Search Results (24)

Background/Objective: Topical therapy remains a cornerstone in managing fungal infections due to the deep-seated nature of the pathogens and the persistence of the disease. Ketoconazole (KTZ) is a broad-spectrum antifungal agent, but its highly lipophilic nature presents considerable challenges in developing effective topical formulations. Additionally, oral KTZ has been subject to labeling restrictions and market withdrawal due to its association with severe hepatic adverse effects. This study was conducted to design, optimize, and evaluate KTZ-loaded nanolipid carriers (NLCs; KTZ-NLCs) as a delivery platform that could improve cutaneous bioavailability and enhance antifungal activity. Methods: The optimized KTZ-NLCs were further incorporated into a mucoadhesive system (KTZ-NLCs-C) through the inclusion of Carbopol^® 940 NF, aiming to improve the retention of the formulation on the skin surface. NLCs were characterized in terms of their physical appearance, particle size, polydispersity index, zeta potential, pH, viscosity, drug content, and entrapment efficiency. The optimized KTZ-NLC and KTZ-NLCs-C formulations were subsequently assessed for in vitro drug release, ex vivo skin permeation and deposition, as well as in vivo skin irritation. Results: In vitro release studies revealed that nanocarrier systems provided a sustained release of KTZ over 24 h. The ex vivo transdermal flux and permeability coefficient of KTZ from the lead KTZ-NLCs-C formulation were approximately 2.8-fold greater than those achieved with the marketed cream formulation. The in vivo skin irritation studies indicate that NLC-based formulations are suitable for topical applications. The lead formulation was stable for 90 days (the final time point evaluated) under refrigerated and room-temperature storage conditions. Conclusions: These findings suggest that the NLC-based system is a promising platform for the topical delivery of KTZ and has the potential to enhance the therapeutic outcomes for patients with superficial fungal infections. Full article

To address the durability limitations of conventional crack sealants under coupled extreme temperatures and traffic loads in long-life pavements, a bio-oil composite-modified patching material was developed using 90# base asphalt as the matrix, synergistically modified with crumb rubber (CR) and epoxidized soybean oil (ESO). To resolve the contradictory requirements for high elasticity and thermal expansion/contraction coordination in sealants, ESO was introduced; its polar epoxy groups optimize phase compatibility and promote low-temperature stress relaxation without restricting thermal deformability. Rheological evaluations revealed that the optimal system (OPT) successfully extended the service temperature window from PG 76–−24 °C (baseline) to PG 82–−24 °C, significantly enhancing its adaptability to extreme climatic fluctuations. At −24 °C, OPT exhibited a reduced creep stiffness (S) of 164 MPa and an increased creep rate (m) of 0.312, with a cracking resistance ratio (k) as low as 525.6; the quantitative significance of these metrics lies in granting the sealant superior stress relaxation capacity, enabling it to accommodate dynamic crack widening without interfacial debonding or brittle fracture. Fatigue testing via time sweeps demonstrated that N_f50 reached 2890 cycles, highlighting robust long-term resistance against high-frequency shear strains induced by tire edges. Micro-mechanistic analyses (FTIR, TG/DTG, and DSC) confirmed that the modification is primarily driven by physical blending. The elevation of the thermal decomposition threshold (T5%) to 302.4 °C and the residue at 600 °C to 44.8% provide a critical safety margin for high-temperature construction heating, preventing thermal degradation. Furthermore, the glass transition temperature (T_g) decreased to approximately −35.2 °C. These findings establish a rigorous quantitative and mechanistic framework for designing sustainable, high-performance patching materials for resilient pavement maintenance. Full article

Thin-film composite (TFC) polyamide (PA) nanofiltration membranes are the state of the art for water purification and reclamation, although a selectivity–permeability trade-off often restricts their development. To mitigate this problem, in this work, a novel three-layer structured nanofiltration (NF) membrane was fabricated consisting of a negatively charged poly (sodium 4-styrenesulfonate) (PSS) interlayer, a high-performance polyethyleneimine (PEI)-based PA separation layer and a PEI-grafted top layer. The PSS interlayer aimed to regulate interfacial polymerization (IP) of PEI with trimesoyl chloride (TMC) and enhance water transport, while PEI-grafting ensured high salt rejections. The relevant characterizations indicated that PEI-grafting endowed the resulting membrane (I-TFC-g) with a positive surface charge and increased the crosslinking degree to achieve much higher rejections for Mg⁺² ions through the synergistic effect of Donnan and size-exclusion mechanisms, while the incorporation of the PSS interlayer resulted in an increased pure-water permeability (PWP) value of 7 L m⁻² h⁻¹ bar⁻¹ (a value 2.8 times higher compared to the membrane TFC-g without a PSS interlayer). In specific, the I-TFC-g membrane displayed the highest salt rejections of 91% for MgCl₂, 92% for MgSO₄, 73% for Na₂SO₄ and 58% for NaCl and a good long-term stability. Overall, this work presents a simple strategy to improve NF performance by simultaneous enhancement of water permeability and salt selectivity. Full article

We introduce the Normalising Flow GARCH (NF-GARCH), a two-stage hybrid framework that enhances traditional GARCH models by replacing restrictive parametric innovation distributions with learned densities via normalising flows. Our approach preserves the interpretability of standard variance dynamics while addressing the common issue of innovation misspecification. In the first stage, we estimate standard GARCH variants (sGARCH, TGARCH, and gjrGARCH) to extract standardised residuals. In the second stage, a Masked Autoregressive Flow learns the underlying residual distribution, with samples from the flow subsequently driving the GARCH recursion for out-of-sample forecasting. Evaluated on 13 daily financial series (six FX pairs and seven equities), NF-GARCH demonstrates systematic, statistically significant improvements in forecast accuracy for skewed-t baselines. Wilcoxon signed-rank tests confirm superior performance specifically for gjrGARCH-sstd and sGARCH-sstd specifications. While the framework offers enhanced flexibility and generative realism, we observe that computational overhead is increased, and the log-variance specification of eGARCH exhibits instability when paired with flow-based innovations. These results suggest that while NF-GARCH effectively captures empirical tail behaviour in univariate settings, future research should explore conditional flow architectures and multivariate extensions to account for time-varying innovation shapes. For risk management, gains are most relevant where skewed-t baselines are used and where closer residual realism supports scenario analysis; effect sizes remain modest relative to model risk and implementation cost. Full article

Natural bioactive polysaccharides have been investigated for their ability to modulate antiviral immune responses. Polysaccharide peptide (PSP) from Coriolus versicolor previously restricted human immunodeficiency virus type 1 (HIV-1) entry into monocytic cells through a protein kinase R (PKR)-dependent cytoskeletal mechanism. However, its impact on antiviral signaling in adaptive cluster of differentiation 4 (CD4)+ T-cell models remains incompletely defined. Here, we evaluated concentration- and time-dependent effects of PSP (50–1000 µg/mL) in Jurkat T cells over 3 and 6 days. Cell viability was assessed by MTT, trypan blue exclusion, and viable cell density analysis. Immunoblotting and reverse transcription quantitative polymerase chain reaction (RT-qPCR) were performed to examine Toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), signal transducer and activator of transcription 1 and 2 (STAT1/STAT2), PKR, interferon gamma (IFN-γ), and cofilin-1 signaling. PSP did not induce cytotoxicity at any concentration. Instead, PSP promoted dose- and time-dependent upregulation of intracellular TLR4, PKR, phospho-PKR (Thr446), Cofilin-1, phospho-Cofilin-1 (Ser3), phospho-STAT1 (Tyr701), phospho-STAT2 (Tyr690), phospho-NF-κB (Ser536), and IFN-γ, with amplified responses at Day 6. These changes were paralleled by transcriptional induction of antiviral-associated genes. Collectively, PSP induces coordinated interferon (IFN)-associated and cytoskeletal regulatory signaling in Jurkat T cells without cytotoxicity, providing a mechanistic framework for future evaluation of viral permissiveness and antiviral responses in adaptive immune models. Full article

Drought stress severely restricts the growth of pear trees. As a widely used drought-tolerant rootstock, Pyrus betulifolia exhibits stable growth performance; however, the molecular mechanisms underlying its drought tolerance remain to be elucidated. In this study, we investigated the molecular responses of P. betulifolia leaves to osmotic stress induced by 20% PEG-4000 using time-series RNA-seq technology. A total of 3745 differentially expressed genes were identified, with transcriptional changes peaking at 6 h, indicating a critical phase of transcriptional reprogramming during drought response. Genes associated with osmotic adjustment (e.g., P5CS) and oxidative stress responses (e.g., SOD and POD) were significantly upregulated between 6 and 12 h. Weighted gene co-expression network analysis (WGCNA) identified three distinct temporal modules and screened out NF-Y, RVE1, COL9, COL6, C2C2 zinc finger proteins, and Pseudo ARR-B as putative key regulators, whose expression patterns were validated using qRT-PCR. Collectively, these results provide a comprehensive view of the temporal transcriptional dynamics of drought response in P. betulifolia and offer valuable candidate gene resources for further functional studies and drought tolerance breeding. Full article

Preeclampsia (PE) and intrauterine growth restriction (IUGR) are major pregnancy complications that are linked to placental dysfunction and environmental stimulation such as the use of electronic cigarettes (eCig). This study investigates the molecular impacts of timed eCig exposure in a C57BL/6 mouse model of PE and IUGR using bulk RNA-sequencing of placental tissues. Pregnant mice were exposed to eCig vapor via nose-only system starting at embryonic day 12.5 (eCig-6d, before spiral artery (SA) invasion) or 14.5 (eCig-4d, after SA invasion) until E18.5 (necropsy), with healthy controls exposed to room air (n = 6/group). The eCig-4d group developed PE, whereas the eCig-6d group developed both PE and IUGR. RNA-seq analysis revealed 429 differentially expressed genes (DEGs) in eCig-4d (IUGR-like) group and 64 DEGs in eCig-6d (PE + IUGR-like) group compared to controls. Pathway and gene network analyses indicated that eCig-4d exposure activated NF-κB–driven inflammation, suppressed ECM organization and collagen biosynthesis, and downregulated vasoactive genes/mitochondrial-associated genes (NOS1/2), accompanied by impaired complement initiation and reduced both macrophage and monocyte signals. Similarly, eCig-6d exposure led to downregulation of complement-associated genes and granule-related components, possibly implicating weakened neutrophil responsiveness and compromised inflammatory resolution at the maternal–fetal interface. Our findings align with prior studies on physiological dysfunctions in PE and IUGR, while also providing novel insights into the temporally specific cellular responses induced by eCig exposure. Full article

Lactation is a critical period in which mothers generally increase food intake and metabolism to meet high energy demands. In the present study, we examined the effect of time-restricted feeding (TRF) on lactating striped hamsters. On the day of litter birth, lactating females were assigned into 3 experimental groups that experienced 24-h ad lib feeding (Con), 12-h daytime feeding (DF), or 12-h nighttime feeding (NF). A group of non-lactating females with 24-h feeding (NL) served as an additional control. Our data show that lactating females had increased food intake, oxygen consumption, and small intestine mass but a decreased level of circulating melatonin, compared to the NL females. However, TRF manipulation significantly reduced the mother’s food intake, the pup’s body mass, and survival rate. In addition, TRF had some phase-specific (i.e., DF vs. NF) effects on facilitating body mass loss, decreasing CART, AgRP, and POMC gene expression in the hypothalamus, and increasing abundance in Desulfobacterota and Actinobacteriota in the gut microbiota of lactating females. Together, our data illustrate adaptive changes of lactating hamsters under TRF conditions, and highlight the importance of food access and dietary rhythm regulation in maternal and offspring health, development, and reproductive success. These findings not only expand our understanding of lactation biology and ecological feeding strategies but also highlight the significance of regular dietary patterns for lactating individuals, with particular emphasis on shift workers and other populations with irregular daily schedules. Full article

Background: Zebrafish-based drug discovery systems provide significant advantages over mammalian models for high-throughput in vivo screening. Among these, the NF-κB eGFP reporter system significantly enhances drug discovery in zebrafish by enabling real-time, high-resolution monitoring of pathway activity in live organisms, thereby streamlining mechanistic studies and high-throughput screening. Methods: We developed a novel AI (Quantifish and Orange software)-based zebrafish precision individualized 96-well ZF plates (0–7 dpf) and individualized MT tanks (8 dpf–4 mpf) protocol for the transposon-mediated transgenesis of the NFκB eGFP reporter system. Results: One-cell stage embryos were administered NFκB reporter construct and Tol2 transposase mRNA via microinjection and transferred to separate wells of a 96-well ZF plate. Bright-field and fluorescence images of each well were captured at 5 dpf in the F0, F1, and F2 generations using the automated confocal high-content imager CQ1. The Quantifish software was used for the automated detection and segmentation of zebrafish larval fluorescence intensity in specific regions of interest. Quantitative data on the fluorescence intensity and distribution patterns were measured in Quantifish, and advanced statistical and machine learning methods were applied using Orange. Imaging data with eGFP expression results were assessed to evaluate the efficiency of the transgenic protocol. Discussion: This AI-enhanced precision protocol allows for high-throughput screening and quantitative analysis of NFκB reporter transgenesis in zebrafish, enabling the efficient identification and characterization of stable transgenic lines that exhibit tissue-specific expression of the NF-κB reporter, such as lines with induced expression restricted to the retina following LPS stimulation. This approach streamlines the evaluation of regulatory elements, enhances data consistency, and reduces animal use, making it a valuable tool for zebrafish drug discovery. Full article

Pathogenic variants in the phenylalanine hydroxylase gene can result in phenylalanine (Phe) accumulation leading to phenylketonuria (PKU; OMIM #261600), a metabolic disease diagnosed in newborn screening. Early treatment with a Phe-restricted diet prevents severe mental retardation. Next to several other health complaints, patients with PKU present with low bone mineral density (BMD) more often than the general population. The etiology of the phenotype is not yet fully understood, and current research focuses on improving special medical foods and changes in osteoclasts (OC) and osteoblasts. Analysis of osteoclastic and oxidative stress control gene expression next to the simple number of OC developing from peripheral blood mononucleated cells (PBMCs) in association with dietary compliance and BMD was therefore part of our analysis. PBMCs were obtained from 17 adults with PKU and 17 age- and sex-matched controls on the same day. PBMCs were differentiated into osteoclasts (OC, Trap-positive multi-nucleated cells (≥3 nuclei)) for 14 days by adding human macrophage colony-stimulating factor (MCSF) and receptor activator of NF-κB Ligand (RANKL). Subsequently, quantitative real-time PCR was performed on OC function and oxidative stress control. Data on dietary compliance during the previous 12 months and 5 years and BMD were collected. PBMCs from adults with PKU and controls were differentiated into comparable numbers of OC (PKU: 53 [17–87] vs. controls: 39 [19–52], p = 0.381) without differences in mRNA expression of genes related to OC function and oxidative stress control. Dietary compliance in short-term and mid-term was not associated with OC number or mRNA expression, but CTSK negatively correlated with BMD T-Score in the hips of adults with PKU (Spearman r = −0.518, p = 0.040). Osteoclastogenesis was not changed in adult patients with PKU, nor were most mRNA expressions of OC marker genes or those of oxidative stress control. However, 44% of patients presented with BMD below −1 in their hips, and the OC of these tended to express higher CTSK (above −1: 0.2 [0.2–0.8] vs. below −1: 0.9 [0.6–3.4], p = 0.055). Thus, alternative regulatory mechanisms of OC activity may play a role in the development of low BMD in patients with PKU. Full article

The design of transformers, a key component of radio frequency integrated circuits (RFICs), is traditionally carried out through an iterative process involving extensive electromagnetic simulations. While process design kits (PDKs) offer tools based on interpolation or fitting equations to simplify parameter estimation, these tools are restricted to standard geometries, leaving designers to manually simulate and optimize custom designs. This approach is inefficient and resource intensive. This paper proposes an automated process to generate a database containing the physical and electrical parameters of a wide range of transformers. This database is part of a tool designed to efficiently identify the desired transformer. To evaluate the tool’s effectiveness in reducing the time required for design, a millimeter-wave (mm-Wave) 69.4–74.2 GHz differential low-noise amplifier (LNA) is designed using GlobalFoundries 45 nm silicon-on-insulator (SOI) technology. This circuit demonstrates a noise figure (NF) of 4.1 dB, a gain of 10.1 dB, an input third-order intercept point (IIP3) of −10.78 dBm, and a power consumption of 4.7 mW from a 0.406 V DC supply. Moreover, the simulated performance achieves these specifications within a highly compact area of 0.12 mm². The transformer selection process for the circuit takes only a few seconds, whereas the conventional method of manual transformer design and electromagnetic simulation would require a significantly greater amount of time. Full article

Ischemia-reperfusion injury (IRI) in the kidneys is a major cause of acute kidney injury (AKI). Time-restricted feeding (TRF), known for its metabolic health benefits and alleviation of various chronic diseases without calorie restriction, was investigated for its potential protective effects against IRI-induced AKI. Male C57BL/6 mice underwent unilateral IRI, with their kidneys collected after two days. For two weeks before IRI induction, the TRF group had unlimited access to standard chow but within an 8-hour feeding window during the dark cycle. The study groups were Control, TRF, IRI, and TRF + IRI. In the TRF + IRI group, tubular damage scores significantly decreased compared to the IRI group. Furthermore, the TRF + IRI mice had lower levels of phosphorylated NF-κB and fewer F4/80-positive macrophages than the IRI group. Oxidative stress markers for lipids and proteins were also notably lower in the TRF + IRI group. Additionally, TUNEL-positive tubular cells and cleaved caspase-3 expression were reduced in the TRF + IRI group. Without calorie restriction, TRF mitigated renal damage by reducing inflammation, oxidative stress, and tubular apoptosis in renal IRI. This suggests that TRF could be a promising dietary strategy to prevent IRI-induced AKI. Full article

Although only a few of the ancient masonry arch bridges (MABs) are in fairly good condition today, many ancient arch bridges are still in use. Over time, the condition of the masonry bridges declines and the safety requirements change. Therefore, it is important to examine these bridges under different influences. The strengthening of MABs is generally not essential. The major cause of damage to MABs is their insufficient width and height, and thus, it is not the safety but the usability that has restricted the life-time of the MABs. Therefore, in this investigation, the effect of the arch height on the static and dynamic behavior of a single-span MAB was investigated. For this aim, the Ancient Tokatlı Bridge, built in Karabük, Türkiye, was selected for investigation under near-fault (NF) and far-fault (FF) ground motions (GMs). To observe the altitude of the arch warp on the ancient MAB, first, the finite element model (FEM) was utilized, using ANSYS and SAP 2000. Furthermore, to constitute the arch warp’s influence on a MAB, the FEM was remodeled considering the different arch warps between 7.0 and 9.0 m. Moreover, GMs were applied to the FEM to investigate the effect of dynamic behavior. Under these GMs, stresses and strains (compression and tensile) were observed and compared with each other. Consequently, at the end of these investigations, it was observed that the maximum motions were reduced, while the height of the one-span MAB was increased under NF and FF GMs, and this was also true for the contrary situations. The compression stresses were not observed to be hazardous at the point of destruction, while the altitude of the one-span MAB increased. Full article

Cognitive biases have a significant impact on the etiology and treatment of eating disorders (EDs). These biases, including selective attentional bias (AB) to disliked body parts, may reinforce concerns about body shape, fear of gaining weight and body image disturbances and may contribute to dietary restriction and restraint. Decreasing AB could reduce core symptoms in anorexia nervosa (AN). This study represents a preliminary exploration aiming to assess whether AB towards weight-related (WR) and non-weight-related (NW) body parts could be reduced through an AB modification task in a virtual reality (VR) environment in healthy participants. A total of 54 female participants, aged 22.98 ± 1.89, were recruited. The task consisted of directing the participants’ attention towards all body parts equally in a VR setting. Eye-tracking (ET) measurements (complete fixation time [CFT] and number of fixations [NF]) were made before and after the task. The results showed a significant reduction of the AB in the two groups with an initial AB towards WR body parts or towards NW body parts. Participants showed a tendency to more balanced (non-biased) attention after the intervention. This study provides evidence of the usefulness of AB modification tasks in a non-clinical sample. Full article

Background: Hypoxic brain injury is a condition caused by restricted oxygen supply to the brain. Several studies have reported cognitive decline, particularly in spatial memory, after exposure to intermittent hypoxia (IH). However, the effect and mechanism of action of IH exposure on cognition have not been evaluated by analyzing gene expression after transcranial direct current stimulation (tDCS). Hence, the purpose of this study was to investigate the effects of tDCS on gene regulation and cognition in a rat model of IH-induced brain injury. Methods: Twenty-four 10-week-old male Sprague–Dawley rats were divided into two groups: IH exposed rats with no stimulation and IH-exposed rats that received tDCS. All rats were exposed to a hypoxic chamber containing 10% oxygen for twelve hours a day for five days. The stimulation group received tDCS at an intensity of 200 µA over the frontal bregma areas for 30 min each day for a week. As a behavior test, the escape latency on the Morris water maze (MWM) test was measured to assess spatial memory before and after stimulation. After seven days of stimulation, gene microarray analysis was conducted with a KEGG mapper tool. Results: Although there were no significant differences between the groups before and after stimulation, there was a significant effect of time and a significant time × group interaction on escape latency. In the microarray analysis, significant fold changes in 12 genes related to neurogenesis were found in the stimulation group after tDCS (p < 0.05, fold change > 2 times, the average of the normalized read count (RC) > 6 times). The highly upregulated genes in the stimulation group after tDCS were SOS, Raf, PI3K, Rac1, IRAK, and Bax. The highly downregulated genes in the stimulation group after tDCS were CHK, Crk, Rap1, p38, Ras, and NF-kB. Conclusion: In this study, we confirmed that SOS, Raf, PI3K, Rac1, IRAK, and Bax were upregulated and that CHK, Crk, Rap1, p38, Ras, and NF-kB were downregulated in a rat model of IH-induced brain injury after application of tDCS. Full article