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.

Biomaterials are the basis for the development of medicine because they allow safe contact with a living organism. The aim of this work was to produce innovative oxide layers with a porous microstructure on the surface of commercially pure titanium Grade 4 (CpTi G4), and to characterize their properties as drug carriers. Anodization of the CpTi G4 subjected to mechanical grinding and electrochemical polishing was carried out in a solution of 1M ethylene glycol with the addition of 40 g of ammonium fluoride at a voltage of 20 V for 2, 18, 24 and 48 hours at room temperature. It was found that the longer anodization time, the greater the number of pores formed on the CpTi G4 surface as revealed by FE-SEM method, and the greater the surface roughness determined in profilometric tests. As the anodizing time increases, the amount of the drug in the form of gentamicin sulfate incorporated into the resulting pores decreases. The most favorable drug release kinetics profile determined by UV-VIS absorption spectroscopy was found for the CpTi G4 anodized for 2 h making them the best choice when it comes to the drug carrier allowing full use of the therapeutic dose of the drug.

The development and evaluation of techniques that increase the efficiency of selection for planta plant resistance to pathogens is a challenge in all breeding programmes for disease resistance. Under field and laboratory conditions, hybrid populations (F1) of Coffea arabica derived from sources that carry the rust resistance gene SH1 and the CX.2385 line obtained from the Caturra variety × Timor Hybrid CIFC-1343 were evaluated. By means of survival curves, under controlled conditions, the probable times (P<0.05) for the development of symptoms associated with coffee rust were found to be highly variable. Similarly, phenotypic variation in resistance reactions was detected, and plants with incomplete resistance to rust, late development of the incubation period (PI), and no development of a latency period (PL) were identified. The results suggest the use of the detached leaf method as an alternative for the preselection of genotypes for resistance to coffee rust, which could reduce the number of plants used for field evaluations.

The difficulties faced by the society in its goal of reducing mortality and improving the health status during the period of the COVID-19 pandemic showed that it is necessary to develop new approaches in the therapy of infectious diseases, leading to higher treatment efficiency and few side effects. The subject of the present study is the formation and characterization of the proper-ties of stable liposomes loaded with extracts from Bulgarian medicinal plants and monitoring their antiviral action against the human strain of coronavirus OC43 (HCoV-OC43) in vitro. The hydrodynamic diameter and -potential of the liposomes containing each type of payload were determined with DLS and electrokinetics. The encapsulated amount of extracts was evaluated against quercetin and gallic acid by using colourimetric methods. The BALB 3T3 Neutral Red Uptake (NRU) phototoxicity/cytotoxicity assay was used to estimate the safety of the compounds. For assessment of the antiviral activity against HCoV-OC43 of liposomes (Lip) containing medicinal plant extracts, the cytopathic effect inhibition test was used. Measurements of the virucidal activity and the effect on the virus adsorption stage was carried out using the endpoint dilution method, and ∆lgs were calculated by comparison with untreated controls. The estimated photo irritation factors (PIF) for the Lip containing extracts were < 2 which assigns them to the category of non-phototoxic substances. When the extracts were introduced into the liposomes as their carriers, the antiviral activity of the vesicles against the replication of HCoV-OC43 in vitro in-creased by several times compared to their individual activity described in our previous study. The determination of the effect of structures loaded with extracts on the extracellular virions and the stage of their adsorption to sensitive HCT-8 cells proved that the liposomes do not affect directly the viral surface or cell membrane, but only perform a function of carriers of the active substances and the observed result is due solely to the intracellular action of the extracts.

Neurologic symptoms associated with Long COVID result from the persistent infection of SARS-CoV-2 in the nasal neuroepithelial cells, leading to inflammation in the central nervous sys-tem (CNS). As of today, there is no evidence that vaccines or medications can clear the persistent viral infection in the olfactory mucosa. Recently published clinical data demonstrate that only 5% of Long COVID anosmia patients have fully recovered during the past 2 years and 10.4% of COVID patients are still symptomatic 18 months post infection. Our group demonstrated that ep-igallocatechin-3-gallate-monopalmitate (EC16m) nanoformulations possess strong antiviral activ-ity against human coronavirus, suggesting this green tea-derived compound in nanoparticle for-mulations could be developed as an intranasally delivered new drug targeting the persistent SARS-CoV-2 infection, as well as inflammation and oxidative stress in the CNS, leading to resto-ration of neurologic functions. The objective of the current study is to evaluate the mucociliary safety of the EC16m nasal nanoformulations and the efficacy against human coronavirus. Meth-ods: nanoparticle size and Zeta potential were measured using the ZetaView Nanoparticle Tracking Analysis system; mucociliary safety was determined using MucilAir Human Nasal Epi-thelium Model; contact antiviral activity and post-infection inhibition against OC43 viral strain were assessed by TCID50 assay for cytopathic effect on MRC-5 cells. Results: the saline-based EC16 mucoadhesive nanoformulations containing 0.005 to 0.02% w/v EC16m have no significant difference in comparison to saline (0.9% NaCl) on tissue integrity, cytotoxicity, and cilia beat fre-quency. A 5-minute contact inactivated 99.9% of the β-coronavirus OC43. OC43 viral replication was inhibited by >99% after infected MAR-5 cells were treated with one of the formulations. Con-clusion: the saline-based novel EC16m mucoadhesive nasal nanoformulations rapidly inactivated human coronavirus with mucociliary safety measurements comparable to saline, a solution widely used for nasal applications.

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

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.

Omega-3 polyunsaturated fatty acids (ɷ-3 PUFAs) offer diverse health benefits, such as supporting cardiovascular health, improving cognitive function, promoting joint and musculoskeletal health, and contributing to healthy aging. Despite their advantages, challenges like oxidation susceptibility, low bioavailability, and potential adverse effects at high doses persist. Nanoparticle encapsulation emerges as a promising avenue to address these limitations while preserving stability, enhanced bioavailability, and controlled release. This comprehensive review explores the therapeutic roles of omega-3 fatty acids, critically appraising their shortcomings and delving into modern encapsulation strategies. Furthermore, it explores the potential advantages of Metal-organic framework nanoparticles (MOF NPs) compared to other commonly utilized nanoparticles in improving the therapeutic effectiveness of omega-3 fatty acids within drug delivery systems (DDS). Additionally, it outlines future research directions to fully exploit the therapeutic benefits of these encapsulated omega-3 formulations for cardiovascular disease treatment.

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

Resistance against amitraz in varroa mite populations has become a subject of interest in recent years due to increasing reports of reduced field efficacy of amitraz treatments, especially from some beekeepers in France and the United States. The loss of amitraz as a reliable tool to effectively reduce varroa mite infestation in the field could severely worsen the position of beekeepers in the fight to keep varroa infestation rates in their colonies at low levels. In this publication, we present data from French apiaries, collected in the years 2020 and 2021. These data include field efficacy of an authorized amitraz-based varroa treatment (Apivar®) and results of laboratory sensitivity assays of varroa mites exposed towards the reference LC90 concentration of amitraz. In addition, a total of 240 varroa mites from Eastern, Central, and Southern regions in France that were previously classified as either “sensitive” or “resistant” towards amitraz in a laboratory sensitivity assay were genotyped. The genetic analyses of mite samples are focused on the β−adrenergic-like octopamine receptor, which is considered as the main target site for amitraz in varroa mites. Special attention was given to a single nucleotide polymorphism (SNP) at position 260 of the ORβ-2R-L gene that had previously been described by Hernández Rodríguez et al. (2021) as associated to the resistance to amitraz in French varroa mites. Our findings confirm that amitraz resistance occurs in patches or “islands of resistance” with a less severe reduction in treatment efficacy compared to pyrethroid resistance or coumaphos resistance in varroa mites. The results of our genetic analyses of varroa mites call into question the hypothesis of the SNP at position 260 of the ORβ-2R-L gene being directly responsible for amitraz resistance development.

This paper explores the transformative impact of computational pharmaceutics, integrating AI, multi-scale modeling, quantum computing, AI-driven drug discovery, and blockchain frameworks. Molecular dynamics simulations provide insights into atomic behaviors crucial for drug design. Quantum computing reduces computational costs for simulating protein-drug interactions. AI and Graph Neural Networks accelerate drug discovery and personalized medicine. Blockchain frameworks facilitate secure pharmacogenetic data sharing. These advancements revolutionize drug development, offering unprecedented efficiency, innovation, and personalized treatments.

Our study investigated the innate immune response to Toxoplasma gondii infection by assessing microglial phenotypic changes and sickness behavior as inflammatory response markers post-ocular tachyzoite instillation. Disease progression in Swiss albino mice was compared with documented outcomes in BALB/c mice using identical ocular route and parasite burden (2x105 tachyzoites), with saline as control. Contrary to expectations, Swiss albino mice displayed rapid, lethal disease progression, marked by pronounced sickness behaviors and mortality within 11-12 days post-infection, while survivors showed no apparent signs of infection. Comparative analysis revealed T. gondii-infected BALB/c mice exhibited reduced avoidance of feline odors, while in-fected Swiss albino mice showed enhanced avoidance responses. There was a significant increase in microglial cells in the dentate gyrus molecular layer of infected Swiss albino mice compared to BALB/c mice and their respective controls. Hierarchical cluster and discriminant analyses iden-tified three microglial morphological clusters, differentially affected by T. gondii infection across strains. BALB/c mice exhibited increased microglial branching and complexity, while Swiss al-bino mice showed reduced shrunk microglial arbors, diminishing morphological complexity. These findings highlight strain-specific differences in disease progression and inflammatory reg-ulation, indicating lineage-specific mechanisms in inflammatory responses, tolerance, and re-sistance. These elements are critical in devising control measures for toxoplasmosis.

Drug-induced liver disease represents one of the main problems in the therapeutic field. As with most pathologies, also in this case various risk factors can be recognised, such as age, sex, but also the gut microbiota. Therefore all drugs on the market can, in fact, cause hepatotoxicity of varying degrees. Drugs used in the treatment of IBD can also cause these adverse effects and even lead to DILI. In this review, the various classes of drugs used in the treatment of IBD were taken into consideration and the various adverse effects on the liver were illustrated. In particular, a major role has emerged regarding hepatotoxicity of immunosuppressants. Biological drugs, however, seem to be responsible for these complications to a much lesser extent.

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

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.

The eutrophication of open water bodies, especially in coastal water area, has received intensive public focuses in recent years. Biological treatment of organic pollutants in industrial and domestic wastewater requires microbial flora to participate. The environmental impact of these microbes, particularly in regard to the spread of antibiotic resistance genes and pathogenicity in coastal water, remains largely unknown. We initiate studies to examine antibiotic resistance genes (ARGs) in microbial flora and study the mode of antibiotic spread in the coastal waters of Bohai Bay, North China by using high performance liquid chromatography-mass spectrum analysis and quantitative polymerase chain reaction. The metabolic features of bacteria related to the presence of ARGs in the coastal area showed the enrichment of Pseudomonadale species with triple resistance properties (ampicillin, kanamycin and gentamycin) at the estuary site locating adjacent to a coastal sewage treatment plant where both type I and type II polyketide synthase genes and b-lactam type antibiotics are detected. Pseudomonadale order is phylogenetically belonged to Proteobacteria Phylum, Gamma-proteobacteria Class and contains Pseudomonadaceae family and Pseudomonas genus. QPCR analysis suggests that the percent occupation of Pseudomonadale species to total Proteobacteria in the examined stations is close to several sampling stations close to sewage treatment plants, where consistent release of organic wastes occurred.

Within the context of sustainable material development for the construction sector, this study explores the viability of panels composed of recycled newspaper-derived cellulose (9%), rice husk (14%), borax (15%), and polyvinyl acetate-based glue (62%). The methods employed involve water absorption and density tests, following ASTM C-1763 and C-303 standards. The fire resistance test conforming to the European standard UNE 23-725-90, and a mold growth test using AOAC 2002.11. The composite is prone to absorbing a significant amount of water when exposed to humid conditions. However, the incorporation of rice husk and borax can provide benefits such as improved moisture resistance compared to other cellulitic insulators, which may be advantageous in specific climates. Also, the developed composite has an intermediate density compared to other polymeric materials. This characteristic presents advantages in applications that demand a balance between strength and lightness. During the fire resistance tests, the samples with borax presented less fire propagation, and superficial damage compared with the specimens without borax. This is important, considering the fireproofing property, required in building materials. The presence of borax in the composite has an inhibitory effect on the growth of fungi and yeasts. These findings are consistent with previous research. Nevertheless, further research and testing are imperative to assess its viability and performance for commercial applications.

The present study aimed to determine the genetic diversity of isolates of Mycobacterium tuberculosis (Mtb) from presumed drug resistant tuberculosis patients from several states of Brazil. The isolates had been submitted to conventional drug susceptibility testing for first- and second-line drugs. Multidrug-resistant (MDR-TB) (54.8%) was the most frequent phenotypic resistance profile, in addition to an important high frequency of pre-extensively resistant (p-XDR-TB) (9.2%). Using whole-genome sequencing (WGS), we characterized 298 Mtb isolates from Brazil. Besides analysis of genotype distribution and possible correlations between molecular and clinical data, we determined the performance of an in-house WGS pipeline with other online pipelines for Mtb lineages and drug resistance profile definition. Sub-lineage 4.3 (52%) was the most frequent genotype and the genomic approach revealed a p-XDR-TB level of 22.5%. We detected 20 novel mutations in three resistance genes, and six of these were observed in eight phenotypically resistant isolates. Cluster analysis of 170 isolates showed that 43.5% of the TB patients belonged to 24 genomic clusters, suggesting considerable ongoing transmission of DR-TB, including two interstate transmissions. The in-house WGS pipeline showed the best overall performance in drug-resistance prediction, presenting the best accuracy values to five of nine drugs tested. Significant associations were observed between suffering from fatal disease and genotypic p-XDR-TB (p = 0.03) and either phenotypic (p = 0.006) and genotypic (p = 0.0007) ethambutol resistance. The use of WGS analysis improved our understanding of the population structure of MTBC in Brazil, genetic and clinical data correlations and demonstrating its utility for surveillance efforts for spread of DR-TB, hopefully helping to avoid the emergence of even more resistant strains and to reduce TB incidence and mortality rates.

Wilms tumor (WT), the most prevalent type of renal cancer in children, exhibits overall survival rates exceeding 90%. However, chemotherapy resistance, which occurs in approximately 10% of WT cases, is a major challenge for the treatment of WT, particularly for advanced-stage patients. In this study, we aimed to discover potential mutation markers and drug targets associated with chemotherapy resistance in advanced stage WT. We performed exome sequencing to detect somatic mutations and molecular targets in 43 WT samples, comprising 26 advanced stage WTs, of which 7 cases are chemotherapy-resistant. Our analysis revealed four genes (ALPK2, C16orf96, PRKDC, and SVIL) that correlated with chemotherapy resistance and reduced disease-free survival in ad-vanced-stage WT. Additionally, we identified driver mutations in 55 genes within the chemo-therapy-resistant group, including 14 druggable cancer driver genes. Based on the mutation profile of the resistant WT samples, we propose potential therapeutic strategies involving platinum-based agents, PARP inhibitors, and antibiotic/antineoplastic agents. Our findings provide insights into the genetic landscape of WT and offer potential avenues for targeted treatment, particularly for patients with chemotherapy resistance.

In the current study we test the hypothesis that the consumption of macrolides in food-animals is positively associated with the prevalence of macrolide resistance in M. pneumoniae at a country-level. The prevalence of M. pneumoniae macrolide resistance was positively associated with the consumption of macrolides for both food animals (Rho = 0.66; P=0.007) and humans (Rho = 0.54; P=0.040). Linear regression analysis revealed that macrolide consumption in food animals but not humans was borderline significantly associated with macrolide resistance (coef. 5547 [95% CI -596-11691] and coef. 0.006 [95% CI -0.008-0.020], respectively).

The integration of three-dimensional (3D) printed resin denture teeth represents a significant ad-vancement in digital dentistry. This study aimed to assess their ability to withstand chipping and indirect tensile fractures, comparing them with conventionally manufactured resin denture teeth. Four groups, each comprising 30 specimens, were examined: Group 1 featured 3D printed denture teeth (NextDent, 3D Systems, Soesterberg, The Netherlands), while the others included commer-cially obtained Ivostar Shade, SpofaDent Plus, and Major Super Lux teeth. Stereolithography 3D printing was utilized to produce methacrylate-based photopolymerized resin teeth models for Group 1, while the remaining groups were commercially sourced. Chipping and indirect tensile fracture tests were performed at a speed of 1 mm/min until fracture occurred. Statistical analysis was conducted using one-way analysis of variance (ANOVA) with Tukey's honestly significant difference multiple comparisons test (p < 0.05). Results indicated that 3D-printed teeth exhibited higher indirect tensile fracture resistance than Major Super Lux and Ivostar Shade but lower than SpofaDent Plus. Additionally, in the chipping test, buccal chipping occurred in 3D-printed resin teeth without distortion. In the indirect tensile test, the fracture line emerged near the loading point, extending cervically from the inner incline of both cusps. Overall, denture teeth produced via 3D printing with printable resin materials demonstrated sufficient fracture resistance, making them suitable for prosthetic applications.

Background: Scientific literature on COVID-19 is still limited about long-term impacts on the all-body systems and they treatments. The aim of the study was to create a safe protocol-based in-tervention to improve functional and equilibrium abilities in older adults impacted by COVID-19. Methods: The study completed 46 people (intervention group: n=26; control group: n=20). Re-sistance training (RT) was held twice a week, 60 min per session for 8 weeks. The postural stability and quality of life questionnaire (WHQOOL) were conducted during pre- and post-testing. Results: Results indicated significant differences in overall stability index (OSI) with eyes open (EO), ante-rior-posterior stability index (APSI) EO, fall risk index 6-2 (FRI6-2) values in males (p

Functional genomics, a multidisciplinary subject, investigates the functions of genes and their products in biological systems to better understand diseases and find new drugs. Drug repurposing is an economically efficient approach that entails discovering novel therapeutic applications for already-available medications. Genomics enables the identification of illness and therapeutic molecular characteristics and interactions, which in turn facilitates the process of drug repurposing. Techniques like gene expression profiling and Mendelian randomization are helpful in identifying possible medication candidates. Progress in computer science allows for the investigation and modelling of gene expression networks that involve large amounts of data. The integration of data from DNA, RNA, and protein activities has resemblance to pharmacogenomics, which is of utmost importance in the development of cancer drugs. Functional genomics in drug discovery, particularly for cancer, is still not thoroughly investigated, despite the existence of a significant amount of literature on the subject. Next-generation sequencing and proteomics present highly intriguing opportunities. Publicly available databases and mining techniques facilitate the development of cancer treatments based on functional genomics. Expanding the study and application of functional genomics has great promise to advance the process of discovering and repurposing drugs, especially in the field of oncology.

Fungal infections caused by Candida spp. are responsible for high hospital morbidity and mortality rates. Therefore, there is a continuous search for new antifungal medicines, particularly ones with anti-Candida activity. This review analyzed articles published between 2002 and 2023 considering the anti-Candida activity of chemical compounds identified or isolated in plants of the Anacardiaceae family. In addition, the in-silico prediction of the isolated compounds described was performed. The analysis of 35 studies showed that extracts, essential oils, and compounds from the anti-Candida activity were frequently determined in vitro using the minimum inhibitory concentration (MIC). The most commonly tested species were Candida albicans, C. tropicalis, C. parapsilosis, C. glabrata, C. krusei, and C. guilliermondii, respectively. Essential oils were the most used form (37% of the studies). The isolated compounds with antifungal effects include cardanol, estragole, trans-anethole, β-caryophyllene, myrcene, catechin-3-o-rhamnoside, β-sitosterol-3-O-glucoside, 24Z-isomasticadienolic acid, oleanolic acid, and oleanolic aldehyde. The in-silico evaluation of those isolated compounds revealed the compounds' drug-likeness and possible antifungal activity. However, some of them showed high toxicity. In conclusion, compounds from the Anacardiaceae family show promise for developing new therapeutic antifungal drugs, especially in combination with conventional antifungals.

mRNA-lipid nanoparticle (LNP) medicinal products can be considered a platform technology because the development process is similar for different diseases and conditions, with similar noncoding mRNA sequences and lipid nanoparticles and essentially unchanged manufacturing and analytical methods utilised often for different products. It is critical not to lose the momentum built using the platform approach during the development, regulatory approval and rollout of vaccines for SARS-CoV-2 and its variants. This Review proposes a set of modifications to existing regulatory requirements for mRNA products, based on a platform perspective for quality, manufacturing, preclinical and clinical data. For the first time, we address development and potential regulatory requirements when the mRNA sequences and LNP composition vary in different products as well. In addition, we propose considerations for self-amplifying mRNA, individualised oncology mRNA products and mRNA therapeutics. Providing a predictable development pathway for academic and commercial groups, so they can know in detail what product characterisation and data are required to develop a dossier for regulatory submission, has many potential benefits. These include reduced development and regulatory costs; faster consumer/patient access and more agile development of products in the face of pandemics; and for rare diseases where alternatives may not exist or to increase survival and the quality of life in cancer patients. Therefore, achieving consensus around platform approaches is both urgent and important. This approach with mRNA can be a template for similar platform frameworks for other therapeutics and vaccines to enable more efficient development and regulatory review.

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.

Same-day desensitization (SDD) is a procedure in which desensitization to the drug suspected of causing the hypersensitivity reaction (HR) is performed on the same day as the patient's reaction. In rapid drug desensitization (RDD), desensitization to the suspected drug is performed after an allergological study. The aim of the study was to analyze the diagnostic capacity of the allergist in Oncology Day Hospital (ODH) to establish the phenotype of the HR, in the context of SDD, based exclusively on clinical biomarkers. This is a study of patients treated with desensitization on the same day they had a HR. Later an allergological study (clinical history, skin test, risk assessment, serological biomarkers, drug provocation test if applicable) was performed prior to the following administrations. A total of 35 successful SDDs were performed. A high concordance (91.5% of patients) was found between the phenotype suspected by the allergist after the initial assessment of the patient prior to SDD and the final phenotype after subsequent allergological study performed in the Allergy Department. The presence of the allergist at the ODH allows, in addition to initial treatment according to phenotype, desensitization on the day of the reaction. This will lead to personalized and precision allergology.

Background: Antibiotic resistance is an overwhelming serious difficulty globally. This necessitates the exploration of novel sources of antibiotics to overcome this challenge. Aim of the study: Bacterial Myxopyronin A production from various soil environments Egypt; as well as testing its antimicrobial activity in preclinical animal testing and randomized human clinical trials phases 1/2. Type of the study: Screening experimental study. Methodology: Different soil environments in Egypt were screened for the growth of bacterial isolates producing Myxopyronin A as an antimicrobial agent. Purification of Myxopyronin A was performed via reversed-phase HPLC. Paper disc diffusion assay, as well as the Broth dilution technique, were exploited to assess the invitro antimicrobial and minimum inhibitory concentration( MIC) of the test antibiotic. Furthermore, in vivo antimicrobial spectrum, adverse drug reactions, and pharmacokinetics were detected during animal model testing stages and human randomized clinical trials phases 1/2. Results: From the culture supernatant of the Myxobacterium Myxococcus fulvus 124B02 which was the predominant soil bacterial isolate grown on the Casein yeast peptone plate, Myxopyronin A was produced. The test antibiotic blocked the growth of many Gram +ve bacteria with MICs less than 100 mcg/ ml. In contrast, it inhibited the growth of a few Gram -ve bacteria such as Escherichia coli at MICs greater than 100 mcg/ ml. On the other hand, Eukaryotic cells such as fungal and human cells were not affected. Prokaryotic DNA-dependant-RNA polymerase( RNLP) was noticed to be inhibited via the test antibiotic suggesting its bactericidal action. The maximum concentration was 7-8 mcg/ ml at a maximum time of 2 hours when 600 mg dose was orally administered in randomized human clinical trials phases 1/2, and T1/2 reached 2.5 hours following first-order kinetics of elimination. The duration of its action was nearly 12 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 cholestatic jaundice in less than 5 % of experimental candidates. Conclusion: The present study was promising due to the bactericidal antibiotic Myxopyronin A production from Myxococcus fulvus 124B02 isolated from different soil environments in Egypt.

Abstract Octreotide is the first synthetic peptide hormone, consisted of eight amino acids, that mimics the activity of somatostatin, a natural hormone in the body. During the past decades, advanced instrumentation and crystallographic software established X-ray Powder Diffraction (XRPD) as a valuable tool for extracting structural information of biological macromolecules. The latter was demonstrated by the successful structural determination of octreotide at a remarkably high d-spacing resolution (1.87 Å) (PDB code: 6vc1). This study focuses on the response of octreotide to different humidity levels and temperatures, with a particular focus on the stability of the polycrystalline sample. XRPD measurements were accomplished employing an Anton Paar MHC-trans humidity-temperature chamber installed within a laboratory X’Pert Pro diffractometer (Malvern Panalytical). The chamber is employed to control and maintain precise humidity and temperature levels of samples during XRPD data collection. Pawley analysis of the collected data sets revealed that the octreotide polycrystalline sample is remarkably stable and no structural transitions were observed. The compound retains its orthorhombic symmetry (space group: P212121, a = 18.57744(4) Å, b = 30.17338(6) Å, c = 39.70590(9) Å, d~ 2.35 Å). However, a characteristic structural evolution in terms of lattice parameters and volume of the unit-cell is reported mainly upon controlled relative humidity variation. In addition, an improvement of signal-to-noise ratio in the XRPD data under a cycle of dehydration/rehydration is reported. These results underline the importance of considering the impact of environmental factors, as humidity and temperature, in the context of structure-based drug design, thereby contributing to the development of more effective and stable pharmaceutical products.

Background: Antibiotic resistance is an urgent issue everywhere in the globe. It is necessary to look into new sources of antibiotics to address this issue. Aim of the study: studying the purification of Corallopyronin B from various soil conditions in Egypt, as well as the antibacterial effectiveness of Corallopyronin B in preclinical animal testing and randomized human clinical trials phases 1/2. Type of the study: Screening experimental study. Methodology: Several soil conditions in Egypt were examined to create bacterial isolates that generated the antibiotic chemical Corallopyronin B. Using reversed-phase HPLC, Myxopyronin B was purified. The test antibiotic's minimum inhibitory concentration( MIC) and in vitro antibacterial activity were ascertained using the paper disc diffusion assay and the broth microdilution technique. Furthermore, in stages 1/2 of randomized clinical trials including human and animal models, pharmacokinetics, adverse drug reactions, and the in vivo antibacterial spectrum were discovered. Results: The soil bacterial isolate Corallococcus coralloides DSM 2259, which was grown on a Casein yeast peptone( CYP) plate, produced Corallopyronin B from its culture supernatant. At MICs more than 100 mcg/ml, the test antibiotic inhibited the growth of many Gram -ve bacteria, including Escherichia coli, while also preventing the growth of numerous Gram +ve bacteria, with MICs ranging from 1 to 10 mcg/ml. Eukaryotic cells, on the other hand, including those in humans and fungi, were unharmed. The test antibiotic was shown to have a bactericidal effect by inhibiting bacterial DNA-dependent RNA polymerase( RNLP). In phases 1/2 of randomized human clinical trials, when 600 mg of the dose per 70 kg of body weight was administered SC, the Cmax was 8.6 mcg/ml at Tmax 1 hour; T1/2 reached 136 min following first-order kinetics of elimination. It stopped acting around 6-7 hours after SC was administered. In the preclinical and randomized human clinical trial phases 1/2, less than 6 percent of experimental candidates had uncommon toxicity, which showed up as reduced bile flow. Protein binding with plasma albumin was detected which reached about 83%. Conclusion: The current work was noteworthy since it involved the production of the bactericidal antibiotic Corallopyronin B from Corallococcus coralloides DSM 2259 which was isolated from several soil environments in Egypt.

The legume-rhizobia symbiosis is one of the most important plant-microbe interactions in sustainable agriculture due to its ability to provide much needed N to cropping systems. This interaction is mediated by the mutual recognition of signaling molecules from the two partners, namely legumes and rhizobia. With legumes, these molecules are in the form of flavonoids and anthocyanins, which are responsible for the pigmentation of plants parts, such as seeds, flowers, fruits and even leaves. Seed coat pigmentation in legumes is a dominant factor influencing gene expression relating to N2 fixation, and may be responsible for the different N2-fixing abilities observed among legume genotypes under field conditions in African soils. Cowpea, Kersting’s bean and Bambara groundnut landraces with black seed coat color are reported to release higher concentrations of nod-gene-inducing flavonoids and anthocyanins when compared to the Red and Cream landraces, hence the black seed coat pigmentation is considered a biomarker for enhanced nodulation and N2 fixation. Cowpea, Bambara groundnut and Kersting’s bean with differing seed coat colors are known to attract different native soil rhizobia, confirmable by PCR-RFLP analysis of bacterial DNA from root nodules of these legumes. Even when seeds of the same legume with diverse seed coat colors were planted together in one hole, the nodulating bradyrhizobia clustered differently in the PCR-RFLP dendrograms. In one study, Kersting’s groundnut, Bambara groundnut and cowpea with differing seed coat colors were selectively nodulated by different bradyrhizobial species. Multilocus sequence analysis showed that different Bradyrhizobium species nodulated the Kersting's bean based on seed coat color. Phylogenetic analysis also placed the bradyrhizobial isolates in close proximity to different Bradyrhizobium species such as B. vignae 7-2T, B. subterraneum 58 2-1T, B. kavangense 14-3T, B. liaoningense 2281 (USDA 3622)T, B. yuanmingense LMG 21827T, B. huanghuaihaiense CCBAU 23303T, B. pachyrhizi PAC48T, and a reference type strain of B. elkanii according to seed coat color. Using 16S rDNA amplicon sequencing, we also found significant selective influences of seed coat pigmentation on microbial community structure in the rhizosphere of five Kersting’s groundnut landraces. For example, the rhizosphere of Belane Mottled landrace was dominated by Proteobacteria, while Bacteroidetes dominated the rhizospheres of the other landraces. With legumes, seed coat pigmentation therefore plays a dominant role in the selection of the bacterial symbiotic partner.

Bananas, a staple food globally and a key agricultural commodity, face a severe threat from the fungus Fusarium oxysporum form specialis cubense (Foc), significantly impacting production. Genetic improvement to develop resistant cultivars stands out as a crucial strategy to mitigate this disease. This study focused on assessing and recommending enhanced diploid banana varieties for resistance against Foc subtropical race 4 (ST4) and Foc race 1 (R1). Twenty-five improved diploids developed by Embrapa, Brazil, underwent evaluation. Utilizing a scale for internal symptoms at 90 days post-inoculation, genotypes were categorized from highly resistant to highly susceptible based on the internal symptom index. The diploid M53 exhibited high resistance to R1 and resistance to Foc ST4, while only the diploid CNPMF 0534 demonstrated complete resistance to both R1 and ST4, with resistance to the latter likely associated with penetration. These findings provide valuable insights for banana and plantain breeding programs, offering selected diploids for crossbreeding with commercial cultivars to develop new, resistant genotypes against Foc.

The Maastricht VI/Florence consensus recommends, as one of the measures to enhance the efficacy of Helicobacter pylori (H. pylori) infection eradication, a personalized treatment approach involving the selection of an antimicrobial agent based on the pre-determined resistance of H. pylori. To meet the need to develop test systems for personalized drug selection, we conducted a study of H. pylori molecular resistance in Moscow using a self-developed Sanger sequencing test platform. We validated our test system on 25 pure culture samples of H. pylori with known resistance. Sensitivity and specificity for detecting resistance to clarithromycin was 100%, and to levofloxacin - 93% and 92%, respectively. Then we tested our platform on 112 H. pylori -positive patients who had not previously received proton pump inhibitors (PPI) or antibacterial drugs. Mutations indicating resistance to clarithromycin were found in 27 (24%) samples, and to levofloxacin in 26 (23%) samples. Double resistance was observed in 16 (14%) samples. The most common mutations leading to clarithromycin resistance were 2143G and 2142G, to levofloxacin resistance – 261A and 271A in the gyrA gene, which account for 69% of all identified genetic determinants in levofloxacin-resistant bacteria. Thus, a personalized approach to the selection of H. pylori eradication therapy based on the detection of bacterial resistance before prescribing first-line therapy could help avoid the prescription of ineffective H. pylori eradication therapies and, overall, contribute to the control of antibiotic resistance of H. pylori.

For the first time, the effect of a significant change in the resistance of the aquatic environment of a population of protozoan microorganisms under the influence of radiofrequency electromagnetic radiation from cell phones has been experimentally studied. The results of the experiment demonstrate the biological nature of the changes occurring in the “water population of protozoa” system, which indicates that the impact of radiation directly affects the cell. This conclusion is confirmed by the same order of magnitude time of information exchange between individual individuals of the population in the calculation and in the experiment. An extremely low concentration of protozoa in the experiment was established, equal to 1000 pcs./liter, at which the indicated effect is observed.An unambiguous dependence of the biological effect in the “water – amoeba population” system on the average power of electromagnetic radiation of cell phones, both in standby mode and in talk mode, has been established. It is concluded that the presented method of changing the physical properties of the aquatic environment of a population of protozoa under the influence of electromagnetic fields can be a model experiment in identifying the mechanisms of interaction of biological systems with electromagnetic radiation, determining the response time of biological systems to external electromagnetic influence, and establishing the degree of influence of radiation in the 4G, 5G ranges.

The domestic ducks (Anas platyrhynchos domesticus) are resistant to most of the highly pathogenic avian influenza virus (HPAIV) infections. In this study, we characterized the lung proteome and phosphoproteome of ducks infected with HPAI H5N1 virus (A/duck/India/02CA10/2011/Agartala) at 12 hr, 48 hr and 5 days post infection condition. Total 2082 proteins were differentially expressed and 320 phosphorylation sites mapping to 199 phosphopeptides corresponding to 129 proteins were identified. Functional annotation of proteome data analysis reveals activation of RIG-I-like receptor and Jak-STAT signaling pathways, that lead to induction of interferon stimulated genes (ISGs) expression. The pathway analysis of phosphoproteome datasets also confirms the activation of RIG I, Jak-STAT signaling, NF-kappa B signaling and MAPK signaling pathways in the lung tissues. The induction of ISGs proteins (STAT1, STAT3, STAT5B, STAT6, IFIT5 and PKR) establishes protective antiviral immune response in duck lung tissue. Further, the protein-protein interaction network analysis identified proteins like AKT1, STAT3, JAK2, RAC1, STAT1, PTPN11, RPS27A, NFKB1 and MAPK1 as main hub proteins that might play important roles in disease progression in ducks. Together, functional annotation of proteome and phosphoproteome datasets reveals the molecular basis of the disease progression and disease resistance mechanism in ducks infected with HPAI H5N1 virus.

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

Fusarium wilt (FW) caused by Fusarium oxysporum f. sp. Cucumerinum (Foc) of cucumber is a destructive soil-borne disease in cucumber (Cucumis sativus.L). There is limited knowledge on molecular mechanisms to FW resistance-mediated defense responses in cucumber. In this study, metabolome and transcriptome profiling were carried out in two FW, resistant (NR) and susceptible (NS), near isogenic lines (NILs) before and after Foc inoculation. The NILs showed consistent and stable FW resistances in multiple greenhouse and laboratory screening tests. Widely targeted metabolomic analysis identified differentially accumulated metabolites (DMAs) with significantly more accumulation in NR in response to Foc infection including many phenolic acid and flavonoid compounds from the flavonoid biosynthesis pathway. Transcriptome analysis identified differentially expressed genes (DEGs) between the NILs upon Foc inoculation including genes for secondary metabolite biosynthesis in or transcription factor genes regulating the flavonoid biosynthesis pathway. Joint analysis of the metabolomic and transcriptomic data identified DAMs and DEGs closely associated with biosynthesis of phenolic acid and flavonoid DAMs. The association of these compounds with NR-conferred FW resistance was exemplified by in vivo assays in which two phenolic acid compounds, bis (2-ethylhexyl) phthalate and diisooctyl phthalate, and the flavonoid compound gallocatechin 3-O-gallate were shown to have significant inhibitory effect on Foc growth. The antifungal effect of three compounds seems to be a novel finding. We conclude that phenolic acids and flavonoids play an important role in NR mediated FW resistance in cucumber.

Glioblastoma (GBM) is the most common malignant brain tumor in adults. Despite advancements in treatment, the prognosis for patients with GBM remains poor due to its aggressive nature and resistance to therapy. CRISPR-based genetic screening has emerged as a powerful tool for identifying genes crucial for tumor progression and treatment resistance, offering promising targets for tumor therapy. In this review, we provide an overview of the recent advancements in CRISPR-based genetic screening approaches and their applications in GBM. We highlight how these approaches have been used to uncover genetic determinants of GBM progression and susceptibility to various therapies. Furthermore, we discuss ongoing challenges and future directions of CRISPR-based screening methods in advancing GBM research.

Antibody-drug conjugates (ADCs), a groundbreaking advancement in cancer therapy, synergistically combine the precision of monoclonal antibodies with the potent destruction capabilities of cytotoxic drugs, signifying a new era in the targeted oncological treatments. This comprehensive paper delves into the evolving field of antibody-drug conjugates (ADCs) and their pivotal role in cancer therapy. We have conducted an in-depth exploration of the structural components of ADCs, including target antigens, monoclonal antibodies, chemical linkers, and cytotoxic payloads, each playing a crucial role in determining the efficacy and safety profile of these novel therapies. A detailed market analysis reveals the leading pharmaceutical companies shaping the ADC landscape, reflecting the growing interest and potential in this therapeutic approach. We further dissect the engineering intricacies of ADCs, focusing on their ability to target specific cancer cell antigens while minimizing off-target effects, thus offering a more focused treatment with reduced systemic side effects compared to traditional chemotherapy. This approach holds promise in a heightened therapeutic index and decreased toxicity. The mechanisms and effector functions of ADCs are explored, highlight- ing their multifaceted strategy in combating cancer. We include a comprehensive look at how ADCs operate from initial blood circulation to the induction of apoptosis in cancer cells. We also review several key ADCs currently in use or under investigation, offering insights into their unique mechanisms of action, pharmacokinetics, and clinical implications. The discussion extends to drug creation modalities, focusing on innovative conjugation techniques that enhance ADC homogeneity and therapeutic efficacy. In conclusion, the paper underscores the transformative potential of ADCs in the realm of cancer treatment, marking a shift towards more precise and targeted therapeutic approaches. By offering a thorough analysis of ADC technology, this paper sheds light on the prospects of these groundbreaking therapies in the ongoing fight against cancer.

The delivery of therapeutical molecules through the skin, particularly to its deeper layers is impaired due to the stratum corneum layer, which acts as barrier to foreign substances. Thus, for the past years, scientists have focused on the development of more efficient methods to deliver molecules to skin distinct layers. Microneedles, as a new class of biomedical devices, consists on an array of microscale needles. This particular biomedical device had been drawing attention due to their ability to breach the stratum corneum, forming micro-conduits to facilitate the passage of therapeutical molecules. The microneedle device has several advantages over conventional methods, such as better medication adherence, easiness and painless self-administration. Moreover, it is possible to deliver the molecules swiftly or over time. Microneedles can vary in shape, size and composition. The design process of a microneedle device must take in account several factors, like the location delivery, the material and manufacturing process. Microneedles have been used in a large number of fields from drug and vaccine application, cosmetics, therapy, diagnosis, tissue engineering, sample extraction, cancer research, wound healing, among others.

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

This aim of this study was to investigate the relationships between lifestyle factors, insulin resistance, and male fertility in 73 men with and without insulin resistance. The participants were divided based on insulin resistance status. Their physical activity, diet, perceived stress, sleep quality, libido level, and the duration of sexual abstinence were assessed on the basis of a number of parameters, including indices proposed by the authors. The results highlighted associations between a number of parameters, i.e., micronutrient and vitamin intake, diet quality, body composition, insulin resistance, and the duration of sexual abstinence, and semen quality, as measured by sperm motility. Significantly, the presence or absence of insulin resistance was linked to male fertility. A multivariate model was developed, incorporating parameters such as the Matsuda index, vitamin intake, and sexual abstinence duration, to predict motility scores. The study underscores the negative impact of modern civilization’s lifestyle choices on male fertility. Notably, vitamin and mineral consumption, especially from antioxidant-rich diets like the Mediterranean diet, emerged as key modifiable factors affecting fertility. Routine diagnostics for insulin resistance in fertility-related interventions is recommended. The study also highlights the importance of considering sexual abstinence duration during semen collection for accurate diagnostic results. Future research should focus on validating the proposed multivariate model and exploring the effects of lifestyle modifications, particularly vitamin supplementation, on fertility outcomes in men, especially in the context of insulin resistance.

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.

This study proposes an innovative pharmacovigilance approach, VIGI-4, leveraging ChatGPT Teams Pro version. Our method involves aggregating data from all phase 4 studies published in February 2024 to identify adverse reactions. These results are categorized by disease state alphabetically, demonstrating the method's capacity to generate structured and easily navigable outputs. The results section is tailored to exemplify the valuable, actionable insights attainable through our workflow. This research emphasizes the game-changing potential of integrating advanced technologies such as ChatGPT into pharmacovigilance, signaling a new era in safeguarding drug safety.

Background: The Coronavirus Disease 2019 (COVID-19) pandemic presented a new challenge in modern medicine. The development of vaccines was followed by massive population vaccinations. A few reports on post-vaccination allergic reactions have made patients and medical personnel uneasy as to anti-COVID-19 vaccines’ allergising potential. Most of the studies in this area to date have been small, and some that were based on global databases skipped most of the allergic diseases and concentrated only on anaphylaxis. We aimed to analyse the incidence of serious allergic reactions based on the EudraVigilance (EV) database, regardless of the reported symptoms and allergy mechanism. Methods: The total number of administrated vaccine doses was extracted on the 5th October 2023 from Vaccine Tracker and included all administrations since vaccinations began in the European Economic Area (EEA). Data on serious allergic reactions to COVID-19 vaccines was extracted from the EudraVigilance database with the same time point. The code names of 147 allergic symptoms or diseases were used. Results: The frequency of serious allergic reactions per 100,000 administered vaccine doses was 1.53 for Comirnaty, 2.16 for Spikevax, 88.6 for Vaxzevria, 2.11 for Janssen, 7.9 for Novavax, 13.3 for VidPrevtyn Beta and 3.1 for Valneva. The most prevalent reported reactions were oedema (0.46) and anaphylaxis (0.40). Only 6% of these reactions were delayed hypersensitivity-oriented. Conclusions: The overall frequency of potential serious allergic reactions to COVID-19 is very rare. Therefore, COVID-19 vaccines seem to be safe for human use. The lowest frequency of allergic reaction was observed for Comirnaty and the highest for Vaxzevria.

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

Neurodegenerative diseases (NDs) are a set of progressive, chronic, and incurable diseases characterized by the gradual loss of neurons, culminating in the decline of cognitive and/or motor functions. Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common NDs and represent an enormous burden both in terms of human suffering and economic cost. The available therapies for AD and PD only provide symptomatic and palliative relief for a limited period and are unable to modify the diseases’ progression. Over the last decades, research efforts have been focused on developing new pharmacological treatments for these NDs. However, to date, no breakthrough treatment has been discovered. Hence, the development of disease-modifying drugs able to halt or reverse the progression of NDs remains an unmet clinical need. This review summarizes the major hallmarks of AD and PD and the drugs available for pharmacological treatment. It also sheds light on potential directions that can be pursued to develop of new, disease-modifying drugs to treat AD and PD, thereby decreasing the social and economic burdens linked to these NDs.

Dysregulation of the Cyclin-dependent kinase 8 (CDK8) activity has been associated to many diseases including the colorectal and breast cancer. As usual in the CDK family, the activity of CDK8 is controlled by a regulatory protein called cyclin C (CycC). But while human CDK family members are generally activated in two steps that is, the binding of the cyclin to CDK and the phosphorylation of a residue in the CDK activation loop, CDK8 does not require the phosphorylation step to be active. Another peculiarity of CDK8 is its ability to be associated to CycC while adopted an inactive form. These specificities raise the question of the role of CycC in the complex CDK8-CycC, which appears to be more complex than for the other members of CDK family. Through MD simulations and binding free energy calculations, we investigated the effect of CycC on the structure and dynamics of CDK8 on the one hand, and the structural molecular basis of the protein-protein interaction between the two partners on the other hand. We found that CycC has a stabilizing effect on CDK8 and identified specific interaction hotspots within its interaction surface compared to other human CDK/Cyc pairs. Targeting these specific interaction hotspots could be a promising approach in terms of specificity, to effectively disrupt the interaction between CDK8. The simulation of the conformational transition from the inactive to the active form of CDK8 suggests that the residue Glu99 of the CycC may assume the role of the missing phosphorylation step in the activation mechanism of CDK8. In a more general view, these results point the importance of keeping the CycC in computational studies when studying the human CDK8 protein in both the active and the inactive form.

The PAX8/PPARγ rearrangement, producing the PAX8–PPARγ fusion protein (PPFP), is thought to play an essential role in the oncogenesis of thyroid follicular tumors. To identify PPFP-targeted drug candidates and establish an early standard of care for thyroid tumors, we performed ensemble docking-based compound screening. Specifically, we investigated which pocket structure should be adopted to search for a promising ligand compound for the PPFP; the position of the ligand binding pocket on the PPARγ side of the PPFP is common to that of PPARγ; however, the shape is slightly different between them due to environmental factors. We developed a method for selecting a PPFP structure with a relevant pocket and high prediction accuracy for ligand binding. This method was validated using PPARγ, whose structure and activity values are known for many compounds. Then, we performed docking calculations to PPFP for 97 drug or drug-like compounds with a thiazolidine backbone, which is one of the characteristics of ligands that bind well to PPARγ, registered in the DrugBank database. Furthermore, the binding affinities of promising ligand candidates were estimated more reliably using the molecular mechanics-Poisson–Boltzmann surface area method. Thus, we propose promising drug candidates for the PPFP with a thiazolidine backbone.

Probiotics are microorganisms infused in products for health benefits including acceleration of nutrient digestion, however, it is also important to ensure the safety prior to incorporation. Here, we present evidence of the ability of two probiotic isolates,Lacticaseibacillus paracasei BCRC-16100 and Lacticaseibacillus paracasei ZFM54, in the (1) enhancement of carbohydrate digestion, (2) tolerance to stress, and (3) antibiotic resistance. Approaches include whole genome sequence (WGS) analysis and bioactivity assays. WGS revealed genes suggesting the ability of the two isolates to promote carbohydrate digestion, tolerance to stress and antibiotic resistance. Carbohydrate digestive ability was confirmed through a biochemical assay where the two isolates cause glucose release from starch. The two isolates also showed versatility in a range of temperature and alcohol concentration. For antibiotic resistance particularly on vancomycin, there are three mechanisms namely transporter control, transcriptional regulation, and efflux pump. Furthermore, promoter and transposable element analysis showed that some of the active antibiotic resistant (AbR) genes can be laterally transferred. Altogether, we show the potential of two probiotic isolates to be incorporated in products for improved carbohydrate digestion and the need to address the removal of active and mobile antibiotic resistance genes that may compromise safety.

Post-operative chemotherapy is still required for the treatment of glioblastoma (GBM), and nanocarrier-based drug delivery has been identified as one of the most effective methods. However, the blood-brain barrier (BBB) and non-specific delivery to non-tumor tissues can significantly limit drug accumulation in tumor tissues and cause damage to nearby normal tissues. This study describes a targeted cancer therapy approach that uses AS1411 aptamer-conjugated nanospheres, 100-300 nm in size, loaded with doxorubicin (Dox) to selectively identify tumor cells overexpressing nucleolin (NCL) proteins. The study demonstrates that the active target model, which employs aptamer-mediated drug delivery, is more effective than nonspecific enhanced permeability and maintenance (EPR)-mediated delivery and passive drug delivery in improving drug penetration and maintenance in tumor cells. Additionally, the study shows the potential for anticancer effects through 3D spheroidal and in vivo GBM xenograft models. The DNA-protein hybrid nanospheres utilized in this study offer numerous benefits, such as efficient synthesis, structural stability, high drug loading, dye labelling, biocompatibility, and biodegradability. When combined with nanospheres, the 1411 aptamer has been shown to be an effective drug delivery carrier for precisely targeting tumors. This combination has the potential to produce anti-tumor effects in active targeted therapy of GBM.

Geopolymer concrete (GPC) represents an innovative green and low-carbon construction material, offering a viable alternative to ordinary Portland cement concrete in building applications. However, existing studies tend to overlook the recyclability aspect of GPC for future use. Various structural applications necessitate the use of concrete with distinct strength characteristics. The recyclability of the parent concrete is influenced by these varying strengths. This study examined the recycling potential of GPC across a spectrum of strength grades (40, 60, 80 and 100 MPa, marked as C40, C60, C80 and C100) when subjected to freeze-thaw conditions. The cementitious material comprised 60% metakaolin and 40% slag, with natural gravel serving as the coarse aggregate, and the alkali activator consisting of sodium hydroxide solution and sodium silicate solution. The strength of the GPC was modulated by altering the Na/Al ratio. After 350 freeze-thaw cycles, the GPC specimens underwent crushing, washing, and sieving to produce recycled geopolymer aggregates (RGAs). Subsequently, their physical properties and microstructure were thoroughly examined. The findings indicated that GPC with strength grades of C100, C80, and C60 were capable of enduring 350 freeze-thaw cycles, in contrast to C40, which did not withstand these conditions. RGAs derived from GPC of strength grades C100 and C80 complied with the criteria for Class II recycled aggregates, whereas RGAs produced from GPC of strength grade C60 aligned with the Class III level. A higher strength grade in the parent concrete correlated with enhanced performance characteristics in the resulting recycled aggregates.

Lead optimization in drug discovery is a crucial phase where initial hits are refined into compounds with improved pharmacological properties. While traditional methods rely on manual experimentation and modifications, AI-driven techniques have revolutionized this process by leveraging big data and predictive modeling. This review explores how AI-driven approaches accelerate lead optimization, showcasing examples like deep neural networks and reinforcement learning. Integration of multi-omic data and experimental validation further enhances AI-driven strategies. The future lies in refining these AI methods, democratizing tools, and interdisciplinary collaboration to streamline drug discovery and address medical needs efficiently.

Aquaculture is an important source of food for the growing global population. To meet the increasing demand for fish, intensive aquaculture methods are commonly used. However, these methods can lead to stress and disease in fish, which can result in significant economic losses. Gamma-aminobutyric acid (GABA) is a non-protein amino acid that is found in the brain and central nervous system of animals as inhibitory neurotransmitter. It has been shown to have a variety of physiological functions, including stress reduction and immune enhancement. This study investigated the effects of dietary supplementation of GABA on growth, serum biochemistry, innate immunity and disease resistance in juvenile olive flounder (Paralichthys olivaceus) challenged with Edwardsiella tarda under high stocking density. A control diet and three experimental diets were prepared, with 150 mg/kg (GABA150), 200 mg/kg (GABA200), and 250 mg/kg (GABA250) of GABA added to each diet, respectively. The actual GABA content of the experimental diets was analyzed and found to be 63.9 mg/kg (CON), 231.3 mg/kg (GABA150), 291.6 mg/kg (GABA200), and 323.9 mg/kg (GABA250). Each experimental diet was fed to olive flounder with an initial weight of 12.75 g ± 0.3 g in 40 L tanks at two stocking densities: normal density (20 fish/tank) and high density (40 fish/tank). The experiment was conducted in triplicate for each diet and stocking density. The water temperature was maintained at 17.5 ± 1℃ and the salinity at 33 ± 1 ppt. After 8 weeks of feeding trial, growth, feed utilization, whole-body proximate composition, blood analysis, non-specific immune response, and challenge test were performed. There were no significant difference in weight gain and specific growth rate among the GABA concentrations and density × GABA concentration interaction groups. However, the low-density groups showed significantly higher values than the high-density groups (P &lt; 0.05). There was no significant difference in feed efficiency and protein efficiency ratio among all groups. Moreover, there was no significant difference in the whole-body general composition analysis (P &gt; 0.05). In the hematological analysis, there was no significant difference in cortisol in terms of diet and density × GABA concentration interaction, but the high-density experimental group showed a significantly higher value. Blood GABA significantly increased in proportion to the addition amount regardless of the density group (P&lt;0.05). Superoxide dismutase activity in the non-specific immune response showed that the GABA-added experimental group had a significantly higher value than the control group, but there was no significant effect of the density densities or density × GABA concentration interaction (P&lt;0.05). Myeloperoxidase activities in fish fed the GABA200 and GABA250 diets showed significantly higher values, and a density × GABA concentration interaction effect was observed (P&lt;0.05). Lysozyme activity was significantly higher in the GABA150 group than in the CON, GABA200, and GABA250 groups (P &lt; 0.05). After 15 days of challenge test by intraperitoneal injection of Edwardsiella tarda, the cumulative survival rates of the GABA150, GABA200, and GABA250 groups were significantly higher than that of the CON group (P &lt; 0.05). The results suggested that the optimal dietary GABA level for juvenile olive flounder culture is 150 mg/kg, regardless of rearing density, to enhance growth, immune function and disease resistance.

Drugs are known to cause substantial liver injury, with hepatotoxicity ranging from asymptomatic increase of liver enzymes to hepatic failure. HIV/AIDS patients, with compromised immune systems, are especially vulnerable to opportunistic infections such as tuberculosis (TB). Patients with co-infection frequently get combined antiretroviral (ART) and antitubercular (ATD) regimens, which can cause hepatotoxicity. Hepatotoxicity has been linked to commonly administered antiretroviral drug regimens as well as first-line antitubercular agents such isoniazid, rifampin, and pyrazinamide, which are required for the treatment of both drug-sensitive and drug-resistant tuberculosis. As a result, there is an urgent need to investigate treatments based from traditional herbs known for their hepatoprotective abilities against ART and ATD-induced liver injury. Many researchers have investigated the effectiveness of medicinal plants in treating chemically caused hepatotoxicity. Medicinal plants are high in phytochemicals and secondary metabolites, both of which have a variety of medicinal benefits. Currently, there is a lack of specific therapeutic regimens to address this adverse effect, and management often relies on symptomatic treatment or therapy withdrawal. Traditional medicinal plants may have the potential to restore normal liver function, enzyme activity, and cellular structure in response to ART and ATD-induced hepatotoxicity. This review aims to examine the scientific evidence supporting the use of medicinal plants as hepatoprotective agents against liver damage induced by ART and ATDs.

Abstract: Colistin is a last-resort antimicrobial for treating multidrug-resistant Gram-negative bacteria. Phe-notypic colistin resistance is highly associated with plasmid-mediated mobile colistin resistance (mcr) genes. mcr-bearing Enterobacteriaceae have been detected in many countries, with the emergence of colistin-resistant pathogens a global concern. This study assessed the distribution of mcr-1, mcr-2, mcr-3, mcr-4, and mcr-5 genes with the phenotypic colistin resistance in isolates from diarrheal infants and children in Bangladesh. Bacteria were identified using the API-20E biochemical panel and 16s rDNA gene sequencing. Polymerase chain reac-tions detected mcr gene variants in the isolates. Their susceptibilities to colistin were determined by agar dilu-tion and E-test by minimal inhibitory concentration (MIC) measurements. Over 30.0% (69/225) of isolates showed colistin resistance by agar dilution assessment (MIC> 2.0 μg/mL). Overall, 15.5% of isolates carried mcr genes (7, mcr-1; 17, mcr-2; 13, mcr-3; and co-occurrence occurred in 2 isolates). Clinical breakout MIC val-ues (≥ 4 μg/mL) were associated with 91.3% of mcr-positive isolates. The mcr-positive pathogens include twenty Escherichia spp., five Shigella flexneri, five Citrobacter spp., two Klebsiella pneumoniae, and three Pseudo-monas parafulva. mcr-genes appeared to be significantly associated with phenotypic colistin resistance phe-nomena (p=0.000), with 100% colistin-resistant isolates showing MDR phenomena. Age and sex of patients showed no significant association with detected mcr variants. Overall, mcr-associated colistin-resistant bacte-ria have emerged in Bangladesh, which warrants further research to determine their spread and instigate ac-tivities to reduce resistance.

The development of multiple drug resistant (MDR) cancer all too often signals the need for alternative toxic therapy or palliative care. Our recent in vivo and in vitro studies using canine MDR lymphoma cancer cells demonstrated that the Anaphase Promoting Complex (APC) is impaired in MDR cells compared to normal canine control and drug sensitive cancer cells. Here, we sought to establish whether this phenomena is a generalizable mechanism independent of species, malignancy type or chemotherapy regime. To test the association of blunted APC activity with MDR cancer behavior, we used matched parental and MDR MCF7 human breast cancer cells, and a patient derived xenograft (PDX) model of human breast cancer. We show that APC activating mechanisms, such as APC subunit 1 (APC1) phosphorylation and CDC27/CDC20 protein associations, are reduced in MCF7 MDR cells when compared to chemosensitive matched cell lines. Consistent with impaired APC function in MDR cells, APC substrate proteins failed to be effectively degraded. Similar to our previous observations in canine MDR lymphoma cells, chemical activation of the APC using Mad2 Inhibitor-1 (M2I-1) in MCF7 MDR cells enhanced APC substrate degradation and resensitized MDR cells in vitro to the cytotoxic effects of the alkylating chemotherapeutic agent, Doxorubicin (DOX). Using cell cycle arrest/release experiments we show that chemo-sensitive and -resistant MCF7 cells progress through the cell cycle at similar rates, but mitosis is delayed in MDR cells with elevated substrate levels. When treated with M2I-1, MDR cells progress through mitosis at a faster rate that coincides with reduced levels of APC substrates. In our PDX model, mice growing a clinically-MDR human breast cancer tumor show significantly reduced tumor growth when treated with M2I-1, with evidence of increased DNA damage and apoptosis. Thus, our results strongly support the hypothesis that APC impairment is a driver of aggressive tumor development and that targeting the APC for activation has the potential for meaningful clinical benefits in treating recurrent cases of MDR malignancy.

Background: Targeting Hepatitis B virus (HBV) infection in human is crucial due to its adverse. Herbal medicine has long been significant in this regard, with flavonoids demonstrating promising results. Hence, establishing a way of identifying flavonoids with anti-HBV activities is the aim of the present study. Methods: Flavonoid structures with anti-HBV activities were retrieved. A flavonol-based pharmacophore model was established using LigandScout v4.4. Screening was performed using the PharmIt server. A QSAR equation was developed and validated with independent sets of compounds. Applicability domain (AD) was defined using Euclidean distance calculations for model validation. Results: The best model, consisting of 57 features was generated. HTS using the flavonol-based model resulted in 509 unique hits. The model's sensitivity and specificity were 71% and 100%, respectively. The QSAR model with two predictors, x4a and qed, exhibited strong predictive performance with an adjusted-R² value of 0.85 and 0.90 of Q2. Conclusion: The QSAR model has been validated with two separate chemical sets, guaranteeing the model's reproducibility and usefulness for other flavonols by utilizing the predictive characteristics of X4A and qed. These results provide new possibilities for discovering future anti-HBV drugs by integrating modeling and experimental research.

Lung adenocarcinoma is the most prevalent form of lung cancer, and drug resistance is a significant obstacle in its treatment. This study aimed to investigate the overexpression of long non-coding RNAs (lncRNAs) as a mechanism that promotes intrinsic resistance in tumor cells from the onset of treatment. Drug-tolerant persister cells (DTP) are a subset of cancer cells that survive and proliferate after exposure to therapeutic drugs, making them an essential object of study for cancer treatment. The molecular mechanisms underlying DTP cell survival are not fully understood; however, long non-coding RNAs (lncRNAs) have been proposed to play a crucial role. DTP cells from lung adenocarcinoma cell lines were obtained after a single exposure to tyrosine kinase inhibitor TKIs (erlotinib or osimertinib). After establishing DTPs, RNA sequencing was performed to investigate the differential expression of the lncRNAs. Some lncRNAs and one mRNA were found to be overexpressed in DTP cells. The clinical relevance of lncRNAs was evaluated in a cohort of patients with lung adenocarcinoma from The Cancer Genome Atlas (TCGA). RT-qPCR validated the overexpression of lncRNAs and mRNA in residual DTP cells and LUAD biopsies. Knockdown of these lncRNAs increases the sensitivity of DTP cells to therapeutic drugs. This study provides an opportunity to investigate the involvement of lncRNAs in the genetic and epigenetic mechanisms underlying intrinsic resistance. The identified lncRNAs and CD74 mRNA may serve as potential prognostic markers or therapeutic targets to improve the overall survival of patients with lung cancer.

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

Abstract: Lipidic carriers employed for the entrapment, encapsulation and precise targeting the bioactive compounds offer significant advantages to the biomedical, pharmaceutical, nutraceutical and cosmeceutical industries. These lipid and phospholipid-based vesicles can improve the solubility, permeation, pharmacokinetics, pharmacodynamics and bioavailability of the encapsulated material. As a matter of fact, nano-sized phospholipid vesicles have attained the highest success rate in commercialization among the available drug encapsulation technologies. Nevertheless, developing industrially acceptable products still remains a challenge. Among the main disadvantages of conventional lipidic carriers are their instability in the biological environments, and their sensitivity to changes in the pH, temperature and enzymes. To overcome these problems, the new generation of phospho/lipid-based carrier systems was developed using ingredients from microorganisms living in extremely harsh environments (i.e., archeaeobacteria). The present entry aims to review unique features of archaeolipids and recent developments in their application for the encapsulation of genetic material as well as their role and function as adjuvants and vaccine candidates.

Several efforts have been made to estimate the prevalence of different types of antibiotic resistance in different regions of Nigeria. The study investigated the prevalence of Klebsiella pneumoniae encoding genes for CTX-M, TEM, and SHV-1 extended-spectrum beta-lactamases (ESBL) enzymes isolated from urine samples of non-hospitalized patients with suspected UTI in Lagos State, Nigeria. A 4-month retrospective study, spanning from May 2023 to August 2023, was conducted. K. pneumoniae was isolated from urine samples using standard microbiological methods. The modified Kirby-Bauer disc diffusion method was used to test for antibiotic susceptibility, and Clinical and Laboratory Standard Institute (CLSI) guidelines were followed for interpretation. The double-disk synergy method was used to confirm the phenotypic identity of ESBL producers, and the results were interpreted in accordance with CLSI guidelines. The phenotypic method was utilized for ESBL screening, employing the standard disk diffusion method. The CTX-M ESBL gene, TEM gene, and SHV gene were found using multiplex PCR. Results revealed that 41 K. pneumoniae isolates were resistant to third-generation Cephalosporins; the isolates showed resistance to ceftazidime in 100% of cases and ceftriaxone in 80.49% of cases respectively. It was determined that 8 (19.51%) of the isolates produced ESBL. Among Klebsiella isolates, the frequencies of the SHV, TEM, and CTX-M genes were 31 (75.61%), 4 (9.76%), and 10 (24.39%), in that order. Four isolates (9.67%) had the SHV, TEM, and CTX-M genes, while eight (19.51%) of the isolates possessed both the SHV and CTX-M genes. This investigation demonstrates high frequency, wide range of patterns and coexistence of ESBL genes in K. pneumoniae isolates from outpatient UTI patients. Although several phenotypic tests have been used for ESBL detection, testing directly for the presence of ESBL genes is always more accurate. The majority of the isolates of Klebsiella pneumoniae ESBL producers had the SHV gene identified.

The proliferation of SARS-COV-2 through enhanced viral replication and its subsequent triggering of cytokine storm, are some of the hallmark phenotypes in severe COVID-19 patient cases. Cyclosporine, an immunosuppressant drug and Selinexor, an inhibitor of nuclear transporter protein, both have been successfully demonstrated to be effective against SARS-COV-2 infection by targeting those functions individually. However, the highly multifactorial pathology of SARS-COV-2 infection hinders any mono-therapeutic strategy to become an optimal option. In this study, we assess the potential efficacy of the Cyclosporine-Selinexor combination on an integrated interactome by adopting a network-medicine-based repositioning technique, where disease proximity, functional proximity and their topological separation are evaluated, followed by a robust statistical significance test. Results have shown that both drug target modules are highly proximal to the SARS-COV-2 disease modules in terms of network topology and functional associations, in a statistically significant manner, individually. Functional enrichment of both drug modules and SARS-COV-2 infected modules has shown that two drugs target the functions related to viral replication and cytokine storm during infection. Moreover, a high degree of network separation been those two drug target modules has been observed, revealing ``complementary exposure`` patterns, rendering this drug combination as an effective one against SARS-COV-2 infection. We hope that our results will encourage researchers to further investigate the potency of Cyclosporine and Selinexor combination in vivo or in vitro, and ultimately lead that up to clinical trials to treat SARS-COV-2 patients.

This review article focuses on the role of Artificial Intelligence (AI) in transforming healthcare in Africa, specifically in combatting infectious diseases, neglected tropical diseases (NTDs), and antimicrobial resistance. We provide a comprehensive overview of the significance of AI in the healthcare industry, highlighting its urgency and importance in addressing these specific health challenges in Africa. We begin by discussing the role of AI in infectious disease surveillance and outbreak detection. We explore how AI technology can be employed for real-time tracking and prediction of outbreaks, providing examples of successful AI applications in infectious disease surveillance within the African context.Next, we examine the potential of AI-enabled diagnosis and treatment for faster and more accurate diagnoses of infectious diseases and NTDs. We highlight specific examples of AI applications in diagnosing and treating these diseases in Africa, showcasing the potential of AI to improve clinical outcomes and save lives.Furthermore, we focus on how AI-driven drug discovery and development can expedite the search for new treatments for infectious diseases and combat antimicrobial resistance. We present examples of AI applications in drug discovery within the African context, illustrating the potential for AI to revolutionize the development of effective therapeutics.In addition, we delve into how AI-powered public health interventions can enhance the design and implementation of targeted interventions. We explore how AI can optimize resource allocation and facilitate data-driven decision-making processes, providing examples of AI applications in public health in Africa.Finally, we address the challenges and limitations of implementing AI in combatting infectious diseases, NTDs, and antimicrobial resistance in Africa. We discuss potential barriers and ethical concerns surrounding AI applications in healthcare, aiming to encourage informed and responsible utilization of AI technologies.Overall, this review emphasizes the importance and potential of AI in combatting infectious diseases, NTDs, and antimicrobial resistance in Africa. It positions AI as a catalyst for revolutionizing healthcare in the region, leading to more effective disease surveillance, diagnosis, treatment, drug discovery, and public health interventions.

Alteration in heparan sulfate (HS) biosynthesis has been described to impact a range of pivotal processes involved in cancer progression. HS 3-O-sulfotransferase 3B1 (HS3ST3B1) catalyzes the reaction of 3-O-sulfation within HS chains. Over the past few years, a growing number of studies has reported a tumor-promoting effect of this HS-modifying enzyme in various cancers. Consistent with these studies, we previously reported that HS3ST3B1 overexpression increased survival and resistance to apoptosis in MDA-MB-231 breast cancer (BrCa) cells. In the present study, we further investigated the biological and clinical significance of HS3ST3B1 expression in BrCa. Interrogation of public databases revealed that high expression levels of HS3STB1 are associated with invasive and mesenchymal-like phenotype in BrCa cells and predict poor clinical outcome in BrCA patients with chemotherapy. In vitro, HS3ST3B1 overexpression increased the invasive properties of MDA-MB-231 cells and enhanced chemo-resistance to conventional anticancer drugs. Mechanistically, we found that the advantage given by HS3ST3B1 was linked to the expression and activation of PDGF-Rβ. Silencing the expression of this receptor reversed the effects driven by HS3ST3B1 overexpression. Altogether, our results suggest that HS3ST3B1 may play an important role in the progression of aggressive BrCa and offer a potentially druggable target for therapeutic application.

Drug hypersensitivity reactions (DHR) to platinum-based compounds (PC) are on the rise, and their personalized and safe management is essential to enable first-line treatment of these cancer patients. This study aimed to evaluate the usefulness of basophil activation test by flow cytometry (BAT-FC) and the newly developed sIgE-microarray and BAT-microarray in diagnosing IgE-mediated hypersensitivity reactions to PC. 24 patients with DHR to PC (20 oxaliplatin and four carboplatin) were evaluated: 13 patients diagnosed as allergic with positive skin tests (STs) or drug provocation tests (DPTs), six patients diagnosed as non-allergic with negative STs and DPTs, and five patients classified as suspected allergic because DPTs could not be performed. In addition, four carboplatin-tolerant patients were included as controls. BAT-FC was positive in 2 of 13 allergic patients, with a sensitivity of 15.4% and specificity of 100%. However, the sIgE- and BAT-microarrays were positive in 11 of 13 DHR patients, giving a sensitivity of over 84.6% and a specificity of 90%. Except for one patient, all samples from the non-allergic and control group were negative for the sIgE- and BAT-microarrays. Our experience indicates that sIgE- and BAT-microarray could be helpful in the endophenotyping of IgE-mediated hypersensitivity reactions to PC and may provide an advance in decision-making for drug provocation testing.

Rice blast and brown planthopper (BPH) are two of the most destructive diseases and pests in rice (Oryza sativa L.) production in China. The development of multi-resistant varieties is widely recognized as the most efficient and environmentally friendly approach to controlling crop diseases and pests. Functional molecular markers (FMMs) have been developed from functional variants in the genic region associated with trait variation, greatly enhancing the efficiency of identifying and pyramiding valuable genes in crop breeding. In this study, two FMMs and a multiplex PCR amplification system were developed for two major broad-spectrum BPH resistance genes, Bph6 and Bph9. By assistance of FMMs in multi-resistant rice restorer line development pipeline, two lines (Huahui7713 and Huahui3006) with blast and BPH resistance were developed by pyramiding three resistance genes Pigm, Bph6 and Bph9. Huahui7713 and Huahui3006 as male lines, two new hybrid rice varieties (WeiLiangYou7713 and Xuanliangyou3006) were certificated and commercial released in China. WeiLiangYou7713 and Xuanliangyou3006 showed improved blast and BPH resistance, and no penalty on yield and grain-quality. Annual promotion area of WeiLiangYou7713 has exceeded 53.3 thousand hectares, indicating its widespread adoption and success in the market. Huahui7713 and Huahui3006 could have great potential for utilization in blast and BPH resistance rice breeding.

Additive manufacturing (AM) or 3D printing of metals is gaining popularity due to its flexibility in fabricating parts with highly complex designs, as well as simplifying manufacturing steps and optimizing process times. In this investigation, 17-4 PH stainless steel was additively manufactured using Laser-Powder Bed Fusion (L-PBF), followed by functionalization through a DUPLEX treatment. This treatment involved a plasma-assisted nitriding process, followed by deposition of an arc-PVD c-Al0.7Cr0.3N hard coating. The microstructural modifications resulting from plasma nitriding (such as the formation of Fe2,3N and Fe4N, and the αN or expanded martensite phases), and the surface improvements with the c-Al0.7Cr0.3N coating on the 3D-printed 17-4 PH steel, are evaluated in comparison to conventionally manufactured 17-4 PH steel. These microstructural characteristics are correlated with the mechanical response of the treated surfaces. As a result of the plasma nitriding process, the hardness of the 3D-printed 17-4 PH SS increased by approximately 260%. The wear, measured through dynamic and static scratch-testing, was reduced by approximately 31%. This improvement was attributed to the modification of adhesive failure mechanisms, leading to a reduction in wear volume, improved coating adhesion, and enhanced scratch resistance.

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

In this study, a simple machine learning-based quantitative structure-activity relationship (QSAR) model was developed to predict the inhibitory potency (pIC50 values) of FLT3 tyrosine kinase inhibitors, pivotal in treating Acute Myeloid Leukemia (AML). Distinctively, our model leverages an extensive and diverse dataset, 14 times larger than those employed in prior studies within this field, enabling an unparalleled scope of compound analysis. This vast dataset, combined with further exploration of molecular descriptors, enabled predictions of extraordinary precision, covering a broader spectrum of FLT3 inhibitors than was previously possible. The Random Forest Regressor (RFR) algorithm, selected for its superior predictive performance, was trained with 1080 inputs and validated through comprehensive external and internal methods. It achieved an remarkable coefficient of determination (R^2) of 0.941 and a standard deviation of 0.235 on a test set of 270 compounds, highlighting the efficacy of model in predicting FLT3 inhibitory activity. Key molecular descriptors were identified, enhancing our understanding of structural requirements for inhibitor potency. Additionally, we developed a user-friendly computational tool that enables the rapid prediction of pIC50 values. Utilizing this tool, potential FLT3 inhibitors were identified through ligand-based virtual screening. This study represents a major advancement in FLT3 inhibitor discovery by utilizing a simple QSAR-machine learning model. It enables more efficient and precise identification of potential drug candidates at an early stage, promising a faster development of targeted therapies and streamlining the ligand-based drug design process.

In the context of improving aircraft safety, this study focuses on the development and evaluation of a graphene-based ice detection system using an environmental chamber. The research is driven by the need for more accurate and efficient ice detection methods, crucial in mitigating in-flight icing hazards. The methodology employed involves testing flat graphene-based sensors in a controlled environment, simulating a variety of climatic conditions that could be experienced in an aircraft during its entire flight. The environmental chamber enabled precise manipulation of temperature and humidity levels, thereby providing a realistic and comprehensive test bed for sensor performance evaluation. The results were significant, revealing the graphene sensors’ heightened sensitivity and rapid response to the subtle changes in environmental conditions, especially the critical phase transition from water to ice. This sensitivity is the key to detecting ice formation at its onset, a critical requirement for aviation safety. The study concludes that graphene-based sensors, tested under varied and controlled atmospheric conditions, exhibit a remarkable potential in enhancing ice detection systems for aircraft. Their lightweight, efficient and highly responsive nature makes them a superior alternative to traditional ice detection technologies, paving the way for more advanced and reliable aircraft safety solutions.

Abstract: The SARS-CoV-2 pandemic has reemphasized the urgent need for broad-spectrum antiviral therapies. We developed a computational workflow using scRNA-Seq data to assess cellular metabolism during viral infection. With this workflow we predicted the capacity of cells to sustain SARS-CoV-2 virion production in patients and found a tissue-wide induction of metabolic pathways that support viral replication. Expanding our analysis to influenza A and dengue viruses, we identified metabolic targets and inhibitors for potential broad-45 spectrum antiviral treatment. These targets were highly enriched for known interaction partners of all analyzed viruses. Indeed, phenformin, an NADH:ubiquinone oxidoreductase inhibitor, suppressed SARS-CoV-2 and dengue virus replication. Atpenin A5, blocking succinate dehydrogenase, inhibited SARS-CoV-2, dengue virus, respiratory syncytial virus, and influenza A with high selectivity indices. In vivo, phenformin showed antiviral activity against SARS-CoV-2 in a Syrian hamster model. Our work establishes host metabolism as druggable for broad-spectrum antiviral strategies, providing invaluable tools for pandemic preparedness.

Acetamiprid is a broad-spectrum neonicotinoid insecticide used in agriculture to control aphids. While recent studies have documented resistance to acetamiprid in several aphid species, the underlying mechanisms are still not fully understood. In this study, we analyzed the transcriptome and metatranscriptome of a laboratory strain of the pea aphid, Acyrthosiphon pisum (Harris, 1776), with reduced susceptibility to acetamiprid after nine generations of exposure to identify candidate genes and the microbiome involved in the adaptation process. Sequencing of the transcriptome of both selected (RS) and non-selected (SS) strains allowed the identification of 14858 genes and 4938 new transcripts. Most of the differentially expressed genes were associated with catalytic activities and metabolic pathways involving carbon and fatty acids. Specifically, the alcohol-forming fatty acyl-CoA reductase (FAR) and acyl-CoA synthetase (ACSF2), both involved in the synthesis of epidermal wax layer components, were significantly upregulated in RS, suggesting that adaptation to acetamiprid involves the synthesis of a thicker protective layer. Metatranscriptomic analysis revealed subtle shifts in the microbiome of RS. These results contribute to a deeper understanding of acetamiprid adaptation by the pea aphid and provide new insights for aphid control strategies.

Soil-borne Trichoderma spp. have been extensively studied for their biocontrol activities against pathogens and growth promotion ability with plants. However, the beneficial effect of Trichoderma on inducing resistance against insect herbivores has been considered only recently. Among diverse Trichoderma species, consistent with previous reports, we showed that root colonization by T. virens triggered induced systemic resistance (ISR) to leaf-infecting fungal pathogens. Whether T. virens induces ISR to insect pests has not been tested before. In this study, we investigated whether T. virens affects jasmonic acid (JA) biosynthesis and defense against fall armyworm (FAW) and western corn rootworm (WCR). Unexpectedly, the results showed that T. virens colonization of maize seedlings grown in autoclaved soil suppressed wound-induced production of JA, resulting in reduced resistance to FAW. Similarly, the bacterial endophyte Pseudomonas chlororaphis 30-84 suppressed systemic resistance to FAW due to reduced JA. Further comparative analyses of the systemic effects of these endophytes when applied into sterile or non-sterile field soil showed that both T. virens and P. chlororaphis 30-84 triggered ISR against hemibiotrophic fungal pathogen Colletotrichum graminicola in both soil conditions, but only suppressed resistance to FAW in sterile soil. In contrast to the effect on FAW defense, T. virens colonization of maize roots suppressed WCR larvae survival and weight gain. This is the first report suggesting the potential role of T. virens as a biocontrol agent against WCR.

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.

The subject of the conducted study was focused on the development of new type of technical blends reinforced with natural fillers. The study was divided into two parts, where in the firsts stage of the research unmodified POM was reinforced with different types of natural fillers: cellulose, wood flour and husk particles. In order to select the type of filler intended for further modification, the mechanical characteristics was assessed. The 20% wood flour (WF) filler system was selected as the reinforcement. The second stage of research involved the use of combination of polyoxymethylene POM and poly(lactic acid) PLA. POM/PLA blend (ratio 50/50 %) were modified with elastomeric compound (EBA) and chain extender as reactive compatibilized (CE). The microscopic analysis revealed that for POM/PLA system the filler-matrix interface is characterized by better wettability, which might suggest higher adhesion. The mechanical performance revealed that for POM/PLA-based composites the properties were very close to the results for POM-WF composites; however, there is still large difference in thermal resistance in favor of POM-based materials. The increase in thermomechanical properties for POM/PLA composites occurs after heat treatment. The increasing crystallinity of the PLA phase allows for an significant increase of the head deflection temperature (HDT), even above 125 °C.

Abstract: Exercise has been repeatedly shown to be safe and beneficial for cancer survivors. However, there is no normative guideline for exercise prescription, and it is under exploration. Therefore, this literature review aims to provide some advice for the formulation of exercise prescriptions for patients with breast cancer-related lymphedema (BCRL) from the perspective of reducing lymphedema severity. A review of relevant studies published before November 2023 was conducted using three scientific databases PubMed, Embase, and Scopus. A total of 2696 articles were found. Eventually, 13 studies fulfilled the inclusion criteria and were included in this literature review. We concluded daily, or nearly daily exercise at home can be recommended. Moreover, reduced lymphedema severity may not be maintained after ceasing the exercise program, so exercise should be a lifelong practice.

Public restrooms are often a hub of microbial contamination, and the examination of bacterial contamination in these facilities can serve as an important indicator of the transmission of infectious diseases. This study was conducted to determine the prevalence of bacterial contamination in public restrooms based on the economic class of the building. Samples were collected from various spots in 32 restrooms found in 10 shopping malls, classifying them into two categories: upper-end restrooms and lower-end restrooms. The findings showed that the level of contamination was higher in the lower-end restrooms, with the seat being the most contaminated area. The most dominant Gram-positive bacteria were coagulase-negative staphylococci species, making up 86% of the identified Gram-positive isolates. The most dominant Gram-negative bacteria identified were Klebsiella pneumoniae and Pseudomonas aeruginosa. The antibiotic sensitivity test results revealed the presence of multi-drug resistant bacteria among the Gram-positive and negative isolates, including Staphylococcus haemolyticus, Staphylococcus kloosi, Acinetobacter baumanii, and Pseudomonas aeruginosa. In conclusion, the study underscores the significance of monitoring bacterial contamination in public restrooms and the need for measures to reduce the spread of infectious diseases. Further research is crucial to gain a complete understanding of the bacterial contamination in public restrooms and their resistance patterns, to ensure the safety and health of the public. The implementation of improved cleaning practices and hands-free designs in restrooms can help reduce the risk of cross-contamination and prevent the spread of diseases.

Hard tissue apposition along the root canal walls is a slow, normally occurring physiological aging process. In response to tooth wear, local deposition of hard tissue may also occur in the pulp at a slow pace. Sometimes, the rate of hard tissue deposition acceleration may seem to be uncontrolled after dental trauma, autotransplantation, and orthodontic therapy, leading to rapid partial or total obliteration of the root canal space. This situation is called calcific metamorphosis (CM) or pulp canal obliteration (PCO). Although the incidence of pulpal necrosis in these teeth is believed to be infrequent, conventional endodontic therapy in severely calcified canals poses extreme difficulties and a higher risk for procedural accidents. This article aims to review the available approaches for the predictable negotiation of calcified canals and to introduce the buckling resistance activation test (BRAT) technique.

Background: Several studies recently confirmed the emergence of resistance to antimalarial drugs in sub-Saharan Africa. Multiple first-line treatment (MFT) is one of the measures envisaged to respond to the emergence and spread of this resistance. The aim of this study was to identify perceived advantages and disadvantages of several MFT deployment strategies and to better understand potential implementation drivers and barriers. Methods: A qualitative survey was conducted in seven sub-Saharan countries amongst key opinion-leaders, national decision-makers, and end users. A total of 200 individual interviews were conducted and findings were analyzed following a thematic inductive approach. Results: From a policy perspective, the new MFT intervention would require endorsement at the global, national, and regional levels to ensure its inclusion in guidelines. Funding of the MFT intervention could be a bottleneck due to costs associated with additional training of healthcare workers, adaptation of drug delivery mechanisms, and higher costs of drugs. Concerning the MFT deployment strategies, a slight preference for the segmentation strategy was expressed over the rotation and geographic approaches, due to the perception that a segmentation approach is already in place at country level. Conclusions: The findings highlighted the need for a collective approach to MFT deployment through the engagement of stakeholders at all levels of malaria management.

Introduction: Atrial fibrillation (AF) is a common cardiac arrhythmia whose prevalence rises with age and is linked to increased morbidity and mortality due to the risk of thromboembolism. Management typically involves anticoagulation and rhythm control, but the treatment of elderly patients with multiple comorbidities requires careful consideration of drug side effects and interactions. Cibenzoline, a Vaughan-Williams class IA antiarrhythmic, is effective against AF but has risks of toxicity, especially in older people and those with renal impairment, due to its renal excretion and prolonged half-life in these populations. Discussion: This paper presents a case of an 80-year-old woman with paroxysmal AF who suffered cardiac arrest due to cibenzoline toxicity despite receiving standard adjusted dosages. The patient's cibenzoline blood concentration was significantly higher than the therapeutic range, leading to cardiotoxicity, which was exacerbated by drug interactions with bisoprolol and edoxaban, both metabolized by the CYP3A4 enzyme. Venoarterial extracorporeal membrane oxygenation (V-A ECMO) and intra-aortic balloon pump (IABP) successfully managed the cardiac arrest. This case emphasizes the unpredictable pharmacokinetics of cibenzoline in elderly patients with renal impairment and the need for vigilant therapeutic drug monitoring to avoid adverse events. Conclusions: Cibenzoline can pose a significant risk of severe toxicity in elderly patients with renal impairment, and drug interactions may potentiate this risk. The paper underscores the importance of careful dose adjustment and monitoring of drug levels in this population. In cases of cibenzoline-induced cardiac arrest, V-A ECMO and IABP are effective treatment modalities. The case study serves as a critical reminder for clinicians to remain vigilant for drug-induced complications and to apply aggressive supportive treatments when necessary.

This article delves into the intersection of generative AI and digital twins within drug discovery, exploring their synergistic potential to revolutionize pharmaceutical research and development. Through various instances and examples, we illuminate how generative AI algorithms, capable of simulating vast chemical spaces and predicting molecular properties, are increasingly integrated with digital twins of biological systems to expedite drug discovery. By harnessing the power of computational models and machine learning, researchers can design novel compounds tailored to specific targets, optimize drug candidates, and simulate their behavior within virtual biological environments. This paradigm shift offers unprecedented opportunities for accelerating drug development, reducing costs, and, ultimately, improving patient outcomes. As we navigate this rapidly evolving landscape, collaboration between interdisciplinary teams and continued innovation will be paramount in realizing the promise of generative AI and digital twins in advancing drug discovery.

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

Waste biogenic materials from seafood exploitation are valuable resources of new compounds exploitation within the blue bioeconomy concept. Here, we describe the effectiveness of Raman technology implementation as an in-line tool for demineralization process control of crustaceans or gastropods. We produced transparent chitin polymer foils from three waste crustacean shells (C. sapidus, S. mantis and M. squinado) using a slow, green chemical approach employing acetic acid, and showed the progressive process of biogenic carbonate dissolution and increasing the Raman characteristic signal of chitin, in a time dependence manner. It turned that chitin foils obtaining is species-specific, and the demineralization bath of waste shell mixture can be effectively tracked by Raman spectroscopy, for solvent control and the recovery of the calcium acetate as valuable by-product. Comparatively, calcium acetate drug, a compound widely used in kidney failure diseases, or as additive in nutraceuticals and food industry, has been obtained here, following a green demineralization path of the sea snail Rapana venosa intact shell, assisted by Raman tech-nology, using 9% acetic acid (vinegar) solution for 14 days. To validate the final products identity and quality, The process of waste shells demineralization and the final products of the treatment were investigated using various Raman techniques and technologies, cross-validating the results with FT-IR, XRD and SEM-EDX techniques. NIR Raman spectroscopy revealed chitin bands in a time-dependent manner, while Resonance Raman spectroscopy showed the preservation of ca-rotenoids after two weeks of acetic acid treatment. A hand-held flexible TacticID Raman system with a 1064 nm excitation demonstrated its effectiveness as a rapid, in-line decision making tool during process control and revealed excellent reproducibility of the lab-based instrument signal, suitable for in situ evaluation of the demineralization status and solvent saturation control. The calcium acetate recovered from residual treatment solutions was assessed regarding its hydration status, purity, and suitability as recrystallized material for further use as pharmaceutical product or ingredient in complex formulations.

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

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

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

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

Oral bone defects occur as a result of trauma, cancer, infections, periodontal diseases, and caries. Autogenic and allogenic grafts are the gold standard used to treat and regenerate damaged or defective bone segments. However, these materials do not possess the antimicrobial properties necessary to inhibit the invasion of the numerous deleterious pathogens present in the oral microbiota. In the present study poly(ε-caprolactone) (PCL), nano-hydroxyapatite (nHAp), and a commercial extract of Humulus lupulus L. (hops) were electrospun into polymeric matrices to assess their po-tential for drug delivery and bone regeneration. The fabricated matrices were analyzed by scanning electron microscopy (SEM), tensile analysis, thermogravimetric analysis (TGA), FT-IR assay, and in vitro hydrolytic degradation. The antimi-crobial properties were evaluated against the oral pathogens Streptococcus mutans, Porphyromonas gingivalis, and Aggregatibacter actinomycetemcomitans. The cytocompatibility was proved by the MTT assay. SEM analysis proved the nanostructured matrices have suitable fiber size. The present research provides new information about the interaction of natural compounds with ceramic and polymeric biomaterials. The hop extract and other natural or synthetic medicinal agents can be effectively loaded into PCL fibers and has the potential to be used in biomedical applications.

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

Lumpy skin disease (LSD), caused by a virus within the Poxviridae family and Capripoxvirus genus, induces nodular skin lesions in cattle, spreading through direct contact and insect vectors, significantly affecting global cattle farming. Despite available vaccines, their effectiveness is limited by poor bioavailability and adverse effects. Our study aimed to identify potential inhibitors targeting LSD-associated DNA polymerase protein, selecting LSDV039 for further investigation through comprehensive analysis and computational methods. Virtual screening revealed rhein and taxifolin as potent binders among 380 phytocompounds, with respective affinities of -8.965 and -7.195 kcal/mol. Canagliflozin and tepotinib exhibited strong affinities (-9.858 and -8.856 kcal/mol) among 718 FDA-approved antiviral drugs. Molecular dynamics simulations of canagliflozin, tepotinib, rhein, and taxifolin highlighted taxifolin's superior stability and binding energy. Rhein displayed compactness in RMSD and RMSF but fluctuations in Rg and SASA, while canagliflozin demonstrated stability compared to tepotinib. The study highlights the promising potential of repurposed drugs and phytocompounds as LSD therapeutics. However, extensive validation through in-vitro, in-vivo, and clinical trials is crucial for their practical application.

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

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

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

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

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

Sheep’s milk is a significant source of nucleotides monophosphate (NMPs) but can also contain undesirable residues from veterinary drugs, posing a potential human health risk. This study introduces a novel application of 2D-LC, in heart-cutting mode, for the simultaneous determination of nucleotides and veterinary drug residues in sheep’s milk. Two-dimensional liquid chromatography (2D-LC) allows for the separation of these compounds in a single chromatographic run despite their differing physicochemical properties. The proposed method separates six veterinary drug residues and five NMPs in a single injection. The compounds were separated using a C18 reversed-phase column in the first dimension and a Primesep SB analytical column in the second dimension. The method performance was evaluated in terms of linearity range, detection and quantification limits, matrix effects, precision, and accuracy. The results demonstrated good linearity and sensitivity, with quantification limits allowing for the quantification of veterinary drugs at the maximum residue level and nucleotides at typical levels found in milk samples. The method has been successfully applied to the analysis of sheep’s milk samples acquired from local supermarkets, with recoveries within a range of 70-119 % and 82-117 % for veterinary residues and NMPs, respectively.

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

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

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