: Considering that Einstein's relation between the diffusion coefficient and the drift mobility of the free randomly moving charge carriers in homogeneous materials including metals is always valid, it is shown that the effective electric force acting on free electrons in metal depends on the ratio between the kinetic free electron energy at the Fermi surface to the classical particle energy 3kT/2. The electrical resistivity of elemental metals dependence on very low temperatures has the quadratic term, which has been explained by electron-electron scattering. In this paper, it is shown that the quadratic term of the electrical resistivity at low temperatures is caused by scattering of the free RM electrons by electronic defects due to linear effective free electron scattering cross-section dependence on temperature, but not by electron-electron scattering.

The aim of this study was to assess the influence of thermocompression conditions on lignocellulosic biomass such as sugarcane bagasse (SCB) in the production of 100% binderless bio-based materials. Five parameters were investigated: pressure applied (7-102 MPa), molding temperature (60-240°C), molding time (5-30 min), fiber/fine particle ratio (0/100-100/0) and moisture content (0-20%). These parameters affected the properties and chemical composition of the materials. The density ranged from 1198 to 1507 kg/m3, the flexural modulus from 0.9 to 6.9 GPa and the flexural strength at breaking point from 6.1 to 43.6 MPa. Water absorption (WA) and thickness swelling (TS) respectively ranged from 21% to 240% and from 9% to 208%. Higher mechanical properties were obtained using SCB with fine particles, low moisture content (4-10%), high temperature (≥ 200°C) and pressure (≥ 68 MPa), while water resistance was improved using more severe thermocompression conditions with the highest temperature (240°C) and time (30 min) or a higher moisture content (≥ 12.5%). Correlations were noted between the mechanical properties and density, while the material obtained with only fine particles had the highest mechanical properties and density. Material obtained with a 30 min molding time had the lowest WA and TS due to internal chemical reorganization followed by hemicellulose hydrolysis into water-soluble extractables.

C. auris is a newly emerging yeast, raising public health concerns due to its outbreak potential, lack of protocols for decontamination and isolation of patients or contacts, increased resistance to common antifungals and associated high mortality. This research aimed to describe the challenges related to identifying the outbreak, limiting further contamination, and treating affected individuals. We retrospectively analysed all cases of C. auris detected between October 2022 and August 2023, but our investigation focused on a three-month-long outbreak in the department of cardio-vascular surgery and the related intensive care unit. Along with isolated cases in different wards, we identified 13 patients who became infected or colonized in the same area and time, even though the epidemiological link could be traced only in 10 patients, according to the epidemiological investigation. In conclusion, our study emphasizes the substantial challenge encountered in clinical practice when attempting to diagnose and limit the spread of an outbreak. Therefore, it is crucial to promptly apply contact precaution measures and appropriate environmental cleaning, from the first case detected positive.

Insulin resistance/hyperinsulinemia as an independent risk factor for the development and worsening of HFpEF. Serafino Fazio MD¹, Valentina Mercurio MD, PhD2, Valeria Fazio MD3, Antonio Ruvolo MD⁴, Flora Affuso MD, PhD⁵. Authors’ Affiliation: ¹ Department of Internal Medicine (retired Professor). Federico II University, Via Sergio Pansini 5. 80135 Naples, Italy. 2 Department of Translational Medical Sciences. Federico II University. Via Sergio Pasini 5. 80135 Naples, Italy. ³ UOC Medicina Interna, Azienda Ospedaliera di Caserta, 81100 Caserta, Italy, ⁴ UOC Cardiologia AORN dei colli PO CTO, Viale Colli Aminei 21, 80100 Naples, Italy. ⁵ Independent researcher, Viale Raffaello 74, 80129 Naples, Italy. Abstract Heart failure (HF) has become a subject of continuous interest since it has been declared new pandemic in 1997 because of the exponential increase in hospitalizations for HF in the latest years. HF is the final state to which all heart diseases of different etiologies lead if not adequately treated, therefore it is highly prevalent worldwide, with a progressive increase with age, reaching a prevalence of 10% in subjects over the age of 65 years. It should also be underlined that lately, while the prevalence of HF with left ventricular reduced ejection fraction (HFrEF) is slowly decreasing, the incidence of HF with left ventricular preserved ejection fraction (HFpEF) is progressively increasing. In deed, among patients consecutively hospitalized for HF between 1987 and 2001 in a study from the Mayo Clinic Hospitals in Olmsted County, Minnesota, prevalence of HFpEF increased from 38% to 54%. HFpEF is typically characterized by concentric remodeling of the left ventricle (LV) with impaired diastolic function and increased filling pressures. Over the years, also the prevalence of insulin resistance/hyperinsulinemia in the general adult population has progressively increased, primarily due to lifestyle changes, particularly in developed and developing countries, with a range that globally ranges between 15.5% and 46.5%. Notably, insulin resistance (IR)/hyperinsulinemia (Hyperins) is present in up to 60% of patients with HF and is significantly higher in subjects with HfpEF. In the scientific literature it has been well highlighted that the increased circulating levels of insulin are associated with conditions of insulin resistance are responsible for progressive cardiovascular alterations over the years. In the setting of HFpEF, insulin stimulates the concentric remodeling of the left ventricle with associated diastolic dysfunction, which, coincidentally. Unfortunately, IR/Hyperins, despite being a well-known cardiovascular risk factor, is still not screened in the general population and is not treated as promptly as it should be, and this could at least in part concur in the progressive increase in prevalence of HFpEF in the general adult population. The aim of this manuscript was to review scientific literature that support a pathophysiologic connection between IR/Hyperins and HFpEF to stimulate the scientific community towards the identification of hyperinsulinemia associated with insulin resistance as an independent cardiovascular risk factor in development and worsening of HF, believing that its adequate screening in the general population and appropriate treatment could reduce the prevalence of HFpEF and improve its progression.

A new Mg-Zn-Zr-Ca alloy in powder state was obtained via mechanical alloying method, from pure elemental powder. Further, the obtained powder-alloy was processed by selective laser melting (SLM) procedure to obtain 3D printed samples for small biodegradable implants. A series of microstructural, mechanical and corrosion analysis were performed. The SEM analysis of powder-alloy reveal a good dimensional homogeneity, with uniform colored, no agglutinated and almost rounded particles, suitable for selective laser melting procedure. Further, the SLM samples reveal a robust and unbreakable morphology, with a suitable porosity and without undesirable balling effect. The tested Young’s modulus of the SLM samples, of 42 GPa, is close to cortical bone one, of 30 GPa. The corrosion tests performed in PBS (Phosphate-buffered saline) solution show that the corrosion parameters have a satisfactory evolution.

Neonatal sepsis is a leading cause of morbidity and mortality in neonates, particularly in low and middle-income countries. The emergence of antimicrobial resistance is a rapidly growing global problem. A significant proportion of the pathogens that commonly cause neonatal sepsis are resistant to multiple antibiotics. Therefore, for the empirical treatment of neonatal sepsis, the repurposing of older antibiotics that are effective against multidrug-resistant pathogens is being investigated. This review aims to provide an overview of current research and experience using the repurposed antibiotics, Colistin and Fosfomycin, for the empirical treatment of neonatal sepsis. Based on current knowledge, Colistin and Fosfomycin may be potentially helpful for the empirical treatment of sepsis in neonates due to their efficacy against a wide range of pathogens and acceptable safety profile.

(1) Background: We aimed to determine the prevalence of hepatitis B virus (HBV) resistance-associated mutations (RAMs) in people with HBV and human immunodeficiency virus (HBV/HIV) in Botswana. (2) Methods: We sequenced HBV from participants with HBV/HIV from the Botswana Combination Prevention Project study (2013-2018) using the Oxford Nanopore GridION platform. Consensus sequences were analyzed for genotypic and mutational profiles. (3) Results: Overall, 98 HBV sequences had evaluable reverse transcriptase region coverage. The median participant age was 43 years (IQR: 37, 49) and 66/98 (67.4%) were female. Most participants, 85/97 (87.6%) had suppressed HIV viral load (VL). HBV RAMs were identified in 61/98 (62.2%) participants. Most RAMs were in positions 204 (60.3%), 180 (50.5%) and 173 (33.3%), mostly associated with lamivudine resistance. The triple mutations, rtM204V/L180M/V173L and was the most predominant (17/61 [27.9%]). Most participants (96.7%) with RAMs were on antiretroviral therapy for a median duration of 7.5 years (IQR: 4.8, 10.5). Approximately 27.9% (17/61) of participants with RAMs had undetectable HBV VL, 50.8% (31/61) had VL <2000IU/mL and 13/61 (21.3%) had VL ≥2000 IU/mL. (4) Conclusions: The high prevalence of lamivudine RAMs discourages the use of ART regimens with 3TC as the only HBV-active drug in people with HIV/HBV.

Background: Bacteria can survive antibiotic exposure by mechanisms like tolerance without a shift in antimicrobial susceptibility. In this study, we investigated the presence of tolerance to three antimicrobials, ceftriaxone (CRO), azithromycin (AZM), and ciprofloxacin (CIP), in clinical isolates and WHO reference panel of N. gonorrhoeae and explored the prevalence between urogenital and anorectal infection sites. Methods: We examined 66 N. gonorrhoeae clinical isolates, evenly divided between anorectal and urogenital infection sites, using a modified tolerance disk (TD test) for three antibiotics. The isolates underwent a three-step incubation process wherein the isolates were exposed to an antibiotic disc for 20 hours of incubation (Step I), followed by the replacement of the antibiotic disc with a nutrient disc for overnight incubation (Step II) and additional overnight incubation with extra nutrients (Step III). Results: Four isolates were lost due to contamination. Of 62 clinical isolates, 7 exhibited tolerance to AZM, with 6 from anorectal and 1 from urogenital sites (p = 0.0496). Tolerance to CRO was observed in 11 isolates, which was significantly associated with the infection site, with 9 from the anorectum, and 2 from the urogenital site being tolerant (p = 0.02). Tolerance to CIP was found in 11 isolates, but was not significantly associated with the infection site. Tolerance was also detected in 8 (K, M, N, O, P, U, V, W) out of the 14 WHO (World Health Organization) reference strains, with varying patterns of tolerance to CRO (n=8), CIP (n=2) and AZM (n=1). Conclusion: This study identified CRO, AZM, and CIP tolerance in clinical Neisseria gonorrhoeae isolates. Significant variations in tolerance proportions between anorectal and urogenital infection sites, particularly for CRO, were observed. Additionally, tolerance was detected in WHO reference strains.

Non-coding RNAs have been described as crucial regulators of gene expression and guards for cellular homeostasis. Some recent papers are focused on vault RNAs, one of the classes of non-coding RNA, and their role in cell proliferation, tumorigenesis, apoptosis, cancer response to therapy, and autophagy, which made them potential therapy targets in oncology. In the human genome, four vault RNA paralogues can be distinguished. They are associated with vault complexes, considered the largest ribonucleoprotein complex. The protein part of these complexes consists of a major vault protein (MVP) and two minor vault proteins (vPARP and TEP1). The name of the complex, as well as vault RNA, comes from the hollow barrel-shaped structure that reminds a vault. Their sequence and structure are highly evolutionary conserved and show many similarities in comparison with different species, but vault RNAs show various roles. Vaults were discovered in 1986, and their functions remained unclear for many years. Although not much is known about their contribution to cell metabolism, it has become clear that vault RNAs are involved in various processes and pathways associated with cancer progression and modulating cell functioning in normal and pathological stages. In this review, we discuss known functions of the human vault RNAs in the context of cellular metabolism, emphasizing processes related to cancer and cancer therapy efficacy.

Rubber compounds based on styrene-butadiene rubber, ethylene-propylene-diene-monomer rubber and the combinations of both rubbers were cured with different sulfur and peroxide curing systems. In sulfur curing systems, two type of accelerators, namely N-cyclohexyl-2-benzothiazole sulfenamide, tetramethylthiuram disulfide and combinations of both accelerators were used. In peroxide curing systems, dicumyl peroxide, and combination of dicumyl peroxide with zinc diacrylate or zinc dimethacrylate, respectively were applied. The work was focused on investigation of the curing system composition as well as type of the rubber or rubbers combinations on curing process, cross-link density and physical-mechanical properties of vulcanizates. The dynamic-mechanical properties on the selected vulcanizates were examined, too. The result revealed correlation between the cross-link density and physical-mechanical properties. Similarly, there was recorded certain correlation between cross-linking degree and glass transition temperature. The tensile strength of vulcanizates based on rubbers combinations was higher when compared to that based on pure rubbers, which points out the fact that by rubbers combination, not only the features of both elastomers can be combined, but also improved tensile characteristics can be achieved. When compared to vulcanizates cured with dicumyl peroxide, materials cured with sulfur system exhibited higher tensile strength. By application of co-agents in peroxide vulcanization, the tensile strength overcame the tensile behavior of sulfur cured vulcanizates.

The impact of systemic vascular resistance (SVR) in hypertrophic (HCM) and amyloid cardio-myopathies has been seldom investigated. We studied pressure-strain loop derived myocardial work (MW) indices and SVR in patients with either sarcomere HCM or wild type transthyretin cardiac amyloidosis (ATTR), presented with heart failure and preserved left ventricular ejection fraction (HFpEF) at the outpatient cardiology units at Messina and Catania University Hospitals (Italy). Patients were in sinus rhythm and needed to have good transthoracic ultrasound imaging quality to undergo transthoracic strain-echocardiography. Other than conventional parameters, SVR and GWI (global work index) were measured. Based on cross-tabulation (a way to assess the ventricular-arterial coupling), the patients were then classified in 4 classes according to the cut-off values suggested by previous studies of 1,440 dyne/s/cm-5 for SVR (Stefadouros et al., 1973) and 1576 mm Hg% for GWI (Olsen et al., 2022). Sixty patients, 30 in each group, aged 61±16 years, 78% males, were studied. HCM were younger than ATTR patients and in a better clinical status (23% HCM vs 77% ATTR were NYHA class 3, p<0.001). Overall, 51 patients (85%) showed high SVR, of whom 21 were HCM (70%) and 30 ATTR (100%) (p<0.005). Both, SVR and GWI were impaired (the poorest class C) in 43% HCM patients (with greater left ventricular concentric hypertrophy) vs 93% of ATTR patients (in advanced NYHA class) (p<0.001). In conclusion, assessing SVR and GWI in HFpEF patients with HCM or ATTR can help clinicians to interpret the pathophysiological and clinical features of such complex diseases.

This study investigates the effects of Zinc (4wt.%) and severe plastic deformation on the mechanical properties of AZ61 magnesium alloy through the stir-casting process. The severe plastic deformation (equal channel angular pressing (ECAP)) has been done followed by T4 heat treatment. The microstructural examinations revealed that the addition of 4wt.%Zn enhances the uniform distribution of β-phase, contributing to a more uniformly corroded surface in corrosive environments. Additionally, dynamic recrystallization (DRX) significantly reduces the grain size of as-cast alloys after undergoing ECAP. The attained mechanical properties demonstrate that after a single ECAP pass, AZ61 + 4wt.%Zn alloy exhibits optimal yield strength (YS), ultimate compression strength (UCS), and hardness. This research highlights the promising potential of AZ61 + 4wt.%Zn alloy for enhanced mechanical and corrosion-resistant properties, offering valuable insights for applications in diverse engineering fields.

Background: The resurgence of syphilis, primarily in MSM populations, has necessitated novel prophylactic strategies, such as the use of doxycycline post-exposure prophylaxis (doxy-PEP). However, the potential for increased doxycycline use to select for tetracycline resistance represents significant challenges in managing this sexually transmitted infection. This study aims to identify chromosomal mutations associated with tetracycline resistance in Spirochaetales to inform treatment strategies and surveillance measures.Methods: Whole genome sequences (WGS) from the Spirochaetales order, including 4,355 genomes, were analyzed for the presence of mutations in 16S rRNA and non-synonymous mutations in the rpsC and rpsJ genes. The study utilized WGS from GenBank® and sequence data from the PubMLST Treponema pallidum isolate collection. Genetic resistance to tetracycline was detected using a combination of BLASTN searches and gene-gene analysis. Results: A transition mutation TGA to TGG at positions 965-967 in the 16S rRNA gene was detected in 5.6% of Treponema spp. and 3.97% of Spirochaeta spp. genomes. The rpsJ gene exhibited a V57G amino acid substitution across a significant subset of Treponema spp. Notably, the V57K mutation was common in Spirochaeta spp. The rpsC gene had the H178Q mutation and was found to be present in the Spirochaetales bacterium.Conclusion: The identification of mutations associated with tetracycline resistance in Spirochaetales provides a foundation for the development of rapid molecular diagnostics and guides the clinical selection of antibiotics for syphilis treatment. This study underscores the complexity of antibiotic resistance mechanisms and the critical importance of surveillance in the era of antibiotic prophylaxis for STI management.

Pseudomonas aeruginosa infections are the focus of new treatment alternatives due to their frequent development of resistance to antibiotics and formation of biofilms. Recently, emphasis has been placed on combinations of antibiotics with drugs used for different indications. In this study the combined effects of metformin with imipenem, ceftazidime, cefepime, ciprofloxacin and levofloxacin has been investigated. 50 P. aeruginosa isolates isolated from patients with cystic fibrosis come to Gaziantep University Microbiology Laboratory were included in the study. The susceptibilities of the isolates to antibiotics were investigated by the liquid microdilution method and the combined effect of metformin and antibiotics by the chequerboard synergy test. In our study, as a result of the chequerboard synergy test; synergy between ceftazidime and metformin 6%, partial synergistic 22% isolates; while no synergistic effect was detected between cefepime and metformin in any isolate, partially synergy 46%; synergy between imipenem and metformin 4%, partial synergy 10%; synergy between ciprofloxacin and metformin 6%, partial synergy 6%, antagonist effect 2%; synergy was detected between levofloxacin and metformin 2% and a partial synergy was detected 12%. This study shows that metformin could be a potential antibiotic in its current form or in different chemical forms to be produced synthetically.

Ionic channels are present in eucaryotic plasmatic and intracellular membranes. They coordinate and control several functions. One of the most diverse ionic channels family are the potassium (K) channels. Within this family are the ATP-dependent potassium channels (KATP), which belong to the potassium rectifier channel family. These channels were initially described in heart muscle, yet they are also present in different types of tissues such as pancreatic, skeletal muscle, brain, and vascular and non-vascular smooth muscle. In ß-pancreatic cells, KATP are primarily responsible for maintaining membrane potential and for the depolarization mediated insulin release. KATP density/activity seems to be determinant in physiological the outcome, in pancreatic cells decrease of this density/activity may be related to Insulin resistance (IR). In extra pancreatic tissues KATP relation with IR is beginning to be explored. It is possible that in skeletal muscle, the KATP are involved in insulin dependent glucose recapture and that KATP activation leads to IR. In adipose tissue, KATP containing Kir6.2, could be related to increase in free fatty acids and insulin resistance, therefore, pathological processes leading to a prolonged adipocyte KATP inhibition might promote obesity related to insulin resistance. In central nervous system KATP activation can regulate peripheric glycemia and lead to brain IR which could be a much earlier manifestation of peripheral alterations that lead to the development of pathologies such as obesity and type 2 diabetes mellitus. In this review we aim to discuss the KATP channel characteristics, its relationship to known clinical disorders and the mechanisms and potential relations with peripheral and central insulin resistance.

Previous studies showed that some lamellarin-resembling annelated azaheterocyclic carbaldehydes and related imino adducts, sharing the 1-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline (1-Ph-DHPIQ) scaffold, are cytotoxic in tumor cells and may reverse multidrug resistance (MDR) mediated by P-glycoprotein (P-gp). Herein, we synthesized and evaluated for their antiproliferative activity in four tumor cell lines (RD, HCT116, HeLa, A549) and ability of inhibiting P-gp-mediated MDR some ten diversely substituted 1-Ph-DHPIQ derivatives bearing at position 2 carboxylate groups (COOH, COOEt), nitriles (CN) and Mannich bases (e.g., morpholinomethyl derivatives). Lipophilicity parametrization and molecular docking calculations improved the understanding of the structure-activity relationships in cytotoxicity and P-gp inhibition of the investigated 1-Ph-DHPIQs, which led us to disclose a novel Mannich base HCl salt (8b’), which proved to be cytotoxic to all the tested tumor cell lines in the low micromolar range (IC50 &lt; 20 M) and to inhibit in-vitro the efflux pumps P-gp and MRP1 responsible for MDR, with IC50s of 0.45 and 12.1 M, respectively.

Infections caused by KPC-producing K. pneumoniae continue to pose a significant clinical challenge due to emerging resistance to new antimicrobials. We investigated the association between two drugs whose roles have been repurposed against multidrug-resistant bacteria: fosfomycin and temocillin. Temocillin exhibits unusual stability against KPC enzymes, while fosfomycin acts as a potent “synergizer”. We conducted in vitro antimicrobial activity studies on 100 clinical isolates of KPC-producing K. pneumoniae using a combination of fosfomycin and temocillin. The results demonstrated synergistic activity in 91% of the isolates. Subsequently, we assessed the effect on Galleria mellonella larvae using 5 different KPC-Kp isolates. The addition of fosfomycin to temocillin increased larvae survival from 73 to 97% (+Δ 32%; isolate 1), from 93 to 100% (+Δ 7%; isolate 2), from 63 to 86% (+Δ 36%; isolate 3), from 63 to 90% (+Δ 42%; isolate 4), and from 93 to 97% (+Δ 4%; isolate 10), respectively. Among the temocillin-resistant KPC-producing K. pneumoniae isolates (24 isolates), the addition of fosfomycin reduced temocillin MIC values below the resistance breakpoint in all isolated except one. Temocillin combined with fosfomycin emerges as a promising combination against KPC-producing K. pneumoniae, warranting further clinical evaluation.

Heteroresistance (HR) to colistin is especially concerning in settings where multi-drug resistant (MDR) K. pneumoniae are prevalent and empiric use of colistin might lead to treatment failures. This study aimed to assess the frequency of occurrence of colistin HR (CHR) among (MDR) K. pneumoniae (n=676) isolated from patients hospitalized in 13 intensive care units (ICUs) in 6 European countries in a clinical trial assessing the impact of decolonization strategies. All isolates were whole-genome-sequenced and studied for in vitro colistin susceptibility. Majority were colistin-susceptible (CS) (n=597, MIC 2 µg/ml). 288 CS isolates were randomly selected for population analysis profiling (PAP) to assess CHR prevalence. CHR was detected in 108/288 CS K. pneumoniae. No significant association was found between the occurrence of CHR and country, MIC-value, K-antigen type and O-antigen type. Overall, 92% (618/671) of the K. pneumoniae were MDR with high prevalence among CS (540/592) and CR (98.7%, 78/79) isolates. In contrast, proportion of carbapenemase-producing K. pneumoniae (CP-Kpn) was higher among CR (72.2%, 57/79) than CS isolates (29.1%, 173/594). Proportions of MDR and CP-Kpn were similar among CHR (MDR: 85%, 91/107; CP-Kpn: 29.9%, 32/107) and CS isolates (MDR: 91%, 539/592; CP-Kpn: 29.1%, 153/59). WGS analysis of PAP isolates showed diverse insertion elements in mgrB or even among technical replicates underscoring the stochasticity of the CHR phenotype. CHR isolates showed high ST diversity (Simpson’s diversity index, SDI: 0.97, in 52 of the 85 STs tested). CR (SDI: 0.85) isolates were highly associated with specific STs (ST101, ST147, ST258/ST512, P ≤ 0.003). The widespread nature of CHR among MDR K. pneumoniae in our study urge the development of rapid HR detection methods to inform on the need for combination regimens.

Gold nanoparticles (AuNPs) exhibit improved optical and spectral properties compared to bulk materials, making them suitable for detection of DNA, RNA, antigens, and antibodies. Here, we describe a simple, selective, and rapid non-cross linking detection assay, using approx. 35 nm spherical Au nanoprobes, for a common mutation occurring in exon 19 of the epidermal growth factor receptor (EGFR), associated with non-small cell lung cancer cells. AuNPs were synthesized based on the seed-mediated growth method and functionalized with a specific 16 bp thiolated oligonucleotide using a pH-assisted method. Both AuNPs and Au nanoprobes proved to be highly stable and monodisperse by ultraviolet-visible spectrophotometry, dynamic light scattering (DLS) and electrophoretic light scattering (ELS). Our results indicate a detection limit of 1.5 µg mL−1 using a 0.15 nmol dm−3 Au nanoprobe concentration. In conclusion, this work is an effective possibility for a straight-forward, fast, and inexpensive alternative for the detection of DNA sequences related to lung cancer, leading to a potential platform for an early diagnosis of lung cancer patients.

Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy worldwide. Despite the latest advances, a major clinical issue in EOC is the disappointing prognosis related to chemoresistance in almost one-third of cases. Drug resistance relies on heterogeneous cancer stem cells (CSCs), endowed with tumor-initiating potential, leading to relapse. No biomarkers of chemoresistance have been validated yet. Recently, major signaling pathways, micro ribonucleic acids (miRNAs), and circulating tumor cells (CTCs) have been advocated as putative biomarkers and potential therapeutic targets for drug resistance. However, further investigation is mandatory before their routine implementation. In accordance with the increasing rate of therapeutic efforts in EOC, the need for biomarker-driven personalized therapies is growing. This review aims to discuss the emerging hallmarks of drug resistance with an in-depth insight into the underlying molecular mechanisms lacking so far. Finally, a glimpse of novel therapeutic avenues and future challenges will be provided.

The global craft beer market is witnessing substantial growth, with a particular spotlight on sour beers. These unique brews are created through lactic fermentation initiated by lactic acid bacteria (LAB). However, the presence of hops, renowned for their antimicrobial properties, can pose a limitation within the realm of sour beer production. This research aims to explore and assess the potential of sour beer as a probiotic beverage. It involves a comparative analysis of the viability of Lacticaseibacillus paracasei subsp. paracasei F19 (F19) and 431 (L431) in a sour beer with an International Bitterness Unit (IBU) value of 26.65, alongside examining the ex-pression of genes such as horA, horB, horC, hitA, bsrA, and recA, which are associated with hop resistance. The study encompasses the development of two formulations of sour beers characterized by both high hop content and a robust probiotic count (8.44 – 8.77 log CFU/mL). The findings suggest that both probiotic strains of F19 and L431, are well-suited to produce sour beers with elevated hop levels, demonstrating excellent stability. Notably, the expression of genes responsible for hops resistance exhibited distinct modulation patterns among the two strains. It appears that a higher concentration of bsrA, as observed in strain L431, may be more effective in mitigating the effects of hop-related stress, potentially surpassing the combined expression of horA and bsrA. Nonetheless, further research is essential to validate this observation in gene expression. F19 and L431 emerge as promising candidates for the development of sour beers with increased hop intensity.

Elevated circulating triglyceride levels have been linked to an increased risk of diabetes, although the precise mechanisms remain unclear. This study aimed to investigate whether low-density lipoprotein (LDL) cholesterol, homeostatic model assessment (HOMA) for insulin resistance, and C-reactive protein served as mediators in this association across a sample of 18,435 US adults. Mediation analysis was conducted using the PROCESS Version 4.3 Macro for SPSS. Simple medi-ation analysis revealed that all three potential mediators played a role in mediating the associa-tion. However, in the parallel mediation analysis, where all three mediators were simultaneously included, HOMA for insulin resistance remained a significant mediator (indirect effect coefficient, 0.47; 95% confidence interval [CI], 0.43—0.52; p < 0.05) after adjusting for all tested confounding factors. Conversely, LDL cholesterol (indirect effect coefficient, -0.13; 95% CI, -0.31—0.05; p > 0.05) and C-reactive protein (indirect effect coefficient, 0.01; 95% CI, -0.003—0.02; p > 0.05) ceased to be significant mediators. HOMA for insulin resistance accounted for 49% of the association between triglycerides and diabetes. In conclusion, HOMA for insulin resistance was the dominant mediator underlying the association between triglycerides and diabetes. Therefore, reducing triglyceride levels may hold promise for improving insulin sensitivity in diabetic patients.

Water recycling and reuse are corner stones in the water management that may be compromised by the presence of pollutants. Among them, pharmaceuticals can overcome the standard water treatments and require sophisticated approaches to remove them. Sorption is an economically affordable alternative limited by the need of sorbents that exhibit sorption coefficient (Kd) higher than 500 L/kg to be useful in wastewater treatment plants (WWTPs). We report that th cross-linking of dextrin (Dx) with divinyl sulfone (DVS) in presence of 1 mmol or 5 mmol of ibuprofen (IBU) yields the insoluble polymers pDx1 and pDx5 with improved affinity for IBU, Kd higher than 600 L/kg for ciprofloxacin (CIP) and ofloxacin and an outstanding Kd higher than 4000 L/kg for erythromycin (ERY), when assayed against a cocktail of 6 drugs. The characterization of the polymers by XRPD, TGA and SEM reveals that both pDx1 and pDx5 share similar features, with an ERY Kd of 13 x 103 for pDx1 and 6.4 x 103 for pDx5. The facts that new affinities and improvements in Kd can be achieved by cross-linking Dx in presence of other molecules that promote a pre-organization, broaden the applications of DVS cross-linked polysaccharide as sustainable and eco-friendly sorbents.

Understanding the dynamics of teamwork and communication among healthcare professionals is crucial in the face of evolving healthcare challenges. This study assessed relational coordination among healthcare professionals in the South Tyrolean healthcare system in Italy, focusing on communication and teamwork dynamics in a cross-sectional survey. Using the validated Relational Coordination Survey (RCS) instrument and 525 completed online responses, the questionnaire aimed to understand the implications of different levels of relational coordination ratings by general practitioners, hospital physicians, nurses, and administrative personnel (response rate 26%). The demographics of the participants revealed a predominance of female professionals (64%), with an average age of 50 and 18 years of service. The resulting RCS scores varied significantly across professional groups, with nurses reporting the highest within-group scores, indicating moderate coordination, and administrators reporting the lowest scores, reflecting areas of weak coordination. Between-group relational coordination was generally perceived as weak across professional groups, with the least weakness observed between general practitioners and nurses. German or Italian language and health district affiliation emerged as significant factors influencing relational coordination ratings, highlighting the need for differentiated understanding and strategies in multilingual and diverse regional settings. Assessments of interdisciplinary feedback and referral practices highlight the variation in teamwork and communication weaknesses and underscore the need for targeted interventions to improve relational coordination. This study provides insights into the complexity of relational dynamics in health care settings. It suggests that improving relational coordination through tailored strategies could significantly improve team effectiveness, quality of patient care, and overall system efficiency.

An optical frequency comb (OFC) generator based on an electro-optic Talbot laser and cross-phase modulation (XPM) in a high nonlinear fiber (HNLF) is designed and demonstrated. The Talbot laser is an electro-optic frequency shifting loop to produce repetition rate multiplied pulses, and these pulses working as a pump signal induce XPM process in the HNLF to modulate the phase of a probe signal. At the output of the HNLF, OFCs with a multiplied line-spacing can be generated. The effects of the pump power and the HNLF length on the performance of the generated OFCs are theoretically analyzed. In the experiments, the line-spacing of the generated OFCs is respectively multiplied to be 10 GHz, 15 GHz and 20 GHz with a factor of 2, 3 and 4. The center of the OFCs is tuned in a 4-nm range by adjusting the wavelength of the probe signal.

The hospital indoor environment plays a significant role in shaping the microbial exposures that humans encounter. Resistance to antibiotics is one of the mechanisms employed by bacteria to develop resilience against stress in indoor environments. The extensive usage of antibiotics has been a key factor in driving changes in the ecological function of antibiotic resistance genes (ARGs) and their acquisition by pathogenic bacteria. By integrating the 16S rRNA Illumina sequencing and high throughput-qPCR approaches with water and air dust samples across seven departments at Peking University Shenzhen Hospital, China, this study yielded intriguing findings regarding the department-specific variation, transmission, and correlation of bacteria, ARGs and MGEs within the hospital indoor environment. One notable observation was that the seasonal variation played a vital role in shaping the bacterial composition in the overall hospital indoor environment across seven studied departments. Nevertheless, a similar significant seasonal impact was only observed in the blood test room and emergency departments, rather than in the other five departments. Another intriguing finding was the correlation between ARGs and MGEs abundance. This correlation was evident in the overall hospital indoor environment, which was conversely not found in the emergency, pneumology and gynecology departments. Additionally, while there was no significant relationship that occurred between bacterial communities and ARGs/MGEs within the hospital, the gynecology department demonstrated a close link between bacterial communities and the presence of ARGs/MGEs. Notably, the gynecology department also stood out as an important source of bacteria and ARGs/MGEs for other departments. This study underscores the need for careful surveillance and monitoring of antibiotic resistance, particularly in Legionella spp. in man-made water systems. The findings also show the importance of monitoring and understanding the genetic elements such as Tp614 involved in gene transfer and recombination, as well as their impact on antimicrobial treatment efficacy.

This research concerns the virtual reconstruction and technical constructive analysis of the emblematic and disappeared Matriz church of Ambato city, whose structure was demolished after the collapse of its vaults in the 1949 earthquake, about which it was said to have had deficiencies in its construction. Through an exhaustive historical review of documents and images, its constructive hypothesis was achieved, and using photogrammetry technique, its virtual reconstruction was obtained, where, through the interpretation and understanding of the generated plans, the verification of its technical and constructive characteristics associated with its hypothetical mechanical behavior inherent to its stone construction was carried out. For the structural study, the principle of the Limit Analysis of Structures was used, where through a graphic static approach, the technical stability conditions of a masonry structure are established, in this case, to give an interpretation to the possible poor execution of the church's work, and eventual cause that could have contributed to the collapse of its vaults.

Rhizobia are biological nitrogen fixing non-pathogenic micro-organisms that make inert nitrogen available to legumes establishing symbiosis and living within their nodules and promoting their growth. Livestock farmers use antibiotics without prescriptions to prevent losses, death and economic wastes, resulting in indiscriminate release of excess, un-utilized antibiotics into the environment causing detrimental effects to soil microbes particularly rhizobia.This study evaluates the susceptibility pattern of selected rhizobia strains. The intrinsic antibiotic resistance (IAR) ability of common rhizobia strains including FA3, B574, RS15, USDA136, USDA9032, R25B, 532C, CC511, RANI22, RAUG1 were investigated. The antibiotics used included Ceftazamine , Florfenicol , Cefpodoxime, Sulphamethoxazole, Ciprofloxacin, Gentamycin , Kanamycin, Ertapenem, Tetracycline , Meropenem and Carbapenem. Results showed different resistance patterns among isolates where high resistance was shown against Carbapenem and least resistance was shown against Ciprofloxacin (40mm), Tetracycline (33mm), kanamycin (45mm) and Gentamycin (50mm). Rani 22 showed most resistant. Most strains showed no resistance to these antibiotics, but it is significant to note that those with resistance can be used for the recovery of antibiotics contaminated sites and may provide potential solutions for futuristic problems associated with AMR.This study suggests that using a consortium of symbiotic rhizobia strains is a strategy to achieve optimal yields in antibiotic contaminated fields as the strains showed differences in their susceptibility pattern. Also, the antibiotics produced or contained active compounds and substances that are detrimental for the growth of rhizobia and may therefore be a hindrance to these plant growth promoting bacteria when they are applied to aid plant growth used during agricultural practises.

Shape-shifting polymers usually require not only reversible stimuli-responsive ability, but also strong mechanical properties. A novel shape-shifting photochromic hydrogel system was designed and fabricated through embedding hydrophobic spiropyran (SP) into double polymeric network (DN) by micellar copolymerization. Here, sodium alginate (Alg) and poly acrylate-co-methyl acrylate-co-spiropyran (P(SA-co-MA-co-SPMA)) were employed as the first network and the second network respectively to realize high mechanical strength. After soaked in the CaCl2 solution, the carboxyl groups in the system undergo metal complexation with Ca2+ to enhance the hydrogel. Moreover, after the hydrogel is exposed to UV-light, the closed isomer of spiropyran in the hydrogel network can be converted into an open zwitterionic isomer MC, which is considered to interact with Ca2+ ions. Interestingly, Ca2+ and UV-light responsive programmable shape of the copolymer hydrogel can recover to its original form by immersing in pure water. Since its excellent metal ion and UV-light stimuli-responsive and mechanical properties, the hydrogel has potential applications in the field of soft actuators.

In agriculture, soil-borne fungal pathogens, especially Fusarium oxysporum strains, are posing a serious threat to efforts to achieve global food security. In the search for safer agrochemicals, silica nanoparticles (SiO2NPs) have recently been proposed as a new tool to alleviate pathogen damage including Fusarium wilt. Hollow mesoporous silica nanoparticles (HMSNs), a unique class of SiO2NPs, have been widely accepted as a desired pesticide carrier. However, their role in enhancing the disease resistance and the specific mechanism remain unknown. In this study, three sizes of HMSNs (19, 96 and 406 nm as HMSNs–19, HMSNs–96 and HMSNs–406, respectively) were synthesized and characterized to determine their effects on seed germination, seedling growth, and Fusarium oxysporum f. sp. phaseolus (FOP) suppression in cowpea roots by foliar spray using phenotypes, fresh biomass and disease progression as indicators. The results revealed that three HMSNs exhibited no adverse impacts on seed germination and tended to improve plant growth. Also, they exert their FOP suppression with a size- and concentration-dependent manner. HMSNs–406 possessed the best control effect at a concentration of 1000 mg/L showing an upto 40.00% decline in the disease severity. The Si(OH)4 control was also effective on FOP suppression at a lower concentration of 100 mg/L, whereas its higher concentrations exhibited obviously adverse impacts on FOP control, seed germination and plant growth. Moreover, we conformed that HMSNs posed their Fusarium wilt suppression in cowpea plant by activating SA (salicylic acid)-dependent SAR (systemic acquired resistance) responses rather than directly suppressing FOP. A higher level of SA content and elevated expression of its maker genes of PR-1 and PR-5 in HMSNs–406 treated cowpea roots provided substantial evidences of this mode of action. Other resistance-related genes, as well as defense-responsive enzymes, were also involved in the HMSNs-activated SAR pathway. Overall, for the first time, our results extended a new role of HMSNs as a potent elicitor to serve as a versatile alternative for plant disease protection of low cost, highly efficiency and sustainability.

The COVID-19-medical emergency has ended worldwide, yet there is still a need to evaluate the psychological impact of these years of unprecedented changes on students’ life. Methods: This study aims to assess and compare COVID-19-related stressors (Relationships-and-Academic-Life; Isolation; Fear-of-Contagion) and psychophysical symptoms reported by university students in April-2020, April 2021, and April 2022. The predictive role of COVID-19-related stressors on psychophysical symptoms within each time was also tested. Data were collected among 637 university students in April-2020 (n = 197), April-2021 (n = 200), April-2022 (n = 240). Results: In April-2022, perceived Isolation and Fear-of-Contagion decreased from the peak registered in April-2021, but stress related to Relationships-and-Academic-Life remained noteworthy high. A sharp and ongoing increase in psychophysical symptoms was found, with more than 50% of students reporting clinical levels of Sleep-Disorders, Depression, Psychoticism, and Interpersonal-Sensitivity. In April-2022, students still perceiving stress related to Relationships-and-Academic-Life and Isolation were at risk for Anxiety, Somatization, and Sleep-Disorders, while those still perceiving stress related to Fear-of-Contagion were also at risk for Depression, Obsessive-Compulsive, and Psychoticism. Conclusion: Findings emphasized the long-lasting detrimental effects of the COVID-19-related stress. Interventions must pinpoint the complex post-pandemic adjustment process and their effects on university students' psychophysical health.

The satellite Earth observation (EO) sector is burgeoning with hundreds of commercial satellites being launched each year, delivering a rich source of data that could be exploited for societal benefit. Data streams from the growing constellation of commercial satellites are of variable quality, limiting the potential for their combined use in science applications that need long time-series data from multiple sources. The quality of calibration performed on optical sensors onboard many satellite systems is highly variable due to calibration methods, sensor design, mission objective, budget, or other operational constraints. A small number of currently operating well-characterised satellite systems with onboard calibration, such as Landsat-8/9, Sentinel-2, and planned future missions like the NASA Climate Absolute Radiance and Refractivity Observatory (CLARREO) Pathfinder, the European Space Agency (ESA) Traceable Radiometry Underpinning Terrestrial and Helio Studies (TRUTHS), and LIBRA from China, are considered benchmarks for optical data quality due to their traceability to international measurement standards. This paper describes the concept of a space-based transfer calibration radiometer called the Satellite Cross-Calibration Radiometer (SCR) that would enable the calibration parameters from satellites such as Landsat-8/9, Sentinel-2, or other benchmark systems to be transferred to a range of commercial optical EO satellite systems while in orbit. A description of the key characteristics of the SCR to successfully operate in orbit and transfer calibration from Reference systems to Client systems is presented. A system like the SCR in orbit could complement SI-Traceable satellites (SITSats) to improve data quality and consistency and facilitate the interoperable use of data from multiple optical sensor systems for delivering higher returns on the global investment in EO.

In the text, the synthesis and characteristics of the novel ONS-type vanadium(V) complexes with thioanilide derivatives of amino acids are described. They have shown inhibition of human protein tyrosine phosphatases (PTP1B, LAR, SHP1 and SHP2) in the submicromolar range, as well as inhibition of non-tyrosine phosphatases (CDC25A and PPA2) similar to bis(maltolato)oxovanadium(IV)(BMOV). The ONS complexes increased [14C]-deoxy-D-glucose transport into C2C12 myocytes, and one of them, VC070, also enhanced this transport in 3T3-L1 adipocytes. These complexes inhibited gluconeogenesis in hepatocytes HepG2, but none of them decreased lipid accumulation in the non-alcoholic fatty liver disease model using the same cells. Compared to the tested ONO-type vanadium complexes with 5-bromosalicylaldehyde and substituted benzhydrazides as Schiff base ligand components, the ONS complexes revealed stronger inhibition of protein tyrosine phosphatases, but the ONO complexes showed greater activity in the cell models in general. Moreover, the majority of the active complexes from both groups showed better effects than VOSO4 and BMOV. Complexes from both groups activated AKT and ERK signaling pathways in hepatocytes to a comparable extent. One of the ONO complexes, VC068, showed activity in all of the above models, also including glucose utilization in the myocytes and glucose transport in insulin-resistant hepatocytes. The discussion section explicates the results within the wider scope of the knowledge about vanadium complexes.

Current VAT rules for cross-border e-commerce companies in the EU are not sustainable, because they are extremely complex and often opaque, due to the lack of tax harmonization. The aim of the research is to explore, using a qualitative method, what kind of harmonization would make the current legislation more uniform, simpler, more transparent, and easier to understand, without conflicting with the rules of any Member State. To this end, the aspects of the new platform regulation introduced on 1 July 2021 and its potential for expansion are assessed through information from possible sales models. The research suggests that the rules on platforms do not cover all possible sales models, which in our view imposes an unnecessary extra administrative burden on some businesses and makes their tax activities less transparent. In the light of the results of the research, we propose that the current EU platform regulation should be extended to cover B2B, B2C transactions and services. As a result of this suggested harmonization, a simpler, more transparent, uniform and sustainable tax system would contribute to the whitening of the economy, generating additional tax revenue for Member States.

Globally increasing antibiotic resistance has been connected to the use of antibiotics in medical, veterinary, and agricultural medicine, contributing to the burden of antibiotic resistance in Asia and Europe. The main objective of this study was to correlations of antimicrobial-resistant of various pathogens in three compartments: humans, animals and the environment in India and Germany. A systematic search was carried out in Medline via PubMed, Google Scholar, and science direct, including studies published in 2022. Out of 532 papers, 24 were considered for meta-analysis. This study reveals that in India, β-lactam is highly resistant in animals. Quinolone, on the other hand, was highly resistant in humans. Furthermore, in the environment and integrated studies, aminoglycosides and β-lactams is resistant. While in Germany, a high rate of AMR resistance in all three sectors was reported in β-lactam. However, E. coli was the most frequent pathogen in both countries and is highly resistant to β-lactam, followed by cephalosporin in all the compartments. Monitoring and evaluating antibiotic-sensitivity patterns and developing proper antibiotic regimens may lead to improved outcomes for inhibiting and controlling E. coli infections in various parts of the world.

Culex quinquefasciatus is an important target for vector control because of its ability to transmit pathogens that cause disease. Most populations are resistant to pyrethroids and often to organophosphates, the two most common classes of active ingredients used by public health agencies. A knockdown resistance (kdr) mutation, resulting in a change from a leucine to phenylalanine in the voltage gated sodium channel, is one mechanism contributing to the pyrethroid resistant phenotype. Enzymatic resistance has also been shown to play a very important role. Recent studies have shown strong resistance in populations even when kdr is relatively low which indicates factors other than kdr may be larger contributors to resistance. In this study, we examined on a statewide scale (over 70 populations), the strength of the correlation between resistance in the CDC bottle bioassay and the kdr genotypes and allele frequencies. Spearman correlation analysis showed only moderate (-0.51) and weak (-0.29) correlation between the kdr genotype and permethrin and deltamethrin respectively. The frequency of the kdr allele was an even weaker correlate. These results indicate, in contrast to Aedes aegypti, assessing kdr in populations of Culex quinquefasciatus is not a good surrogate for phenotypic resistance testing.

Wall Shear Stress (WSS) abnormalities in carotid artery blood flow are key hemodynamic factors leading to arterial endothelial damage, atherosclerotic plaque formation, and carotid artery stenosis. Precise simulation of carotid artery blood flow WSS in vitro play an important role in understanding the underlying hemodynamic mechanism of carotid artery stenosis. This study presents a design for a microfluidic cell culture chamber with a variable cross-section and a step structure, leveraging microfluidic technology and principles of fluid dynamics. We propose an optimization strategy for microchannel dimensions based on Computational Fluid Dynamics (CFD) simulations. This strategy aims to replicate the distinct WSS waveform features found at various locations within the carotid bifurcation as observed in vivo. Our simulations indicate that with a step height of 0.09 mm, a width of 4 mm for the initial segment, and 5 mm for the subsequent wider channel, the device can effectively model the characteristics of low oscillatory WSS seen at sites of carotid sinus stenosis. Furthermore, it accurately represents the high-magnitude pulsatile WSS waveforms in the more uniform arterial sections downstream of the carotid sinus. The study also reveals that vortex formation and variations in low oscillatory WSS within the stepped section of the microchannel correlate with the step's height and width, as well as with the dimensions of the wider channel section. An increase in step width leads to a decrease in both the vortex area and the magnitude of negative WSS oscillations. When the step height is less than 0.03 mm, vortex formation is inhibited, challenging the simulation of low oscillatory WSS patterns. The variable cross-section microfluidic channel developed in this study provides a platform for simulating carotid artery WSS waveforms and facilitates research into the interplay between low oscillatory WSS at sites of carotid sinus stenosis and arterial endothelial dysfunction.

Carbapenem antibiotics are the drug of choice for treating multidrug-resistant bacterial infections. Metallo-beta-lactamases (MBLs) are carbapenemase capable of hydrolyzing nearly all therapeutically available beta-lactam antibiotics. Consequently, a need to assess the frequency and phenotypic resistance phenomena of two MBL genes in diarrheal and urinary tract infections (UTIs). Samples were collected through a cross-sectional study, with MBLs genes detected via PCR. Two hundred twenty eight diarrheal bacteria were isolated from 240 samples. The most predominant pathogens were Escherichia coli (32%) and Klebsiella spp. (7%). Phenotypic resistance to amoxicillin-clavulanic acid, aztreonam, cefuroxime, cefixime, cefepime, imipenem, meropenem, gentamicin, netilmicin, and amikacin was 50.4%, 65.6%, 66.8%, 80.5%, 54.4%, 41.6%, 25.7%, 41.2%, 37.2%, and 42.9%, respectively.  Total 142 UTI pathogens were obtained from 150 urine samples, with Klebsiella spp. (39%) and Escherichia coli (24%) are the major pathogens. Phenotypic resistance to amoxycillin-clavulanic acid, aztreonam, cefuroxime, cefixime, cefepime, imipenem, meropenem, gentamicin, netilmicin, and amikacin was 93.7%, 75.0%, 91.5%, 93.7%, 88.0%, 72.5%, 13.6%, 44.4%, 71.1%, and 43%, respectively.  Twenty four diarrheal isolates carried either blaNDM-1 or blaVIM genes; the overall MBL gene prevalence was 10.5%. Thirty six UTI pathogens carried either blaNDM-1 or blaVIM genes (25.4%). Seven isolates carried both blaNDM-1 and blaVIM genes.  MBL genes exhibited a strong association with phenotypic carbapenem and other beta-lactam antibiotic resistance. Resistance to carbapenems requires active surveillance and stewardship.

Evidence suggests that COVID-19 infection can cause lasting health consequences. Multidiscipli-nary rehabilitation services have been recommended to reduce the sequalae. However, the effec-tiveness of physical exercise interventions remains insufficiently documented. The aim of this study was to develop and implement a specific and well tolerated protocol-based, intervention to reduce muscle weakness in older adults impacted by COVID-19. Forty six older adults random-ized into Intervention and Control Groups. Isometric and isokinetic strength assessments were conducted for selected muscle groups using JBA Staniak® torquemeter and Biodex System 3 dy-namometer. Functional abilities were evaluated with the Time Up and Go test and Chair Stand Tests. Men in intervention group demonstrated a significant improvement in static conditions for knee flexors (KF), trunk extensors (TE) and trunk flexors (TF) and in dynamic conditions for knee extensors (KE). Women in intervention group showed significant improvement in static condition for EF, KF, TE and TF and in dynamic for a KE and for a KF. The interaction GROUP x TESTING SESSION was significant for Chair test (s) and Chair test (n). Our results demonstrate the effec-tiveness of a well-tolerated, protocol-based approach that can be used to diminish long lasting functional deficits in post-covid survivors.

Despite available global efforts and funding, Tuberculosis (TB) continues to affect a considerable number of patients worldwide. Policy makers and stakeholders set clear goals to reduce TB incidence and mortality, but the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) complicate the reach of these goals. Drug-resistance TB needs to be diagnosed rapidly and accurately to effectively treat patients, prevent the transmission of MDR-TB, minimise mortality, reduce treatment costs and avoid unnecessary hospitalisations. In this narrative review, we provide a comprehensive overview of laboratory methods for detecting drug resistance in MTB, focusing on phenotypic, molecular and other drug susceptibility testing (DST) techniques. We found a large variety of methods used, with the BACTEC MGIT 960 being the most common phenotypic DST and the Xpert MTB/RIF being the most common molecular DST. We emphasise the importance of integrating phenotypic and molecular DST to address issues like resistance to new drugs, heteroresistance, mixed infections and low-level resistance mutations. Notably, most of the analysed studies adhered to the outdated definition of XDR-TB and did not consider the pre-XDR definition, thus posing challenges in aligning diagnostic methods with the current landscape of TB resistance.

Abstract: A. baumannii exhibits resilience in harsh environments and progressively develops resistance to diverse antibacterial agents over time. This adaptability poses a significant challenge in treating an infection caused by this bacterium within healthcare settings. The presence of peptidoglycan, a crucial precursor for cell wall synthesis, contributes to this challenge. Peptidoglycan serves not only as a structural support in bacterial cells but also provides protection against adverse environmental conditions. The synthesis of the peptidoglycan layer involves a group of substrates such as N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc), within a three-partitioned process occurring in the membrane, periplasmic space, and cytoplasm of each bacterium. Initiated in the cytoplasm and extending to the inner cell membrane, this synthesis starts with the production of nucleotide precursors. The first step involves the synthesis of UDP-GlcNAc, orchestrated by Glm (GlmS, GlmM, and GlmU) enzymes using fructose-6-phosphate. Subsequently, enzymes from the Mur family, namely MurB, MurA, MurD, MurC, MurI, MurF, and MurE, synthesize UDP-N-acetylmuramyl-pentapeptide (UDP-Mpp) from UDP-GlcNAc. Concurrently, on the cytosolic side, the production of membrane-surrounded undecaprenyl phosphate occurs, involving membrane-side proteins MraY and MurG in the biosynthesis of peptidoglycan. This review emphasizes updated information on Mur family proteins, encompassing physicochemical properties, nature of binding site, number and type of binding site residues, functional domain details, three-dimensional structural aspects, and their functions within bacterial cells. Special attention is directed towards their enzymatic role in peptidoglycan biosynthesis due to the limited availability of precursors in the market. Additionally, the review provides a comprehensive summary of existing inhibitors and ongoing efforts in identifying new targeted inhibitors, recognizing these enzymes as potential candidates for antibacterial drug design and discovery.

In recent years, humanity has faced a growing challenge posed by the rise of antibiotic-resistant bacteria, resulting in an alarming surge in fatalities and the emergence of increasingly hard-to-manage diseases. Among these resilient pathogens is Acinetobacter baumannii, due to its escalating prevalence in hospitals, elevated mortality rates, and resistance to treatment. Despite its clinical significance, our understanding of this pathogen in non-hospital settings and its virulence factors remains limited. Therefore, this review aims to shed light on the latest research regarding its ecological niche, microbiological traits, and antibiotic resistance profiles. Recent investigations have expanded its detection to various environmental niches, including rivers, treatment plants, and soils. Moreover, this bacterium has been discovered in diverse food sources such as meat and vegetables, as well as in farm animals and household pets like dogs and cats. This broader presence of Acinetobacter baumannii outside of hospital environments underscores a significant risk of environmental contamination, necessitating heightened awareness and preventive measures to address potential public health implications.

Correlations among estrus cycle, pyometra, and canine diabetes mellitus (CDM) have been described since the late 1950s, and substantial progress in understanding mechanisms beyond was achieved nowadays. Progesterone-related diabetes mellitus (PRDM) in dogs is known for its particular potential for diabetes remission. Thus, a deep understanding of the physiopathological aspects involved is crucial to postulate treatment guidelines to improve the PRDM remission rate, as well as to inform preventive measures. This narrative review aims to provide relevant detailed information on 1) canine estrus cycle and its impact on CDM etiology and management, 2) the role of pyometra as a further cause of insulin resistance, and 3) useful individual therapeutic and preventive strategies. Pharmacological annulment of progesterone effects, as well as inflammatory and progesterone-related conditions resolution in association with adequate exogenous insulin therapy, and residual beta cell function, are key aspects to achieve remission, or at least to improve diabetic clinical control. In this way, spaying should be considered mandatory in most PRDM cases. Preventive measures against CDM can include spaying recommendations; however, individual-based recommendations should be considered since castration may be associated with some long-term health issues.

Immune checkpoint inhibitors (ICI’s) are in the forefront of advanced Non Small Cell Lung Cancer (NSCLC) treatment. Still, only 27- 46% of patients respond to initial therapy with ICI’s and of those, up to 65% develop resistance within four years. After disease progression (PD), treatment options are limited, with 10% Objective Response Rate (ORR) to second or third-line chemotherapy. In this context, ICI rechallenge is an appealing option for NSCLC. Most data on the efficacy of ICI rechallenge are based on retrospective real-world studies of small, heavily pretreated, and heterogeneous patient groups. Despite these limitations, these studies suggest that ICI monotherapy rechallenge in unselected NSCLC patient populations who discontinued initial ICI due to PD is generally ineffective, with a median Progression-Free Survival (PFS) of 1.6-3.1 months and a Disease Control Rate (DCR) of 21.4%-41.6%. However, there is a subpopulation that benefits from this strategy, and further characterization of this subgroup is essential. Furthermore, immunotherapy rechallenge in patients who discontinued initial immunotherapy following treatment protocol completion and progressed after an immunotherapy-free interval showed promising efficacy, with a DCR of 75-81%, according to post-hoc analyses of several clinical trials. Future research of ICI rechallenge for NSCLC should focus on better patient stratification, to reflect the underlying biology of immunotherapy resistance more accurately.

Infections with multi-drug-resistant (MDR) pathogens in food-animals threaten public health and food security. However, the epidemiology and factors associated with MDR Escherichia coli on Ugandan farms are not well known. This study investigated the prevalence, resistance patterns and factors associated with MDR E. coli carriage on chicken farms. A total of 158 E. coli strains were isolated from 158 chicken farms. The disc diffusion method for susceptibility testing was performed. Clinical breakpoints were interpreted according to Clinical and Laboratory Standards Institute guidelines. MDR was defined as resistance to three or more classes of antimicrobials. MDR E. coli prevalence on chicken farms was 62.7% (95% CI: 55.0 – 70.3). High resistance was observed against ampicillin 79.8% (95% CI: 72.7–85.4), tetracycline 72.8% (95% CI: 65.2–79.2), cotrimoxazole 55.7% (95% CI: 47.8–63.3), and ciprofloxacin 38% (95% CI: 30.7–45.9). Farmers who were males (APR = 0.72, CI: 0.55, 0.93), and attained at least secondary education (APR=0.64, CI: 0.46, 0.88) and administration of recommended antibiotic doses (APR = 0.76, CI: 0.59–0.96) posed a lower risk of MDR E. coli carriage. Farms without footbaths posed a heighten risk (APR=1.48, CI: 1.16–1.88). MDR E. coli were highly prevalent on chicken farms. This study underscores the need for antimicrobial stewardship and improved infection prevention strategies on chicken farms.

The origin of neurodegenerative diseases is linked to the abnormal folding of disease-associated proteins. The traditional amyloid hypothesis has been a focal point of research, but recent findings suggest a more complex picture. This review explores the role of physiological conformation of aggregation-prone domain (also known as prion-like low complexity domain) and multiple co-misfolded proteins in neurodegenerative diseases. We highlight the importance of targeting multi-heterotypic misfolded proteins for effective treatments and emphasize the irreversible neurodegeneration stemming from the loss of physiological folding in prion-like disease-causing proteins underscores the criticality of refolding. Additionally, we introduce the concept of ReproFold Therapeutics, a novel approach aimed at restoring the cellular prion-like folding of disease-causing proteins to rebuild normal cross-β interactomes and mitigate neurodegeneration. Baicalein, a potential drug candidate for this approach, shows promise in vitro and in animal models. Moreover, prion-like low complexity domains implicated in neurodegeneration are also associated with other disorders such as diabetes, cancers, and mental illnesses. Understanding the core pathology of neurodegenerative diseases and the broader implications of prion-like LC domains could revolutionize healthcare approaches and policies worldwide.

Toxoplasmosis is a zoonosis of warm-blooded animals, affecting also humans, caused by Toxo-plasma gondii, an obligate intracellular parasite with a complex biological cycle. Toxoplasmosis is considered a re-emerging zoonosis and an important public health threat, also for the absence, up to now, of efficient vaccines and preventive measures. Sources of transmission to humans are environmental or food-borne, mainly through the consumption of raw and undercooked meat, predominantly of Sus scrofa, considered highly susceptible to T. gondii. Mainly in the last dec-ades, an effective strategy to counter animal infectious diseases was based on the discovery of resistance immuno-genetic markers, possibly to be used for association studies between geno-typic and phenotypic traits and consequently in Marker Assisted Selection. Until now, this gen-otyping approach has never been adopted for T. gondii infection, so this study aimed, for the first time, to fill this gap. In particular, pigs, reared in different farms of Central Italy, were serologically characterized by an ELISA assay performed on diaphragm meat juice. Out of 179 tested animals, 98 resulted seropositive (54.74%), 57 seronegative (31.84%) and 24 doubtful (10.6%), underlining a possible re-emerging diffusion of this protozoan in the investigated areas. Atten-tion was firstly focused on IL-18 gene, encoding for a pro-inflammatory cytokine that plays a key role starting from the upstream steps of the immunity pathway towards T. gondii. A RT-PCR assay followed by Sanger sequencing of IL-18 cDNA was de novo developed. For this interleukin, at this stage, genetic analysis has not highlighted significant polymorphic variations compared to the reference sequence, except for a seropositive animal. However, the outcomes of this pre-liminary innovative study will be investigated in depth analyzing other relevant genetic re-gions and other target genes.

The worldwide competition to vaccinate against COVID-19 has highlighted the importance of immunization measures in containing the virus. Saudi Arabia, like the rest of the globe, must assess socio-demographic subtleties, chronic illnesses, vaccination effects, and public health policy implications as it navigates this complicated environment. This cross-sectional study examined Saudi COVID-19 vaccine in many ways. It examined the socio-demographic makeup of vaccine recipients, the prevalence of chronic conditions in this population, vaccine administration patterns, post-vaccination side effects, and vaccine-infection rates. A questionnaire-based online survey of 401 participants ensured gender, nationality, age, weight, and educational diversity. We analyzed vaccine manufacturer choice for each dosage, side effects after the first and second doses, and chronic diseases in the sample. Pfizer/BioNTech vaccines are preferred for all three doses, reflecting worldwide vaccination acceptance patterns. Side effects were not significantly different between vaccination kinds. Interestingly, immunization reduced infection rates, demonstrating the efficacy of COVID-19 vaccines. The data fills important information gaps and illuminates Saudi COVID-19 vaccination kinetics. These data support the global preference for mRNA vaccines, demonstrating the faith in this breakthrough technology. They also sponsor COVID-19 vaccine safety and effectiveness studies. The dramatic drop in infection rates among vaccinated people shows how vaccinations suppress the pandemic. These findings inform Saudi Arabia's immunization efforts. As booster doses become more common, long-term vaccination research is crucial. Vaccine reluctance, especially in certain demographics, must be addressed. Due to vaccines' protective potential, equitable vaccine distribution and large immunization programs are essential for herd immunity and pandemic management. This thorough cross-sectional study helps policymakers and healthcare practitioners build successful and inclusive COVID-19 immunization regimens in Saudi Arabia.

This paper illustrates an experimental activity for the closed-loop position control of an actuator made using shape memory alloy (SMA) wire. A solution with the self-sensing effect was implemented to miniaturize the systems, i.e., without external sensors. A proportional control algorithm was initially used, demonstrating the idea's feasibility: the wire can behave simultaneously as an actuator and sensor. An experimental investigation was subsequently conducted for the optimization of the developed actuator. As for the material, a Flexinol wire, Ni-Ti alloy, with a diameter of 0.150 mm and a length of 200 mm, was used. Preliminarily, a characterization of the SMA wire at constant and variable loads was carried out: the characteristics detected are elongation vs. electric current and elongation vs. electrical resistance. The control system is PC-based with a data acquisition card (DAQ). A drive board has been designed and built to read the wire's electrical resistance and power it by pulse width modulation (PWM). A notable result is that the actuator works with good precision and in dynamic conditions, even when it is called to support a load up to 65% different from that for which the electrical resistance-length correlation has previously been experimentally obtained, on which the control is based. This opens up the possibility of using the actuator in a counteracting configuration with a spring, which makes hardware implementation and control management simple.

Diabetes mellitus is one of the most common endocrinopathies, estimated to affect about 5.4% of the world's population around 2025. It is thought that nearly a third of diabetic patients have some type of skin condition. Frequently, the cutaneous effects of this heterogeneous syndrome are ac-curately detected late in the progressive form of the disease. The main objective of the present study was to identify the main cellular characteristics of the cutaneous microenvironment in exper- imentally induced diabetes mellitus. Skin fragments were harvested from adult white Wistar rats of both sexes, with the weight of 200 g, 12 weeks after streptozotocin diabetes was induced. In parallel with histopathological diagnosis by using hematoxylin and eosine staining, samples were processed by transmission electron microscopy technique and examined with a Philips CM100 microscope. In the apparently macroscopically unchanged tegument, photon microscopy revealed both progres ive thinning of the epidermis in the early stages of diabetes and a significant process of fibrosis and collagen hyalinization in the dermis. In addition, in the early stages, the electron microscopic study provided ultrastructural details characteristic of a senescent phenotype with reduced cell proliferation. The morphological changes in the skin may be the first signs of disruption of carbohydrate metabolism and in the case of established diabetes may reflect its progression and the efficacy of therapy.

From their discovery in 2002, BRAF mutations have been identified as clear drivers of oncogenesis in several cancer types. Currently, their incidence rate is nearly 7% of all solid tumors with BRAF V600E constituting approximately 90% of these diagnoses [1]. In melanoma, thyroid cancer, and histiocytic neoplasms, BRAF hotspot mutations are found at a rate of about 50%, while in lung and colorectal cancers they range from 3 to 10% of reported cases [2-5]. Though present in other malignancies such as breast and ovarian cancers, they constitute a small portion of diagnoses (<1%). Given their frequency along with advancements in screening technologies, various methods are used for the detection of BRAF-mutant cancers. Among these are targeted next-generation sequencing (NGS) on tumor tissue or circulating tumor DNA (ctDNA) and immunohistochemistry (IHC)-based assays. With advancements in detection technologies, several approaches have been taken for the treatment of BRAF mutant cancers. In this review we retrace the milestones that led to the clinical development of targeted therapies currently available for these tumors.

Drug repurposing, rebranding an existing drug for a new therapeutic indication, is deemed a beneficial approach for a quick and cost-effective drug discovery process by skipping preclinical, Phase 1 trials and pharmacokinetic studies. Several psychotropic drugs including selective serotonin reuptake inhibitors (SSRIs) and tricyclic antide-pressants (TCAs) were studied for their potential application in different diseases es-pecially in cancer therapy. Fluoxetine (FLX) is one of the most prescribed psychotropic agents from SSRIs class for the treatment of several neuropsychiatric disorders with a favourable safety profile. FLX exhibited different oncolytic effects via mechanisms dis-tinct from its main serotonergic activity. Taking advantage of its ability to rapidly pen-etrate the blood-brain barrier, FLX could be particularly useful in brain tumors. This was proved by different in vitro and in vivo experiments using FLX as a monotherapy or combination with temozolomide (TMZ) or radiotherapy. In this review of literature, we summarize the potential pleiotropic oncolytic roles of FLX against different cancers highlighting the multifaceted activities of FLX and its ability to interrupt cancer prolif-eration via several molecular mechanisms and even surmount multidrug resistance (MDR). We elaborated on the successful synergistic combinations such as FXR/temozolomide and FXR/raloxifene for the treatment of glioblastoma and breast cancer, respectively. We showcased beneficial pharmaceutical trials to load FLX on car-riers to enhance its safety and efficacy on cancer cells. This is the first review article ex-tensively summarizing all previous FLX repurposing studies for the management of cancer.

With the aim to develop novel scaffolds for sustained release of drugs, we initially developed an easy approach for the synthesis of α,ω-homobifunctional mercaptoacyl poly(alkyl oxide)s. This was based on the esterification of the terminal hydroxyl groups of poly(alkyl oxide)s with suitably S-4-methoxytrityl (Mmt) protected mercapto acids, followed by removal of the acid labile S-Mmt group. This method allowed the efficient synthesis of the title compounds in high yield and purity, which were further used in the development a thioether cross-linked liposome scaffold, by thia-Michael reaction of the terminal thiol groups with preformed nano-sized liposomes bearing maleimide groups on their surface. The reaction process was followed by 1H-NMR, using a Carr-Purcell-Meiboom-Gill (CPMG) relaxation dispersion NMR experiment (1H-NMR CPMG), which allowed real-time monitoring and optimization of the reaction process. The thioether cross-linked liposomal scaffold that was synthesized was proven to preserve the nanosized characteristics of the initial liposomes and allowed sustained release of calcein (which was used as a chromophore), providing evidence for the efficient synthesis of a novel drug release scaffold consisted of nanoliposome building blocks.

Since the introduction of Cross-laminated Timber (CLT) in Austria in the early 1990s, the adoption of this 90°-crosswise-laminated product has seen exponential growth worldwide. Compared to traditional laminated timber products (e.g. glulam), CLT provides improved dimensional stability, but with reduced out-of-plane bending stiffness. To improve the bending stiffness, while maintaining relative dimensional stability, a modified orientation of the inner layers in a diagonal direction can be used. This novel product is Diagonal-Cross-laminated Timber (DCLT), a composite timber product, consisting of inner layers which are rotated at different angle-ply orientations between 0 and 90 degrees to the outer layers. To properly model the out-of-plane bending behavior of the DCLT, analytical models and Finite Element Analysis (FEA) were used and the results were validated by third-point bending tests performed on DCLT panels with angle-ply orientations of 10°, 20°, 40°, 70°, and a conventional CLT 90° panel. The results indicate that DCLT panels with angle-ply cross-layers have a structural advantage in out-of-plane bending over traditional CLT (90°) panels. The development of DCLT and its introduction to the industry could enable the use of lower-quality timber that would not otherwise satisfy structural requirements for CLT.

Urinary infections are defined as the presence of microorganisms in any part of the urinary system, with the exception of the distal urethra. The majority are uncomplicated infections, resolved on an outpatient basis, with empirical therapy. The objectives of this work were to study the sociodemographic characteristics of patients, analyze associated strains and examine the response of the main microorganisms to antibiotics. A retrospective observational study of all positive urine cultures between 2018 and 2022 was carried out in an Institution (8340 samples). Sociodemographic data were also collected. 61.3% were women, with an average age of 63.4 years, 43.2% from the Emergency Department. 13.5% were fitted, 56% of whom were women. 95.9% were not taking any antibiotics and among the individuals who were taking antibiotics, 50% were injected. Escherichia coli (53.5%) and Klebsiella pneumoniae (13,8%) are identified as the most prevalent strains. In the time periods analyzed, Escherichia coli decreased its resistance to 11 antibiotics and increased to 5 antibiotics, while Klebsiella pneumoniae decreased to 7 and increased to 7, with emphasis on the presence of 3 antibiotics with a resistance rate of 100 % to all Klebsiella pneumoniae strains identified in 2022.

Clusterin (CLU) protein is involved in various pathophysiological processes including carcinogenesis and tumor progression. In recent years, the role of the secretory isoform has been demonstrated in tumor cells, where it inhibits apoptosis and favors the acquisition of resistance to conventional treatments used to treat cancer. To determine the possible therapeutic potential of inhibiting this protein, numerous studies have been carried out in this field. In this paper, we show the existing knowledge on the inhibition of this protein in different types of cancer and discuss the importance it could have in the development of new therapies directed against this pathology.

This study aimed to investigate the effect of potassium poly-γ-glutamate (PGA-K) on mice fed a high-fat diet consisting of 60% of total calories for a duration of 12 weeks. PGA-K administration reduced the increase in body weight, epididymal fat, and liver weight caused by a high-fat diet compared to the obese group. The triglyceride, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels, which are blood lipid indicators, were significantly increased in the obese group but were significantly decreased in the PGA-K-treated group. The administration of PGA-K resulted in a significant inhibition of pro-inflammatory cytokines, including tumor necrosis factor α and interleukin 6. Moreover, the levels of leptin and insulin, which are insulin resistance indicators, significantly increased in the obese group but were significantly decreased in the PGA-K-treated group. These results suggest that PGA-K exhibits a protective effect against obesity induced by a high-fat diet, underscoring its potential as a candidate for obesity treatment.

This study aimed to investigate the fatigue performance and interfacial strengthening mechanisms of Al6061-to-Cu dissimilar lap joints via electromagnetic pulse welding (EMPW). The load-bearing capacity of the joints at discharge voltages of 14 kV and 16 kV was superior to that of 12 kV. Furthermore, the fatigue life of the 14 kV joints was one order of magnitude higher compared to the 12 kV joints. SEM observation of the fatigue fracture surface revealed the presence of typical "tire-mark" fatigue striations only in the 14 kV joint, indicating higher ductility and the ability to withstand extended plastic deformation. Notably, ultra-fine nanocrystalline Al2Cu phase, amorphous phase, and numerous dislocations hindered EBSD acquisition in the transition zone. Nevertheless, dense low-angle grain boundaries (LAGBs) and refined grains were examined at the bonding interface. This suggests that the high-velocity collision caused severe plastic deformation and led to the formation of substructures. The interfacial strength was attributed not only to the "wave-like" or "inverted hook-like" diffusion layer but also to the presence of refined grains along the interface and nanocrystalline Al2Cu in the transition zone. Furthermore, the hybrid nanocrystalline-amorphous microstructure strengthened the joint by regulating the balance between strength and ductility.

Antimicrobial resistance (AMR) is a worldwide healthcare problem. Multidrug resistant organisms (MDRO) have the ability to spread quickly owing to their resistance mechanisms. Although colonized individuals are crucial MDRO dispensers, colonizing microbes have the potential to turn pathogenic under certain conditions, leading to symptomatic infections in carriers. Carbapenemase producing Enterobacterales (CPE) are among the most important MDRO involved in infections and colonizations, associating with multiple resistance mechanisms and virulence factors, causing infections with severe outcomes. All research papers identified in the most comprehensive online databases which contained information related to the topic of this article were analyzed, and relevant data was extracted and included. The first information on CPE could be traced back to the mid-2000s, but pertinent data for many African countries was established in the past 5-8 years. Information is presented chronologically for each country. Although no clear conclusions could be drawn for some countries, it was observed that CPE colonizations are present in most African countries and carbapenem-resistance levels are rising. The most common CPE involved are Klebsiella pneumoniae and Escherichia coli, and the most prevalent carbapenemases are NDM-type and OXA-48-type enzymes. Prophylactic measures, such as screening, are required to combat this phenomenon.

In this study, we aimed to determine the trend of antimicrobial resistance pattern of pathogens isolated in samples collected from patients hospitalized in the intensive care unit (ICU), in selected periods before and after COVID-19. A retrospective study of bacterial pathogens was performed on 1267 patients. The resistance patterns were analyzed using Vitek 2 Compact system. Positive-bacterial culture data of 1695 samples from pre-COVID-19 period and 1562 from post-COVID-19 period were obtained. The most frequently isolated in both periods were Staphylococcus aureus and Klebsiella spp. Klebsiella spp. had a statistically significant increase in resistance rates in the post COVID-19 period, against colistin, gentamicin and aztreonam. For E. coli strains, it was registered a significant increase against colistin and a significant decrease against levofloxacin and imipenem. For Acinetobacter spp. strains it was observed a significant increase against colistin. More than 50% from the Staphylococcus aureus strains were MRSA with statistically significant increases in antimicrobial resistance rate in the post-COVID-19 period against doxycycline, linezolid, rifampicin and teicoplanin. The study revealed a significantly increasing trend of the antimicrobial resistance rate of Gram-negative pathogens (Klebsiella spp., Acinetobacter spp.) against certain antibiotics, including those used only in cases where there are no other therapeutic options.

This study investigates the application of regression neural networks, in particular the fitrnet model, in predicting the hardness of steels. The experiments involve extensive tuning of hyperparameters using Bayesian optimization and employ 5-fold and 10-fold cross-validation schemes. The trained models are rigorously evaluated, and their performances are compared using various metrics such as mean square error (MSE), root mean square error (RMSE), mean absolute error (MAE), and coefficient of determination (R2). The results provide valuable insights into the effectiveness of the models and their ability to generalize to unseen data. In particular, Model 4208 (8-85-141-1) emerges as the top performer with an impressive RMSE of 1.0790 and an R² of 0.9900. The research paper contains an illustrative example that demonstrates the practical application of the developed model in determining the hardenability band for a specific steel grade and shows the effectiveness of the model in predicting and optimizing heat treatment results.

The soybean yield per unit area and soybean acreage are increased to boost overall soybean production as two effective solutions. There is a large area of saline soils in northeast China, where if soybeans could be grown with the help of isolated saline-tolerant rhizobia, the cultivation area of soybeans in China can be effectively expanded. Several rhizobia with different salt-, acid- and alkali-resistant characteristics were obtained in this research by isolating, identifying, and analyzing the nitrogen-fixing activities of indigenous rhizobia from different soybean planting soils, and further analyzed the host compliance between rhizobia and different soybean germplasm concerning 30 representative germplasm resources in the northeast region. Collectively, the results of the resistance study of HLNEAU2 isolated from the Shaanxi region are great references for guiding the application of rhizobia on soybeans.

Chaotic theory is commonly being researched for application in image encryption scheme (IES). In this paper, a novel two-dimensional cross hyperchaotic Sine-modulation-Logistic map (2D-CHSLM) based on the famous Sine and Logistic maps. The hyperchaotic behaviors of 2D-CHSLM is testified with the help of their bifurcation diagrams, trajectory plots, Lyapunov exponents, sample entropy, C0 complexity, permutation entropy and 0-1 test. A new bit-level IES with traditional encryption structure is proposed utilizing 2D-CHSLM. The 2D-CHSLM-IES performs a 2D-CHSLM-based bit-level confusion using zig-zag transform and a 2D-CHSLM-based cross coupled diffusion operations for generating a highly secure cipher-image. Then the simulations and security analyses are further carried out with the help of key space, key sensitivity, histogram, correlation, information entropy, differential attack, noise and data loss attacks, prove that the security of the proposed 2D-CHSLM-IES

This study investigated the fatigue properties and interfacial strengthening mechanisms of Al6061-to-Cu dissimilar welded joints via electromagnetic pulse welding (EMPW). The load-bearing capacity of the joints at discharge voltages of 14 kV and 16 kV was superior to that of 12 kV. Meanwhile, the fatigue life of 14 kV joints was one order of magnitude higher than that of 12 kV. The SEM observation on the fatigue fracture surface shows that the typical “tire-mark” fatigue striation just appeared on the 14 kV joint, indicating higher ductility for handling more extended plastic deformation. The high EBSD acquisition was achieved except for the transition zone due to the formation of ultra-fine nanocrystalline Al2Cu phase and amorphous phase, along with many dislocations. Dense low-angle grain boundaries (LAGBs) and refined grains are formed along the bonding interface. This indicates that severe plastic deformation induced dislocations to form the substructure in such an instant (40-60 μs) during the high-velocity collision. The interfacial strength is not only due to the continuous interfacial diffusion layer with a “wave-like” or “inverted hook-like” pattern but also benefits from refined grains along the interface and in the transition zone, as well as the hybrid amorphous-nanocrystalline microstructure, which strengthens the joint through increasing ductility induced by refined grains and regulating amorphous or nanocrystalline phases to affect the balance between strength and ductility of the Al/Cu joint.

Skin and soft-tissue infections (SSTI) are common cases of hospital-acquired infections with aetiologic agents exhibiting antimicrobial resistance (AMR). We determined the prevalence, proportion of laboratory-investigated cases, AMR-profiles, and factors associated with SSTI and multi-drug resistance (MDR). This study was based on archived data of patients suspected of SSTI from 2019-2021 at Jinja Regional Referral Hospital. The analysis involved 268 randomly selected patient reports. Prevalence of SSTI was 66.4%. Laboratory-investigated cases were 14.11%. Staphylococcus aureus (n=51) was the most isolated organism. MDR pathogens explained 47% of infections. Methicillin-resistant S. aureus was up to 44%. In addition, 61% of Gram-negatives had the potential to produce extended-spectrum beta-lactamases, while 27% were non-susceptible to carbapenems. Ward of admission was significantly associated with infection (aPR=1.78, 95% CI: 1.003-3.18, p-value=0.04). Age category (19-35) was an independent predictor for MDR infections (aPR=2.30, 95%CI:1.02-5.23, p-value=0.04). The prevalence is relatively high with MDR pathogens responsible for almost half of the infections. Routine use of culture and sensitivity testing should be done for proper infection management. Gentamicin and ciprofloxacin can be considered for empirical management of emergency SSTI suspected of S. aureus. Recognizing SSTI under the Global Antimicrobial resistance Surveillance System would lead to improved preparedness and response to AMR.

This study investigated the presence, distribution, and antimicrobial resistance profiles of extend-ed-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae in a dairy herd located in Northern Italy. A questionnaire was administered, and the feces of clinically healthy pre-weaned dairy calves, their mothers, and the cows treated for mastitis, waste milk, water, and environmental samples, were collected and inoculated on Chromagar ESBL™ medium. The questionnaire identi-fied several risk factors including administration of waste milk to male calves, lack of routine cleaning of calf feeding and housing equipment, and blanket dry cow therapy. Escherichia coli was identified by MALDI-TOF MS in the feces of 28 of 37 (75.67%) calves, 2 of 3 (66.67%) treated cows, 8 of 14 (57.15%) environmental samples, and the waste milk. Six of 14 (42.85%) environmental samples were also positive for ESBL Acinetobacter baumannii, while all fecal samples were negative. ESBL production was confirmed for all E. coli isolates based on the double disk susceptibility test (DDST), while none were carbapenemase producers. Upon minimal inhibitory concentration (MIC) analysis, all of them showed multiple resistances and were categorized as multi-drug resistant (MDR). This study confirms the widespread presence of MDR, ESBL-E. coli in dairy calves and highlights their diffusion in the farm environment.

The normal ageing process significantly affects resistance arteries, leading to various biological and physiological consequences. Systolic hypertension is a common occurrence in ageing individuals, accompanied by increased large artery stiffening, heightened pulsatility, small artery remodeling, and damage to critical microvascular structures. Starting from young adulthood, there is a progressive elevation in mean arterial pressure, supported by clinical and epidemiological evidence as well as findings from animal models. The myogenic response, a protective mechanism for the microcirculation, may face disruptions during ageing. Dysregulation of calcium entry channels (T-type, L-type, TRP channels), dysfunction in intracellular calcium storage and extrusion mechanisms, altered expression of potassium channels, and a change in smooth muscle calcium sensitization may contribute to age-related dysregulation of myogenic tone. Flow-mediated vasodilatation, a hallmark of endothelial function, is compromised in ageing. This result of endothelial dysfunction is related to oxidative stress, lower nitric oxide bioavailability and a low-grade inflammatory response, further exacerbating vascular dysfunction. Resistance artery remodeling in ageing emerges as a hypertrophic response of the vessel wall, often seen in conjunction with outward remodeling (in normotension), but can also present as inward hypertrophic remodeling (in hypertension). The remodeling process involves oxidative stress, inflammation, reorganization of extracellular matrix fiber proteins and actin cytoskeletal components. Reactive oxygen species (ROS) signaling and chronic low-grade inflammation, often referred to as "inflammaging”, play substantial roles in age-related vascular dysfunction. Due to its role in regulation of vascular tone as well as structural proteins, the RhoA/Rho-kinase pathway becomes a new target in age-related vascular dysfunction and associated diseases. Understanding the intricate interplay of these factors is crucial for developing targeted interventions to mitigate the consequences of ageing on resistance arteries and enhance overall vascular health.

Zn2+ has been implicated in the regulation of intestinal redox and microbial homeostasis, and we recently reported that transient receptor potential canonical (TRPC) 6 channel activity contributes to intracellular Zn2+ homeostasis in mammalian cells. This study aims to investigate the role of TRPC6-mediated Zn2+ influx in stress resistance of intestine. Expression profile of TRPC1-C7 mRNAs in the actively inflamed mucosa from inflammatory bowel disease (IBD) patients was analyzed using GEO database. Systemic TRPC3-knockout (KO) and TRPC6-KO mice were treated with dextran sulphate sodium (DSS) to induce colitis. The Zn2+ concentration and the mRNA expression levels of oxidative/inflammatory markers in colon tissues were quantitatively analyzed, and gut microbiota profiles were compared. TRPC6 mRNA expression level was increased in IBD patients and DSS-treated mouse colon tissues. DSS-treated TRPC6-KO mice, but not TRPC3-KO mice, showed severe weight loss and increased disease activity index compared with DSS-treated WT mice. The mRNA abundances of antioxidant proteins were basically increased in TRPC6-KO colon, with changes in gut microbiota profiles. Treatment with TRPC6 activator prevented the DSS-induced colitis progression accompanied by increasing Zn2+ concentration. We suggest that TRPC6-mediated Zn2+ influx activity plays a key role in stress resistance against IBD, providing a new strategy for treating colitis.

The formation of a rigid tough interface based on a nacre-like structure in carbon fiber (CF) composites is a promising way to eliminate low delamination resistance. An effective method of coating CFs is electrophoretic deposition (EPD), which, in the case of dissimilar components like graphene oxide (GO) and polymeric glue, usually requires their chemical bonding/ strong interactions. In this work, we focus on chitin nanocrystals (ChNCs), leading to an excellent mechanical performance of artificial nacre, where favorable interactions and bonding with GO were controlled by degrees of deacetylation (5, 15 and 30 %). We have prepared coatings based on GO/ChNCs adducts with 95/5, 90/10,50/50 and 25/75 ratios using optimized EPD conditions (pH, concentration, voltage and time). The prepared materials were characterized using FTIR, TEM, XPS, SEM, DLS, and XRD. SEM evaluation indicates the formation of a homogeneous interlayer, which possesses a fair ability of chemical bonding with the epoxy matrix. Short beam testing of epoxy matrix composites indicates that coating does not decrease stiffness and its relatively low dependence on composition. Therefore, all coatings are promising for a detailed study of delamination resistance using laminate samples. Moreover, facile EPD from water solution/ suspension has a fair potential for industrial applications.

Despite extensive use of intravitreal anti-vascular endothelial growth factor (anti-VEGF) biologics for over a decade, neovascular age-related macular degeneration (nAMD) or choroidal neovascularization (CNV) continues to be a major cause of irreversible vision loss in developed countries. Many nAMD patients demonstrate persistent disease activity or experience declined responses over time despite anti-VEGF treatment. The underlying mechanisms of anti-VEGF resistance are poorly understood, and no effective treatment strategies are available to date. Here we review evidence from animal models and clinical studies that supports the roles of neovascular remodeling and arteriolar CNV formation in anti-VEGF resistance. Cholesterol dysregulation, inflammation, and ensuing macrophage activation are critically involved in arteriolar CNV formation and anti-VEGF resistance. Combination therapy by neutralizing VEGF and enhancing cholesterol removal from macrophages is a promising strategy to combat anti-VEGF resistance in CNV.

Salmonella enterica serovar Typhi, is one of the major infection spreading from consuming contaminated food and water. The poor sanitation is one the major cause for successful infection. S. typhi is responsible for causing typhoid fever, which is a growing public health concern in developing countries. This bacterium has acquired antimicrobial resistance to many promising which is a growing health concern for community. This study is aim to elucidate the molecular complexity of flouroquinolone resistance in S. Typhi isolates (n=286). Genomic data was downloaded from NCBI and analysis was done by Resfinder, MLST, and Pointfinder. Genomic analysis unveils a complex resistance profile, featuring antimicrobial resistance genes (ARG) including blaCTXM-15, blaTEM-1D, catA1, dfrA7, qnrS1, sul1, sul2, and tetA(B). The investigation focuses on mutations in DNA gyrA, parC, and qnrS1 genes which plays an important role in quinolone resistance. Mutation analysis reveals mutations such as DNA gyrA_S83F, DNA gyrA_D87N, DNA gyrA_S83Y, DNA gyrB_S464F, parC_S80I, and parE_L416F with the presence of qnrS1 gene produces resistance against quinolones. The Docking studies was conducted by “Autodock vina” and visualize by “Discovery studio” which demonstrate that these mutations leads to ciprofloxacin resistance, indicating reduced binding affinity, and altered solvent accessibility which indicates the structural changes at mutation sites. This study provides crucial insights into the molecular mechanisms driving flouroquinolone resistance in S. typhi, guiding future strategies to combat antibiotic resistance. Further validation through experimental mutagenesis is recommended, for targeted therapeutic interventions against the mounting threat of antibiotic-resistant S. typhi.

The South Asian economy is on the rise but struggling with power shortages and heavy dependence on fossil fuels. For sustained growth, there is a need for access to readily available energy sources, such as electricity. Trading clean electrical energy among neighbouring countries can ensure access to readily available points. South Asia has a diverse range of energy sources, including hydropower, that are available in the region. However, sectorial barriers can impede energy trading. This study has attempted to assess the readiness and barriers to Nepal’s cross-border energy trade with India and Bangladesh using the Analytic Hierarchy Process (AHP). This study also recommends possible measures to strengthen preparedness and address the challenges in energy trade that can be tailored and applied to other cross-country situations.

Given that evaluating suspected child maltreatment is a challenging task, we aimed to begin to explore how laboratory test results may assist in its detection. Hence, we have examined biomarker differences between 137 children entering out-of-home care and 126 children living in their own homes. Each child entering Majorcan institutionalized care was randomly matched for gender and age with children living in their homes and the same health area. Concerning basic hematological and biochemical values, children placed in out-of-home care differed significantly from children remaining at home in four distinct ways. Children at care entry had significantly higher eosinophil counts than children at home; and also had significantly lower levels of transaminase, thyroid-stimulating hormone, triglycerides and LDL-Cholesterol than children living at home. Oxidative stress linked to anxiety disorders and underweight are common features found in children at entry into the care system. The present study shows a relationship between some underweight or oxidative stress biomarkers and the risk of entry into out-of-home care. Medical diagnoses require physicians to select and assemble relevant data from all available information. Accordingly, we should consider the implementation of laboratory checkups in order to identify the abused from the non-abused child better.

Verticillium wilt (VW) is an important and widespread disease of cotton and once established is long lived and difficult to manage. In Australia, the non-defoliating pathotype of Verticillium dahliae is the most common, and extremely virulent. Breeding cotton varieties with increased VW resistance is the most economical and effective method of controlling this disease and is greatly aided by understanding the genetics of resistance. In this study, VW resistance was investigated in 240 F7 recombinant inbred lines (RIL) derived from a cross between MCU-5 that has good resistance and Siokra 1-4 which is susceptible. Using a controlled environment bioassay, we found that resistance based on plant survival or shoot biomass was complex but with major contributions from chromosomes D03 and D09, with genomic prediction analysis estimating a prediction accuracy of 0.73 based on survival scores compared to 0.36 for shoot biomass. Transcriptome analysis of MCU-5 and Siokra 1-4 roots uninfected or infected with V. dahliae revealed that the two cultivars displayed very different root transcriptomes and responded differently to V. dahliae infection. Ninety-nine differentially expressed genes were located in the two mapped resistance regions and so are potential candidates for further identifying the genes responsible for VW resistance.

The increasing focus on the development of positioning techniques reflects the growing interest in applications and services based on indoor positioning. Many applications necessitate precise indoor positioning or tracking of individuals and assets, leading to rapid growth in products based on these technologies in certain market sectors. Ultrasonic systems have already proven effective in achieving the desired positioning accuracy and refresh rates. The typical signal used in ultrasonic positioning systems for estimating the range between the target and reference points, specifically the linear chirp, can undergo shape aberration due to the effects of acoustic diffraction when the aperture exceeds a certain limit. The extent of the aberration is influenced by the shape and size of the transducer, as well as the angle at which the transducer is observed by the receiver. This aberration also impacts the shape of the cross-correlation, causing it to lose its characteristic easily detectable single global peak. In such instances, cross-correlation techniques yield results with a significantly higher error than anticipated. In this study, an alternative technique to global peak detection is proposed, leveraging the inherent symmetry observed in the shape of the aberrated cross-correlation. The numerical simulations, performed using the academic acoustic simulation software Field II, conducted using a typical ultrasonic chirp and ultrasonic emitter, compare the classical and the proposed range techniques in a standard office room. The results demonstrate that the proposed technique enables accurate range estimation even in the presence of severe cross-correlation shape aberrations. This allows the use of emitting transducers with a much larger aperture than that allowed by the classical cross-correlation technique. Consequently, it becomes possible to have greater acoustic power available, leading to improved Signal-to-Noise Ratio (SNR).

Background and objective K. pneumoniae appeared to be a significant problem due to its ability to accumulate antibiotic-resistance genes. After 2013, alarming colistin resistance rates among carbapenem-resistant K. pneumoniae have been reported in the Balkans. The study aims to perform an epidemiological, clinical, and genetic analysis of a local outbreak of COLr CR-Kp. Material and methods All carbapenem-resistant and colistin-resistant K. pneumoniae isolates observed among patients in the ICU unit of Military Medical Academy, Sofia from 1 January to 31 October 2023 were included. The results were analyzed according to the EUCAST criteria. All isolates were screened for blaVIM, blaIMP, blaKPC, blaNDM, and blaOXA-48. Genetic similarity was determined using the Dice coefficient as a similarity measure and the unweighted pair group method with arithmetic mean (UPGMA). mgrB genes and plasmid-mediated colistin resistance determinants (mcr-1, mcr-2, mcr-3, mcr-4, mcr-5) were investigated. Results There was a total of 379 MDR-K. pneumoniae isolates, 88% of which were carbapenem-resistant. Of them, there were 9 (2.7%) colistin-resistant isolates in six patients. A time and space cluster for five patients was found. Epidemiology typing showed that two isolates belonged to clone A (pts. 1, 5) and the rest to clone B (pts. 2-4) with 69% similarity. Clone A were coproducers of blaNDM-like and blaOXA-48-like and had mgrB-mediated colistin resistance (40%). Clone B isolates had only blaOXA-48-like and intact mgrB genes. All isolates were negative for mcr-1,-2,-3,-4,-5 genes. Conclusions The study describes a within-hospital spread of two clones of COLr CR-Kp with a 60% mortality rate. Clone A were coproducers of NDM-1 and OXA-48-like enzymes and had mgrB-mediated colistin resistance. Clone B isolates had only OXA-48-like enzymes and intact mgrB genes. No plasmid-mediated was found. The extremely high mortality rate and limited treatment options warrant strict measures to prevent outbreaks.

Enterococci are widely acknowledged as prominent pathogens in hospitals, with the potential to transfer resistance genes, virulence factors, or other characteristics that increase their ability to survive in humans. Healthy cattle, sheep, and goats can be reservoirs for gastrointestinal pathogenic fecal enterococci, some of which could be multidrug-resistant to antimicrobials. The objective of this study was to determine the prevalence and diversity of Enterococcus species in healthy sheep, goat, and cattle carcasses, as well as to analyze the antimicrobial resistance phenotype/genotype and the virulence gene content. During 2019–2020, carcass surface samples of 150 ruminants were collected in a slaughterhouse. A total of 90 enterococci, comprising 5 species, were obtained. The overall prevalence of enterococci was found to be 60%, out of which 37.7% were identified as E. hirae, 33.3% as E. casseliflavus, 15.5% as E. faecium, 12.2% as E. faecalis, and 1.1% as E. gallinarum. Virulence-associated genes of efaA (12.2%) were commonly observed in the Enterococcus isolates, followed by gelE (3.3%), asaI (3.3%), and ace (2.2%). Characteristic resistance genes were identified by PCR with an incidence of 6.6%, 2.2%, 1.1%, 1.1%, 1.1%, and 1.1% for the tetM, ermB, ermA, aac(6’)Ie-aph(2")-la VanC1, and VanC2 genes, respectively. The high resistance to quinupristin-dalfopristin (28.8%), tetracycline (21.1%), ampisilin (20%), and rifampin (15.5%) was distributed among two, four, four, and five of the five species, respectively. The resistance of Enterococcus isolates to 11 antibiotic groups was determined and multidrug-resistant (MDR) strains occupied 18.8% of the Enterococcus isolates. Efflux pump genes causing multidrug resistance were detected in Enterococcus isolates (34.4%). The study's results showed that there were enterococci in the slaughterhouse that were multidrug resistant (MDR) and had a number of genes linked to virulence that could be harmful to human health.

High temperature (HT) geothermal wells can provide green power 24h a day 7 days a week. Harsh environmental and operational conditions, long-term durability requirements of such wells require special cementitious composites for well construction. This paper reports a comprehensive assessment of geothermal cement composites in cyclic pressure function laboratory tests, field exposures in an HT geothermal well (300-350oC) as well as a numerical model to complement the experimental results. Performances of calcium-aluminate-cement (CAC)-based composites and calcium free cement were compared against reference Ordinary Portland Cement (OPC)/silica blend. The stability and degradation of the tested materials was characterized by crystalline composition, thermo-gravimetric, and elemental analyses, morphological studies, water-fillable porosity, and mechanical properties measurements. All CAC-based formulations outperformed the reference blend both in the function and exposure tests. The reference OPC/silica lost its mechanical properties during the 9-month well exposure through extensive HT carbonation, while properties of the CAC-based blends improved over that period. The Modified Cam-Clay (MCC) plasticity parameters of several HT cement formulations were extracted from triaxial and Brazilian tests and verified against the experimental results of function cyclic tests. These parameters can be used in well integrity models to predict field-scale behavior of the cement sheath under geothermal well conditions.

Fusarium wilt caused by Fusarium oxysporum f. sp. cubense (Foc) is one of the most destructive diseases in banana farming worldwide. Knowledge of the factors of genetic diversity and virulence of the pathogen contributes to the development of resistant cultivars and in management strategies based on exclusion. In this study, phenotypic traits such as virulence and aggressiveness in a sample of 52 Foc isolates, were analyzed and their relationship to the presence of putative effectors of gene SIX (Secreted in Xylem) pathogenicity homologues, verified. According to the dissimilarity matrix, there were three isolates closest to the standard Foc race 1 strain. Isolates 229A and 218A, were selected according to their aggressiveness profile in 'Grand Naine' and 'Prata-Anã', respectively, I order to replace the standard isolate of race 1 in the resistance screening process carried out by the breeding program. Two homologues of the SIX8 gene, SIX8a and SIX8b, are present in isolates of Foc from Brazil and the SIX8b gene correlates with avirulence in the cultivar ‘Grand Naine’ (Cavendish). These results are important to support the banana genetic breeding program by identification of sources of resistance to Foc and contribute in the establishment of the function of SIX effector proteins.

Biofilm-associated bacterial infections are the major reason for treatment failure in many diseases including burn trauma infections. Uncontrolled inflammation induced by bacteria leads to materiality, tissue damage and chronic diseases. Specialized proresolving mediators (SPMs), including maresin-like lipid mediators (MarLs), are enzymatically biosynthesized from omega-3 essential long-chain polyunsaturated fatty acids, especially docosahexaenoic acid (DHA) by macrophages and other leukocytes. SPMs exhibit strong inflammation-resolving activities, especially inflammation provoked by bacterial infection. In this study, we explored the potential direct inhibitory activities of three MarLs on gram-positive (Staphylococcus aureus) and gram-negative (Pseudomonas aeruginosa and Escherichia coli) bacteria in their biofilms that are leading bacteria in burn trauma related infections. We also examined the effects of MarLs on the bactericidal activities of a typical broad-spectrum antibiotics carbenicillin on these bacteria in their preformed biofilms. The results revealed that MarLs combined with carbenicillin can inhibit the survival of gram-positive and gram-negative bacteria in their biofilms although MarLs alone did not exhibit bactericidal activity. Thus, our findings suggest that the combination of MarLs and carbenicillin can lower the antibiotic requirements to kill the bacteria in preformed biofilms.

Due to the ongoing global warming on the Earth, permafrost degradation has been extensively taking place, which poses a substantial threat to civil and industrial facilities and infrastructure elements, as well as to the utilization of natural resources in the Arctic and high-latitude regions. In order to prevent the negative consequences of permafrost thawing under the foundations of constructions, various geophysical techniques for monitoring permafrost have been proposed and applied so far: temperature, electrical, seismic and many others. At the same time, non-stationary electromagnetic methods seem to have significant potential and a number of important practical advantages. We propose a cross-borehole exploration system for the highest localization of target objects in the cryolithozone. A novel mathematical apparatus for three-dimensional modeling of transient electromagnetic (TEM) signals by the vector finite element method has been developed. The original combination of the latter, the Sumudu integral transform and artificial neural networks makes it possible to examine spatially heterogeneous objects of the cryolithozone with a high contrast of geoelectric parameters, significantly reducing computational costs. We have studied the sensitivity of the TEM signals to the boundary between thawed and frozen rocks depending on the inter-borehole distance and spatial orientations of the transmitters and receivers. Numerical simulation results of the TEM monitoring of industrial facilities located on permafrost are considered. The formation of a talik has been shown to significantly manifest itself in the measured electromagnetic responses, which enables timely prevention of industrial disasters and environmental catastrophes.

The aberrant glycosylation is a hallmark of cancer progression and chemoresistance. It is also an immune therapeutic target for various cancers. Tunicamycin (TM) is one of the potent nucleo-side antibiotics and an inhibitor of aberrant glycosylation in various cancer cells, including breast cancer, gastric cancer, and pancreatic cancer, parallel with inhibition of cancer cell growth and progression of tumors. Thus, TM can be considered a potent antitumor drug in various cancers and may promote chemosensitivity. Mechanistically, TM impedes the role of the UDP-HexNAc enzyme in the biosynthesis of oligosaccharides, specialized macromolecules instrumental in N-linked glycosylation. Further, like chemotherapies such as doxorubicin (DOX), 5'fluorouracil, etoposide, and Cisplatin, TM induces the unfolded protein response (UPR) by blocking aberrant glycosylation. Despite TM's antitumor effectiveness, its lack of cell-type specific cytotoxicity impedes its anticancer efficacy. Thus, various nanoencapsulation techniques and materials have been considered for use in experiments to reduce TM's cytotoxicity and improve efficacy as a targeted therapy. The current review is a profound audit of the benefits and pitfalls of TM in various cancers, focusing on breast, colon, and pancreatic cancers. Additional progressive studies have also discussed the use of TM in immune checkpoints and other unique pathways. Cytotoxicity and other possibly adverse effects of TM are highlighted based on the data from in vitro and in vivo assays. In addition, the recent advances in nano-based drug delivery systems regarding TM have been emphasized. However, the potential of this nucleoside inhibitor re-quires thorough investigation and research to determine its likeliness as a viable chemotherapeutic.

Background: Antimicrobial Stewardship Programs (ASP) were introduced in healthcare as a public health priority to promote appropriate prescribing of antimicrobials, reduce antimicrobials adverse events as well as control challenges of antimicrobial resistance. To deliver aimed outcome objectives, ASPs involve multiple implementation measures. A review of systematic review was conducted to evaluate ASPs process and outcome measures. Guided by PRISMA frames, published systematic reviews (SR) focusing on ASPs restricted to secondary healthcare were evaluated over the past 10 years by examining major and primary databases involving all age groups. Out of 265 identified SR studies, 63 met inclusion criteria, the majority were conducted in European and North American regions. All age groups were examined in the studies but mainly conducted in adults when compared to children and infants . Both ASPs process and outcomes measures were examined equally and simultaneously through 25 different concepts, dominated by efficacy , antimicrobial resistance , and economic impact while information technology as well as role of pharmacy and behavioural factors were equally examined . The main broad conclusions from the review , that across the globe, ASPs demonstrated effectiveness, proved efficacy, and confirmed efficiency while focused evaluation advocate that developed countries should target medium and small sized hospitals while developing countries should continue rolling ASPs in their healthcare facilities . Additionally , the future of ASPs should focus on embracing evolving information technology to bridge gaps in knowledge, alter attitude and enhance decision making .

Corrugated board, widely used in the packing industry, is a recyclable and durable material. Its strength and cushioning, influenced by geometry, environmental conditions like humidity and temperature, and paper quality, make it versatile. Double-walled (or five-ply) corrugated board, comprising two flutes and three liners, enhances these properties. This study introduces a novel approach to analyze 5-layered corrugated board, extending a previously published algorithm for single-walled boards. Our method focuses on measuring layer and overall board thickness, flute height, and center lines of each layer. Integrating image processing and genetic algorithms, the research successfully developed an algorithm for precise geometric feature identification of double-walled boards. Images were recorded using a special device with a sophisticated camera and image sensor for detailed corrugated board cross-sections. Demonstrating high accuracy, the method faced limitations only with very deformed or damaged samples. This research contributes significantly to quality control in the packaging industry and paves the way for further automated material analysis using advanced machine learning and image sensors. It emphasizes the importance of sample quality and suggests areas for algorithm refinement to enhance robustness and accuracy.

Skin wounds and their infections by antibiotic resistant bacteria (ARB)are very common in small animals, posing the risk of acquiring ARB by pet owners or antibiotic resistance gene (ARG) transfer to the owners’ microbiota. The aim of this study was to identify the most common pathogens infecting wounds of companion animals, assess their antibiotic resistance and determine the ARGs using culture-based, molecular and proteomic methods. A total of 136 bacterial strains were isolated from wound swabs. Their species was identified using chromogenic media, followed by MALDI-TOF spectrometry. Disk diffusion was used to test the antibiotic resistance and twelve ARGs were detected using PCRs. The dominant species included Staphylococcus pseudintermedius (9.56%), E. coli and E. faecalis (both n=11, 8.09%). Enterobacterales were mostly resistant to amoxicillin/clavulanic acid (68.3% strains), all Pseudomonas were resistant to ceftazidime, piperacillin/tazobactam, imipenem and tylosin, Acinetobacter was mostly resistant to tylosin (55.5%), all Enterococcus were resistant to imipenem, 39.2% of Staphylococci were resistant to clindamycin. Among ARGs, strA (streptomycin resistance), sul3 (sulfonamide resistance) and blaTEM, an ESBL determinant, were the most frequent. The risk of ARB and ARD transfer between animals and humans causes the need to search for new antimicrobial therapies in the future veterinary medicine.

Abstract Background: Metabolic syndrome (MetS) is a complex disorder characterized by insulin resistance (IR), central obesity, atherogenic dyslipidemia and higher glucose levels. It increases the risk of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM), imposing an economic burden on the healthcare system. However, the historical origins of MetS as well as the development and evolution of its definitions have not been conclusively documented in the literature. Aim: This study seeks to enhance the understanding of the developmental trends of MetS during the preceding two decades, placing particular emphasis on the definition, diagnosis and prevalence. Methods: An extensive search was performed from 1920 to 2023 across prominent scientific research engines, including Scopus, PubMed, MDPI, and others. Results: Despite advancements, many aspects of MetS remain inadequately understood. As the understanding of the nature and pathophysiology of MetS progresses, the development and refinement of its diagnostic criteria, and assessment and treatment guidelines will continue. Additionally, there exists significant variation in the global prevalence of metabolic syndrome, ranging from 14 to 39%. This prevalence is projected to increase due to the adoption of less healthy dietary patterns and sedentary lifestyles. The observed disparities in metabolic syndrome prevalence can be attributed to multiple factors, including demographic characteristics. Furthermore, the lack of a standardized definition across studies also contributes to the variation in reported prevalence rates. Conclusion: Further studies focusing on the standardization of the MetS definition across different research are crucial. The establishment of consistent criteria would enhance the reliability and validity of research findings, enabling more meaningful comparisons and interpretations.

Bacteria of the genus Staphylococcus are a significant a challenge for medicine, as many species are resistant to multiple antibiotics and even to all of the antibiotics used. One of the approaches to develop new therapeutics to treat staphylococcal infections is the use of bacteriophages specif-ic to these bacteria or lysins of such bacteriophages capable to hydrolyze the cell walls of these bacteria. In this study, a new bacteriophage St_134 specific to Staphylococcus epedermidis was de-scribed. This small podophage belonging to the Andhravirus genus showed relatively wide host range and was able to infect more than 60 strain of Staphylococcus spp., including a clinical strain from the Staphylococcus aureus complex. Two genes encoding different phage lysins were identi-fied in the Ste134 genome. Both lysins LysSte134_1 and LysSte134_2 were produced in Escherichia coli cells. Endolysin LysSte134_1 was demonstrated catalytic activity against a wide panel of staphylococcal peptidoglycans (4 species, 6 strains), was active against S. aureus and S. epidermidis planktonic cultures and destroyed biofilms formed by clinical strains of S. aureus and S. epider-midis.

Antimicrobial resistance is a major public health concern. Rodents and shrews live in closer proximity to humans and animals and serve as reservoirs for the transmission of several diseases, including AMR pathogens. There is no data available from India on surveillance of AMR bacteria in rodents and shrews. In this study, bacterial pathogens viz, Staphylococcus sp, Escherichia coli and Salmonella sp were isolated from rodents and shrews and genetic elements conferring antimicrobial resistance in the pathogens were screened by PCR. Bacterial pathogens in the oropharyngeal and anal swabs collected from the rodents and shrews trapped (n=100) were cultured on selective media such as Mannitol salt, Mac Conkey and Xylose lysine deoxycholate media to isolate Staphylococcus sp., E. coli and Salmonella sp. respectively. A total of 76 (80%) S. aureus and 19 (20%) Staphylococcus non aureus were isolated. E. coli was isolated in 89 samples and among the Salmonella sp (n=59), 16 (27%) were S. enteritidis and 29 (49.1%) were S. typhimurium. In S. aureus isolates, mec A and mec C (MRSA) were detected in 40 (52.6%) and 6 (7.9%) isolates respectively. Also, 7 (36.84%) and 1 (5.3%) Staphylococcus non aureus isolates were tested to harbour mec A and mec C genes. A total of 77 (86.5%) E. coli isolates had genes encoding ESBL [TEM in 21 (23.59%), SHV in 45 (50.6%) and CTXM in 11 (12.4%)]. Among the 45 pathogenic Salmonella sp, 44 (97.78%) harboured AMR genes [tet in 13 (28.9%), sul3 & sul4 in 20 (44.4%) and qnrA in 11 (24.4%)]. Thirty-eight animals harboured more than one zoonotic pathogen and 21 with multi-drug resistant genes. Our findings signify that these rodents and shrews may serve as sentinels to screen environment spillover of AMR pathogens and also act as reservoir to transmit MRSA, ESBL, Salmonella sp. human/animals. Also these animals aid in the transfer of antimicrobial resistance genetic elements to non-pathogenic organisms.

In CNS drug discovery, estimation of brain exposure of lead compounds is critical for their optimization. Compounds need to cross the blood-brain barrier (BBB) to reach the pharmacological targets in the CNS. The BBB is a complex system involving passive and active mechanisms of transport and efflux transporters such as P-glycoproteins (P-gp) and breast cancer resistance protein (BCRP), which play an essential role in CNS penetration of small molecules. Several in vivo, in vitro and in silico methods are available to estimate human brain penetration. Preclinical species are used as in vivo models to understand the unbound brain exposure by deriving the Kp,uu parameter, the brain/plasma ratio of exposure corrected with the plasma and brain free fraction. MDCK-mdr1 (Madin Darby canine kidney cells transfected with the MDR1 gene encoding for the human P-gp) assay is the most commonly used in vitro assay to estimate compound permeability and human efflux. The in silico methods to predict brain exposure, such as CNS MPO, CNS BBB scores and various Machine Learning models, help save costs and speed up compound discovery and optimization at all stages. These methods enable the screening of virtual compounds and building of a CNS penetrable compounds library as well as optimization of lead molecules for CNS penetration. Therefore, it is crucial to understand these methods' reliability and ability to predict CNS penetration. We review the in silico, in vitro and in vivo data and their correlation with each other and assess published in silico approaches to predict the BBB penetrability of compounds.

Pancreatic Ductal Adenocarcinoma (PDAC) is the most frequent infiltrating type of pancreatic cancer. The poor prognosis is due to the absence of specific biomarkers, aggressiveness and treatment resistance. PDAC is a deadly malignancy bearing distinct genetic alterations, the most common being those that cause cancer-causing versions of the KRAS gene. Cannabigerol (CBG) is a non-psychomimetic cannabinoid with anti-inflammatory property. Regarding CBG anticancer ef-fect, up to now there are only few evidence in human cancers. We investigated CBG effects on PDAC cell lines, PANC-1 and MIAPaCa-2. It was investigated CBG activity on cell viability, cell death and its effect of EGFR-RAS-associated signalling. Moreover, the potential synergistic effect of CBG in combination with gemcitabine (GEM) and paclitaxel (PTX) was investigated. MTT was applied to investigate CBG effect on PDAC cell lines viability. Annexin-V and Acridine Orange staining followed by cytofluorimetric analysis and Western blot were used to evaluate CBG effect on cell death. Modulation of EGFR-RAS-associated pathways was determined by Western Blot analysis and Milliplex multiplex assay. Moreover, by MTT data and Synergy finder software analysis the effect of the combination of CBG and chemotherapeutic drugs, was determined.

High rates of resistance to antibiotics are associated with healthcare-related infections, thus appealing for the urgent need for effective antimicrobials against these maladies. The present study aims to determine the chemical composition of essential oil (EO) from Clausena anisata leaves, and evaluate their antibacterial activity against selected nosocomial bacteria. Fresh leaves of Clausena anisata were subjected to a steam distillation using a Clevenger apparatus to afford the essential oil. The phytochemical composition of this oil was analyzed using gas chromatography-mass spectrometry (GC-MS). The essential oil was further tested against selected nosocomial bacteria, including Staphylococcus and Klebsiella species, among others, using a microdilution method. As a result, 0.77% of essential oil was extracted from fresh leaves of Clausena anisata. The GC-MS analysis revealed that the as-prepared essential oil contain E-anethole (70.77%), methyl isoeugenol (13.85%), estragole (4.10%), γ-terpinene (3.33%), myrcene (2.82%) and sabinene (0.77%), with E-anethole being the major constituent. Meanwhile, twenty two compounds were identified in the EO of Clausena anisata leaves through gas chromatography. Upon antibacterial test against selected nosocomial pathogens, the E-anethole-rich essential oil exhibited minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values ranging from 3.91 to 125 µg/mL and 7.81 to 125 µg/mL, respectively, indicative of a bactericidal orientation of the plant’s essential oil (MIC/MBC ratio: 4). This novel contribution highlights the scientific validation of the use of Clausena anisata leaves in the traditional treatment of various infectious diseases. However, toxicity and pharmacokinetic studies, mechanistic basis of the antibacterial action, and in vivo antibacterial experiments of the E-anethole-rich essential oil of Clausena anisata should be investigated to successfully use this plant in the treatment of infectious diseases.

Acquired immunodeficiency syndrome (AIDS) is an enormous global health threat stemming from human immunodeficiency virus (HIV-1) infection. Up to now, the tremendous advances in combination antiretroviral therapy (cART) have shifted HIV-1 infection from a fatal illness into a manageable chronic disorder. However, the presence of latent reservoirs, multifaceted nature of HIV-1, drug resistance, severe off-target effects, poor adherence, and high cost restrict the efficacy of current cART targeting the distinct stages of the virus life cycle. Therefore, there is an unmet need for discovery of new therapeutics that not only bypass the limitations of the current therapy but also protect the body health at the same time. The main goal for complete HIV-1 eradication is purging latently infected cells from the patients’ bodies. A potential strategy called “lock-in apoptosis” targeting the budding phase of life cycle of virus leading to susceptibility to apoptosis of HIV-1 infected cells for elimination of HIV-1 reservoirs and ultimately for a complete eradication. The current work intends to present the main advantages and disadvantages of United States Food and Drug Administration (FDA) approved anti-HIV-1 drugs as well as plausible strategies for the design and development of more anti-HIV-1 compounds with better potency, favorable pharmacokinetic profiles, and improved safety issues.

The assessment of photovoltaic devices, which convert light energy into electricity, becomes significantly relevant due to the aspiration to reduce pollution on a global scale. In this context, the pursuit of optimizing the efficiency in converting light energy into electrical energy involves exhaustive studies and structural analyses of solar cells, all directed toward achieving this goal. This study introduces a research proposal aimed at analyzing the losses associated with series resistance (Rs). The analysis takes into account each component comprising this resistance, pro-posing a network of resistances that precisely models each of these elements. The aforementioned research focused on simple-structured crystalline silicon cells. During this investigation, the junction depth (xj) of n-p materials was varied with the aim of achieving efficiencies in the range of 12%. However, in the pursuit of this desired efficiency, a significant impact on series resistance was observed when analyzing the I-V curves of the cells obtained in each manufacturing process.

Animal trypanosomiasis (AT) is a complex of veterinary diseases known under various names such as nagana, surra, dourine and mal de caderas, depending on the country, the infecting trypanosome species and the host. AT is caused by parasites of the genus Trypanosoma, and the main species infecting domesticated animals are T. brucei brucei, T. b. rhodesiense, T. congolense, T. vivax, T. evansi and T. equiperdum. AT transmission, again depending on species, is through tsetse flies or common Stomoxys and tabanid flies or through copulation. Therefore, the geographical spread of all forms of AT together is not restricted to the habitat of a single vector like the tsetse fly and currently includes almost all of Africa, and most of South America and Asia. The disease is a threat to millions of companion and farm animals in these regions, creating a financial burden in the billions of dollars to developing economies as well as serious impacts on livestock rearing and food production. Despite the scale of these impacts, control of AT is neglected and under-resourced, with diagnosis and treatments being woefully inadequate and not improving for decades. As a result, neither the incidence of the disease, nor the effectiveness of treatment is documented in most endemic countries, although it is clear that there are serious issues of resistance to the few old drugs that are available. In this review we particularly look at the drugs, their application to the various forms of AT, and their mechanisms of action and resistance. We also discuss the spread of veterinary trypanocide resistance and its drivers, and highlight current and future strategies to combat it.

Urinary tract infections (UTIs) are a prevalent bacterial infection in both community and healthcare settings. They account for approximately 40% of all bacterial infections and require around 15% of all antibiotic prescriptions. Although antibiotics have traditionally been used to treat UTIs for several decades, the significant increase in antibiotic resistance in recent years has made many previously effective treatments ineffective. Biofilm on medical equipment in healthcare settings creates a reservoir of pathogens that can be easily transmitted to patients. Urinary catheter infections are frequently observed in hospitals and are caused by microbes that form a biofilm after the catheter is inserted into the bladder. Managing infections caused by biofilms is challenging due to the emergence of antibiotic resistance. Biofilms enable pathogens to evade the host's innate immune defences, resulting in long-term persistence. The incidence of sepsis caused by urinary tract infections that have spread to the bloodstream is increasing, and drug-resistant infections may be even more prevalent. While the availability of upcoming tests to identify the bacterial cause of infection and its resistance spectrum is critical, it alone will not solve the problem; innovative treatment approaches are also needed. This review analyses the main characteristics of biofilm formation and drug resistance in recurrent uropathogen-induced UTI. The importance of innovative and alternative therapies to combat biofilm-caused UTI is emphasised.

Previously, we reported that metronidazole MICs are not dependent on the expression levels of nim genes in B. fragilis strains; and we also compared the proteomes of metronidazole-resistant laboratory B. fragilis strains to those of their susceptible parent strains. Here, we used RT-qPCR to correlate the expression levels of 18 candidate genes in a panel of selected, clinical nim gene-positive and -negative B. fragilis strains to their metronidazole MICs. Metronidazole MICs were correlated to the expression of certain tested genes. Specifically, lactate dehydrogenase expression correlated positively, whereas cytochrome fumarate reductase/succinate dehydrogenase, malate dehydrogenase, phosphoglycerate kinase redox and gat (GCN5-like acetyltransferase), and relA (stringent response) regulatory gene expressions correlated negatively with metronidazole MICs. This result provides evidence for the involvement of carbohydrate catabolic enzymes in metronidazole resistance in B. fragilis. This result was supported by direct substrate utilization tests. However, the exact roles of these genes/proteins should be determined in deletion–complementation tests. Moreover, the exact redox cofactor(s) participating in metronidazole activation need to be identified.

Walnut (Juglans regia L.) is a monoecious species and although it exhibits self-compatibility, presents incomplete overlap of pollen shed and female receptivity. Thus, cross-pollination is prerequisite for optimal fruit production. Cross-pollination can occur naturally by the wind, the insects, artificially, or by hand. Pollen has been recognized as one possible pathway for Xanthomonas arboricola pv. juglandis infection, a pathogenic bacterium responsible for walnut blight disease. Other than the well-known cultural and chemical control practices, artificial pollination technologies with the use of drones could be a successful tool for walnut blight disease management of orchards. Drones may carry pollen and release it over crops or mimic the action of bees or other pollinators. Although this new pollination technology could be regarded as a promising tool, pollen germination and knowledge of pollen as a possible pathway for the dissemination of bacterial diseases remain crucial information for design and manufacture of aerial pollinator robot for walnut trees. Thus, our purpose was to describe a pollination model with fundamental components, the identification of the “core” pollen microbiota, specify an appropriate flower pollination algorithm, design an autonomous precision pollination robot, and minimize the average errors of flower pollination algorithm parameters through machine learning and meta-heuristic algorithms.

The fate of critically sick patients with infections in intensive care units (ICUs) is significantly influenced by antimicrobial resistance, which has become a serious concern in developing nations. This observational study was conducted at the IBN Sina Specialised Hospital in Dhaka, Bangladesh, over a 12-month period from January 2021 to December 2021, in order to track the pattern of antibiotic resistance among the patients admitted to the intensive care unit (ICU). Aspiration pneumonia (29%) and diabetes mellitus (24%), among 200 patients, were the most common main diagnoses. 65 samples (or 26%) of the 250 samples had 85 bacteria identified from them. Urine (14.12%) and tracheal aspirate (64.71%) were the most frequently found sites of infection. In the sample from the tracheal aspirate, Pseudomonas spp. (30.59%), Escherichia coli (24.71%), Acinetobacter spp. (20%), and Klebsiella spp. (14.12) were the most frequently isolated microorganisms. The following antibiotics were shown to have the highest overall patterns of resistance: levofloxacin (68.24), amikacin (64.71), meropenem (49.41), ceftazidime (75.29), ciprofloxacin (78.82), and gentamicin (82.35). The most effective antibiotic against Klebsiella species was meropenem (64.61%), while Acinetobacter species were mostly susceptible to cotrimoxazole (64.67%) and piperacillin + tazobactam (60.50%). Most susceptible to netilmicin (70.48%) and meropenem (49.32%) were Escherichia coli, while Pseudomonas spp. were mostly responsive to colistin (55.14%) and netilmicin (52.25%). Antibiotic resistance is common among intensive care unit (ICU) patients, and most isolated microbes have resistance to traditional medicines.

Background: In antibiotic naïve populations, there is a strong association between the use of an antimicrobial and resistance to this antimicrobial. Less evidence is available as to whether this relationship is weakened in populations highly exposed to antimicrobials. Individuals taking HIV PrEP have a high intake of antimicrobials. We previously found that there was no difference in the prevalence of pheno- and genotypic antimicrobial resistance between two groups of PrEP clients who had, and had not, taken antimicrobials in the prior 6-months. Both groups did, however, have a higher prevalence of resistance than a sample of the general population. Methods: In the current study, we used zero-inflated negative binomial regression models to evaluate if there was an individual level association between the consumption of antimicrobials and 1. the minimum inhibitory susceptibilities of oral Neisseria subflava and 2. the abundance of antimicrobial resistance genes in the oropharynges of these individuals. Results: We found no evidence of an association between the consumption of antimicrobials and the minimum inhibitory susceptibilities of oral Neisseria subflava or the abundance of antimicrobial resistance genes in these individuals. Conclusions: We conclude that in high antimicrobial consumption populations, the association between antimicrobial consumption and resistance may be attenuated.

Diarrhea-related mortality remains an important public health concern, particularly in developing countries, and has become difficult to treat because of antibacterial resistance. The development of synergistic antimicrobial agents appears to be a promising alternative treatment against diar-rheal infections. In this study, the combined effect of tetracycline together with either nitroxoline, sanguinarine, or zinc pyrithione (representing various classes of alkaloid-related compounds) was evaluated in vitro against selected diarrheagenic bacteria (Enterococcus faecalis, Escherichia coli, Listeria monocytogenes, Shigella flexneri, Vibrio parahaemolyticus, and Yersinia enterocolitica). The chequerboard method in 96-well microtiter plates was used to determine the sum of the fractional inhibitory concentration indices (FICIs). Three independent experiments were performed per combination, each in triplicate. It was observed that the combinations of tetracycline with either nitroxoline, sanguinarine, or zinc pyrithione produced synergistic effects against most of the pathogenic bacteria tested, with FICI values ranging from 0.086 to 0.5. Tetracycline-nitroxoline combinations produced the greatest synergistic action against S. flexneri at a FICI value of 0.086. Combinations of the agents tested in this study can thus be used for the development of new anti-diarrheal medications. However, studies focusing on their in vivo anti-diarrheal activity and safety are required before any consideration for utilization in human medicine.