Insulin resistance is a prominent pathophysiologic syndrome in a plethora of metabolic disorders including obesity, prediabetes, type 2 Diabetes Mellitus (Ten et al., 2007), impaired glucose tolerance, dyslipidemia, polycystic ovary syndrome and hypercoagulability (Smith & LeRoith, 2004). It is strongly associated with obstructive sleep apnea, hypoventilation syndrome, pancreatitis, nonalcoholic fatty liver disease, steatohepatitis, cirrhosis, gall bladder disease, multiple cancers (breasts, uterus, cervix prostate, kidney, colon, esophagus, pancreas and liver), stroke, cataracts, coronary heart disease, and hypertension. It is also associated with causation of abnormal menses, infertility, polycystic ovary syndrome, osteoarthritis, phlebitis and other venous diseases. Insulin resistance is thought to be caused by intrinsic and extrinsic factors that contribute to its development. Once present, insulin resistance affects the metabolism, behavior, physical appearance and has lasting effects. This paper will review the latest evidence in development of insulin resistance, its pathogenesis and manifestation and its relation to other conditions. The final aim is to raise awareness of its role on diet, metabolic, genetics and microbiome.

HER2/neu positive breast tumors predict a high mortality and comprise 25-30% of breast cancer. We have shown that Flavokawain A (FKA) preferentially reduces the viabilities of HER2 overexpressing breast cancer cell lines (i.e. SKBR3 and MCF7/HER2) versus those with less HER2 expression (i.e. MCF7 and MDA-MB-468). FKA at cytotoxic concentrations to breast cancer cell lines also has minimal effect on the growth of non-malignant breast epithelial MCF10 cells. FKA induces G2M arrest in cell cycle progression of HER2 overexpressing breast cancer cell lines through inhibition of Cdc2 and Cdc25C phosphorylation and down-regulation of Myt1 and Wee1expression leading to increased Cdc2 kinase activities. In addition, FKA induces apoptosis in SKBR3 cells by increasing the protein expression of Bim and BAX and decreasing expression of Bcl₂, Bcl_x/L , XIAP and survivin. FKA also down-regulates the protein expression of HER-2 and inhibits AKT phosphorylation. Herceptin plus FKA treatment leads to enhanced growth inhibitory effect on HER-2 overexpressing breast cancer cell lines through down-regulation of Myt1, Wee1, Skp2, Survivin and XIAP. Our results suggest the promise of FKA as a novel apoptosis inducer and G2 checkpoint abrogating agent in combination with Herceptin for treatment of HER2 overexpressing breast cancer.

This study explored the effects of cryogenic treatment on the microstructure, hardness, and wear-resistance of diamond-like carbon (DLC) by cryogenically treating NAK 80 mold steel coated with DLC. Raman spectroscopy analyzed the structure of the DLC film. Nanoindenter analyzed the hardness and Young’s modulus of the film, and their relationship determined the wear resistance. Wear test assessed the wear rate and friction coefficient of the DLC film. The results showed that cryogenic treatment increased the rate of carbide precipitation and refined the grain structure. Raman spectroscopy indicated that the Raman intensity rate (I_D/I_G) of treated DLC films was smaller than those without cryogenic treatment. When the sp3 bond increased, the hardness and wear-resistance of the DLC film also increased.

The challenge posed by multi-drug resistance (MDR) of pathogenic organisms, spectacularly manifested in the 6 “ESKAPE” bacterium (two Gram-positive, four Gram-negative) species, should invoke new comprehensive strategies, and needs cooperation of scientists with medical, veterinary and natural science background. This review is aimed at informing newcomers, coming from the field of biology and genetics, about problems related to rapidly emerging, new multi-drug resistant, pathogenic, bacteria. Unlike persistence, the antibiotic resistance is inherited. A functioning “resistance gene” makes a susceptible organism resistant to a given antibiotic, encoding for polypeptides capable of acting either as decomposing enzymes, or acting as trans-membrane pumps, or membrane structure components capable of modifying the permeability implementing a «by pass» mechanism enabling the antibiotic molecule to reach its cellular target(s). A functioning “sensitivity gene” encode for a polypeptide, capable (directly or indirectly) of transferring toxic molecules into target cells, or of metabolizing non-transferable to transferable, or non-toxic molecules to toxic derivatives. A gene of a normal function could act as a “sensitivity” gene in the presence of antibiotics of chemical structures similar to the natural substrate of the gene product, (enzyme or binding/ trans-membrane protein). The Agrocin 84 story is a good example. Multi-drug resistance is a phenotypic consequence of the sequential accumulation of mutations, and/or up-take of plasmids or genomic islands carrying resistance genes from the environment via horizontal gene transfer, mediated by conjugative plasmid or bacteriophage carrying mobile genetic elements. Both multi-drug resistance and collateral sensitivity are evolutionary products. Some revealed evolutionary process and their Lamarckian and Darwinian interpretations are discussed. Toolkits of comparative full-genome sequencing, genomics, experimental evolution and population genetics may provide perspectives for overcoming the invincibility of multi-drug panresistance. The status of some recently emerging pathogenic bacterium species with zoonic features and of veterinary background is also discussed.

Sources of resistance to powdery mildew in wild barley (Hordeum vulgare subsp. spontaneum) collected in Jordan, Lebanon, and Libya Jerzy H. Czembor 1, *, Elżbieta Czembor 1 1 Plant Breeding and Acclimatization Institute – National Research Institute (IHAR-PIB), Radzikow, 05-870 Błonie, Poland; [email protected] (E.C.) *Correspondence: [email protected]) Abstract Barley powdery mildew (BPM) is caused by the pathogen Blumeria graminis f.sp. hordei (Bgh). It is an economically important disease and plant pathologists are looking for new sources of resistance to BPM. Barley genetic resources present in gene banks are often a rich source of disease resistance to be used by breeders. These new sources of resistance to BPM are often used in combination (pyramiding) with those that are already used in modern cultivars. Barley accessions, including the wild subspecies Hordeum vulgare subsp. spontaneum (Hvs), are stored in many gene banks and often are a valuable source of economically important characteristics. This source of biodiversity should be more efficiently used to improve barley in the process of plant breeding. However, their proper characterization and availability are urgently needed. The resistance to BPM in 81 accessions of wild barley (Hvs) collected in Jordan (47), Lebanon (23), and Libya (11) was investigated. The seed samples of these accessions were obtained from the ICARDA gene bank and collected in 10 expeditions from 1981 to 1995. Twenty European differential isolates of BPM were used to select accessions with efficient resistance. Thirty-one resistant single plant lines were selected from 15 accessions from Jordan and Libya based on tests performed with the most avirulent isolate of Bgh available. These resistant single plant lines were tested for the presence of specific resistance genes using a differential set of Bgh isolates. After analysis of obtained results, it was concluded that all tested 31 single plant lines of wild barley have genes for resistance that are not represented in the Pallas isolines differential s. Twenty-six lines of Hvs selected from accessions originated in Jordan and Libya showed resistance reaction to all isolates used. Identified new sources of effective resistance to BPM in single plant lines of Hvs will be further tested and used in barley pre-breeding programs. Keywords: Blumeria graminis; resistance genes; resistance; germplasm; gene bank;

Bacterial infections occur when wound healing fails to reach the final stage of healing, usually hindered by the presence of different pathogens. Different topical antimicrobial agents are used to inhibit bacterial growth due to antibiotic failure in reaching the infected site accompanied very often by an increased drug resistance and other side effects. In this review, we focus on antimicrobial peptides (AMPs), especially those with a high potential of efficacy against multidrug-resistant and biofilm-forming bacteria and fungi present in wound infections. Currently, different AMPs undergo preclinical and clinical phase to combat infection-related diseases. AMP dendrimers (AMPDs) have been mentioned as potent microbial agents. Various AMP delivery strategies, such as polymers, scaffolds, films and wound dressings, organic and inorganic nanoparticles, to combat infection and modulate the healing rate have been discussed as well. New technologies such as CRISPR-Cas are taken into consideration as potential future tools for AMP delivery in skin therapy.

Background: While it is established that intravenous catheter placement duration is strongly linked to the risk of catheter colonization and bloodstream infections, there are still substantial knowledge gaps concerning the varying durations of PICC placement that lead to either infection or colonization by common pathogens, particularly MDR pathogens. The present study aims to compare the dwell time required for MDR pathogens to colonize with the time required to cause Central Line-Associated Bloodstream Infections (CLABSIs) in critically ill patients with PICCs and compares it with non-MDR pathogens, shedding light on the significance of preventive procedures to control MDR infections in clinical settings. Methods: Data from critically ill patients with PICCs admitted consecutively to «Metropolitan» Hospital in Athens, Greece, from May 2017 to May 2020 were retrospectively analysed. Results: In this study, 86 hospitalized patients, consisting of 56 (65.1%) males and 30 (34.9%) females, with a mean age of 55.67±21.1 years (range 16-91 years), presented with both CLABSIs and colonization following PICC placements. Specifically, 42 (48.8%) of them presented with CLABSIs, while 44 (51.2%) presented with colonization. Among the total participants, an MDR pathogen was isolated from 26 (30.2%) PICCs, while other pathogens were isolated from 60 (69.8%). The mean duration of catheter dwell time for all participants was 20.94±14.22 days (range 3-72 days). When analysed separately for each group, the dwell time for PICCs with CLABSIs was 25.73±16.19 days and 16.36±10.28 days for those with colonization (T test, p=0.002). Additionally, the mean dwell time for PICCs infected by non-MDROs was 22.48±15.64 days whereas for PICCs with MDROs, it was 17.38±9.5 days (T test, p=0.005). In PICCs with CLABSIs, the mean indwelling time for MDR pathogens was 21.50±12.31 days, while for non-MDROs, it was 27.73±16.98 days (T test, p=0.417). In PICCs with colonization, the mean dwell time for MDR pathogens was 15.55±7.73 days, while for non-MDROs, it was 16.92±11.85 days (T test, p=0.124). Among PICCs with MDR pathogens (n=26), the mean duration in CLABSIs events (n=18) was 21.5±12.31 days and in colonization events 15.55±7.73 days, (n=8) (T test, p=0.146). Conclusions: The present study reveals that colonization of PICCs exhibited a shorter dwell time compared to those with CLABSIs. Moreover, PICCs infected by MDROs had a shorter mean dwell time than those with non-MDROs. These findings underscore the importance of considering infection status and microbial resistance patterns when evaluating PICC dwell times.

In this study we evaluate performance of two American surveillance systems for monitoring the spread of antimicrobial-resistant (AMR) gonorrhea: the Gonococcal Isolate Surveillance Project (GISP) and the enhanced Gonococcal Isolate Surveillance Project (eGISP) which includes the non-urethral isolates in addition to the urethral ones utilized in the original surveillance system. A continuous-time agent-based model of gonorrhea transmission among the US men who have sex with men (MSM) population was developed and used for this purpose. Our results show that the accuracy of eGISP was nearly 10% higher than the accuracy of GISP (97.8% (95% uncertainty interval: 83.5%, 100%) vs. 87.9% (55%, 100%)). Most of time, GISP detects the moment when the resistance to the first-line antibiotic reaches the switch threshold recommended by the WHO later than when it was actually reached. This leads to the additional spread of AMR gonorrhea. We also found that including the extragenital isolates in the surveillance is more important for the accurate monitoring than increasing the number of isolates. Finally, our results demonstrate that rectum and pharynx can serve as a niche for fostering antimicrobial resistance. These findings provide a scientific basis which can be used to inform the decision made by the policymakers on how many GISP and eGISP sites to establish each year.

Estrogen receptor-positive (ER+) breast cancer is common among postmenopausal women and is frequently treated with Letrozole. Letrozole inhibits aromatase from synthesizing estrogen from androgens. Decreased estrogen slows the growth of tumors and can be an effective treatment. Letrozole resistance is increasingly being observed, which poses a unique problem for patients. We reanalyzed transcriptomic data comparing individuals who responded to Letrozole therapy (responders) to those who were resistant to treatment (non-responders). We identified SOX11 and S100A9 as two genes that significantly differed between these patients; with “PLK1 signaling events” being the most significant signaling pathway. We also identified PRDX4 and E2F8 as the top transcriptional biomarkers for ER+ treatment resistance. Many of the other significant gene products play a known role in ER+ breast cancer or other types of cancer, which partially validate our results. Several of the gene products we identified do not have a characterized role in ER+ breast cancer. Our analysis identified a set of genes that warrant further research to elucidate the molecular mechanism of Letrozole resistance in this patient population, as well as novel high-performing biomarkers. We anticipate that these findings could contribute to improved therapeutic outcomes in human patients.

Biotic stressors pose serious threats to crop yield, jeopardizing food security and resulting in over US$220 billion per year losses to the agriculture industry. Plants activate innate defense mechanisms upon pathogen perception and invasion. The plant immune response comprises numerous concerted steps, including the recognition of invading pathogens, signal transduction, and activation of defensive pathways. However, pathogens have evolved various structures to evade plant immunity. Given these facts, genetic improvements of plants are required for sustainable disease management to ensure global food security. Advanced genetic technologies have provided new opportunities to revolutionize and boost plant disease resistance against devastating pathogens. Furthermore, targeting susceptibility (S) genes, such as OsERF922 and BnWRKY70, through CRISPR methodologies offers novel frontiers to disrupt the molecular compatibility of pathogens and introduce durable resistance against them in plants. Here, we provide a critical overview of advances in understanding disease resistance mechanisms. The review also critically examines management strategies under challenging environmental conditions and R gene-based plant genome engineering systems intending to enhance plant responses against emerging pathogens. This work underscores the transformative potential of modern genetic engineering practices in revolutionizing plant health and crop disease management while emphasizing the importance of responsible application to ensure sustainable and resilient agricultural systems.

To mitigate pyrethroid resistance in mosquito vectors of emerging and re-emerging human pathogens, there is an urgent need to discover insecticides with novel modes of action. Natural alternatives, such as extracts derived from plants, may serve as substitutes for traditional synthetic insecticides if they prove to be sustainable, cost-effective, and safe for non-target organisms. Hemp (Cannabis sativa) is a sustainable plant known to produce various secondary metabolites with insecticidal properties, including terpenoids and flavonoids. The goal of this study was to assess the larvicidal activity of hemp leaf extract on 1st instar mosquito larvae from both pyrethroid-susceptible (PS) and pyrethroid-resistant (PR) strains of Aedes aegypti Another goal was to identify which components of the extracts were responsible for any observed larvicidal activity. We found that methanol extract of hemp leaves induced similar concentration-dependent larvicidal activity against PS (LC50: 4.4 ppm) and PR (LC50: 4.3 ppm) strains within 48 hours. Partitioning of the dried leaf extract between methanol and revealed that full larvicidal activity was restricted to the methanol fraction. Analysis of this fraction by gas chromatography-mass spectrometry and nuclear magnetic resonance showed it to be dominated by cannabidiol (CBD). Larvicidal assays using authentic CBD confirmed this compound was primarily responsible for the toxicity of hemp leaf extract against both strains. We conclude that hemp leaf extracts and CBD have the potential to serve as viable sources for the development of novel mosquito larvicides.

Background: Across the world, antibiotic resistance is a grave problem. To address this issue, it is necessary to investigate new antibiotic sources. Aim of the study: Egypt's diverse soil habitats were used to produce bacterial Myxopyronin B, which was then tested for antimicrobial activity in preclinical animal studies and randomized human clinical trials stages 1/2. Type of the study: Screening experimental study. Methodology: Egypt's various soil conditions were examined for the development of bacterial isolates that produced the antibiotic compound Myxopyronin B. Reversed phase HPLC was used to purify Myxopyronin B. To determine the test antibiotic's minimum inhibitory concentration( MIC) and invitro antibacterial activity, the Broth microdilution method and the Paper disc diffusion assay were utilized. Moreover, in vivo antibacterial spectrum, adverse medication responses, and pharmacokinetics were found in preclinical animal testing stages and phases 1/2 of randomized clinical studies involving volunteer humans. Results: Myxopyronin B was generated from the culture supernatant of Myxococcus SDU36, the main soil bacterial isolate cultured on a Casein yeast peptone plate. With MICs less than 100 mcg/ml, the test antibiotic prevented the growth of several Gram +ve bacteria, whereas, at MICs higher than 100 mcg/ml, it inhibited the development of a small number of Gram -ve bacteria, including Escherichia coli. However, eukaryotic cells—such as those found in fungi and humans—were unaffected. The test antibiotic was seen to inhibit prokaryotic DNA-dependent RNA polymerase( RNLP), indicating its bactericidal activity. Mean Cmax was 9-10 mcg/ ml at mean Tmax 1 hour when 600 mg dose was orally administered in randomized human clinical trials phases 1/2, and T1/2 reached 2.25 hours following first-order kinetics of elimination. Duration of its action was nearly 8 hours after oral administration. Rare toxicity was detected during preclinical and randomized human clinical trials phases 1/2 in the form of mild diarrhea and GI upset in less than 7 % of experimental candidates. It exhibited approximately 90% plasma protein binding, especially with albumin which resulted in prolonged therapeutic action. It showed a concentration dependant antibiotic killing effect. With the concentration-dependent killing pattern, the higher the drug concentration relative to the pathogen minimum inhibitory concentration( MIC), the greater the rate and extent of antimicrobial activity. Conclusion: The present study was promising due to the production of the bactericidal antibiotic Myxopyronin B from Myxococcus sp. SDU36 isolated from different soil environments in Egypt.

Background: Across the world, antibiotic resistance is a critical challenge. To address such a problem, it has to be done to investigate new antibiotic sources. Aim of the study: Study of the antibacterial activity of Corallopyronin A in preclinical animal testing and randomized human clinical trials stages 1/2, as well as investigating the purification of Corallopyronin A from different soil conditions in Egypt. Type of the study: Screening experimental study. Methodology: Egypt's various soil conditions were tested to develop bacterial isolates that produced the antibiotic compound Corallopyronin A. Reversed phase HPLC was used to purify Myxopyronin A. The broth microdilution method and the paper disc diffusion assay determined the test antibiotic's minimum inhibitory concentration( MIC) and in vitro antibacterial activity. Moreover, in vivo antibacterial spectrum, adverse medication responses, and pharmacokinetics were found in phases 1/2 of randomized clinical studies involving humans and animal models. Results: Corallopyronin A was generated from the culture supernatant of the soil bacterial isolate Corallococcus coralloides M2, cultivated on a Casein yeast peptone( CYP) plate. The test antibiotic prevented the growth of several Gram-ve bacteria, including Escherichia coli, at MICs higher than 100 mcg/ ml; while blocking the development of many Gram +ve bacteria, with MICs ranging from 3 to 15 mcg/ ml. However, eukaryotic cells—such as those found in fungi and humans—were unaffected. A bactericidal consequence of the test antibiotic was detected in the inhibition of prokaryotic DNA-dependent RNA polymerase( RNLP). Conclusion: The synthesis of the bactericidal antibiotic Corallopyronin A from Corallococcus coralloides M2 isolated from different soil settings in Egypt intrigued the current investigation.

The reduction in rheological parameters and dissolution rate of precursors in geopolymer coatings during early hydration significantly contributes to sagging. This study aims to improve the sag resistance of these coatings by incorporating diatomite filler. Rheological testing was conducted to assess the impact of diatomite and its concentration on yield stress, plastic viscosity, and thixotropy of the geopolymer coatings. The results indicated that diatomite's large specific surface area and high reactivity have a significant influence on the rheological parameters and early dissolution rate of precursors. With a diatomite concentration of 1.1%, the coating exhibited a yield stress of 2.749 Pa and a plastic viscosity of 0.921 Pa·s, maintaining stability, homogeneity, and no sagging at a thickness of 600 μm. Furthermore, the highly active SiO2 in diatomite participates in the secondary hydration reaction of the geopolymer materials, leading to the formation of substantial C-(A)-S-H gel. This gel enhances internal interconnectivity within the coating, thereby improving its rheological and mechanical properties.

Text-based CAPTCHA remains the most widely adopted security scheme, which is the first barrier to securing websites. Deep learning methods, especially Convolutional Neural Networks (CNNs) are the mainstream approach for text-CAPTCHA recognition, which are widely used in CAPTCHA vulnerability assessment and data collection. However, verification code recognizers are mostly deployed on the CPU platform as part of a web crawler and security assessment, they are required to have both low complexity and high recognition accuracy. Due to the specifically designed anti-attack mechanisms like noise, interference, geometric deformation, twisting, rotation, and character adhesion in text CAPTCHAs, some characters are difficult to efficiently identify with high accuracy in these complex CAPTCHA images. This paper proposed a recognition model named Adaptive-CAPTCHA with a CRNN module and trainable and configurable filtering networks, which effectively handle the interference and learn the correlation between characters in CAPTCHAs to enhance recognition accuracy. Experimental results on two datasets of different complexity show that compared with the baseline model Deep-CAPTCHA, the number of parameters of our proposed model is reduced by about 70% and the recognition accuracy is improved by more than 10 percentage points in the two datasets. In addition, the proposed model has a faster training convergence speed.

The purpose of this study was to identify candidate novel species performing beneficial ecological functions from soil. The hypothesis was that novel culturable species with antibiotic production potential could be readily found from soil in the Nature Canyon at Los Angeles Pierce College. 137 bacterial isolates from soil were grown on nutrient agar, ISP-6 medium, or LB agar and partial 16S was ascertained using the Sanger platform for regions V1-V4. One of the potentially novel isolates, Pseudomonas sp. 21-C3-ER, was isolated on nutrient agar from fallow soil in an agricultural nature preserve in Los Angeles. The soil conditions were 3.7% moisture, clay texture by touch, 13.37% organic matter, pH=6.63, TDS=638, 150 ppm nitrogen, 114 ppm phosphate, and 42 ppm potash. Whole genome sequencing was performed on the DNBseq platform and species identification was performed with TRUEBacID; the closest relative was Pseudomonas brassicacearum subsp. neoaurantiaca which was 92.05% similar by genomic evidence. 197 virulence factors were identified including flagellar biosynthesis, motor proteins, Beta-lactamase, Fosfomycin, copper, and sulfur drug resistance. Gram stain of strain 21-C3-ER revealed gram negative rods. Rods were visualized with scanning electron microscopy, revealing individuals approximately 1 µm in length. Secondary metabolite analysis using antiSMASH showed a variety of post-translationally modified proteins and a promysalin analog. The qualitative test for pyoverdine siderophore production using UV light was positive. Metabolic analysis using RAST indicated genes were present for pyoverdine production, antimicrobial resistance, and ammonification. The nitrate reduction test was positive. Denitrifying bacteria may prevent leaching of nitrates from soil, since ammonia has a higher affinity to soil and organic matter than nitrate. We propose Pseudomonas fernandeno as a novel species. The type stain is 21-C3-ER.

Background and Objectives: In this current state, Type 2 Diabetes Mellitus (T2DM) is more prevalent in the population, and metformin is used as a first-line medication for treating it. There was up surge in the utilization of alternative therapies in the management of diabetes. Especially in diabetes, Herbal medicines are considered safe and reliable by majority of the population. Aim: The purpose of this research is aimed to estimate the safety and efficacy of Polyherbal Metabolite Compounds (PHMC) capsules in adults with T2DM. Materials and Methods: In this study, 60 T2DM patients aged 18-60 years were randomly assigned to Groups A (30) receiving Metformin 500 mg twice a day after food and Group B (30) receiving PHMC capsule 500 mg twice a day after food in a prospective, randomized and open-label clinical study. The in-silico simulation study was performed to selected plants major compounds on target protein Insulin-like Growth Factor-1 (1K3A). Result: The PHMC is found to be safe and effective in the management of T2DM. The FBS, PPBS and HbA1c were significantly lowered (p

The nickel-chromium-molybdenum alloy 625 exhibits an excellent combination of mechanical properties and corrosion resistance. However, the high temperature plastic deformation process and the heat treatment represent critical aspects and the adoption of non-optimal parameters can result in excessive grain coarsening and loss in mechanical strength. This detrimental behavior is worsened by the presence of a narrow region of temperatures and strain rates for complete recrystallization and the absence of phase transformation temperatures. In this alloy, the presence of sufficient amounts of niobium, titanium and aluminum permits slow age-hardening response upon single-aging treatments. Therefore, when the soft- or solution-annealed condition is associated with insufficient mechanical properties, this potentiality can be exploited to improve the mechanical strength and prevent waste of material and resources. Since the precipitation kinetic of the hardening γ^'' phase can be accelerated by prior nucleation treatment, different time-temperature combinations of double aging at 732 °C and 621 °C are investigated to reduce the overall heat treatment time. However, the simultaneous formation of Cr-rich carbides can dramatically affect the intergranular corrosion resistance. For this reason, a performance map is developed to compare all the tested conditions and identify the best compromise in terms of mechanical strength and corrosion rate.

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

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

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

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

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

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

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

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

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

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

Evidence from large epidemiological studies has shown that obesity may predispose to increased Th2 inflammation and increase the odds of developing asthma. On the other hand, there is growing evidence suggesting that metabolic dysregulation that occurs with obesity, and more specifically hyperglycemia and insulin resistance, may modify immune cell function and in some degree systemic inflammation. Insulin resistance seldom occurs on its own, and in most cases constitutes a clinical component of metabolic syndrome, along with central obesity and dyslipidemia. Despite that, in some cases, hyperinsulinemia associated with insulin resistance has been proven a stronger risk factor than body mass in developing asthma. This finding has been supported by recent experimental studies showing that insulin resistance may contribute to airway remodeling, promotion of airway smooth muscle (ASM) contractility and proliferation, increase of airway hyper-responsiveness and release of pro-inflammatory mediators from adipose tissue. All these effects indicate the potential impact of hyperinsulinemia on airway structure and function, suggesting the presence of a specific asthma phenotype with insulin resistance. Epidemiologic studies have found that individuals with severe and uncontrolled asthma have a higher prevalence of glycemic dysfunction, whereas longitudinal studies have linked glycemic dysfunction to an increased risk of asthma exacerbations. Since the components of metabolic syndrome interact with one another so much, it is challenging to identify each one's specific role in asthma. This is why, over the last decade, additional studies have been conducted to determine whether treatment of type 2 diabetes mellitus affects comorbid asthma as shown by the incidence of asthma, asthma control and asthma-related exacerbations. The purpose of this review is to present the mechanism of action, and existing preclinical and clinical data, regarding the effect of insulin resistance in asthma.

Recent evidence suggests that the lower gut microbiome of ruminants presents roles in their health and environment, including the development of the mucosal immune system, milk production efficiency and quality and subsequent methane emissions. However, there are proportionately fewer studies on this complex microbial community in cattle and region-focus studies are non- existent. Herein, we present the research protocol of the GUTBIOME CY project pertaining to determine the composition of the lower gut microbiome in dairy cows situated in 37 farms across five districts of the island of Cyprus. Detailed questionnaires on animal husbandry and farming practices will be gathered from each farm. Faecal, milk (individual and bulk) and water samples will also be collected from cows and their offspring. Samples will be analysed using a combination of molecular biology and bioinformatics pipelines to define microbiome profiles and antimicrobial resistance (AMR). Information collected from the questionnaires will be use to test for associations between animal husbandry or farming practices and microbiome components and AMR. Collected samples will establish the first dairy cattle biobank in the country for contributing substantially towards scientific advancements in microbiome research and providing insights to all stakeholders, tailored to the unique agricultural context of Cyprus.

Yersiniosis is a common zoonotic enteral disease among humans, which has been linked to pigs and contaminated food, especially pork. Studies on yersiniosis in pets are very scarce. In this study, we performed pheno- and genotypic characterization of 50 Yersinia strains isolated from pets in Finland between 2012 and 2023. Y. enterocolitica 4/O:3/ST135, the most common type in human yersiniosis, was also the most common Y. enterocolitica type (68%) found in clinical faecal samples in our study. Also, human pathogenic Y. enterocolitica 2/O:9/ST139 and Y. pseudotuberculosis O:1/ST9 and O:1/ST42 strains carrying all essential pathogenic genes were identified. Three Y. enterocolitica 4/O:3/ST9 strains were multi-drug resistant and two of them were highly related showing one allelic difference (AD) with core-genome multi-locus sequence typing. Non-pathogenic, genotypically highly diverse Y. enterocolitica 1A strains, showing more than 1000 ADs and missing the essential virulence genes, were also recognized in dogs and cats. Our study demonstrates that pets can excrete human pathogenic Y. enterocolitica and Y. pseudotuberculosis in their faeces and may serve as an infection source for human yersiniosis, especially in families with small children in close contact with their pets.

Nutrition is one of the most influential environmental factor in both taxonomical shifts in gut microbiota as well as development of Type 2 Diabetes Mellitus (T2DM). Emerging evidence has shown that the effects of nutrition on both these parameters is not mutually exclusive and that changes in gut microbiota and related metabolites such as short chain fatty acids (SCFA) and branched chain amino acids (BCAA) may influence systemic inflammation and signaling pathways that contribute to pathophysiological processes associated with T2DM. With this background, our review highlights the effects of macronutrients, carbohydrates, proteins and lipids, as well as micronutrients, vitamins, and minerals, on T2DM, specifically through their alterations in gut microbiota and the metabolites they produce. Additionally, we describe the influences of common food groups, which incorporate varying combinations of these macronutrients and micronutrients, on both microbiota and metabolic parameters in the context of diabetes mellitus. Overall, nutrition is one of the first line modifiable therapies in the management of T2DM and better understanding of the mechanisms by which gut microbiota influence its pathophysiology provides opportunities for optimizing dietary interventions.

ATP-binding cassette (ABC) transporters, acting as cellular "pumps," facilitate solutes translocation through membranes via ATP hydrolysis. Their overexpression is closely tied to multidrug resistance (MDR), a major obstacle in chemotherapy and neurological disorder treatment, hampering drug accumulation and delivery. Extensive research has delved into the intricate interplay between ABC transporter structure, function, and potential inhibition for MDR reversal. Cryo-electron microscopy has been instrumental in unveiling structural details of various MDR-causing ABC transporters, encompassing ABCB1, ABCC1, ABCG2, as well as recently revealed ABCC3 and ABCC4 structures. The newly obtained structural insight has deepened our understanding of substrate and drug binding, translocation mechanisms, and inhibitor interactions. Given the growing body of structural information available for human MDR transporters and their associated mechanisms, we believe it is timely to compile a comprehensive review of these transporters and compare their functional mechanisms in the context of multidrug resistance. Therefore, this review primarily focuses on the structural aspects of clinically significant human ABC transporters linked to MDR, with the aim of providing valuable insights to enhance the effectiveness of MDR reversal strategies in clinical therapies.

In recent years, the emergence of cancer drug resistance is one of the crucial tumor hallmarks which is supported by the level of genetic heterogeneity and complexities at cellular levels. Oxidative stress, immune evasion, metabolic reprogramming, overexpression of ABC transporters and stemness are among the several key contributing molecular and cellular response mechanisms. Topo-active drugs, e.g., doxorubicin and topotecan, are clinically active and are utilized extensively against a wide variety of human tumors and often results in the development of resistance and failure to therapy. Thus, there is an urgent need for an incremental and comprehensive understanding of mechanisms of cancer drug resistance specifically in the context of topo-active drugs. This review delves into the intricate mechanistic aspects of these intracellular and extracellular topo-active drug resistance mechanisms and explores use of potential combinatorial approaches by utilizing various topo-active drugs and inhibitors of pathways involved in drug resistance. We believe that this review will help guide basic scientists, pre-clinicians, clinicians, and policymakers toward holistic and interdisciplinary strategies that transcend resistance, renewing optimism in the ongoing battle against cancer.

In obesity, white adipose tissue expresses inflammatory cytokines leading to insulin resistance. Non-physiological meta-tyrosine and ortho-tyrosine (meta-Tyr and ortho-Tyr), produced from phenylalanine by free radicals, may contribute to the development of insulin resistance. The resulting insulin resistance may have a significant impact on macrophage function. In this study we aim to investigate microscopically the effect of meta- and ortho-Tyr on insulin sensitivity and M1/M2 polarization of macrophages using Akt phosphorylation and the arginase 1/iNOS ratio. Macrophage cell lines were cultured in media containing para-, meta- or ortho-Tyr, 5 mmol/L or 25 mmol/L glucose (para25-Tyr group) and treated with insulin. Para25, meta- and ortho-Tyr increased pAkt levels and decreased the arginase 1/iNOS ratio in macrophages in the absence of insulin. In the case of physiological para-tyrosine treatment, insulin increased the amount of pAkt and decreased the arginase 1/iNOS ratio. Both meta- and ortho-Tyr treatment were able to abolish or reverse the insulin’s increasing effect on pAkt and the decreasing effect on arginase 1/iNOS ratio. Our results suggest that non-physiological tyrosine isomers may affect the insulin signaling of macrophages and influence their M1/M2 polarization.

Background: Resistance to antimalarial drugs often used in emerging countries, including combination therapies, has forced scientists to search for and develop drugs with novel mechanisms of action, especially resistance to Plasmodium falciparum and Plasmodium vivax, which are highly prevalent in Southeast Asia, Africa, and South America. Objective: evaluate whether there is a relationship between urinalysis and resistance to in-hospital treatment of malaria in Angola. Methodology: This was a cross-sectional, prospective study with a quantitative approach. Results: of the 214 patients, the resistance rate was 24.1%, men (53.6%), between 21 and 40 years old (72.7%), employees (46.4%), from peri-urban regions (77.7%), treated with artemether (90.9), with high parasitemia (57.7%) and after 5 days of treatment, remained hospitalized (61.4%). Was a significant relationship between resistance in unemployed individuals [OR: 0.03 (95% CI: 0.01-0.29), p =0.003] and high levels of parasitemia [OR: 1.09 (95% CI: 1.09-3.95), p=0.040], remained hospitalized for more than 5 days [OR: 5.28 (95% CI: 0.65-43.1), p=0.121] and death [OR: 2.59 (95% CI: 0.32-20.9), p=0.371] when compared with other subgroups. Was a significant relationship between resistance to clear urine [OR: 5.55 (95% CI: 0.72-42.7), p =0.016], few urinary crystals [OR: 11.3 (95% CI: 5.07-25.3), p <0.001] and who presented some microorganisms that were not bacteria or fungi [OR: 3.02 (95% CI: 1 .32-6.90), p=0.009]. Conclusion: urine results, especially the appearance of cloudy urine, the presence of few crystals, and the presence of other microorganisms that are not bacteria or fungi, may be clear signs of resistance to hospital treatment with injectable antimalarials.

Boron carbide (B4C) powders with defined stoichiometry, high crystallinity, minimal impurity content, and a fine particle size are imperative for realizing the exceptional properties of this compound in advanced high-technology applications. Nevertheless, achieving the desired stoi-chiometry and particle size using traditional synthesis methods, which rely on prolonged, high-temperature processes, can be challenging. The primary objective of this study is to syn-thesize fine B4C powders characterized by high crystallinity and a sub-micron particle size, em-ploying a fast, and energy-efficient method. B4C powders are synthesized from elemental boron and carbon in a high-frequency induction heating furnace using the Electromagnetic Induction Synthesis (EMIS) method. The rapid heating rate achieved through contactless heating promotes the ignition and propagation of the exothermic chemical reaction between boron and carbon. Additionally, electromagnetic effects accelerate atomic diffusion, allowing the reaction to be completed in an exceptionally short timeframe. The grain size and crystallinity of B4C can be finely tuned by adjusting various process parameters, including the post-ignition holding temperature and the duration of heating. As a result, fine B4C powders can be synthesized in under 10 minutes. Moreover, these synthesized B4C powders exhibit high resistance to oxidation when exposed to air.

The emerging whitefly-transmitted crinivirus Tomato chlorosis virus (ToCV) causes substantial economic losses by inducing yellow leaf disorder in tomato crops. This study explores potential resistance mechanisms by examining early-stage molecular responses to ToCV. A time-course transcriptome analysis compared naïve, mock and ToCV-infected plants at 2, 7, and 14 days post-infection (dpi). Gene expression changes were most notable at 2 and 14 dpi, likely corresponding to whitefly feeding and viral infection. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed key genes and pathways associated with ToCV infection, including those related to plant immunity, flavonoids and steroids biosynthesis, photosynthesis, and hormone signalling. Additionally, virus-derived small interfering RNAs (vsRNAs) originating from ToCV predominantly came from RNA2 and were 22 nucleotides in lengt. To confirm these findings, two genes involved in plant immunity, Hsp90 (heat shock protein 90) and its co-chaperone Sgt1 (suppressor of the G2 allele of Skp1) were targeted through viral-induced gene silencing (VIGS), showing potential contribution to basal resistance against viral infections since their reduction correlated with increased ToCV accumulation. This study provides insights into tomato plants responses to ToCV, with potential implications for developing effective disease control strategies.

Contagious pathogens have very high costs for dairy herds, and they may have zoonotic and reverse-zoonotic potentials, and may contribute in spreading antimicrobial resistance. One of the most important risk factors for spreading these infections is milking, when liner contamination may transfer the pathogens from infected to healthy cows. There is no effective protocol for avoiding the transmission of infection out of the segregation of infected cows. Recently, the availability of elastomers including patented antimicrobial components in their formulations has opened the way to explore alternative methods to decrease infection risk. Two different types of elastomers (rubber and silicon) and 9 different receipts were challenged by three major mastitis pathogens (S. aureus, S. agalactiae, and E. coli). The results showed interesting and unexpected results. Indeed, for the first time to our knowledge, we have shown that basic rubber materials have intrinsic antimicrobial activity. Silicon elastomers did not exhibit the same levels of killing activity, although they did exhibit some antibacterial capacity. Generally, a significant decrease in bacterial survival curves was observed with the tested formulations. The results observed for the various products are likely due to the specific activity of the chemical components, as well as the diverse chemical reactions that occur during their production. The availability of new tools able to reduce the risks for the spread of infections and generally decrease the bacterial load at milking, would be an important step forward to achieve a higher global sustainability of dairy production from a One Health perspective.

Lupinus mutabilis, also known as tarwi or chocho, is an important agricultural species cultivated in South America since ancient times. Tarwi is native from the Andean regions of Peru, Bolivia, and Ecuador and has a very high protein content. Despite its high nutritional value and promotion efforts by regional researchers and breeders, tarwi is not a widely cultivated crop in its center of origin. In this review, we present the work carried out by public breeding programs of L. mutabilis at national agricultural research institutes, universities, and other institutions in Ecuador, Peru, and Bolivia. The main breeding method used in the Andes to improve local landraces has been mass selection to adapt lines to specific environments. At least 25 cultivars or ecotypes have been selected and released over the last 40 years using this breeding system. Notwithstanding, breeders are currently struggling to develop new varieties that are high yielding, suitable for mechanized harvesting, have a low content of alkaloids or other anti-nutritional properties, and to anthracnose (Colletotrichum acutatum). Therefore, it is necessary to reassess the potential of this crop and invest in its research to incorporate new techniques and breeding strategies to optimize the development of new varieties in the Andes which address the current cultivation challenges of the species.

This comprehensive review examines the critical issue of antimicrobial resistance (AMR), a growing global concern with profound societal implications. This article presents an overview of the causes of AMR, including the misuse and overuse of antibiotics in healthcare, agriculture, and veterinary practices. Various conventional and advanced detection methodologies have been explored, highlighting the importance of the accurate and timely identification of resistant strains. The challenges associated with tackling AMR, encompassing scientific, economic, and regulatory aspects have been discussed in depth. In addition, this article sheds light on the far-reaching societal implications of AMR, including increased healthcare costs, treatment complexities, and potential disruptions to healthcare systems. This emphasizes the urgency of adopting proactive strategies to combat AMR and underscores the need for global cooperation, policy interventions and public awareness campaigns. By unraveling the multifaceted dimensions of AMR, this review aims to enhance our understanding, stimulate further research, and promote concerted efforts to mitigate the threat of antimicrobial resistance.

Imidacloprid, a neonicotinoid, has proven as efficacious against hemipterans including the brown planthopper, Nilaparvata lugens (Stål). Frequent use, however, has resulted in high levels of resistance to imidacloprid among brown planthopper populations. Endosymbionts of insects are important for host insect growth and development and seem to play a role in resistance to imidacloprid. In this study, polymerase chain reaction denaturing gradient gel electrophoresis (PCR-DGGE) was used to analyze the bacterial and yeast-like-symbiont communities of imidacloprid-resistant and imidacloprid-susceptible brown planthopper populations. The Shannon-Weaver diversity index and the evenness index indicated that there were no differences in the composition of the symbiotic communities of resistant and susceptible with a similarity coefficient of 0.53 for bacterial symbionts and 0.56 for yeast-like symbionts for the two planthopper populations. Sequence comparison analysis showed that the numbers of bacterial species in the imidacloprid-resistant versus the imidacloprid-susceptible populations were not significantly different. The bacterial species in the susceptible population were members of the Enterobacteriaceae and Moraxellaceae, while these in the resistant population were members of the Enterobacteriaceae, Oxalobacteriaceae, Rhodobacteriaceae, and Sphingomonadaceae. The imidacloprid-susceptible population had more yeast-like symbiont species than the resistant population.

Laser heat treatment is applied after coating. Evaluation of the results was performed by studying the microstructures by metallographic, SEM/EDX microscopy and the mechanical properties were obtained by microscopic hardness and abrasion resistance. The objective of this study was to investigate the effect of laser heat treatment on the wear resistance of metal coatings. The results show the influence of the microstructure and chemical composition of the electrodes used on the micro-hardness and wear resistance of the metal coatings.

Infectious illnesses have always posed a threat to human health, with tuberculosis (TB) being a major concern. The use of various medications and antibiotics in the fight against such illnesses has led to the emergence of drug-resistant infectious diseases, which have become increasingly dif-ficult to manage as medical and scientific research has advanced. Inadequate medical infrastruc-ture, incorrect treatment practices that exacerbate resistance patterns, and transmission within communities and healthcare facilities are the main factors contributing to the spread of drug-resistant TB. Though treating individuals with multiple drug resistance (MDR) and extreme drug resistance (XDR) strains is challenging, early identification of resistance and the imple-mentation of a well-designed treatment regimen can result in a cure. Community-based inter-ventions that address socioeconomic barriers to adherence can also enhance treatment outcomes. While there have been few studies and proposed conceptual models on how to manage and prevent various drug-resistant TB mutations and lineages, a model aimed at limiting and controlling such mutations has been developed. This paradigm seeks to bridge the gap by facilitating the exchange of knowledge among healthcare professionals (HCP) in healthcare facilities (HCF), diagnostic laboratories (DL), and research institutes (RI), particularly for underprivileged communities in the Eastern Cape. The model guide will also monitor and evaluate TB management plans

To identify soil microbial communities, it is essential to understand their phenotypic and genetic characteristics. Plant growth-promoting rhizobacteria (PGPR) are bacteria capable of promoting plant growth. In addition, rhizobacteria also serve as biological control agents. In addition to fixing atmospheric nitrogen, solubilising insoluble phosphate and secreting hormones such as indoloacetic acid, kinetics and gibberellins, plant growth-promoting rhizobacteria help plants grow directly. Furthermore, they facilitate plant growth indirectly by inducing systemic resistance, siderophores, antibiotics, lytic enzymes, hydrogen cyanide production and stress regulation. This review examines in detail the direct and indirect mechanisms of PGPR action and their interaction in plant growth and resistance.

Acne vulgaris has multifactorial pathogenesis which may include insulin resistance. To investigate whether insulin resistance is a causative factor in acne vulgaris development, this study and a systematic review were conducted. 41 acne vulgaris patients and 47 healthy BMI-matched controls were involved. Glucose and insulin fasting serum levels were obtained, HOMA-IR was calculated, insulin resistance was diagnosed in cases with HOMA-IR value over 2.1. The mean±SD values for glucose fasting serum level were as follows: 94.88±7.731 [mg/dl] in study group and 79.51±7.175 [mg/dl] in controls (p&lt;0.001). The mean±SD insulin fasting serum levels were 14.47±6.394 [µIU/mL and 11.83±4.309 [µIU/mL](p=0.059), respectively. The HOMA-IR mean±SD value calculated for the study group was 3.4±1.49 and in the control group 2.34±0.909 (p&lt;0.001).Out of 41 patients 32 were diagnosed with insulin resistance (78%) and 26 of the 47 controls 26 were diagnosed with IR (55%) (p=0.026). Insulin resistance diagnosis was statistically more common among the acne patients compared to the controls. In the articles reviewed insulin resistance was found to be more frequent in acne vulgaris patients. Both our study and the papers analysed indicate that insulin resistance might be an independent factor in acne vulgaris development and should be considered when diagnosing and treating acne.

Helicobacter pylori (H. pylori) is a common bacterial infection linked to gastric malignancies. While H. pylori infection and gastric cancer rates are decreasing, antibiotic resistance varies greatly by community. Little is known about resistance rates among rural Indigenous populations in the United States. From 2018 to 2021, 396 endoscopy patients were recruited from a Northern Arizona clinic, where community H. pylori prevalence is near 60%. Gastric biopsy samples positive for H. pylori (n=67) were sequenced for clarithromycin and metronidazole-associated mutations, 23S ribosomal RNA (23S), and oxygen-insensitive NADPH nitroreductase (rdxA) regions. Medical record data were extracted for endoscopic findings and prior H. pylori history. Data analysis was restricted to individuals with no history of H. pylori infection. Of 49 individuals, representing 64 samples that amplified in the 23S region, a clarithromycin-associated mutation was present in 38.8%, with T2182C the most common mutation, 90%. While prevalence of metronidazole resistance-associated mutations was higher, 93.9%, mutations were more variable, with D95N the most common, followed by L62V. No statistically significant sex differences were observed for either antibiotic. Given the risk of treatment failure with antibiotic resistance, there is a need to consider the resistance profile during treatment selection. The resistance rates in this population of American Indian patients undergoing endoscopy are similar to other high-risk populations. This is concerning given the high H. pylori prevalence and low rates of resistance testing in clinical settings. The mutations reported are associated with antibiotic resistance, but clinical resistance must be confirmed.

Buckground: Although ceftazidime/avibactam (CAZ/AVI) has become important option for treating adults and children, no recommendations exist for neonates. We report a neonatal sepsis case due to CAZ/AVI-resistant KPC-2 producing-Klebsiella pneumoniae carrying blaVEB-25 and the use of a customized active surveillance program in conjunction to infection control measures. Methods: The index case was an extremely premature neonate hospitalized for 110 days that had been previously treated with multiple antibiotics. Customized molecular surveillance was implemented at hospital level and enhanced infection control measures were taken for early recognition and prevention of outbreak. Detection and identification of blaVEB-25 was performed by next-generation sequencing. Results: That was the first case of a bloodstream infection caused by KPC producing K. pneumoniae that was resistant to CAZ/AVI without the presence of a metalo-β-lactamase in the multiplex PCR platform in a neonate. All 36 additional patients tested (12 in the same NICU and 24 from other hospital departments) carried wild-type blaVEB-1 but they did not harbor blaVEB-25. Conclusion: The emergence of VEB-25 is signal for horizontal transfer of plasmids at hospital facilities and it is of greatest concern for maintaining a sharp vigilance for surveillance of novel resistance mechanisms. Molecular diagnostics can guide appropriate antimicrobial therapy and early implementation of infection control measures against antimicrobial resistance.

Type 2 diabetes mellitus (T2DM) has emerged as a major health care concern in modern society, primarily due to lifestyle changes and dietary habits. Obesity-induced insulin resistance is considered as the major pathogenic factor in T2DM. In this study, we have investigated the effect of vindoline, an indole alkaloid of Catharanthus roseus on insulin resistance, oxidative stress and inflammatory responses in high glucose induced insulin resistant L6-myoblast cells, and dexamethasone (IR inducer)/1L-β (inflammation inducer) induced dysfunctional 3T3-L1 adipocytes. Results showed that dexamethasone induced dysfunctional 3T3-L1 adipocytes treated with different concentrations of vindoline significantly enhanced basal glucose consumption, accompanied by increased expression of GLUT-4, IRS-1 and adiponectin. Vindoline treatment significantly suppressed the ROS production and upregulated pro-inflammatory mediators in IL-1β induced dysfunctional adipocytes. Similarly, vindoline treated insulin resistant L6 myoblasts exhibited significantly enhanced glycogen content accompanied with upregulation of IRS-1 and GLUT-4. Thus, in vitro studies of vindoline in insulin resistant skeleton muscle and dysfunctional adipocytes confirmed that vindoline treatment significantly mitigate insulin resistance in myotubes and improves functional status of adipocytes. These results demonstrated that vindoline has the potential to be used as a therapeutic agent to ameliorate obesity-induced T2DM associated insulin resistance profile in adipocytes and skeletal muscles.

The first half of the 20th century was noteworthy for the introduction of a unique group of drugs – antibiotics. It drastically changed concepts of infectious diseases treatment, which for centuries remained a scourge of the human population. With improvement of the antibiotic treatment efficacy, humanity has faced the problem of a dramatic increase in antibiotic resistance in bacteria. The COVID-19 pandemic has only exacerbated the problem and posed a new challenge to the medical community in finding solutions, both clinical and organizational and methodological, to fight antibiotic resistance widespread all over the globe. This publication covers some aspects of evolutionary processes in either pathogens or diseases, including ethical perspective.

The current study aims to first, isolate H. pylori in cultures from gastric biopsy samples and test their susceptibility. Secondly, we aim to assess the efficacy of the standard triple therapy from patients coming of the western central region of Colombia. Patients with H. pylori positive re-ceived standard triple therapy with PPI [40 mg b.i.d.], clarithromycin [500 mg b.i.d.], amoxicillin [1g b.i.d.] for 14 days. Thereafter, antibiotic susceptibility of the isolates was assessed by E-Test. From 94 patients enrolled, 67 were positive for H. pylori by histology or culture. Resistance to metronidazole, levofloxacin, rifampicin, clarithromycin and amoxicillin was 81, 26.2, 23.9, 19 and 9.5%, respectively. No resistance was found for tetracycline. 54 patients received standard triple therapy, 48 attended follow-ups testing and of them, 30 had resistance test reports. Overall eradication rate was 81.2%, 4 patients underwent second-line management and only one patient remained H. pylori positive by urea breath test during the follow-up [six weeks]. Eradication was significantly higher in patients with clarithromycin susceptible than in resistant strains [95.6% vs. 42.8% p= 0.001]. The updated percentages of resistance to clarithromycin in this geographical area have increased, so this value must be considered when choosing the treatment regimen.

Companion animals are increasingly being recognized as important contributors to the spreading of antimicrobial resistant bacteria. The present work aimed to measure the antimicrobial drug prescribing in dogs and cats in the Campania region, Italy by analyzing the Veterinary Electronic Prescriptions (VEPs) between 2019 and 2020. The medical records associated with antimicrobial drug prescription were collected considering the drug delivery (systemic or local) and the rationale for the treatment chosen. In the period under investigation, 166879 drugs were prescribed of which 129116 (73.37 %) were antimicrobial. A total of 83965 (65.03 %) antibiotics were prescribed to dogs, 40477 (31.35 %) to cats, and 4674 (3.62 %) to other companion animals. In dogs the 90.48 % of VEPs prescribed for systemic treatment included an antimicrobial Critically Important or Highly Important or Important for human medicine (WHO, 2018). The most widely commonly prescribed class were fluoroquinolones. The main prescribed antimicrobials were the metronidazole-spiramycin (29.71%), amoxicillin-clavulanic (19.58%), enrofloxacin and cephalexin in dogs (16.52 %) and enrofloxacin (22.64%) and amoxicillin-clavulanic acid (21.37 %) in cats. Based on the results the wide use of broad-spectrum or second-line antibiotics is emerged together with the use of the critically important antimicrobials for human medicine.

Nonalcoholic fatty liver disease (NAFLD) has become a widely studied subject due to its increasing prevalence and links to diseases such as type 2 diabetes and obesity. It has severe complications, including nonalcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma, and portal hypertension that can lead to liver transplantation in some cases. To better prevent and treat this pathology, it is important to understand its underlying physiology. Here, we identify three main factors that play a crucial role in the physiopathology of NAFLD: oxidative stress, insulin resistance, and the key role of carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1). We discuss the pathophysiology linking these factors to NAFLD pathophysiology.

Antimicrobial resistance (AMR), the capacity of microbial pathogens to survive in the presence of antimicrobials, is considered one of the greatest threats to human health worldwide and is growing rapidly in importance. AMR is thought to be driven in part by the use of antimicrobials (AMU) in livestock production. AMU reduction in agriculture is therefore important, but doing so may endanger farmers’ incomes and hamper broader food security. Understanding drivers for farmers' antibiotics use is essential to designing interventions which avoid harming agricultural output and safeguard farmers’ economic security. In this study, we analyse AMUSE survey data from poultry farmers in Senegal to explore the effects of vaccination, attitudes towards AMR, and biosecurity practices on: AMU, animal mortality, and farm productivity. We found that farmers with more “AMR-aware” attitudes may be less likely to use antibiotics in healthy birds. Stronger on-farm biosecurity was associated with less use of antibiotics in healthy birds, and in some specifications was linked to higher broiler productivity. Vaccination and AMU were both linked with higher disease prevalence, and both factors appeared conducive to higher broiler productivity. Overall, there is evidence that awareness-raising and biosecurity improvements could encourage prudent use of antibiotics, and that biosecurity and vaccination could to some extent replace antibiotic use as productivity-enhancing and disease-management tools in broiler farms. Finally, issues of farm antimicrobial stewardship must be considered at the structural level, with farm behaviours contingent on interaction with state and private stakeholders.

Due to the global warming and dynamic changes in pathogenic virulence, leaf rust caused by Puccinia triticina has greatly expanded its epidermic region and become a severe threat to global wheat production. Genetic bases of wheat resistance to leaf rust mainly relies on the leaf rust resistance (Lr) gene or quantitative trait locus (QLr). Although these genetic loci have been insensitively studied during the last two decades, an updated overview of Lr/QLr in a genome-wide level is urgently needed. This review summarized recent progresses in genetic studies of wheat resistance to leaf rust. Wheat germplasms with great potentials in genetic improvement of resistance to leaf rust were highlighted. Key information about the genetic loci carrying Lr/QLr were summarized. A genome-wide chromosome distribution map for all the Lr/QLr was generated based on the released wheat reference genome. In conclusion, this review has provided valuable sources for both wheat breeders and researchers to understand the genetics of resistance to leaf rust in wheat.

Cryptococcus neoformans threaten the health, causing cryptococcal meningitis and pneumonia, especially in immunosuppressed patients, which can be fatal. Recently, our research group evaluated and studied the mechanisms of action of four synthetic peptides (SP) against C. neoformans. Here, in silico and in vitro analyses help deepen understanding of peptides' mechanisms of action. The interaction of the peptides with a membrane receptor was analyzed by docking analysis, in addition to ROS overproduction and the modulation of redox metabolism, inhibition of ergosterol biosynthesis, and release of cytochrome c. Out of four, three peptides interacted with membrane receptor PHO36 altering its structure and function and leading to a higher accumulation of O₂- and H2O2. C. neoformans cells treated with SP presented a reduction in the activity of antioxidant enzymes, corroborating ROS accumulation. However, in the presence of the antioxidant ascorbic acid, some peptides could not induce this oxidative stress and have the activity against C. neoformans affected. Curiously, two of these SPs still maintained the activity against C. neoformans and even induced the membrane pore formation as revealed by propidium iodide uptake assay, revealing their mechanism of action is ROS-independent. Additionally, SPs inhibited the biosynthesis of ergosterol, which corroborates the pore formation on the membrane of C. neoformans cells, inhibited the lactate dehydrogenase activity affecting the cell metabolism, and induced the release of Cyt c from the mitochondria inducing death by apoptosis in the cryptococcal cells. Our findings strongly suggest that SPs act by multiple mechanisms, making it difficult for C. neoformans to acquire resistance highlighting the potential of SPs as alternative molecules in treating infections caused by C. neoformans.

Background Polycystic ovary syndrome (PCOS) is a common hormonal disorder worldwide among women of reproductive age. It is characterized by endocrine, reproductive, and metabolic abnormalities. Insulin resistance (IR) is one of its most important clinical features, associated with metabolic disorders and increased risk of type 2 diabetes (T2D). This study aimed to explore the whole blood gene expression profiling related to IR in PCOS patients compared to controls. Methods Blood RNA was extracted from 5 PCOS and 5 non-PCOS women with matched age and BMI. Homeostasis model assessment (HOMA-IR) was used to estimate the IR. The expression of IR genes was analyzed by Profiler PCR array. Results Both groups have similar levels of HOMA-IR (p>0.05). However, differential expression levels were observed between them. Fourteen genes were upregulated and 26 genes were downregulated in PCOS samples. Among the upregulated genes (>2 fold-change, p-value<0.05) are ADIPOQ, ADIPOR1, OLR, IGF-1, and APOE. Downregulated genes (>-2 fold-change, p-value<0.05) include HK-2, IRS1, and SERPINE1. These genes are involved in insulin and adipokines signaling, commonly dysregulated in T2D. They are also involved in innate immunity and inflammatory processes and are essential for lipid and carbohydrate metabolism. Conclusion Our finding suggests that despite both groups having no difference in IR level, there are differentially expressed genes involved in the IR pathway.

Bacillus thuringiensis (Bt) is a spore-forming bacterium that produces insecticidal proteins and other virulence factors and is considered one of the most successful bioinsecticides available to control pests in agriculture. Bt strains have been reported as endophyte or rhizospheric bacteria, but little is known about the implications of this property of Bt in crop protection. Here, we review if Bt can establish as an endophyte/rhizobacterium and evaluate if Bt as an endophyte/rhizobacterium can simultaneously act against different phytopathogens (fungi, bacteria, insects and viruses) plus promote plant growth. The implications of the proposed review will broaden our understanding of Bt as a versatile entomopathogen by exhibiting differential behavior depending on context.

One of the modern methods of improving operating characteristics of titanium and titanium-based alloys under conditions of friction and increased contact loads is the method of ion-plasma nitriding. The effect of nitriding of VT5 alloy (Al 4,5-6,7 %, V to 1,2 %, Mo to 0,8 % − analogue 3.7115) in the plasma of a glow discharge excited in a hollow cathode on its tribological characteristics in pairs with different materials in T-1 fuel and under dry friction conditions has been studied. For research and tribological tests, samples of VT5 alloy were nitrided in the plasma of a glow discharge excited in a hollow cathode at a temperature of 975 ± 15°C and a pressure of 58 ± 2 PA in a nitrogen-argon gas mixture with a nitrogen content of 78 %. Studies of samples of VT5 alloy after nitriding showed that the surface roughness Ra was in the range of 0.58-0.64, and the surface hardness HV5 was 525 ± 20 kgf/mm² at a base hardness of 325 ± 15 kgf/mm². Tribological tests were performed on a friction machine 2070 SMT-1 according to the scheme "cube - roller". Tests under conditions of friction with oil were performed at a load of 200 N. The sliding speed during the tests was 1.3 m/s, the test time was 75 sec. The test under dry friction conditions was carried out at a load of 100 N and a sliding speed of 0.785 m/s, the test time was 30 minutes. Low wear ability in relation to the nitrided titanium alloy VT5 (<2.4x10^-4 mm³/s), as well as friction coefficients at the level of 0.08 to 0.12 in the order of their growth had bronze VB-23NTS (Pd 18–22 %, Ni 3–4 %, Zn 3–4 %, Sb 3–4 %, P 0.15–0.3) r.O10C2N3, VB-24 (Sb 4.7–6, 2 %, P 0.4–0.9), steel 1.3505, cast iron GGG80, cemented steel 20Cr3MoWV.

Verticillium wilt (VW) is a soil borne fungal diseases caused by Verticillium dahliae Kleb, and lead to serious damage to cotton production annually in the world. In our previous study, a transmembrane protein 214 protein (TMEM214) gene associated with VW resistance was map-based cloned from Gossypium barbadense (G. barbadense). TMEM214 proteins are a kind of transmembrane protein, but their function in plants is rarely studied. To reveal the function of TMEM214s in VW resistance, all six TMEM214s were cloned from G. barbadense in this study. These genes were named as GbTMEM214-1, GbTMEM214-4 and GbTMEM214-7 according to their location on the chromosomes, and the encoded proteins are all located on cell membrane. TMEM214 genes were all induced by Verticillium dahliae inoculation and showed significant differences between resistant and susceptible varieties, but the expression patterns of GbTMEM214s under different hormone treatments were significantly different. Virus-induced gene silencing analysis showed the resistance to VW of GbTMEM214s-silenced lines decreased significantly, which further proves the important role of GbTMEM214s in the resistance to Verticillium dahliae. Our study provides an insight into the involvement of GbTMEM214s in VW resistance, which was helpful to better understand the disease resistance mechanism of plants.

The soil-borne pathogens, particularly Fusarium oxysporum f. sp. niveum (FON) and southern root-knot nematode (RKN, Meloidogyne incognita) are the major threat to watermelon production in the south-eastern United States. The role of soil micronutrients on induced resistance (IR) to plant diseases is well-documented in soil-based mediums. However, soil-based mediums limit the determination of the role(s) of individual micronutrients in IR. In this manuscript, we utilized hydroponics to assess the effect of controlled application of micronutrient, including iron (Fe), manganese (Mn), and zinc (Zn) on the expression of some IR genes (PR1, PR5, and NPR1 from salicylic acid (SA) pathway, and VSP, PDF, and LOX genes from jasmonic acid (JA) pathway) in watermelon seedlings upon inoculation with either FON or RKN or both. Plants were treated with higher (3X) or lower (0.5X) concentrations of micronutrients in Steiner solution (X= standard dose of micronutrient) for 7 days in a hydroponics system under greenhouse conditions. A subset of micronutrient-treated plants was inoculated (on the 8th day of micronutrient application) with FON and RKN (single and mixed). The expression of the IR genes in treated and control samples were evaluated using qRT-PCR. Although, significant phenotypic differences were not observed with respect to the severity of wilt symptoms or RKN galling with any of the micro-nutrient treatments within the 30 day-experimental-period, differences in the induction of IR genes were observed. However, the level of gene expression varied with sampling period, type and concentration of micro-nutrients ap-plied, and pathogen-inoculation. In the absence of pathogens, no significant changes were observed in the expression level of IR genes on 7th day of micronutrient treatment. However, pathogen inoculation affected the expression levels of the IR genes at 3-day post-inoculation. In FON inoculated plants, PDF was upregulated in high Fe treatment, whereas in RKN inoculated plants, low Mn treatment resulted in up-regulation of VSP. In the case of mixed inoculation with FON and RKN, the plants with low Zn treatment resulted in the upregulation of PR1. These observations suggest that the type and concentration of micronutrients in watermelon may potentially induce systemic resistance against FON and RKN through SA and JA pathways.

Infectious keratitis (IK) represents a major cause of corneal blindness. This study aims to investigate the demographics, risk factors, microbiological characteristics and antibiotic susceptibility patterns of IK in Taiwan over the past 15 years. A retrospective population-based study was conducted using the Chang Gung Research Database. Patients with IK were identified by diagnostic codes for corneal ulcer from 2004 to 2019. Of 7807 included subjects, 45.2% of patients had positive corneal cultures. The proportion of contact lens-related IK declined, while that of IK related to systemic diseases grew. The percentage of isolated gram-positive bacteria surpassed that of gram-negative bacteria in the 15-year period. The prevalence of Pseudomonas aeruginosa showed a decreasing trend (p = 0.004), whereas coagulase-negative Staphylococcus (CNS) and Propionibacterium species were increasingly detected (p &lt; 0.001). Overall, the trend of antibiotic susceptibility of both gram-positive and gram-negative bacteria did not change throughout the study period. The susceptibility to the test antibiotics maintained over 90% in gram-negative isolates during 15 years. Vancomycin preserved 100% susceptibility to all gram-positive isolates. Since most tested antibiotics exhibited stable susceptibility over decades, this study reinforced that fluoroquinolones and fortified vancomycin continue to be good empiric therapies for treating bacterial keratitis in Taiwan.

The mosaic disease in maize is caused by Sugarcane mosaic virus (SCMV), a member of the Potyviridae family. The best strategy to cope with viral infections is the use of disease-resistant maize lines. To better understand the resistance response to SCMV, we analyzed differentially expressed genes among a resistant line (CI-RL1), a susceptible line (B73), and the F1 progeny from a cross between both lines using RNA-Seq data. We also analyzed transcript expression pattern clustering to allocate previously reported resistance candidate genes. GO enrichment analysis of biological processes highlighted a strong regulation in ROS detoxification in both the susceptible and resistant lines. The enrichment of cellular components led to the identification of an integral component of the plasma membrane in the RL line. Transcript expression patterns provide evidence of the importance of host translation in virus response, showing the diverse and complex behavior of eIF4E homologs and the presence of eleven eEF1α factors in maize. In addition, we identified two genes putatively implied in long-distance movement: ZmPiezo and ZmPVIP1. Finally, we propose an ABC transporter to be associated with viral resistance.

Cryptococcus neoformans causes meningoencephalitis in immunocompromised individuals, which is treated with Fluconazole (FLC) monotherapy when resources are limited. This can lead to azole resistance, which can be mediated by overexpression of ABC transporters, a class of efflux pumps. ABC pump-mediated efflux of FLC is also augmented in 10-generation old C. neoformans cells. Here, we describe a new ABC transporter Afr3 (CNAG_06909), which is overexpressed in C. neoformans cells of advanced generational age, that accumulate during chronic infection. The delta-afr3 mutant strain showed higher FLC susceptibility by FLC E-Test strip testing and also by a killing test that measured survival after 3 h FLC exposure. Furthermore, delta-afr3 cells exhibited lower Rhodamine 6G efflux compared to the H99 wild type cells. Afr3 was expressed in the Saccharomyces cerevisiae AD-delta strain, which lacks several drug transporters, thus reducing background transport. The AD-delta + Afr3 strain demonstrated a higher efflux with both Rhodamine 6G and Nile Red, even though the FLC MICs were not changed. Characterization of the delta-afr3 mutant revealed unattenuated growth but a prolongation (22%) of the replicative life span. In addition, delta-afr3 exhibited decreased resistance to macrophage killing and attenuated virulence in the Galleria mellonella infection model. In summary, our data indicate that a novel ABC pump Afr3p, which is upregulated in C. neoformans cells of advanced age may contribute to their enhanced FLC tolerance, by promoting drug efflux. Lastly, its role in macrophage resistance may also contribute to the selection of older C. neoformans cells during chronic infection.

Background: New insecticides with novel modes of action such as neonicotinoids have recently been recommended for public health use by WHO. Resistance monitoring of such novel insecticides requires a robust protocol to monitor the development of resistance in natural populations. In this study, we comparatively used three different solvents to assess the susceptibility of malaria vectors to neonicotinoids across Africa.Methods: Mosquitoes were collected from May to July 2021 from three agricultural settings in Cameroon (Njombe-Penja, Nkolondom, and Mangoum), the Democratic Republic of Congo (Ndjili-Brasserie), Ghana (Atatam), and Uganda (Mayuge). Using the CDC bottle test, we compared the effect of three different solvents (ethanol, acetone, acetone+MERO) on the efficacy of neonicotinoids against Anopheles gambiae s.l. In addition, TaqMan assays were used to genotype key pyrethroid-resistant markers in An. gambiae and to evaluate potential cross-resistance between pyrethroids and clothianidin.Results: Lower mortalities were observed for all populations when using absolute ethanol or acetone alone as solvent (11.4- 51.9% mortality for Nkolondom, 31.7- 48.2% for Mangoum, 34.6- 56.1% for Mayuge, 39.4- 45.6% for Atatam, 83.7- 89.3% for Congo and 71.05- 95.9% for Njombe pendja) compared to acetone + MERO for which 100% mortality was observed for all the populations. Synergist assays (PBO, DEM and DEF) revealed a significant increase of mortality suggesting that metabolic resistance mechanisms are contributing to the reduced susceptibility. A negative association was observed between the L1014F-kdr mutation and clothianidin resistance with a greater frequency of homozygote resistant mosquitoes among the dead than among survivors (OR=0.5; P=0.02). However, the I114T-GSTe2 was in contrast significantly associated with a greater ability to survive clothianidin with a higher frequency of homozygote resistant among survivors than other genotypes (OR=2.10; P=0.013). Conclusions: This study revealed a contrasted susceptibility pattern depending on the solvents with ethanol/acetone resulting in lower mortality, thus possibly overestimating resistance, whereas the addition of MERO consistently increased the efficacy of neonicotinoids in terms of percentage mortalities and time to final mortality. The addition of MERO could however prevent the early detection of resistance development. We therefore recommend monitoring susceptibility using both acetone alone and acetone+MERO (8-10µg/ml for clothianidin) to capture the accurate resistance profile of the mosquito populations.

Metastasis is the leading cause of cancer death and can be realized through the phenomenon of tumor cell fusion. The fusion of tumor cells with other tumor or normal cells leads to the appearance of tumor hybrid cells (THCs) exhibiting novel properties such as increased proliferation and migration, drug resistance, decreased apoptosis rate and avoiding immune surveillance. Experimental studies showed the association of THCs with a high frequency of cancer metastasis; however, the underlying mechanisms remain unclear. Many other questions also remain to be answered: the role of genetic alterations in tumor cell fusion, the molecular landscape of cells after fusion, the lifetime and fate of different THCs, and the specific markers of THCs, and their correlation with various cancers and clinicopathological parameters. In this review, we discuss the factors and potential mechanisms involved in the occurrence of THCs, the types of THCs, and their role in cancer drug resistance and metastasis, as well as potential therapeutic approaches for the prevention and targeting of tumor cell fusion. In conclusion, we emphasize the current knowledge gaps in the biology of THCs that should be addressed to develop highly effective therapeutics and strategies for metastasis suppression.

Intrammary infections are a major problem for dairy sheep farms, and Streptococcus uberis is one of the main etiological agents of ovine mastitis. Surveys on antimicrobial resistance are still limited in sheep and characterization of isolates is important for acquiring information on resistance and for optimizing therapy. In this study, a sampling of 124 S. uberis isolates collected in Sardinia (Italy) from sheep milk was analysed by multilocus-sequence typing (MLST) and pulsed field gel electrophoresis (PFGE) for genetic relatedness. All isolates were also subjected to antimicrobial susceptibility analysis by the disk diffusion test using a panel of 14 antimicrobials. Resistance genes were detected by PCR assays. MLST analysis revealed that the isolates were grouped into 86 sequence types (STs), of which 73 were new genotypes, indicating a highly diverse population of S. uberis. The most frequently detected lineage was the clonal complex (CC)143, although representing only 13.7% of all characterized isolates. A high level of heterogeneity was also observed among the SmaI PFGE profiles, with 121 unique patterns. Almost all (96.8%) isolates were resistant to at least one antimicrobial, while all exhibited phenotypic susceptibility to oxacillin, amoxicillin-clavulanic acid and ceftiofur. Of the antimicrobials tested, the highest resistance rate was found against streptomycin (93.5%), kanamycin (79.8%) and gentamicin (64.5%), followed by novobiocin (25%) and tetracycline-TE (19.3%). Seventy-four (59.7%) isolates were simultaneously resistant to all aminoglycosides tested. Seventeen isolates (13.7%) exhibited multidrug resistance. All aminoglycosides-resistant isolates were PCR negative for aad-6 and aphA-3’ genes. Among the TE-resistant isolates, the tetM gene was predominant, indicating that the resistance mechanism is mainly mediated by the protection of ribosomes and not through the efflux pump. Three isolates were resistant to erythromycin, and two of them harboured the ermB gene. This is the first study reporting a detailed characterization of the S. uberis strains circulating in Sardinian sheep. Further investigations will be needed to understand the relationships between S. uberis genotypes, mastitis severity, and intra-mammary infection dynamics in the flock, as well as to monitor the evolution of antimicrobial resistance.

Chronic wasting disease is a fatal transmissible spongiform encephalopathy (TSE) of cervids caused by a misfolded variant of the normal cellular prion protein, and is closely related to sheep scrapie. Variations in a host’s prion gene, PRNP, and its primary protein structure, dramatically affect susceptibility to specific prion disorders, and breeding for PRNP variants that prevent scrapie infection has led to steep declines in the disease in North American and European sheep. While resistant alleles have been identified in cervids, a PRNP variant that completely prevents CWD has not yet been identified. Thus, control of the disease in farmed herds traditionally relies on quarantine and depopulation. In CWD-endemic areas, depopulation of private herds becomes challenging to justify, leading to opportunities to manage the disease in situ. In the present study, we developed a selective breeding program for farmed white-tailed deer in a CWD-endemic area, focused on reducing frequencies of highly susceptible PRNP variants and introducing animals with less-susceptible variants into historically high prevalence areas. We found that breeding followed predictable Mendelian inheritance, and early data support our project’s utility in reducing CWD prevalence. This project represents a novel approach to CWD management, with future efforts building on these findings.

Silicone rubber formulations in the form of thin discs have been studied under room ambient conditions for their surface characteristics. The samples were silicone rubber manufactured in laboratory and those industrially manufactured. The measurements were done using an electrometer high resistance meter, applying dc voltage under normal room ambient conditions. The results show that the silicone rubber samples show higher values of surface resistivity when the dc voltage was applied. Silicone rubber samples manufactured in laboratory seem to exhibit erratic behaviour unlike their corresponding silicone rubbers manufactured in industry; this could be due to manufacturing shortcomings in laboratory and the irregularities in the way the silicone rubber adhered to the concentric ring electrodes. The empirical current traversing the surface of the silicone rubbers does not decay exponentially but rather it decays as an exponential power of the energization time.

Dirofilaria immitis infection is one of the most severe parasitic diseases of dogs. Prevention is achieved by the administration of drugs containing macrocyclic lactones (MLs). These products are very safe and highly effective, targeting the third and fourth larval stages (L3, L4) of the parasite. Until 2011, claims of ineffectiveness of MLs, reported as “Lack of Efficacy” (LOE), were generally attributed to owners’ non-compliance, or other reason for inadequate preventative coverage. There was solid argumentation that a resistance problem is not likely to occur because of i) the great extent of refugia, ii) the complexity of resistance development to MLs, and iii) the possible big number of genes involved in resistance selection. Nevertheless, today it is unequivocally proven that ML resistant D. immitis strains exist, at least in the Lower Mississippi region, USA. Accordingly, tools have been developed, to evaluate and confirm the susceptibility status of D. immitis strains. A simple, in-clinic, microfilariae suppression test, 14-28 days after ML administration, and a “decision tree” (algorithm), including compliance and preventatives’ purchase history, and testing gaps, may be applied for assessing any resistant nature of the parasite. On the molecular level, specific SNPs may be used as markers of ML resistance, offering a basis for validation of clinically suspected resistant strains. In Europe, no LOE/resistance claims have been reported so far, and the existing conditions (stray dogs, rich wildlife, majority of owned dogs not on preventive MLs treatment) do not favor selection pressure on the parasites. Considering the genetic basis of resistance and the epizootiological characteristics of D. immitis, ML resistance neither establishes easily nor spreads quickly, a fact confirmed by the current known dispersion of the problem, which is limited. Nevertheless, ML resistance may propagate from an initial geographical point, via animal and vector mobility, to other regions, while it can also emerge as an independent evolutionary process in a new area. For these reasons and considering the current chemoprophylaxis recommendations and increasing use of ML endectoparasiticides as a potential selection pressure, it is important to remain vigilant for timely detection of any ML LOE/resistance, in all continents where D. immitis is enzootic.

Under the pressure of fluoroquinolones, Pasteurella multocida (PM) can easily develop resistance to fluoroquinolones mediated by QRDR target mutation. It is imperative to find new drug resistance inhibitor targets to combat the rapid development of drug resistance. In order to overcome these problems, we sequenced the transcriptome of PM with different levels of resistance to ENR(0.03 μg/mL; 8 μg/mL; 32μg/Ml, Enrofloxacin). The results showed that with the increase of resistance to fluoroquinolones, the expression of satP gene was significantly up-regulated. The satP gene deletion strain and replenishment strain were constructed, and their drug resistance and tolerance were determined. The results showed that the deletion of satP gene did not affect the resistance of PM to fluoroquinolones, rather affected the time when PM developed resistance to fluoroquinolones. After 10 generations of drug induction, the MIC (minimum inhibitory concentration) of fluoroquinolones for wild strain was 64 μg/mL, while the MIC for satP gene deletion strain was only 8 μg/mL. The MDK99 test (time to kill 99% bacteria),agar diffusion test and mutation frequency test showed that the tolerance of satP gene deletion strain was significantly lower than that of wild strain. At the same time, the virulence of gene deletion strain and wild strain was tested, and about 400 times decreased virulence was observed for satP gene deletion strain. The mouse infection model confirmed that mice infected with satP gene deletion strains were more likely to be treated with ENR than mice infected with wild-type bovine PM strains. The results show that satP has potential to be a target of fluoroquinolone resistance inhibitors.

Inappropriate antimicrobial treatment can pose a risk for developing resistance against antimi-crobial drugs in bacteria. Close human contact might have a higher chance of being transmitted to humans from sheep if the sheep population is a potential reservoir of zoonotic pathogens such as shiga toxin-producing Escherichia coli (E. coli) (STEC). Therefore, this study aimed to exam-ine the sheep population in rural Bangladesh for antimicrobial resistant STEC. We screened 200 faecal samples collected from sheep in three Upazila from the Chattogram district. Phenotypical-ly positive E. coli isolates were examined for two shiga toxin-producing genes – stx1 and stx2. PCR positive STEC isolates were investigated for the presence of antimicrobial resistance genes- blaTEM, sul1 and sul2. In total, 123 of the 200 tested samples were confirmed positive E. coli by cul-tured based methods. PCR results show 17(13.8%) E. coli isolates harboured ≥ one virulent gene (stx1 or/and stx2) of STEC. Six of the tested STEC isolates exhibited blaTEM gene; eight STEC isolates had sul1 gene, and sul2 gene was detected in ten STEC isolates. To our knowledge, this study is the first to reveal a significant proportion of STEC isolated from sheep in rural Bangla-desh harbouring antimicrobial resistance genes.

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.