Clopidogrel is one of the thienopyridine antiplatelet drugs commonly used as a prophylactic medication to prevent coagulation in vessels and cardiovascular events. The molecule of clopidogrel is metabolized in the liver via phase-I and phase-II metabolism pathways. The sulfenic acid clopidogrel metabolite undergoes phase-II metabolism through conjugation with glutathione by the glutathione-s-transferase (GST) to form a glutathione conjugate of clopidogrel (inactive metabolite). A glutaredoxin enzyme removes the glutathione conjugated with clopidogrel to form cis-thiol-clopidogrel. This review focused on the polymorphisms of genes related to phase-II metabolism during the clopidogrel bioactivation process. Overall, no well-controlled studies were done about the relationship between the clopidogrel bioactivation process and genes related to phase-II metabolism’s enzymes. Nevertheless, some polymorphisms of G6PD, GCLC, GCLM, GSS, GST, GSR, HK, and GLRX genes could be responsible for clopidogrel resistance due to low glutathione conjugate or glutaredoxin plasma levels. Studies needed to be concerned with the relationship between clopidogrel resistance and phase-II metabolism issues in the near future.

Patients with lean NAFLD make up an increasing subset of liver diseases. The association between lean NAFLD and feutin-A, which serves as a hepatokine and adipokine, has never been examined. Our study aimed to explore the association of serum fetuin-A among lean and nonlean patients. The study comprised 606 adults from the community, stratified into lean or nonlean (BMI </≥ 24 kg/m2) and NAFLD or non-NAFLD (scoring of ultrasonographic fatty liver indicator, US-FLI ≥ 2/<2). Multivariate logistic regression analyses were performed to estimate the odds ratio of having NAFLD among the tertiles of fetuin-A after adjustment. The least square means were computed by general linear models to estimate marginal means of the serum fetuin-A concentrations in relation to the NAFLD groups. The OR of having NAFLD for the highest versus the lowest tertile of fetuin-A was 2.62 (95% CI: 1.72-3.98; P for trend<0.001). Stratifying by BMI, the OR of having lean NAFLD for the highest versus the lowest tertile of fetuin-A was 2.09 (95% CI: 1.09-3.98; P for trend 0.026), while nonlean NAFLD had no significant association with the fetuin-A gradient after adjustments. Fetuin-A was positively associated with lean NAFLD after adjusting for central obesity and insulin resistance.

In this study, grit blasting pretreatment was used to improve the adhesion and corrosion resistance and microhardness of Ni-W/SiC nanocomposite coatings fabricated using conventional electrodeposition technique. Prior to deposition, grit blasting and polishing (more commonly used) pretreatment were used to prepare the surface of the substrate and the 3D morphology of the pretreated substrates was characterized using laser scanning confocal microscopy. The coatings surface and the cross section morphology were analyzed using scanning electron microscopy (SEM). The chemical composition, crystalline structure, microhardness, adhesion, and the corrosion behavior of the deposited coatings were characterized using energy dispersive spectroscopy (EDS), X-ray diffraction (XRD), microhardness tester, scratch tester and electrochemical workstation, respectively. The results indicated that the grit blasting and SiC addition, improved the microhardness, adhesion and corrosion resistance. The Ni-W-SiC nanocomposites pretreated by grit blasting exhibited the best adhesion strength, up to 36.5 ± 0.75 N. Its hardness was the highest and increased up to 673 ± 5.47Hv and its corrosion resistance was the highest compared to the one pretreated by polishing.

Fusarium head blight (FHB) can cause contamination of cereal grain with mycotoxins. Winter wheat is also infected with FHB. It is more resistant than durum wheat to head infection and less than other small grain cereals. The aim of this study was to identify winter wheat lines that combine low head infection and kernel damage with low toxin contamination. Resistance to FHB of 27 winter wheat lines and cultivars was evaluated over a three-year experiment established in two locations. At the anthesis stage, heads were inoculated with Fusarium culmorum isolates. The FHB index was scored and the percentage of Fusarium-damaged kernels (FDKs) assessed. The grain was analysed for type B trichothecenes (deoxynivalenol and derivatives, nivalenol) and zearalenone content. The average FHB index was 12.9%. The proportion of FDK was 6.9% (weight) and 8.5% (number). An average content of deoxynivalenol amounted to 3.543 mg/kg and nivalenol to 2.115 mg/kg. In total, it was 5.804 m/kg of type B trichothecenes. The zearalenone content in the grain was 0.214 mg/kg. Relationships between FHB index, FDK and mycotoxin contents were highly significant for wheat lines; however, they were stronger for FDK versus mycotoxins. Breeding lines combing all types of FHB resistance were found, and five of them had resistance similar to that of wheat lines with the Fhb1 gene.

Antibiotic inefficacy in treating bacterial infections is largely studied in the context of developing resistance mechanisms. However, little attention has been paid to combined diseases mechanisms, interspecies pathogenesis and the resulting impact on antimicrobial treatment. This review will consider the co-infections of Salmonella and Schistosoma mansoni. It summarises the protective mechanisms that the pathophysiology of the two infections confer, which leads to an antibiotic protection phenomenon. This review will elucidate the functional characteristics of the gut microbiota in the context of these co-infections, the pathogenicity of these infections in infected mice, and the efficacy of the antibiotics used in treatment of these co-infections over time. Salmonella-Schistosoma interactions and the mechanism for antibiotic protection are not well established. However, antimicrobial drug inefficacy is an existing phenomenon in these co-infections. The treatment of schistosomiasis to ensure the efficacy of antibiotic therapy for bacterial infections should be considered in co-infected patients.

The present paper investigates numerically the resistance at full-scale of a zero-emission, high-speed catamaran in both deep and shallow water, with the Froude number ranging from 0.2 to 0.8. The numerical methods are validated by two means: a) comparison with available model tests; b) a blind validation using two different flow solvers. The resistance, sinkage and trim of the catamaran, as well as the wave pattern, longitudinal wave cuts and cross-flow fields, are examined. The total resistance curve in deep water shows a continuous increase with the Froude number while in shallow water, a hump is witnessed near the critical speed. This difference is mainly caused by the pressure component of total resistance, which is significantly affected by the interaction between the wave systems created by the demihulls. The pressure resistance in deep water is maximised at a Froude number around 0.58, whereas the peak in shallow water is achieved near the critical speed (Froude number ≈ 0.3). Insight into the underlying physics is obtained by analysing the wave creation between the demihulls. Profoundly different wave patterns within the inner region are observed in deep and shallow water. Specifically, in deep water, both crests and troughs are generated and moved astern as the increase of the Froude number. The maximum pressure resistance is accomplished when the secondary trough is created at the stern, leading to the largest trim angle. In contrast, the catamaran generates a critical wave normal to the advance direction in shallow water, which significantly elevates the bow and creates the highest trim angle as well as pressure resistance. Moreover, significant wave elevations are observed between the demihulls at supercritical speeds in shallow water which may affect the decision for the location of the wet deck.

Background: The extended-spectrum beta-lactamase (ESBL) Klebsiella pneumoniae is one of the leading causes of health-associated infections (HAI), whose antibiotic treatments have been severely reduced. Besides, HAI bacteria may harbor pathogenic factors such as siderophores, enzymes, or capsules, which increase the virulence of these strains. Thus, new therapies such as antimicrobial photodynamic inactivation (aPDI) are needed. Method: A collection of 118 clinical isolates of K. pneumoniae were characterized susceptibility and virulence through the determination of the minimum inhibitory concentration (MIC) of Amk, Cfx, Cfz, Imp, Mer, and Pip-taz, and by PCR, the frequency of the virulence genes, K2, magA, rmpA, entB, ybtS, and allS. Susceptibility to innate immunity, such as human serum, macrophages, and polymorphonuclear cells, was tested. All the strains were tested for sensitivity to the photosensitizer PSIR-3 (4µg/mL) in a 17µW/cm2 for 30 min aPDI. Results: A significantly higher frequency of virulence genes in ESBL than non-ESBL bacteria were observed. The isolates of the genotype K2+, ybtS+, and allS+ display enhanced virulence since they showed higher resistance to human serum as well as to phagocytosis. All strains are susceptible to the aPDI with PSIR-3 decreasing viability in 3log10. The combined treatment with Cfx improved the aPDI to 6log10 for the ESBL strains. The combined treatment is synergistic as it showed an FIC index value of 0.15. Conclusions: The aPDT effectively inhibits clinical isolates of K. pneumoniae, including the more risky strains of ESBL-producing bacteria and the K2+, ybtS+, and allS+ genotype. The aPDI with PSIR-3 is synergistic with Cfx.

Faba bean (Vicia faba L.) was considered a minor crop in the Canadian prairies until recently, but its potential for cultivation is increasing due to its positive environmental impact and economic value. This review provides a historical summary of faba bean improvement in western Canada. Although traditional breeding methods have proved useful, in the last decade faba bean improvement has benefited from advances in genetics, biochemistry and molecular breeding tools. The overall breeding goal is to develop high yielding germplasm with improved agronomic characteristics that will be of economic value to the emerging faba bean sectors, including the plant protein industry. To maximize value and acceptance by producers, processors and the food industry as a source of protein and dietary fibre, future faba bean varieties need to be high-yielding, have diverse seed size classes, disease resistance, genetically low vicine-convicine concentration, and have wider adaptation to different agro-ecological zones of Canada. The experiences over the last 40 years of faba bean improvement in western Canada may be useful to other breeding programs globally located in regions with similar agroecology. In the past 10–15 years, faba bean genetic development in Canada has benefited greatly from research and development interactions with most of the faba bean research programs in northern Europe.

Zinc is a redox-inert trace element that is second only to iron in abundance in biological systems. In cells, zinc is typically buffered and bound to metalloproteins, but may also exist as a labile or chelatable (free ion) form. Zinc plays a critical role in prokaryotes and eukaryotes ranging from structural to catalytic to replication to demise. This review discusses the influential properties of zinc on various mechanisms of bacterial proliferation and synergistic action as anti-microbial element. We also touch upon the significance of zinc among eukaryotic cells and how it may modulate their survival and death through its inhibitory or modulatory effect on certain receptors, enzymes, and signaling proteins. A brief discussion on zinc chelators is also presented and chelating agents may be used with or against zinc to affect therapeutics against human diseases. Overall, the multidimensional effects of zinc in cells attest to the growing numbers of scientific research that reveal the consequential prominence of this remarkable transition metal in human health and disease.

Antibiotic resistance (ABR) is an emerging global threat to public health. Substantial evidence has indicated that community pharmacists (CPs) can play a critical role in managing the ever-increasing threat of antibiotic resistance. The study aimed to determine the knowledge, attitude, and practices of CPs (n=180) towards antibiotics and antibiotic resistance as well as to improve the rational use of antibiotics. Two phases of mixed methods (quantitative and qualitative) online study were conducted in Pakistan from August 2019 to March 2020 by using validated questionnaires and semi-structured interview data. Different statistical methods were used to tabulate the quantitative data whereas inductive thematic analysis was conducted to categorize themes from the qualitative data and draw conclusions. Approximately 64.4% were male (mean: 29-33 years old). Overall, CPs had good knowledge of and were familiar with superbugs and their roles in ABR (65.6%, Median=1, IQR=1) although they were poor in differentiating some antibiotic groups with their respective ABR patterns (31.1%, Median=1, IQR=1). Most CPs have a positive attitude towards antibiotics with most (90.0%) having identified ABR as a critical issue in public health (Median=1, IQR=0). Overall, CPs' practices towards antibiotics were reasonable where they tend to educate patients about the rational use of antibiotics (52.8%, Median=1, IQR=1). Two main themes (antibiotics and counseling of patients) were related to self-medication with while educational interventions are the sub-theme. ABR is multifactorial where the subthemes related to budget, time constraints incompetent staff, the absence of CPs, the lack of training, enforcement of laws and regulations are the need of the hour in Pakistan. Effective antibiotic stewardship programs, patient education, and awareness campaigns about antibiotics and ABR along with training of the CPs are important factors that have to be addressed in a timely manner.

Abstract:Salmonella species (spp) and Escherichia coli (E. coli) are the most common infectious pathogens in poultry. Antimicrobials were given either for the treatment or growth promoters that can increase the possibility of emergence of bacterial resistance towards antimicrobials. The aim of this study was to determine the prevalence of antimicrobial resistant (AMR) Salmonella spp and E. coli isolated from a sample of broiler farms in East Coast Malaysia from 2018-2019. A total of 384 cloacal swabs were collected from broilers farms in Kelantan, Terengganu, and Pahang. The bacteria were isolated and confirmed by bacteriological and serological methods. Following that, confirmed isolates were subjected to antimicrobial susceptibility test. Salmonella spp and E. coli were recovered from the cloacal swabs samples with the overall prevalence of 6.5% and 51.8% respectively. In Kelantan, Terengganu and Pahang, the prevalence of Salmonella spp were 7%, 6.5% and 5.8% respectively, while the prevalence for E. coli were 50%, 48.3% and 58% respectively. Salmonella spp and E. coli displayed resistance towards the following antimicrobials: erythromycin (100% for both pathogens), chloramphenicol (76.2%, 84.5%), tetracycline (62%, 94.6%), ampicillin (47.7%, 87%), sulfamethoxazole/trimethoprim (42.9%, 83.3%), ciprofloxacin (4.8%, 23.8%), nalidixic acid (9.6%, 60.7%), streptomycin (19%,66%), and kanamycin (28.6%,57%), cephalotin (0%, 11%), gentamicin (0%, 20.2%) respectively. No resistance were recorded towards colistin for both pathogens. Multidrug resistance (MDR) was recorded in 82% of Salmonella spp and 100% of E. coli. These findings demonstrate the high prevalence of MDR Salmonella spp. and E. coli in broiler farms in East coast Malaysia. This could be attributed to the excessive use of antimicrobial agents by the poultry farm owners. Enhanced control measures and a strong monitoring system should be urgently implemented to reduce the emergence of antimicrobial resistance that is harmful to public health.

Antimicrobial resistance (AMR) represents a growing crisis in both human and veterinary medicine. We evaluated the use of two categories of antibiotic alternatives – heavy metals and essential oils – in beef cattle, and their effects on gram-negative and gram-positive bacteria. In this randomized controlled field trial, we measured the impact of supplemental zinc and menthol on antimicrobial resistance among commensal enteric bacteria of feeder cattle. Fecal suspensions were plated onto plain- and antibiotic-supplemented MacConkey and m-Enterococcus agar for quantification of total and antimicrobial-resistant Escherichia coli and Enterococcus spp., respectively. Temporal effects on overall E. coli growth were significant (P&lt; 0.05); however, there were no significant effects on antibiotic-supplemented agar. Zinc was associated with significant increases in growth on erythromycin-supplemented m-Enterococcus agar. Cattle fed zinc exhibited significantly higher macrolide resistance among fecal enterococci isolates.

Erlotinib inhibits epithelial growth factor receptor (EGFR) kinase activity and is used to treat non-small cell lung cancer (NSCLC). Despite its high efficacy, recurrence can occur in patients who become resistant to the drug. To address the underlying mechanism of Erlotinib resistance, we investigated additional mechanisms related to mode-of-drug-action, by multiple protein-binding interactions, besides EGFR by using drug affinity responsive target stability (DARTS) and liquid chromatography-mass spectrometry (LC-MS/MS) methods with non-labeled Erlotinib. DNA polymerase alpha subunit B (POLA2) was identified as a new Erlotinib binding protein that was validated by the DARTS platform, complemented with cellular thermal shift assays. Genetic knock-down of POLA2 promoted the anti-proliferative effect of the drug in the Erlotinib-resistant cell line H1299 with high POLA2 expression, whereas overexpression of POLA2 restored anti-proliferative effects in the Erlotinib-sensitive cell line HCC827 with low POLA2 expression. Importantly, POLA2 expression levels in four NSCLC cell lines were positively correlated with anti-proliferative Erlotinib efficacy, verified by bio-statistical analysis (Pearson correlation coefficient, R=0.9886). These results suggest that POLA2 is a novel complementary target protein of Erlotinib, and could clinically provide validity as a surrogate marker for drug resistance in patients with NSCLC.

The prevalence of diabetes mellitus (DM), considered one of the most common metabolic disorders, has dramatically increased and resulted in higher rate of morbidity and mortality around the world, in the past decade. It is well known that insulin resistance in target tissues and a deficiency in insulin secretion from pancreatic β-cells are the main characteristic of type 2 diabetes. The aim of this study was the bio-evaluation of compounds isolated from three selected plant species; namely, Salvia africana-lutea, Leonotis ocymifolia and Plectranthus madagascariensis, for their glucose uptake ability. Methanolic extracts were produced from the arterial part of each plant. Compounds were identified using different spectroscopic techniques. The glucose uptake ability of each compound was then evaluated in mammalian cells using 2-deoxyglucose-6-phosphate. The cytotoxicity of each compound was established via the MTT assay. Chromatographic purification of the three plant species yielded fifteen pure terpenoids. Compounds 1 (p = 0.0031), 8 (p = 0.0053), and 6 (p = 0.0086), showed a marked increase in glucose uptake, with p values of p=0.0031, p=0.0053 and p=0.0086, respectively. Additionally, 1, 4 and 6 exhibited cytotoxicity toward mammalian tissue with a decrease in cell viability of ~70%, ~68% and ~67%, respectively. The results suggested that several compounds demonstrated a marked increase in glucose uptake while two of the compounds exhibited signs of cytotoxicity. It may, therefore, be suggested that these compounds be considered as potential candidates for novel plant-derived alternative therapies in the treatment of type 2 diabetes.

There are overwhelming empirical evidences highlighting the contribution of indiscriminate antibiotic usage (ABU) in food animals to the overall burden of antibiotic resistance (ABR) in humans, thus making antibiotic use the main selective pressure driving antibiotic resistance. Social and behavioral perspective on antibiotic use and resistance in poultry is limited. Our study therefore aimed at obtaining information on antibiotic usage, awareness of ABR, and the attitude and perceptions towards prudent antibiotic usage and ABR. A cross-sectional survey using a structured questionnaire was conducted in 125 poultry farms in Kwara state in December 2019. Most farmers (69.6%, n=87/125) were aware of ABR and had satisfactory knowledge about ABR with a mean knowledge score of 3.16±1.47. The age, gender, level of education of farmers, and their flock size were significantly associated with a satisfactory knowledge of ABR (p<0.05). Tertiary education was significantly associated with ABR awareness (OR: 4.7; 95% CI: 0.0690, 0.654; p=0.007) and the ABR knowledge level (OR: 7.8269; 95% CI: 3.2693, 18.7381; p < 0.01). Higher flock size was significantly associated with a satisfactory knowledge of ABR (OR: 9.4551; 95%CI: 3.7928, 23.5707; p<0.01). Most of the poultry farmers (68%) had positive attitudes towards prudent antibiotic use with a mean score of 2.75±0.89. On the contrary, only 32.8% of poultry farmers had a good perception of ABR with a mean perception score of 4.95±1.12. The ABR knowledge level was significantly associated with the perceptions of farmers (p<0.05) but not their attitudes toward ABU and ABR (P=0.083). There was evidence of unprescribed use of antibiotics in poultry and a failure to observe antibiotic withdrawal periods. These constitute a risk of exposure to unacceptable levels of drug residues from poultry products and an increased risk of ABR. Improving education and communication on antibiotic stewardship programs are crucial to prevent the looming antibiotic apocalypse.

Type 2 diabetes mellitus (T2DM) is an endocrine illness associate with various changes in the immune system and adaptor protein levels. Cytokine dependent hematopoietic cell linker (CLNK) is an adapter protein that regulates immune receptor signaling and acts as a regulator of the receptor signaling of T-cells and natural killer T-cell. The role of CLNK in T2DM is not studied previously. In the present study, serum CLNK level was measured and correlated with some sociodemographic and insulin resistance (IR) parameters. This is achieved by performing measurement of CLNK and insulin parameters (glucose, insulin, and HbA1c in addition to the calculation of the functions of IR (HOMA2IR), insulin sensitivity (HOMA%S), and beta-cell function (HOMA%B)) in 60 T2DM patients and 30 controls. The results indicated a significant increase (p=0.025) in serum CLNK in patients group in comparison with the controls. Multivariate generalized linear model (GLM) analysis revealed no significant effect of age, BMI, and sex on the CLNK level. The results of tests for between-subjects showed that the CLNK affects diagnosis significantly (F=7.445, p=0.008, partial η² =0.081) and its effect is approximately the same as the effect of insulin (F=8.107, p=0.006, partial η² =0.087). The correlation study showed a highly significant positive correlation between CLNK and the duration of disease (rho=0.420, p<0.001). It can be concluded that the increase CLNK in T2DM revealing the role of the adaptor proteins level in the nature of disease. Elevation of CLNK level may be used as a predictor for diabetes complications, which needs more investigations.

Objective: About a third of schizophrenia patients are treatment-resistant to antipsychotic therapy. No studies established the fingerprints or pathway-phenotypes of treatment-resistant schizophrenia. The present study aimed to delineate the pathway-phenotypes of non-responders (NRTT) and partial responders (PRTT) to treatment using machine learning. Methods: We recruited 115 schizophrenia patients and 43 healthy controls and measured schizophrenia symptom dimensions, neurocognitive tests, plasma CCL11, interleukin-(IL)-6, IL-10, Dickkopf protein 1 (DKK1), high mobility group box-1 protein (HMGB1), κ- and µ-opioid receptors (KOR and MOR, respectively), endomorphin-2 (EM-2), and β-endorphin. Results: Machine learning showed that the NRTT group is a qualitatively distinct class and is significantly discriminated from PRTT with an accuracy of 100% using a neuro-immune-opioid-cognitive (NIOC) pathway-phenotype with as main determinants list learning, controlled word association, and Tower of London test scores, CCL11, IL-6, and EM2. The top-5 symptom domains separating NRTT from PRTT were in descending order: psychomotor retardation, negative symptoms, psychosis, depression, and mannerism. Moreover, a NIOC pathway also discriminated PRTT from healthy controls with an accuracy of 100% while all PRTT and controls were authenticated as belonging to their respective classes. Conclusion: A non-response to treatment with antipsychotics is determined by increased severity of specific symptom profiles coupled with deficits in executive functions, and episodic and semantic memory, and aberrations in neuro-immune and opioid pathways. No patients showed complete remission after treatment indicating that non-remitting in PRTT is attributable to increased HMGB1 and residual deficits in attention, executive functions, and semantic memory.

Mutation in the ethionamide (ETH) activating enzyme, EthA, is the main factor determining resistance to this drug, used to treat TB patients infected with MDR and XDR Mycobacterium tuberculosis isolates. Many mutations in EthA of ETH resistant (ETH-R) isolates have been described but their roles in resistance remain uncharacterized, partly because structural studies on the enzyme are lacking. Thus, we took a two-tier approach to evaluate two mutations (Y50C and T453I) found in ETH-R clinical isolates. First, we used a combination of comparative modeling, molecular docking, and molecular dynamics to build an EthA model in complex with ETH that has hallmark features of structurally characterized homologs. Second, we used free energy computational calculations for the reliable prediction of relative free energies between the wild type and mutant enzymes. The ΔΔG values for Y50C and T453I mutant enzymes in complex with FADH₂-NADP-ETH were 3.34 (+/−0.55) and 8.11 (+/−0.51) kcal/mol, respectively, compared to the wild type complex. The positive ΔΔG values indicate that the wild type complex is more stable than the mutants, with the T453I complex being the least stable. These are the first results shedding light on the molecular basis of ETH resistance, namely reduced complex stability of mutant EthA.

Wildland-Urban Interfaces (W-UI) are at high risk of wildfires. Defensible spaces and home ignition zones are the two main aspects to protect lives and livelihoods of W-UI in the United States, Canada and Australia. The different part of the world has different rules and regulations for W-UI land management. We have discussed the defensible spaces in fire-prone areas, current ignition zone distances from structures, building materials, architectural design, the fire resistance trees, ground cover, landscaping and some other precautions to save lives and assets in the prominent fire-prone zones for three different countries (United States, Canada and Australia) of the world.

Resistance of tumor cells to anticancer drugs is a major obstacle in tumor therapy. In this study, we investigated the mechanism of cordycepin-mediated resensitization to cisplatin inT24R2, a derived T24 cell line. Treatment with cordycepin or cisplatin (2 g/ml) alone could not induce cell death of T24R2, but combination treatment of these drugs significantly induced apoptosis of the cells through mitochondrial pathway including depolarization of mitochondrial membrane, decrease of anti-apoptotic proteins, Bcl-2, Bcl-xL, and Mcl-1, and increase of pro-apoptotic proteins, Bak and Bax. . High expression of MDR1 was the cause of cisplatin resistance in T24R2, and cordycepin significantly reduced MDR1 expression through inhibition of MDR1 promoter activity. MDR1 promoter activity was dependent on a transcription factor, Ets-1, in T24R2 cells. Although there is a correlation between MDR1 and Ets-1 expression in bladder cancer patients, active Ets-1, Thr-38 phosphorylated form (pThr-38), was critical to induce MDR1 expression. Cordycepin decreased pThr-38 Ets-1 level through inhibition of AKT, which reduced MDR1 transcription and induced the resensitization of T24R2 to cisplatin. The results suggest that cordycepin effectively resensitizes cisplatin-resistant bladder cancer cells to cisplatin, thus serving as a potential strategy for treatment of anti-cancer drug resistant patients.

Background: Schizophrenia and treatment-resistant schizophrenia (TRS) are associated with aberrations in immune-inflammatory pathways. Increased High Mobility Group Protein 1 (HMGB1), an inflammatory mediator, and Dickkopf-Related Protein (DKK1), a Wnt/β-catenin signaling antagonist, affect the blood-brain-barrier and induce neurotoxic effects and neurocognitive deficits.Aim of the study: The present study aims to examine HMGB1 and DDK1 in non-responders to treatments with antipsychotics (NRTT, n=60), partial RTT (PRTT, n=55) and healthy controls (n=43) in relation to established markers of schizophrenia including IL-6, IL-10 and CLL11 (eotaxin); and to delineate whether these proteins are associated with the schizophrenia symptom subdomains and neurocognitive impairments.Results: HMGB1, DKK1, IL-6 and CCL11 were significantly higher in schizophrenia patients than in controls. DKK1 and IL-6 were significantly higher in NRTT than in PRTT and controls while IL-10 was higher in NRTT than in controls. Binary logistic regression analysis showed that schizophrenia was best predicted by increased DDK1 and HMGB1 while NRTT (versus PRTT) was best predicted by increased IL-6 and CCL11 levels. A large part of the variance in psychosis, hostility, excitation, mannerism and negative (PHEMN) symptoms, and formal thought disorders was explained by HMGB1, IL-6, and CCL11 while most neurocognitive functions were predicted by HMGB1, DDK1 and CCL11. Conclusion: The neurotoxic effects of HMGB1, DKK1, IL-6 and CCL11 including effects on the blood-brain-barrier and the Wnt/β-catenin signaling pathway may cause impairments in executive functions, and working, episodic and semantic memory and explain, in part, PHEMN symptoms and a non-response to treatment with antipsychotic drugs.

Preeclampsia (PE) is a common pregnancy complication. It is associated with high maternal morbidity and mortality rates and intrauterine foetal growth restriction. This condition is characterised by high blood pressure and urinary protein levels. Apelin and galectin-3 (Gal- 3) are peptides involved in the regulation of body fluid homeostasis, inflammation and cardiovascular functions. This study aimed to determine the correlations amongst serum apelin and Gal-3 levels and insulin resistance (IR) in women with PE. Sixty patients with PE and 30 healthy controls participated in this study. The PE group had significantly lower apelin levels (p < 0.01) and higher Gal-3 levels (p < 0.05) than the control group. The PE group had higher serum glucose levels and β-cell functions than the control group. Moreover, patients with PE exhibited dyslipidaemia. Correlation analysis indicated that apelin and Gal-3 levels were not significantly correlated. Moreover, no correlation existed between the apelin levels and any measured parameters of the PE group. In conclusion, the elevations in serum Gal-3 levels with increments in IR-related parameters and lipid profiles reflect the possible contribution of Gal-3 to the harmful effects of IR and dyslipidemia levels on women with PE.

Clinical pathogens especially Gram-negative bacteria developing resistance to third-generation cephalosporins are making the clinical outcome more complicated and serious. This study was undertaken to evaluate the distribution of extended-spectrum beta-lactamases in Tamil Nadu regions in India. For this study, clinical samples were collected from five different hospitals located in Tamil Nadu and ESBL producing Gram-negative isolates were characterized. Minimal inhibitory concentration (MIC) was performed using cefotaxime and ceftazidime. The blaESBL producing genes were screened using multiplex PCR for the genes, CTX-M group-1,-2,-8,-9,-26. Conjugation studies were performed using E. coli AB1157 as a recipient for the isolates harbouring plasmid-borne resistance following broth-mating experiment. In total, 1500 samples were collected and 599 Gram-negative bacteria were isolated that included Escherichia coli (n=233), Klebsiella pneumoniae (n=182), Pseudomonas aeruginosa (n=79), Citrobacter spp. (n=30), Proteus mirabilis (n=28), Salmonella spp. (n=21), Acinetobacter baumannii (n=12), Serratia spp. (n=6), Shigella spp. (n=4), Morganella morganii (n=3) and Providencia spp. (n=1). MIC results showed that 358 isolates were resistant to cefotaxime and ceftazidime. Further, ESBL gene amplification results showed that 19 isolates had CTX-M group-1 gene including E. coli (n=16), K. pneumoniae (n=2) and P. aeruginosa (n=1) whereas one M. morganii isolate had CTX-M group-9 gene in their plasmid. Through conjugation studies, 12/20 isolates were found to be involved in the transformation of its plasmid-borne resistance gene. Our study highlighted the role of horizontal gene transfer in the dissemination of plasmid-borne blaCTX-M resistance genes among ESBL producing isolates.

Mealybugs cause economic loss to vineyards through physical damage, fouling fruit and leaves with honeydew, and the transmission of viruses. Planococcus ficus is one of several mealybug species in vineyards, and one that causes economic damage over a relatively large global range. To develop novel management tools, host resistance to P. ficus, which has not previously been identified for any grape cultivars, was studied. Ten grape lines (species, cultivars, and rootstocks) were evaluated for P. ficus resistance across two separate potted plant assays. Significant differences were detected among cultivars and rootstocks in the recorded number of P. ficus juveniles, adults and egg sacs. Cabernet Sauvignon and Chardonnay were two of the most susceptible grape cultivars for mealybug population growth, whereas rootstocks IAC 572, 10-17A and RS-3 all demonstrated some level of resistance. Southern fire ant (Solenopsis xyloni) was positively associated with mealybug populations, but did not have a negative effect on the observed presence of other arthropod species including potential predators.

Plant pathogens utilize effectors to subvert host cell biology for facilitating infection. However certain effectors, called as the avirulence proteins, trigger immune responses in the host. AvrPi54 is an avirulence protein from fungus Magnaporthe oryzae which induces the defense reactions in rice cells that contain Pi54 resistance gene. The characterization of such proteins and elucidation of their function facilitate the understanding of the mechanism of disease establishment. In present study, physiochemical properties of AvrPi54 were analysed using computational methods. We found that mature AvrPi54 is a small, hydrophobic and secretary protein with 134 amino acids. It is rich in small amino acids with no significant homology with other proteins in databases. The gene ORF was cloned in pET28a(+) vector and expressed in E. coli BL21(DE3)pLysS. The protein was purified using affinity chromatography. Transient expression of the gene in epidermal cells of onion bulb is a powerful tool to predict the subcellular localization in plant cells. We fused AvrPi54 to eYFP and transformed epidermal cell layer of onion bulb. Fused protein localized to the plasma membrane and nucleus of plant cells. Therefore, AvrPi54 might be functioning in the host cell as transcription factor or chromatin remodelling factor to modify pathogenesis-related processes.

With the increasing use of genome sequencing as a surveillance tool for molecular epidemiology of antimicrobial resistance (AMR), databases and clear nomenclature for AMR gene families are critical. Due to the convoluted nomenclatural history of the integron-associated trimethoprim-resistant dihydrofolatereductase (dfr) gene family, we decided to conduct a literature review, comparative sequence analysis, and phylogenetic investigation of the dfr family, the results of which are presented here and available at the Comprehensive Antibiotic Resistance Database (CARD). Overall, literature review and phylogenetic analysis resolved gene name synonyms based on sequence. We recommend adoption of phylogenetic methods to help guide AMR gene naming efforts and relegation of misleading names to synonyms.

Background: The maximal one-repetition test (1-RM) is widely used in scientific research; however, there are conflict results regarding its reproducibility in elderly population. The present study aimed to analyze the reproducibility the test both before and after a 12 week training period by using the bench press and leg press 45° 1-RM tests in the elderly taking into consideration the training experience and strength level of the women. Methods: Elderly women (n = 376; age, 68.5 ± 14.1 years; height, 162.7 ± 5.5 cm; body mass, 71.2 ± 16.0 kg) who underwent ≥3 months of resistance training performed an initial week of familiarization and a second week of testing and retest, with a 48–72 hour interval. Results: The results showed maximal and relative load strength of 39.3 kg and 0.59 kg/body mass for lower limbs and 20.9 kg and 0.31 kg/body mass for upper limbs. The Kappa indices were 0.93 and 0.95, and the intraclass correlation coefficients were 0.99 and 0.99 for the lower and upper limbs, respectively. Conclusion: Therefore, the present study confirms that the 1-RM test has high reliability and reproducibility in the elderly, for both upper and lower limbs.

S100A10, which is also known as p11 is located in the plasma membrane and forms a heterotetramer with annexin A2. The heterotetramer, comprising of 2 subunits of annexin A2 and S100A10, activates the plasminogen activation pathway which is involved in cellular repair of normal tissues. Increased expression of annexin A2 and S100A10 in cancer cells leads to increased levels of plasmin which promote degradation of the extracellular matrix, increased angiogenesis and invasion of the surrounding organs. Although many studies have investigated the functional role of annexin A2 in cancer cells including ovarian cancer, S100A10 has been less studied. We recently demonstrated that high stromal annexin A2 and high cytoplasmic S100A10 expression is associated with a 3.4 fold increased risk of progression and 7.9 fold risk of death in ovarian cancer patients. Other studies have linked S100A10 with multidrug resistance in ovarian cancer, however, no functional studies to date have been performed in ovarian cancer cells. This article reviews the current understanding on S100A10 function in cancer with a particular focus on ovarian cancer.

Identification of recurrent driver mutations in genes encoding tyrosine kinases has resulted in the development of molecularly targeted strategies designed to improve the outcomes for patients diagnosed with acute myeloid leukemia (AML). The receptor tyrosine kinase FLT3, is the most commonly mutated gene in AML, with internal tandem duplications within the juxtamembrane domain (FLT3-ITD) or missense mutations in the tyrosine kinase domain (FLT3-TKD), present in 30%-35% of AML patients at diagnosis. An established driver mutation and marker of poor prognosis, the FLT3 tyrosine kinase has emerged as an attractive therapeutic target, and thus has encouraged the development of FLT3 tyrosine kinase inhibitors (TKIs). However, the therapeutic benefit of FLT3 inhibition, particularly as monotherapy, frequently results in the development of treatment resistance and disease relapse. Commonly, FLT3 inhibitor resistance is induced by the emergence of secondary lesions in the FLT3 gene, particularly in the second tyrosine kinase domain at residue Asp835 (D835) to form a ‘dual mutation’ (ITD-D835). Individual FLT3-ITD and FLT3-TKD mutations influence independent signaling cascades however, currently little is known which divergent signaling pathways are controlled by each of these FLT3 specific mutations, particularly in the context of patients harboring dual ITD-D835 mutations. This review provides a comprehensive analysis of the known discrete and cooperative signaling pathways regulated by each of the FLT3 specific mutations, as well as the therapeutic approaches that hold the most promise for development of more durable and personalized therapeutic approaches targeting mutant FLT3, to improve the treatment of AML.

Here is shown method for the hydraulic solution of a looped gas-pipeline networks. Calculation of presented network is done according to principles of Hardy Cross method. The optimization was carried out by iteration of the pipes diameters, node consumptions are known and flow velocities through pipes have to stand below certain values. Accent is on determination of appropriate friction factor, and on selection of representative equation for natural gas flow under presented conditions in the network. Inappropriate usage of friction factor, equally as inappropriate usage of gas flow equation can lead to inaccurate final results. Here is shown new facts in comparison to previous calculation of gas distribution network in Kragujevac, Serbia which is done in 1994. After the implementation, measurements in situ have performed, and real measured values deviate from calculated. Causes for these errors are investigated, and improved and more accurate procedure is shown.

Conyza canadensis is a species invading large agricultural areas throughout the world, mainly to its ability to evolve herbicide resistance. Specifically, in Hungary, extensive areas have been infested by this species due to the difficulty in controlling it with glyphosate. To corroborate this fact as resistance and not as an incorrect herbicide application, eight suspicious glyphosate-resistant C. canadensis populations from different Hungarian regions were studied. In dose-response assays with glyphosate, the LD50 and GR50 values indicated that populations 1 to 5 were resistant to this herbicide (H-5 population the most resistant). Besides, the shikimic acid accumulation tests corroborated the results observed in the dose-response assays. 11 alternative herbicides from 6 different mode of action (MOA) were applied at field doses as control alternatives on populations H-5 and H-6 (both in the same regions). The H-5 population showed an unexpected resistance to flazasulfuron (ALS-inhibitor). The ALS enzyme activity studies indicated that the I50 for H-5 was 63.3 fold higher compared to its correspondent susceptible population (H-6). Therefore, the H-5 population exhibited multiple-resistance to flazasulfuron and glyphosate, being the first case reported in Europe for this two MOA. For that reason, the other herbicides with different MOA have to be tested here.

The Chagas disease (CD) is an endemic infectious disease in a large part of Latin America. This disease is characterized by the fact of being caused by the parasite Trypanosoma cruzi. Some symptoms of this disease are cardiopathies and gastrointestinal problems. Therefore, the commonly used treatment consists of nitro drugs such as benznidazole and nifurtimox, which target the nitroreductase enzyme that docks to the coenzyme flavin mononucleotide (FMN) and an oxidation-reduction reaction is generated. From this reaction, the nitro chemical function of benznidazole and nifurtimox is reduced to amine. This amine in turn interacts with the parasite´s DNA. In vitro tests experimentally help in the study of the parasite resistance to the drug benznidazole. This fact could explain how nonsynonymous mutations in the nitroreductase (NTR) enzyme do not allow the anchorage of the FMN coenzyme and as a consequence the parasite susceptibility to benznidazole decreases as the drug cannot be reduced. The structural relations from the hybrid Quantum Mechanics-Molecular Mechanics (QM/MM) allow to detect the small changes generated in the system, considering a charge distribution associated with the structure, angle changes, interaction distances, potential surface calculations between the wildtype enzyme and the mutation found.

Oral cancer is a major public health burden worldwide. The lack of biomarkers for early diagnosis has increased the difficulty in managing this disease. Recent studies have reported that neutrophil gelatinase-associated lipocalin (NGAL), a secreted glycoprotein, is upregulated in various tumors. In our study we found that NGAL was significantly downregulated in primary malignant and metastatic tissues of oral cancer compared to normal tissues. The downregulation of NGAL was strongly correlated with the degree of differentiation and stage (I-IV), and can serve as a prognostic biomarker for oral cancer. Tobacco carcinogens were also found to be involved in the downregulation of NGAL. Mechanistic studies revealed that knockdown of NGAL increased oral cancer cell proliferation, survival, and migration, and also induced resistance against cisplatin. Silencing of NGAL activated mTOR signaling and reduced autophagy by the LKB1-AMPK-p53-Redd1 signaling axis. Moreover, cyclin-D1, Bcl-2, and MMP-9 were upregulated, and caspase-9 was downregulated, suggesting that silencing of NGAL increases oral cancer cell proliferation, survival, and migration. Thus, from our study it is evident that downregulation of NGAL activates the mTOR pathway and helps in the progression of oral cancer.

Lung adenocarcinoma with EGFR-TKI (epidermal growth factor receptor-tyrosine kinase inhibitor) resistance was reported to harbor higher ability of invasion and migration than those sensitive to EGFR-TKI, but the function of MMPs (matrix metalloproteinases) has not been explored in EGFR-TKI resistant lung adenocarcinoma. In this study, the correlation between immunohistochemical status of MMP-1 and clinicopathological factors were analyzed in 89 lung adenocarcinoma. We performed microarray, migration assay and invasion assay using EGFR-TKI sensitive cell lines and EGFR-TKI resistant cell lines. To clarify the mechanism of MMP-1 induction, we treated lung adenocarcinoma cells with EGF and rapamycin, performed phosphorylation antibody array and analyzed the correlation between MMP-1 expression and EGFR or mTOR (mammalian target of rapamycin) pathway. As a result, we firstly demonstrated that MMP-1 played an important role in migration and invasion abilities of EGFR-TKI resistant lung adenocarcinoma, and that mTOR pathway could be associated with an induction of MMP-1. We demonstrated the significant positive correlation between MMP-1 status in lung adenocarcinoma cells and the history of smoking, and the subtype of invasive mucinous adenocarcinoma. In conclusion, This study provides insights into the development of a possible alternative therapy manipulating MMP-1 and mTOR signaling pathway in EGFR-TKI resistant lung adenocarcinoma.

Triple negative breast cancer (TNBC) is associated with a generally poor prognosis due to its highly aggressive and metastatic nature, lack of targetable receptors, as well as the frequent development of resistance to chemotherapy. We previously reported that AU1, a small molecule developed as an inhibitor of BPTF (bromodomain PHD finger containing transcription factor), was capable of sensitizing preclinical models of triple negative breast cancer to chemotherapy, in part via the promotion of autophagy. In studies reported here, we identify an additional property of this compound, specifically that sensitization is associated with inhibition of the P-glycoprotein efflux pump. In silico molecular docking studies indicate that AU1 binds to active regions of the efflux pump, in a manner consistent with inhibition of pump function. This work identifies a novel chemical structure that can influence multidrug efflux, an established mechanism of drug resistance in triple negative breast cancer, that has not yet been successfully addressed by clinical efforts.

A new clothing resistance model is described and applied to characterize the human thermal and moisture climates. The climate was described by the thermal (rcl,t) and evap-orative (rcl,e) resistances of comfortable, imaginary clothing. The key input variable of the model is the rate of sweating (λEsw). Since sweating is an individual-specific process, the model applies to the individual. The observations were carried out by a single individual in Martonvásár (Hungarian lowland, Central Europe) in the summer of 2023 and the winter of 2024. During the observations, the observer walked at a speed of 1.1-1.7 ms-1 in weather-appropriate clothing. Among the results, we would highlight the following: Dur-ing large environmental heat surpluses, the rcl,t values were found to be between 0.1-0.5 clo-t (clo-t = 0.155 m2·℃·W-1), while the rcl,e values fell between 0.4-0.8 clo-e (clo-e = 0.155 m2·hPa·W-1). The values of the parameters close to 0 were caused by intense sweating (λEsw > 200 Wm-2). The applicability of the model is limited and largely depends on the rela-tionship between λEsw and the metabolic heat flux density.

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.

Objectives: To compare the effects of high-velocity resistance training to slow-velocity re-sistance training on neuromuscular and functional parameters and to analyze the relationship between changes in walking speed and improvements in neuromuscular parameters following intervetions. Methods: 40 participants were randomly assigned to either a high-speed resistance training group (GHS, n = 18; age = 80.41 ± 10.12 years; BMI = 23.81 ± 3.45 kg/m²) or a low-speed resistance training group (GLS, n = 22; age = 82.89 ± 5.32 years; BMI = 23.81 ± 3.45 kg/m²). Before and after the interventions, gait speed (m/s) was assessed using a 10-minute walking test, and relative maximal force (Relative F max, N/kg) was evaluated during maximal voluntary isometric con-traction of the plantar flexors. From the force-time curve, early (0 – 50 ms) and late (100 – 200 ms) rates of force development (RFD) were extracted from the linear slopes (Δ force / Δ time). Results: Gait speed significantly improved in both groups (p < 0.05). However, the improvement was more pronounced in the GHS compared to the GLS (p < 0.05). Relative Fmax showed a more significant increase in the GLS than in the GHS (p < 0.05). Moreover, a significant 10% increase in early RFD in the GLS and a 20.1% increase in the GHS were observed (p < 0.05). The improvement in early RFD was greater in the GHS (p < 0.05). Additionally, late RFD improved significantly only in the GHS (+20.4%, p < 0.05). Conclusion: High-velocity resistance training appears particularly effective in improving the ability to rapidly generate force, which is essential for many daily activities re-quiring explosive movements and quick responses.

This study evaluates the antimicrobial efficacy of chitosan nanoparticles (CNP), varying in size, against E. coli, S. aureus, E. faecalis, C. albicans, and clinical isolates of Mycobacterium tuberculosis (MTB), as well as the antimicrobial effects of aqueous extracts and lyophilized powders of Allium (garlic) species. CNP were synthesized through ionotropic gelation and characterized by Z potential, hydrodynamic diameter (Dynamic Light Scattering, DLS) and SEM. Aqueous garlic extracts were prepared via decoction. We assessed antimicrobial activity using disk diffusion and broth microdilution methods; besides a modified agar proportion method in blood agar was used for antimicrobial activity against MTB. CNP inhibited MTB growth at 300 μg for 116.6 nm particles and 400 μg for 364.4 nm particles. The highest antimicrobial activity was observed against E. faecalis with nanoparticles between 200 and 280 nm. Allium sativum extract produced inhibition for C. albicans at 100 μg. The results indicate that CNP possess significant antimicrobial properties against a range of pathogens, including MTB, at high concentrations. On the other hand, aqueous Allium sativum extracts exhibited antimicrobial activity, but given their instability in solution, the use of lyophilized Allium sativum powder is preferable.

Direct-acting antivirals (DAAs) revolutionized therapeutics of chronic hepatitis C. The emergence and transmission of HCV variants with resistance-associated substitutions (RASs) can undermine HCV treatment. This study aimed to assess the prevalence and temporal trends of RASs in HCV with a particular focus on the clinically-relevant RASs (cr-RASs). Near-complete HCV GenBank sequences archived in the Los Alamos HCV Database were analyzed. The study period was divided into two phases; before 2011 and 2011 onwards. Identification of RASs across three DAA classes; NS3, NS5A, and NS5B inhibitors was based on the 2020 EASL guidelines. The AASLD-IDSA recommendations were used to identify cr-RASs for three HCV genotypes/subtypes (1a, 1b, and 3) for four DAA regimens; ledipasvir/sofosbuvir; elbasvir/grazoprevir; sofosbuvir/velpatasvir; and glecaprevir/pibrentasvir. The final HCV dataset comprised 3443 sequences and the prevalences of RASs were 50.4%, 60.2%, and 25.3% in NS3, NS5A, and NS5B, respectively. In subtype 1a, resistance to ledipasvir/sofosbuvir was 32.8%, while resistance to elbasvir/grazoprevir was 33.0%. For genotype 3, resistance to sofosbuvir/velpatasvir and glecaprevir/pibrentasvir was 4.2% and 24.9%, respectively. Significant increase in cr-RASs was observed across the two study phases as follows: for ledipasvir/sofosbuvir in subtype 1a, cr-RASs increased from 30.2% to 35.8% (p=0.019); for elbasvir/grazoprevir in subtype 1a, cr-RASs increased from 30.4% to 36.1% (p=0.018); In subtype 1b, neither ledipasvir/sofosbuvir nor elbasvir/grazoprevir showed any cr-RASs in the first phase, but both were present at a prevalence of 6.5% in the second phase (p&lt;0.001); for sofosbuvir/velpatasvir in genotype 3, cr-RASs increased from 0.9% to 5.2% (p=0.006); and for glecaprevir/pibrentasvir, cr-RASs increased from 12.0% to 29.1% (p&lt;0.001). Rising prevalence of HCV RASs and cr-RASs was discernible. This highlights the necessity for ongoing surveillance and adaptation of novel therapeutics to manage resistance effectively. Updating of the clinical guidelines and treatment regimens are recommended to counteract the evolving resistance to DAAs.

Preventing or treating infections at implantation sites where the risk of bacterial contamination is high requires the development of intelligent drug delivery systems. In this work, honeycomb structures as a potential drug carrier were obtained for the first time in a fast, one-step anodization process of titanium grade 4, lasting only 60 seconds. Fourth generation oxide nanotube layers were obtained from an aqueous solution of 0.5% AgNO3 in the voltage range from 50 to 80 at 15(1) °C. The FE-SEM method showed the length of the oxide nanotubes from 1.02(2) µm at 50 V to 230(8) nm at 80 V. The EDS analysis revealed that during anodizing, silver particles are deposited on the Ti G4 up to 2.2(5) wt.%. Electrochemical measurements by open circuit potential and anodic polarization curves methods proved the improvement of in vitro corrosion resistance as a result of Ti G4 anodizing. Assessment of the anodized Ti G4 as gentamicin sulfate carrier carried out using ATR-FTIR and UV-VIS absorption spectroscopy revealed that the obtained oxide nanotube layers can be used for application of drugs directly to the tissue around the implant. This method of application allows full use of the therapeutic dose of the antibiotic used.

The exponential rise of bacterial resistance poses a threat to antibiotic efficacy, with a great impact on public health. This study aims to analyze the correlation between antibiotic consumption and the emergence of bacterial resistance. Conducted retrospectively at Charles Nicolle Hospital in Tunis, Tunisia from 2010 to 2022, this study was based on STKMED® software for antibiotic consumption data, hospital administrative records for the number of hospitalization days, and SIRSCAN® software for bacteriological data. Data processing was performed using Excel® software, and analysis was conducted using SPSS23®. In 2022, Consumption was almost evenly split between the two major “AWaRe” groups, with 49.33% for "Access" and 46.89% for "Watch", and the consumption of the "Reserve" group also increased, accounting for 3.77% of the total. Bacterial resistances, notably carbapenem-resistant Klebsiella pneumoniae, increased. Seventy-four significant correlations were identified, including those be-tween carbapenem consumption and resistance in Escherichia coli and Klebsiella pneumoniae strains. However, no significant corre-lation was observed with imipenem-resistant Pseudomonas aeruginosa strains. The significant correlations between the emergence of bacterial resistance and antibiotic use, particularly with antibiotics in the "Watch" and "Reserve" groups, underscore the urgent need to continue efforts to combat this threat through rational antibiotic use.

Melatonin, a naturally occurring chemical, has pleiotropic effects across various species. It plays a vital role in animals by regulating the body clock, while in plants, it is known to resist aging. Melatonin is associated with various plant physiological processes, including stress response, plant growth, and flowering time. It has prospects in enhancing and promoting plant growth and development, as well as in strengthening crop yield and increasing sustainability in agriculture. This review summarized the potential roles of melatonin in several plant species, as well as its biosynthetic modes. In addition, we described the recently uncovered melatonin features in plants, summarized the issues and challenges facing plant melatonin research and some feasible solution ideas are proposed.

Aim: We estimated the correlation between serum bilirubin concentrations and insulin resistance in advanced maternal age without diabetes mellitus. Method: The cross-sectional study involved consecutive 50 women of advanced maternal age without diabetes mellitus, and insulin resistance (IR) was diagnosed according to the homeostatic model assessment insulin resistant (HOMA-IR) formula and the cut-off point was set to more than 2.5. Serum bilirubin and HOMA-IR were compared between the IR (+) and IR (-) groups. Results: We found that serum bilirubin levels in the IR subjects were significantly decreased compared to those without IR (p = 0.0252). Serum bilirubin concentrations were negatively correlated with the weight and the fasting insulin concentrations in all subjects (r=−0.282, p=0.047, r=-0.424, p=0.002). Additionally, serum bilirubin had a negatively correlation with HOMA-IR (r = -0.410, p = 0.003) in all subjects. The multiple linear regression analysis found that serum total bilirubin levels were independently correlated with HOMA-IR (beta = -0.392, p= 0.015) in these subjects. Conclusions: The study demonstrated that serum bilirubin concentrations had negatively correlation with insulin resistance in advanced pregnant women without diabetes mellitus, and decreased serum bilirubin may forebode increased gestational diabetes mellitus risk in our study population.

M184V is a single-base mutation in the YMDD domain of reverse transcriptase (RT). The M184V resistance-associated mutation is related to virological unresponsiveness to lamivudine (3TC) and emtricitabine (FTC) and induces high-level resistance to these two antiretroviral agents. M184V is rapidly selected in the setting of non-suppressive antiretroviral therapy (ART) and accumulates in the HIV reservoir. There were continuous efforts to evaluate the impact of M184V mutation on the treatment outcomes in people with HIV (PWH). Since lamivudine remains an extensively used part of recommended antiretroviral combinations, M184V is commonly detected in patients with virological failure. ART guidelines do not recommend the use of drugs impacted by resistance-associated mutations as they have been confirmed to comprise a risk factor for virological failure. However, previous authors suggest that 3TC/FTC can remain active even in the presence of M184V. Obtaining the viral resistance profile for each individual both treated or ART-naïve is a key challenge for lifelong treatment management.Given the potential benefits of lamivudine in the ART combinations, the investigation of M184V remains of high interest for clinicians and researchers. This is a review of literature for the challenges in treating both naïve and experienced individuals carrying the M184V resistance mutation, including virological failure, virological suppression, and resistance to ART.

Antimicrobial resistance (AMR) is a major public health threat linked to increased morbidity and mortality. It has the potential to return us to the pre-antibiotic era. Antimicrobial stewardship (AMS) programs are recognized as a key intervention to improve antimicrobial use and combat AMR. However, implementation of AMS programs remains limited in Africa, particularly in Rwanda. This qualitative study, conducted at King Faisal Hospital (KFH) in Rwanda, aimed at assessing current prescription practices to identify areas for improvement and promote adherence to AMS principles. The interviews were recorded, transcribed, and thematically analyzed, revealing four emerging themes. First, emerged on AMS activities that were working well which includes availability of microbiology laboratory results, and prescription guidelines as factors influencing antibiotic prescription adjustments. Second, Implementations challenges to AMS which identified the prescription of broad-spectrum antibiotics, limited local data on AMR patterns, stock-outs of essential antibiotics, Thirdly, the importance of adhering to AMR management guidelines at KFH was underscored. Lastly, participant recommendations centered on regular training for healthcare workers, widespread dissemination of AMR findings across departments, and the enforcement of antibiotic restriction policies. These actions can improve prescription behaviors, upholding the highest standards of patient care, and strengthening the nascent AMS program.

The spread of antimicrobial resistance (AMR) is a global challenge. Close and continuous surveillance for quick detection of AMR can be difficult, especially in remote places. This narrative review focuses on the contributions of pharmacovigilance (PV) as an auxiliary tool for identifying and monitoring the ineffectiveness of, resistance to, and inappropriate use of antibiotics (ABs). The terms “drug ineffective,” “therapeutic failure,” “drug resistance,” “pathogen resistance,” and “multidrug resistance” were found in PV databases and dictionnaires, and denote ineffectiveness. These terms cover a range of problems that should be better investigated because they are useful in warning about possible causes of AMR. “Medication errors,” especially those related to dose and indication, are highlighted in the literature, suggesting inappropriate use of ABs. Hence, the included studies show that the terms of interest related to AMR are not only present but frequent in PV surveillance programs. This review illustrates the feasibility of using PV as a complementary tool for antimicrobial stewardship activities, especially in scenarios where other resources are scarce.

The performance of Yttrium-Barium Copper Oxide (YBCO) high-temperature superconductors in high-frequency applications is significantly affected by the microwave surface resistance (Rs). The paper delves into the basics, measuring methods and factors affecting the resistance (Rs) in YBCO, highlighting its high critical temperature (Tc) and low resistance, positioning it as a promising material. YBCO's compatibility with epitaxial growth and microstructure engineering offers opportunities to reduce grain boundary effects and improve Rs, making it advantageous for high-frequency electronics, communication systems, and MRI coils. This is due to its high critical current density (Jc) and exceptional Rs at practical temperatures. Challenges remain in comprehending and managing Rs in YBCO, despite its favorable characteristics. Utilizing advanced fabrication methods and incorporating nanotechnology allow for customization of YBCO-based devices. Multi-scale modeling and simulation are essential for guiding experimental work and understanding YBCO's performance in high-frequency settings. This study highlights the promise of YBCO for future high-frequency technologies and stresses the importance of more research to overcome hurdles and fully exploit its capabilities, potentially transforming superconducting devices for practical use.

Enterococcus faecalis is a growing cause of nosocomial and antibiotic-resistant infections. Treating drug-resistant E. faecalis requires novel approaches. The use of bacteriophages (phages) against multidrug-resistant (MDR) bacteria has recently garnered global attention. Biofilms play a vital role in E. faecalis pathogenesis as they enhance antibiotic resistance. Phages eliminate biofilms by producing lytic enzymes, including depolymerases. In this study, Enterococcus phage vB_Efs8_KEN04 (ФKEN04), isolated from a sewage treatment plant in Nairobi, Kenya, was tested against clinical strains of MDR Enterococcus faecalis. This phage had a broad host range against 100% (26/26) of MDR E. faecalis clinical isolates and cross-species activity against Enterococcus faecium. It was able to withstand acidic and alkaline conditions, from pH 3 to 11, as well as temperatures between -80ᵒC and 37ᵒC. It could inhibit and disrupt the biofilms of MDR E. faecalis. Its linear double-stranded DNA genome of 142,402 bp contains 238 coding sequences with a G+C content and coding gene density of 36.01% and 91.46%, respectively. Genomic analyses showed that ФKEN04 belongs to the genus Kochikohdavirus in the family Herelleviridae. It lacked antimicrobial resistance, virulence, and lysogeny genes, and its stability, broad host range, and cross-species lysis indicate strong potential for the treatment of Enterococcus infections.

Lean body mass (LBM) is correlated with powerlifting performance in athletes competing in different bodyweight classes. However, it remains unknown whether changes in LBM are correlated with performance changes in powerlifters preparing for a competition. Aim of the study was to investigate the changes in LBM and performance in powerlifters preparing for a competition. Eight male powerlifters (age 31.7±9.8years, height 1.77±0.06m, weight 99.2±14.6kg) and three female powerlifters (age 32.7±16.3years, height 1.54±0.06m, weight 66.6±20.9kg), participated in the study. Athletes followed individualized periodized training programs for 12 weeks aiming to maximize their performance for the national championship. Maximum strength (1-RM) in squat, bench press, and deadlift, body composition, grip strength, anaerobic power, quadriceps’ cross sectional area and vastus lateralis muscle architecture were measured before and after the training period. Significant increases were found after the training period in squat (5.8±7.0%, P

Probiotics play an important role as immunostimulants in improving growth and health status in fish. However, little is known on the effects of probiotics when fish offered a low fish meal diet. This study evaluated the effects of three probiotic bacteria isolated from the fish intestine to replace antibiotics in a reduced fish meal diet fed to the juvenile olive flounder Paralichthys olivaceus. A basal diet without feed additives was used as a control (CON) and five other diets were formulated by supplementation with Bacillus subtilis WB60 (BSWB60) at 1×108 CFU/g, B. subtilis SJ10 (BSSJ10) at 1×108 CFU/g, Enterococcus faecium SH30 (EFSH30) at 1×107 CFU/g, amoxicillin (AMO) at 4 g/kg and oxytetracycline (OTC) at 4 g/kg of the basal diet. Triplicate groups of 25 fish averaging 12.1±0.09 g (mean±SD) were fed one of the six experimental diet groups for 8 weeks. Then, 45 fish from each group were intraperitoneally injected with the pathogenic bacteria, Edwardsiella tarda, and mortality was recorded for 14 days. At the end of the feeding trial, weight gain, specific growth rate and feed efficiency of fish fed the BSWB60 diet were significantly greater than those of fish fed the CON, OTC and AMO diets (P &lt; 0.05). Furthermore, feeding efficiency and protein efficiency ratio of fish fed the BSWB60 diet were significantly greater than those of fish fed the CON, OTC and AMO diets. However, there were no significant differences in survival, hepatosomatic indices, viscerosomatic indices and condition factors among the fish fed the experimental diets. The whole-body proximate composition of the fish was unaffected by the dietary treatments. The serum biochemistry parameters, such as aspartate aminotransferase levels were significantly greater in fish fed the BSSJ10 diet than in those fed the BSWB60 diet. However, serum alanine aminotransferase, glucose and total protein levels were not significantly affected by the experimental diets. The lysozyme activity of fish fed the BSSJ10, BSWB60 and EFSH30 diets was significantly greater than that of the CON, OTC and AMO diets. The myeloperoxidase activity of fish fed the BSWB60 diet was significantly greater than that of the fish fed the CON and AMO diets. The flounder growth hormone levels of fish fed the BSSJ10, BSWB60, EFSH30 and AMO diets were significantly greater than that of the fish fed the CON diet. The interleukin 1β (IL-1β) gene expression levels in fish fed the BSSJ10 and EFSH30 diets were significantly greater than those in fish fed the CON, OTC and AMO diets. The interleukin 10 (IL-10) gene expression levels in fish fed the BSSJ10, BSWB60, EFSH30 and OTC diets were significantly greater than those of fish fed the CON and AMO diets. Intestinal histology revealed that the average villus length of fish fed the BSSJ10, BSWB60, and EFSH30 diets was significantly greater than that of fish fed the CON, OTC and AMO diets. The cumulative survival rates of fish fed the EFSH30 and BSWB60 diets were significantly greater than those of fish fed the CON diet after the 15th day of the challenge test. Overall, the results of the present study demonstrated that the supplementation of autochthonous bacteria, B. subtilis (108 CFU/g diet) or E. faecium (107 CFU/g diet) in the diet could be ideal probiotics to replace antibiotics based on growth performance, the serum biochemical composition, immune responses and disease resistance in olive flounder fed a low fish meal diet..

Rice, as a staple crop feeding billions, faces constant threats from various diseases jeopardizing global food security. Precise understanding of disease resistance mechanisms is crucial for developing resilient rice varieties. Traditional genetic mapping methods, such as QTL mapping, provide valuable insights into the genetic basis of diseases. However, the complex nature of rice diseases demands a holistic approach to gain accurate knowledge of it. Omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, enable a comprehensive analysis of biological molecules, uncovering intricate molecular interactions within the rice plant. Integration of various mapping techniques using multi-omics data has revolutionized our understanding of rice disease resistance. By overlaying genetic maps with high-throughput omics datasets, researchers can pinpoint specific genes, proteins, or metabolites associated with disease resistance. This integration enhances the precision of disease-related biomarkers with better understanding of their functional roles in disease resistance. Improvement of rice breeding for disease resistance through this integration represents a significant stride in agricultural science because better understanding of the molecular intricacies and interactions underlying disease resistance architecture leads to more precise and efficient development of resilient and productive rice varieties. In this review, we explore how the integration of mapping and omics data can give a transformative impact on rice breeding for enhancing disease resistance.

Abstract: Lung cancer, characterized by its heterogeneity, presents a significant challenge in ther-apeutic management, primarily due to the development of resistance to conventional drugs. This resistance is often compounded by the tumour’s ability to reprogram its metabolic pathways, a survival strategy that enables cancer cells to thrive in adverse conditions. This review article ex-plores the complex link between drug resistance and metabolic reprogramming in lung cancer, offering a detailed analysis of the molecular mechanisms and treatment strategies. It emphasizes the interplay between drug resistance and changes in metabolic pathways, crucial for developing effective lung cancer therapies. The review examines the impact of current treatments on metabolic pathways and the significance of considering metabolic factors to combat drug resistance. It highlights the different challenges and metabolic alterations in non-small cell lung cancer and small cell lung cancer, underlining the need for subtype-specific treatments. Key signalling pathways, including PI3K/AKT/mTOR, MAPK, and AMPK, have been discussed for their roles in promoting drug resistance and metabolic changes, alongside the complex regulatory networks involved. The article evaluates emerging treatments targeting metabolism, such as metabolic inhibitors, dietary management, and combination therapies, assessing their potential and challenges. It concludes with insights into the role of precision medicine and metabolic biomarkers in crafting personalized lung cancer treatments, advocating for metabolic targeting as a promising approach to enhance treatment efficacy and overcome drug resistance. The review underscores ongoing advancements and hurdles in integrating metabolic considerations into lung cancer therapy strategies.

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.

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.

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.

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.

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.

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.

Superficial mycoses, encompassing a range of fungal infections affecting the outer layers of the skin, hair, and nails, have become increasingly prevalent in recent years. While these infections are generally non-life-threatening, the emergence of antifungal resistance poses a growing threat to effective treatment strategies. In this article we explore the escalating specter of antifungal resistance in superficial mycoses, focusing on the underlying mechanisms driving resistance, the clinical implications, and potential avenues for mitigation. The rise of antifungal resistance in superficial mycoses is multifactorial. Consequently, the efficacy of conventional treatments is diminishing, leading to persistent or recurrent infections. Understanding the molecular mechanisms underlying antifungal resistance is crucial for developing targeted therapeutic approaches. Research efforts aimed at unraveling these mechanisms are essential for identifying new drug targets and designing innovative treatment strategies to combat resistant strains. In response to the escalating threat of antifungal resistance, a multifaceted approach is required. This includes enhanced surveillance of antifungal susceptibility patterns, the development of novel antifungal agents, and the implementation of stringent guidelines for antifungal use. Additionally, educational initiatives targeting healthcare professionals and the public are essential to promote responsible antifungal use, reduce the risk of resistance emergence, and improve treatment outcomes.

This review centers on the pivotal role of the oncoprotein FOSL1, within the dimeric AP-1 transcription factor consisting of FOS-related elements. FOSL1 emerges as a key regulator governing invasion and metastatic dissemination, therefore making it a promising target for therapeutic intervention in cancer patients. The review provides a comprehensive survey of the regulatory mechanisms that exert influence over FOSL1. These encompass a spectrum of transcriptional and post-translational modifications. Notably, we unveiled the intricate involvement of diverse non-coding RNAs, specifically microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), in the modulation of FOSL1 expression through targeted interactions with its mRNA transcripts. Furthermore, an exploration into the functional dimensions of FOSL1 unfolds, encompassing apoptosis, proliferation, and migration. This investigation is accompanied by a thorough examination of the elaborate signaling pathways that underpin these multifaced roles. Additionally, emphasis is placed on the role of FOSL1 in orchestrating the stimulation of various cytokines, including TGF-beta, and the initiation of IL-6 and VEGF production in tumor-associated macrophages (TAMs) that transverse into the tumor microenvironment. A distinct focus is dedicated to appraising the prognostic implications associated with FOSL1. Finally, insights emerge into the evolving roles of FOSL1 in the context of mechanisms governing resistance and dependency on targeted therapeutic modalities.

This study conducted an extensive analysis of campylobacteriosis surveillance in Portugal from 2009 to 2021, aiming to investigate demographic shifts, seasonal variations, and antimicrobial resistance (AMR) within Campylobacter isolates. Surveillance network and sentinel laboratory-based system data revealed a substantial under-notification of campylobacteriosis cases, suggesting an underestimated disease burden. A paradigm shift was observed in notification rates, with a notable prevalence among the pediatric population, particularly in children aged 1-4 years, diverging from European reports. However, the study also highlighted an emerging trend of Campylobacter infections in younger adults (15-44 years). The study unveiled a unique seasonal distribution of cases, defying typical summer peaks seen elsewhere. AMR analysis revealed extremely to very high-level resistance to ciprofloxacin and tetracycline, both in C. jejuni (93.7% and 79.2%, respectively) and in C. coli (96.5% and 93.2%, respectively), stable throughout the studied period (2013-2021). C. coli also exhibited significantly higher resistance to erythromycin, gentamicin, ampicillin, amoxicillin-clavulanic acid (decreased resistance), and ertapenem compared to C. jejuni (P&lt;0.001). In conclusion, the study highlights the need for enhanced surveillance efforts and emphasizes worrying AMR levels. The implementation of WGS-based surveillance is recommended to attain a more profound comprehension of disease patterns and the evolving landscape of AMR.

Tungsten carbide (WC) was well known as a wear-resistant material. Iron-based pow-der was suitable for remanufacturing of cast iron engine parts. To improve the wear resistance of the remanufactured iron-based cast iron engine parts, WC-Co was intro-duced into iron-based powders to prepare composite coatings for cast iron engine components. In this work, FeAlC-x(WC-Co) composite coatings were prepared by plasma transfer arc on compacted graphite cast iron. The influences of WC-Co con-tents in the Fe-AlC-x(WC-Co) composite coatings on the microstructure and properties of the composite coatings were investigated. The composite coatings contained γ-Fe, α-Fe, WC and Fe3W3C mainly. The microhardness of FeAlC-x(WC-Co) composite coatings had the highest hardness of 814 HV0.2, the-lowest coefficient of 0.5 and the lest wear mass loss of 1.3mg when the weight content of WC-Co in the composite coating was 20wt%. As compared with the FeAlC coating, FeAlC-x(WC-Co) composite coating achieved the effect of reducing friction and wear resistance simultaneously, which resulted from the self-lubricating effect of graphite and high wear-resistance of carbides in the claddings.

Research is scarce regarding antimicrobial use and antimicrobial resistance (AMR) for specific localities in Northern Ireland (NI). Additionally, the effects of COVID-19 on antimicrobial pre-scribing patterns and AMR are unknown. Between the European Union (EU) and United States (US), AMR causes approximately 68,000 deaths annually. This study will provide a better understanding of antimicrobial use and prescribing patterns in Belfast and link with AMR. An electronic survey was developed and distributed to eighty-five community pharmacists in Belfast. Yearly and monthly prescription data was gathered from the Business Services Organisation and COVID-19 statistics from Gov.uk. All data was analysed on Microsoft Office Excel® and IBM® SPSS® Statistics 25. Overall response rate was 46%. Most pharmacists (82%) failed to address prescriber non-compliance with guidelines and antimicrobial dosing errors (59%). The most common in-dication for antibiotics was upper respiratory tract infections (URTIs). Overprescribing of anti-biotics was perceived as the leading cause of AMR, therefore 69% of pharmacists indicated in-creased General Practitioner (GP) compliance with guidelines would reduce AMR. Pharmacists’ are in an ideal position to reduce AMR through patient education however, it is demonstrated that pharmacists failed to adequately counsel patients on antibiotic use. All GP practices demonstrated inappropriate antibiotic use, especially for URTIs which suggests antibiotic appropriateness should be reviewed. Many patients avoided contact with GP’s during COVID-19 which may have resulted in reduced antibiotic use. This research established amoxicillin as the most commonly prescribed antibiotic, which is contributing to increased AMR with its broad-spectrum activity and has recognised a decrease in antibiotic prescribing during COVID-19. Based on the results found and a critical review of the literature it is recommended antimicrobial guidelines should be re-viewed and improved, enhanced training should be provided to pharmacists and the antibiotic guardian (AG) campaign should be reenergised.

Although conventional chemotherapeutic drugs are the first line of treatment for cancer, they have numerous side effects. One of the emerging challenges in cancer treatment is drug resistance. Nat-ural compounds have proven effective against various hallmarks of cancer for their multi-target inhibition properties, but especially for their ability to synergistically bypass low bioavailability. Methods: The present study investigated the in vivo antitumor effects of a combination of two natural dietary agents, epigallocatechin-3-gallate (EGCG) from Camelia Sinensis and curcumin, a component of turmeric (Curcuma longa). We aimed to compare, for the first time in vivo, the antiangiogenic and antitumor effects of sunitinib with the combination of curcumin and EGCG in a mouse model of renal cell carcinoma (ccRCC). It was shown that they are able to inhibit cell survival, proliferation of several type of cancer, including renal cell carcinoma (ccRCC), by mod-ulating different signaling pathways and that their combination respect to single compound syn-ergistically decreased angiogenesis. Results: Herein, we highlighted that these compounds inhib-ited the growth of xenografted renal cancer in nude mice by significant inhibition of tumor vol-ume, tumor weight and CD31 expression with no signs of hepatic toxicity. Moreover, mice treated with these natural compounds showed a significant reduction in angiogenesis and an improve-ment in survival rate with p<0.05. Finally, pretreatment of mice with a diet containing 0.6% curcumin before injection of tumor cells showed a significant inhibition of tumor engraftment in 60% of mice with respect to controls and other groups. Conclusions: Taken together, our data in-dicate, for the first time, that the combination of curcumin and EGCG acts in a synergistic manner to inhibit the growth and angiogenesis of ccRCC and with less toxicity than sunitinib and provide an important rationale for future clinical development for chemoprevention and treatment of re-nal cancer.

Salmonella infection is one of major challenges to the poultry industry because of its pressing effects on health of poultry, food safety and human well-being that later may devastate economic losses to the poultry sector. The paper reviews public health implications and the use of antibiotics together with the risk of drug resistance. In recent years, the usage of probiotics in poultry industry has been growing to mitigate an increasing pressure to adopt sustainable farming practices. The mechanisms which probiotics may control Salmonella and important criteria for selecting effective probiotics in poultry are reported. Various studies highlighting the additional benefits of probiotics in poultry production in addition to Salmonella controls are also included. While probiotics offer promise in enhancing poultry health, challenges and limitations in their utilization must also be carefully considered.

Type 2 diabetes (T2D) has a complex pathophysiology which makes modeling the disease difficult. We aimed to develop a novel model for simulating T2D in vitro, including hyperglycemia, hyperlipidemia, and variably elevated insulin levels targeting muscle cells. We investigated insulin resistance (IR), cellular respiration, mitochondrial morphometry and the associated function in different T2D -mimicking conditions in rodent skeletal (C2C12) and cardiac (H9C2) myotubes. Physiological controls included 5mM glucose with 20mM mannitol as osmotic controls. To mimic hyperglycemia, cells were exposed to 25mM glucose. Further treatments included insulin, palmitate, or both. After short-term (24h) or long-term (96h) exposure, we performed radioactive glucose uptake and mitochondrial function assays. Mitochondrial size and relative frequencies were assessed by morphometric analyses using electron micrographs. C2C12 and H9C2 cells treated short- or long-term with insulin and/or palmitate and HG showed IR. C2C12 myotubes exposed to T2D -mimicking conditions showed significantly decreased ATP-linked respiration and spare respiratory capacity, and less cytoplasmic area occupied by mitochondria, implying mitochondrial dysfunction. In contrast, H9C2 myotubes showed elevated ATP-linked and maximal respiration and increased cytoplasmic area occupied by mitochondria, indicating better adaptation to stress and compensatory lipid oxidation in a T2D environment. Both cell lines displayed elevated fractions of swollen/vacuolated mitochondria after T2D -mimicking treatments.Our stable and reproducible in vitro model of T2D rapidly induced IR, changes in ATP-linked respiration, shifts in energetic phenotypes, and mitochondrial morphology, which are comparable to the muscles of patients suffering from T2D. Thus, our model should allow studying disease mechanisms, potential new targets, and screen candidate therapeutic compounds.

This article explains how resistance alleles have become rare or have disappeared from honey bee populations in Europe (and probably also in North America). Honeybees have the highest recombination frequency of all animals, indicating that pathogenic bacteria, viruses, fungi and microsporidia are an important source of selection. To respond to new virulent strains of pathogens, honeybees need to have access to rare alleles that could foster immunity against a new pathogen. By mating in a large panmictic population, new rare alleles can be recruited, which can then be combined into new genotypes through recombination with useful alleles of other genes. Bee breeders, by selecting small samples from a large population tend to select common alleles and lose the rare ones. Rare alleles can become important when a new virulent pathogen arrives. The loss of rare alleles makes bees vulnerable to disease and parasites and explains, together with the problems caused by modern agriculture, why managed bees have high mortality rates.

Excessive use of antibiotics to control colibacillosis on poultry farms in Morocco contributes to the development of multiresistant avian pathogenic E. coli. Autogenous vaccines are an alternative to antibiotic usage; the main goal of this study was to assess the efficacy of this approach to control recurrent outbreaks of colibacillosis in a large broiler production flow. A tetravalent autogenous vaccine (serotypes O78, O88, O91, and O185) was produced from E. coli strains isolated from clinical lesions in breeding hens and used on two farms (65,000 breeding hens in total). On each farm, contemporaneous groups were included: groups vaccinated twice (12 and 18 weeks of age) and unvaccinated control groups. The performances of these flocks, as well as the performances of broilers hatched from these breeders (12 farms, over 600,000 broilers in total), were recorded. A significant reduction in lesion scores, mortality rate and a significant increase in the number of saleable day-old chicks were observed among vaccinated hens. In broilers, body weight at slaughter, lesion scores, food conversion ratio, mortality and condemnation rates were significantly improved. This is the first field observation of a lasting effect of breeder hens immunization with an autogenous vaccine against E. coli on their offspring.

The effect of plasma electrolytic nitrocarburizing on the wear resistance of carbon tool steel in friction couples with hardened steel and lead-tin bronze is considered. The microgeometry of friction tracks and its change with increasing duration of friction tests are analyzed. The equilibrium roughness is determined, which is optimal for the friction couple and ensures minimal wear. The type and mechanism of wear of carbon tool steel after plasma electrolytic nitrocarburizing has been determined. The optimal values of the plasma electrolytic nitrocarburizing parameters, which provide the lowest values of the friction coefficient and weight wear, have been determined. The phase and elemental composition of the surface layer was studied using X-ray diffraction analysis and EDX analysis. The relationship of the microstructure of the nitrocarburized layer of tool steel with the friction coefficient and weight wear is established.

The effect of ferromagnetic CaMnO3 (CMO) addition on structural, magnetic, dielectric, and ferroelec-tric properties of BiFeO3 are presented. X ray diffraction and Raman investigation allowed the identifi-cation of single pseudo cubic perovskite structure. The magnetic measurement showed that the pre-pared films exhibit a ferromagnetic behavior at low temperature with both coercive field and remnant magnetization increased with increasing CMO content. However, a deterioration of magnetization was observed at room temperature. Ferroelectric study revealed an antiferroelectric like behavior with a pinched P-E hysteresis loop for 5%CMO doping BFO resulting in low remnant polarization and double hysteresis loops. Whereas, high remnant polarization and coercive field with a likely square hysteresis loop are obtained for 10 % CMO addition. Furthermore, a bipolar resistive switching behavior with a threshold voltage of about 1.8V is observed for high doped film that can be linked to the ferroelectric polarization switching.

Indoor residual spray (IRS), mainly employing pyrethroid insecticides, is the most common intervention to prevent malaria transmission in many regions of Latin America; the use of long-lasting insecticidal nets (LLINs) has been more limited. Knockdown resistance (kdr) is a well-characterized target-site resistance mechanism associated with pyrethroid and DDT resistance. Most mutations detected in acetylcholinesterase-1 (Ace-1) and voltage-gated sodium channel (VGSC) genes are non-synonymous, resulting in a change of amino acid leading to non-binding of the insecticide. In the present study, we analyzed target-site resistance in Nyssorhynchus darlingi, the primary malaria vector in the Amazon, in multiple malaria endemic localities. We screened 988 wild-caught specimens of Ny. darlingi from three localities in Amazonian Peru and four in Amazonian Brazil. Collections were conducted between 2014-2021. Criteria were Amazonian localities with a recent history as malaria hotspots, primary transmission by Ny. darlingi and the use of both IRS and LLINs as interventions. Fragments of Ace-1 (456 bp) and VGSC (228 bp) were amplified, sequenced and aligned with Ny. darlingi sequences available in GenBank. We detected only synonymous mutations in the frequently reported Ace-1 codon 280 known to confer resistance to organophosphates and carbamates, but detected three non-synonymous mutations in other regions of the gene. Similarly, no mutations linked to insecticide resistance were detected in the frequently reported codon (995) at the S6 segment of domain II of VGSC. The lack of genotypic detection of IR mutations by sequencing the Ace-1 and VGSC genes from multiple Ny. darlingi populations in Brazil and Peru could be associated with low-intensity resistance, or possibly the main resistance mechanism is metabolic.

Transferrin (TF) is a key iron carrier protein. Studies in human cohorts and in cultured adipocytes suggested that decreased transferrin expression and intracellular iron in adipocytes leads to impaired insulin responsiveness and causes differential expression of genes involved in metabolism, insulin action, and obesity. While suggestive, these studies did not definitively prove in an intact organism that altering TF expression in adipocytes is sufficient to affect glucose homeostasis and insulin resistance. In this study we created a mouse model of decreased transferrin expression only in adipocytes (Trf+/-Cre+/-) to test the hypothesis that iron trafficking in adipose tissue is sufficient to affect insulin sensitivity. Area under the glucose curve (AUCg) after intraperitoneal glucose administration was increased in the Trf+/-Cre+/- mice compared to wild type (WT) mice on a normal chow diet, and the mice were slightly heavier (p=0.02 for both). Homeostasis Model of Insulin Resistance (HOMA-IR) values were also significantly higher in the Trf+/- Cre+/- mice (p<0.05). Thus, supporting our hypothesis, analysis of mice with decreased expression of TF restricted to adipocytes showed that a decrease in adipocyte TF is sufficient to affect insulin resistance, weight, and glucose homeostasis.

The bean weevil (Acanthoscelides obtectus (Say.)) is one of the main pests of stored beans in the world. Heterogeneous Inbreed Families (HIF) Population of Near Isogenic Lines (NILs) could be an exceptional strategy to study the inheritance of the resistance against A. obtectus. We developed a HIF population of NILs of R-bufa-80-12 (Phaseolus vulgaris) to study the inheritance related to bean weevil resistance and to search NILs with high resistance to the pest within the HIF population. The objective of this research was to study the inheritance in a HIF population and to identify the best lines to provide weevil resistance in bean breeding for commercial genotypes that could reduce pesticide applications. To achieve this objective, we developed a set of 148 NILs which were near-homozygous in the genome, except in the region under study. The HIF were evaluated in two environments under natural infestation with A. obtectus in free choice bioassays in a warehouse highly infested. The population showed wide variability for the traits studied, from 17.2 to 29.2 g for 100 seed weight, 0.0-0.8 for consumption in grams, 2.0-30.0 for consumption in percent and 1.2-9.6 for preference (number of adults in the bottle to the end of the experiments. The heritabilities for resistance traits were from very low to low 0.0 to 0.19. The heritability for 100 seed weight was the highest, with a value of 0.90. All traits studied in this research have a normal distribution, so they are considered to be quantitatively inherited. However, a great variability was found for the traits studied, which allows selecting lines with a high level of resistance within the R-bufa-80-12 HIF population. All traits studied in present research are of quantitative inheritance. The best lines of the HIF population for resistance to A. obtectus were the Line-45, Line-129, Line-124, Line-108 and Line-47.

Vanadium is a well-known essential trace element, which usually exists in oxidation states in form of vanadate cation intracellularly. The pharmacological study of vanadium begins at the discovery of its unexpected inhibitory effect on ATPase. Thereafter, the protective effects on cells and the abilities in glucose metabolism regulation were observed from vanadium compound, leading to the application of vanadium compounds in clinical trials for curing diabetes. Alzheimer’s dis-ease (AD) is the most common dementia disease in elderly people. However, there is still no efficient agents for treating AD safely to date. This is mainly because of the complexity of the pathology, which are characterized by the senile plaques composed by amyloid-beta (Aβ) protein in the parenchyma of brain and the neurofibrillary tangles (NFTs) derived from hyperphosphorylated tau protein in neurocyte, along with mitochondrial damage, and eventually the central nervous system (CNS) atrophy. AD was also illustrated as type-3 diabetes, because of the observations of insulin deficiency and the high level of glucose in cerebrospinal fluid (CSF), as well as the im-paired insulin signaling in brain. In this review, we summarized the advance of applicating vanadium compound on AD treatment in experimental research and pointed out the limitation of the current study on using vanadium compounds in AD treatment. We hope it will help the future study in this field.

Antimicrobial resistance (AMR) has a significant global impact on human, animal, and environmental health. Misuse and overuse of antibiotics in clinical and animal production settings are the main drivers behind the emergence of antimicrobial resistant bacteria. However, other compounds with antimicrobial activity may also contribute to this global public health problem. The aim of this comprehensive review is to provide detailed insights into the impact of metals and organic acids on the emergence and spread of AMR in the food chain, for which their role is not fully understood. The review examines the widespread use of organic acids in the food industry as feed additives or disinfectants, the crucial role of copper in animal growth and the harmful effects of mercury and arsenic as pollutants in food-producing environments. Additionally, it explores the antimicrobial mechanisms of metals and organic acids, the tolerance mechanisms developed by bacteria, and the interplay between genes responsible for metal tolerance and AMR. The comprehensive and integrated data presented highlights the need to further explore and understand the role of metals and organic acids as drivers of AMR to develop well-defined strategies effectively mitigating the AMR crisis within the food chain context.

Ditching-rotary tiller was widely used in tillage and ditching furrow during rapeseed sowing. As its ditching furrow system (consist of four identical ditching plows) would bear great drag resistance from the soil during operation, the ditching plow was optimized based on differential geometry analysis and EDEM simulation. Resistance-velocity simulation indicated the plow with parabolic type guide curve had better reduce-drag characteristics. Differential geometry analysis indicated decay rate of E and growth rate of G could represent the variable regularity of drag resistance with the increase of velocity. The L value could represent the magnitude of drag resistance. The smaller L value, decay rate of E and growth rate of G, the better drag-reduce characteristics. Quadratic rotation orthogonal combination design shown the optimal structural parameter values were: Δθ=15°, θmin=45°, h=250mm, l=100mm. The minimum average drag resistance was 230.1N. The differential geometry analysis of optimal ditching plow shown |dE/dκ| and |dG/dκ| could obtain minimum value, indicating growth rate of drag resistance for optimal plow was the lowest within the experimental level. Field experiment indicated the operation effect of optimized ditching furrow system could met the requirements of rapeseed sowing. The research provided in-depth theoretical guidance for Drag-reduce design of plow.

The emergence of CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, has revolutionized the treatment landscape for hormone receptor-positive breast cancer. These agents have demonstrated significant clinical benefits in terms of both progression-free survival and overall survival. However, resistance to CDK4/6 inhibitors remains a challenge, limiting their long-term efficacy. Understanding the complex mechanisms driving resistance is crucial for the development of novel therapeutic strategies and improvement of patient outcomes. Translational research efforts, such as preclinical models and biomarker studies, offer valuable insight into resistance mechanisms and may guide the identification of novel combination therapies. This review paper aims to outline the reported mechanisms underlying CDK4/6 inhibitor resistance, drawing insights from both clinical data and translational research in order to help direct the future of treatment for hormone receptor positive metastatic breast cancer.

Arterial hypertension is a common condition worldwide and an important risk factor for cardio- and cerebrovascular events, renal diseases as well as microvascular eye diseases. Established hypertension leads to chronic vasoconstriction of small arteries as well as to decreased lumen diameter and thickening of the arterial media or wall with a consequent increased media-to-lumen ratio (MLR) or wall-to-lumen ratio (WLR). This process, defined as vascular remodeling, was first demonstrated in small resistance arteries isolated from subcutaneous biopsies and measured by micromyography, and this is still considered the gold-standard method for the assessment of structural alteration in small resistance arteries; however microvascular remodeling seems to represent a generalized phenomenon. An increased MLR may impair organ flow reserve, being relevant in the maintenance and, probably, also in the progressive worsening of hypertensive disease, as well as in the development of hypertension-mediated organ damage/cardiovascular events, possessing, therefore, a prognostic relevance. New, non-invasive techniques, such as Scanning Laser Doppler Flowmetry or Adaptive Optics, are presently under development, focusing mainly on the evaluation of WLR in retinal arterioles; recently, also retinal microvascular WLR was demonstrated to have a prognostic impact in term of cardio- and cerebrovascular events. A rarefaction of capillary network has also been reported in hypertension which may contribute to flow reduction and impairment in oxygen delivery to different tissues. These microvascular alterations seem to represent an early step in hypertension-mediated organ damage since they might concur to microvascular angina, stroke, and renal dysfunction. In addition, they could be a marker useful in monitoring the beneficial effect of antihypertensive treatment. Also conductance arteries may be affected by a remodeling process in hypertension, and a cross-talk may exist between structural changes in the small and large arteries. The review will address the possible relations between structural microvascular alterations and hypertension-mediated organ damage and their potential improvement with antihypertensive treatment.

The concept of omics-based technological approaches has promoted translational research by integrating knowledge from diverse areas to understand their dynamics by exploring the molecular mechanisms underlying various processes paving the way for further improvements in the crops quality by providing sound knowledge on controlling plant diseases. This area is not profoundly investigated a decade back and hence this knowledge has become exceedingly important in modern times as it has got potential for being utilized in crop improvement programs. In this review, the contributions of different omics technologies including genomics, transcriptomics, proteomics, and metabolomics in understanding and materializing the ways involved in the plant pathogen interaction (PPI) is discussed. Furthermore, opportunities, challenges, and perspectives of omics linked to signaling mechanisms have also been highlighted that are significantly linked to plant-microbe interactions.

This study aimed to determine the pathogenicity of the bacteria isolated and characterized from the kpètè kpètè used to produce two fermented beers in Benin. Species were identified by specific biochemical tests such as catalase, coagulase, and API 20 E. Antibiotic sensitivity was tested according to the French Society of Microbiology Antibiogram Committee. The crystal violet microplate technique and conventional PCR evaluated biofilm production to identify genes encoding virulence and macrolide resistance. Our data shows that Kpètè Kpètè used to produce beers are contaminated by Enterobacteriaceae species (Klebsiella terrigena, Enterobacter aerogens, Providencia rettgeri, Chryseomonas luteola, Serratia rubidae, and Enterobacter cloacae) and Staphylococcus spp. These multidrug-resistant strains can produce biofilms with a strong predominance of Enterobacter aerogens, Klebsiella terrigena (100%), and Staphylococcus spp (60%). Enterobacter cloacae (4%) and Coagulase negative Staphylococcus (5.55%) harbor the macrolide resistance gene. For other strains, these genes were not detected. Foods contaminated with bacteria resistant to antibiotics and carrying a virulence gene could constitute a potential public health problem. There is a need to increase awareness campaigns on hygiene rules in preparing and selling these traditional beers.

We are living in a business context characterized by change, which today behaves with an unprecedented intensity, driven by the technological revolution and increased competition. As a result, increasingly large and complex companies are facing profound transformation processes in which the role of the human factor and of managers in particular, due to their high capacity to impact the organization, is essential. In response to this reality, the literature has developed a large number of approaches from different areas of knowledge: from business economics to psychology, including technical disciplines. This article offers a classification of these approaches that provides an overview of research on the role of managers in change management.

Acinetobacter baumannii (AB) is a bacterium that causes infections, particularly in immunocompromised patients. Treatment is challenging due to biofilm formation by AB strains, which hinders antibiotic effec-tiveness and promotes drug resistance. The aim of our study was to analyze the biofilm-producing capacity of AB isolates from various forms of infections in relation to biofilm-related genes and their drug resistance. We tested one hundred isolates for biofilm formation using the crystal violet microplate method. Drug re-sistance analyses were performed based on EUCAST and CLSI guidelines, and biofilm genes were detected using PCR. All tested strains were found to form biofilms, with 50% being ICU strains and 72% classified as strong biofilm-producers. Among these, 87% were extensively drug-resistant (XDR) and 2% were extra extensively drug-resistant (E-XDR). The most common gene set was bap, bfmS, csuE, and ompA, found in 57% of all isolates. Our research has shown that, regardless of the form of infection, biofilm-forming strains can be expected among AB isolates. The emergence of E-XDR and XDR strains among non-ICU infections highlights the necessity for the rational use of antibiotics to stop or limit the further acquisition of drug re-sistance by A. baumannii.

Antimicrobial resistance (AMR) is a growing public health concern worldwide, and it poses a significant threat to human, animal, and environmental health. The overuse and misuse of antibiotics have contributed significantly to the emergence and spread of antimicrobial resistance, which may lead to significant economic consequences like reduced productivity and increased healthcare costs. Nanotechnology offers a promising platform for addressing this challenge. Nanoparticles have unique properties that make them highly effective in combating bacterial infections by inhibiting the growth and survival of multidrug-resistant bacteria in three areas of health: human, animal, and environmental. To conduct an economic evaluation of surveillance in this context, it is crucial to have a comprehension of the connections to be addressed by several nations by implementing national action policies based on the One Health strategy. This review provides an overview of the progress made thus far and presents potential future directions to optimize the impact of nanobiotics on AMR.

Japanese apricot (Prunus mume) is a culturally and economically important fruit tree in East Asia. ‘Nanko’, the primary cultivar of the Japanese apricot well known in Japan, usually suffers from scab, a disease caused by Venturia carpophila. Scab results in the development of black spots on the fruit surface, which considerably reduces its commercial value. Despite being an economic concern for Japanese apricot, there have been few reports on the phenotypic variation in scab resistance/susceptibility, the underlying genetic factors, and the development of DNA markers. Therefore, in this study, we performed a comprehensive trait analysis for scab resistance and susceptibility for four years and conducted a genome-wide association study (GWAS) to identify the associated loci. The results showed that significant GWAS peaks were detected in 2017 and 2018. Promising candidate gene encoding domains associated with disease resistance were found at the nine single-nucleotide polymorphisms (SNPs) identified in 2017 and 2018. These SNPs were thought to be associated with scab susceptibility of ‘Nanko’ lineages. These findings shed light on the mechanisms of scab resistance in P. mume and will assist future breeding programs to improve scab resistance in ‘Nanko’ lineages.

Background. The treatment for patients with high-grade gliomas includes radiation therapy and temozolomide. However, some patients do not respond to temozolomide because they have a methylation reversal mechanism through the enzyme O6-methylguanine-DNA-methyltransferase. This biomarker has been used as a prognostic factor in patients receiving treatment with temozolomide. However, not all patients respond in the same way, which suggests the existence of other genes involved in resistance to temozolomide. Materials and Methods. A group of 31 patients with high-grade gliomas was recruited and were clinically, image pattern, and pathologically characterized. The sequencing of 324 genes related to different types of cancer was performed to detect mutations. Subsequently, a statistical analysis was conducted to determine the mutated genes that were most related to resistance to treatment. Results. The genes related to the second relapse of patients with high-grade glioma after the use of temozolomide according to Stupp protocol and metronomic dose were PIK3C2B, KIT, ERBB3, and MLH1. Conclusions. Considering the results obtained, we suggest that the mutations in the four genes and the methylation of the gene promoter that codes for MGMT protein could be related to the clinical evolution of patients with high-grade gliomas and its response to treatment with temozolomide.

Pancreatic ductal adenocarcinoma (PDAC) is still one of the deadliest cancers in Oncology be-cause of its increasing incidence and poor survival rate. More than 90% of PDAC patients are KRAS mutated (KRASmu), with KRASG12D and KRASG12V being the most common mutations. Despite this critical role, its characteristics have made direct targeting of the RAS protein ex-tremely difficult. KRAS regulates development, cell growth, Epigenetically-dysregulated differ-entiation, and survival in PDAC through activation of key downstream pathways, such as MAPK-ERK and PI3K-AKT-mammalian target of rapamycin (mTOR) signaling, in a KRAS-dependent manner. KRASmu induces the occurrence of Acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) and leads to an immunosuppressive tumor microenvironment (TME). In this context, the oncogenic mutation of KRAS induces an epigenetic program that leads to the initiation of PDAC. Several studies have identified multiple direct and indirect inhibitors of KRAS signaling. Therefore, KRAS dependency is so essential in KRASmu PDAC that cancer cells have secured several compensatory escape mechanisms to counteract the efficacy of KRAS inhibitors, such as activation of MEK/ERK signaling or YAP1 upregulation. This review will provide insights into KRAS dependency in PDAC and analyze recent data on inhibitors of KRAS signaling, focusing on how cancer cells establish compensatory escape mechanisms.

The identification of biomarkers is crucial for cancer diagnosis, understanding the underlying biological mechanisms, and developing targeted therapies. In this study we propose a machine learning approach to predict the outcome and platinum resistance status of ovarian cancer patients using public available gene expression data. Six classical machine learning algorithms are compared on their predictive performance. Those with the highest score are analyzed by their feature importance using the SHAP algorithm. We were able to select multiple genes that were correlating with the outcome and platinum resistance status of the patients and validated those using Kaplan-Meier plots. In comparison to similar approaches the performance of the models were higher and different genes using feature importance analysis were identified. The most promising identified genes that could be used as biomarkers are: TMEFF2, ACSM3, SLC4A1 and ALDH4A1.

The aim of this study was to evaluate and compare the fracture resistance of definitive zirconia dioxide restorations obtained using a computer-aided design and manufacturing (CAD/CAM) system. Methods: Two groups of ten samples were analyzed for each material (n: 20), the first group was Zolid Gen X Amann Girrbach (ZGX) and the second group was Cercon HT Dentsply Sirona (CDS). The restorations were designed with identical parameters and milled with a CAD/CAM system. Each specimen was load tested at a speed of 0.5 mm/min with a direction parallel to the major axis of the tooth and with an initial preload of 10N until fracture using a universal testing machine (Universal/Tensile Testing Machine, Autograph AGS-X Series) equipped with a 20 kN load cell. The results obtained were recorded in Newtons (N), using software connected to the testing machine. Results: Statistically significant differences were found, and the fracture toughness of the monolithic zirconia crowns was lower in the CDS group (1744.84 ± 172.8 N), compared to the ZGX group (2387.41 ± 516 N). Conclusions: The monolithic zirconia CAD-CAM zirconia crowns showed sufficient fracture strength to be used in posterior molar and premolar zones with either material as they withstood fracture loads greater than the maximum masticatory force.

Background: Blood flow restriction training (BFRT) uses occlusion during low-intensity resistance training (&lt;50% of repetition maximum, 1RM) to reduce arterial blood flow and venous return, imposing greater metabolic stress but similar muscular hypertrophy and strength gains as high-intensity resistance training (HIRT). However, no study, to date, has incorporated BFRT in a collegiate strength and conditioning setting to assess ecological validity. We aimed to investigate the effects of adding 6-weeks of accessory BFRT or HIRT to NCAA Division III soccer players prescribed resistance training regimen on muscle strength and hypertrophy. Methods: Male and female (n=17) athletes were randomly assigned to complete biceps curls 2x/week under BFRT or control (HIRT), following the regularly scheduled strength training. Bicep strength (1RM) and circumference (BC) were assessed at weeks 0, 3, and 6. Results: In men, no significant interaction between time and condition was observed for BC (p=0.861), though condition (BFRT vs Control, p=0.025) and time (p=0.024) were significant. For 1RM, there was no significant interaction between time and condition (BFRT vs HIRT, p=0.067) or of condition (p=0.598), but there was a significant effect of time (p=0.004). In women, there was no significant interaction between time and condition (p=0.765) or of condition (p=0.971) on BC, but time was significant (p=0.045). For 1RM, there was no significant interaction between time and condition (p=0.227) or of condition (p=0.741), but time was (p=0.018). Conclusion: BFRT induced similar increases in muscle strength and hypertrophy as HIRT in soccer players, suggesting that BFRT could be incorporated into collegiate athlete training.

A novel flexible humidity sensor, incorporating gold nanoparticles (Au NPs) and a trifunctional organosilica compound, has been developed through the integration of sol-gel processing, free radical polymerization, and self-assembly techniques. The trifunctional organosilica was initially synthesized by modifying (3-mercaptopropyl)trimethoxysilane (thiol-MPTMS) with 3-(trimethoxysilyl)propyl methacrylate (vinyl-TMSPMA). Subsequently, a hydrophilic polyelectrolyte, [3(methacryloylamino)propyl]trimethyl ammonium chloride (MAPTAC), was grafted onto the MPTMS-TMSPMA gel. The Au NPs were assembled onto the thiol groups present in the MPTMS-TMSPMA-MAPTAC gel network. The compositional and microstructural properties of the Au NPs/MPTMS-TMSPMA-MAPTAC composite film were investigated utilizing Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). The presence of thiol groups and mesoporous silica skeletons ensured the stability of the humidity-sensing film on the substrate under highly humid conditions, while the hydrophilic groups functioned as humidity-sensitive sites. This innovative humidity sensor demonstrated high sensitivity, acceptable linearity, minimal hysteresis, and rapid response time across a broad range of working humidity levels. Based on the complex impedance spectra analysis, hydronium ions (H₃O⁺) were determined to govern the conductance process of the flexible humidity sensor.

Rapid in vitro assessment of antimicrobial drug efficacy under clinically relevant pharmacokinetic conditions is an essential element of both drug development and clinical use. Here we present an overview of a novel integrated methodology for rapid assessment of such efficacy, particularly against emergence of resistant bacterial strains, as jointly researched by the authors in recent years. This methodology enables rapid in vitro assessment of antimicrobial efficacy of a single or multiple drugs in combination, following clinically relevant pharmacokinetics. The proposed methodology entails (a) automated collection of longitudinal time-kill data in an optical-density instrument; (b) processing of collected time-kill data with the aid of a mathematical model to de-termine optimal dosing regimens under clinically relevant pharmacokinetics for a single or mul-tiple drugs; and (c) in vitro validation of promising dosing regimens in a hollow fiber system. Proof-of-concept of this methodology through a number of in vitro studies is discussed. Future directions for refinement of optimal data collection and processing are discussed.

To explore the effects of pymetrozine on the reproductive behavior of N. lugens, we established a bioassay method to accurately evaluate the toxicity of pymetrozine in N. lugens and establish the level of pymetrozine resistance of N. lugens in the field. In this study, pymetrozine’s effects on the fecundity of N. lugens were evaluated using the topical application method and rice-seedling dipping method. Moreover, the resistance of N. lugens to pymetrozine in a pymetrozine-resistant strain (Pym-R) and two field populations (YZ21 and QS21) was determined using the rice-seedling dipping method and fecundity assay methods. The results showed that treatment of N. lugens third-instar nymphs with LC15, LC50, and LC85 doses of pymetrozine resulted in significantly reduced male fertility and female fecundity. In addition, N. lugens adults treated with pymetrozine using the rice-seedling dipping and topical application method also exhibited significantly in-hibited male courtship, fertility, and female receptivity. Using the rice-stem dipping method, pymetrozine resistance was shown to be at high levels in Pym-R (194.6-fold), YZ21 (205.9-fold), and QS21 (212.8-fold), with LC50 values of 522.520 mg/L (Pym-R), 552.962 mg/L (YZ21), and 571.315 (QS21) mg/L. However, when using the rice-seedling dipping or topical application fe-cundity assay method, Pym-R (EC50: 14.370 mg/L, RR=12.4-fold; ED50: 0.560 ng/adult, RR=10.8-fold), YZ21 (EC50: 12.890 mg/L, RR=11.2-fold; ED50: 0.280 ng/adult; RR=5.4-fold), and QS21 (EC50: 13.70 mg/L, RR=11.9-fold) exhibited moderate or low levels of resistance to pymet-rozine. Our studies show that pymetrozine can significantly inhibit the fecundity of N. lugens. The fecundity assay results showed that N. lugens only developed low to moderate levels of resistance to pymetrozine, indicating that pymetrozine can still achieve effective control on the next gen-eration of N. lugens populations.

Information about molecular mechanism of pesticide resistance in the rust-red flour beetle, a major pest destroying grains and flour across Nigeria is grossly lacking, hindering evidence-based con-trol. Here, we identified to species level three populations of the red-flour beetle from Kano, Ni-geria, as Tribolium castaneum, and investigated the mechanism driving their insecticide resistance. IRAC susceptibility bioassays established high cypermethrin resistance, with LC50s of 4.35-5.46mg/ml in the three populations, NNFM, R/Zaki and Yankaba. High DDT and malathion resistance was observed in NNFM, with LC50s of 15.32- and 3.71mg/ml, respectively. High sus-ceptibility was observed towards dichlorvos in all three populations with LC50s of 0.17-0.35mg/ml, respectively. Synergist bioassay with piperonylbutoxide significantly restored cypermethrin sus-ceptibility, with mortality increasing almost threefold, from 24.8% obtained from 1.25mg/ml of cypermethrin, to 63.3% in synergised group (p=0.013), suggesting a preeminent role of P450s. The two major knockdown resistance (kdr) mutations, T929I and L1014F in the IIS4 and IIS6 fragments of voltage-gated sodium channel were not detected in both cypermethrin-alive and cyperme-thrin-dead beetles, suggesting lesser role of target-site insensitivity. These findings highlight the need to explore alternative control tools for this pest and/or explore incorporation of synergists, like piperonylbutoxide as additional chemistries into pesticides formulations to improve their ef-ficacy.

The emergence of drug-resistant tuberculosis forced the development of new drugs and screnning of more effective or less toxic analogs. Mycolic acids biosynthesis is targeted by several antituberculosis drugs toped by the isoniazid being one of the most important in tuberculosis therapy. Recently, perchlozone, acting on another step in FAS-II cycle, received official approval and was included in the Russian national clinical guidelines. Using the serial dilution method on agar 7H10 plates for perchlozone and Sensititre MYCOTB microdilution plate we analyzed the phenotypic properties of primary M. tuberculosis clinical isolates and analyzed the molecular determinants of resistance to isoniazid, ethionamide and perchlozone. We found a wide variation in the MIC of perchlozone from 2 to 64 mg/L, correlating with the overall resistance profile: the MIC was higher for MDR and pre-XDR isolates. The cross-resistance between the ethionamide and the perchlozone was driven by mutations in ethA gene encoding monooxygenase responsible for activation of both drugs. Presumably susceptible to perchlozone wild-type strains had MICs ranged 2–4 mg/L, and the breakpoint estimated to be at 4 or 8 mg/L. In conclusion, susceptibility to perchlozone retained for a part of MDR strains, as does suceptibility to ethionamide, providing the possibility of therapy for such cases based on phenotypic or molecular analysis.

The replacement of chloroquine with artemisinin-based combination therapies (ACTs) for over a decade has had varying impacts on the ability of malaria parasite to sustain its chloroquine resistance prowess in different malaria-endemic regions. We evaluated the frequency of Plasmodium falciparum chloroquine resistance transporter (PfCRT) mutations in an endemic area of southwest Nigeria 17 years after replacement of chloroquine with ACTs for malaria treatment. Genomic DNA was isolated from dried blood spot samples obtained from 129 patients (aged 1-35 years) with microscopically confirmed P. falciparum infection. PfCRT fragments covering codons 72-76, CVMNK (wildtype) and A220 were amplified and sequenced. Two mutant PfCRT haplotypes on residues 72-76 (CVIET and CVINT) were identified with a prevalence of 18.6% and 2.3%, respectively. Interestingly, the CVINT haplotype was identified for the first time in this region. A220S changes were found in 16.3% of samples occurring concurrently with the CVIET haplotype, while a Q271E mutation occurred in a wildtype isolate. The reduced prevalence of the PfCRT mutant alleles in this study may suggest a gradual disappearance of chloroquine-resistant malaria parasites following reduced drug pressure. It may also be an indicator of the ability of malaria parasites to develop resistance gradually against the current first-line regimen.

Cryptococcus neoformans is a multidrug-resistant human pathogenic yeast responsible for infections in immunocompromised patients. Here, Itraconazole (ITR), a commercial antifungal drug with low effectiveness against C. neoformans, was combined with different synthetic peptides Mo-CBP3-PepII, RcAlb-PepII, RcAlb-PepIII, PepGAT, and PepKAA. The mechanisms of action responsible for the synergistic effect were evaluated for the best combinations by Fluorescence Microscopy (FM). The synthetic peptides enhanced the activity of ITR by 10-fold against C. neoformans. Our results demonstrated that the combinations could induce pore formation in the membrane and overaccumulation of ROS on C. neoformans cells. Our findings indicate that our peptides successfully potentialize the activity of ITR by reducing it by 10-fold to reach antifungal activity against C. neoformans. Therefore, synthetic peptides are potential molecules to act as co-adjuvant agents in treating Cryptococcal infections.

Electrode degradation in continuous resistance spot welding process of BH 220 steel was evaluated by electrode life test, and weldability tests were conducted by geometry features measurement, mechanical property analysis, and electrode diameter measurement with 88 or 176 weld intervals. The analysis of weld geometry shows that the HAZ width, nugget diameter, and nugget area tend to decrease rapidly, while the nugget height tends to firstly increase with the weld repetitions till the welding heat input becomes too small to form the valid nugget. The peak load shows a rapid downward trend, while failure energy and maximum displacement slightly increase till the 176th weld and then decrease. The cavities and pores in the nugget mainly appear after the 176th spot weld. The electrode diameter increases during welding. The reason for the increase in electrode diameter may be that the contact area between the electrode and BH 220 steel sheets becomes smaller in the welding process, which causes the continuous sticking phenomenon between the electrode and the BH 220 steel sheets. In the absence of alloying, the edge of the electrode is geometrically deformed, while Cu-Zn-Fe alloying occurs in the area in contact with the BH 220 steel sheet.

Antibiotic resistance is a pressing global and planetary health challenge. Links between climate change, antibiotic use and the emergence of antibiotic resistance have been well documented, but less attention has been given to the impact(s) of earth systems on specific bacterial livestock diseases at a more granular level. Understanding the precise impacts of climate change on livestock health – and in turn the use of antibiotics to address that ill-health – is important in providing an evidence base to tackle such impacts and to develop practical, implementable and locally acceptable solutions within and beyond current antibiotic stewardship programmes. In this paper, we set out the case for better integration of earth scientists and their specific disciplinary skill set (specifically, problem-solving with incomplete/fragmentary data; the ability to work across four dimensions and at the interface between the present and deep/geological time) into planetary health research. We then discuss a methodology that makes use of risk mapping, a common methodology in earth science but less frequently used in health science, to map disease risk against changing climatic conditions at a granular level. This will enable predictions of future disease risk and risk impacts based on predicted future climate conditions, and thus provide an evidence base for planetary health activists to influence policy and develop mitigations. Our case study – of climate conditions’ impact on livestock health in Karnataka, India – clearly evidences the benefit of integrating earth scientists into planetary health research.

Background: The Ibizan Hound is a canine breed native to the Mediterranean region, where leishmaniasis is an endemic zoonosis. Several studies indicate a low prevalence of this disease in dogs, whereas other canine breeds present a high prevalence. However, the molecular underlaying mechanisms yet remains unknown. Methods: In this study, we analyze the haplotypes of genes encode cytokines related to immune response of Leishmania infantum infection in twenty-four Boxer and twenty-four Ibizan hound apparently healthy using CanineHD DNA Analysis BeadChip including 165,480 mapped positions. Results: The results show that several haplotypes of genes encoding Interleukin 6 (IL6) and Interferon gamma (IFNG) are related to Interferon gamma (IFN-γ), and Interleukins (IL) 2 and 18 serum levels. Our results indicate that the regulation of immune response is different in the two canine breeds analyzed and are related to the haplotype compositions of the genes encoding these cytokines. Conclusions: Future studies are needed to elucidate whether these differences and haplotypes are related to different phenotypes in immune response and expression gene regulation to L. infantum infection in dogs.