Search Results (12,519)

Objective: Visceral leishmaniasis (VL), a Neglected Tropical Disease caused by Leishmania donovani, remains insufficiently addressed by current therapies due to high toxicity, poor efficacy, and immunosuppressive complications. This study aimed to identify and characterize repurposed drugs that simultaneously target parasite-encoded and host-associated mechanisms essential for VL pathogenesis. Methods: Two complementary in silico drug repurposing strategies were employed. The first method utilized electron–ion interaction potential (EIIP) screening followed by molecular docking and molecular dynamics (MD) simulations targeting two L. donovani proteins: Rab5a and pteridine reductase 1 (PTR1). The second approach employed network-based drug repurposing using the Drugst.One platform, prioritizing candidates via STAT3-associated gene networks. Predicted drug–target complexes were validated by 100 ns MD simulations, and pharmacokinetic parameters were assessed via ADMET profiling using QikProp v7.0 and SwissADME web server. Results: Entecavir and valganciclovir showed strong binding to Rab5a and PTR1, respectively, with Glide Scores of −9.36 and −9.10 kcal/mol, and corresponding MM-GBSA ΔG_bind values of −14.00 and −13.25 kcal/mol, confirming their stable interactions and repurposing potential. Network-based analysis identified nifuroxazide as the top candidate targeting the host JAK2/TYK2–STAT3 axis, with high stability confirmed in MD simulations. Nifuroxazide also displayed the most favorable ADMET profile, including oral bioavailability, membrane permeability, and absence of PAINS alerts. Conclusions: This study highlights the potential of guanine analogs such as entecavir and valganciclovir, and the nitrofuran derivative nifuroxazide, as promising multi-target drug repurposing candidates for VL. Their mechanisms support a dual strategy targeting both parasite biology and host immunoregulation, warranting further preclinical investigation. Full article

Multimodal knowledge graphs have recently been successfully applied to tasks such as those relating to information retrieval, question and answer, and recommender systems. In this study, we propose a dual-path fine-tuning mechanism technique with a low-rank adapter and an embedded cueing layer, aiming to improve the generalization and accuracy of the model in analogical reasoning tasks. The low-rank fine-tuning (LoRA) technique with rank-stable scaling factor is used to fine-tune the MKGformer model, and a cue-embedding layer is innovatively added to the input layer, which enables the model to better grasp the scale of the relationship between entities according to the dynamic cue vectors during the fine-tuning process and ensures that the model achieves the best results during training. The experimental results show that the R-MKG model improves several evaluation indexes by more than 20%, which is significantly better than the traditional DoRA and FA-LoRA methods. This research provides technical support for multimodal knowledge graph analogical reasoning. We hope that our work will bring benefits and inspire future research. Full article

Background/Objectives: Understanding the stabilization mechanisms of amino acid conformations in different solvent environments is crucial for elucidating biomolecular interactions and crystallization processes. This study presents a comprehensive computational investigation of glycine, the simplest amino acid, in both its canonical and zwitterionic forms when interacting with dimethyl sulfoxide (DMSO) molecules. Methods: Using density functional theory (DFT) calculations at the B3LYP/6-311++G(d,p) level with empirical dispersion corrections, we examined the conformational landscape of glycine–DMSO clusters with one and two DMSO molecules, as well as implicit solvent calculations, and compared them with analogous water clusters. Results: Our results demonstrate that while a single water molecule is insufficient to stabilize the zwitterionic form of glycine, one DMSO molecule successfully stabilizes this form through specific interactions between the S=O and the methyl groups of DMSO and the NH₃⁺ and the oxoanion group of zwitterionic glycine, respectively. Topological analysis of the electron density using QTAIM and NCI methods reveals the nature of these interactions. When comparing the relative stability between canonical and zwitterionic forms, we found that two DMSO molecules significantly reduce the energy gap to approximately 12 kJ mol⁻¹, suggesting that increasing DMSO coordination could potentially invert this stability. Implicit solvent calculations indicate that in pure DMSO medium, the zwitterionic form becomes more stable below 150 K, while remaining less stable at room temperature, contrasting with aqueous environments where the zwitterionic form predominates. Conclusions: These findings provide valuable insights into DMSO’s unique role in biomolecular stabilization and have implications for protein crystallization protocols where DMSO is commonly used as a co-solvent. Full article

Piping systems can be analogized to the “vascular systems” of vessels, but their transmission characteristics often result in loud noises and large vibrations. The integration of flexible inserts within these piping systems has been shown to isolate and/or mitigate such vibrations and noise. In this work, a novel sandwich flexible insert (NSFI) was presented specifically to reduce the vibrations and noise associated with piping systems on vessels. In contrast to conventional flexible inserts, the NSFI features a distinctive three-layer configuration, comprising elastic inner and outer layers, along with a honeycomb core exhibiting a zero Poisson’s ratio. The dynamic characteristics, specifically axial impedance, of the fluid-filled NSFI are examined utilizing a fluid–structure interaction (FSI) four-equation model. The validity of the theoretical predictions is corroborated through finite element analysis, experimental results, and comparisons with existing literature. Furthermore, the study provides a comprehensive evaluation of the effects of geometric and structural parameters on the dynamic characteristics of the NSFI. It is worth noting that axial impedance is significantly affected by these parameters, which suggests that the dynamic characteristics of the NSFI can be customized by parameter adjustments. Full article

Arginine kinase is a key phosphagen kinase in invertebrates that facilitates rapid ATP regeneration by reversibly transferring phosphate groups between phosphoarginine and ADP. Structural studies have shown that the enzyme adopts distinct conformations in its ligand-free and ligand-bound states, known as the “open” and “closed” forms, respectively. These conformational changes are crucial for catalytic activity, enabling precise positioning of active-site residues and loop closure during phosphoryl transfer. Transition-state analog complexes have provided additional insights by mimicking intermediate states of catalysis, supporting the functional relevance of the open/closed structural model. Furthermore, studies across multiple species reveal how monomeric and dimeric forms of arginine kinase contribute to its allosteric regulation and substrate specificity. Beyond its metabolic role, arginine kinase is also recognized as a major allergen in crustaceans. Its structural uniqueness and absence in vertebrates make it a promising candidate for selective drug targeting. By integrating crystallographic data with functional context, this review highlights conserved features and species-specific variations of arginine kinase that may inform the design of inhibitors. Such molecules have the potential to serve both as antiparasitic agents and as novel therapeutics to manage crustacean-related allergic responses in humans. Full article

This study presents an algorithm for non-invasive blood pressure (BP) estimation in neonates using photoplethysmography (PPG), suitable for resource-constrained neonatal telecare platforms. Using the Windkessel model, the algorithm processes PPG signals from a MAX 30102 sensor, (Analog Devices (formerly Maxim Integrated), based in San Jose, CA, USA) filtering motion noise and extracting cardiac cycle time and systolic time (ST). These parameters inform a derived blood flow signal, the input for the Windkessel model. Calibration utilizes average parameters based on the newborn’s post-conceptional age, weight, and gestational age. Performance was validated against readings from a standard non-invasive BP cuff at SES Hospital Universitario de Caldas. Two parameter estimation methods were evaluated. The first yielded root mean square errors (RMSEs) of 24.14 mmHg for systolic and 19.13 mmHg for diastolic BP. The second method significantly improved accuracy, achieving RMSEs of 2.31 mmHg and 5.13 mmHg, respectively. The successful adaptation of the Windkessel model to single PPG signals allows for BP calculation alongside other physiological variables within the telecare program. A device analysis was conducted to determine the appropriate device based on computational capacity, availability of programming tools, and ease of integration within an Internet of Things environment. This study paves the way for future research that focuses on parameter variations due to cardiovascular changes in newborns during their first month of life. Full article

Low-frequency (LF) time code timing technology holds significant importance in civilian applications such as radio-controlled clocks. This study focuses on the design and implementation of a high-precision Binary Phase Code (BPC) LF time code signal generator. A generator system was constructed, demonstrating good stability, superior resolution, and flexible adjustment capabilities for both amplitude and phase. The system employs an ARM + FPGA cooperative architecture: the ARM processor is responsible for parsing and scheduling the time code data, while the FPGA implements carrier wave generation and high-precision digital modulation. This digital processing is combined with analog circuitry to achieve digital-to-analog (D/A) signal conversion. Compared to traditional methods, carrier generation is achieved using Direct Digital Synthesis (DDS) technology. Digital modulation techniques enable the precise control of the modulation depth (adjustable between 70% and 90%) and phase (with a resolution of 1 ns). A sliding window algorithm was utilized for time difference calculation and compensation. Testing confirmed the stability of key signal parameters, including integrity, carrier frequency and modulation depth. These results validate the feasibility and superiority of the digital LF time code generation technology proposed in this study, providing a valuable reference for the development of next-generation timing equipment. Full article

Semiclassical (SC) approximations for various representations of a quantum state are constructed on a single (Lagrangian) surface in the phase space but such surface is not available for chaotic systems. An analogous evolution surface underlies SC representations of the evolution operator, albeit in a doubled phase space. Here, it is shown that corresponding to the Fourier transform on a unitary operator, represented as a Green function or spectral Wigner function, a Legendre transform generates a resolvent surface as the classical basis for SC representations of the resolvent operator in the double-phase space, independently of the integrable or chaotic nature of the system. This surface coincides with derivatives of action functions (or generating functions) depending on the choice of appropriate coordinates, and its growth departs from the energy shell following trajectories in the double-phase space. In an initial study of the resolvent surface based on its caustics, its complex nature is revealed to be analogous to a multidimensional sponge. Resummation of the trace of the resolvent in terms of linear combinations of periodic orbits, known as pseudo orbits or composite orbits, provides a cutoff to the SC sum at the Heisenberg time. Here, it is shown that the corresponding actions for higher times can be approximately included within true secondary periodic orbits, in which heteroclinic orbits join multiple windings of relatively short periodic orbits into larger circuits. Full article

Study Design: Prospective observational study. Background: Lumbar spinal stenosis (LSS) impairs balance and gait function, increasing fall risk and limiting quality of life. Although postoperative recovery of balance is clinically important, longitudinal data using multidimensional balance assessments are limited. Methods: A prospective cohort study was conducted in 101 patients (mean age 74.9 ± 6.9 years) undergoing surgery for LSS. The Brief Balance Evaluation Systems Test (Brief BESTest), Oswestry Disability Index (ODI), Modified Falls Efficacy Scale (MFES), Zurich Claudication Questionnaire (ZCQ), and Visual Analog Scales (VAS) for pain/numbness were evaluated preoperatively and at 6 and 12 months postoperatively. Changes over time and correlations between Brief BESTest and PROMs were analyzed. Results: The total Brief BESTest score significantly improved from 13.3 ± 5.3 preoperatively to 16.1 ± 5.1 at 6 months and 16.0 ± 5.1 at 12 months (p < 0.01). Subdomains including Anticipatory Adjustments, Postural Responses, Sensory Orientation, and Stability in Gait improved significantly, while Stability Limits did not. At 12 months postoperatively, ODI decreased by 19.1%, ZCQ symptom and function scores improved by 0.8 and 0.9 points, respectively, and VAS scores improved by 17.1 mm for low back pain, 26.5 mm for lower limb pain, and 19.5 mm for numbness, all showing marked improvements from baseline. MFES also increased significantly postoperatively. The Brief BESTest score correlated significantly with MFES and ZCQ-PFS at baseline, and with ODI, ZCQ, and VAS scores at 12 months. Conclusions: Balance ability in LSS patients improved after surgery, as measured by the Brief BESTest, with clinically meaningful changes maintained for 12 months. Improvements in balance were significantly associated with reductions in pain, disability, and fear of falling, suggesting the Brief BESTest is a comprehensive indicator of postoperative recovery. Full article

Background: Metastatic melanoma is a highly aggressive malignancy with poor prognoses and frequent resistance to conventional chemotherapy. Approximately 40% of melanoma cases carry the BRAF^V600E mutation, for which vemurafenib, a selective BRAF^V600E inhibitor, is approved. Despite initial clinical benefits, vemurafenib often leads to drug resistance and relapse, highlighting the need for improved therapeutic strategies. Objectives, methods: In this study, we designed, synthesized, and characterized five novel vemurafenib analogs—RF-86A, RF-87A, RF-94A, RF-94B, and RF-96B—with the aim of enhancing anti-proliferative and anti-metastatic effects against human melanoma cells. Results: All compounds induced apoptosis in BRAF^V600E-mutated A375 cells, with RF-86A displaying the lowest IC₅₀ value among the series, comparable to that of vemurafenib. Moreover, RF-86A exhibited the highest selectivity index, as determined using HEK293T cells as a non-tumorigenic control. Additionally, migration assays and gelatin zymography demonstrated that the analogs, unlike vemurafenib, significantly inhibited matrix metalloproteinases MMP-2 and MMP-9, key enzymes involved in tumor invasion and metastasis. Conclusions: These findings suggest that structural modifications to the vemurafenib scaffold may improve therapeutic efficacy and offer a promising strategy to overcome acquired resistance. Full article

Background/Objectives: Mitotane is a key component in the treatment of adrenocortical carcinoma (ACC), but its endocrine side effects in children remain under-characterized. Methods: We conducted a retrospective analysis of 11 pediatric patients (6 males, 5 females) diagnosed with ACC and followed between 2000 and 2025. Seven received mitotane therapy. Data included age at diagnosis, treatment duration and dosage, serum mitotane levels, and endocrine complications. Results: The mean age at diagnosis was 6.6 ± 1.45 years, with a mean follow-up of 10.05 ± 2.45 years. Patients received mitotane for an average of 2.5 ± 0.54 years, with a mean daily dose of 2805.5 ± 145.82 mg and a mean serum level of 16.1 ± 5.92 mg/mL. All mitotane-treated patients developed adrenal insufficiency, requiring supraphysiological hydrocortisone replacement. Four also required mineralocorticoid therapy. Five developed precocious puberty; two males presented with prepubertal gynecomastia; three females were managed with GnRH analogs or aromatase inhibitors followed by estrogen receptor antagonists. Four patients developed central hypothyroidism, treated with levothyroxine. A positive correlation was found between mean serum mitotane levels and the onset of precocious puberty (p = 0.04), while mitotane levels correlated negatively with the development of central hypothyroidism (p = 0.001). Conclusions: Mitotane therapy in pediatric ACC is strongly associated with significant endocrine dysfunction. These findings emphasize the need for proactive, multidisciplinary endocrine management throughout treatment. Full article

For further investigation of the properties of the muon component in the core regions of extensive air showers (EASs), a new underground hodoscopic set-up with a total sensitive area of 22 m² was built at the Tien Shan High Mountain Cosmic Ray Station. The hodoscope is based on a set of large-sized scintillation charged particle detectors with an output signal of analog type. The installation ensures a (5–8) GeV energy threshold of muon registration and a ∼${10}^4$ dynamic range for the measurement of the density of muon flux. A program facility was designed that uses modern machine learning techniques for automated search for the typical scintillation pulse pattern in an oscillogram of a noisy analog signal at the output of the hodoscope detector. The program provides a ∼99% detection probability of useful signals, with a relative share of false positives below 1%, and has a sufficient operation speed for real-time analysis of incoming data. Complete verification of the hardware and software tools was performed under realistic operation conditions, and the results obtained demonstrate the correctness of the proposed method and its practical applicability to the investigation of the muon flux in EASs. In the course of the installation testing, a preliminary physical result was obtained concerning the rise of the multiplicity of muon particles around an EAS core in dependence on the primary EAS energy. Full article

The purpose of this work was to study the effects of lactoferrin (Lf) on acute (days 3 and 15) and early-delayed (day 30) changes in the dentate gyrus of mouse hippocampus caused by whole-body gamma-irradiation. Male C57BL/6 mice received Lf (4 mg per mouse, i.p. injection) immediately after whole-body gamma-irradiation at a dose of 7.5 Gy from a ⁶⁰Co source. The effect of Lf on mouse behavior was evaluated using “Open field” and “Elevated plus-maze” tests. The proportion of cells with DNA replication was determined by 5-ethynyl-2′-deoxyuridine incorporation (thymidine analog) and detected by a click reaction with azide Alexa Fluor 568. Lf treatment increased animal survival during the experiment (30 days), compensated for radiation-induced body weight loss, and prevented suppression of motor and exploratory activities. A pronounced anti-radiation effect of Lf on mouse brain cells has been demonstrated. A single injection of the protein allowed preserving 2-fold more proliferating cells and immature neurons in the dentate gyrus of the hippocampus of irradiated animals during the acute period of post-radiation injury development. Full article

This paper presents a microcontroller-based technique for accurately measuring resistive sensors over a wide dynamic range using an adaptive constant current source. Unlike conventional voltage dividers or fixed-current methods—often limited by reduced resolution and saturation when sensor resistance varies across several decades—the proposed system dynamically adjusts the excitation current to maintain optimal Analog-to-Digital Converter (ADC) input conditions. The measurement circuit employs a fixed reference resistor and an inverting amplifier configuration, where the excitation current is generated by one or more pulse-width modulated (PWM) signals filtered through low-pass RC networks. A microcontroller selects the appropriate PWM channel to ensure that the output voltage remains within the ADC’s linear range. To support multiple sensors, an analog switch enables sequential measurements using the same dual-PWM current source. The full experimental implementation uses four op-amps to support modularity, buffering, and dual-range operation. Experimental results show accurate measurement of resistances from 1 kΩ to 100 kΩ, with maximum relative errors of 0.15% in the 1–10 kΩ range and 0.33% in the 10–100 kΩ range. The method provides a low-cost, scalable, and digitally controlled solution suitable for embedded resistive sensing applications without the need for high-resolution ADCs or programmable gain amplifiers. Full article

Cancer-related cognitive impairment (CRCI)—encompassing anxiety, depression, and memory deficits—significantly diminishes the quality of life in patients with cancer, yet remains underrecognized in clinical practice. In this study, we investigated the therapeutic potential of tabernanthalog (TBG), a non-hallucinogenic analog of psychedelic compounds, as a novel intervention for CRCI using a Lewis lung carcinoma (3LL) mouse model. Behavioral assessments revealed heightened anxiety-like behavior and memory impairment following 3LL cell transplantation. Biochemical analysis revealed reduced tryptophan levels in both blood and hippocampal tissue, accompanied by the downregulation of serotonergic receptor genes and upregulation of pro-inflammatory cytokine genes in the hippocampus of tumor-bearing mice. Additionally, microglial density and morphological activation were markedly elevated. TBG treatment reversed these behavioral deficits, improving both anxiety-related behavior and memory performance. These effects were associated with the normalization of microglial density and morphology, as well as the restoration of serotonergic receptor and cytokine gene expression. In vitro, TBG partially suppressed neuroinflammatory gene expression in BV-2 microglial cells exposed to conditioned medium from 3LL cells. Collectively, these findings suggest that TBG alleviates CRCI-like symptoms by modulating neuroinflammation and microglial activation. This study highlights TBG as a promising therapeutic candidate for improving cognitive and emotional functioning in patients with cancer. Full article