The expedited development of drugs targeting gene products associated with insulin resistance holds the potential to enhance our comprehension of type 2 diabetes mellitus (T2DM). The virtual screening based on a three-dimensional (3D) protein structure has been expected as potential technique to accelerate a development of molecular target drugs. Among the targets implicated in insulin resistance, genetic characterization and protein function of Grb14 have been clarified without contradiction. The Grb14 gene displays notable variations in T2DM, and its gene product known to inhibit the function of the insulin receptor (IR) by directly binding to the tyrosine kinase domain. In the present study, a virtual screening, based on 3D structure of IR tyrosine kinase domain (IRβ) in complex with part of Grb14, was conducted to find compounds that can disrupt the complex formation between Grb14 and IRβ. First, ten compounds were selected from 154,118 compounds via hierarchical in silico structure-based drug screening, composed of grid docking-based and genetic algorithm-based programs. The experimental validations suggested that the one compound can affect blood glucose level. The molecular dynamics simulations and co-immunoprecipitation analysis showed that the compound did not completely suppress the protein–protein interaction between Grb14 and IR, though competitively bound to IR with the tyrosine kinase pseudosubstrate region in Grb14.

Onchocerciasis treatment and control relies mainly on the use of ivermectin which has high activity against the microfilarial stage of Onchocerca volvulus but limited activity against the long lived, tissue dwelling adult nematodes. As this neglected tropical disease has now been targeted for elimination there is an urgent need for new drugs to combat these parasites, ideally with macrofilaricidal activity. In this study we have examined the anti-Onchocerca activity of a range of existing FDA approved drugs with a view to repurposing, which can lead to rapid and relatively inexpensive development. From the Pharmakon-1600 library, 106 drugs were selected and tested against O. gutturosa adult male parasites using a concentration of 1.25 x 10-5 M in an in vitro 5-day standard assay to assess motility and viability (using MTT/formazan colorimetry). The findings revealed that 44 drugs produced marginal/moderate activity (50-99% motility and/or MTT reductions) including cefuroxime sodium, methenamine, primaquine phosphate, rivastigmine tartrate, while 23 drugs produced good activity (100% motility reductions and significant MTT reductions), including atovaquone, isradipine, losartan, rifaximin, cefaclor and pyrantel pamoate. Although this study represents only a first step, some of the identified hits indicate there are potential anti-Onchocerca drug candidates worthy of further investigation.

Multiple sclerosis is a chronic, autoimmune disease that mainly affects the central nervous system, including the brain, spinal cord, and optic nerve. This disease can cause clinical symptoms such as cognitive decline, muscle weakness, spasms, and fatigue in patients, and the onset tends to be younger. Current medication can only prevent or alleviate symptoms, so early diagnosis of this disease can increase patients' chances of treatment. Although the use of nuclear magnetic resonance detection can improve the efficiency of early auxiliary diagnosis, it still requires experienced doctors to spend too much time and energy on comprehensive judgment. To reduce the time cost and improve the efficiency of multiple sclerosis diagnosis, this article proposes a detection and recognition algorithm for multiple sclerosis based on wavelet entropy and self-adaptive particle swarm optimization. Firstly, a triple discrete wavelet transform is performed on the brain image of multiple sclerosis, and then 10 wavelet entropies are extracted from the decomposed wavelet subbands, which can reduce the feature dimensions of the image; Then, the algorithm of self-adaptive particle swarm optimization is used to optimize the feedforward neural network, in order to obtain the optimal connection weights and thresholds during the training process. The result of the model is with an average sensitivity of 92.29±1.89, specificity of 92.54±0.67, precision of 92.48±0.59, accuracy of 92.42±0.88, and F1 score of 84.85±1.74, Matthews correlation coefficient of 92.37±0.96, and Fowlkes223 Mallows Index of 92.38±0.96. The experimental results indicate that this algorithm has a very important data support role in detecting multiple sclerosis.

Human serum albumin (HSA) is multifunctional protein, known to be a natural carrier for a number of endogenous and exogenous compounds, including drugs. Formulating anticancer drugs with HSA is a clinically validated approach to improve the pharmacological properties and provide targeted delivery (passive and active) of cytotoxic payload to the tumor (such as in Abraxane). A number of receptors facilitating HSA uptake from systemic circulation have been characterized. What is interesting, such uptake may differ depending on the nature and quantity of ligands bound to HSA. Based on this, one might like to modify the HSA in a way that its distribution is more favorable for certain therapeutic purposes, thus ensuring more efficient delivery of the therapeutic cargo to disease site. E.g. Levofloxacin (LV), broad spectrum antibiotic drug, could benefit from extended systemic exposure, and stronger interaction with plasma proteins could be useful for this purpose. We have engrafted monomeric or polymeric CDs on the surface of HSA molecules to strengthen the LV adsorption (CD-LV dissociation constant is three orders of magnitude lower than that for HSA-LF). We have found that (HSA-HPolS)conj+LV exhibited the highest activity against E. coli, whereas (HSA-HPCD)conj+LV was the most effective against B. subtilis; and both HSA conjugates were more potent than LV alone or LV with HSA. Further fine-tuning of HSA could yield an improvement in biodistribution, and thus a more favorable risk/benefit ratio.

This article reviews the introduction of Alzheimer's Disease (AD), neural networks, training and learning of neural networks, applications of neural networks in early diagnosis of AD, applications of neural networks in AD drug discovery, other brain diseases, and challenges faced by AD. First, the paper introduces the background and characteristics of AD. AD is a degenerative neurological disorder characterized by impaired memory, decreased cognitive function, and loss of neurons. These characteristics place a huge burden on the lives and families of patients. Next, the basic principle and structure of neural network are discussed. A neural network is a computational model made up of multiple neurons that can perform tasks by learning and adapting to input data. In particular, the key concepts of neural network hierarchy, activation function and weight adjustment are discussed. Then, the training and learning methods of neural networks are discussed. Common techniques such as backpropagation algorithm and gradient descent optimizer are introduced in detail, as well as the importance of data preprocessing and model evaluation. Next, the paper focuses on the application of neural network in early diagnosis of AD. By extracting features from brain image data, neural networks can automatically identify differences between AD patients and healthy subjects, enabling early diagnosis and intervention. In addition, the application of neural networks in AD drug discovery is also discussed. By analyzing and predicting a database of known drugs, neural networks can help discover potential treatments for AD and speed up the drug discovery process. The paper further explores the application of neural networks in other brain diseases and highlights the challenges faced by AD, such as the lack of reliable biomarkers, complex pathological mechanisms, etc. In summary, this paper presents a systematic overview of AD, neural networks, training and learning of neural networks, applications of neural networks in early diagnosis of AD and drug discovery, and other brain diseases and challenges associated with AD.

Adenylosuccinic acid (ASA) is a small molecule dicarboxylate that could be a strong clinical development candidate for inherited myopathies involving dysregulated purine nucleotide metabo-lism. Currently, there are no published pharmacokinetic/dynamic or toxicology data available, albeit 10-year clinical trial data in Duchenne muscular dystrophy patients suggests a chronically safe drug. In this study, we tested the toxicity of ASA to cultured myoblasts in vitro and acute systemic toxicity in mice. ASA is a non-toxic small molecule with an LD50> 5000mg/kg. Some background necrotic foci in the liver, kidney and gastrointestinal tract were shown that are likely incidental but warrant follow-up sub-/chronic oral exposure studies.

Stellatolides are natural compounds that have shown promising biological activities, including antitumor, antimicrobial, and anti-inflammatory properties, making them potential candidates for drug development. Chemical Reactivity Theory (CRT) is a branch of chemistry that explains and predicts the behavior of chemical reactions based on the electronic structure of molecules. Conceptual Density Functional Theory (CDFT) and Computational Peptidology (CP) are computational approaches used to study the behavior of atoms, molecules, and peptides. In this study, we present the results of our investigation of the chemical reactivity and ADMET properties of Stellatolides A-H using a novel computational approach called Conceptual DFT-based Computational Peptidology (CDFT-CP). Our study uses CDFT and CP to predict the reactivity and stability of molecules and to understand the behavior of peptides at the molecular level. We also predict the ADMET properties of the Stellatolides A-H to provide insight into their effectiveness, potential side effects, and optimal dosage and route of administration. This study sheds light on the potential of Stellatolides A-H as promising candidates for drug development and highlights the potential of CDFT-CP for the study of other natural compounds and peptides.

Background. Extracorporeal therapies (ET) are increasingly used in pediatric settings as adjuvant therapeutic strategies for overwhelming inflammatory conditions. Although these treatments seem to be effective for removing inflammatory mediators, their influence on antimicrobials pharmacokinetic should not be neglected. Methods: Prospective observational study of children admitted to the pediatric intensive care unit (PICU) with a diagnosis of sepsis/septic shock. All critically ill children received hemoadsorption treatment with Cytosorb (CS) in combination with CKRT. Therapeutic drug monitoring has been performed in 10 critically ill children, testing four antimicrobial molecules: meropenem, ceftazidime, amikacin and levofloxacin . In order to evaluate the total and the isolated CKRT and CS contribution to antibiotics removal, blood samples at each circuit point (post-hemofilter, post-CS and in the effluent line) were performed. Therefore Clearance and Mass Removal (MR) of hemofilter and CS were calculated. Results. Our preliminary report describes a different impact of CS on these target drugs removal: CS clearance resulted low for amikacine (6-12%), moderate for ceftazidime (43%) and moderate to high for levofloxacine (52-72%). Higher MR and clearance were observed with CKRT compared to CS. To the best of our knowledge this is the first report regarding pharmacokinetic dynamics in critically ill children treated with CKRT and CS for septic shock.

The drug delivery systems receive more and more attention for the control and treatment of many diseases due to their increased number in recent years. The main aims of this study were to develop and to characterize a polyurethane drug delivery system that it is intended to be used for the transmembrane transport of nucleosides. Three different samples have been synthesized based on aliphatic diisocyanates (hexamethylene diisocyanate, isophorone diisocyanate and lysine diisocyanate) as organic phase, respectively a mixture of polyethylene glycol, polycaprolactone diol and low molecular weight diols as aqueous phase. The samples were characterized by pH, refractivity index and solubility measurements, drug loading efficacy and release investigations, thermal behavior, Zetasizer, cells viability and irritation tests on mice skin. The results indicate the obtaining of different populations of neutral acido-basic particles with size between 132 and 190 nm; the Zeta potential values and SEM images show a medium tendency to form clusters, while UV-Vis evaluations indicate an almost 70% encapsulation efficacy, a prolonged release (45% of encapsulated substance is released in the first 5 days) and around 70% of particles have penetrated an artificial membrane in the first 24h. The synthesized products can be tested in further clinical trials, the currently tests on cells culture and mice skin revealing no side effects.

New hybrid composites based on the inclusion of a vegetal extract, i.e., Boswellia Serrata extract (BSE), rich in boswellic acids, well known as a potent anti-inflammatory natural drug, in a lamellar solid layered double hydroxide (LDH), i.e. a Magnesium Aluminum Carbonate, were developed and characterized in the present work. The adopted LDH exhibits a layered crystal structure, comprised of positively charged hydroxide layers and interlayers composed of carbonate anions and water molecules, thus it was expected to embed negatively charged boswellic acids. In the present case, a calcination process was also adopted on LDH to increase organic acids loading, based on the replacement of original inorganic anions. An accurate investigation was carried out by TGA, PXRD, FT-IR/ATR, XPS and LC-MS to ascertain the nature, interaction, and quantifica-tion of the active molecules of the vegetal extract loaded in the developed hybrid materials. As a result, a significant disruption of the original layered structure was observed in LDH subjected to calcination (LDHc), and this material was able to include a higher amount of organic acids when its composite with BSE was prepared. However, in vitro tests on composites bioactivity, expressed in terms of antimicrobial and anti-inflammatory activity, evidenced LDH-BSE as a better material compared to BSE and to LDHc-BSE, thus suggesting that, though the embedded organic acids amount was lower, they could be more available since not firmly bound to the clay. The composite was able to significantly decrease the number of viable pathogens such as Escherichia Coli and Staphylococcus aureus, as well as the internalization of toxic active species into human cells imposed to oxidative stress in comparison to the BSE.

Despite being an abundant marine organism in Indonesia, black sea cucumber is still underutilised due to its slightly bitter taste. Previous studies have hinted at the potential of black sea cucumber as an anti-cancer agent. However, specific identification of bioactive compounds that can interact with cancer proteins is still lacking. In the same place, cancer ranks third as Indonesia's leading cause of death. Therefore, this study aims to identify potential anti-cancer compounds from black sea cucumbers using a comprehensive in silico drug discovery approach. This research uses machine learning, molecular docking, and ADMET analysis to identify bioactive compounds that specifically interact with cancer proteins. A combination of the Cascade Deep Forest algorithm and ECFP-AAIndex1 feature combination proved to be the most effective in predicting these interactions. Through molecular docking validation, four bioactive compounds with strong binding affinity were identified: Afimoxifene, Danazol, Taxifolin, and Terfenadine. ADMET analysis highlighted Taxifolin as the most promising candidate, as it passed most ADMET parameters. Further wet laboratory studies are required to confirm the effects and potential of these compounds as anti-cancer agents. This study builds a foundation for future investigations into alternative cancer treatments using abundant natural resources.

The potential to improve the effectiveness and efficiency of potential estrogen-based oral contraceptives (fertility control) for possums was investigated by comparing the inhibitory potential of hepatic CYP3A and UGT2B catalytic activity using a selected compound library (CYP450 inhibitor-based compounds) in possums to that of three other species (mouse, avian, and human). The results showed higher CYP3A protein levels in possum liver microsomes compared to other test species (up to a 4-fold difference). Also, possum liver microsomes had significantly higher basal p-nitrophenol glucuronidation activity than other test species (up to an 8-fold difference). However, no CYP450 inhibitor-based compounds significantly decreased the catalytic activity of possum CYP3A and UGT2B below the estimated IC₅₀ and 2-fold IC₅₀ values and were therefore not considered to be potent inhibitors of these enzymes. However, compounds such as isosilybin (65%), ketoconazole (72%) and fluconazole (74%) showed reduced UGT2B glucuronidation activity in possums, mainly at 2-fold IC₅₀ values compared to control (p<0.05). Given the structural features of these compounds, these results could provide opportunities for future compound screening. More importantly, however, this study provided preliminary evidence that the basal activity and protein content of two major drug metabolising enzymes differ in possums compared to other test species, suggesting that this could be further exploited to reach the ultimate goal, a potential target-specific fertility control for possums in New Zealand.

The novel coronavirus disease 19 (COVID-19) has resulted in an estimated 20 million excess deaths and the recent resurgence of COVID-19 in China is predicted to result in up to 1 million deaths over the next few months. With vaccines unable to halt transmission it is important to continue our quest for safe, effective, affordable drugs that will be available to all countries. Drug repurposing is one of the strategies being explored in this context. Recently, out of 7,817 approved drugs, 214 candidates were systematically down-selected using a combination of 11 filters including approval status, assay data against SARS-CoV-2, pharmacokinetic, pharmacodynamic and toxicity profiles. These drugs were subjected in this study to virtual screening against various targets of SARS-CoV-2 followed by molecular dynamic studies of the best scoring ligands against each target. The chosen molecular targets were Spike receptor binding domain, Nucleocapsid protein RNA binding domain, and key non-structural proteins 3, 5, 12, 13 and 14. Four drugs approved for other indications — alendronate, cromolyn, natamycin and treprostinil — look sufficiently promising from our in silicostudies to warrant further in vitro and in vivo investigations as appropriate to ascertain their extent of anti-viral activities.

Nanosized drug delivery systems (DDS) have been studied as a novel strategy against cancer due to their potential to simultaneously decrease drug inactivation and systemic toxicity and increase passive and/or active drug accumulation within the tumor(s). Triterpenes are plant-derived compounds with interesting therapeutic properties. Betulinic acid (BeA) is a pentacyclic triterpene which has great cytotoxic activity against different cancer types. Herein, we developed a nanosized protein-based DDS of bovine serum albumin (BSA) as the drug carrier combining two compounds: doxorubicin (Dox) and the triterpene BeA using an oil-water-like micro-emulsion method. Spectrophotometric assays were performed to determine protein and drug concentrations in the DDS. The biophysical properties of these DDS were characterized using dynamic light scattering (DLS) and circular dichroism (CD) spectroscopy confirming nanoparticle (NP) formation and drug loading into the protein structure, respectively. The encapsulation efficiency was 77% for Dox and 18% for BeA. More than 50% of both drugs were released within 24 h, at pH 6.8, while less drug was released at pH 7.4 in this time period. Co-incubation viability assays of Dox and BeA alone for 24 h demonstrated synergistic cytotoxic activity in the low μM range against the non-small cell lung carcinoma (NSCLC) A549 cells. Viability assays of the BSA(Dox+BeA) DDS demonstrated a higher synergistic cytotoxic activity than the two drugs with no carrier. Moreover, confocal microscopy analysis confirmed cellular internalization of the DDS and nucleus accumulation of the Dox. We determined the mechanism of action of the BSA(Dox+BeA) DDS, confirming S-phase cell cycle arrest, DNA damage, caspase cascade activation, and downregulation of the epidermal growth factor receptor (EGFR) expression. This DDS has the potential to synergistically maximize the therapeutic effect of Dox and diminish chemoresistance induced by EGFR expression using a natural triterpene against NSCLC.

3-(3,4-Dichlorophenyl)-5-(1H-indol-5-yl)-1,2,4-oxadiazole was synthesized via the condensation of 3,4-dichlorobenzamidoxime and methyl 1H-indole-5-carboxylate using superbasic medium (NaOH/DMSO). The compound was tested as a potential inhibitor of human monoamine oxidase (MAO) A and B. It demonstrated notable inhibition with an IC50 value of 0.036 μM for MAO-B and isoform specificity. The product was characterized by 1H NMR, 13C NMR, and HRMS. In conclusion, the new active MAO-B inhibitor may serve as a candidate for the future discovery of therapeutic agents for neurodegenerative disorders such as Parkinson’s disease.

Nutraceuticals have taken the spotlight during the past two decades as evidenced by the exponential publications on them. Long a part of routine in Traditional Medicine Systems, the rise of their mainstream use globally raises both safety concerns and need for better understanding of efficacious dosing. We attempt to answer these questions in this preliminary scoping review by an analysis of current literature on nutraceutical use as a personalized or prescription medicine. Using Covidence, Rayyan, and manual searches of PubMed, 598 unique publications were selected. 32 are systematic reviews, of which we overview the scope. We also overview 30 papers that address adverse drug reactions. To obtain an unbiased landscape of the 598 papers, we analyzed keywords using multiple methods. Expectedly, the most frequent keywords were probiotics and vitamins. Unexpectedly and remarkably, among the highest keyword yield was ‘COVID’. Further exploring this aspect, we review 15 pertinent papers, that not only provide robust evidence for nutraceutical benefits as part of SARS-CoV-2 treatment, but also amplify the notion that nutraceuticals are protective. Overall, the strident note is that further robust targeted research is needed in order to reap the full benefits of nutraceuticals in a safe and efficacious manner.

The monkeypox virus (MPXV) has become a major threat due to the increasing global caseload and the ongoing multi-country outbreak in non-endemic territories. Due to limited research in this avenue and the lack of intervention strategies, the present study was aimed to virtually screen bioactive phytochemicals against envelope proteins of MPXV via rigorous computational approaches. Molecular docking and molecular dynamic (MD) simulations were used to investigate the binding affinity of 12 phytochemicals against three envelope proteins of MPXV, viz., D13, A26, and H3. Silibinin, oleanolic acid, and ursolic acid were computationally identified as potential phytochemicals that showed strong binding affinity towards all the tested structural proteins of MPXV through molecular docking. The stability of the docked complexes was also confirmed by MD simulations. ADME analysis also computationally confirmed the drug-like properties of the phytochemicals, thereby asserting their suitability for consumption. Hence, this study envisions the candidature of bioactive phytochemicals as promising inhibitors against the MPXV, serving as template molecules that could further be experimentally evaluated for their efficacy against monkeypox.

Mathematical modeling is crucial in investigating the pandemic of the ongoing coronavirus disease (COVID-19). The primary target area of the SARS-CoV-2 virus is epithelial cells in the human lower repertory track. During this viral infection, infected cells can initiate innate and adaptive immune responses to viral infection. Immune response in COVID -19 infection can lead to longer recovery time and more severe secondary complications. We formulate a target cell limited mathematical model by incorporating a saturation term for SARS-CoV-2 infected epithelial cell loss reliant on infected cell levels. Forward and backward bifurcation between disease-free and endemic equilibrium points has been analyzed. Global stability of both disease-free and endemic equilibrium is provided. We have seen that the disease-free equilibrium is globally stable for $R_0<1$, and endemic equilibrium exists and is globally stable for $R_0>1$. Impulsive application of drug dosing has been applied for the treatment of covid-19 patients. Also, the dynamics of the impulsive system are discussed when a patient takes drug holidays. The numerical simulations are performed in support of our analytical findings and for the qualitative analysis of the system's dynamics with and without impulse drug dosing.

Cytochrome P450 oxidoreductase (POR) is the redox partner of steroid and drug-metabolizing cytochromes P450 located in the endoplasmic reticulum. Mutations in POR cause a broad range of metabolic disorders. The POR variant rs17853284 (P228L) identified by genome sequencing has been linked to lower testosterone levels and reduced P450 activities. We expressed POR wild type and the P228L variant in bacteria, purified the proteins, and performed protein stability and catalytic functional studies. Variant P228L affected the stability of the protein as evidenced by lower unfolding temperatures and higher sensitivity to urea denaturation. A significant reduction of small molecule metabolism was observed with POR P228L while activities of CYP3A4 were reduced by 25%, and activities of CYP3A5, and CYP2C9 were reduced by more than 40% compared to WT POR. The 17,20 lyase activity of CYP17A1 responsible for production of main androgen precursor dehydroepiandrosterone, was reduced to 27% of WT in presence of P228L variant of POR. Based on in silico and in vitro studies we predict that the change of proline to leucine may change the rigidity of the protein, causing conformational changes in POR, leading to altered electron transfer to redox partners. A single amino acid change can affect protein stability and cause a severe reduction in POR activity. Molecular characterization of individual POR mutations is crucial for a better understanding of the impact on different redox partners of POR.

Enterovirus 71 (EV71) is an etiological agent of hand foot and mouth disease and can also cause neurological complications in young children. However, there are no approved drugs to treat EV71 infections. In this study, we conducted an antiviral drug screening by using a Food and Drug Administration (FDA)-approved drug library. We identified five drugs that showed dose-dependent inhibition of viral replication. Sertraline was further characterized because it exhibited the most potent antiviral activity with the highest selectivity index among the five hits. The antiviral activity of sertraline was noted for other EV serotypes. The drug’s antiviral effect is not likely associated with its approved indications as an antidepressant and its mode-of-action as a selective serotonin reuptake inhibitor. The time-of-addition assay revealed that sertraline inhibited an EV71 infection at the entry stage. We also showed that sertraline partitioned into acidic compartments, such as endolysosomes, to neutralize the low pH levels. In agreement with the findings, the antiviral effect of sertraline could be relieved greatly by exposing virus-infected cells to extracellular low-pH culture media. Together, we have identified an FDA-approved antidepressant with the new indication for the broad-spectrum EV inhibition by blocking viral entry through the alkalization of the endolysosomal route.

Breast cancer is the most widespread malignancy in women from corner to corner of the world. Nanostructured lipid carrier (NLC) proved its efficacy in the treatment of cancer. NLC loaded with Imatinib (IMA) (NANIMA) was prepared and evaluated for in vitro efficacy in MCF-7 breast cancer cells. Hot homogenization method was used for the preparation of NANIMAs. Aqueous solution of surfactants (hot) was mixed with molten mixture of stearic acid and sesame oil (hot) under homogenization. The prepared NANIMAs were characterized and evaluated for size, polydispersity index, zeta potential, encapsulation efficiency, release studies, stability studies and MTT assay (cytotoxicity studies). The optimized NANIMA revealed particle size of 104.63 ± 9.55 d.nm, PdI of 0.227 ± 0.06 and EE of 99.79 ± 0.03. All NANIMAs revealed slow and sustained release behaviour. The surfactants used in the preparation of NANIMAs exhibited their effects on particle size, zeta potential, encapsulation efficiency, stability studies and release studies. The cytotoxicity studies unveiled 8.75 times increase in cytotoxicity for optimized NANIMA (IC50 = 6 µM) when compared with IMA alone (IC50 = 52.5 µM) on MCF-7 breast cancer cells. After this, NLC containing IMA possibly will be employed for the cure of breast cancer. A lesser amount of IMA loaded NLC will be sufficient than IMA alone for the treatment of breast cancer. Moreover, the patient will exhibit not as much of adverse effects as in case of IMA alone. Consequently, NANIMA could prove to be useful for effective therapeutic outcome in breast cancer treatment.

Abstract: This review presents current literature on different nanocomposites coatings and surface finishing for different substrates (such as textiles, concrete, plastics, stones, metals and so on). In particular, this study is focused on smart materials, drug delivery systems, and industrial, antifouling and nano/ultrafiltration membrane coatings. Each of these nanostructured coatings shows interesting properties for different fields of application. In this review, particular attention is paid to the synthesis and the consequent physico-chemical characteristics of each coating and, therefore, to the different parameters that influence the substrate deposition process. Several techniques used in the characterization of these surface finishing coatings are also described. In this review, the sol-gel and polymerization method for preparing stimuli-responsive coatings as smart sensor materials is described; functional polymers and nanoparticles sensitive to pH, temperature, phase, light and biomolecules are also treated. Finally, nanomaterials based on phosphorus, borates, hydroxy carbonates and silicones are used and described as flame retardant coatings; organic/inorganic hybrid sol-gel coatings for industrial applications are illustrated, together with functional nanofiller (carbon nanotubes, metallic oxides, etc.) and polymers employed for nano/ultrafiltration membrane and antifouling coatings. In the last decades, several research institutes and industries have collaborated for the advancement of nanotechnology by optimizing conversion processes of conventional materials into coatings with new functionalities for intelligent, innovative, eco-sustainable and advanced applications.

Drug repositioning (also called drug repurposing) is a strategy for identifying new therapeutic targets for existing drugs. This approach is of great importance in pharmacology as it is a faster and cheaper way to develop new medical treatments. In this paper, we present, to our knowledge, the first application of multiplex-heterogeneous network embedding to drug repositioning. Network embedding learns the vector representations of nodes, opening the whole machine learning toolbox for a wide variety of applications including link prediction, node labelling or clustering. So far, the application of network embedding for drug repositioning focused on heterogeneous networks. Our approach for drug repositioning is based on multiplex-heterogeneous network embedding. Such method allows the richness and complexity of multiplex and heterogeneous networks to be projected in the same vector space. In other words, multiplex-heterogeneous networks aggregate different multi-omics data in the same network representation. We validate the approach on a task of link prediction and on a case study for SARS-CoV2 drug repositioning. Experimental results show that our approach is highly robust and effective for finding new drug-target associations.

Primary hyperoxalurias (PHs) are a group of inherited alterations of the hepatic glyoxylate metabolism. PHs classification based on gene mutations parallel a variety of enzymatic defects, and all involve the harmful accumulation of calcium oxalate crystals that produce systemic damage. These geographically widespread rare diseases have a deep impact in the life quality of the patients. Until recently, treatments were limited to palliative measures and kidney/liver transplants in the most severe forms. Efforts made to develop pharmacological treatments succeeded with the biotechnological agent lumasiran, a siRNA product against glycolate oxidase, which has become the first effective therapy to treat PH1. However, small molecule drugs have classically been preferred since they benefit from experience and have better pharmacological properties. The development of small molecule inhibitors designed against key enzymes of glyoxylate metabolism is on the focus of research. Enzyme inhibitors are successful and widely used in several diseases and their pharmacokinetic advantages are well known. In PHs, effective enzymatic targets have been determined and characterized for drug design and interesting inhibitory activities have been achieved both in vitro and in vivo. This review describes the most recent advances towards the development of small molecule enzyme inhibitors in the treatment of PHs, introducing the multi-target approach as a more effective and safe therapeutic option.

New pharmaceutically acceptable salts of trazodone for the treatment of central nervous system disorders are synthesized and described. Each salt (trazodone hydrogen bromide and trazodone 1-hydroxy-2-naphthoate) was obtained by two or three different methods leading to the same crystalline form. Although trazodone salts are poorly crystalline, single-crystal X-ray diffraction data for trazodone 1-hydroxy-2-naphthoate were collected and analyzed as well as compared to the previously described crystal structure of commercially available trazodone hydrochloride. The powder samples of all new salts were characterized by Fourier transform infrared spectroscopy and 13C solid-state nuclear magnetic resonance spectroscopy. Spectroscopic studies were supported by gauge including projector augmented wave (GIPAW) calculations of carbon chemical shielding constants. The main goal of our research was to find salts with better physicochemical properties and to make an attempt to associate them with both the anion structure and the most prominent interactions exhibited by the protonated trazodone cation. The dissolution profiles of trazodone from tablets prepared from various salts with lactose monohydrate were investigated. The studies revealed that salts with simple anions show a fast release of the drug while the presence of more complex anion, more strongly interacting with the cation, effects a slow-release profile of the active substance and can be used for the preparation of the tables with a delay or prolonged mode of action.

Intravitreal injection is the gold standard therapeutic option for posterior segment pathologies, and long-lasting release is necessary to avoid reinjections. There is no effective intravitreal treatment for glaucoma or other optic neuropathies in daily practice, nor is there a non-invasive method to monitor drug levels in the vitreous. Here we show that a glaucoma treatment combining a hypotensive and neuroprotective intravitreal formulation (IF) of brimonidine-Laponite (BRI/LAP) can be monitored non-invasively using vitreous imaging captured with optical coherence tomography (OCT) over 24 weeks of follow-up. Qualitative and quantitative characterization was achieved by analysing the changes in vitreous (VIT) signal intensity, expressed as a ratio of retinal pigment epithelium (RPE) intensity. Vitreous hyperreflective aggregates mixed in the vitreous and tended to settle on the retinal surface. Relative intensity and aggregate size progressively decreased over 24 weeks in treated rat eyes as the BRI/LAP IF degraded. VIT/RPE relative intensity and total aggregate area correlated with brimonidine levels measured in the eye. The OCT-derived VIT/RPE relative intensity may be a useful and objective marker for non-invasive monitoring of BRI/LAP IF.

Background. To determine the effectiveness and safety of meropenem in routine clinical practice, in terms of clinical and microbiological response. Methods. A real-world, observational, descriptive, longitudinal study with daily monitoring of clinical history records was conducted on all patients who were medically prescribed meropenem during a period between October 2015 and March 2016 at a university hospital in Bucaramanga (Colombia). Results. The study evaluated 84 patients with an average age of 63.2 years, mostly older adults with multiple comorbidities, of whom 54.8% were men. A positive clinical or microbiological response was obtained in 98.8% of the patients. At the end of the treatments, significant improvements in dysthermia (0% vs 29% at the beginning, p = 0.000), tachycardia (13% vs 47%, p = 0.049) and leukocytosis (39% vs 15% at the beginning, p = 0.008) were evidenced. The improvement in the indicator that combines all the SIRS criteria was also significant (p = 0.000). The treatment was well tolerated, although we identified some non-serious and expected adverse reactions. Conclusions. Generic meropenem proved to be effective and well tolerated for different types of infection in routine clinical practice. The results are consistent with the findings of the clinical studies with the innovator drug.

Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder. One of the important therapeutic approaches of AD is the inhibition of β‐site APP cleaving enzyme‐1 (BACE1). This enzyme plays a central role in the synthesis of the pathogenic β-amyloid peptides (Aβ) in Alzheimer's disease. A group of potent BACE1 inhibitors with known x-ray structures (PDB ID 5i3X, 5i3Y, 5iE1, 5i3V, 5i3W, 4LC7, 3TPP) were studied by molecular dynamics simulation and binding energy calculation employing MM_GB(PB)SA. The calculated binding energies gave Kd values 0.139 µM, 1.39 nM, 4.39 mM, 24.3 nM, 1.39 mM, 29.13 mM and 193.07 nM, respectively. These inhibitors showed potent inhibitory activities in enzymatic and cell assays. The Kd values were compared with experimental values, the structures were discussed in view of the energy contributions to binding. Drug likeness of these inhibitors is also discussed. Accommodation of ligands in the catalytic site of BACE1 is discussed depending on the type of fragment involved in each structure. Molecular dynamics (MD) simulations and energy studies were used to explore the recognition of the selected BACE1 inhibitors by Asp 32, Asp228 and the hydrophobic flap. The results show that selective BACE1 inhibition may be due to the formation of strong electrostatic interactions with Asp32 and Asp228 and a large number of hydrogen bonds, π-π and Van der Waals interactions with the amino acid residues located inside the catalytic cavity. Interactions with the ligands show a similar binding mode with BACE1. These results help to rationalize the design of selective BACE1 inhibitors.

Gastrointestinal tumors including pancreatic and colorectal cancers represent one of the greatest public health issues worldwide, leading to million global deaths. Recent research demonstrated that the human heavy chain ferritin (HFt) can encapsulate different type of drugs in its cavity and can bind to its receptor, CD71, in several solid and hematological tumors, thus highlighting the potential use of ferritin for tumor-targeting therapies. Here, we describe the development and characterization of a novel nanomedicine based on the HFt that is named The-0504. In particular, this novel system is a nano-assembly comprising an engineered version of HFt that entraps about 80 molecules of a potent, wide-spectrum, non-camptothecin topoisomerase I inhibitor (Genz-644282). The-0504 can be produced by a standardized pre-industrial process as a pure and homogeneously formulated product with favourable lyophilization properties. The preliminary anticancer activity was evaluated in cultured cancer cells and in a mouse model of pancreatic cancer. Overall results reported here make The-0504 a candidate for further preclinical development against CD-71 expressing deadly tumors

Neurokinin-1 receptor (NK-1R) antagonists exert an antitumor action, are safe and do not cause serious side-effects. These antagonists (via the NK-1R) exerted multiple actions against cancer: antiproliferative and anti-Warburg effects, apoptosis, anti-angiogenic and antimetastatic. These multiple effects have been shown in a broad-spectrum of cancers. The drug aprepitant (an NK-1R antagonist) is currently used in clinical practice as antiemetic. In in vivo and in vitro studies, aprepitant also showed the aforementioned multiple antitumor actions against many types of cancer. A successful combination therapy (aprepitant and radiotherapy) has recently been reported in a patient suffering from lung carcinoma: the tumor mass disappeared and side-effects were not observed. Aprepitant could be considered as an intelligent bullet against cancer. The administration of aprepitant in cancer patients to prevent recurrence and metastasis after surgical procedures, thrombosis and thromboembolism is discussed as well as the possible link, through the SP/NK-1R system, between cancer and depression. Our main aim is to review the multiple antitumor actions exerted by aprepitant and the use of this drug is suggested in cancer patients. Altogether, the data support the reprofiling of aprepitant for a new therapeutic use as an antitumor agent.

SARS-CoV-2 or COVID-19, a new seventh human corona virus, has out-broken in Wuhan, China since 31^st December 2019, and quickly escalated to take the form of pandemic which killed many human beings throughout almost all countries across continents. The rapidity of its transmission from human to human is far greater than all previous human corona viruses which came into existence like SARS-CoV, MERS-CoV, etc. The nucleotide sequence of SARS-CoV-2 (isolates Wuhan-Hu-1) is 29,875 bp in ss-RNA. Symptoms of SARS-CoV-2 infected pneumonia include from asymptomatic to high fever and/or respiratory illnesses. Coronavirus virion (spherical/round /elliptical in shape) consists of three parts- outer membrane or envelope, nucleocapsid and genome (RNA). SARS-CoV-2 was shown to use receptor, angiotensin converting enzyme 2 (ACE2) for attachment to the cells through its surface spike (S) protein (S1), and the virion enters into the host cell through two routes- direct membrane fusion and endocytotic pathway. The RNA of SARS-CoV acts directly as mRNA and here minus(-) 1 programmed ribosomal frameshift (-1PRF) is being operated by slippery sequence and pseudoknot, so it translates 16 nonstructural proteins including RNA dependent RNA replicase. Then genomic RNA replicated continuously on – strand RNA template and subgenomic RNA transcribed discontinuously on –RNA template to sgmRNA. Subgenomic RNAs/sgmRNAs synthesize all structural proteins. This article takes into consideration the details of established theories of viral structure, viral attachment, mode of entry into human cells, different models of replication and transcription of virus genome proposed by eminent scientists over the years, and makes an in depth examination highlighting meaningful points or important target cites of viral propagation or synthesis, which are conserved, for prompt development of potent drugs or vaccine to counter COVID-19 for which human race is anxiously and eagerly waiting.

An elevated level of endoplasmic reticulum (ER) stress is considered an aggravating factor for inflammatory bowel disease (IBD). To develop an ER stress attenuator that is effective against colitis, 4-phenylbutyric acid (4-PBA), a chemical chaperone that alleviates ER stress, was conjugated with acidic amino acids to yield a 4-PBA-glutamic acid conjugate (PBA-GA) and a 4-PBA-aspartic acid conjugate (PBA-AA). The PBA derivatives were converted to 4-PBA in the cecal contents, where the conversion was greater with PBA-GA. After oral administration of PBA-GA (oral PBA-GA), millimolar levels of PBA were accumulated in the cecum, whereas 4-PBA was not detected in the blood, indicating the targeting of PBA-GA to the large intestine. At concentrations in the cecum achievable by oral PBA-GA, 4-PBA effectively attenuated ER stress in human colon epithelial cells. In 2,4-dinitrobenzenesulfonic acid-induced colitis in rats, oral PBA-GA alleviated the damage and inflammation in the colon. Moreover, oral PBA-GA substantially reduced the elevated levels of ER stress marker proteins in the inflamed colon. Moreover, PBA-GA was as effective as the currently used anti-IBD drug, sulfasalazine. In conclusion, PBA-GA is a colon-targeted prodrug of 4-PBA and is effective against rat colitis probably through the attenuation of ER stress in the inflamed colon.

Nucleoid-associated proteins (NAPs) play an architectural role by bending, bridging, and wrapping the DNA along with a regulatory role of controlling various transcriptional units in the cell. Previews reviews have highlighted the role of HU and its paralog IHF plays in intracellular function as a transcriptional regulator, nucleoid bending protein and sometimes also moonlights in other functions. This review highlights along with the canonical functions of HU and IHF which affects genes responsible for translational machineries, cell wall biosynthesis, aerobic respiration and virulence ; other non-canonical roles which HU plays outside the cellular milieu, notably in acting as an adhesin and playing role in host-cell adhesion, its role in biofilm architecture and its association with cationic low complexity region, resembling histone like H1 proteins. HU and IHF thus has evolved as a hub protein performing a vast type of functions which makes it a important drug target for antibacterial therapy.

Beyond their significant contribution to the dietary and industrial supplies, marine algae are considered to be a potential source of some unique metabolites with diverse health benefits. The pharmacological properties, such as antioxidant, anti-inflammatory, cholesterol homeostasis, protein clearance and anti-amyloidogenic potentials of algal metabolites endorse their protective efficacy against oxidative stress, neuroinflammation, mitochondrial dysfunction, and impaired proteostasis which are known to be implicated in the pathophysiology of neurodegenerative disorders and the associated complications after cerebral ischemia and brain injuries. As was evident in various preclinical studies, algal compounds conferred neuroprotection against a wide range of neurotoxic stressors, such as oxygen/glucose deprivation, hydrogen peroxide, glutamate, amyloid β, or 1-methyl-4-phenylpyridinium (MPP+) and, therefore, hold therapeutic promise for brain disorders. While a significant number of algal compounds with promising neuroprotective capacity have been identified over the last decades, a few of them have had access to clinical trials. However, the recent approval of an algal oligosaccharide, sodium oligomannate, for the treatment of Alzheimer's disease enlightened the future of marine algae-based drug discovery. In this review, we briefly outline the pathophysiology of neurodegenerative diseases and brain injuries for identifying the targets of pharmacological intervention, and then review the literature on the neuroprotective potentials of algal compounds along with the underlying pharmacological mechanism, and present an appraisal on the recent therapeutic advances. We also propose a rational strategy to facilitate algal metabolites-based drug development.

Once a wheat sheaf has been sealed and tied up, its packed down straws display the same orientation and zero-divergence. This observation brings us to the mathematical notion of presheaf, i.e., a topological structure in which diverging functions are locally superimposed. We show how the concepts of presheaves and the correlated globular sets, borrowed from category theory and algebraic topology, allow a well-founded mathematical approach to otherwise elusive activities of the brain. The mathematical assessment of brain functions in terms of presheaves: a) explains why spontaneous random spikes synchronize; b) leads to the counterintuitive intuition of antidromic effects in neuronal spikes: when an entrained oscillation propagates from A to B, changes in B lead to changes in A. We provide testable previsions: a) we suggest the proper locations of transcranial magnetic stimulation’s coils to improve the clinical outcomes of drug-resistant epilepsy; b) we advocate that axonal stimulation by external sources backpropagates and alters the neuronal electric oscillatory frequency. Further, we describe how the hierarchical information transmission inside globular sets provides fresh insights concerning different issues at various coarse-grained scales, such as object persistence, memory reinforcement in spite of random noise, Bayesian inferential circuits.

Background: Iranian traditional medicine is a holistic school of medicine with a long prolific history. It describes numerous concepts and the relationships between them. However, no unified terminology has been proposed for the concepts of this medicine up to the present time. Considering the extensive use of concepts in the numerous textbooks written by the scholars over centuries, comprehending the totality of the terminology is obviously a very challenging task. To resolve this issue and overcome the obstacles, and code the concepts in a reusable manner, constructing an ontology of the concepts of Iranian traditional medicine seems a necessity.Methods: Makhzan al-Advieh, an encyclopedia of materia medica compiled by Mohammad Hossein Aghili Khorasani, was selected as the resource to create an ontology of Mizaj. The steps followed to accomplish this task included (1) compiling the list of classes for Mizaj; (2) arranging the classes in taxonomy; (3) determining object properties and their cardinalities; (4) specifying annotation properties including codes, labels, synonyms, and definitions for each concept; (5) reviewing the fields pertaining to Mizaj of all monographs in Makhzan al-Advieh. The ontology was created using Protégé with adherence to the principles of ontology development provided by the Open Biological and Biomedical Ontology (OBO) foundry. Results: Mizaj ontology was constructed with a final inclusion of 105 classes, three object properties, and 1078 axioms in the Iranian Traditional Medicine General Ontology database, IrGO, freely available at http://jafarilab.com/irgo/. An indented tree view and an interactive graph view using WebVOWL were used to visualize the ontology. All classes were linked to their instances in the UNaProd database to create a knowledge-base of Mizaj. Conclusion: We constructed an ontology-based knowledge base of ITM concepts of Mizaj in the domain of materia medica to help offer a shared and common understanding of this concept, enable reuse of the knowledge, and make the assumptions explicit. Extending IrGO will bridge the gap between traditional and conventional schools of medicine and help guide future research on new treatment options.

The activation of halogen bonding by the substitution of the pentafluorosulfanyl (SF5) group was studied using a series of SF5-substituted iodobenzenes. The simulated electrostatic potential values of SF5-substituted iodobenzenes, ab initio molecular orbital calculations of intermolecular interactions of SF5-substituted iodobenzenes with pyridine, and the 13C NMR titration experiments of SF5-substituted iodobenzenes in the presence of pyridine or tetra (n-butyl) ammonium chloride (TBAC) indicated the obvious activation of halogen bonding, although this was highly dependent on the position of SF5-substitution on the benzene ring. 3,5-Bis-SF5-iodobenzene was the most effective halogen bond donor followed by o-SF5-substituted iodobenzene, while the m- and p-SF5 substitutions did not activate the halogen bonding of iodobenzenes. The 2:1 halogen bonding complex of 3,5-bis-SF5-iodobenzene and 1,4-diazabicyclo[2.2.2]octane (DABCO) was also confirmed. Since SF5-containing compounds have emerged as promising novel pharmaceutical and agrochemical candidates, the 3,5-bis-SF5-iodobenzene unit should be an attractive fragment of rational drug design capable of halogen bonding with biomolecules.

Sea anemones are a remarkable source of active principles due to a decentralized venom system. Blood vessel formation or angiogenesis is a very promising target against cancer, but the few available anti-angiogenic compounds have a limited efficacy. In this study, a protein fraction was purified from tentacles of Anemonia viridis able to limit endothelial cells proliferation and vessel network formation or angiogenesis at low concentration (14 nM). The sequences in this protein fraction were determined with Edman degradation and Mass Spectrometry In Source Decay and revealed homologies with BDS sea anemones. The presence of a two turn alpha helix observed with Circular Dichroism and a trypsin activity inhibition suggested that the active principle could be a Kunitz-type inhibitor, which may interact with an integrin due to a RGD motif well exposed to the solvent as revealed by Molecular Modeling. This active principle could improve antiangiogenic therapy from existing antiangiogenic compounds binding on the VEGF.

Using the techniques of computer-aided drug design, the docking of Survivin and known active small molecules was simulated and then the key amino acid residue fragment of the target protein was analyzed. It led to the discovery of active groups capable of binding to the critical sites. Through the use of the natural product, Oleanolic Acid, as a lead compound, the introduction of the active groups onto the A-ring, and the modification of the carboxyl group at the C-28 position using esterification or amidation, twenty new Oleanolic acid derivatives had been designed and synthesized.A549 and SGC-7901 cells were used to screen the antitumor activity in vitro through the standard MTT method. The compounds, II₃, III₅ and Ⅳ_4, exhibited more potent cytotoxicity than positive drugs.

Insulin resistance is a condition characterized by a reduced biological response to insulin. It is one of the most common metabolic diseases of modern civilization. Numerous naturally occurring substances have shown to have a positive effect in restoring the proper sensitivity to insulin. Mature 3T3-L1 adipocytes with artificially induced insulin resistance by palmitic acid (16:0) were used for the study. Cinnamic acid and 1,2-dicinnamoyl-sn-glycero-3-phosphocholin (1,2-diCA-PC) were tested at three concentrations: 25 μM, 50 μM, and 125 μM. The number of mitochondria and the expression of genes encoded by mtDNA were elucidated in control and experimental cells. In experimental cells treated with 1,2-diCA-PC, we displayed increased insulin-stimulated glucose uptake in a dose-dependent manner, accompanied by an increase in mtDNA copy number. Moreover, in experimental cells treated with 1,2-diCA-PC at the concentration of 125 μM, we observed a significant increase in the expression level of all analyzed genes encoded by mtDNA compared to control cells. Our study showed a relationship between improved cellular sensitivity to insulin by 1,2-diCA-PC and an increase in the number of mitochondria and expression levels of genes encoded by mtDNA. Summarizing, the results suggest a therapeutic potential of cinnamic acid derivative 1,2-diCA-PC in enhancing the insulin sensitivity of adipocytes.

The global need for rapid diagnostic methods for pathogen identification and antimicrobial susceptibility testing (AST) is underscored by the increasing bacterial resistance and limited therapeutic options, especially critical in sepsis management. The evolution from traditional phenotype-based methods to rapid molecular and mass spectrometry techniques has significantly decreased result turnaround times, improving patient outcomes. Despite advancements, the complex decision-making in antimicrobial therapy often exceeds the capacity of many clinicians, highlighting the importance of antimicrobial stewardship programs (ASP). These programs, integrating mHealth and eHealth, leverage technology to enhance healthcare services and patient outcomes, particularly in remote or resource-limited settings. However, the application of such technologies in antimicrobial management remains underexplored in hospitals. The development of platforms combining antimicrobial prescription data with pharmacotherapeutic algorithms and laboratory integration can significantly reduce costs and improve hospitalization times and mortality rates. Yet, the effectiveness of empirical antibiotic therapy, influenced by rapid diagnostic tests, becomes cost-effective when error rates exceed 20%, emphasizing the need for technological integration in ASPs to combat the rising challenge of antimicrobial resistance (AMR) and healthcare sustainability.

Staphylococcus aureus is an opportunistic human pathogen and a leading cause of bloodstream infections. It can acquire different antibiotic resistance genes, leading to treatment failure. Aim: We elaborate on the genomic characteristics; antibiotic resistance, virulence, pathogenicity, phylogenomics and clonal diversity of S. aureus implicated in bloodstream infections. Six multidrug-resistant (MDR) S. aureus, three methicillin-resistant S. aureus (MRSA) and three methicillin-sensitive S. aureus obtained from blood cultures underwent whole genome sequencing and bioinformatics analysis. All isolates carried different permutations and combinations of resistance genes including, blaZ, mecA, aac(6')-aph (2''), ant(9)-Ia, ant(6)-Ia, mepR, fosB, norA, norC, lmrS, arlS, arlR, mgrA, kdpD and sdrM. We found 6 spa types (t9475, t355, t045, t1265, t1257, and t7888) with varying profiles of virulence genes responsible for immune invasion, enterotoxins, adhesion/biofilm, haemolysins, and leukotoxins. Panton-Valentine leukocidin (Luk-PV) was found in one MSSA isolate. Two SCCmec types IVd(2B) and I(1B) were identified. Isolates belonged to four multilocus sequence types (MLSTs), the most common of which was ST5 (n=3). The STs were clustered into two clonal complexes CC5 and CC8. We found two MRSA clones typed as ST5-CC5-t045-SCCmec_I(1B), and the human-associated MRSA endemic clone ST612-CC8-t1257-SCCmec_IVd(2B). The insertion sequences IS30 and IS6 associated with virulence were found in two isolates. The presence of virulent MDR S. aureus in bloodstream infections poses a clinical concern because of limited treatment options and increased risk of mortality.

The application possibilities of austenitic stainless steels in high friction, abrasion and sliding wear conditions are limited by their inadequate hardness and tribological characteristics. In order to improve these properties, thermochemical treatment of their surface by plasma nitriding is suitable. This article is focused on corrosion resistance of the conventionally plasma nitrided AISI 304 stainless steel (530 °C, 24 hours) in 0.05 M and 0.5 M sodium chloride solutions at room temperature (20 ± 3 °C), tested by potentiodynamic polarization and electrochemical impedance spectroscopy. The optical microscopy, scanning electron microscopy, energy-dispersive X-ray spectroscopy and X-ray photoelectron spectroscopy are used for the nitrided layer characterization. The experiment results point to a significant reduction in corrosion resistance after performed plasma nitriding even in a solution with a very low chloride concentration (0.05 mol/L).

Puccinia graminis f. sp. tritici (Pgt), the causal agent of wheat stem rust, poses a significant threat to global wheat production. Genetic resistance offers a cost-effective and sustainable solution. The durum wheat landrace PI 94701 was previously hypothesized to carry two stem rust resistance (Sr) genes, but their chromosomal locations were unknown. In this study, we mapped and characterized an all-stage Sr gene in PI 94701, temporarily designated as SrPI94701. In seedling tests, SrPI94701 was effective against all six Pgt races tested. Using a large segregating population (2,302 gametes), we mapped SrPI94701 within a 0.17-cM region flanked by markers pku69124 and pku69228, corresponding to 1.04- and 2.15-Mb genomic regions in the Svevo and Chinese Spring reference genomes. Within the candidate region, eight genes exhibited differential expression between the Pgt-inoculated resistant and susceptible plants. Among them, two NLR genes, TraesCS5B03G1334700 and TraesCS5B03G1335100, showed high polymorphism between parental lines, with upregulation observed in the resistant F4 line compared to its susceptible sister line. However, the flanking and completely linked markers developed in this study could not accurately predict the presence of SrPI94701 in uncharacterized wheat genotypes. SrPI94701 holds promise as a valuable component in breeding programs aimed at enhancing resistance against Pgt.

Drug resistance in melanoma is a major hindrance in cancer therapy. Growth hormone (GH) plays a pivotal role in contributing to resistance to chemotherapy. Knocking down or blocking the GH receptor has been shown to sensitize the tumor cells to chemotherapy. Extensive studies have demonstrated that exosomes, a subset of extracellular vesicles, play an important role in drug resistance by transferring key factors to sensitize cancer cells to chemotherapy. In this study, we explore how GH modulates exosomal cargoes from melanoma cells and their role in drug resistance. We treated the melanoma cells with GH, doxorubicin, and GHR antagonist, pegvisomant, and analyzed the exosomes released. Additionally, we administered these exosomes to recipient cells. The GH-treated melanoma cells released exosomes with elevated levels of ABC transporters (ABCC1 and ABCB1), N-cadherin and MMP2, enhancing drug resistance and migration in recipient cells. GHR antagonism reduced these exosomal levels, restoring drug sensitivity and attenuating migration. Overall, our findings highlight a novel role of GH in modulating exosomal cargoes that drive chemoresistance and metastasis in melanoma. This understanding provides insights to the mechanisms of GH in melanoma chemoresistance and suggests GHR antagonism as a potential therapy to overcome chemoresistance in melanoma treatment.

Rice blast is the most harmful disease caused by Magnaporthe oryzae, leading to yield loss. The aim of the work is to improve resistance of rice to blast by introducing and pyramiding genes using conventional breeding technique and modern MAS analysis. Pyramiding is the combination of several resistance genes in one genotype, in this case it improves the resistance of rice to pathogens. MAS analysis revealed that 3 out of 4 studied domestic high-yielding rice cultivars (Bakanasski, Aisaule and Aru) contain 1 blast resistance gene (Pi-2). It was discovered 7 pyramidal lines with the introduction of a combination of 2 blast resistance genes (Pi-1 and Pi-ta) into 6 hybrids and 3 genes (Pi-1, Pi-33 and Pi-ta) into 1 line. Phytopathological test of local cultivars and pyramidal lines of rice showed that 3 out of 7 pyramidal lines have moderate resistance: 2 lines (F2 Bakanasski/7667 (var. vulgaris Koern.) and F2 Aisaule/7664 (var. italica Alef.)), containing 2 resistance genes (Pi-1 and Pi-ta) and 1 line – F2 Aisaule/7689 (var. zeravschanica Brsch.), carrying 3 genes (Pi-1, Pi-33 and Pi-ta), while the local cultivars Bakanasski, Aisaule and Aru are susceptible. As a result, the blast resistance of rice was improved by creating pyramidal lines. Pyramided lines can be used for germplasm exchange and in rice breeding programs to improve blast resistance in rice.

Background Neisseria gonorrhoeae can acquire antimicrobial resistance (AMR) through horizontal gene transfer (HGT) from other Neisseria spp. such as commensals like Neisseria subflava. The prevalence of Neisseria subflava in the oropharynx is close to 100%. Low doses of antimicrobials in food could select for AMR in N. subflava, which could then be transferred to N. gonorrhoeae. In this study, we aimed to determine the lowest concentration of ciprofloxacin that can induce ciprofloxacin resistance (minimum selection concentration – MSC) in N. subflava. Methods Neisseria subflava Co000790/2 was serially passaged on GC agar plates containing ciprofloxacin concentrations ranging from 1:100- to 1:10,000-below its ciprofloxacin MIC (0.006 µg/ml) for six days. Results After 6 days of serial passaging at ciprofloxacin concentrations 1/100th of the MIC, 24 colonies emerged on the 0.06 µg/ml ciprofloxacin plate. Their ciprofloxacin MICs were between 0.19 to 0.25 µg/ml, and whole genome sequencing revealed a missense mutation T91I in the gyrA gene, which has previously been found to cause reduced susceptibility to fluoroquinolones. Conclusion The N. subflava MSCde novo was determined to be 0.06 ng/mL or 1:100 below the MIC. The implications of this finding are that the low concentrations of antibiotics found in certain environmental samples and even the food we eat may be able to select for ciprofloxacin resistance in N. subflava.

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.

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.

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.

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.

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.

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.

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.

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

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

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

Klebsiella pneumoniae is a leading cause of healthcare acquired infections. The severity of the infections is multifactorial including virulence and antimicrobial resistance properties. The objective of the study was to investigate the virulence determinants of K. pneumoniae strains colonizing patients hospitalized in the intensive care units (ICU) of a tertiary hospital in Uganda. A hospital based cross-sectional study involving 103 patients admitted in the ICU of Mulago National Referral hospital was conducted from January 2022 to April 2022. A total of 31 identified clinical strains of K. pneumoniae isolated from rectal swabs of the same number of patients were characterized. Susceptibility testing of colistin was performed by broth microdilution method, thereafter, 5 colistin resistant K. pneumoniae were purposefully selected for whole genome sequencing. Bioinformatics analysis was performed using established web-based tools to detect virulence genes, sequence type and other genomic features. Numerous virulence factor genes related to pathogenicity of K. pneumoniae were identified. They ranged from those related to colonization to those of persistence and dissemination including capsule genes (wzi), siderophore systems; yersiniabactin (ybt15), aerobactin (iutA), enterobactin (entC, entD, entF, entS, fepB, fepD, fepG, fes), and salmochelin (iroN), secretion systems; type II (T2SS) and type VI (T6SS-1). Furthermore, the isolates harbored outer membrane protein (ompA) gene, biofilm synthesis gene (fimH) and several adhesion genes. The results demonstrate the dual-risk of K. pneumoniae strains combining high level of virulence and colistin resistance which is a great concern as it leads to unmanageable infection outbreaks with high morbidity and mortality.

Tomato is one of the most important vegetable crops grown worldwide. Tomato brown rugose fruit virus (ToBRFV), a seed-borne tobamovirus, poses a serious threat to tomato productions due to its ability to break the resistant genes (Tm-1, Tm-2, Tm-22) in tomato. The objective of this work was to identify new resistance source(s) of tomato germplasm against ToBRFV. To achieve this aim, a total of 476 accessions from 12 Solanum species were tested with the ToBRFV US isolate for their resistance and susceptibility. As a result, a total of 44 asymptomatic accessions were identified as resistance/tolerance, including 31 accessions of S. pimpinellifolium, one accession of S. corneliomulleri, four accessions of S. habrochaites, three accessions of S. peruvianum and five accessions of S. subsection lycopersicon hybrid. Further analysis using serological tests identified four highly resistant S. pimpinellifolium lines, PI 390713, PI 390714, PI 390716 and PI 390717. The inheritance of resistance in the selected lines was verified in next generation and confirmed by RT-qPCR. To our knowledge, this is a first report of high resistance to ToBRFV in S. pimpinellifolium. These new genetic resources will expand the genetic pool available for breeders to develop new resistant cultivars of tomato against ToBRFV.

Apple latent spherical virus (ALSV) is widely used as a virus-induced gene silencing (VIGS) vector for function genome study. However, the application of ALSV in soybean is limited by the resistance of many varieties. In this study, the genetic loci linked to the resistance of a resistant soybean variety Heinong 84 was mapped by high-throughput sequencing‒Bulk Segregation Analysis (HTS‒BSA) using a hybrid population crossed from Heinong 84 and a susceptible variety Zhonghuang 13. Results showed that the resistance of Heinong 84 to ALSV is controlled by two genetic loci located on chromosome 2 and 11, respectively. Cleaved amplified polymorphic sequences (CAPS) markers were developed for identification and genotyping. Inheritance and biochemical analyses suggest that the resistance locus on chromosome 2 plays a dominant dose-dependent role, while the other locus contributes a secondary role in resisting ALSV. The resistance locus on chromosome 2 might encode a protein that can directly inhibit viral proliferation, while the secondary resistance locus on chromosome 11 may encode a host factor required for viral proliferation. Together, these data reveal novel insights on the resistance mechanism of Heinong 84 to ALSV, which will benefit for the application of ALSV as a VIGS vector.

Ruxolitinib has been approved by FDA for the treatment of myeloproliferative neoplasms such as polycythemia vera and idiopathic myelofibrosis. Although ruxolitinib has been in the clinic for more than ten years, surprisingly, no JAK2 drug resistant mutations have been identified in patients. At the moment, it is not clear whether the absence of JAK2 mutations in MPN patients is due to a lack of JAK2 addiction or residues that mediate the drug resistance compromising the JAK2 function. To find out this, we established a Ba/F3 cell-based screening strategy to predict mutations in JAK2-V617F that cause resistance towards ruxolitinib. In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles. All the ruxolitinib resistant JAK2 variants displayed sensitivity towards Type II JAK2 inhibitor CHZ-868. Finally, our study also shows that HSP90 inhibitors are potent against ruxolitinib resistant variants through the JAK2 degradation and provides the rationale for clinical evaluation of potent HSP90 inhibitors in genetic resistance driven by JAK2 inhibitors.

Fire blight, caused by Erwinia amylovora, is a devastating bacterial disease that threatens world-wide production of apples and pears. In Canada and the US, streptomycin and kasugamycin are commonly used for the control of this pathogen. There is an urgent need for development of biocontrol agents (BCAs) that can be easily incorporated into integrated pest management pro-grams with high efficacy against streptomycin sensitive and resistant strains of E. amylovora. In addition, excessive use of antibiotics in agriculture has increased awareness of the possibility of antibiotic resistance gene transfer to human, animal and environmental microbes. To address this issue, a phage-carrier system (PCS) that combines Pantoea agglomerans as an antagonistic bacterial carrier of Erwinia phages as a double-pronged treatment for fire blight have been de-veloped. The low viability of P. agglomerans cells following spray drying challenged the industrial scale production of this PCS. In the present research, a spray drying protocol was developed for P. agglomerans by modifying the growth medium and the bacterial cell formulation using D(+)-trehalose and maltodextrin. The developed protocol is amenable to industrial scale pro-duction of the BCA/PCS. The P. agglomerans viability was greater than 90% after spray drying, had a prolonged shelf life of 4 months at 4 C, and the reconstituted cells showed an approximate 3 log reduction in E. amylovora counts with a green pear disc challenge assay.

Cholesterol siRNA conjugates attract attention because they allow the delivery of siRNA into cells without the use of transfection agents. In this study, we compared the efficacy and duration of silencing induced by cholesterol conjugates of selectively and totally modified siRNAs and their heteroduplexes of the same sequence and explored the impact of linker length between the 3' end of the sense strand of siRNA and cholesterol on the silencing activity of “light” and “heavy” modified siRNAs. All 3'-cholesterol conjugates were equally active under transfection, but the conjugate with a C3 linker was less active than those with longer linkers (C8 and C15) in a carrier-free mode. At the same time, they are significantly inferior in activity to the 5'-cholesterol conjugate. Shortening the sense strand carrying cholesterol by 2 nucleotides from the 3'-end did not have a significant effect on the activity of the conjugate. Replacing the antisense strand or both strands with fully modified ones has a significant effect on silencing as well as improving the duration in transfection-mediated and carrier-free modes. A significant 78% suppression of MDR1 gene expression in KB-8-5 xenograft tumors developed in mice promises an advantage from the use of fully modified siRNA cholesterol conjugates in combination chemotherapy.

We aimed to evaluate the survival benefits of coadministering statins and multityrosine kinase inhibitors (TKIs) in patients with advanced hepatocellular carcinoma (HCC). Data from the Health Insurance Review and Assessment Service in Korea (2010–2020) were utilized. Statin use (≥28 cumulative defined daily doses) was analyzed, with 1,534 statin users matched to 6,136 non-users (1:4 ratio) using propensity scores. Primary and secondary outcomes were overall survival (OS) and progression-free survival (PFS). Statin use significantly improved OS (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.72–0.82, P&lt;0.001) and PFS (HR 0.78, 95% CI 0.74–0.84, P&lt;0.001). Continuous or post-TKI statin users had better OS, while discontinuation after TKI use led to poorer OS. Both lipophilic and hydrophilic statins improved OS and PFS, particularly with ≥730 cumulative defined daily doses. In conclusion, combining statins and TKIs in patients with advanced HCC yielded significant survival benefits, influenced by statin dosage and duration. Continuous statin administration post-TKI treatment is crucial for improving outcomes in patients with HCC.

Solid tumors are composed of a highly complex and heterogenic microenvironment, with increasing metabolic status, playing a crucial role in the clinical therapeutic outcome of conventional treatments and innovative tumor nanomedicines. Scientists, have devoted great effort in conquering the tumor microenvironment (TME) challenges, in respect of effective drug accumulation and activity in tumor site, overcoming the obstacles of abnormal vasculature, dense stroma and extracellular matrix, hypoxia, and pH gradient acidosis. In this conquest, nanomedicines targeting distinct TME features have flourished, in order to increase site specificity and deep penetration, for effective antitumor activity, and further reprogram TME promoting suppression of cancer stem cells and metastasis. Thereby, several successful nanomedicine therapeutics have been under clinical trials, and further applied in clinical practice. Various novel strategies have been employed in preclinical studies and clinical trials, among which nanomedicines based on biomaterial, that have shown great promise in improving the therapeutic efficacy, reducing side effects, and promoting synergistic activity for TME targeting. In this review, we have focused on the targeting mechanisms for solid TME by nanomedicines based on the application of natural and synthetic biomaterials. We have described critical formulations that have been considered for the design of stimuli-responsive nanomedicines for TME. The development of such systems, has significantly advanced the application of biomaterials, in combinational therapies and in immunotherapies, for improved effectiveness.

Breast cancer is the most common cancer among women worldwide, and estrogen receptor-positive (ER+) breast cancer accounts for a significant proportion of cases. While various treatments are available, endocrine therapies are often the first-line treatment for this type of breast cancer. However, the development of drug resistance poses a significant challenge in managing this disease. ESR1 mutations have been identified as a common mechanism of endocrine therapy resistance in ER+ breast cancer. The first-generation selective estrogen receptor degrader (SERD) fulvestrant has shown some activity against ESR1 mutant tumors. However, due to its poor bioavailability and need for intramuscular injection, it may not be the optimal therapy for patients. Second-generation SERDs have been developed to overcome these limitations. These newer drugs have improved oral bioavailability and pharmacokinetics, making them more convenient and effective for patients. Several oral SERDs are now in phase III trials for early and advanced ER+ breast cancer. This review summarizes the background of oral SERD development, the current status, and future perspectives.

Obesity affects nearly 660 million adults worldwide and is known for its many comorbidities. Although the phenomenon of obesity is not fully understood, science regularly reveals new determinants of this pathology. Among them, the persistent organic pollutants (POPs) have been recently highlighted. Mainly lipophilic, POPs are normally stored in adipose tissue and can lead to adverse metabolic effects when released into the bloodstream. The main objective of this narrative review is to discuss the different pathways by which physical activity may counteract POPs adverse effects. The research that we carried out seems to indicate that physical activity could positively influence several pathways negatively influenced by POPs, such as insulin resistance, inflammation, lipid accumulation, adipogenesis and gut microbiota dysbiosis that are associated with the development of obesity. This review also indicates how, through the controlled mobilization of POPs, physical activity could be a valuable approach to reduce the concentration of POPs in the bloodstream. These findings suggest that physical activity should be used to counteract the adverse effects of POPs. However, future studies should accurately assess its impact in specific situations such as bariatric surgery where weight loss promotes POPs blood release.

This paper uses probability method to evaluate the fire safety performance of prestressed steel-concrete beam bridges based on simulation experimental research. Firstly, fire simulation experimental sample analysis was conducted on actual small box girder bridges to obtain the structural response of prestressed steel-concrete structures under fire, which is in line with engineering practice. Next, construct a reliability analysis model for the fire resistance performance of prestressed steel-concrete beam bridges; Combining reliability theory with finite element method, establish a reliability analysis method for the fire resistance performance of prestressed steel-concrete beam bridges. Subsequently, a safety factor evaluation model for the fire resistance performance of prestressed steel-concrete beam bridges was proposed, and a safety factor evaluation method for the fire resistance performance of prestressed steel-concrete beam bridges based on reliability back analysis was established. Finally, based on the analysis of the structural response after a fire in a specific case of a simply supported to continuous prestressed steel-concrete continuous beam bridge project, a structural resistance sample of the prestressed steel-concrete beam bridge is generated through uniform design method, and statistical analysis is conducted. Subsequently, probability methods are used to evaluate the safety of the prestressed steel-concrete beam bridge after a fire. Through analysis, it can be concluded that the time of fire has a significant impact on the structural performance of prestressed steel-concrete beam bridges, and the randomness of parameters has a significant impact on the safety reserve of prestressed steel-concrete beam bridges after fire. It is necessary to pay attention to it in specific engineering practice and strengthen the monitoring and statistics of structural random characteristics.

Pathogenic microorganisms can cause a range of infectious diseases and are often treated with antimicrobial agents. The rise of antimicrobial resistance caused by inappropriate use of these agents in various settings has become a global health threat. There is, therefore, a need to find new and effective agents to combat infections caused by resistant pathogens. Nanotechnology has seen significant growth and development in recent years and has a wide range of applications in various fields, including health, agriculture, and industry. This novel area offers the potential for the synthesis of nanoparticles (NPs) with antimicrobial activity, such as iron oxide nanoparticles (IONPs). The use of IONPs is a promising way to overcome antimicrobial resistance or pathogenicity because of their ability to interact with several biological molecules and to inhibit microbial growth. This review focuses on the most common green synthesis methods for producing IONPs using bacteria, fungi, plants, and organic waste, as well as the most common methods for the characterization of these IONPs. Finally, it summarizes their application as promising antibacterial, antifungal, antiparasitic, and antiviral agents.

Although 4Ce4YSZ has high corrosion resistance, it faces challenges concerning sinterability and ionic conductivity. Therefore, we studied destabilization behavior caused by corrosion and oxygen vacancy ordering according to ZnO doping. The powders of (4Ce4YSZ)1-x(ZnO)x (x=0.5, 1, 2, 4 mol%) were synthesized through the sol-gel method. With the addition of ZnO, the cubic phase increased, and secondary phases were not observed. The (111) peak showed a higher angle shift in ZnO-doped 4Ce4YSZ compared to 4Ce4YSZ, and TEM-SAED revealed a reduction in the spacing of the (011)t plane, suggesting lattice contraction due to the substitution of the smaller Zn2+ (60 Å) for Zr4+ (84 Å) in the lattice. The local atomic structure analysis was conducted using EXAFS to investigate the oxygen vacancy ordering behavior. Zr K-edge Fourier-transform data revealed a decrease in the Zr-O1 peak intensity with an increasing amount o ZnO doping, indicating an increase in oxygen vacancies. The Zr-O1 peak position shifted to the right, leading to an increase in the Zr-O1 interatomic distance. In the Y K-edge Fourier-transform data, the Y-O1 peak intensity did not decrease, and there was little variation in the Y-O1 interatomic distance. These results suggest that the oxygen vacancies formed due to ZnO doping are located in the neighboring oxygen shell of Zn, rather than in the neighboring oxygen shells of Y and Zr. Impedance measurements were conducted to measure the conductivity, and as the amount of ZnO doping increased, the total conductivity increased, while the activation energy decreased. The increase in oxygen vacancies by ZnO doping contributed to the enhancement of conductivity and it is considered that these created oxygen vacancies did not interact with Zn2+ and did not form defect associations. Fluoride-based molten salts were introduced to the specimens to assess corrosion behavior in a molten salt environment. Yttrium depletion layers (YDLs) were formed on the surfaces of all specimens due to the leaching of yttrium. However, Ce remained relatively stable at the interface according to EDS line scans, suggesting a reduction in the phase transformation (cubic, tetragonal to monoclinic) typically associated with yttrium leaching in YSZ.

Diabetes mellitus (DM) is a metabolic disease characterized by chronic hyperglycemia associated with impaired carbohydrate, lipid and protein metabolism, with concomitant absence of insulin secretion or reduced sensitivity to its metabolic effects. Patients with diabetes mellitus have 30% more risk of developing heart failure and cardiovascular disease with respect to healthy people. Heart and cardiovascular problems are the first cause of death worldwide and the main complications which lead to high healthcare costs. Such complications can be delayed or avoided by taking prescribed medications in conjunction with a healthy lifestyle (i.e. diet and physical activity). The American College of Sports Medicine and the American Diabetes Association recommend that diabetic people reduce total sedentary time by incorporating physical activity in their weekly routine. This narrative literature review has the aim to summarize and present the main guidelines, pre-exercise cardiovascular screening recommendations, and considerations for patients with diabetes and comorbidities who are planning to participate in regular exercise regimens.

Bacterial resistance to antibiotics is a public health menace that needs urgent efforts to mitigate and forestall their transmission in the general environment. Plasmid-mediated metallo beta-lactamase (MBL) gives bacteria an exceptional ability to transmit resistance genes. This study investigated plasmid-mediated resistance in MBL P. aeruginosa isolates from poultry food chain settings. Cloacal swab samples (n=120) were bacteriologically analyzed for the isolation of P. aeruginosa isolates. Susceptibility studies were performed by the CLSI guideline using selected antibiotics. MBL was phenotypically detected using modified Hodges test, and confirmed using PCR technique. Plasmid curing studies detected the presence of plasmids in the isolates. P. aeruginosa isolates (n=48) showed high levels of reduced susceptibility to cefoxitin (93.8%), imipenem (81.3%), gentamicin (85.4%), amikacin (85.4%), nitrofurantoin (83.3%), ofloxacin (72.9%) and cefotaxime (77.1%). MBL was phenotypically detected in 7 (14%) isolates of P. aeruginosa. The presence of blaIMP-1 and blaIMP-2 MBL genes in P. aeruginosa (n=5) isolates was confirmed by PCR. The PCR did not detect blaVIM-1 and blaVIM-2 MBL genes. The P. aeruginosa isolates were multidrug resistant, with about 50% of the isolates showing multidrug resistance (MDR) to the antibiotics. The genes for MDR in the P. aeruginosa isolates were borne on plasmids, indicating a high possibility of community transmission of MBL resistance genes. Finally, the P. aeruginosa isolates from poultry food chain milieus are multidrug resistant, produce MBL, and harbour their resistance genes on plasmids. Since many antibiotic resistance genes in bacteria are associated with mobile genetic elements (MGEs) like plasmids, it is important to step up actions to mitigate incessant use of antibiotics in poultry and other agricultural practices in Nigeria in order to diminish the evolution and spread of plasmid-mediated resistance which is capable of initiating community acquired infections that may prove difficult to treat in our hospitals with the available antibiotics.

Background: Epithelial-mesenchymal transition (EMT) is a biological process where epithelial cells lose their adhesive properties and gain invasive, metastatic, and mesenchymal properties. Maintaining the balance between epithelial and mesenchymal stage is essential for tissue homeo-stasis. Many of the genes promoting mesenchymal transformation has been identified; however, our understanding of the genes responsible for maintaining the epithelial phenotype is limited. Our objective was to identify genes responsible for maintaining the epithelial phenotype and in-hibiting EMT. Methods: RNA seq was performed using an vitro model of EMT. CTGF expres-sion was determined by qPCR and Western blot analysis. Knockout of CTGF was done using the CTGF sgRNA CRISPR/CAS9. Tumorigenic potential was determined using NCG mice. Results: Knocked-out of CTGF in epithelial ovarian cancer cells leads to the acquisition of functional characteristics associated with the mesenchymal phenotype such as Anoikis resistance, cytoskel-eton remodeling, increased cell stiffness, and acquisition of invasion and tumorigenic capacity. Conclusions: We identified CTGF is an important regulator of the epithelial phenotype, and its loss is associated with early cellular modifications required for EMT. We describe a novel role for CTGF, regulating cytoskeleton and the extracellular matrix interactions necessary for conserva-tion of epithelial structure and function. These findings provide a new window to understand the early stages on mesenchymal transformation

In sustainable agriculture, plant nutrients are the most important elements. Biofertilizers introduce microorganisms that improve the soil nutrients and increase their accessibility to crops. In order to meet the demands of a growing population, healthy crops need to be produced using the right type of fertilizers to provide them with all the major nutrients they require. However, an increasing dependency on chemical fertilizers is destroying the environment and negatively af-fecting the health of humans. Thus, using microbes as bioinoculants as the best replacement of chemical fertilizers as eco-friendly way for plant growth and soil fertility is believed to be the best method for improving plant growth and soil fertility. In sustainable agriculture, these microbes provide significant benefits to crops. In addition to colonizing plant systems (epiphytic, endo-phytic, and rhizospheric), beneficial microbes play a key role in absorbing nutrients from surrounding ecosystems. Plant associate microbes can promote plant growth regardless of natural and extreme conditions. Plant growth promoting microbes promote plant growth through a variety of direct and indirect methods, such as nitrogen fixation, plant growth hormone production, siderophores, HCN, several hydrolytic enzymes, and potassium, zinc, and phosphorus solubilization. Research on biofertilizers has been extensive and even available, which demonstrates how these microbes can deliver nutrients to crops in sufficient quantities to enhance their yield. This review examines in detail the direct and indirect mechanisms of PGPR action and their interaction in plant growth and resistance.

Z-ligustilide is a main active ingredient in the volatile oil of Angelica sinensis, a traditional Chinese medicine. Cisplatin is a commonly used chemotherapy drug for the treatment of lung cancer. Efficacy is often limited by the development of drug resistance after long-term treatment. Here, we investigated the effect of the combination of Z-ligustilide and cisplatin (Z-ligustilide+cisplatin) on resistance of cisplatin-resistant lung cancer cells and its action mechanism. Cell viability was analyzed by cell counting kit-8 (CCK-8) assay. Cell cycle and cell apoptosis were examined by flow cytometry assay. mRNA and protein levels of factors related to cell cycle and apoptosis were analyzed by real-time PCR and western blot. Liquid chromatography-mass spectrometry (LC-MS) analysis and RNA sequencing in A549, A549/DDP and A549/DDP cells treated with the Z-ligustilide+cisplatin were performed. The expression of PLPP1 was analyzed by the Cancer Genome Atlas (TCGA). The correlation between PLPP1 and prognosis was evaluated by immunohistochemistry and Kaplan-Meier (KM) plotter analysis. We found that Z-ligustilide+cisplatin could decrease the cell viability of cisplatin-resistant lung cancer cells. Z-ligustilide+cisplatin induced cell cycle arrest, and promoted cell apoptosis of cisplatin-resistant lung cancer cells. Metabolomics combined with transcriptomics revealed that Z-ligustilide+cisplatin inhibited phospholipid synthesis by upregulating the expression of PLPP1. Furthermore, PLPP1 expression was positively correlated with good prognosis. Knockdown of PLPP1 abolished the effects of Z-ligustilide+cisplatin on cell cycle and apoptosis. Z-ligustilide+cisplatin inhibited the activation of AKT by reducing the levels of PIP3 levels. Z-ligustilide+cisplatin induced cell cycle arrest and promoted cell apoptosis of cisplatin-resistant lung cancer cells by inhibiting PLPP1-mediated phospholipid synthesis.

The WRKY gene family in plants regulates the plant's response to drought through regulatory networks and hormone signaling. AfWRKY20 (MT859405) was cloned from A. fruticosa (Amorpha fruticosa,A. fruticosa) seedlings using RT-PCR. The binding properties of the AfWRKY20 protein and the W-box (a DNA cis-acting element) were verified both in vivo and in vitro using EMSA and Dual-Luciferase activity assays. RT-qPCR detected that the total expression level of AfWRKY20 in leaves and roots was 22 times higher in the 30% PEG6000 simulated drought treatment compared to the untreated group. Under the simulated drought stress treatments of sorbitol and ABA (abscisic acid,ABA), the transgenic tobacco with the AfWRKY20 gene showed enhanced drought resistance at the germination stage, with significantly increased germination rate, green leaf rate, fresh weight, and root length compared to the WT (wild type,WT) tobacco. In addition, the SOD (superoxide dismutase,SOD)activity, chlorophyll content, and Fv/Fm ratio of AfWRKY20 transgenic tobacco were significantly higher than those of the WT tobacco under natural drought stress, while the MDA (malondialdehyde,MDA) content and DAB (3,3'-diaminobenzidine,DAB) and NBT (nitroblue tetrazolium,NBT) staining levels were lower. The expression levels of oxidation kinase genes (NbSOD, NbPOD, and NbCAT) in transgenic tobacco under drought stress were significantly higher than those in WT tobacco. This enhancement in gene expression improved the ability of transgenic tobacco to detoxify ROS (reactive oxygen species,ROS). The survival rate of transgenic tobacco after natural drought rehydration was four times higher than that of WT tobacco. In summary, this study revealed the regulatory mechanism of AfWRKY20 in response to drought stress-induced ABA signaling, particularly in relation to the ROS. This finding provides a theoretical basis for understanding the pathways of WRKY20 involved in drought stress, and offers genetic resources for molecular plant breeding aimed at enhancing drought resistance.

In this work, we present an analytical model of dynamic power losses for enhancement-mode AlGaN/GaN high-electron-mobility transistor power devices (eGaN HEMTs). To build this new model, the dynamic on-resistance (Rdson) is first accurately extracted by our ex-traction circuit based on a double-diode isolation (DDI) method for a high operating frequency up to 1 MHz and a large drain voltage up to 600 V, thus the unique problem of an increase in the dynamic Rdson is presented. Then the impact of the current operation mode on the on/off transi-tion time is evaluated by a dual-pulse-current-mode test (DPCT) which including a discontinu-ous conduction mode (DCM) and a continuous conduction mode (CCM), thus the transition time is revised for different current mode. Afterward the discrepancy between the drain current and the real channel current is qualitative investigated by an external shunt capacitance (ESC) meth-od, thus the losses due to device parasitic capacitance are also taken into account. After these improvements, the dynamic model will be more compatible for eGaN HEMTs. Finally, the dynamic power losses calculated by this model are verified to be in good agreement with experimental results. Based on this model, we propose a superior solution with qua-si-resonant mode (QRM) to achieve lossless switching and accelerate switching speed.

The objective of the present study is to isolate phages targeting multidrug resistant (MDR), extended spectrum beta lactamase (ESBL) positive clinical isolate of E. coli ( U1007), sequence and analyze the phage genome and use machine learning tools to predict host cell surface receptor and finally evaluate the efficiency of monophage and phage cocktail in vitro and in vivo in a zebrafish model. Phage specific for E. coli U1007 was isolated from Ganges River (designated as U1G), Cuoom River (designated as CR) and Hospital waste water (designated as M phage). The obtained phages were triple purified and enriched. U1G phages had a greater burst size of 124 PFU/cell and a latent time of 25 min.M phage had a burst size of 150 PFU/cell with a shortlatent time of 20min. Similarly CR phage has a short latent 20 min and a burst size of 115 PFU/cell. Based on capsid architecture, U1G phage resembles Podoviridae, CR phage is structurally similar to Myoviridae and M phage has morphology that resembles Siphoviridae. Genome sequencing and analysis revealed that the size of the U1G phage genome is 73275 bp Whereas that of CR phage and M phage are 45236 bp and 45294 bp, respectively. All three genomes were marked by the absence of genes encoding tRNA sequence, antibiotic resistant or virulent genes. A machine learning (ML) based multi-class classification model using algorithms such as Random Forest, Logistic Regression, and Decision Tree were employed to predict the host receptor targeted by all 3 phages and the best performing algorithm Random Forest predicted LPS O antigen , LamB or OmpC for U1G FhuA, OmpC for CR phage and FhuA, LamB, TonB or OmpF for the M phage as the host receptor targeted by the receptor binding protein (RBP) of the phages. In vitro time kill assay showed that treatment with monophages alone and along with colistin resulted in regrowth whereas phage combinations significantly reduced the regrowth and by 24h the phage cocktail along with colistin produced a significant 3 log declinein cell counts relative to the untreated control. In vivo intramuscular infection study in zebrafish showed that phages were non toxic and a cocktail of dual (U1G +M) phage along with colsitin resulted in a significant 3.5 log decline in cell counts whereas triple phage combination along with colistin resulted in 3 log decline in cell counts probably due to host receptor competition. Our study highlights the potential of phage cocktail therapy in mitigating MDR clinical isolate of E. coli in vitro and in vivo.

Bovine mastitis (BM) has been causing great economic and financial losses in the dairy industry worldwide and one of its major pathogenic agents is S. aureus. BM treatment still relies on antibiotics. The extensive use of antimicrobials gives rise to bacterial strains such as methicillin-resistant S. aureus (MRSA) and mupirocin-resistant S. aureus (MuRSA). This study aimed to investigate and compare the prevalence of MRSA and MuRSA and antimicrobial susceptibility in S. aureus isolates from bovine mastitis milk in conventional and organic dairy farms. Milk samples were taken from mastitis-infected cattle in 6 conventional and 7 organic dairy farms from South Korea. According to the Food Codex, 163 suspected S. aureus colonies were isolated from the pooled milk samples from each farm. Further rapid coagulase test confirmed 11 out of 74 isolates from 4 conventional farms (CF1, CF2, CF3, CF4) while 17 out of 89 isolates from 3 organic farms (OF1, OF2, OF3) exhibited coagulase activity. Multiplex PCR amplification showed that the nuc gene marker for S. aureus was found in all coagulase-positive isolates from OF 1 and at least one isolate from CF1, CF2, CF3, and CF4. Conversely, only 2 isolates from CF2 contained mecA gene for MRSA while none had the mupA gene for MuRSA. Antimicrobial susceptibility testing revealed that conventional farm isolates were more resistant to antibiotics particularly, against ampicillin and tetracycline, and, in turn, could imply a potential to develop multidrug resistance if stringent measures to control antimicrobial use in dairy farms is not implemented properly.

Wheat has a large and diverse repertoire of NLRs involved in disease resistance, with over 1,500 NLRs detected in some studies. These NLR genes occur as singletons or clusters containing copies of NLRs from different phylogenetic clades. The number of NLRs and cluster size can differ drastically among ecotypes and cultivars. Primarily, duplication has led to the evolution and diversification of NLR genes. Among the various mechanisms, whole genome duplication (WGD) is the most intense and leading cause, contributing to the complex evolutionary history and abundant gene set of hexaploid wheat. Tandem duplication or recombination is another major mechanism of NLR gene expansion in wheat. The diversity and divergence of duplicate NLR genes are responsible for the broad-spectrum resistance of most plant species with limited R genes. Understanding the mechanisms underlying the rapid evolution and diversification of wheat NLR genes will help improve disease resistance in crops. The present review focuses on the diversity and divergence of duplicate NLR genes and their contribution to wheat disease resistance. Moreover, we provide an overview of disease resistance-associated gene duplication and the underlying strategies in wheat.

Pseudomonas aeruginosa is an antibiotic-resistant priority pathogen as listed by the World Health Organization. P. aeruginosa, a gram-negative, rod-shaped bacterium, is frequently encountered in hospital settings as an opportunistic pathogen in nosocomial infections. P. aeruginosa has shown high antibiotic resistance, which has been attributed to several mechanisms, such as intrinsic, acquired, and adaptive resistance. This study investigates several genes which may be attributed to the acquisition of antibiotic resistance in the bacteria P. aeruginosa, as it transitions from its planktonic form to the more threatening and resistant biofilm form. Subsequently, the study assesses the comparative efficacy of three antibiotics, Ofloxacin (OFX), Tobramycin (TOB), and Ceftazidime (CAZ), in altering the expression levels of the identified multidrug efflux pump genes associated with the ability to extrude antibiotics from the cell when in the biofilm form. Efflux transporter gene expression in P. aeruginosa was conducted via extraction of total RNA in planktonic and biofilm- both untreated and treated - with Tobramycin (TOB), Ofloxacin (OFX), and Ceftazidime (CAZ). Real-time quantitative reverse transcriptase PCR was employed to analyze alterations in expression levels of the Mex A, Mex B, Mex X, Mex Y, OprM, and RPSL genes in the collected samples. In samples where no antibiotics were administered, an increase in expression of the Mex B efflux pump gene was observed compared to all other efflux pump genes in the biofilm form, providing multidrug resistance when active. The gene of interest, Mex B, was assessed for antibiotic resistance by P. aeruginosa culturing in the planktonic and biofilm forms with simultaneous treatment with TOB, OFX, and CAZ. Of the three antibiotics used, OFX showed more effectiveness in preventing biofilm growth by reducing the expression level of the Mex B efflux pump gene in the biofilm form, making P. Aeruginosa more antibiotic sensitive to OFX. TOB has similar results compared to OFX but was slightly less effective in reducing the expression of Mex B. Conversely, CAZ was not effective in reducing expression of the Mex B gene in the biofilm form or the planktonic form and was determined to be ineffective at eradicating the organism.

Of late, the focus has been shifted towards quorum sensing inhibitors which reduce bacterial virulence and lower the probability of resistance and refining infections. In this work, meta-bromo-thiolactone (mBTL), a potent quorum and virulence inhibitor against Staphylococcus aureus and MRSA phenotypes, was formulated in chitosan nanoparticles (ChNPs) using ionic gelation method. mBTL-loaded-ChNPs were characterized for particle size, polydispersity index, zeta potential. Morphology was visualized by Transmission Electron Microscopy (TEM), drug release profile and antibiofilm analysis using Confocal Laser Scanning Microscope (CLSM) and Scanning Electron Microscopy (SEM) were performed. Synthesized mBTL-loaded-CNPs showed homogenized nano-size particles ranging from 158+1.3 to 284+5.6 nm with spherical particles that exhibited sustainable release profile over 48 hr at 37 °C. These findings revealed successful preparation of mBTL-loaded-ChNPs, that further showed effective antibiofilm activity at MIC50 (0.5 mg/mL) where all strains displayed reduced biofilm formation compared to untreated strains. CLSM results showed a significant reduction in the number of viable cells, indicating the effectiveness of m-BTL as an antibacterial agent. SEM analysis permitted visualization of biofilm structure in relation to the spatial localization of important biofilm matrix components, the formed biofilms were clearly distinguished in the SEM images. Bacterial cells in the control group were enclosed in thick biofilms. In contrast, there was a considerable reduction in biofilm production when mBTL was present, where bacterial cells seemed less ordered and more scattered with no detectable biofilms. In conclusion, mBTL-loaded-ChNPs is a potential alternative treatment to overcome antimicrobial resistance and condensed MRSA infections.

Cancer is a devastating disease, causing tremendous morbidity and mortality each year. Cancer can be considered as a genetic disease in the sense that instabilities in protooncogenes and tumor suppressor genes are among the hallmarks of cancer progression and metastasis. However, a particular cancer can express different proteins in different patients, making cancer a heterogeneous disease. This heterogeneity in part influences treatment resistance and failure. Therefore, it is crucial to understand the mechanism by which cancer cells develop and enhance resistance to different agents. This review aims to present the general paradigm and recent updates on cancer cell resistance to different antitumor agents. It demonstrates that tumor resistance results from a myriad of factors, including tumor microenvironment, supporting immune cells, and cancer stem cells. This interaction contributes to cancer cells overcoming the therapeutic effects of different classes of antitumor agents, such as cytotoxic chemotherapeutics, targeted agents, and immunotherapies. With the development of advanced molecular analysis, specialized genomic assessment has assisted clinicians and researchers in choosing selected agents combating cancer cells. Together, this approach can potentially reduce treatment toxicity, health system burden, and financial costs while improving patient quality of life. Understanding the exact mechanism of drug resistance in cancer cells can open the way to new effective and less toxic therapeutics.

Wood has been used in the construction, furniture, and automotive industries since ancient times. In areas where wood material is used, it is combined with various fasteners. The durability of the products produced using wooden materials depends on the performance of the fasteners. Since wood is a hydroscopic and biodegradable material, various changes occur in its structure when exposed to external weather conditions. Wood materials used especially in the field of construction and urban furniture are exposed to effects such as extreme temperatures, freezing, moisture, or drying depending on the seasons. In this study, the effect of freeze-thaw cycling (FTC) process on screw direct withdrawal resistance (SDWR) of plywood produced from beech, ozigo, and okoume species was investigated. In this context, the effects of screwing time (before or after), screw orientation (face or edge), number of cycles (0 to 7) in the FTC process and plywood type parameters on SDWR were investigated. As a result of the tests, when the mean SDWR values were examined according to the plywood type, the highest values were obtained in beech, ozigo, and okoume plywood, respectively. Considering the screwing time parameter, it was determined that there was no statistically significant difference between the mean SDWR values in other plywood types except beech plywood (p&lt;0.05). When the screw orientation parameter is examined, screwing in the face direction gave better results than screwing in the edge direction in all plywood types. There was a decrease in the mean SDWR values inversely proportional to the increase in the number of cycles in FTC-treated plywood.

The increasing prevalence of methicillin-resistant S. aureus (MRSA) in the dairy industry has become a fundamental concern. Endolysins are bacteriophage-derived peptidoglycan hydrolases that induce the rapid lysis of host bacteria. We investigated endolysin candidates with lytic activity against MRSA and evaluated the lytic activity of the endolysin candidate against S. aureus and MRSA. To identify endolysins, we used the following bioinformatic strategy: (1) retrieval of genetic information, (2) annotation, (3) selection of MRSA, (4) selection of endolysin candidates, and (5) evaluation of protein solubility. We then characterized the endolysin candidate under various conditions. Approximately 67% of S. aureus was detected as MRSA and a total of 114 putative endolysins were found. The 114 putative endolysins were divided into three groups based on their combination of conserved domains. Considering the protein solubility, we selected putative endolysins 177 and 117. Putative endolysin 117 was successfully overexpressed and renamed LyJH1892. LyJH1892 lysed approximately 85% of S. aureus. LyJH1892 showed more potent lytic activity against MRSA than normal S. aureus (relative lytic activity &gt; 125%). LyJH1892 showed broad lytic activity against coagulase-negative Staphylococci (CNS). In conclusion, These findings provide a rapid and useful strategy for the development of specific endolysins against antibiotic-resistant bacterial strains.

Background: Multidrug-resistant bacteria present resistance mechanisms against β-lactam antibiotics, such as Extended-Spectrum Beta-lactamases (ESBL) and Metallo-β-lactamases enzymes (MBLs) operon encoded in Gram-negative species. Likewise, Gram-positive bacteria have evolved other mechanisms through mec genes, which encode modified penicillin-binding proteins (PBP2). This study aimed to determine the presence and spread of β-lactam antibiotic resistance genes and the microbiome circulating in Quito’s Public Transport (QTP). Methods: A total of 29 station turnstiles were swabbed to extract the surface environmental DNA. PCRs were performed to detect the presence of 13 antibiotic resistance genes and to identify 16S rDNA barcoding, followed by clone analysis, Sanger sequencing and BLAST search. Results: ESBL genes blaTEM-1 and blaCTX-M-1 and MBL genes blaOXA-181 and mecA were detected along QPT stations. Two subvariants were found for blaTEM-1, blaCTX-M-1, and blaOXA-181. Almost half of the circulating bacteria found at QPT stations were common human microbiota species including those classified by the WHO as pathogens of critical and high-priority surveillance. Conclusions: β-lactam antibiotic resistance genes are widely spread throughout QPT. This is the first report of blaOXA-181 in environmental samples in Ecuador. Moreover, we detected a new putative variant of this gene. Some commensal coagulase-negative bacteria may have a role as mecA resistance reservoirs

Commonwealth Partnerships for Antimicrobial Stewardship (AMS) uses a health partnership model to establish AMS in Commonwealth countries. The University Hospital of Kwame Nkrumah University of Science and Technology in partnership with Ulster University, in Northern Ireland undertook an AMS project from November 2021 to May 2022. We report on the implementation and its effect on antibiotic use and infections management at the University Hospital. The Global-Point Prevalence Survey (PPS) protocol was used to assess antibiotics use at the hospital at the beginning, midpoint and end of the project. Feedback on each PPS was given to staff to inform behaviour change and improve antibiotic prescribing. Antibiotic use reduced from 65% at baseline to 59.7% at the end of the project. The rate of health-associated infections also reduced from 17.5% at baseline to 6.5%. In addition, the use of antibiotics belonging to the WHO Access group at the hospital was 40% initially but increased to 50% at the project endpoint. Culture and antibiotic susceptibility requests increased from the beginning of the project from 111 total requests to 330 requests over 7 months. The AMS model implemented improved antibiotic use as well as requests for culture and susceptibility test which must be sustained.

Pregnancy is a dynamic state with multiple metabolic changes occurring including insulin resistance. Gestational diabetes mellitus (GDM), a form of diabetes that appears during pregnancy, develops if metabolic aberrations occur, in particular, in normal pregnancy-induced insulin resistance. Multi-omics is a powerful approach for uncovering the mechanisms driving metabolic change in different physiologic and pathologic states. A recent study demonstrated that the gestational gut microbiome mediates pregnancy metabolic adaptations through effects on gut indoleamine-2,3 dioxygenase 1 activity and the production of kynurenine. Using the dataset generated from this highly controlled study, we performed a comprehensive analysis of the pregnancy-specific physiological and metabolic profiles, 16S rRNA microbiome, and plasma untargeted LC-MS metabolome data. To facilitate the utilization of these analysis results by other researchers, we developed MOMMI-MP, a database that provides an easy-to-use platform to browse and search differential abundant microbial taxa and metabolites, and to examine metabolic pathways. The datasets consist of data collected from 3 genetically diverse strains of mice (C57BL/6J, CD1, and NIH-Swiss) over 6 time points during the gestational (days 0, 10, 15, and 19 during gestation) and postpartum (days 3 and 20 after delivery) states, totaling 180 samples for each strain. The computational results are presented in various tables and plots, and organized in MOMMI-MP to empower exploratory analyses by other researchers. In conclusion, MOMMI-MP is a resource to facilitate the investigation of novel mechanisms governing metabolic changes during pregnancy.

Multiple biological pathways manifest and latent, meant for human survival, become a liability in cancer cure. With an increasing understanding of innumerable complex paths, cancer progression and development of resistance is no surprise. For the three “vasculature-immune-phenotypic” fundamental changes, hypoxia is the maestro orchestrating the whole gamut of changes (through the master manipulator - HIF-1 α), simultaneously transactivating hundreds of pro-angiogenic genes. Such a complex molecular bio-network begs the question, “Is our cancer research caught in such a tangled web that we have lost sight of the Spider?”. Hypoxia is this Spider weaving compensatory webs with every intervention/ obstruction. Anti-angiogenic (AAG) research has been conducted mainly in silos – exploring independent paths. This review conceptualizes a convergence of a multitude of research worldwide to a single theme of normalizing vasculature as a primary baseline for overcoming resistance to AAGs or their combinations.

Fouling represents a bottleneck problem for promoting the use of membranes in filtration and separation applications. It becomes even more persistent when it comes to the filtration of fluid emulsions. In this case, a gel-like layer that combines droplets, impurities, salts, and other materials form at the membrane's surface, blocking its pores. It is, therefore, a privilege to combat fouling by minimizing the accumulation of these droplets that work as seeds for other incoming droplets to cluster and coalesce with. In this work, we explore the use of the newly developed and novel periodic feed pressure technique (PFPT) in combating the fouling of ceramic membranes upon the filtration of oily water systems. The PFPT is based on alternating the applied transmembrane pressure (TMP) between the operating one and zero. A PFPT cycle is composed of a filtration half-cycle and a cleaning half-cycle. Permeation occurs when the TMP is set at its working value, while the cleaning occurs when it is zero. Three PFPT patterns were examined over two feeds of oily water systems with oil contents of 100 and 200ppm, respectively. The results show that the PFPT is very effective in minimizing the problem of fouling compared to a non-PFPT normal filtration. Furthermore, the overall drops in permeate flux during the cleaning half cycles are compensated by appreciable enhancement due to the significant elimination of fouling development such that the overall production of filtered water is even increased. Inspection of the internal surface of the membrane post rinsing at the end of the experiment proves that all PFPT cycles maintained the ceramic membranes as clean after a 2-hours operation. This can ensure a prolonged lifespan of the ceramic membrane use and a continuous greater permeate volume production. The advantage of the PFPT is that it can be implemented on existing units with minimal modification, ease of operation, and saving energy.

Background: Insecticide resistance in Anopheles gambiae s.l. is a major challenge for malaria vector control in Nigeria. Both target-site insensitivity and metabolic resistance have been im-plicated in resistance process, with the latter receiving little attention in Nigeria. Therefore, we investigated metabolic enzyme activities in Anopheles gambiae s.l populations resistant to Del-tamethrin and Diethyldichlorotriethylethane (DDT) in South-West Nigeria. Methods: Anopheles larvae were collected from Ibadan, Oyo and Badagry, Lagos. Adults were exposed to Deltamethrin and DDT using WHO method. Cohorts of populations were further exposed to Pyperonil Butoxide (PBO) and Deltamethrin. Insecticide-exposed and unexposed co-horts were examined for metabolic enzyme activities. Results were compared between exposed and unexposed samples ANOVA (P<0.05). Results: Mosquitoes were identified as An. gambiae (89%, Ibadan; 0%, Badagry) and An. coluzzii (11%, Ibadan; 100%, Badagry). The populations showed varied level of resistance to Deltamethrin (26%, Ibadan; 71%, Badagry) and DDT (2%, Ibadan; 44%, Badagry). Mortality to Deltamethrin in-creased from 26% to 64% (Ibadan) and 71% to 84% (Badagry) when populations were pre-exposed to PBO. Biochemical analysis revealed significant high levels (P<0.05) of cytochrome P450 and GST in exposed samples. Conclusions: Cytochrome P450 and GST are involved in Deltamethrin and DDT resistance in Anopheles gambiae s.l populations in South-West Nigeria.

Developing countries are confronted with general issues of municipal wastewater management and treatment. Untreated faecal sludges and wastewaters from septic tanks and traditional toilet are rejected into rivers and sometimes using for urban agriculture without any treatment to reduce the biorisk. Consequently, there are potential environmental and public health risks. In this study, a wastewater treatment plant prototype coupled with Moringa Oleifera seeds treatment was developed to evaluate their effectiveness for the reduction of faecal indicator bacteria and antibiotics resistant bacteria in domestic wastewater. Results indicate that our performed prototype system presents high capacity to reduce bacteria with abatements up to 99.34%. High reductions of bacteria load were obtained after add of Moringa Oleifera seeds into waters, with reductions varied from 36.6-78.8% for E. coli, 28.3-84.6% for Faecal coliform, 35.3-95.6% for Vibrio cholerae and 32.1-92.4% for total flora. Same effects of Moringa Oleifera seeds were noted for reducing antibiotic resistant bacteria, Extended Spectrum Beta-lactamases and Carbapenem-Resistant Enterobacteriaceae with abatements up to 98% for E. coli and faecal coliform, 100% for Vibrio cholerae and 91.96% for total flora. Our results supported high capacity of Moringa Oleifera seeds as an excellent alternative for pathogens and antibiotics resistant bacteria reduction/purification from domestic wastewater

Zinc protection of galvanized steel is initially dissolved in alkaline solutions. However, passive layer is formed over time which protects the steel from corrosion. The behavior of galvanized steel exposed to strong alkaline solutions (pH values of 12.7) with a fixed concentration of sulfate ion of 0.04M is studied. Electrochemical measurement techniques such as corrosion potential, linear polarization resistance and electrochemical impedance spectroscopy are used. Synergistic effect of sulfate ion is also studied together with other anions such as chloride Cl- or bicarbonate ion HCO3- and with other cations such as calcium Ca2+, ammonium NH4+ and magnesium Mg2+. Presence of sulfate ions can depassivate the steel, leading to corrosion density of 0.3 µA/cm2 at the end of the test. The presence of other ions in the solution increases this effect. The increase in corrosion density caused by cations and anions responds to the following order (greater to lesser influence): NH4+&gt;Ca2+&gt;Mg2+ and HCO3- &gt;Cl- &gt;SO42-.

(1) Background: Disinfection of medical devices designed for clinical use associated or not with the growing area of tissue engineering is an urgent need. However, traditional disinfection methods are not always suitable for some biomaterials, especially those sensitive to chemical, thermal, or radiation. Therefore, the objective of this study was to evaluate the minimal concentration of ozone gas (O3) necessary to control and kill a set of sensitive or multi-resistant Gram-positive and Gram-negative bacteria. The cell viability, membrane permeability, and the levels of reactive intracellular oxygen (ROS) species were also investigated; (2) Material and Methods: Four standard strains and a clinical MDR strain were exposed to low doses of ozone at different concentrations and times. Bacterial inactivation (cultivability, membrane damage) was investigated using colony counts, resazurin as a metabolic indicator, and propidium iodide (PI). A fluorescent probe (H2DCFDA) was used for the ROS analyses; (3) Results: No reduction in the count colony was detected after O3 exposure, compared to the control group. However, the cell viability of E. coli (30%), P. aeruginosa (25%), and A. baumannii (15%) was reduced considerably. The bacterial membrane of all strains was not affected by O3 but presented a significant increase of ROS in E. coli (90 ± 14%), P. aeruginosa (62.5 ± 19%), and A. baumanni (52.6 ± 5%); (4) Conclusion: Low doses of ozone were able to interfere in the cell viability of most strains studied, and although it does not cause damage to the bacterial membrane, increased levels of reactive ROS are responsible for causing a detrimental effect in the lipids, proteins, and DNA metabolism.

Susceptibility to economically-important diseases of grapes is critical to the evaluation of germplasm recommended for commercial production and for development of sustainable production systems. In 2018-2019, nine cold-hardy grape cultivars including ‘Brianna’, ‘Crimson Pearl’, ‘Itasca’, ‘Louise Swenson’, ‘Marechal Foch’, ‘Marquette’ ‘Petite Pearl’, ‘St. Pepin’, and ‘Verona’ were evaluated on non-treated vines for susceptibility to downy mildew, powdery mildew, black rot, anthracnose, Phomopsis leaf spot and fruit rot, and Botrytis bunch rot. No cultivars were consistently disease-free, and all exhibited some degree of black rot and powdery mildew infection. Relative susceptibility to disease was not consistent across both years, but ‘Brianna’ had greater incidence of black rot and ‘Louise Swenson’ showed lower incidence of powdery mildew in both years. The relatively new cultivars ‘Crimson Pearl’ and ‘Verona’ exhibited comparatively moderate disease susceptibility overall. Growers typically manage diseases with fungicides on commercial farms, so cultivar susceptibility is just one component of a sustainable pest management and production system.

Both academic literature and global organizations have emphasized the need for responsible water consumption, as stated in the Sustainable Development Goal 12. However, individuals’ water-saving behaviors in their current state are not enough. This situation entails a resistance to change (RC) in consumer habits and a lack of perceived risk of scarcity. The novelty of this study lies in examining the influence of RC (through its emotional, cognitive, and confidence components) and perceived risk on water-saving intention. Interviews (n = 384) were conducted in the southeast Mediterranean area of Spain by interviewers using a paper-and-pencil questionnaire. The results of the structural equation modeling show that the perceived risk and the components of cognitive rigidity and negative emotions exert a direct influence on water-saving habits and an indirect influence on water-saving intention. None of the components of RC directly influence intention, and a lack of confidence in the outcomes of water saving does not influence water-saving habits or water-saving intention. In addition to the results obtained, the novelty of the work lies in the idea that in order to influence the perception of the risk of water scarcity through awareness campaigns, it is better to use an emotional message rather than showing facts or information, because this does not drive water saving behavior.

Current hypotheses implicate insulin resistance of the brain as a pathogenic factor in the development of Alzheimer’s disease and other dementias, Parkinson’s disease, type 2 diabetes, obesity, major depression, and traumatic brain injury. A variety of genetic, developmental, and metabolic abnormalities that lead to disturbances in the insulin receptor signal transduction may underlie insulin resistance. Insulin receptor substrate proteins are generally considered to be the node in the insulin signaling system that is critically involved in the development of insulin insensitivity during metabolic stress, hyperinsulinemia, and inflammation. Emerging evidence suggests that lower activation of the insulin receptor (IR) is another common, while less discussed, mechanism of insulin resistance in the brain. This review aims to discuss causes behind the diminished activation of IR in neurons, with a focus on the functional relationship between mitochondria and IR during early insulin signaling and the related roles of oxidative stress, mitochondrial hypometabolism, and glutamate excitotoxicity in the development of IR insensitivity to insulin.

Current hypotheses implicate insulin resistance of the brain as a pathogenic factor in the development of Alzheimer’s disease and other dementias, Parkinson’s disease, type 2 diabetes, obesity, major depression, and traumatic brain injury. A variety of genetic, developmental, and metabolic abnormalities that lead to disturbances in the insulin receptor signal transduction may underlie insulin resistance. Insulin receptor substrate proteins are generally considered to be the node in the insulin signaling system that is critically involved in the development of insulin insensitivity during metabolic stress, hyperinsulinemia, and inflammation. Emerging evidence suggests that lower activation of the insulin receptor (IR) is another common, while less discussed, mechanism of insulin resistance in the brain. This review aims to discuss causes behind the diminished activation of IR in neurons, with a focus on the functional relationship between mitochondria and IR during early insulin signaling and the related roles of oxidative stress, mitochondrial hypometabolism, and glutamate excitotoxicity in the development of IR insensitivity to insulin.