Anti-Acanthamoebic effects of silver-conjugated tetrazole nanoparticle.

Tetrazoles are five-membered ring aromatic heterocyclic molecules that consist of one carbon and four nitrogen atoms. Several tetrazole-based drugs have shown promising activities against bacteria, fungi, asthma, cancer, hypertension etc. The overall aim of this study was to determine anti-Acanthamoebic properties of tetrazoles and tetrazole-conjugated silver nanoparticles. Tetrazole-conjugated silver nanoparticles were synthesized and confirmed using ultraviolet-visible spectrometry, Dynamic light scattering, and Fourier-transform infrared spectroscopy. Using amoebicidal, encystment, and excystment assays, the findings revealed that tetrazoles exhibited antiamoebic properties and these effects were enhanced when conjugated with silver nanoparticles. When tested for parasite killing, the minimum inhibitory concentration was reduced from ∼20µM with tetrazole alone to 10µM with tetrazole-conjugated silver nanoparticles. Importantly, conjugation with silver nanoparticles increased parasite-mediated human cell death in vitro, as measured by lactate dehydrogenase release, but it reduced toxic effects of drugs alone on human cells. In cytopathogenicity assays, the minimum inhibitory concentration was reduced from ∼15µM with tetrazole alone to less than 50µM with tetrazole-conjugated silver nanoparticles. Overall, these results showed clearly that tetrazoles exhibit potent antiamoebic properties which can be enhanced by conjugation with silver nanoparticles and have potential role in the rational development of therapeutic interventions against parasitic infections such as keratitis and granulomatous amoebic encephalitis due to pathogenic Acanthamoeba.

Identification of Novel Antileishmanial Chemotypes By High-Throughput Virtual and In Vitro Screening.

BACKGROUND: Leishmaniasis is a deadly protozoan parasitic disease and a significant health problem in underdeveloped and developing countries. The global spread of the parasite, coupled with the emergence of drug resistance and severe side effects associated with existing treatments, has necessitated the identification of new and potential drugs. OBJECTIVE: This study aimed to identify promising compounds for the treatment of leishmaniasis by targeting two essential enzymes of Leishmania donovani: trypanothione reductase (Try-R) and trypanothione synthetase (Try-S). METHODS: High-throughput virtual and in vitro screening of in-house and commercial databases was conducted. A pharmacophore model with seven features was developed and validated using the Guner-Henery method. The pharmacophore-based virtual screening yielded 690 hits, which were further filtered through Lipinski's rule, ADMET analysis, and molecular docking against Try-R and Try-S. Molecular dynamics studies were performed on selected compounds, and in vitro experiments were conducted to evaluate their activity against the promastigote and amastigote forms of L. donovani. RESULTS: The virtual screening and subsequent analysis identified 33 promising compounds. Molecular dynamics studies of two compounds (comp-1 and comp-2) demonstrated stable binding interactions with the target enzymes and high affinity. In vitro experiments revealed that 13 compounds exhibited moderate activity against both the promastigote (IC50, 41 µM-76 µM) and the amastigote (IC50, 44 µM-72 µM) forms of L. donovani. Compounds 1 and 2 showed the highest percent inhibition and the lowest IC50 values. CONCLUSION: The identified compounds demonstrated significant inhibitory activity against Leishmania donovani and stable interactions with target enzymes. These findings suggest that the compounds could serve as promising leads for developing new treatments for leishmaniasis.

Low-Resistance Membrane vs. High-Resistance Membrane Performance Utilizing Electrodialysis-Evaporator Hybrid System in Treating Reject Brine from Kuwait Desalination Plants.

This work is an effort to mitigate the existing environmental issues caused by brine discharge from Kuwait's desalination plants and to find an economical and efficient way of managing reject brine from local desalination plants. Low- and high-resistance membranes (LRMs and HRMs, respectively) were used to produce salt and low-salinity water from brine effluent utilizing an electrodialysis (ED)-evaporator hybrid system. The effect of high current densities of 300, 400, and 500 A/m2 and brine flowrates of 450 and 500 L/h on the quality of produced salt and diluate were investigated for LRM and HRM. The recovered salt purity for LRM is up to 90.58%. Results show that the low-resistance membrane (LRM) achieved higher water recovery, energy consumption, desalination rate, operation time and ion removal rate than those of the high-resistance membrane (HRM) under the same operating conditions. The difference in concentration for 300 A/m2 between LRM and HRM increased from 0.93% at 10 min to 8.28% at 140 min. The difference in diluate concentration effluent is negligible for both membranes, whereas LRM produced higher concentrate effluent than HRM for all current densities and low flowrate (400 L/h). The maximum difference between LRM and HRM (with LRM achieving higher concentrations) is 10.7% for 400 A/m2. The permselectivity of LRM for monovalent cations decreased with current density, whereas the effect on permselectivity for HRM was insignificant for the current density values. The addition of a neutral cell was effective in reducing the buildup of divalent ions on the inner membrane of the cathode side.

African swine fever; insights into genomic aspects, reservoirs and transmission patterns of virus.

African swine fever is a hemorrhagic disease of pigs with high mortality rates. Since its first characterization in 1921, there has been sufficient information about African swine fever virus (ASFV) and related diseases. The virus has been found and maintained in the sylvatic cycle involving ticks and domestic and wild boars in affected regions. The ASFV is spread through direct and indirect contact with infected pigs, their products and carrier vectors especially Ornithodoros ticks. Severe economic losses and a decline in pig production have been observed in ASFV affected countries, particularly in sub-Saharan Africa and Europe. At the end of 2018, the ASFV adversely affected China, the world's leading pork-producer. Control strategies for the disease remained challenging due to the unavailability of effective vaccines and the lack of successful therapeutic measures. However, considerable efforts have been made in recent years to understand the biology of the virus, surveillance and effective control measures. This review emphasizes and summarizes the current state of information regarding the knowledge of etiology, epidemiology, transmission, and vaccine-based control measures against ASFV.

Prevalence and associated factors of clubfoot in the eastern province of Saudi Arabia: A hospital-based study.

BACKGROUND: Clubfoot, or congenital talipes equinovarus, is a widely recognized cause of disability and congenital deformity worldwide, which significantly impacts the quality of life. Effective management of clubfoot requires long-term, multidisciplinary intervention. It is important to understand how common this condition is in order to assess its impact on the population. Unfortunately, few studies have investigated the prevalence of clubfoot in Saudi Arabia. AIM: To determine the prevalence of clubfoot in Saudi Arabia via the patient population at King Fahad University Hospital (KFUH). METHODS: This was a retrospective study conducted at one of the largest hospitals in the country and located in one of the most densely populated of the administrative regions. RESULTS: Of the 7792 births between 2015 to 2023 that were included in the analysis, 42 patients were diagnosed with clubfoot, resulting in a prevalence of 5.3 per 1000 live births at KFUH. CONCLUSION: The observed prevalence of clubfoot was significantly higher than both global and local estimates, indicating a substantial burden in the study population.

Designing a multiepitope mRNA-based vaccine against enterotoxigenic Escherichia coli infection in calves: Immunoinformatics and molecular modeling approach.

Background: Escherichia coli is one of the serious pathogens causing various infections in the animal field, such as neonatal calf diarrhea, which is responsible for mortality associated with diarrhea during the first days of life. Aim: Current work is aimed at designing an effective and safe multiepitope vaccine candidate against E. coli infection in calves based on the fimbrial protein K99 of Enterotoxigenic E. coli (ETEC) and Immuno-informatics. Methods: A conserved sequence of K99 protein was generated, and then highly antigenic, nonallergic, and overlapped epitopes were used to construct a multiepitope vaccine. Five THL, six MHC II, and four beta cell epitopes were targeted to create the candidate. The candidate vaccine was produced utilizing 15 epitopes and three types of linkers, two types of untranslated region (UTR) human hemoglobin subunit beta (HBB), UTR beta-globin (Rabb), and RpfE protein as an immunomodulation adjuvant. Results: Immuno-informatics analysis of the constructed protein showed that the protein was antigenic (antigenic score of 0.8841), stable, nonallergen, and soluble. Furthermore, the Immuno-informatics and physiochemical analysis of the constructed protein showed a stable, nonallergic, soluble, hydrophilic, and acidic PI (isoelectric point). of 9.34. Docking of the candidate vaccine with the toll-like receptor TLR3 was performed, and results showed a strong interaction between the immune receptor and the vaccine. Finally, the expression efficiency of the construct in E. coli was estimated via computational cloning of the vaccine sequence into Pet28a. Conclusion: Results of immunoinformatics and in silico approaches reveal that the designed vaccine is antigenic, stable, and able to bind to the immune cell receptors. Our results interpret the proposed multiepitope mRNA vaccine as a good preventive option against E. coli infection in calves.

The effect of educational animation compared to leaflets on patients' knowledge regarding root canal treatment: a randomized controlled trial.

BACKGROUND: Incorporating video as a tool for education offers a multitude of advantages. However, it is unknown what is the best educational tool to use for increasing public awareness, consequently reducing fear about root canal treatment. For this reason, this study aimed to compare the effectiveness of educational animation and leaflets as delivery methods for providing information on root canal treatment to patients and to assess their ability to retain the information. METHODS: One hundred fifty adult volunteers were recruited via social media and Umm Al-Qura University Dental Hospital to participate in this randomized control trial study. The volunteers were divided into the study group (SG) and the control group (CG). The SG was provided with information through animations created by the research team, while the CG received the same information through a leaflet. Pre-intervention (T1), immediate post-intervention (T2), and one-month post-intervention (T3) validated questionnaires were completed by the participants to assess the changes in their knowledge. To evaluate the impact of the information delivery method, the knowledge scores of T2 and T3 were compared to T1 within each group using Paired T-tests. Additionally, the study compared the knowledge scores of the two groups using unpaired T-tests. The significance level was set at a P-value of less than 0.05. RESULTS: A significant improvement in endodontic therapy knowledge among the participants in both groups (T1 compared to T2 in the same group) was noted (P < 0.050). However, when comparing T2 between groups, no significant difference was found in delivering the information and improving the knowledge (P = 0.080). Still, the mean differences between T1 and T2, as well as T1 and T3, were greater (P < 0.050) in the SG than in the CG. Furthermore, the total knowledge score in the SG at T3 was significantly higher than the CG. CONCLUSION: Both educational animation and leaflets are practical tools to increase patients' awareness about root canal treatment. However, educational videos are more effective than leaflets in delivering and retaining information about root canal treatment. TRIAL REGISTRATION: This study was retrospectively registered as a randomized control trial at the ISRCTN registry with the document number ISRCTN18413241, 15/05/2023.

Investigating mechanistic insights of curcumin in blocking the Interleukin-8 signaling pathway associated with Breast Cancer: An in-silico approach.

Interleukin-8 (IL-8) is a chemokine, a type of signaling molecule that has a role in immunological responses and inflammation. In recent years, IL-8 is additionally related to cancer growth and recurrence. Breast cancer growth, progression, and metastatic development are all linked to IL-8. Breast cancer cells are known to develop faster when IL-8 stimulates their proliferation and survival. It can also cause angiogenesis, or the creation of new blood vessels, which is necessary for tumor nutrition and growth. IL-8 and curcumin have been subjects of interest in drug design, particularly in the context of inflammation-related disorders and cancer. This study aims to give an overview of the role of IL-8. Inhibitor-based treatment approaches were being used to target IL-8 with curcumin. Molecular docking method was employed to find a potential interaction to supress competitive inhibition of IL-8 with curcumin. PASS analysis and ADMET characteristics were also being carried out. In the end, IL-8 complexed with curcumin is chosen for MD simulations. Overall, our results showed that during the simulation, the complex stayed comparatively stable. It is also possible to investigate curcumin further as a possible treatment option. The combined results imply that IL-8 and their genetic alterations can be studied in precision cancer therapeutic treatments, utilizing target-driven therapy and early diagnosis.

Spontaneous Splenic Rupture in a Young Patient: A Comprehensive Case Report and Literature Review.

Spontaneous splenic rupture (SSR), a rare but potentially life-threatening condition, typically occurs in the absence of trauma or underlying splenic disease. This report aims to contribute to the limited body of knowledge regarding its occurrence, diagnosis, and management in this demographic. We describe the case of a 20-year-old patient with no significant medical history who presented with acute abdominal pain and hypovolemic shock. Imaging revealed an unexpected splenic rupture without any preceding trauma or identifiable risk factors. The patient's clinical progression, diagnostic challenges, and therapeutic approach are discussed in detail. This case underscores the importance of considering SSR in the differential diagnosis of acute abdomen in young patients, even in the absence of predisposing factors. We review the literature to highlight the epidemiology, possible etiologies, diagnostic modalities, and treatment options for SSR. The peculiarities of managing such cases in young patients are also discussed, emphasizing a tailored approach to balance the risks of conservative management against surgical intervention. In conclusion, SSR, though rare in young patients, should be a diagnostic consideration in cases of unexplained acute abdomen. Early recognition and appropriate management are crucial for favorable outcomes. This case adds to the existing literature by providing insight into the presentation and management of this condition in a young, healthy individual, thereby aiding in enhancing clinical vigilance and patient care.

Varicella-zoster virus-related neurological complications: From infection to immunomodulatory therapies.

The Varicella-zoster virus (VZV), classified as a neurotropic member of the Herpesviridae family, exhibits a characteristic pathogenicity, predominantly inducing varicella, commonly known as chickenpox, during the initial infectious phase, and triggering the reactivation of herpes zoster, more commonly recognized as shingles, following its emergence from a latent state. The pathogenesis of VZV-associated neuroinflammation involves a complex interplay between viral replication within sensory ganglia and immune-mediated responses that contribute to tissue damage and dysfunction. Upon primary infection, VZV gains access to sensory ganglia, establishing latent infection within neurons. During reactivation, the virus can spread along sensory nerves, triggering a cascade of inflammatory mediators, chemokines, and immune cell infiltration in the affected neural tissues. The role of both adaptive and innate immune reactions, including the contributions of T and B cells, macrophages, and dendritic cells, in orchestrating the immune-mediated damage in the central nervous system is elucidated. Furthermore, the aberrant activation of the natural defence mechanism, characterised by the dysregulated production of immunomodulatory proteins and chemokines, has been implicated in the pathogenesis of VZV-induced neurological disorders, such as encephalitis, myelitis, and vasculopathy. The intricate balance between protective and detrimental immune responses in the context of VZV infection emphasises the necessity for an exhaustive comprehension of the immunopathogenic mechanisms propelling neuroinflammatory processes. Despite the availability of vaccines and antiviral therapies, VZV-related neurological complications remain a significant concern, particularly in immunocompromised individuals and the elderly. Elucidating these mechanisms might facilitate the emergence of innovative immunomodulatory strategies and targeted therapies aimed at mitigating VZV-induced neuroinflammatory damage and improving clinical outcomes. This comprehensive understanding enhances our grasp of viral pathogenesis and holds promise for pioneering therapeutic strategies designed to mitigate the neurological ramifications of VZV infections.

Phosphonium chloride-based deep eutectic solvents inhibit pathogenic Acanthamoeba castellanii belonging to the T4 genotype.

Herein, we investigated the anti-amoebic activity of phosphonium-chloride-based deep eutectic solvents against pathogenic Acanthamoeba castellanii of the T4 genotype. Deep eutectic solvents are ionic fluids composed of two or three substances, capable of self-association to form a eutectic mixture with a melting point lower than each substance. In this study, three distinct hydrophobic deep eutectic solvents were formulated, employing trihexyltetradecylphosphonium chloride as the hydrogen bond acceptor and aspirin, dodecanoic acid, and 4-tert-butylbenzoic acid as the hydrogen bond donors. Subsequently, all three deep eutectic solvents, denoted as DES1, DES2, DES3 formulations, underwent investigations comprising amoebicidal, adhesion, excystation, cytotoxicity, and cytopathogenicity assays. The findings revealed that DES2 was the most potent anti-amoebic agent, with a 94% elimination rate against the amoebae within 24 h at 30 °C. Adhesion assays revealed that deep eutectic solvents hindered amoebae adhesion to human brain endothelial cells, with DES2 exhibiting 88% reduction of adhesion. Notably, DES3 exhibited remarkable anti-excystation properties, preventing 94% of cysts from reverting to trophozoites. In cytopathogenicity experiments, deep eutectic solvent formulations and dodecanoic acid alone reduced amoebae-induced human brain endothelial cell death, with DES2 showing the highest effects. Lactate dehydrogenase assays revealed the minimal cytotoxicity of the tested deep eutectic solvents, with the exception of trihexyltetradecylphosphonium chloride, which exhibited 35% endothelial cell damage. These findings underscore the potential of specific deep eutectic solvents in combating pathogenic Acanthamoeba, presenting promising avenues for further research and development against free-living amoebae.

Nanomedicine: Patuletin-conjugated with zinc oxide exhibit potent effects against Gram-negative and Gram-positive bacterial pathogens.

With the emergence of drug-resistance, there is a need for novel anti-bacterials or to enhance the efficacy of existing drugs. In this study, Patuletin (PA), a flavanoid was loaded onto Gallic acid modified Zinc oxide nanoparticles (PA-GA-ZnO), and evaluated for antibacterial properties against Gram-positive (Bacillus cereus and Streptococcus pneumoniae) and Gram-negative (Samonella enterica and Escherichia coli) bacteria. Characterization of PA, GA-ZnO and PA-GA-ZnO' nanoparticles was accomplished utilizing fourier-transform infrared spectroscopy, efficiency of drug entrapment, polydispersity index, zeta potential, size, and surface morphology analysis through atomic force microscopy. Using bactericidal assays, the results revealed that ZnO conjugation displayed remarkable effects and enhanced Patuletin's effects against both Gram-positive and Gram-negative bacteria, with the minimum inhibitory concentration observed at micromolar concentrations. Cytopathogenicity assays exhibited that the drug-nanoconjugates reduced bacterial-mediated human cell death with minimal side effects to human cells. When tested alone, drug-nanoconjugates tested in this study showed limited toxic effects against human cells in vitro. These are promising findings, but future work is needed to understand the molecular mechanisms of effects of drug-nanoconjugates against bacterial pathogens, in addition to in vivo testing to determine their translational value. This study suggests that Patuletin-loaded nano-formulation (PA-GA-ZnO) may be implicated in a multi-target mechanism that affects both Gram-positive and Gram-negative pathogen cell structures, however this needs to be ascertained in future work.

In silico identification of phytochemical inhibitors for multidrug-resistant tuberculosis based on novel pharmacophore generation and molecular dynamics simulation studies.

BACKGROUND: Multidrug-resistant tuberculosis (particularly resistant to pyrazinoic acid) is a life-threatening chronic pulmonary disease. Running a marketed regime specifically targets the ribosomal protein subunit-1 (RpsA) and stops trans-translation in the non-mutant bacterium, responsible for the lysis of bacterial cells. However, in the strains of mutant bacteria, this regime has failed in curing TB and killing pathogens, which may only because of the ala438 deletion, which inhibit the binding of pyrazinoic acid to the RpsA active site. Therefore, such cases of tuberculosis need an immediate and effective regime. OBJECTIVE: This study has tried to determine and design such chemotypes that are able to bind to the mutant RpsA protein. METHODS: For these purposes, two phytochemical databases, i.e., NPASS and SANCDB, were virtually screened by a pharmacophore model using an online virtual screening server Pharmit. RESULTS: The model of pharmacophore was developed using the potential inhibitor (zr115) for the mutant of RpsA. Pharmacophore-based virtual screening results into 154 hits from the NPASS database, and 22 hits from the SANCDB database. All the predicted hits were docked in the binding pocket of the mutant RpsA protein. Top-ranked five and two compounds were selected from the NPASS and SANCDB databases respectively. On the basis of binding energies and binding affinities of the compounds, three compounds were selected from the NPASS database and one from the SANCDB database. All compounds were found to be non-toxic and highly active against the mutant pathogen. To further validate the docking results and check the stability of hits, molecular dynamic simulation of three compounds were performed. The MD simulation results showed that all these finally selected compounds have stronger binding interactions, lesser deviation or fluctuations, with greater compactness compared to the reference compound. CONCLUSION: These findings indicate that these compounds could be effective inhibitors for mutant RpsA.

Self-assembled micelles loaded with itraconazole as anti-Acanthamoeba nano-formulation.

Acanthamoeba castellanii are opportunistic pathogens known to cause infection of the central nervous system termed: granulomatous amoebic encephalitis, that mostly effects immunocompromised individuals, and a sight threatening keratitis, known as Acanthamoeba keratitis, which mostly affects contact lens wearers. The current treatment available is problematic, and is toxic. Herein, an amphiphilic star polymer with AB2 miktoarms [A = hydrophobic poly(ℇ-Caprolacton) and B = hydrophilic poly (ethylene glycol)] was synthesized by ring opening polymerization and CuI catalyzed azide-alkyne cycloaddition. Characterization by 1H and 13C NMR spectroscopy, size-exclusion chromatography and fluorescence spectroscopy was accomplished. The hydrophobic drug itraconazole (ITZ) was incorporated in self-assembled micellar structure of AB2 miktoarms through co-solvent evaporation. The properties of ITZ loaded (ITZ-PCL-PEG2) and blank micelles (PCL-PEG2) were investigated through zeta sizer, scanning electron microscopy and Fourier-transform infrared spectroscopy. Itraconazole alone (ITZ), polymer (DPB-PCL), empty polymeric micelles (PCL-PEG2) alone, and itraconazole loaded in polymeric micelles (ITZ-PCL-PEG2) were tested for anti-amoebic potential against Acanthamoeba, and the cytotoxicity on human cells were determined. The polymer was able to self-assemble in aqueous conditions and exhibited low value for critical micelle concentration (CMC) 0.05-0.06 µg/mL. The maximum entrapment efficiency of ITZ was 68%. Of note, ITZ, DPB, PCL-PEG2 and ITZ-PCL-PEG2 inhibited amoebae trophozoites by 37.34%, 36.30%, 35.77%, and 68.24%, respectively, as compared to controls. Moreover, ITZ-PCL-PEG2 revealed limited cytotoxicity against human keratinocyte cells. These results are indicative that ITZ-PCL-PEG2 micelle show significantly better anti-amoebic effects as compared to ITZ alone and thus should be investigated further in vivo to determine its clinical potential.

Evolutionary analysis of LMP-1 genetic diversity in EBV-associated nasopharyngeal carcinoma: Bioinformatic insights into oncogenic potential.

EBV latent membrane protein 1 (LMP-1) is an important oncogene involved in the induction and maintenance of EBV infection and the activation of several cell survival and proliferative pathways. The genetic diversity of LMP-1 has an important role in immunogenicity and tumorigenicity allowing escape from host cell immunity and more metastatic potential of LMP-1 variants. This study explored the evolutionary of LMP-1 in EBV-infected patients at an advanced stage of nasopharyngeal carcinoma (NPC). Detection of genetic variability in LMP-1 genes was carried out using Sanger sequencing. Bioinformatic analysis was conducted for translation and nucleotide alignment. Phylogenetic analysis was used to construct a Bayesian tree for a deeper understanding of the genetic relationships, evolutionary connections, and variations between sequences. Genetic characterization of LMP-1 in NPC patients revealed the detection of polymorphism in LMP-1 Sequences. Motifs were identified within three critical LMP-1 domains, such as PQQAT within CTAR1 and YYD within CTAR2. The presence of the JACK3 region at specific sites within CTAR3, as well as repeat regions at positions (122-132) and (133-143) within CTAR3, was also annotated. Additionally, several mutations were detected including 30 and 69 bp deletions, 33 bp repeats, and 15 bp insertion. Although LMP-1 strains appear to be genetically diverse, they are closely related to 3 reference strains: prototype B95.8, Med- 30 bp deletion, and Med + 30 bp deletion. In our study, one of the strains harboring the 30 bp deletion had both bone and bone marrow metastasis which could be attributed to the fact that LMP-1 is involved in tumor metastasis, evasion and migration of NPC cells. This study provided valuable insights into genetic variability in LMP-1 sequences of EBV in NPC patients. Further functional studies would provide a more comprehensive understanding of the molecular characteristics, epidemiology, and clinical implications of LMP-1 polymorphisms in EBV-related malignancies.

Prospective virtual screening combined with bio-molecular simulation enabled identification of new inhibitors for the KRAS drug target.

Lung cancer is a disease with a high mortality rate and it is the number one cause of cancer death globally. Approximately 12-14% of non-small cell lung cancers are caused by mutations in KRASG12C. The KRASG12C is one of the most prevalent mutants in lung cancer patients. KRAS was first considered undruggable. The sotorasib and adagrasib are the recently approved drugs that selectively target KRASG12C, and offer new treatment approaches to enhance patient outcomes however drug resistance frequently arises. Drug development is a challenging, expensive, and time-consuming process. Recently, machine-learning-based virtual screening are used for the development of new drugs. In this study, we performed machine-learning-based virtual screening followed by molecular docking, all atoms molecular dynamics simulation, and binding energy calculations for the identifications of new inhibitors against the KRASG12C mutant. In this study, four machine learning models including, random forest, k-nearest neighbors, Gaussian naïve Bayes, and support vector machine were used. By using an external dataset and 5-fold cross-validation, the developed models were validated. Among all the models the performance of the random forest (RF) model was best on the train/test dataset and external dataset. The random forest model was further used for the virtual screening of the ZINC15 database, in-house database, Pakistani phytochemicals, and South African Natural Products database. A total of 100 ns MD simulation was performed for the four best docking score complexes as well as the standard compound in complex with KRASG12C. Furthermore, the top four hits revealed greater stability and greater binding affinities for KRASG12C compared to the standard drug. These new hits have the potential to inhibit KRASG12C and may help to prevent KRAS-associated lung cancer. All the datasets used in this study can be freely available at ( https://github.com/Amar-Ajmal/Datasets-for-KRAS ).

Successful treatment of gastric bleeding caused by left phrenic artery pseudoaneurysm post-surgery with endovascular embolization: A case report.

Pseudoaneurysms are rare but potentially life-threatening complications that may occur after surgical procedures. This report presents the case of a 28-year-old woman who developed a pseudoaneurysm in the Left Inferior Phrenic Artery (LIPA) following a Laparoscopic Sleeve Gastrectomy (LSG). The complication manifested as severe gastrointestinal bleeding. Upper GI Endoscopy and multislice CT scan, repeated twice, failed to localize the bleeding source to treat it. Successful endovascular embolization using a Glue/Lipidol mixture was achieved despite difficulties in localizing the pseudoaneurysm, resulting in immediate symptomatic relief and avoiding surgical intervention. This case shows the importance of prompt identification and management of LIPA pseudoaneurysms following LSG, highlighting the importance of early diagnosis to prevent further hemodynamic deterioration and other adverse outcomes.

Structure-based investigation of pyruvate dehydrogenase kinase-3 inhibitory potential of thymoquinone, targeting lung cancer therapy.

Protein kinases are an attractive therapeutic target for cardiovascular, cancer and neurodegenerative diseases. Cancer cells demand energy generation through aerobic glycolysis, surpassing "oxidative phosphorylation" (OXPHOS) in mitochondria. The pyruvate dehydrogenase kinases (PDKs) have many regulatory roles in energy generation balance by controlling the pyruvate dehydrogenase complex. Overexpression of PDKs is associated with the overall survival of cancer. PDK3, an isoform of PDK is highly expressed in various cancer types, is targeted for inhibition in this study. PDK3 has been shown to binds strongly with a natural compound, thymoquinone (TQ), which is known to exhibit anti-cancer potential. Detailed interaction between the PDK3 and TQ was carried out using spectroscopic and docking methods. The overall changes in the protein's structures after TQ binding were estimated by UV-Vis spectroscopy, circular dichroism and fluorescence binding studies. The kinase activity assay was also carried out to see the kinase inhibitory potential of TQ. The enzyme inhibition assay suggested an excellent inhibitory potential of TQ towards PDK3 (IC50 = 5.49 µM). We observed that TQ forms a stable complex with PDK3 without altering its structure and can be a potent PDK3 inhibitor which may be implicated in cancer therapy after desired clinical validation.

A NiO-nanostructure-based electrochemical sensor functionalized with supramolecular structures for the ultra-sensitive detection of the endocrine disruptor bisphenol S in an aquatic environment.

Herein, NiO nanoparticles (NPs) functionalized with a para-hexanitrocalix[6]arene derivative (p-HNC6/NiO) were synthesized by using a facile method and applied as a selective electrochemical sensor for the determination of bisphenol S (BPS) in real samples. Moreover, the functional interactions, phase purities, surface morphologies and elemental compositions of the synthesized p-HNC6/NiO NPs were investigated via advanced analytical tools, such as Fourier-transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and energy dispersive X-ray spectroscopy (EDX). Additionally, the synthesized p-HNC6/NiO NPs were cast on the surface of a bare glassy carbon electrode (GCE) via a drop casting method, which resulted in uniform deposition of p-HNC6/NiO/GCE over the surface of the GCE. Additionally, the developed p-HNC6/NiO/GCE sensor demonstrated an outstanding electrochemical response to BPS under optimized conditions, including a supporting electrolyte, a Briton-Robinson buffer electrolyte at pH 4, a scan rate of 110 mV s-1 and a potential window of between -0.2 and 1.0 V. The wide linear dynamic range was optimized to 0.8-70 µM to obtain a brilliant linear calibration curve for BPS. The limit of detection (LOD) and limit of quantification (LOQ) of the developed sensor were estimated to be 0.0059 and 0.019 µM, respectively, which are lower than those of reported sensors for BPS. The feasibility of the developed method was successfully assessed by analyzing the content of BPS in waste water samples, and good recoveries were achieved.

Identification of potential therapeutic targets for COVID-19 through a structural-based similarity approach between SARS-CoV-2 and its human host proteins.

Background: The COVID-19 pandemic caused by SARS-CoV-2 has led to millions of deaths worldwide, and vaccination efficacy has been decreasing with each lineage, necessitating the need for alternative antiviral therapies. Predicting host-virus protein-protein interactions (HV-PPIs) is essential for identifying potential host-targeting drug targets against SARS-CoV-2 infection. Objective: This study aims to identify therapeutic target proteins in humans that could act as virus-host-targeting drug targets against SARS-CoV-2 and study their interaction against antiviral inhibitors. Methods: A structure-based similarity approach was used to predict human proteins similar to SARS-CoV-2 ("hCoV-2"), followed by identifying PPIs between hCoV-2 and its target human proteins. Overlapping genes were identified between the protein-coding genes of the target and COVID-19-infected patient's mRNA expression data. Pathway and Gene Ontology (GO) term analyses, the construction of PPI networks, and the detection of hub gene modules were performed. Structure-based virtual screening with antiviral compounds was performed to identify potential hits against target gene-encoded protein. Results: This study predicted 19,051 unique target human proteins that interact with hCoV-2, and compared to the microarray dataset, 1,120 target and infected group differentially expressed genes (TIG-DEGs) were identified. The significant pathway and GO enrichment analyses revealed the involvement of these genes in several biological processes and molecular functions. PPI network analysis identified a significant hub gene with maximum neighboring partners. Virtual screening analysis identified three potential antiviral compounds against the target gene-encoded protein. Conclusion: This study provides potential targets for host-targeting drug development against SARS-CoV-2 infection, and further experimental validation of the target protein is required for pharmaceutical intervention.