-down therapy in an outpatient setting to reinforce the global relevance of CMZ and FMOX in a broader treatment framework, underscoring their potential for outpatient administration where clinically appropriate. Full article

Hypoxia represents a critical environmental stressor in aquaculture, significantly disrupting aquatic organisms’ physiological homeostasis and thereby constraining the sustainable development of aquaculture industries. To elucidate the mechanisms underlying hypoxia-induced metabolic regulation in aquatic species, this study employed hybrid yellow catfish (Pelteobagrus vachelli ♀ × Leiocassis longirostris ♂) as a model organism to systematically investigate the multidimensional physiological responses in brain, liver, and muscle tissues under hypoxia (0.7 mg/L) and reoxygenation (7.0 mg/L) conditions. Through qRT-PCR and enzymatic activity analyses, we comprehensively assessed molecular alterations associated with oxygen sensing (HIF-1α gene), respiratory metabolism (PFKL, HK1, PK, CS, and LDHA genes and corresponding enzyme activities), oxidative stress (SOD1, SOD2, GSH-PX, and CAT genes, along with LPO, MDA, PCO, T-SOD, GSH-PX, and CAT levels), apoptosis (Caspase-3, Bax/Bcl-2), inflammatory response (IL-1β, IKKβ), and mitochondrial function (COXIV, PGC-1α, ATP5A1). Key findings demonstrated pronounced HIF-1α activation across all examined tissues. Hepatic tissues exhibited adaptive metabolic reprogramming from aerobic to anaerobic metabolism, whereas cerebral tissues displayed suppressed anaerobic glycolysis during prolonged hypoxia, and muscular tissues manifested concurrent inhibition of both glycolytic and aerobic metabolic pathways. Notably, skeletal muscle exhibited marked oxidative stress accompanied by mitochondrial dysfunction, exacerbated inflammation, and apoptosis activation during hypoxia/reoxygenation cycles. This study delineates tissue-specific adaptive mechanisms to hypoxia in yellow catfish, providing theoretical foundations for both piscine hypoxia physiology research and aquaculture practices. Full article

Purpose: Pellucid Marginal Degeneration (PMD) is a rare ectatic corneal disorder characterized by inferior peripheral thinning and significant irregular astigmatism. Despite its clinical similarities to keratoconus, PMD presents unique diagnostic and therapeutic challenges. This review aims to provide a comprehensive update on the pathophysiology, clinical features, diagnostic approaches, and management strategies for PMD, emphasizing the latest advancements in treatment options. Methods: A systematic literature search was performed in MEDLINE (via PubMed), Google Scholar, and Scopus up to February 2025 using the terms: “pellucid marginal degeneration,” “PMD,” “ectatic corneal disorders,” “keratoplasty in PMD,” “corneal cross-linking in PMD,” “ICRS in PMD,” “toric IOL PMD” and their Boolean combinations (AND/OR). The search was restricted to English-language studies involving human subjects, including case reports, case series, retrospective studies, clinical trials, and systematic reviews. A total of 76 studies met the inclusion criteria addressing treatment outcomes in PMD. Results: PMD is characterized by a crescent-shaped band of inferior corneal thinning, leading to high irregular astigmatism and reduced visual acuity. Diagnosis relies on advanced imaging techniques such as Scheimpflug-based corneal tomography, which reveals the characteristic “crab-claw” pattern. Conservative management includes rigid gas-permeable (RGP) lenses and scleral lenses, which provide effective visual rehabilitation in mild to moderate cases. Surgical options, such as CXL, ICRS, and toric IOLs, are reserved for advanced cases, with varying degrees of success. Newer techniques such as CAIRS, employing donor tissue instead of synthetic rings, show promising outcomes in corneal remodeling with potentially improved biocompatibility. Penetrating keratoplasty (PK) and deep anterior lamellar keratoplasty (DALK) remain definitive treatments for severe PMD, though they are associated with significant risks, including graft rejection and postoperative astigmatism. Conclusions: PMD is a complex and progressive corneal disorder that requires a tailored approach to management. Early diagnosis and intervention are critical to optimizing visual outcomes. While conservative measures are effective in mild cases, surgical interventions offer promising results for advanced disease. Further research is needed to refine treatment protocols and improve long-term outcomes for patients with PMD. Full article

The assessment of the efficacy of antiseizure medications (ASMs) in animal models of acute seizures has played a critical role in these drugs’ success in clinical trials for human epilepsy. One of the most widely used animal models for this purpose is the maximal electroshock seizure (MES) model. While there are numerous published reports on the efficacy of conventional ASMs in MES models, there is a need to expand the understanding on the brain concentrations that are needed to achieve optimal levels of efficacy in this model. We assessed the pharmacokinetic/pharmacodynamic (PK/PD) profiles of six ASMs, namely carbamazepine (CBZ), phenytoin (PHT), valproic acid (VPA), lacosamide (LSM), cenobamate (CNB), and retigabine (RTG), using MES models in mice and rats. EC₅₀ values for plasma and the brain were generally higher in mice than rats, with fold differences ranging from 1.3- to 8.6-fold for plasma and from 1.2- to 11.5-fold for brain. Phenytoin showed the largest interspecies divergence. These results suggest that rats may exhibit greater sensitivity to seizure protection in the MES model, likely reflecting species differences in metabolism and brain penetration. These findings highlight the value of considering concentration–response variations and species-specific differences when assessing the efficacy of both conventional ASMs and novel compounds exhibiting anticonvulsant activity. Full article

The mental health of prekindergarten (PK)-12th grade students is of extreme importance. Therapy dogs are a unique intervention to address mental health needs in educational frameworks. The purpose of this pilot study is to examine the components of a PK-12 district-wide therapy dog program and the implications for the mental health and well-being of students, faculty, and staff. This research used qualitative methods for semi-structured interviews with therapy dog handlers, observations including photographs, and researcher field notes of therapy dogs and handlers in their education environment. Thematic analysis of transcripts from semi-structured interviews was used for qualitative analysis. The results indicated that the strategic implementation of a district-wide therapy program supported a sustainable program that is integrated into the educational ecosystem. The participants perceived that the therapy dogs impacted mental health in the domains of social, emotional, and behavioral support. A district-wide systematic approach to addressing mental health and well-being needs of students, faculty, and staff with therapy dogs’ hinges on a comprehensive training and evaluation process, district-level support, and consistent implementation across educational settings. Therapy dogs can be embedded within educational structures to create a multilevel impact from the classroom to school to district level for a sustainable program. Therapy dogs positively contribute to the mental health and well-being of students, faculty, and staff in PK-12 education settings. Full article

Synthetic biology has fundamentally advanced cell engineering and helped to develop effective therapeutics such as chimeric antigen receptor (CAR)-T cells. For these applications, the detection, localization, and quantification of heterologous fusion proteins assembled from interchangeable building blocks is of high importance. The V5 tag, a 14-residue epitope tag, offers promising characteristics for these applications but has only rarely been used in this context. Thus, we have systematically evaluated the murine anti-V5 tag antibody mu_SV5-Pk1 as well as its humanized version, hu_SV5-Pk1, to analyze cells expressing V5-tagged receptors in samples from various in vitro and in vivo experiments. We found that the V5 tag signal on cells is affected by certain fixation and detachment reagents. Immunohistochemistry (IHC) on formalin-fixed paraffin-embedded (FFPE) mouse tissue samples was performed to sensitively detect cells in tissue. We improved IHC by applying the hu_SV5-Pk1 monoclonal antibody (mAb) to avoid cross-reactivity within and unspecific background signals arising on fixed mouse tissue. Conversely, the absence of unspecific binding by the mu_SV5-Pk1 mAb was evaluated on 46 human normal or cancer tissues. Our findings present a robust toolbox for utilizing the V5 tag and cognate antibodies in synthetic biology applications. Full article

This study investigated the isoforms of porcine-origin Ral guanine nucleotide dissociation stimulator (RalGDS) in LLC-PK1 cells using reverse transcription-polymerase chain reaction (RT-PCR) and sequencing. Through segmented amplification, sequence assembly, and comparative genomics analysis, seven RalGDS isoforms were identified, characterized by insertions, deletions, and frameshift mutations. These genetic variations may significantly alter RalGDS’s protein structure and function, potentially impacting its role in Ral GTPase-mediated signaling pathways. This work provides foundational insights into the genetic diversity of porcine RalGDS and its implications for porcine physiology and economically significant traits. Full article

Determining the optimal duration of antibiotic therapy for infections caused by multidrug-resistant Gram-negative bacteria (MDR-GNB) is a critical challenge in clinical medicine, balancing therapeutic efficacy against the risks of adverse effects and antimicrobial resistance. This narrative review synthesises current evidence and guidelines regarding antibiotic duration for MDR-GNB infections, emphasising bloodstream infections (BSI), hospital-acquired and ventilator-associated pneumonia (HAP/VAP), complicated urinary tract infections (cUTIs), and intra-abdominal infections (IAIs). Despite robust evidence supporting shorter courses (3–7 days) in uncomplicated infections caused by more susceptible pathogens, data guiding optimal therapy duration for MDR-GNB remain limited, particularly concerning carbapenem-resistant Enterobacterales (CRE), difficult-to-treat Pseudomonas aeruginosa (DTR-Pa), and carbapenem-resistant Acinetobacter baumannii (CRAB). Current guidelines from major societies, including IDSA and ESCMID, provide explicit antimicrobial selection advice but notably lack detailed recommendations on the duration of therapy. Existing studies demonstrate non-inferiority of shorter versus longer antibiotic courses in specific clinical contexts but frequently exclude critically ill patients or those infected with non-fermenting MDR pathogens. Individualised duration decisions must integrate clinical response, patient immunologic status, infection severity, source control adequacy, and pharmacologic considerations. Significant knowledge gaps persist, underscoring the urgent need for targeted research, particularly randomised controlled trials assessing optimal antibiotic duration for the most challenging MDR-GNB infections. Clinicians must navigate considerable uncertainty, relying on nuanced judgement and close monitoring to achieve successful outcomes while advancing antimicrobial stewardship goals. Full article