Search Results (161)

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder characterized by impaired mucociliary clearance due to defects in motile cilia. This study investigates the impact of loss-of-function mutations in the CFAP300 gene on the ciliary structure and function in three PCD patients. Using a multimodal approach, we integrated molecular genetic testing, transmission electron microscopy, the high-speed video microscopy assay and immunofluorescence staining to analyze ciliary motility and protein expression in both ex vivo and in vitro-obtained ciliary cells. Our results revealed that the pathogenic variant c.198_200delinsCC (p.Phe67ProfsTer10) in CFAP300 led to the absence of the functional CFAP300 protein, the complete loss of outer and inner dynein arms and immotile cilia. Air–liquid interface (ALI)-cultured cells from patients exhibited no ciliary beating, contrasting with healthy controls. Immunostaining confirmed the absence of CFAP300 in patient-derived cilia, underscoring its critical role in dynein arm assembly. These findings highlight the diagnostic utility of ALI cultures combined with functional and protein analyses for PCD, offering a clinically actionable framework that can be readily incorporated into standard diagnostic workflows. Full article

Neuropathic pain is a significant global clinical issue that poses substantial challenges to both public health and the economy due to its complex underlying mechanisms. It has emerged as a serious health concern worldwide. Recent studies involving dorsal root ganglion (DRG) stimulation have provided strong evidence supporting its effectiveness in alleviating chronic pain and its potential for sustaining long-term pain relief. In addition to that, there has been ongoing research with clinical evidence relating to the role of small non-coding ribonucleic acids known as microRNAs in regulating gene expressions affecting pain signals. The signal pathway involves alterations in neuronal excitation, synaptic transmission, dysregulated signaling, and subsequent pro-inflammatory response activation and pain development. When microRNAs are dysregulated in the dorsal root ganglia neurons, they polarize macrophages from anti-inflammatory M2 to inflammatory M1 macrophages causing pain signal generation. By reversing this polarization, a therapeutic activity can be induced. However, the direct delivery of these nucleotides has been challenging due to limitations such as rapid clearance, degradation, and reduction in half-life. Therefore, safe and efficient carrier vehicles are fundamental for microRNA delivery. Here, we present a comprehensive analysis of miRNA-based nano-systems for chronic neuropathic pain, focusing on their impact in dorsal root ganglia. This review provides a critical evaluation of various delivery platforms, including viral, polymeric, lipid-based, and inorganic nanocarriers, emphasizing their therapeutic potential as well as their limitations in the treatment of chronic neuropathic pain. Innovative strategies such as hybrid nanocarriers and stimulus-responsive systems are also proposed to enhance the prospects for clinical translation. Serving as a roadmap for future research, this review aims to guide the development and optimization of miRNA-based therapies for effective and sustained neuropathic pain management. Full article

Pregnancy introduces significant physiological changes that alter the pharmacokinetics (PK) of antiretroviral therapy (ART), impacting its safety and efficacy in HIV-positive women. Optimizing ART during pregnancy is critical to maintaining maternal virological suppression and preventing mother-to-child transmission (MTCT) of HIV. This review evaluates the impact of pregnancy-induced PK changes on ART and proposes strategies for tailored regimens to improve outcomes. A comprehensive review of published literature was conducted, focusing on PK adaptations during pregnancy and their implications for different ART classes, including protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), and nucleoside reverse transcriptase inhibitors (NRTIs). Key studies were analyzed to assess drug exposure, efficacy, and safety. Pregnancy significantly alters the PK of antiretrovirals, with increased hepatic metabolism, renal clearance, and changes in plasma protein binding leading to reduced drug exposure. For example, drugs like lopinavir and atazanavir require dose adjustments, while dolutegravir maintains efficacy despite reduced plasma levels. Integrase inhibitors demonstrate favorable virological suppression, although cobicistat-boosted regimens show subtherapeutic levels. Tailored approaches, such as therapeutic drug monitoring (TDM), optimize ART efficacy while minimizing toxicity. Pregnancy-specific PK changes necessitate evidence-based ART adjustments to ensure virological suppression and reduce MTCT risk. Incorporating TDM, leveraging pharmacogenomic insights, and prioritizing maternal and neonatal safety are critical for personalized ART management. Further research into long-acting formulations and global guideline harmonization is needed to address disparities in care and improve outcomes for HIV-positive pregnant women. Full article

An unprecedented outbreak of Oropouche virus (OROV) is occurring in the Americas, characterized by thousands of confirmed cases and a wide geographical spread, including areas outside the Amazon Basin. Little is known about this neglected arbovirus regarding its pathophysiological aspects and potentially different transmission modes. This study describes the clinical course of a man who returned from a trip to Cuba and presented to our hospital 4 days after the onset of febrile symptoms. The patient was diagnosed with Oropouche fever and was followed for 177 days after the onset of symptoms. We performed a longitudinal investigation of the samples collected from several body sites (whole blood, serum, urine, and semen) with the aim of providing further insights into OROV infection dynamics, using the detection of antigenomic RNA as a marker of active viral replication. Clinical samples that were longitudinally collected over the course of OROV infection showed consistently higher amounts of antigenomic RNA compared to genomic RNA, even after viral clearance from serum. Moreover, our case study showed the persistence of OROV RNA in serum of less than 15 days from the onset of symptoms, as compared to up to one month in urine, three months in semen, and four months in whole blood. Our study suggests that Oropouche virus may persist in an actively replicating state in different body sites for long periods of time, with important implications for transmission dynamics. Furthermore, our results provide a diagnostic indication, suggesting that serum is inferior to both urine and whole blood as preferred diagnostic samples. Further studies are needed to determine the pathogenetic implications of these findings, as they have been derived from a single case and must be confirmed using a larger number of cases. Full article

Pseudomonas aeruginosa is a gram-negative opportunistic pathogen that poses a significant threat due to its increasing multidrug resistance, particularly in clinical settings. This study aimed to isolate and characterize a novel bacteriophage, phiLCL12, from hospital wastewater and evaluate its potential in combination with antibiotics to combat P. aeruginosa infections and biofilm formation. Transmission electron microscopy revealed that phiLCL12 possesses a long contractile tail. The isolated phage exhibited a broad host range of 82.22% and could adsorb up to 98% of its target within 4 min. It was effective against multidrug-resistant strains at both high and low multiplicities of infection (MOIs) levels in lysis tests. Taxonomic classification was determined using PhaGCN2 and Whole genomic analysis, and the results identified phiLCL12 as a member of the Pbunavirus. In vitro experiments demonstrated that phiLCL12 significantly enhanced biofilm clearance and inhibited biofilm formation when combined with sub-inhibitory concentrations of imipenem. Furthermore, in vivo experiments using a zebrafish model showed that phage–antibiotic synergy (PAS) improved survival rate compared to antibiotic treatment alone. This study demonstrates that phiLCL12 is effective in both eradicating and preventing P. aeruginosa biofilm formation. The combination of phiLCL12 and imipenem provides a synergistic effect, significantly enhancing survival outcomes in a zebrafish model. These findings highlight the potential of phage–antibiotic synergy as a promising therapeutic strategy against biofilm-associated infections. Full article

Background/Objectives: Lipoxins, particularly Lipoxin A4 (LXA4), are endogenous lipid mediators with potent anti-inflammatory and pro-resolving properties, making them promising candidates for the treatment of inflammatory and neurodegenerative disorders. However, their therapeutic application is limited by poor stability and bioavailability. This study aimed to develop and characterize nanomicelles encapsulating LXA4 (nano-lipoxin A4) to improve its pharmacological efficacy against Alzheimer’s disease (AD), a neurodegenerative condition marked by chronic inflammation and beta-amyloid (Aβ) accumulation. Methods: Nano-lipoxin A4 was synthesized using Pluronic F-127 as a carrier and characterized in terms of morphology, physicochemical stability, and in vitro activity against Aβ fibrils. Dissociation of Aβ fibrils was assessed via Thioflavin-T fluorescence assays and transmission electron microscopy. In vivo biodistribution and pharmacokinetic profiles were evaluated using technetium-99m-labeled nano-lipoxin A4 in rodent models. Hepatic biochemical parameters were also measured to assess potential systemic effects. Results: In vitro studies demonstrated that nano-lipoxin A4 effectively dissociated Aβ fibrils at concentrations of 50 nM and 112 nM. Electron microscopy confirmed the disruption of fibrillar structures. In vivo imaging revealed predominant accumulation in the liver and spleen, consistent with reticuloendothelial system uptake. Pharmacokinetic analysis showed a prolonged half-life (63.95 h) and low clearance rate (0.001509 L/h), indicating sustained systemic presence. Biochemical assays revealed elevated liver enzyme levels, suggestive of increased hepatic metabolism or potential hepatotoxicity. Conclusions: Nano-lipoxin A4 exhibits significant therapeutic potential for Alzheimer’s disease through effective modulation of Aβ pathology and favorable pharmacokinetic characteristics. However, the elevation in liver enzymes necessitates further investigation into systemic safety to support clinical translation. Full article

In the past 5 years, the COVID-19 pandemic has experienced frequently changing variants contextualizing immune evasion. The emergence of Omicron with >30–50 mutations on the spike gene has shown a sharp divergence from its relative VOCs, such as WT, Alpha, Beta, Gamma, and Delta. The requisition of prime boosting was essential within 3–6 months to improve the Nab response that had been not lasted for longer. Omicron subvariant BA.1.1 was less transmissible, but with an extra nine mutations in next variant BA.2 made it more transmissible. This remarkable heterogeneity was reported in ORF1ab or TRS sites, ORF7a, and 10 regions in the genomic sequences of Omicron BA.2 and its evolving subvariants BA.4.6, BF.7, BQ.2, BF. 7, BA.2.75.2, and BA.5 (BQ.1 and BQ.1.1). The mutational stability of subvariants XBB, XBB 1, XBB 1.5, and XBB 1.6 conferred a similar affinity towards ACE-2. This phenomenon has been reported in breakthrough infections and after booster vaccinations producing hybrid immunity. The reduced pathogenic nature of Omicron has implicated its adaptation either through immunocompromised individuals or other animal hosts. The binding capacity of RBD and ACE-2, including the proteolytic priming via TMPRSS2, reveals its (in-vitro) transmissibility behavior. RBD mutations signify transmissibility, S1/S2 enhances virulence, while S2 infers the effective immunogenic response. Initial mutations D614G, E484A, N501Y, Q493K, K417N, S477N, Y505H, and G496S were found to increase the Ab escape. Some mutations such as, R346K, L452R, and F486Vwere seen delivering immune pressure. HR2 region (S2) displayed mutations R436S, K444T, F486S, and D1199N with altered spike positions. Later on, the booster dose or breakthrough infections contributed to elevating the immune profile. Several other mutations in BA.1.1-N460K, R346T, K444T, and BA.2.75.2-F486S have also conferred the neutralization resistance. The least studied T-cell response in SARS-CoV-2 affects HLA- TCR interactions, thus, it plays a role in limiting the virus clearance. Antigenic cartographic analysis has also shown Omicron’s drift from its predecessor variants. The rapidly evolving SARS-CoV-2 variants and subvariants have driven the population-based immunity escape in fully immunized individuals within short period. This could be an indication that Omicron is heading towards endemicity and may evolve in future with subvariants could lead to outbreaks, which requires regular surveillance. Full article

Airports are complex environments where efficient localization and intelligent traffic management are essential for ensuring smooth navigation and operational efficiency for both pedestrians and Autonomous Guided Vehicles (AGVs). This study presents an Artificial Intelligence (AI)-driven airport traffic management system that integrates Visible Light Communication (VLC), rerouting techniques, and adaptive reward mechanisms to optimize traffic flow, reduce congestion, and enhance safety. VLC-enabled luminaires serve as transmission points for location-specific guidance, forming a hybrid mesh network based on tetrachromatic LEDs with On-Off Keying (OOK) modulation and SiC optical receivers. AI agents, driven by Deep Reinforcement Learning (DRL), continuously analyze traffic conditions, apply adaptive rewards to improve decision-making, and dynamically reroute agents to balance traffic loads and avoid bottlenecks. Traffic states are encoded and processed through Q-learning algorithms, enabling intelligent phase activation and responsive control strategies. Simulation results confirm that the proposed system enables more balanced green time allocation, with reductions of up to 43% in vehicle-prioritized phases (e.g., Phase 1 at C1) to accommodate pedestrian flows. These adjustments lead to improved route planning, reduced halting times, and enhanced coordination between AGVs and pedestrian traffic across multiple intersections. Additionally, traffic flow responsiveness is preserved, with critical clearance phases maintaining stability or showing slight increases despite pedestrian prioritization. Simulation results confirm improved route planning, reduced halting times, and enhanced coordination between AGVs and pedestrian flows. The system also enables accurate indoor localization without relying on a Global Positioning System (GPS), supporting seamless movement and operational optimization. By combining VLC, adaptive AI models, and rerouting strategies, the proposed approach contributes to safer, more efficient, and human-centered airport mobility. Full article

Time-varying mesh stiffness (TVMS) of the internal mesh transmission is a significant source of excitation that causes vibration and noise in planetary gear systems, and is also an important parameter in dynamics analysis. Currently, the calculation of mesh stiffness for internal gear pairs primarily relies on finite element simulation, and there still lacks a mesh stiffness analytical model that accounts for tooth surface nonlinear contact. Therefore, this paper proposes an analytical model for nonlinear contact mesh stiffness that comprehensively accounts for tooth surface modification and the flexibility of the ring gear. Firstly, a mesh stiffness calculation model for a sliced tooth pair was established using the potential energy method, which accounted for the influence of gear ring flexibility. Secondly, the tooth deviation ease-off diagram was derived from the modified tooth surface equations, which provided data support for the nonlinear contact analysis. On this basis, slicing element pairs that met the contact conditions were identified by combining elastic deformation with mesh clearance. The comprehensive mesh stiffness in nonlinear contact was calculated by integrating the deformation coordination equation with the principle of minimum potential energy. Finally, using a group of internal helical gear pairs as an example, the validity of the proposed method was verified through finite element simulation. The effects of load, modification amount, and face width on the TVMS and load transmission error (LTE) of an internal helical gear pair were investigated by the analytical model. The results show that the analytical model can provide a reference for the optimal design of internal gear transmission. Full article

Introduction: Freshwater snails, particularly snails from the genus Biomphalaria, play a key role in the transmission of schistosomiasis, a parasitic disease prevalent in tropical regions. Schistosomiasis poses a significant public health challenge in these regions, leading to chronic illness, reduced productivity, and impaired childhood development, particularly in communities with limited access to healthcare and sanitation. Understanding the seasonal and spatial variations in snail populations and infection rates is crucial for controlling schistosomiasis, especially in areas like Southwest Ethiopia, where the disease burden is high. Methods: This study was conducted in Mizan Aman, Southwest Ethiopia, across two seasons, dry and wet. A total of 1150 snail samples were collected from 20 freshwater sites, and their species, abundance, and infection status were assessed. Environmental parameters, including temperature, pH, salinity, and conductivity, were measured to analyze their impact on snail populations. Results: Four snail species were identified, Biomphalaria pfeifferi, Biomphalaria sudanica, Lymnaea natalensis, and Bulinus globosus, with B. pfeifferi and B. sudanica being the most prevalent. Snail abundance varied by site and season, with 598 in the dry season and 552 in the wet season. Snail abundance and species composition showed significant spatial variation, with higher counts in sites like Sasin and Agu 1, while some sites had no snails. Biomphalaria snails, particularly B. pfeifferi, are the principal intermediate host for Schistosoma mansoni. The overall prevalence of Biomphalaria snails exceeded 85% in both seasons, and their average infection rate in Mizan Aman was 13.5%. This infection rate showed a strong correlation (r = 0.733, p < 0.001) with the incidence of schistosomiasis cases in the community. Seasonal variation in environmental factors, such as temperature and pH, had no significant effect on snail abundance; however, water salinity showed to be correlated with snail abundance during the dry season. Furthermore, community-led vegetation clearance at selected sites significantly reduced snail abundance. Conclusions: This study highlights the seasonal and spatial dynamics of freshwater snails, particularly Biomphalaria species, in relation to schistosomiasis transmission in Mizan Aman, Southwest Ethiopia. The findings confirm that B. pfeifferi species is the predominant intermediate host for schistosoma in this region and that schistosomiasis infection rates among snails significantly correlate with human cases in the community. While environmental factors such as temperature and pH showed no significant influence on snail abundance, water salinity had an impact during the dry season. Additionally, community-led vegetation clearance was an effective intervention in reducing snail populations. These results emphasize the need for targeted, site-specific control measures integrating ecological and community-based interventions to sustainably reduce schistosomiasis transmission. Full article

The nonlinear contact force between gears and bearings exhibits intricate dynamics. This paper focuses on the coupling relationship between the time-varying meshing parameters of the gears, dynamic backlash, and dynamic bearing clearance in gear-bearing transmission systems. A dynamic model of a gear-bearing transmission system considering dynamic meshing parameters is established. The coupling mechanism between meshing stiffness, gear backlash, bearing clearance, and gear vibration response in gear transmission systems is analyzed. The results demonstrate a negative correlation between the gears’ geometric center distance and meshing stiffness amplitude. Gear vibration can affect the relative position of the gears. Changes in the relative position of the gears lead to an increase in the number of frequency components in the frequency domain of gear meshing stiffness. During gear rotation, the meshing parameters of the gears and tooth side clearance fluctuate with gear vibration. With increasing speed, the model’s dynamic meshing parameters also increase accordingly. The model achieves a feedback calculation of the system parameters and vibration responses in gear-bearing system dynamics. Full article

Scutellaria baicalensis Gorg is a medicinal herb of significant value in traditional Chinese medicine. Root rot is a major issue in S. baicalensis-producing areas. The aim of this study was to evaluate whether indole-3-carboxaldehyde, a metabolite derived from Purpureocillium lilacinum, has a significant effect on Fusarium solani (one of the main pathogenic fungi causing S. baicalensis root rot), and to clarify its antifungal mechanism. We evaluated the toxicity of indole-3-carboxaldehyde to F. solani using the growth rate assay and found that the EC₅₀ value was 59.563 μg/mL; we also performed additional pot experiments under greenhouse conditions. The effects of indole-3-carboxaldehyde on fungal hyphal morphology and ultrastructure were evaluated through scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Indole-3-carboxaldehyde was found to induce the disintegration of the mitochondrial double membrane in F. solani, as well as cause cell wall separation. Further probing into the effects of indole-3-carboxaldehyde on mitochondrial aspects was conducted using enzyme activity test kits and real-time quantitative PCR. The findings indicated that indole-3-carboxaldehyde decreases the mitochondrial membrane potential; reduces the activities of SOD, CAT, POD, and GR enzymes; and hampers the growth of F. solani by suppressing the activity of mitochondrial electron transport chain complex I, resulting in H₂O₂ accumulation. This disruption of the mitochondrial antioxidant pathway impedes the effective clearance of reactive oxygen species (ROS), ultimately leading to the death of F. solani. Future studies of indole-3-carboxaldehyde should focus on its effect on metabolic pathways, which could facilitate the development of innovative pesticides. Full article

Tip leakage flow interacts with the mainstream, impacting the energy transmission process within the impeller of the fan and causing a significant flow loss. Understanding the flow characteristics within the impeller is a prerequisite and foundation for achieving efficient operation of the fan. Therefore, numerical simulations and experimental methods were employed to obtain the internal flow field of the mining counter-rotating axial flow fan, and the influence of flow rate on the tip leakage flow pattern was mastered. The spatial trajectory of the leakage vortex was quantified, and the distribution characteristics of the backflow were explored. The mechanism of energy loss caused by the leakage flow was revealed. The research findings indicate that when the flow rate exceeds 1.0 Q_BEP (Q_BEP is flow rate at the best efficiency point), the complex flow field near the blade tip is mainly caused by the tip leakage flow. However, the tip leakage flow and the leading edge overflow are the main factors causing disturbances in the flow field within the impeller at small flow rates. At large flow rates, the starting positions of the tip leakage vortex cores for both the front and rear impellers are located near the middle of the blade tip. As the flow rate decreases, the starting position of the vortex core gradually shifts toward the leading edge point, and the vortex structure evolves from an initial circular shape to an elliptical shape. The tip leakage flow and the leading edge overflow are the main cause of the backflow at the impeller inlet. The helical vortices caused by the tip leakage flow and the leading edge overflow, as well as the backflow in the impeller, are the key factors causing energy loss in the tip clearance flow field. Full article

Spring viremia of carp virus (SVCV) is a significant pathogen that has notably hindered the advancement of cyprinid aquaculture in recent years. Infections caused by SVCV are often associated with substantial economic losses due to the absence of effective treatment options. Previous reports indicated that N-(4-methyl-2-oxo-2H-chromen-7-yl) benzenesulfonamide (N6) exhibits inhibitory effects on SVCV proliferation. This study aims to comprehensively evaluate the anti-SVCV effects of N6 using healthy young carp as the experimental model. The research investigates the antiviral activity of this compound in vivo, the immune response of interferon (IFN)-related genes, its impact on the horizontal transmission of SVCV, and histopathological changes. The results indicate that N6 significantly inhibits SVCV infectivity and apoptosis in EPC cells in vitro. Furthermore, while N6 reduced horizontal transmission of SVCV in a static cohabitation challenge model, the N6-treated SVCV-infected group showed a nearly 3-fold decrease in viral load compared to the control group, it did not completely prevent transmission at established antiviral dosages. Histopathological analysis of the affected fish revealed that N6 effectively mitigated tissue damage induced by SVCV. Additionally, the up-regulation of six IFN-related genes suggests that N6 may indirectly activate IFNs to facilitate the clearance of SVCV in the kidney and spleen, as demonstrated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). These findings provide a foundation for further investigations into the mechanisms by which N6 acts against SVCV and may aid in the development of novel anti-SVCV therapeutics. Full article

The effectiveness of copper-based composites, specifically cupric ion (Cu²⁺)-modified phyllosilicate minerals, was evaluated in reducing the concentration of infectious agents in the environment while minimizing metal ion release. The phyllosilicate minerals, vermiculite, exfoliated and unexfoliated, and sepiolite, all modified with Cu²⁺, were compared with copper oxide for their antiviral activity against non-enveloped porcine parvovirus (PPV) and enveloped human coronavirus 229E (HCoV). Sepiolite effectively removed PPV and HCoV from the solution, regardless of Cu²⁺ presence, while vermiculite showed substantial viral clearance only when Cu²⁺ was present. The kinetics of viral clearance was fast, with complete clearance within one hour in many cases. To better understand the mechanism of virus clearance, EDTA was added at different times during the clearance study for PPV. EDTA prevented virus clearance in all vermiculite samples, whereas sepiolite containing copper still demonstrated substantial virus clearance. The addition of BSA before the virus binding was able to block binding in all cases. It was determined that binding is the key mechanism, and PPV can be eluted from the minerals with EDTA and still be infectious. This study provides the potent antiviral mechanisms of Cu²⁺-modified phyllosilicate minerals, offering insights for designing paints and plastics for high-touch surfaces to reduce viral transmission and enhance public health significantly. Full article