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.

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

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.

In this work, we studied light-output properties, efficiency function as well as PSD capability of p-Terphenyl scintillator. The selected solid cylindrical scintillation detector has a size of (45 x 45) mm with PSD properties. Recently presented studies of light-output functions have been meas-ured only for low neutron energies. Our motivation has been to determine more accurate the light output function for p-Terphenyl scintillator over a wider neutron energy range. The measurements have been carried out with mono-energetic neutron beams in the wide energy range from 2.5 to 19 MeV. The neutron-gamma spectrometric system, which we developed has been used for the measurement. The input analogue signal from the detector is digitized with fast 12-bits analogue to digital converter with sampling frequency of 1 GHz. Measured data from the detector are processed into gamma and neutron spectra. The light output function for protons has been determined by finding the position of the protons for given neutron energies. The more accurate light output function for p-Therphenyl scintillator has been calculated. The pulse-shape discrimination capability as well as efficiency of p-Terphenyl scintillator in comparison with NE-213 equivalent detector is lower.

Silica aerogels and their derivatives have outstanding thermal properties with exceptional values in the thermal insulation industry. However, the brittle nature restricts its large-scale commercialization. Thus, enhancing their mechanical strength without affecting their thermal insulating properties is essential. Therefore, for the first time, highly thermally stable Poly(acrylamide-Co-acrylic acid) partial sodium salt is used as a reinforcing polymer to synthesize hybrid P(AAm-CO-AAc)-silica aerogels via epoxy ring-opening polymerization in the present study. Functional groups in P(AAm-CO-AAc) partial sodium salts, such as CONH2 and COOH, acted as nucleophiles for the epoxy ring-opening reaction with (3-glycidyloxypropyl)trimethoxysilane, which resulted in a seven-fold enhancement in mechanical strength compared to that of a pristine silica aerogel while maintaining the thermal conductivity at less than 30.6 mW/mK and porosity of more than 93.68%. Moreover, the hybrid P(AAm-CO-AAc)-silica aerogel demonstrated improved thermal stability up to 343 ⁰C owing to the synergetic effect between P(AAm-CO-AAc) and the silica aerogel, corresponding to thermal stability and strong covalent bonding among them. These excellent results illustrate that this new synthetic approach for producing hybrid P(AAm-CO-AAc)-silica aerogels is useful for enhancing the mechanical strength of a pristine silica aerogel without impairing its thermal insulating property and shows potential as an industrial heat insulation material.

In this paper, a study of modeling PV cell (solar cell), PV module (solar modules) and PV array solar array) using Matlab/Simulink software is presented. This study is focused on the study to design photovoltaic cell, photovoltaic modules, photovoltaic panels and PV array (solar array) and to analyze the change in PV performance according to changes in different parameters such temperature, solar irradiation, reverse saturation current, series resistance and shunt resistance. This study shows the PV and IV characteristics curve for each model from which MPP (maximum power point) is determined. In this study, different PV and IV characteristic curves are gained for varying temperatures with specified solar irradiation conditions,s and then the MPP is tracked. The highest power output is also compared between the designed PV module and the selected PV module (MX Solar USA MX60-245)

The main goal of the present paper is to construct some families of the Carlitz’s q-Bernoulli polynomials and numbers. We firstly introduce the modified Carlitz’s q-Bernoulli polynomials and numbers with weight (α, β) and investigate their some explicit properties and identities arising from the bosonic q-Volkenborn integral on ℤ_p. We then define the modified degenerate Carlitz’s q-Bernoulli polynomials and numbers with weight (α, β) and obtain some recurrence relations and other identities. Moreover, we derive some correlations with the modified Carlitz’s q-Bernoulli polynomials with weight (α, β), the modified degenerate Carlitz’s q-Bernoulli polynomials with weight (α, β), the Stirling numbers of the first kind and second kind.

This paper explores the pivotal role of personalized product recommendations in enhancing the e-commerce experience. As online shopping becomes increasingly prevalent, the demand for tailored user experiences has surged, prompting the development of sophisticated recommendation systems. This study presents a comprehensive analysis of various methodologies employed to deliver personalized suggestions, including collaborative filtering, content-based filtering, and hybrid approaches. The implementation of a user-centric recommendation engine demonstrates significant improvements in user engagement, satisfaction, and conversion rates. Furthermore, the paper discusses the importance of real-time adaptation mechanisms and user feedback loops in optimizing recommendations. By providing insights into the challenges and solutions associated with recommendation systems, this research aims to equip e-commerce businesses with the tools necessary to leverage personalization effectively, ultimately leading to enhanced customer experiences and increased sales.

African swine fever (ASF) is a lethal disease in pigs that has grave socio-economic implications worldwide. For the development of vaccines against African swine fever virus (ASFV), immunogenic antigens that generate protective immune responses need to be identified. There are over 150 viral proteins - many of which are uncharacterized – and humoral immunity to ASFV has not been closely examined. To profile antigen specific antibody responses, we developed luciferase-linked antibody capture assays (LACAs) for a panel of ASFV capsid proteins and screened sera from inbred and outbred animals that were previously immunized with low virulent ASFV before challenge with virulent ASFV. Antibodies to B646L/p72, D117L/p17, M1249L and E120R/p14.5 were detected in this study; however, we were unable to detect B438L specific antibodies. Although OURT88/1 induced viremia was observed in the presence of anti-B646L/p72 antibodies as well as B602L antibodies they were associated with recovery from lethal disease in inbred and outbred animals. However, these antibodies did not correlate with protection against Georgia 2007/1 infection. Antibody responses against M1249L and E120R/p14.5 were observed in animals with reduced clinical signs and viremia. Here we present LACAs as a tool for targeted profiling of antigen specific antibody responses to inform vaccine development.

Cardiac vascular diseases, especially acute myocardial infarction (AMI), are one of the leading causes of death worldwide. Therefore cardio-specific biomarkers such as cardiac Troponin I (cTnI) play an essential role in diagnostics. In order to enable rapid and accurate measurement of cTnI with the potential of online measurements, a proof of concept of a chemiluminescence-based biosensor is presented. A flow cell was designed and combined with a sensitive CMOS camera allowing an optical readout. In addition, a microfluidic setup was established, and cTnI was determined selectively. The biomarker cTnI was expressed in E. coli, and its characterization and correct folding were investigated by different analytical methods. This recombinant cTnI was used for enzyme-linked immunosorbent assays (ELISA), calibrated against commercially available recombinant cTnI, and applied for the biosensor measurements. Based on chemiluminescence detection, the biosensor was successfully tested, and the cTnI biomarker could be reproducibly determined in buffer, spiked blood serum, and plasma.

The rigged Hilbert spaces (RHS) are the right mathematical context which includes many tools used in quantum physics, or even in some chaotic classical systems. It is particularly interesting that in RHS coexist discrete and continuous basis, abstract basis along basis of special functions and representations of Lie algebras of symmetries by continuous operators. This is not possible in Hilbert spaces. In the present paper, we study a model showing all these features, based on the one dimensional P\"oschl-Teller Hamiltonian. Also, RHS support representations of all kinds of ladder operators as continuous mappings. We give an interesting example based on one dimensional Hamiltonians with an infinite chain of SUSY partners, in which the factorization of Hamiltonians by continuous operators on RHS plays a crucial role.

Epigenetic mechanisms, including histone post-translational modifications (PTMs), play a critical role in regulating pain perception and the pathophysiology of burn injury. However, the epigenetic regulation and molecular mechanisms underlying burn injury-induced pain remain insufficiently explored. Spinal dynorphinergic (Pdyn) neurons contribute to heat hyperalgesia induced by severe scalding-type burn injury through p-S10H3-dependent signaling. Beyond p-S10H3, burn injury may impact various other histone H3 PTMs. Double immunofluorescent staining and histone H3 protein analyses demonstrated significant hypermethylation at H3K4me1 and H3K4me3 sites and hyperphosphorylation at S10H3 within the spinal cord. By analyzing Pdyn neurons in the spinal dorsal horn, we found evidence of chromatin activation with a significant elevation in p-S10H3 immunoreactivity. We used RNA-seq analysis to compare the effects of burn injury and forma-lin-induced inflammatory pain on spinal cord transcriptomic profiles. We identified 98 DEGs for burn injury and 86 DEGs for formalin-induced inflammatory pain. A limited number of shared differentially expressed genes (DEGs) suggest distinct central pain processing mechanisms between burn injury and formalin models. KEGG pathway analysis supported this divergence, with burn injury activating Wnt signaling. This study enhances our understanding of burn injury mechanisms and uncovers converging and diverging pathways in pain models with different origins.

Alpha-methyl-p-tyrosine (AMPT; also referred as metyrosine) is an approved medication for the treatment of pheochromocytoma. As a tyrosine hydroxylase inhibitor AMPT may be a potential candidate for the treatment of diseases involving catecholamine alterations. However, only small-scale clinical trials have tested AMPT repurposing in few other illnesses. Chronic fatigue syndrome (CFS) is an heterogenous disorder with genetically associated vulnerability of catecholamine metabolism (e.g. catechol O-methyltransferase polymorphisms) holding an important impact of environmental factors. The current case report compiles genetic and longitudinal biochemical data for over a year follow-up of one patient sequentially diagnosed with sustained overstress, neurasthenia, CFS, and POTS (postural orthostatic tachycardia syndrome) over a 10-year period, and reports patient’s symptom improvement in response to low-medium doses of AMPT.

Motivated by Kurt's work [Filomat 30 (4) 921-927, 2016], we first consider a class of a new generating function for (p, q)-analog of Apostol type polynomials of order a including Apostol-Bernoulli, Apostol-Euler and Apostol-Genocchi polynomials of order a. By making use of their generating function, we derive some useful identities. We also introduce (p, q)-analog of Stirling numbers of second kind of order v by which we construct a relation including aforementioned polynomials.

Stress protein HSP70 administered exogenously demonstrated high potential as efficient adjuvant in anti-tumor immune response. To enhance the antigen-presenting activity and stability of pure HSP70 we suggest here its incorporation in nanometer vesicles made of plant juice. Earlier we found such packing in grapefruit-derived extracellular vesicles (GEV) was able to store the protein with no loss of its major function, chaperonic activity. To check whether HSP70 in composition of GEV can elicit immune response we purified the vesicles, loaded them with recombinant human HSP70 (GEV-HSP70) and after characterization of the protein quantity and activity injected in Balb/c mice with growing CT-26 colon carcinoma tumor. The injections course reduced the tumor growth rate by 40% and expand the life span by 50%; the effect was corroborated with lowering of TGF-b1 and Il-10 levels in blood; this is comparable to the effect of soluble HSP70 with a concentration 25 times higher than that of GEV-HSP70. In vitro analysis of immunomodulatory activity of GEV-HSP70 showed that anti-tumor response in GEV-HSP70-treated mice was associated with the accumulation of CD8+ cells. These results demonstrate high feasibility and efficacy of novel HSP70-based technique in activation of the specific response to colon tumors.

Gold nanoparticles (NPs) have demonstrated significance in several important fields, including drug delivery and anticancer research, due to their unique properties. Gold NPs possess significant optical characteristics that enhance their application in biosensor development for diagnosis, photothermal and photodynamic therapies for anticancer treatment, as well as in targeted drug delivery and bioimaging. The broad surface modification possibilities of gold NPs have been utilized in the delivery of various molecules, including nucleic acids, drugs, and proteins. Moreover, gold NPs possess strong localized surface plasmon resonance (LSPR) properties, facilitating their use in surface-enhanced Raman scattering for precise and efficient biomolecule detection. These optical properties are extensively utilized in anticancer research. Both photothermal and photodynamic therapies show significant results in anticancer treatments using gold NPs. Additionally, the properties of gold NPs demonstrate potential in other biological areas, particularly in antimicrobial activity. In addition to delivering antigens, peptides, and antibiotics to enhance antimicrobial activity, gold NPs can penetrate cell membranes and induce apoptosis through various intracellular mechanisms. Among other types of metal NPs, gold NPs show more tolerable toxicity capacity, supporting their application in wide-ranging areas. Gold NPs hold a special position in nanomaterial research, offering limited toxicity and unique properties. This review aims to address recently highlighted applications, current status of gold NP research and discuss their future in nanomedicine.

The quest for effective cancer treatments has driven transformative strategies in drug discovery, and biosensors have emerged as indispensable tools, renowned for their precision, sensitivity, and real-time monitoring capabilities. The review begins with a brief overview of cancer drug discovery, underscoring the pivotal role of biosensors in advancing cancer research. Various types of biosensors employed in cancer drug discovery, including fluorescence- and bioluminescence-based biosensors, are then explored. Emphasis is placed on the integration of biosensors in high throughput screening (HTS) and validation for cancer drug compounds, elucidating their pivotal role in accelerating the identification of potential therapeutics. Real-time monitoring of cellular responses through biosensors yields invaluable insights into cancer cell signaling pathways, drug efficacy, and resistance mechanisms. The review illuminates how biosensors contribute to unraveling the dynamic nature of cancer cells, thereby facilitating the development of more targeted and personalized therapies. Challenges linked to biosensor applications in cancer drug discovery are addressed, alongside a discussion of emerging trends and future perspectives. In conclusion, this review offers a comprehensive analysis of biosensor applications in the dynamic field of cancer drug discovery. The integration of biosensor technologies holds the promise of revolutionizing the discipline, presenting novel avenues for the development of targeted and personalized cancer therapies.

Islatravir (ISL) is the first-in-class nucleoside reverse transcriptase translocation inhibitor (NRTtI) with novel modes of action. Data on ISL resistance is currently limited, particularly to HIV-1 non-B subtypes. This study aimed to assess prevalent nucleos(t)ide reverse transcriptase inhibitor (NRTI) resistance mutations in HIV-1 subtype C for phenotypic resistance to ISL. Prevalent single and combinations of NRTI resistance mutations were selected from a routine HIV-1 genotypic drug resistance testing database and introduced into HIV-1 subtype C-like pseudoviruses, which were then tested for ISL susceptibility. Single NRTI resistance mutations were susceptible or showed only a low level of resistance to ISL. This included thymidine analogue mutations (TAMs, i.e., M41L, D67N, K70R, T215FY, K219EQ) and non-TAMs (i.e., A62V, K65R, K70ET, L74IV, A114S, Y115F, M184V). Combinations of M184V with one or more additional NRTI resistance mutations generally displayed reduced ISL susceptibilities. This was more prominent for combinations that included M184V+TAMs, and particularly M184V+TAM-2 mutations. Combinations that included M184V+K65R did not impact significantly on ISL susceptibility. Our study suggests that ISL would be effective in treating people living with HIV (PLWH) failing tenofovir disoproxil fumarate (TDF)/lamivudine (3TC) or TDF/emtricitabine (FTC)-containing regimens but would be less effective in PLH failing zidovudine (AZT) with 3TC or FTC-containing regimens.

The drug discovery process is a complex and time-consuming endeavor that can greatly benefit from advancements in computational biology. This study explores the implementation of GPU-accelerated computational methods to enhance molecular docking simulations and virtual screening techniques, two crucial components of drug discovery. By leveraging the parallel processing capabilities of Graphics Processing Units (GPUs), we significantly accelerate the analysis of protein-ligand interactions and the identification of potential lead compounds. Our approach utilizes optimized algorithms and software frameworks to achieve substantial speedups over traditional CPU-based methods. Results demonstrate that GPU-accelerated molecular docking simulations and virtual screening can reduce computation times by up to 10-fold, enabling rapid and accurate identification of promising drug candidates. This accelerated workflow has the potential to revolutionize the drug discovery pipeline, facilitating the development of novel therapeutics and reducing the time and cost associated with bringing new treatments to market.

Background: Injecting drug use is a global public health challenge with multifaceted consequences, not only for Injecting Drug Users (IDUs) but also for society at large. Their vulnerability necessitates a deeper exploration of their health information needs, aiming to leverage evidence-based research to shape effective interventions for their well-being. Method: This study employed a qualitative method to gain insights into disease conditions and health information needs of IDUs. Through purposive sampling, 71 in-depth interviews were conducted and thematically analyzed. Results: The study included 43 males and 28 females, predominantly aged 26-35 (59.2%) who had poor socioeconomic status. The most commonly reported disease conditions varied and included malaria, infections and diabetes. Findings revealed a complex understanding of their disease conditions and management practices. Participants emphasized a critical need for access to reliable and comprehensive health information, while also highlighting the significant barriers they face in obtaining this information. Additionally, their preference for receiving health information in video formats, written articles, and through outreach programs underscored their desire for knowledge to make informed decisions. As co-creators and stakeholders in their health, participants expressed a clear demand for sustainable and free healthcare, mosquito nets, and regular outreach programs. Conclusions: While drug use presents a significant public health issue, effective interventions for IDUs require a multifaceted approach that begins with understanding their perspectives and actively involving them as co-creators of their health solutions. Abandoning this population contradicts the Sustainable Development Goals' mandate to ensure no one is left behind. Thus, all stakeholders must prioritize inclusive and participatory approaches to address the complex health information needs of IDUs.

Cancer cells display elevated reactive oxygen species (ROS) and altered redox status, Here based on these characteristics, we develop a multi-drug delivery platform AMB@PDAP-Fe (APPF), from magnetotactic bacterium AMB-1 and realize MRI-visualized tumor microenvironment-responsive photothermal-chemodynamic therapy. The Fe3+ in PDAP-Fe is reduced by the GSH at tumor site and is released in the form of highly active Fe2+, which catalyzes the generation of ROS through Fenton reaction and inhibits tumor growth. At the same time, the significant absorption of the mineralized magnetosomes in AMB-1 cells in the NIR region enable them to efficiently convert near-infrared light into heat energy for photothermal therapy (PTT), to which PDAP also contributes. The heat generated in the PTT process accelerates the process of Fe2+ release, thereby achieving an enhanced Fenton reaction in tumor microenvironment. In addition, the magnetosomes in AMB-1 are used as MRI contrast agent, and the curing process is visualized. This tumor microenvironment-responsive MTB-based multi-drug delivery platform displays a potency to combat tumor and demonstrates the utility and practicality of understanding the cooperative molecular mechanism when designing multi-drug combination therapies.

Safety signal detection, an integral component of Pharmacovigilance (PhV), aims to identify new or known adverse events (AEs) resulting from the use of pharmacotherapeutic products. Post-marketing spontaneous reports from different sources are commonly utilized as a data source for detecting these signals but there are underlying challenges arising from data complexity. This paper investigates the implementation of the Apriori algorithm, a popular method in association rule mining, to identify frequently co-occurring drugs and AEs within safety data. We discuss previous applications of the Apriori algorithm for safety signal detection and conduct a detailed study of an improved method specifically tailored for this purpose. This enhanced approach refines the classical Apriori method to effectively reveal potential associations between drugs/vaccines and AEs from post-marketing safety monitoring datasets, especially when AEs are rare. Detailed comparative simulation studies across varied settings, coupled with the application of the method to vaccine safety data from the Vaccine Adverse Event Reporting System (VAERS), demonstrate the efficacy of the improved approach. In conclusion, the improved Apriori algorithm is shown to be a useful screening tool for detecting rarely occurring potential safety signals from the use of drugs/vaccines using post-marketing safety data.

Ten new Schiff bases, including thiocarbohydrazone derivatives (1–10), were synthesized using an efficient, uncomplicated, and environmentally friendly approach using the reaction of alkyl-substituted aldehydes. The thiocarbohydrazones that were obtained were derived from o-phthalaldehyde. The chemical structures of the compounds were identified by the utilization of UV-Vis spectroscopy, Fourier transform infrared (FT-IR), ¹H nuclear magnetic resonance (¹H NMR), ¹³C nuclear magnetic resonance (¹³C NMR), and elemental analysis methods. The thermal stability of thiocarbohydrazones was examined using thermogravimetric analysis (TGA-DSC). Investigations were conducted on urease inhibition tests, pharmacokinetic property research, and molecular docking. The collection of samples with the urease enzyme revealed significant molecular docking findings, with MolDock scores ranging from -153 to -189. The compounds have the potential to be effective drug candidates for treating certain diseases, as indicated by the consistent results of molecular docking, urease inhibition tests, and pharmacokinetic characteristics investigations.

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

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

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

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

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

Malaria, leishmaniasis, and African trypanosomiasis are protozoan diseases that constitute a major global health problem, especially in developing countries; however the development of drug resistance coupled with the toxicity of current treatments have hindered their management. The implication of certain enzymes (dihydrofolate reductase, DHFR) or proteins (potassium channels) in the pathogenesis of these protozoan diseases is undeniable. In this study, a series of three DHFR inhibitors (6-5 fused heterocyclic derivatives X, Y and Z) and one K+ channel blocker (E4031) were screened for their inhibitory effect on Leishmania donovani, Plasmodium falciparum, and Trypanosoma brucei. Resazurin assay was used to assess antitrypanosomal and antileishmanial activities of test compounds, whereas the antimalarial activity was appraised through SYBR Green I test. Moreover, cytotoxicity of test compounds was evaluated on Vero, Raw 264.7 and HepG-2 cells using the resazurin-based test, whilst their pharmacokinetic properties were predicted using the online tool pkCSM. As a result, compound Y revealed a selective (selectivity index range: 2.69 - &gt;61.4; Vero, Raw 264.7 and HepG-2 cells) and broad-spectrum antiprotozoal activity against L. donovani promastigotes (IC50: 12.4 µM) and amastigotes (IC50: 4.28 µM), P. falciparum (IC50: 0.028 µM), and T. brucei brucei (IC50: 0.81 µM). In addition, compound X inhibited the growth P. falciparum (IC50: 0.0052 µM) and T. brucei brucei (IC50: 6.49 µM). In silico screening of the active antiprotozoal compounds revealed positive drug-likeness scores as none of Lipinski's rule of five’s criteria was violated by these compounds. However, in-depth pharmacokinetic and mechanistic studies are warranted to support discovery of novel antiprotozoal agents against malaria, leishmaniasis, and African trypanosomiasis by repurposing K+ channel blocker and DHFR inhibitors.

Chemo-resistance is a substantial challenge in the realm of cancer treatment that requires exploring new therapeutic approaches for effective mitigation. Achieving this goal requires examination of the molecular mechanisms involved in both tumor growth and therapeutic interventions. The potential of NRF2 (Nuclear factor E2-related factor 2) in addressing resistance to chemotherapy across diverse cancer types highlights its value as a promising therapeutic approach based on cancer characteristics. Manipulating the NRF2 signaling pathway has a dual impact, offering promise for both preventing and treating cancer, as well as inhibiting carcinogenesis. The influence of the NRF2/KEAP1 pathway on the progression of tumor formation and resistance to drugs has been well-documented. The interplay between the NRF2 signaling pathway and processes such as endoplasmic reticulum (ER) stress, unfolded protein response (UPR), and autophagy plays a crucial protective role. A deeper understanding of NRF2's role in the modulating these pathways is necessary to develop novel approaches for improving chemotherapeutic efficacy. This article discusses the significance of the NRF2-KEAP1 pathway in preventing/promoting cancer and resistance mechanisms to various chemotherapeutic agents, with a focus on the complementary effects of antioxidants via NRF2-mediated signaling pathways. This study aims to provide a molecular basis for targeting NRF2 via inhibitors/activators as promising therapeutic strategies to overcome chemo-resistance.

HIV incidence remains alarmingly high among female sex workers (FSWs) in low- and middle-income countries, with Uganda being no exception. The elevated risk of HIV transmission among this vulnerable population can be attributed to a complex interplay of factors, including engaging in sexual activities with multiple partners, inconsistent condom usage, substance use, and structural barriers, such as legal criminalization and pervasive stigmatization by healthcare providers. To combat this epidemic, various HIV prevention interventions have been devised, targeting these multi-faceted challenges. This study involved conducting focus groups among FSWs and healthcare providers in Uganda, with the overarching objective of informing the development of a tailored HIV prevention intervention aimed squarely at FSWs. Through these discussions, valuable insights were gained into FSWs’ perceptions of their HIV risk, their attitudes regarding HIV prevention strategies, and their recommendations regarding the content and delivery of future interventions.

When it is in the template RNA, the naturally occurring m¹A epitranscriptomic RNA modification was recently reported to be able to stop the RNA polymerization reaction catalyzed by the RNA dependent RNA polymerase (RdRp) of SARS-CoV-2. In this report, we report that m¹A via its triphosphate form (m¹ATP) can be incorporated into RNA by the same RdRp. These two findings point a new direction for antiviral drug development based on m¹A for combatting COVID-19. More broadly, it is possible that the large pool of epigenetic RNA as well as DNA modifications could serve as a treasury for drug discovery aimed at combating various infectious and other diseases.

Complex-structured polymeric microparticles hold significant promise as advance in next-generation medicine mostly due to demand from developing targeted drug delivery. However, the conventional methods for producing these microparticles of defined size, shape and sophisticated composition often face challenges in scalability, reliance on specialized components such as micro-patterned templates, or have limited control over particle size distribution and cargo release kinetics. In this study, we introduce a novel and reliably scalable approach for manufacturing microparticles of defined structures and sizes with variable parameters. The concept behind this method involves the deposition of a specific number of polymer layers on a substrate with low surface energy. Each layer can serve as either the carrier for cargo or a programmable shell-former with predefined permeability. Subsequently, this layered structure is precisely cut into desired-sized blanks using a laser. The manufacturing process is completed by applying of heat to the substrate what results on sealing the edges of the blanks. The combination of the high surface tension of the molten polymer and the low surface energy of the substrate enables the formation of discrete particles, each possessing semi-spherical or other designed geometries determined by their internal composition. Such anisotropic microparticles are envisaged versatile applications.

Tuberculosis (TB) continues to pose a global health challenge, exacerbated by the rise of drug-resistant strains. The development of new TB therapies is an arduous and time-consuming process. To expedite the discovery of effective treatments, computational structure-based drug re-purposing has emerged as a promising strategy. From this perspective, conditionally essential targets present a valuable opportunity, and the mycobactin biosynthesis pathway stands out as a prime example highlighting the intricate response of Mycobacterium tuberculosis (Mtb) to changes in iron availability. This study focuses on the re-purposing and revival of FDA-approved drugs (library) as potential inhibitors of MbtA, a crucial enzyme in mycobactin biosynthesis in Mtb conserved among all species of mycobacteria. Literature suggests this pathway to be associated with drug efflux pumps, which potentially contribute to drug resistance. This makes it a potential target for antitubercular drug discovery. Herein we utilized cheminformatics and structure-based drug repurposing approaches, viz., molecular docking, dynamics, and PCA analysis, to decode the intermolecular interactions and binding affinity of the FDA-reported molecules against MbtA. The virtual screening revealed ten molecules with significant binding affinities and interactions with MbtA. These drugs, originally designed for different therapeutic indications (4: antiviral, 3: anticancer, 1: CYP450 inhibitor, 1: ACE inhibitor, and 1: leukotriene antagonist), are repurposed as potential MbtA inhibitors. Furthermore, our study explores the binding modes and interactions between these drugs and MbtA, shedding light on the structural basis of their inhibitory potential. Principal component analysis highlighted significant motions in MbtA-bound ligands, emphasizing the stability of the top Protein-Ligand Complexes (PLCs). This computational approach provides a swift and cost-effective method for identifying new MbtA inhibitors, which can subsequently undergo validation through experimental assays. This streamlined process is facilitated by the fact that these compounds are already FDA-approved and have established safety and efficacy profiles. This study has the potential to lay the groundwork for addressing the urgent global health challenge at hand, specifically in the context of combating Antimicrobial Resistance (AMR) and Tuberculosis (TB).

Background: This study aimed to estimate the prevalence of sexualized drug use (SDU) in gay, bisexual, and other men who have sex with men living with HIV (HIV+GBMSM) in Madrid during 2019/2020 and compare it with data from 2016/2017. Methods: We analysed the frequency of SDU in a sample of HIV+GBMSM attending HIV clinics, who participated in an anonymous online survey regarding sexual behaviour and recreational drug use. The association between SDU, sexual risk behaviours, and STIs was evaluated. The methodology employed in the present study(U-SEX-2) in 2019/2020 was consistent with that of a previous study(U-SEX-1) in 2016/2017. Results: The study included 424 HIV+GBMSM, with a mean age of 40(10.43) years. Overall, 94% (396) reported being sexually active. Additionally, 33% (140) had been diagnosed with an STI within the previous year. Moreover, 54% (229) had used drugs in the last year, 25% (107) engaged in SDU, and 15% (17) reported engagement in slamsex. After adjusting for confounding factors, SDU was associated with STIs, fisting, unprotected anal intercourse, and having &gt; 24 sexual partners in the last year. According to the DUDIT test scores, 76% (81) probably had problematic drug use (≥6 points), and 5% (8) probable drug dependence (≥25 points). When comparing the U-SEX-1(2016/2017) data with the U-SEX-2(2019/2020) data, no significant differences were found in the proportion of participants practicing SDU or slamsex. Conclusion: The prevalence of SDU among HIV+GBMSM has remained high in recent years and without significant changes. We observed a clear association between SDU, high-risk sexual behaviors, STIs, and the risk of drug related problems.

BACKGROUND: Few studies have examined the use of immunoassay urine drug testing of cancer patients in palliative care clinics. OBJECTIVES: We examined the frequency of immunoassay urine drug test (UDT) abnormalities and the factors associated with aberrancy at a safety-net hospital palliative medicine clinic. METHODS: A retrospective review of the electronic medical records of consecutive eligible patients seen at the outpatient palliative medicine clinic in a resource-limited safety net hospital system was conducted between September 1, 2015 and December 31, 2020. We collected longitudinal data on patient demographics, UDT findings, and potential predictors of aberrant results. RESULTS: Of the 913 patients in the study, 500 (55%) underwent UDT testing, with 455 (50%) having the testing within the first three visits. Among those tested within the first three visits, 125 (27%) had aberrant UDT results; 44 (35%) of these 125 patients were positive for cocaine. In a multivariable regression model analysis of predictors for aberrant UDT within the first 3 visits, non-Hispanic White race (odds ratio [OR]=2.13; 95% confidence interval [CI]: 1.03-4.38; p=0.04), history of illicit drug use (OR=3.57; CI: 1.78-7.13; p< 0.001), and history of marijuana use (OR=7.05; CI: 3.85-12.91; p< 0.001) were independent predictors of an aberrant UDT finding. CONCLUSION: Despite limitations of immunoassay UDT, it was able to detect aberrant drug taking behaviors in a significant number of patients seen at a safety net hospital palliative care clinic, including cocaine use. These findings support universal UDT monitoring and utility of immunoassay-based UDT in resource limited settings.

Area covered: These drugs, particularly calcineurin inhibitors, have very narrow therapeutic windows, i.e., they have numerous drug-related side effects. Herein, we focus on the most frequent immunosuppressive drug-related side effects that we encounter in kidney-transplant recipients: namely nephrotoxicity, post-transplant diabetes mellitus, leukopenia, anemia, dyslipidemia, mouth ulcers, hypertension, and viral reactivations (cytomegalovirus and BK virus). However, other therapies that are used after kidney transplantation, e.g., valcancyclovir, may also contribute to adverse events such as leukopenia. For each side-effect, we suggest how it can be prevented and how to treat it when present.

Tyrosine Kinase Inhibitors work by blocking the tyrosine kinases responsible of the dysregulation of intracellular signalling pathways in tumour cells. This study looked at the impact of age and sex on the levels of imatinib, dasatinib, nilotinib, and ponatinib in plasma and cerebrospinal fluid samples of patients with chronic myeloid leukaemia. Imatinib and dasatinib were used to treat the majority of the enrolled patient and most of them were paediatrics. The 82.4% of patients were men; however, sex-related differences in drugs pharmacokinetics were not found. Age and imatinib plasma concentration were found to be inversely correlated: as patients ages increased, drug levels decreased. The dasatinib concentrations in plasma were found to be substantially lower than those found in cerebrospinal fluid, particularly in paediatrics. Analysing the obtained data, we can state that Therapeutic Drug Monitoring is a useful method for adjusting a patient treatment schedule depending on drug concentrations in biological fluids. The use of Therapeutic Drug Monitoring in conjunction with Tyrosine Kinase Inhibitors for the treatment of chronic myeloid leukaemia is supported by a number of sources of evidence. As a result, as the research develops, Tyrosine Kinase Inhibitors Therapeutic Drug Monitoring classification needs to be refined in terms of factors like sexes and ages.

The current study describes the preparation of chitosan nanoparticles (CNPs) using hydroxychloroquine (HCQ), widely used in traditional medicine due to its diverse phar-macological and medicinal uses. This work aims to combine the HCQ drug with CS NPs to generate a novel nanocomposite with improved characteristics and bioavailability. HCQ@CS NPs is roughly shaped like roadways and has a smooth surface with an average size of 159.3±7.1 nm, a PdI of 0.224±0.101, and a zeta potential of +46.6±0.8 mV. To aid in the development of pharmaceutical systems for use in cancer therapy, the binding mech-anism and affinity of the interaction between HCQ and HCQ@CS NPs and BSA were ex-amined using stopped-flow, other spectroscopic approaches, supplemented by molecular docking analysis. HCQ and HCQ@CS NPs binding with BSA is driven by a ground-state complex formation that may be accompanied by a non-radiative energy transfer process, and binding constants indicated that HCQ@CS NPs-BSA was more stable than HCQ-BSA. The stopped-flow analysis demonstrated that, in addition to increasing BSA affinity, the nano formulation HCQ@CS NPS changes the binding process and may open up new routes for interaction. Docking experiments verified the development of the HCQ-BSA complex, with HCQ binding to the site I on the BSA structure, primarily with the amino acids Thr 578, Gln 579, Gln 525, Tyr 400, and Asn 404. Furthermore, the nano-formulation HCQ@CS NPS not only increased cytotoxicity against the A549 lung cancer cell line (IC50 = 28.57±1.72 g/ml) compared to HCQ (102.21±0.67) g/ml), but also exhibited higher anti-bacterial activity against both Gram-positive and Gram-negative bacteria when compared to HCQ and chloramphenicol which in agreement with the binding constants. The nano formulation developed in this study may offer a viable therapy option for A549 lung cancer.

Prior to clinical trials, preclinical testing of oncology drug candidates is performed by evaluating drug candidates with in vitro and in vivo platforms. For in vivo testing, animal models are used to evaluate the toxicity and efficacy of drug candidates. However, animal models often display poor translational results as many drugs that pass preclinical testing fail when tested in humans, with oncology drugs exhibiting especially poor acceptance rates. The FDA Modernization Act 2.0 promotes alternative preclinical testing techniques, presenting the opportunity to use higher complexity in vitro models as an alternative to in vivo testing, including 3D cell culture models. 3D tissue cultures address many of the shortcomings of 2D cultures by more closely replicating the tumour microenvironment through a combination of realistic drug diffusion, paracrine signaling, cellular phenotype, and vascularization that can better mimic native human tissue. This review will discuss the common forms of 3D cell culture, including cell spheroids, organoids, organs-on-a-chip, and 3D bioprinted tissues. Their advantages and limitations will be presented, aiming to discuss the use of these 3D models to accurately represent human tissue and as an alternative to animal testing. The use of 3D culture platforms for preclinical drug development is expected to accelerate as these platforms continue to improve in complexity, reliability, and translational predictivity.

(1) Background: This article reviews the available scientific literature on drug-related problems and negative outcomes associated with medications identified by medication review with follow-up for end-stage renal disease and discussed with the physicians; (2) Methods: A systematic review was conducted of the scientific literature retrieved from the following databases: MEDLINE (via PubMed), Web of Science, SCOPUS, Cochrane Library: The Cochrane Central Register and Control Trials (CENTRAL) and Literatura Latinoamericana y del Caribe (LILACS), Medicina en Español (MEDES), and the SciELO bibliographic database (collection of scientific journals). The following terms were used as descriptors and searched in free text: "end-stage renal disease", "medication review", and "drug-related problems” and “negative outcomes associated with medication". The following limits were applied: "humans" and "adults (more than 18 years)”; (3) Results: A total of 59 references were recovered and after applying inclusion/exclusion criteria, 16 articles were selected. Of these selected articles, 15 provided information on drug-related problems and only 1 on negative outcomes associated with medications; (4) Conclusions: It can be concluded that drug-related problems and negative outcomes associated with medication affect patients with end-stage renal disease, mainly those receiving renal replacement therapy. More evidence is needed, especially on negative outcomes associated with medication.

In an era of unparalleled technical advancement, the pharmaceutical industry is struggling to transform data into increased research and development efficiency, and as a corollary, new drugs for patients. Here, we briefly review some of the commonly discussed issues around this counterintuitive innovation crisis. Looking at both industry and science related factors, we posit that traditional preclinical research is front-loading the development pipeline with data and drug candidates that are unlikely to succeed in patients. Applying a first principles analysis, we highlight the critical culprits and provide suggestions as to how these issues can be rectified through pursuit of a Human Data-driven Discovery (HD3) paradigm. Consistent with other examples of disruptive innovation, we propose that new levels of success are not dependent on new inventions, but rather the strategic integration of existing data and technology assets. In support of these suggestions, we highlight the power of HD3, through recently published proof-of-concept applications in the areas of drug safety analysis and prediction, drug repositioning, rational design of combination therapies and the global response to the Covid19 pandemic. We conclude that innovators must play a key role in expediting the path to a largely human focused, systems-based approach to drug discovery and research.

Ion channels are integral membrane proteins that facilitate the movement of ions across cell membranes, playing a key role in a range of biological processes. The high cost and time required for wet lab experiments to characterize ion channels has spurred the development of computational methods for this purpose. In our previous work, we demonstrated the effectiveness of protein language models for ion channel prediction, using a logistic regression classifier to distinguish ion channels from non-ion channels (TooT-BERT-C) and transporters from non-transporters (TooT-BERT-T). In this study, we build upon this approach by using a combination of classical machine learning classifiers and a Convolutional Neural Network (CNN) with fine-tuned representations from ProtBERT, ProtBERT-BFD, and MembraneBERT to discriminate ion channels from non-ion channels. The results of our experiments demonstrate that TooT-BERT-CNN-C, a combination of the representations from ProtBERT-BFD and a CNN, outperforms existing state-of-the-art methods for predicting ion channels, with a Matthews Correlation Coefficient (MCC) of 0.86 and an accuracy of 98.35% on an independent test set.

Monkeypox virus infection is a recognized public health emergency. Little research has been done on treatment options for this disease. Until recently, there was not a single published work describing the usage of specific drugs in human patients with monkeypox virus infection. This paper gives the first bibliometric analysis of monkeypox treatment options based on data available on PubMed and Scopus. It also reviews the specific drugs used in the treatment of monkeypox. That includes data on Tecovirimat, Cidofovir, Brincidofovir, and Vaccinia Immune Globulin. Tecovirimat is a promising option in progressive disease in terms of efficacy and safety. However, Brincidofovir has been associated with discontinuation of treatment. Cidofovir is also not the preferred drug among physicians. Currently, Tecovirimat can be further used for the management of aggravating cases. More studies should be conducted on Tecovirimat to treat this condition, mainly through controlled trials.

Intratumoral heterogeneity can exist along multiple axes: Cancer Stem Cells (CSCs)/non-CSCs, drug-sensitive/drug-tolerant states and a spectrum of epithelial-hybrid-mesenchymal phenotypes. Further, these diverse cell-states can switch reversibly among one another, thereby posing a major challenge to therapeutic efficacy. Therefore, understanding the origins of phenotypic plasticity and heterogeneity remains an active area of investigation. While genomic components (mutations, chromosomal instability) driving heterogeneity have been well-studied, recent reports highlight the role of non-genetic mechanisms in enabling both phenotypic plasticity and heterogeneity. Here, we discuss various processes underlying phenotypic plasticity such as stochastic gene expression, chromatin reprogramming, asymmetric cell division and the presence of multiple “attractors”. These processes can facilitate a dynamically evolving cell population such that a subpopulation of (drug-tolerant) cells can survive lethal drug exposure and recapitulate population heterogeneity on drug withdrawal, leading to relapse. These drug-tolerant cells can be both pre-existing and also induced by the drug itself through cell-state reprogramming. The dynamics of cell-state transitions both in absence and presence of the drug can be quantified through mathematical models. Such a dynamical systems approach to elucidating patterns of intratumoral heterogeneity by integrating longitudinal experimental data with mathematical models can help design effective combinatorial and/or sequential therapies for better clinical outcomes.

The resistance of cancer cell subpopulations, including cancer stem cell (CSC) populations, to apoptosis-inducing chemotherapeutic agents is a key barrier to improved outcomes for cancer patients. The cationic amphiphilic drug hexamethylene amiloride (HMA) has been previously demonstrated to efficiently kill bulk breast cancer cells independent of tumor subtype or species, but acts poorly toward non-transformed cells derived from multiple tissues. Here we demonstrate that HMA is similarly cytotoxic toward breast CSC-related subpopulations that are resistant to conventional chemotherapeutic agents, but poorly cytotoxic toward normal mammary stem cells. HMA inhibits the sphere-forming capacity of FACS-sorted human and mouse mammary CSC-related cells in vitro, specifically kills tumor but not normal mammary organoids ex vivo, and inhibits metastatic outgrowth in vivo, consistent with CSC suppression. Moreover, HMA inhibits viability and sphere formation by lung, colon, pancreatic, brain, liver, prostate and bladder tumor cell lines, suggesting that its effects may be applicable to multiple malignancies. Mechanistically, HMA elicits the permeabilization of the limiting lysosomal membrane, a hallmark feature of the lysosome-dependent cell death pathway. Our observations expose a key vulnerability intrinsic to cancer stem cells, and point to novel strategies for the exploitation of cationic amphiphilic drugs in cancer treatment.

Mandibular advancement devices (MAD) are an effective alternative treatment to CPAP. However, different maneuvers have been performed during the performance of drug sleep-induced endoscopy (DISE) to mimic the effect of MAD. Using the Selector Avance Mandibular (SAM) device, we aimed to identify MAD candidates during DISE using a titratable, reproducible, and measurable maneuver. This DISE-SAM protocol may help to find the relationship between the severity of the respiratory disorder and the degree of response, and to determine the advancement required to improve the collapsibility of the upper airway. Explorations were performed in 161 patients (132 males; 29 females) with a mean age of 46.81 (SD = 11.42) years, a BMI of 27.90 (SD = 4.19) kg/m2 and a mean AHI of 26.51 (SD = 21.23). Results showed no relationship between severity and MAD recommendation. Also, there was a weak positive relationship between the advancement required to obtain a response and the disease severity. Using the DISE-SAM protocol, the response and the range of mandibular protrusion were assessed, avoiding the inter-examiner bias of the jaw thrust maneuver. We suggest prescribing MAD as a single, alternative, or multiple treatment approaches following the SAM recommendations in a personalized design.

Oyster mushroom( Pleurotus ostreatus) is belong to the group of healthy foods, as they contain high levels of proteins, vitamins and different classes of compounds, it is discovered that oyster mushrooms could play a key role in maintaining good health. Oyster mushroom (Pleurotus sp.) Class Basidiomycetes and Family Agaricaceae are widely known as ‘dhingri’ in India. Pleurotus Ostreatus have several medicinal properties including ; anti-arthritic , antitumor, immune modulatory , antioxidant, anticancer, anti-inflammatory, antigenotoxic, hypo-cholesterolaemic, antihyperglycaemic antihypertensive, antiplatelet aggregating, antiviral and antimicrobial activities.. In this paper studied that effects of chemical constituents of oyster mushroom(Pleurotus sp.) on DNA damaging protein which analyzed its activity of PARP inhibiting or vice – versa.For this analysis we choose the molecular docking technique to check the effects of different chemical constituents of oyster mushroom(Pleurotus sp.) on DNA damaging protein and compare their results to PARP inhibitory drugs which taken as standard . We perform the molecular docking in between chemical constituents of oyster mushroom(Pleurotus sp.) and 4UND protein compare to performance of molecular docking in between standard PARP inhibitory drugs and 4UND protein with the help of PyRx and BIOVIA Discovery studio software.The analysis of molecular docking shows that some chemical constituents of oyster mushroom(Pleurotus sp.) having more binding affinity than standard PARP inhibitory drugs .The Rutin shows better binding affinity than PARP inhibitory drugs on the same protein.

Microbiome First Medicine is a suggested 21st century healthcare paradigm that prioritizes the entire human, the human superorganism, beginning with the microbiome. To date, much of medicine has protected and treated patients as if they were a single species. This has resulted in unintended damage to the microbiome and an epidemic of chronic disorders [e.g., noncommunicable diseases and conditions (NCDs)]. Along with NCDs came loss of colonization re-sistance, increased susceptibility to infectious diseases, and increasing multimorbidity and polypharmacy over the life course. To move toward sustainable healthcare, the human micro-biome needs to be front and center. This paper presents microbiome-human physiology from the view of systems biology regulation. It also details the ongoing NCD epidemic including the role of existing drugs and other factors that damage the human microbiome. Examples are provided for two entryway NCDs, asthma and obesity, regarding their extensive network of comorbid NCDs. Finally, the challenges of ensuring safety for the microbiome are detailed. Under Microbiome First Medicine and considering the importance of keystone bacteria and critical windows of development, changes in even a few microbiota-prioritized medical decisions could make a significant difference in health across the life course.

Background: In the present study, cisplatin, artemisinin and oleanolic acid were evaluated alone and in combination, on human ovarian A2780, A2780ZD0473R and A2780cisR cancer cell lines with aim of overcoming cisplatin resistance and side effects. Methods: Cytotoxicity was assessed by MTT reduction assay. CI values were used as a measure of combined drug effect. MALDI TOF/TOF MS/MS and 2-DE gel electrophoresis were used to identify protein biomarkers in ovarian cancer and to evaluate combination effects. Results: Synergism from combinations was dependent on concentration and sequence of administration. Generally, bolus was most synergistic. 49 proteins differently expressed by 2 ≥ fold were: CYPA, EIF5A1, Op18, p18, LDHB, P4HB, HSP7C, GRP94, ERp57, mortalin, IMMT, CLIC1, NM23, PSA3,1433Z, and HSP90B were down-regulated, whereas hnRNPA1, hnRNPA2/B1, EF2, GOT1, EF1A1, VIME, BIP, ATP5H, APG2, VINC, KPYM, RAN, PSA7, TPI, PGK1, ACTG and VDAC1 were up-regulated, while TCPA, TCPH, TCPB, PRDX6, EF1G, ATPA, ENOA, PRDX1, MCM7, GBLP, PSAT, Hop, EFTU, PGAM1, SERA and CAH2 were not-expressed in A2780cisR cells. The proteins were found to play critical roles in cell cycle regulation, metabolism and biosynthetic processes and drug resistance and detoxification. Conclusion: Results indicate that appropriately sequenced combinations of cisplatin with ART and OA may provide a means to reduce side effects and circumvent platinum resistance.

Respiratory transmission is the primary route of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Angiotensin I converting enzyme 2 (ACE2) is the known receptor of SARS-CoV-2 surface spike glycoprotein for entry into human cells. A recent study reported absent to low expression of ACE2 in a variety of human lung epithelial cell samples. Three bioprojects (PRJEB4337, PRJNA270632 and PRJNA280600) invariably found abundant expression of ACE1 (a homolog of ACE2 and also known as ACE) in human lungs compared to very low expression of ACE2. In fact, ACE1 has a wider and more abundant tissue distribution compared to ACE2. Although it is not obvious from the primary sequence alignment of ACE1 and ACE2, comparison of X-ray crystallographic structures show striking similarities in the regions of the peptidase domains (PD) of these proteins, which is known (for ACE2) to interact with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Critical amino acids in ACE2 that mediate interaction with the viral spike protein are present and organized in the same order in the PD of ACE1. In silico analysis predicts comparable interaction of SARS-CoV-2 spike protein with ACE1 and ACE2. In addition, this study predicts from a list of 1263 already approved drugs that may interact with ACE2 and/or ACE1, potentially interfere with the entry of SARS-CoV-2 inside the host cells and alleviate the symptoms of Coronavirus disease (COVID-19).

Causative agent of the viral pneumonia outbreak in the World identified as SARS-CoV2 leads to a severe respiratory illness like SARS and MERS. The pathogen spreading has turned into a pandemic dissemination and increased the mortality rate. Therefore, useful information is urgently necessary for effective control of the disease. Our study shows the existence of unvarying sequence with no mutation, including ORF1ab regions in 134 high-quality filtered genome sequences of SARS-CoV2 downloaded from the GISAID database. We have detected this sequence stability by using MAUVE analysis and pairwise alignment with Global Needleman Wunsch algorithm for each two different sequences, reciprocally. They also confirmed all these results were also with the Clustal W analysis. The first 6500 bp including ORF1ab region is an unvarying sequence. According to the highest TM-score of predicted protein structure analysis, the results showed it is very similar to spike protein of feline infectious peritonitis virus strain UU4 (PDB 6JX7) depending on amino acid sequences encoded by this unvarying region, and N-acetyl-D-glucosamine is the ligand of this protein. These results have confirmed that N-acetyl-D-glucosamine could play an important role in controlling of SARS-CoV-2. Also, our molecular docking analysis data supports a strong protein-ligand interaction of N-acetyl-D-glucosamine with spike receptor-binding domain bound with ACE2 (PDB 6M0J) and RNA-binding domain of nucleocapsid phosphoprotein (PDB 6WKP) from SARS CoV-2. Therefore, binding of N-acetyl-D-glucosamine to these proteins could inhibit SARS CoV-2’s replication. In the present work, we have suggested providing a repurposing compound for further in vitro and in vivo studies and new insights for ongoing clinical treatments as a new strategy to control of SARS-CoV-2 infections.

Aim: this scoping review was designed to identify studies that assess the adverse drug reactions (ADRs) for older people in Australian aged-care facilities. This review critically evaluated each published study to identify the risk of, or actual adverse drug events in older people. Inclusion criteria: This review considered any clinical studies that examined the adverse effects of medications in older people who were living in aged-care facilities. This review considered qualitative studies, analytical studies, RCTs, descriptive cross-sectional studies, and analytic observational studies that explored the use of medications and their adverse effects on older people in clinical settings (including aged care facilities). Methods: An initial search of the PubMed, OvidSP, EBSCOHost, MEDLINE, ScienceDirect, Wiley Online, SAGE, and SCOPUS databases, with full text was performed, followed by an analysis of the article’s title and abstract. Additionally, MeSH was used to describe the article. The initial round of the database search was based on inclusion criteria from studies that assessed tools or protocols aiming to identify the adverse effects of medications on the elderly population suffering chronic conditions or multiple co-morbidities. Two reviewers screened the retrieved papers for inclusion. The data presented in this review are in tabular forms and a narrative summary which aligns with the review’s objectives. Results: Seven studies were identified, and the extracted data from these studies were grouped according their characteristics and the auditing results of each study. Conclusion: There was no comprehensive or broadly adverse drug reaction assessment tool derived from Australian data that has been used on the elderly in an Australian healthcare setting.

The recent outbreak of the new virus in Wuhan city, China from the sea food market has led to the identification of a new strain called the corona virus and named as novel corona virus (2019-nCoV) belonging to Coronaviridae family. This has created major havoc and concern due to the mortality of 250 persons and affecting more than 10,000 people. This virus causes sudden fever, pneumonia and also kidney failure. In this study a computational approach is proposed for drug and vaccine design. The spike protein sequences were collected from a protein database and analysed with various bioinformatics tools to identify suitable natural inhibitors for the N-terminal receptor binding domain of spike protein. Also, it is attempted to identify suitable vaccine candidates by identifying B-Cell and T-cell epitopes. In the drug design, the tanshinone Iia and methyl Tanshinonate were identified as natural inhibitors based on the docking score. In the vaccine design, B-cell epitope VLLPLVSSQCVNLTTRTQLPPAYTN was found to have the highest antigenicity. FVFLVLLPL of MHC class-I allele and FVFLVLLPL of MHC class-II allele were identified as best peptides based on a number of alleles and antigencity scores. The present study identifies natural inhibitors and putative antigenic epitopes which may be useful as effective drug and vaccine candidates for the eradication of novel corona virus.

Prototype of a family of at least nine members, c-src tyrosine kinase is a therapeutically interesting target, because its inhibition might be of interest not only in a number of malignancies, but also in a diverse array of conditions, from neurodegenerative pathologies to certain viral infections. Computational methods in drug discovery are considerably cheaper than conventional methods and offer opportunities of screening very large numbers of compounds in conditions that would be simply impossible within the wet lab experimental settings. We have explored the use of global QSAR models and molecular ligand docking in the discovery of new c-src tyrosine kinase inhibitors. Using a data set of 1038 compounds from ChEMBL and 19 blocks of molecular descriptors, we have developed over 200 QSAR classification models, based on six machine learning algorithms and 17 feature selection methods. We have selected 49 with reasonably good performance (positive predictive value and balanced accuracy higher than 70% in nested cross validation) and the models were assembled by stacking with a simple majority vote and used for the virtual screening of over the “named” ZINC data set (over 100,000 compounds). 744 compounds were predicted by at least 50% of the QSAR models as active, 147 compounds were within the applicability domain and predicted by at least 75% of the models to be active. The latter 147 compounds were submitted to molecular ligand docking using Vina and Ledock, and a number of 90 were predicted to be active based on the binding energy. External data from CHEMBL and PUBCHEM confirmed that at least 7.83% (in the case of QSAR) or 6.67% (in the case of integrated QSAR and molecular docking) of the compounds are active on the c-src target.

Small molecule inhibitors of adipocyte fatty-acid binding protein 4 (FABP4) have got interest following the recent publication of their pharmacologically beneficial effects. Recently it comes out that FABP4 is an attractive molecular target for the treatment of type 2 diabetes, other metabolic diseases, and some type of cancers. In the past years, hundreds of effective FABP4 inhibitors have been synthesized and discovered but, unfortunately, none of them is in the clinical research phase. The field of computer-aided drug design seems to be promising and useful for the identification of FABP4 inhibitors; hence, different structure- and ligand-based computational approaches were already performed for their identification. In this paper, we searched for new potentially active FABP4 ligands in the Marine Natural Products (MNP) database. 14,492 compounds were retrieved from this database and filtered through a statistical and computational filter. Seven compounds were suggested by our methodology to possess a potential inhibitory activity upon FABP4 in the range of 79–245 nM. ADMET properties prediction were performed to validate the hypothesis of the interaction with the intended target and to assess the drug-likeness of these derivatives; from these analyses, three molecules resulted as excellent candidates for becoming new drugs.

G protein-coupled receptors (GPCRs) are critical drug targets. GPCRs convey signals from the extracellular to the intracellular environment through G proteins. There is evidence that some ligands that bind to the GPCRs activate different downstream signaling pathways. G protein activation or -arrestin biased signaling involves ligands binding to receptors and stabilizing conformations that trigger a specific pathway. Molecular dynamics (MD) simulations are especially valuable for obtaining detailed mechanistic information, including identification of allosteric sites and understanding modulators' interactions between receptors and ligands. Here, we highlight recent simulation studies and methods used to study biased G protein-coupled receptor signaling and their conformational dynamics. We also highlight applications of MD simulations to drug discovery.

Compound databases of natural products have a major impact on drug discovery projects and other areas of research. The number of databases in the public domain with compounds from natural origin is increasing. Several countries have initiatives in place to construct and maintain compound databases that are representative of their diversity. Examples are Brazil, France, Panama and recently Vietnam. Herein, we discuss the first version of BIOFACQUIM, a novel compound database with natural products isolated and characterized in Mexico. We discuss its construction, curation, and a complete chemoinformatic characterization of the content and coverage in chemical space. It is reported the profile of physicochemical properties, scaffold content, and diversity, as well as structural diversity based on molecular fingerprints. BIOFACQUIM is freely available.

Cyclic STAT3 decoy (CS3D) is a second-generation, double-stranded oligodeoxynucleotide (ODN) that mimics a genomic response element for signal transducer and activator of transcription 3 (STAT3), an oncogenic transcription factor. CS3D competitively inhibits STAT3 binding to target gene promoters, resulting in decreased expression of proteins that promote cellular proliferation and survival. Previous studies have demonstrated antitumor activity of CS3D in preclinical models of solid tumors. However, prior to entering human clinical trials, the efficiency of generating the CS3D molecule and its stability in biological fluids should be determined. CS3D is synthesized as a single-stranded ODN and must have its free ends ligated to generate the final cyclic form. In this study, we report a ligation efficiency of nearly 95 percent. The ligated CS3D demonstrated a half-life of 7.9 hours in human serum, indicating adequate stability for intravenous delivery. These results provide requisite biochemical characterization of CS3D that will inform upcoming clinical trials.

Biocompatible polymeric materials with potential to form functional structures in association with different therapeutic molecules have a high potential for biological, medical and pharmaceutical applications. Therefore, the protective capability of the inclusion nano-Complex formed between the sodium salt of poly(maleic acid-alt-octadecene) and a β-lactam drug (ampicillin trihydrate) on the chemical, enzymatic and biological degradation was evaluated. PAM-18Na was produced and characterized as reported previously. The formation of polymeric hydrophobic aggregates in aqueous solution was determined, using pyrene as a fluorescent probe. Furthermore, the formation of polymer-drug nano-complexes was characterized by Differential Scanning Calorimetry-DSC, viscometric, ultrafiltration/centrifugation assays, zeta potential and size measurements by dynamic light scattering-DLS. The PAM-18Na capacity to avoid the chemical degradation was studied through stress stability tests. The enzymatic degradation was evaluated from a pure β-lactamase, while the biological degradation was determined by different β-lactamase producing Staphylococcus aureus strains. When ampicillin was associated with PAM-18Na, the half-life time in acidic conditions increased, whereas both the enzymatic degradation and the minimum inhibitory concentration decreased to a 90 and 75%, respectively. These results suggest a promissory capability of this polymer to protect the β-lactam drugs against chemical, enzymatic and biological degradation.

Due to the complexity of Alzheimer's disease, multiple cellular types need to be targeted simultaneously in order for a given therapy to demonstrate any major effectiveness. Ultrasound-sensitive coated microbubbles (in a targeted lipid nanoemulsion) are available. Versatile small molecule drug(s) targeting multiple pathways of Alzheimer's disease pathogenesis are known. By incorporating such drug(s) into the targeted LCM/ND lipid nanoemulsion type, one obtains a multitasking combination therapeutic for translational medicine. This multitasking therapeutic targets cell-surface scavenger receptors (mainly SR-BI), making possible for various Alzheimer's-related cell types to be simultaneously searched out for localized drug treatment in vivo. Besides targeting cell-surface SR-BI, the proposed LCM/ND-nanoemulsion combination therapeutic(s) include a characteristic lipid-coated microbubble [LCM] subpopulation (i.e., a stable LCM suspension); such film-stabilized microbubbles are well known to substantially reduce the acoustic power levels needed for accomplishing temporary noninvasive (transcranial) ultrasound treatment, or sonoporation, if additionally desired for the Alzheimer's patient.

Waddington’s epigenetic landscape, a famous metaphor in developmental biology, depicts how a stem cell progresses from an undifferentiated phenotype to a differentiated one. The concept of “landscape” in the context of dynamical system theory represents a high-dimensional cell state space, in which each cell phenotype is considered as an “attractor” that is determined by interactions among multiple variables (molecular players), and is buffered against environmental fluctuations. Further, biological noise is thought to play an important role during these cell-fate decisions and in fact controls transitions between different phenotypes. Here, we discuss these phenotypic transitions in cancer from a dynamical systems perspective and invoke the concept of “cancer attractors” – hidden stable states of the underlying regulatory network that are not occupied by normal cells. Using epithelial-to-mesenchymal transition (EMT), cancer stem-like properties, metabolic reprogramming and the emergence of drug/hormone resistance as examples, we illustrate how phenotypic plasticity in cancer cells enables them to acquire hybrid phenotypes (such as hybrid epithelial/mesenchymal and hybrid metabolic phenotypes) that tend to be more aggressive and notoriously resilient to drug/hormone treatment. Furthermore, we highlight multiple factors that may give rise to phenotypic plasticity in cancer cells, such as (a) multi-stability or oscillatory behaviors governed by underlying regulatory networks involved in cell-fate decisions in cancer cells, and (b) network rewiring due to conformational dynamics of intrinsically disordered proteins (IDPs) that are highly enriched in cancer cells. We conclude by discussing why a therapeutic approach that promotes ‘recanalization’, i.e. the exit from “cancer attractors” and re-entry into “normal attractors”, is more likely to succeed rather than a conventional approach that targets individual molecules/pathways.

A major reason for failure of the immune system to detect tumor antigens (TA) is the insufficient uptake, processing, and presentation of TA by antigen-presenting-cells (APC). Immunogenicity of public and private TA of the individual patient can be markedly increased by in situ targeting of tumor cells for uptake by APC, without the need to identify and characterize the TA. This is feasible by intra-tumoral administration of alpha-gal micelles comprised of glycolipids presenting the carbohydrate-antigen “alpha-gal epitope” (Galalpha1-3Gal beta1-4GlcNAc-R). Humans produce a natural antibody called “anti-Gal” (constituting ~1% of immunoglobulins) which binds alpha-gal epitopes. Tumor injected alpha-gal micelles spontaneously insert into tumor cell membranes, so that multiple alpha-gal epitopes present on tumor cells. Anti-Gal binding to these epitopes activates the complement system, resulting in killing of tumor cells, and recruitment of multiple APC (dendritic cells and macrophages) into treated tumors by chemotactic complement cleavage peptides C5a and C3a. In this process of converting the treated tumor into personalized TA vaccine, recruited APC internalize anti-Gal opsonized tumor cells and cell membranes, process the internalized TA and transport them to regional lymph-nodes. TA peptides presented on APC activate TA specific T and B cells to proliferate and destroy metastatic tumor cells presenting the TA. Studies in anti-Gal producing mice demonstrated induction of effective protection against distant metastases of the highly tumorigenic B16 melanoma following injection of natural and synthetic alpha-gal micelles into primary tumors. This treatment was further found to synergize with anti-PD1 antibody. Phase-1 clinical-trials indicated that this immunotherapy is safe and can induce infiltration of CD4+ and CD8+ T cells into untreated distant metastases. It is suggested that in addition to converting treated metastases into autologous TA vaccine, this treatment should be considered as neo-adjuvant therapy administering alpha-gal micelles into primary tumors immediately following their detection. Such immunotherapy will convert tumors into personalized anti-TA vaccine for the period prior to their resection.

The efficacy of an intranasal (IN) bovine respiratory syncytial virus (BRSV) administered in the face of passive immunity was assessed. Pooled colostrum was administered by intubation to fifty (50) beef-dairy crossbred calves the day they were born. The calves were transported to a research facility and were blocked by age and sex and randomly assigned into two groups, a sham-vaccinated intranasally with a placebo (sterile water) or vaccinated with a tri-valent modified live viral (MLV) vaccine. The calves were 92 days old when vaccinated (day 0). The calves were challenged by aerosolized BRSV on day 80 and day 81 as a respiratory challenge. The study was terminated on day 88. Lung lesion scores (LLS) were significantly lower for calves vaccinated with tri-valent MLV vaccine than those for calves that were sham-vaccinated. Serum neutralization (SN) antibody against BRSV in calves vaccinated with the tri-valent MLV vaccine demonstrated an anamnestic response on day 88. After challenge, the calves sham-vaccinated with the placebo lost weight while those vaccinated with the tri-valent MLV vaccine gained weight. In this study colostrum-derived antibodies did not interfere with the immune response or protection provided by one dose of the tri-valent MLV vaccine.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but severe adverse event that was first observed during the global vaccination campaign against SARS-CoV-2 infection, specifically in those receiving adenoviral vector-based vaccines for Coronavirus disease 2019 (COVID-19). VITT develops 4 to 42 days post-vaccination and is characterized by the development of platelet-activating anti-platelet factor 4 (PF4) antibodies, leading to thrombocytopenia and thrombosis at unusual sites. The rise in awareness and subsequent prompt recognition of VITT was paramount in reducing mortality. Moreover, as vaccination campaigns around the world continue, a better understanding of VITT not only has important clinical implications but is also crucial for future vaccine development. In this review, we summarize the clinical features, pathophysiology, and incidence rates of VITT as well as highlight other anti-PF4 antibody-mediated disorders of growing clinical significance.

The goal of the manuscript is to design a relatively best control structure for the noise suppression of a drone’s camera gimbal action. The gimbal’s movement can be simplified as a rest-to-rest reorientation system that can achieve the boundary result of a dynamic system. Six different control architectures are proposed and evaluated based on their ability to control the trajectory of the dynamic-system position and speed, their running time, and quadratic cost. The robustness of the control architecture to uncertainties in inertia and sensor noise is also analyzed. Monte Carlo figures are used to assess the performance of the six control systems. The conditions for applying different architectures are identified through this analysis. The analysis and experimental tests reveal the most suitable control of the drone’s camera gimbal rotation.

All severe cases of SARS-CoV-2 infections are characterized by a high risk of disease progression towards ARDS, leading to bad outcome. Respiratory symptoms in COVID-19 patients often do not correspond to disease’s worsening. A dysregulated host response to the large viral load could play a key role in the disease progression. In our sample median age was 74 years (72-75) and 54% were men. Median period of hospitalization was 9 days. Firstly, we observed an asynchronous trend of neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) in 764 selected among 963 patients who were consecutively recruited in two hospitals (Cannizzaro, S. Marco) in Catania, Italy. NLR values in deceased patients showed an increase from baseline over time. By contrast, CRP tended to fall from baseline to median day of hospitalization in all four subgroups, but steeply increased at the end of hospitalization only in ICU-admitted patients. Then we evaluated the relationships between NLR and CRP as continuous variables with PaO2/FiO2 ratio (P/F). Finally, we made mediation and moderation analyses to determine the link between inflammation (CRP), immune system (neutrophils and lymphocytes) and respiratory failure (P/F). CRP, neutrophils and P/F are linked in the same pathogenetic chain leading to respiratory failure.

This article analyzes and compares the integration of two different maximum power point tracking (MPPT) control methods, which are tested under partial shading and fast ramp conditions. These MPPT methods are designed by Improved Particle Swarm Optimization (IPSO) and a combination technique between Neural Network and Perturb & Observe method (NN_P&O). These two methods are implemented and simulated for photovoltaic systems (PV), where various system responses, such as: voltage and power are obtained. The MPPT techniques were simulated using Matlab/Simulink environment. A comparison of the performance of IPSO and NN_P&O algorithms is carried out to confirm the best accomplishment of the two methods in terms of speed, accuracy and simplicity.

The drug discovery process tends to be grueling, lengthy and expensive, with cost estimates approximating $2.6 billion, consuming over 10 years to complete. Such drawbacks have set many eyes locked onto reducing the costs and accelerating the development. The emergence of Deep Reinforced Learning (DRL) within cheminformatics and bioinformatics has broadens the horizons of de novo drug design. Realizing the full potential of DRL in molecular generation requires selecting the appropriate reinforcement learning (RL) algorithm. In this work, we address these problems by utilizing Proximal Policy Optimization (PPO) algorithm within the DRL framework for molecular generation. We proposed a new method by utilizing PPO algorithm within the DRL framework, termed PSQ, to enable the generation of new chemical compounds with desired properties. This methodology has demonstrated significant potential in exploring and generating specific molecules by optimizing for targeted characteristics. The PPO algorithm's superior performance in exploring the chemical space and generating compounds with diverse pharmacophore features, functional groups, and biological activities underscores its potential in drug discovery and chemical synthesis. By systematically comparing the outputs of PPO and REINFORCE, we highlighted the robustness and efficiency of PPO in optimizing molecular properties for targeted therapeutic applications.

Many children suffer from neurodevelopmental aberrations that have long-term effects. To un-derstand the consequences of pathological processes during particular periods in neurodevelop-ment, one has to understand the differences in the developmental timelines of brain regions. The cerebellum is one of the first brain structures to differentiate during development, but one of the last to achieve maturity. This relatively long period of development underscores its vulnerability to detrimental environmental exposures throughout gestation. Moreover, as postnatal functional-ity of the cerebellum is multifaceted, enveloping sensorimotor, cognitive, and emotional domains, prenatal disruptions in cerebellar development can result in a large variety of neurological and mental health disorders. Here, we review major intrauterine insults that affect cerebellar devel-opment in both humans and rodents, ranging from abuse of toxic chemical agents such as alcohol, nicotine, cannabis and opioids, to stress, malnutrition as well as infections. Understanding these pathological mechanisms in the context of the different stages of cerebellar development in hu-mans and rodents can help us to identify critical and vulnerable periods and thereby to prevent the risk of associated prenatal and early postnatal damage that can lead to lifelong neurological and cognitive disabilities. The scope of the review is to raise awareness and to provide information for expecting parents, obstetricians, and other healthcare professionals to eventually de-sign strategies for preventing or rescuing related neurodevelopmental disorders.

This study retrospectively evaluated the prevalence and drug susceptibility of Candida species in patients diagnosed with oral mucosal candidiasis at the Department of Periodontal and Oral Mucosal Diseases, Silesian Medical University, from 2018 to 2022. A total of 1286 patients were examined (788 females, 498 males) through mycological testing to identify Candida strains and assess their drug resistance to amphotericin B, nystatin, flucytosine, econazole, ketoconazole, miconazole, and fluconazole. Among the 958 patients with positive results, Candida albicans accounted for 66.79% of infections, followed by non-albicans Candida (NAC) strains (33.21%), with rare strains identified in 0.82%. Drug resistance in C. albicans was less than 10% for most antifungals but reached 30% for azoles, while NAC strains exhibited more than 40% resistance, with C. krusei being the most resistant. Key risk factors for candidiasis included removable denture use and uncontrolled diabetes mellitus. The study highlights an increase in NAC infections, multi-strain infections, and decreasing efficacy of antifungal treatments, especially for NAC strains, with more severe cases observed in patients with multiple risk factors.

Molecular cages have promising host-guest properties for drug delivery applications. Specifically, guest⊂cage complexes can be used for on-command release of encapsulated guest molecules in response to specific stimuli. This research explores both dynamic and constrictive binding guest⊂cage systems for drug encapsulation and release in biological environments. In dynamic systems, the guest rapidly passes in and out through the portals of the cage, enabling drug delivery in vitro but facing limitations in vivo due to dilution effects that result in guest release. These challenges are addressed by constrictive binding systems, where the guest is trapped in a "gate-closed" state within the cage. In these systems, the on-command release is triggered by a "gate opening" event, which lowers the guest-out energy barrier. The full guest release is achieved when gate opening reduces the cage-guest affinity, making constrictive binding systems more effective for controlled drug delivery. As a result, this study shows that guest⊂cage complexes have suitable properties for drug delivery in biological contexts.

Objective Hypertension is one of the most common chronic diseases, affecting more than 20 % of the population. The side effects experienced due to antihypertensive medications such as tired-ness, muscle pain, and insomnia are often a significant predictor of poor adherence to therapy. The goal of the current study is to present the frequency, type, seriousness, and severity of adverse drug reactions reported to the BDA via Individual Case Safety Reports (ICSR) and following differentiation of messages found in more than one patient. Methods We conducted a retrospective analysis of the reported adverse drug reactions (ADR) reported in the Bulgarian Drug Agency database after treatment with antihyperlipidemic medicines, angiotensin-converting enzyme (ACE) - inhibitors, and sartans for the period 2017-2021. Each ICSR form was observed and data for suspected medicine and type of adverse reaction was analyzed. Results The total number of processed notifications for adverse drug reactions (ADR) included in the database is 142. The highest number of ADRs was reported for ARB (58), followed by antihyperlipidemic medicines (55) and ACE inhibitors (29.) Most of the assessed adverse events experienced by more than one patient fall into the probable and related categories based on Global Introspection method classification. Therefore, they have been investigated and are consistent with exposure in the population. Conclusion Cardiovascular medicines from the groups of ACE inhibitors, sartans and statins are with high share of reported ADRs in the BDA system. Some of them are severe and need further investigation.