Search Results (251)

Background/Objectives: Glioblastoma (GBM) is an aggressive brain tumor known for its profound heterogeneity and treatment resistance. Dysregulated complement signaling and epigenetic alterations have been implicated in GBM progression. This study identifies kynureninase (KYNU), a key enzyme in the kynurenine pathway, as a novel regulator of complement components and investigates its interaction with histone deacetylase 6 (HDAC6) in the context of therapeutic targeting. Methods: KYNU expression, and its association with complement signaling in GBM, were analyzed using publicly available datasets (TCGA, GTEx, HPA). Pathway enrichment was performed via LinkedOmics. In vitro studies in GBM cell lines (U87, U251, T98G) assessed the effects of KYNU silencing and treatment with an HDAC6 inhibitor (tubastatin) and a BET inhibitor (apabetalone) on gene expression and cell viability. Results: Bioinformatic analyses revealed significant overexpression of KYNU in GBM tissues compared to normal brain tissue. KYNU expression was positively associated with genes involved in complement and coagulation cascades. In vitro experiments demonstrated that KYNU silencing reduced the expression of C3, C3AR1, and C5AR1 and suppressed GBM cell viability. Treatment with tubastatin, while reducing viability, paradoxically upregulated complement genes, suggesting potential limitations in therapeutic efficacy. However, this effect was mitigated by KYNU knockdown. Combined treatment with apabetalone and tubastatin effectively suppressed KYNU expression and enhanced cytotoxicity, particularly in cells with high complement expression. Conclusions: Our findings establish the KYNU–HDAC6–complement axis as a critical regulatory pathway in GBM. Targeting KYNU-mediated complement activation through combined epigenetic approaches—such as HDAC6 and BET inhibition—represents a promising strategy to overcome complement-driven resistance in GBM therapy. Full article

To inform the development of effective prevention strategies for reducing pedestrian fatalities in an ageing society, a retrospective analysis was conducted on fatal pedestrian–vehicle collisions in Japan. All pedestrian fatalities caused by motor vehicle collisions between 2013 and 2022 in Shiga Prefecture were reviewed. Among the 164 pedestrian fatalities (involving 92 males and 72 females), the most common scenario involved a pedestrian crossing the road (57.3%). In 61 cases (64.9%), pedestrians crossed from the oncoming traffic lane side to the vehicle’s lane side (i.e., crossing from right to left from the driver’s perspective, as vehicles drive on the left in Japan). In 33 cases (35.1%), pedestrians crossed from the vehicle’s lane side to the oncoming traffic lane side. Among cases of pedestrians crossing from the vehicle’s lane side, 54.5% were struck by the near side of the vehicle’s front, whereas 39.7% of those crossing from the oncoming traffic lane side were hit by the far side of the vehicle’s front (p = 0.02). Therefore, for both crossing directions, collisions frequently involved the front left of the vehicle. When pedestrians were struck by the front centre or front right of the vehicle, the collision speeds were higher when pedestrians crossed from the oncoming traffic lane side to the vehicle’s lane side rather than crossing from the vehicle’s lane side to the oncoming traffic lane side. A significant difference in collision speed was observed for impacts with the vehicle’s front centre (p = 0.048). The findings suggest that increasing awareness that older pedestrians may cross roads from the oncoming traffic lane side may help drivers anticipate and avoid potential collisions. Full article

Our previous study reported that male university rugby players tended to have a gut with a dysbiotic environment, characterized by abundant pathobiont bacteria and an accumulation of succinate, when compared with age-matched, non-rugby playing healthy males. In the present study, we conducted a randomized, double-blinded, placebo-controlled experiment to evaluate the potential of blackcurrant extract and/or partially hydrolyzed guar gum (PHGG) to improve the gut environment of university rugby players. Participants were supplemented with blackcurrant extract and/or PHGG or a placebo for 4 weeks. Beneficial gut bacteria such as Megasphaera spp. tended to increase (p < 0.10) and Bifidobacterium spp. increased (p < 0.05) with the intake of blackcurrant extract and/or PHGG. A subgroup analysis further indicated that, unlike in those with a eubiotic gut environment, the dietary supplements also increased the number of beneficial gut bacteria such as Phascolarctobacterium spp. (p < 0.10) and Faecalibacterium spp. (p < 0.10) and fecal SCFA concentrations (p < 0.05) in participants with a possible dysbiotic gut environment. However, a synergistic effect between blackcurrant extract and PHGG was not clearly observed. Although further investigation is recommended, it was concluded that blackcurrant extract and PHGG can at least be used as functional materials to improve gut dysbiosis in university rugby players. Full article

Background/Objectives: As antimicrobial resistance patterns of Gram-negative bacteria change over time, this study aimed to analyze the antimicrobial susceptibility trends of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii isolates in Tunisia. Methods: From 1999 to 2019, non-duplicate isolates of Gram-negative bacteria were collected from 11 Tunisian hospitals as part of an antimicrobial resistance surveillance program. Antimicrobial susceptibility testing was performed using the disk diffusion method according to the European Committee on Antimicrobial Susceptibility Testing guidelines. Results: Out of 213,434 isolates collected during the study period, 58.8% were E. coli, 22% were K. pneumoniae, 14.4% were A. baumannii, and 4.8% were P. aeruginosa, with 67% of the isolates sourced from urine samples. E. coli showed a significant increase in resistance to third-generation cephalosporins (3GC), from 5.4% in 2004 to 16.5% in 2019, but K. pneumoniae displayed a rising trend of resistance to imipenem, from 1% in 2005 to 18.6% in 2019; meanwhile, amikacin remained effective against K. pneumoniae isolates. P. aeruginosa did not exhibit a significant change in resistance to imipenem. A. baumannii had a high resistance rate to imipenem that increased from 34.5% in 2008 to 84.2% in 2019 and had low susceptibility rates to all other antibiotics tested. Conclusions: This study reveals high carbapenem resistance among K. pneumoniae and A. baumannii in Tunisia. A. baumannii shows alarming multidrug resistance that requires urgent control measures. Full article

Aminopeptidase N (APN), an enzyme expressed in the small intestinal mucosa, is involved in dietary protein digestion. Previous studies have shown that oral administration of fermented milk containing lactic acid bacteria (LAB) enhances mucosal APN activity in young mice. This study aimed to investigate whether LAB strains stimulate mucosal APN activity in aged mice and to evaluate its relevance to age-related changes in body composition. The underlying molecular mechanisms were also explored in vitro. Experiment 1: Aged C57BL/6J mice were fed diets supplemented with heat-killed LAB strains—Enterococcus faecalis OU-23 (EF), Leuconostoc mesenteroides OU-03 (LM), or Lactiplantibacillus plantarum SNK12 (LP). Compared to the aged Control group, the ileal APN activity was significantly higher in the LP group. LP administration also elevated serum Gla-osteocalcin levels and decreased serum CTX-1 levels. Experiment 2: IEC-6 cells were co-cultured with LP that had been treated with RNase, DNase, or lysozyme. APN activity was significantly lower in cells co-cultured with DNase- or lysozyme-treated LP compared to those co-cultured with untreated LP. A specific LAB strain may enhance mucosal APN activity in the aged intestine, potentially contributing to improved bone metabolism. This effect may be mediated by bacterial DNA and peptidoglycan. Full article

The antimicrobial resistance (AMR) surveillance network has been monitoring bloodstream bacterial pathogens and their resistance since 1999 in Tunisia. We report the long-term trends in the distribution of bloodstream bacterial pathogens and their resistance patterns from this surveillance database. We analyzed antibiotic resistance rates in 11 tertiary teaching hospital laboratories under the AMR surveillance network during 2011–2023, focusing on six priority bacterial pathogens, using the Cochrane–Armitage test for trend analysis. Of 22,795 isolates, K. pneumoniae (38.5%) was the most common, followed by S. aureus (20.4%), E. coli (13.6%), and A. baumannii (10.3%). Carbapenem resistance was highest in A. baumannii (77%), followed by Pseudomonas aeruginosa (29.3%), K. pneumoniae (19.4%), and Enterobacter cloacae (6.8%). Carbapenem-resistant Enterobacterales and third-generation cephalosporin-resistant Enterobacterales (3GCREB) increased from 10.6% to 26.3% (p-value < 0.001), and from 39% to 50.2%, respectively, during 2011–2023 (p-value < 0.001). Vancomycin resistance (38.3%) and the emergence of linezolid resistance in 2019 (2.4%) were reported in E. faecium isolates. Resistance to carbapenems and 3GC is a major challenge to controlling BSI in Tunisia. The national AMR surveillance network helps monitor annual patterns and guides empirical therapy. An integrated database combining clinical profiles and resistance data via real-time data-sharing platforms could improve clinical decision-making. Full article

Background and Objectives: Several biologics and oral Janus kinase (JAK) inhibitors have been developed and shown in clinical trials and real-world studies to be effective and safe in moderate-to-severe atopic dermatitis (AD). In this study, we aimed to evaluate the real-world outcomes of patients with moderate-to-severe AD treated with dupilumab and JAK inhibitors in our facility, focusing on their short-term effect on serum galectin-7 levels, a biomarker reflecting skin barrier impairment, and one-year stability based on patient-oriented outcomes. Materials and Methods: In a single-center, retrospective study of AD patients treated with dupilumab or JAK inhibitors between January 2018 and December 2024, we assessed physician-oriented outcomes until 16 weeks and patient-oriented outcomes until 52 weeks. Serum galectin-7 levels at baseline and 4 and/or 16 weeks after treatment were measured in 14 patients. Results: A total of 45 patients starting dupilumab and 10 patients starting JAK inhibitors were enrolled. Percentage reductions in EASI scores from baseline at 4, 8, and 16 weeks were 58.36 ± 22.09, 69.59 ± 20.96, and 75.98 ± 19.70, with no significant differences between patients treated with dupilumab and JAK inhibitors. Serum galectin-7 levels were significantly reduced after treatment at 4 and 16 weeks in the entire population. Both DLQI and POEM scores were reduced at 4 weeks and gradually decreased until 52 weeks. The reduction was faster with JAK inhibitors than with dupilumab. Visits with unstable effectiveness, defined as a visit with a three-point or greater increase in the POEM score at 28, 40, and 52 weeks, were more frequent in JAK inhibitor patients. Conclusions: Both dupilumab and JAK inhibitors showed high effectiveness on skin inflammation and decreased a marker of skin barrier dysfunction within 16 weeks. JAK inhibitors improved patient-reported outcomes more quickly than dupilumab, but instability of effectiveness during 16 and 52 weeks was higher with JAK inhibitors. Full article

Objectives: The objective of this study is to investigate the two-year continuous efficacy, risk factors, and safety profile of selective laser trabeculoplasty (SLT) in Japanese individuals diagnosed with normal-tension glaucoma (NTG) who underwent SLT as either a first-line or second-line treatment. Methods: A retrospective chart review was conducted of patients with NTG who underwent SLT as either an initial or secondary therapy at 26 medical institutions in Japan between January 2020 and December 2021 with a 2-year follow-up. The primary endpoint was a reduction in the rate of intraocular pressure (IOP) over 2 years after SLT. To estimate the time-varying effect of IOP reduction, a linear mixed-effects model was employed. The secondary endpoints were numerical IOP reduction, treatment success rates shown by a Kaplan–Meier analysis, and complications. Success was defined as an outflow pressure improvement rate (ΔOP) ≥ 20% (definition A) or an IOP reduction rate ≥ 20% (definition B) without further treatment. A Cox proportional hazards regression analysis was used to identify the risk factors to successful SLT treatment. The study was registered with UMIN-CTR (ID: UMIN R000064045). Results: A total of 230 eyes from 230 individuals participated in this study, with 148 eyes receiving SLT as an initial (first-line) therapy and 82 eyes undergoing SLT as a secondary (second-line) intervention. In the first-line group, the mean IOP dropped from 16.7 ± 2.3 mmHg to 13.7 ± 2.4 mmHg at two years post-treatment, reflecting a 16.8% reduction. In the second-line group, the average IOP declined from 15.9 ± 2.5 mmHg to 13.2 ± 2.0 mmHg, marking a 14.4% decrease over the same period. The treatment success rate according to definition A (ΔOP ≥ 20%) was 73.7% at 2 years. Analysis using a linear mixed-effects model identified time (p < 0.001), age (p = 0.044), baseline IOP (p < 0.001), and central corneal thickness (CCT) (p < 0.001) as statistically significant contributors to IOP reduction following SLT. However, neither the Group (first-line vs. second-line) variable (p = 0.386) nor the Time × Group interaction (p = 0.298) reached statistical significance. A lower baseline IOP and a thicker CCT were confirmed as significant predictors of SLT treatment failure. Conclusions: Both initial and secondary SLT treatments for NTG proved to be effective and safe over a two-year period, although the extent of IOP reduction was smaller in cases with a lower baseline IOP. Our findings indicate that the IOP-lowering effect of SLT in NTG is influenced by pretreatment IOP levels, aligning with previous studies on primary open-angle glaucoma and ocular hypertension. However, in contrast to those earlier findings, our research identified pretreatment central corneal thickness as a statistically significant factor influencing SLT efficacy in NTG. These results support the role of SLT as a reliable and safe therapeutic option for managing NTG. Full article

A model of the vocal tract that mimicked velopharyngeal insufficiency was created, and acoustic analysis was performed using the boundary element method to clarify the acoustic characteristics of velopharyngeal insufficiency. The participants were six healthy adults. Computed tomography (CT) images were taken from the frontal sinus to the glottis during phonation of the Japanese vowels /i/ and /u/, and models of the vocal tracts were created from the CT data. To recreate velopharyngeal insufficiency, coupling of the nasopharynx was carried out in vocal tract models with no nasopharyngeal coupling, and the coupling site was enlarged in models with nasopharyngeal coupling. The vocal tract models were extended virtually for 12 cm in a cylindrical shape to represent the region from the lower part of the glottis to the tracheal bifurcation. The Kirchhoff–Helmholtz integral equation was used for the wave equation, and the boundary element method was used for discretization. Frequency response curves from 1 to 3000 Hz were calculated by applying the boundary element method. The curves showed the appearance of a pole–zero pair around 500 Hz, increased intensity around 250 Hz, decreased intensity around 500 Hz, decreased intensities of the first and second formants (F1 and F2), and a lower frequency of F2. Of these findings, increased intensity around 250 Hz, decreased intensity around 500 Hz, decreased intensities of F1 and F2, and lower frequency of F2 agree with the previously reported acoustic characteristics of hypernasality. Full article

Purpose: Our aim is to offer an additional surgical option for patients with rectus diastasis, with or without associated abdominal wall hernias, through a minimally invasive approach with endoscopic surgical correction, presenting a new method for abdominal contouring via minimally invasive mini-abdominoplasty (MAMI). Ideas: According to the European Hernia Society (EHS) classification for RD, a widening greater than 2 cm of the linea alba is generally considered an indication for surgical correction. Recent approaches, such as MILA and SCOLA, are indicated for patients with a body mass index (BMI) of up to 28, based solely on height and weight. However, some authors consider this insufficient for determining the best surgical indication. Despite advances in skin retraction, there is still no evidence on how these devices affect postoperative outcomes when added to these techniques, as they depend on multiple factors such as age, skin firmness, number of passes, applied energy, etc. Consequently, even patients with a BMI of up to 28 may present significant flaccidity both above and below the umbilicus, as well as poor skin quality (thin, lax, with stretch marks), making SCOLA or MILA surgery alone unsuitable due to possible skin redundancy after surgery. Similarly, even patients with a high-positioned umbilicus, moderate flaccidity, and rectus diastasis, who in the past would have been strictly indicated for abdominoplasty, may benefit from mini-abdominoplasty with a minimally invasive approach (MAMI). Discussion: The main objective of this study is to provide another surgical option for patients who would otherwise be indicated for abdominoplasty and also for those undergoing MILA or SCOLA who still require minor skin removal to enhance the surgical result. Based on our experience, mini-abdominoplasty with a minimally invasive approach (MAMI) has the potential to serve a larger number of patients, since most present degrees of skin laxity that, even after using technologies, require skin excision. In addition to complementing the results, it reduces complications, results in smaller scars, allows a better correction and visualization of the diastasis, avoids periumbilical scars, and offers faster recovery compared to abdominoplasty. Conclusions: MAMI surgery has proven to be a safe and reproducible approach for selected women who wish to restore feminine body features after pregnancy and achieve a quick recovery. It yields satisfactory esthetic results due to the minimized scar, preservation of the natural umbilical scar, and improved surgical correction of rectus diastasis. Full article

The concept of sustainability in agri-food supply chains (AFSCs) is gaining traction among researchers and practitioners. There has been a considerable effort to define and identify frameworks for assessing, monitoring, and improving sustainability practices within systems and organizations. The multi-capital approach presents an alternative tool for sustainability that integrates various types of capital to provide a deeper understanding and assessment of the impacts across different facets of the system. This review systematically examines existing research on AFSC sustainability indicators and assessment from a multi-capital perspective. Based on 106 articles, 116 indicators from various databases (Web of Science, Scopus, and others) are identified. These indicators are assigned to specific AFSC actors and forms of capital. Their role in evaluating the AFSCs through a sustainability lens is examined. The analysis also identifies the most significant capital associated with each actor. This analysis leads to the development of a structured framework that helps actors assess their resources and pinpoint sustainability challenges. Following this review, a theoretical framework is derived, connecting sustainability capital, key themes, and relevant Sustainable Development Goals. This provides a comprehensive tool for evaluating assets and guiding strategic actions for AFSC. Full article

We constructed a library of Mpp46Ab mutants, in which S¹⁵³ within the transmembrane β-hairpin was randomly replaced by other amino acids. Mutagenesis and subsequent primary screening yielded 10 different Mpp46Ab mutants in addition to the wild type. Remarkably, S¹⁵³ was replaced with a more hydrophobic amino acid in most of the mutants, and the S153I mutant in particular exhibited significantly increased toxicity. Electrophysiologic analysis using artificial lipid bilayers revealed that the single-channel conductance and P_K/P_Cl permeability ratio were significantly increased for S153I pores. This suggests that the formation of highly ion-permeable and highly cation-selective toxin pores increases the influx of cations and water into cells, thereby facilitating osmotic shock. In addition, the S153F, S153L, and S153I mutants exhibited significantly reduced synergistic toxicity with Cry4Aa. Electrophysiologic analysis showed that the S153F, S153L, and S153I mutants form toxin pores with a significantly reduced P_K/P_Na permeability ratio and a significantly increased P_K/P_Ca permeability ratio compared to wild-type pores. Thus, our results suggest that pore formation is central to the insecticidal activity of Mpp46Ab and that the ion permeability of toxin pores is a potential indicator correlated with both toxicity and synergistic toxicity with other toxins. Full article

This study aimed to evaluate the protective effects of peach leaf extract (Prunus persica L.) against metabolic syndrome and oxidative stress in Wistar rats subjected to a high-fructose diet. The Wistar rats were divided into groups and fed a high-fructose diet, with or without supplementation of peach leaf extract. The extract was characterized by its bioactive compounds, including an organic acid yield of 53.8%, total phenolic content (TPC) of 273.36 ± 1.929 mg GAE/g DW, flavonoid content (TFC) at 149.02 ± 57.47 mg QE/g DW, condensed tannins (TCT) at 2.34 ± 0.171 mg CE/g DW, and flavonols at 81.67 ± 0.497 mg DE/g DW. In vitro tests showed significant antioxidant potential, with a total antioxidant capacity (TAC) of 44.11 ± 6.328 mg AAE/g DW, DPPH radical scavenging activity (IC₅₀ = 4.89 mg/mL), and reducing power assay (FRAP, IC₅₀ = 0.525 mg/mL). The results indicated that the extract significantly reduced body weight gain, plasma insulin levels (0.30 ± 0.00 U(IU)/mL), glycemia (0.955 ± 0.068 g/L), total cholesterol (0.555 ± 0.177 g/L), and triglycerides (0.720 ± 0.141 g/L). Regarding oxidative stress markers, the extract decreased levels of malondialdehyde (MDA, 4567 ± 121 μmol/L), hydroperoxides (1304 ± 288 μmol/L), and carbonylated proteins (0.029 ± 0.020 μmol/L), while increasing levels of vitamin C (25.84 ± 3.00 mg AAE/L), Oxygen Radical Absorbance Capacity (ORAC, 6.043 ± 0.345 UA), and catalase activity (0.0052 ± 0.00008 μL/mL). These findings suggest that P. persica L. may alleviate impairments related to metabolic syndrome by improving metabolic profiles and reducing oxidative stress in rats fed a high-fructose diet, making it a potential dietary supplement for managing metabolic syndrome. Full article

The prevalence of sleep deprivation is increasing worldwide. Despite the vital roles that the liver plays in metabolism and immune response, hepatic dysfunctions in acute sleep deprivation (ASD) and chronic sleep deprivation (CSD) remain underexplored. Additionally, the effects of the newly developed chalcone analog, 1-(2,3,4-trimethoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-acrylketone (TAK), were evaluated as a potential therapeutic chemical for mitigating SD-induced hepatic damage. A modified multi-platform method was employed to prepare animal models of 72 h ASD and 21-day CSD in rats. TAK (50 mg/kg/day) was administered through irrigation starting one week before the experiment and continuing until the end. ASD triggered hepatic lipid accumulation and inflammation, whereas CSD resulted in pathological portal area expansion and fibrosis, with comparatively fewer disturbances in liver metabolism and inflammation. TAK effectively alleviated ASD-induced disruptions in glycogen synthesis via PI3K/AKT/GSK3/GYS2 pathways, abnormal lipid accumulation via SREBP1/FASN/ACC, liver inflammation by balancing M1 and M2 macrophages, and liver fibrosis induced by ASD/CSD. This study provides valuable insights into the different mechanisms of liver damage induced by severe ASD and mild CSD. Additionally, TAK has been proposed as a potential therapeutic strategy for ultimate SD-related hepatic complications. Full article

Using mineral prospectivity mapping (MPM), the mineral systems approach enables the identification of geological indicators linked to ore formation. This approach streamlines exploration by minimizing the time and cost required to identify areas with the highest mineral potential. With its extensive till cover and dense forests limiting bedrock exposure, New Brunswick provides an ideal environment to test this approach. The New Brunswick portion of the Canadian Appalachians hosts a diverse range of gold deposits and occurrences that formed during various stages of the Appalachian orogeny. In northern New Brunswick and the adjacent Gaspé Peninsula, the Tobique–Chaleur Zone contains several orogenic and epithermal gold systems that are closely associated with a large-scale crustal fault and its offshoots, i.e., the long-lived trans-crustal Rocky Brook–Millstream Fault system. To identify favorable zones for epithermal gold mineralization in northwestern New Brunswick, this study employed MPM by translating key mineral system components—such as ore metal sources, fluid pathways, traps, and geological controls—into mappable criteria for regional-scale analysis. The data were modeled through the integration of knowledge-based and data-driven methods, including fuzzy logic, geometric average, and logistic regression approaches. The concentration–area (C–A) fractal model was applied to reclassify the final maps based on prospectivity values obtained from these three approaches, dividing the mineral prospectivity maps into six classes, with threshold values emphasizing high-favorability zones. The fuzzy overlay model had the highest predictive accuracy (AUC 0.97), followed by the geometric average model (AUC 0.93), whereas the logistic regression identified more tightly constrained high-potential zones. In the prospectivity models, known epithermal gold mineralization consistently overlaps with regions of high favorability. This suggests a positive result from the use of MPM, indicating that this approach could be applicable to other regions and types of ore deposits. Full article