Search Results (54)

Background/Objectives: Antimicrobial resistance (AMR) poses a major global health challenge, particularly in opportunistic pathogens such as Pseudomonas aeruginosa. This study aimed to identify metabolic adaptations associated with antibiotic resistance by integrating transcriptomic data from drug-resistant clinical isolates with a genome-scale metabolic model (GEM) of P. aeruginosa under four antibiotic treatments: ceftazidime (CAZ), ciprofloxacin (CIP), meropenem (MEM), and tobramycin (TOB). Methods: Transcriptomic data from 414 clinical isolates were integrated with the iPau21 genome-scale metabolic model (GEM) of P. aeruginosa. Differential gene expression analysis was performed using DESeq2, and differentially expressed genes (DEGs) were identified using a false discovery rate (FDR)-adjusted p-value < 0.05 and a fold-change threshold of ≥2 or ≤0.5. Reporter metabolites (RMs) were identified using the Reporter Metabolite algorithm with an FDR-adjusted p-value < 0.05. Pathway enrichment analysis was performed to characterize condition-specific metabolic alterations, and pathway significance was determined using the Benjamini–Hochberg procedure with an adjusted p-value < 0.05. Results: The analysis revealed predominantly antibiotic-specific transcriptional responses, with limited overlap in DEGs across treatment conditions. Reporter metabolite and pathway enrichment analyses identified distinct metabolic adaptations associated with biofilm formation, virulence, and stress response pathways. Several metabolites, including propionic acid, acetic acid, L-inositol, glutamine, glutarate, fumarate, and melatonin, were computationally prioritized candidate metabolites for future metabolite-based adjuvant strategies aimed at enhancing antibiotic efficacy. Conclusions: This systems biology approach provides a comprehensive framework for identifying metabolic vulnerabilities associated with AMR in P. aeruginosa. The identified metabolites represent candidate antibiotic adjuvant molecules generated through computational prioritization and should be regarded as hypotheses for future experimental validation rather than validated therapeutic interventions. These findings provide a foundation for future studies exploring metabolism-based strategies to improve antibiotic efficacy and combat antimicrobial resistance. Full article

This study investigates the effect of stabilizing axial load transfer to the bit on mechanical-specific energy during horizontal well drilling. To analyze drilling regimes, field data on WOB, ROP, RPM, TOB, and MSE were used and processed using z-score standardization, outlier removal based on the IQR criterion, and k-means clustering. The selected number of clusters was determined using the elbow method and silhouette analysis; after filtering, the dataset included 1750 observations, and the six-cluster solution was selected for exploratory interpretation. It was found that the lowest MSE values were characteristic of clusters 0, 1, and 5, among which cluster 5 demonstrated the most favorable combination of WOB, ROP, and energy efficiency. Clustering the modeled data confirmed the possibility of identifying drilling regimes with reduced MSE under a stabilized-load scenario. The predicted MSE reduction should be interpreted as a scenario-based, idealized model-based estimate obtained under quasi-steady assumptions rather than as a field-validated performance gain. The results may be used to support the selection of rational drilling parameters and to guide the further development of drilling control systems for horizontal well drilling. Full article

This paper investigates the anthropological and ethical roots of the global ecological and social crisis, centered on Pope Francis’s critique of the “throwaway culture” (Laudato Si’, LS). While LS identifies this crisis in the linear “take–make–dispose” model and the technocratic paradigm—which prioritizes efficiency over moral reflection—this research argues that these macro-societal failures originate in a foundational spiritual pathology: concupiscence. Drawing upon St. John Paul II’s Theology of the Body (TOB), we analyze concupiscence as “appropriation,” the direct antithesis to the human vocation of the “sincere gift of self.” This study aligns LS’s socio-economic critique with Karol Wojtyła’s personalist anthropology, asserting that the systemic exploitation of nature and the marginalization of the vulnerable are structural extensions of the human failure to reread the “language of the body” in truth. The throwaway culture is thus revealed as an axiological reduction—a societal manifestation of lust that reduces both the body and creation to mere objects of utility. Consequently, a genuine ecological conversion (LS) necessitates embracing the “ethos of redemption” (TOB). This transformation of desire is essential to restoring the harmony between humanity and nature, recognizing that the ‘cry of the earth’ and the ‘cry of the poor’ are inextricably linked within an integral ecology. Full article

Synthetic biomaterials used as bone graft extenders (BGE) in spinal fusion surgery can supplement but do not replace autologous bone. This pilot study evaluated a calcium sulfate/hydroxyapatite (CaS/HA) material as an antibiotic-eluting BGE and a carrier for bone morphogenetic protein-2 (BMP-2) in a rabbit posterolateral lumbar (L4–L5) spinal fusion model (PLF). Pre-set CaS/HA beads were loaded with tobramycin (TOB) and tested for in vitro antibiotic release and antibacterial activity against Staphylococcus aureus. For the in vivo PLF study, CaS/HA beads were used in two treatment strategies: (1) CaS/HA + TOB + autograft (left side) and (2) CaS/HA + BMP-2 (right side). Serum levels of TOB were quantified and spinal fusion was evaluated after 12 weeks. TOB exhibited a rapid initial release, followed by a decline below detectable levels after 6 h in vitro and 48 h in vivo. TOB-loaded CaS/HA beads demonstrated in vitro antibacterial activity for 19 days. In the PLF study, 5/6 and 6/6 specimens were fused radiologically in the TOB and BMP groups, respectively, and 100% using mechanical testing. Micro-CT analysis showed no significant difference in bone volume between the TOB and BMP-2 groups (364 ± 84 vs. 479 ± 95 mm³). Histology verified continuous bone bridging in both groups. Our in vitro findings indicate that locally added TOB could protect the CaS/HA material from bacterial colonization and did not adversely impact the CaS/HA material negatively to act as BGE. The addition of low-dose BMP-2 to the CaS/HA material proved effective in building bone without the need to harvest autologous bone. In summary, this pilot PLF study demonstrates that the tested CaS/HA material combined with BMP-2 could replace autologous bone harvesting in spinal fusion surgery. Addition of TOB could potentially protect the material from bacterial colonization during the early post-operative period but further studies in infection models are warranted. Full article

As dockless bike-sharing systems rapidly expanded, this study aims to develop a flow-integrated framework for assessing bicycle usage efficiency, which addresses a critical gap in conventional static indicators. Existing studies rely primarily on big data to evaluate location-specific efficiency using Time-to-Booking (ToB). However, ToB ignores network flow effects while bicycles departing from the same location may reach destinations with vastly different ToB values. To overcome this, we propose a flow-integrated ToB (FwToB) index that incorporates the idle time at both the trip origin and destination. Applying this index to central Beijing reveals significant spatial heterogeneity while maintaining the original core-periphery pattern, indicating that most bicycles flow to areas with similar efficiency. Geographically weighted regression further shows that factors like population density, healthcare, shopping facilities, and distance to metro stations influence efficiency with substantial spatial non-stationarity. These findings advance the understanding of bike-sharing efficiency and offer insights for operators and urban planners. Full article

Elevated sodium concentrations are commonly observed in tumors and sites of inflammation. Previous studies have shown that high salt levels modulate the phenotype and function of CD4⁺ and CD8⁺ T cells, regulatory T cells, and macrophages. In this study, we performed transcriptomic studies that revealed profound alterations in the neutrophil transcriptome upon high salt exposure, with changes that significantly exceeded those triggered by conventional agonists. By integrating transcriptomic data with functional assays, our findings suggest that high salt-induced neutrophil activation involves mitochondrial ROS production, which subsequently activates p38 MAPK and engages FOS-, Bruton’s tyrosine kinase (BTK)-, and cyclooxygenase 2 (COX2)-dependent pathways. Remarkably, the plasticity of the neutrophil transcriptome in response to high salt was further evidenced by the upregulation of genes typically associated with other cell types, including semenogelin 1 (SEMG1), intercellular adhesion molecule-4 (ICAM4), tripartite motif69 (TRIM69), amphiregulin (AREG), oncostatin (OSM), and transducer of ERBB2-1 (TOB1), suggesting a broader role for neutrophils in different biological processes beyond their participation in innate immunity. Full article

This research was carried out to assess the impact of daidzein supplementation on production performance, serum biochemical indexes, meat quality, and the transcriptome of the longissimus dorsi (LM) muscle in heat-stressed Jinjiang cattle. Twenty 20-month-old Jinjiang cattle (initial mean ± SE: 438 ± 34.6 kg of body weight) were randomly divided into two treatment groups (n = 10 per treatment): control treatment and daidzein treatment (1000 mg/kg concentrate). After a 100-day feeding trial (consisting of a 10-day adaptation period and a 90-day daidzein feeding period), blood and LM muscle samples were collected on day 100. Daidzein significantly increased the average daily dry matter intake (ADMI), the concentration of free fatty acid (FFA) and glutamic-pyruvic transaminase (ALT) in serum, and the marbling score of the LM muscle. Additionally, daidzein significantly decreased the concentration of total cholesterol (TC) and leptin in serum, along with the shear force and L* value of LM in heat-stressed Jinjiang cattle. The transcriptome analysis demonstrated that 238 differentially expressed genes (DEGs) were identified through differential expression analysis, among which 168 genes were downregulated and 70 genes were upregulated. The results of KEGG pathways showed that these DEGs were significantly enriched in pathways related to beef tenderness, including the FoxO signaling pathway, Notch signaling pathway, and regulation of the actin cytoskeleton. Daidzein significantly affected the candidate genes (FOSL1, DGKH, Gadd45G, GAL, SEMA3, TOB, FABP8, TRIB2, Nech1, and GSTA3) involved in adipocyte differentiation, as well as genes (CSTB and ACTN) related to connective tissue structure in heat-stressed Jinjiang cattle. Daidzein plays a positive role in relieving heat stress and improving beef quality in heat-stressed Jinjiang cattle. Full article

Background: Endophthalmitis, associated with intraocular procedures, is an infection of the eye that can rapidly result in substantial irreversible loss of vision and may even lead to removal of the eye. Prevention strategies vary globally and often include antibiotic use—often consisting of a broad-spectrum mono-therapeutic agent. The purpose of this study is to test the efficacy and value of combinations of cefuroxime (cefu), cefazolin (cefa), azithromycin (azith), and/or tobramycin (tob) as alternatives to the use of moxifloxacin. We looked for synergism since these antimicrobials used different mechanisms of inhibition. Methods: Initially, we examined individual antimicrobials to determine the minimal bactericidal concentrations (MBC) of each individual treatment against Klebsiella pneumonia, Pseudomonas aeruginosa, Staphylococcus aureus, two clinical isolates of MRSA, and Staphylococcus epidermidis, by both the Zone of Inhibition (ZOI) and the Colony Forming Unit (CFU) assays. We then used these data in a combinatorial study. Results: We found combinations that were synergistic against all the bacteria tested, resulting in total eradication [8 logs] of all bacteria. We found that the ZOI assay provided less consistent results than the CFU assays. Conclusions: We have found combinations of these antimicrobials that were synergistic in the total eradication (8 logs) of all bacteria tested. These three combinations were: cefuroxime/azithromycin; azithromycin/tobramycin; and cefuroxime/tobramycin. Moxifloxacin (Vigamox) did not completely eradicate Staphylococcus epidermidis. These combinations can then be used as eye drops to serve as a prophylactic for endophthalmitis after eye injections and eye surgery. Full article

Background/Objectives: Biofilm-embedded bacteria, such as Pseudomonas aeruginosa (P. aeruginosa), are highly resistant to antibiotics, making their treatment challenging. Plant-based natural compounds (PBCs) and metal(loid)-based antimicrobials (MBAs) are promising alternatives. This study evaluated the minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and synergistic effects of zinc sulfate (ZnSO₄), carvacrol (CV), and antibiotics (ciprofloxacin [CIP], tobramycin [TOB], and azithromycin [AZM]) against P. aeruginosa PAO1. Methods: The MIC and MBC of ZnSO₄, CV, and antibiotics were determined using a 96-well plate method. Cytotoxicity was assessed via MTT assay. Fractional inhibitory concentration (FIC), fractional bactericidal concentration (FBC), minimal biofilm inhibition concentration (MBIC), and minimum biofilm eradication concentration (MBEC) indices were calculated for each combination of agents. Checkerboard assays identified interactions, and the effectiveness of combinations was further evaluated in a mouse chronic lung infection model with treatments delivered intratracheally, intraperitoneally, and orally. Results: TOB had the lowest MIC and MBC values, proving most effective against P. aeruginosa PAO1. Strong synergy was observed with CV + ZnSO₄ (CV + Zn) combined with CIP, CV with CIP, and CV + Zn with TOB, as indicated by low FIC indices. CV + Zn with TOB and CV with TOB had low FBC indices, while CV + Zn with AZM showed antagonism. In vivo, intratracheal TOB + CV + Zn reduced lung inflammation and tissue involvement, yielding the best histopathological outcomes. The MIC of CIP and TOB was reduced 5-fold and 4-fold, respectively, when combined with CV + Zn. Conclusions: CV + Zn demonstrated strong synergistic effects with antibiotics and effectively managed P. aeruginosa lung infections in mice. These findings highlight its potential as an innovative therapy for biofilm-associated infections. Full article

Background/Objectives: Pulmonary delivered tobramycin (TOB) is a standard treatment for Pseudomonas aeruginosa lung infections, that, along with Staphylococcus aureus, is one of the most common bacteria causing recurring infections in CF patients. However, the only available formulation on the market containing tobramycin, TOBI^®, is sold at a price that makes the access to the treatment difficult. Therefore, this work focuses on the development and characterization of an ionic complex between a polyelectrolyte, hyaluronic acid (HA) and its salt, sodium hyaluronate (NaHA), and TOB to be formulated as an inhalable dry powder. Methods: The solid state complex obtained by spray drying technique was physicochemically characterized by infrared spectroscopy, thermal analysis and X-ray diffraction, confirming an ionic interaction for both complexes. Results: The powder density, geometric size, and morphology along with the aerodynamic performance showed suitable properties for the powder formulations to reach the deep lung. Moisture uptake was found to be low, with the complex HA-TOB remaining physicochemically unchanged, while the NaHA-TOB required significant protection against humidity. The biopharmaceutical in vitro experiments showed a rapid dissolution which can have a positively impact in reducing side effects, while the drug release study demonstrated a reversible polyelectrolyte–drug interaction. Microbiological experiments against P. aeruginosa and S. aureus showed improved bacterial growth inhibition and bactericidal efficacy, as well as better inhibition and eradication of biofilms when compared with to TOB. Conclusions: A simple polyelectrolyte-drug complex technique represents a promising strategy for the development of antimicrobial dry powder formulations for pulmonary delivery in the treatment of cystic fibrosis (CF) lung infections. Full article

The use of hydrogen as fuel presents many safety challenges due to its flammability and explosive nature, combined with its lack of color, taste, and odor. The purpose of this paper is to present an electrochemical sensor that can achieve rapid and accurate detection of hydrogen leakage. This paper presents both the component elements of the sensor, like sensing material, sensing element, and signal conditioning, as well as the electronic protection and signaling module of the critical concentrations of H₂. The sensing material consists of a catalyst type Vulcan XC72 40% Pt, from FuelCellStore, (Bryan, TX, USA). The sensing element is based on a membrane electrode assembly (MEA) system that includes a cathode electrode, an ion-conducting membrane type Nafion 117, from FuelCellStore, (Bryan, TX, USA). and an anode electrode mounted in a coin cell type CR2016, from Xiamen Tob New Energy Technology Co., Ltd, (Xiamen City, Fujian Province, China). The electronic block for electrical signal conditioning, which is delivered by the sensing element, uses an INA111, from Burr-Brown by Texas Instruments Corporation, (Dallas, TX, USA). instrumentation operational amplifier. The main characteristics of the electrochemical sensor for hydrogen leakage detection are operation at room temperature so it does not require a heater, maximum amperometric response time of 1 s, fast recovery time of maximum 1 s, and extended range of hydrogen concentrations detection in a range of up to 20%. Full article

Background: The emergence of multidrug-resistant bacteria presents a significant global health threat. Liposomal antibiotics have shown a potential to improve antibiotic delivery and efficacy. This study aimed to develop liposomes encapsulating tobramycin (TOB) and methylglyoxal (MGO) to enhance TOB activity while reducing bacterial adhesion and biofilm formation. Methods: Clinical isolates of Pseudomonas aeruginosa and Klebsiella pneumoniae were characterized using whole-genome sequencing. Liposomes (Lip-MGO-TOB) were formulated using Manuka honey as a surfactant and loaded with MGO and TOB. Antibacterial activity, biofilm formation, and bacterial cell adhesion assays were performed to compare the efficacy of Lip-MGO-TOB against free TOB. Liposome characterization included analyses of morphology, zeta potential, TOB encapsulation efficiency, and stability under various biological conditions. Results: The Lip-MGO-TOB formulation, at a minimum inhibitory concentration (MIC) of 32 µg/mL, reduced the biofilm formation of the P. aeruginosa isolate (PA85) by 68%. Conversely, free TOB, at a MIC of 64 µg/mL, achieved only a 21% reduction. For the K. pneumoniae isolate (KP57), Lip-MGO-TOB inhibited bacterial adhesion to A549 cells at a lower concentration (256 µg/mL) compared to free TOB (512 µg/mL). Lip-MGO-TOB demonstrated sustained drug release over 24 h under tested conditions and retained over 99% of TOB. Conclusions: The Lip-MGO-TOB formulation significantly enhanced TOB activity against resistant bacteria compared to free TOB. Additionally, it provided a stable drug delivery system with controlled drug release. Liposomal TOB represents a promising advancement in combating antibiotic resistance by improving the efficacy and delivery of conventional antibiotics. Full article

In order to solve the loosening problem caused by stress shielding of femoral stem prostheses in clinical practice, an optimization design method of a personalized porous titanium alloy femoral stem is proposed. According to the stress characteristics of the femur, the porous unit cell structures (TO-C, TO-T, TO-B) under three different loads of compression, torsion, and bending were designed by topology optimization. The mechanical properties and permeability of different structures were studied. Combined with the porous structure optimization, a personalized radial gradient porous titanium alloy femoral stem was designed and manufactured by selective laser melting (SLM) technology. The results show that the TO-B structure has the best comprehensive performance among the three topologically optimized porous types, which is suitable for the porous filling structure of the femoral stem, and the SLM-formed porous femoral stem has good quality. The feasibility of the personalized design and manufacture of porous titanium alloy implants is verified, which can provide a theoretical basis for the optimal design of implants in different parts. Full article

Marginal vitamin B6 (B6) deficiency is common in various segments worldwide. In a super-aged society, sarcopenia is a major concern and has gained significant research attention focused on healthy aging. To date, the primary interventions for sarcopenia have been physical exercise therapy. Recent evidence suggests that inadequate B6 status is associated with an increased risk of sarcopenia and mortality among older adults. Our previous study showed that B6 supplementation to a marginal B6-deficient diet up-regulated the expression of various exercise-induced genes in the skeletal muscle of rodents. Notably, a supplemental B6-to-B6-deficient diet stimulates satellite cell-mediated myogenesis in rodents, mirroring the effects of physical exercise. These findings suggest the potential role of B6 as an exercise-mimetic nutrient in skeletal muscle. To test this hypothesis, we reviewed relevant literature and compared the roles of B6 and exercise in muscles. Here, we provide several pieces of evidence supporting this hypothesis and discuss the potential mechanisms behind the similarities between the effects of B6 and exercise on muscle. This research, for the first time, provides insight into the exercise-mimetic roles of B6 in skeletal muscle. Full article

Despite the extensive research conducted on Alzheimer’s disease (AD) over the years, no effective drug for AD treatment has been found. Therefore, the development of new drugs for the treatment of AD is of the utmost importance. We recently reported the proteolytic activities of JAL-TA9 (YKGSGFRMI) and ANA-TA9 (SKGQAYRMA), synthetic peptides of nine amino acids each, derived from the Box A region of Tob1 and ANA/BTG3 proteins, respectively. Furthermore, two components of ANA-TA9, ANA-YA4 (YRMI) at the C-terminus end and ANA-SA5 (SKGQA) at the N-terminus end of ANA-TA9, exhibited proteolytic activity against amyloid-β (Aβ) fragment peptides. In this study, we identified the active center of ANA-SA5 using AEBSF, a serine protease inhibitor, and a peptide in which the Ser residue of ANA-SA5 was replaced with Leu. In addition, we demonstrate the proteolytic activity of ANA-SA5 against the soluble form Aβ42 (a-Aβ42) and solid insoluble form s-Aβ42. Furthermore, ANA-SA5 was not cytotoxic to A549 cells. These results indicate that ANA-SA5 is a promising Catalytide and a potential candidate for the development of new peptide drugs targeting Aβ42 for AD treatment. Full article