Therapeutic targeting of microtubule affinity-regulating kinase 4 in cancer and neurodegenerative diseases.

Microtubule affinity-regulating kinase 4 (MARK4) is a member of the Ser/Thr protein kinase family, phosphorylates the microtubule-connected proteins and plays a vital role in causing cancers and neurodegenerative diseases. This kinase modulates multiple signaling pathways, including mammalian target of rapamycin, nuclear factor-κB, and Hippo-signaling, presumably responsible for cancer and Alzheimer's. MARK4 acts as a negative controller of the Hippo-kinase cassette for promoting YAP/TAZ action, and the loss of MARK4 detains the tumorigenic properties of cancer cells. MARK4 is involved in tau hyperphosphorylation that consequently affects neurodegeneration. MARK4 is a promising drug target for cancer, diabetes, and Alzheimer's. Developing the potent and selective inhibitors of MAKR4 are promising in the therapeutic management of associated diseases. Despite its great significance, a few reviews are available to discuss its structure, function and clinical significance. In the current review, we aimed to provide detailed information on the structural features of MARK4 targeted in drug development and its role in various signaling pathways related to cancer and neurodegenerative diseases. We further described the therapeutic potential of MARK4 inhibitors in preventing numerous diseases. Finally, the updated information on MARK4 will be helpful in the further development of effective therapeutic molecules.

Antimicrobial peptidase lysostaphin at subinhibitory concentrations modulates staphylococcal adherence, biofilm formation, and toxin production.

BACKGROUND: The ability of antimicrobial agents to affect microbial adherence to eukaryotic cell surfaces is a promising antivirulence strategy for combating the global threat of antimicrobial resistance. Inadequate use of antimicrobials has led to widespread instances of suboptimal antibiotic concentrations around infection sites. Therefore, we aimed to examine the varying effect of an antimicrobial peptidase lysostaphin (APLss) on staphylococcal adherence to host cells, biofilm biomass formation, and toxin production as a probable method for mitigating staphylococcal virulence. RESULTS: Initially, soluble expression in E. coli and subsequent purification by immobilized-Ni2+ affinity chromatography (IMAC) enabled us to successfully produce a large quantity of highly pure ~ 28-kDa His-tagged mature APLss. The purified protein exhibited potent inhibitory effects against both methicillin-sensitive and methicillin-resistant staphylococcal strains, with minimal inhibitory concentrations (MICs) ranging from 1 to 2 µg/mL, and ultrastructural analysis revealed that APLss-induced concentration-specific changes in the morphological architecture of staphylococcal surface membranes. Furthermore, spectrophotometric and fluorescence microscopy revealed that incubating staphylococcal strains with sub-MIC and MIC of APLss significantly inhibited staphylococcal adherence to human vaginal epithelial cells and biofilm biomass formation. Ultimately, transcriptional investigations revealed that APLss inhibited the expression of agrA (quorum sensing effector) and other virulence genes related to toxin synthesis. CONCLUSIONS: Overall, APLss dose-dependently inhibited adhesion to host cell surfaces and staphylococcal-associated virulence factors, warranting further investigation as a potential anti-staphylococcal agent with an antiadhesive mechanism of action using in vivo models of staphylococcal toxic shock syndrome.

Accuracy of Molecular Amplification Assays for Diagnosis of Staphylococcal Pneumonia: a Systematic Review and Meta-analysis.

Rapid and accurate identification of staphylococcal pneumonia is crucial for effective antimicrobial stewardship. We performed a meta-analysis to evaluate the diagnostic value of nucleic acid amplification tests (NAAT) from lower respiratory tract (LRT) samples from suspected pneumonia patients to avoid superfluous empirical methicillin-resistant Staphylococcus aureus (MRSA) treatment. PubMed, Scopus, Embase, Web of Science, and the Cochrane Library Database were searched from inception to 2 September 2020. Data analysis was carried out using a bivariate random-effects model to estimate pooled sensitivity, specificity, positive likelihood ratio (PLR), and negative likelihood ratio (NLR). Of 1,808 citations, 24 publications comprising 32 data sets met our inclusion criteria. Twenty-two studies (n = 4,630) assessed the accuracy of the NAAT for methicillin-sensitive S. aureus (MSSA) detection, while 10 studies (n = 2,996) demonstrated the accuracy of the NAAT for MRSA detection. The pooled NAAT sensitivity and specificity (with 95% confidence interval [CI]) for all MSSA detection were higher (sensitivity of 0.91 [95% CI, 0.89 to 0.94], specificity of 0.94 [95% CI, 0.94 to 0.95]) than those of MRSA (sensitivity of 0.75 [95% CI, 0.69 to 0.80], specificity of 0.88 [95% CI, 0.86 to 0.89]) in lower respiratory tract (LRT) samples. NAAT pooled sensitivities differed marginally among different LRT samples, including sputum, endotracheal aspirate (ETA), and bronchoalveolar lavage (BAL) fluid. Noticeably, NAAT pooled specificity against microbiological culture was consistently ≥88% across various types of LRT samples. A meta-regression and subgroup analysis of study design, sample condition, and patient selection method could not explain the heterogeneity (P > 0.05) in the diagnostic efficiency. This meta-analysis has demonstrated that the NAAT can be applied as the preferred initial test for timely diagnosis of staphylococcal pneumonia in LRT samples for successful antimicrobial therapy.

Therapeutic Potential of Ursolic Acid in Cancer and Diabetic Neuropathy Diseases.

Ursolic acid (UA) is a pentacyclic triterpenoid frequently found in medicinal herbs and plants, having numerous pharmacological effects. UA and its analogs treat multiple diseases, including cancer, diabetic neuropathy, and inflammatory diseases. UA inhibits cancer proliferation, metastasis, angiogenesis, and induced cell death, scavenging free radicals and triggering numerous anti- and pro-apoptotic proteins. The biochemistry of UA has been examined broadly based on the literature, with alterations frequently having been prepared on positions C-3 (hydroxyl), C12-C13 (double bonds), and C-28 (carboxylic acid), leading to several UA derivatives with increased potency, bioavailability and water solubility. UA could be used as a protective agent to counter neural dysfunction via anti-oxidant and anti-inflammatory effects. It is a potential therapeutic drug implicated in the treatment of cancer and diabetic complications diseases provide novel machinery to the anti-inflammatory properties of UA. The pharmacological efficiency of UA is exhibited by the therapeutic theory of one-drug → several targets → one/multiple diseases. Hence, UA shows promising therapeutic potential for cancer and diabetic neuropathy diseases. This review aims to discuss mechanistic insights into promising beneficial effects of UA. We further explained the pharmacological aspects, clinical trials, and potential limitations of UA for the management of cancer and diabetic neuropathy diseases.

Key Electronic, Linear and Nonlinear Optical Properties of Designed Disubstituted Quinoline with Carbazole Compounds.

Organic materials development, especially in terms of nonlinear optical (NLO) performance, has become progressively more significant owing to their rising and promising applications in potential photonic devices. Organic moieties such as carbazole and quinoline play a vital role in charge transfer applications in optoelectronics. This study reports and characterizes the donor-acceptor-donor-π-acceptor (D-A-D-π-A) configured novel designed compounds, namely, Q3D1-Q3D3, Q4D1-Q1D2, and Q5D1. We further analyze the structure-property relationship between the quinoline-carbazole compounds for which density functional theory (DFT) and time-dependent DFT (TDDFT) calculations were performed at the B3LYP/6-311G(d,p) level to obtain the optimized geometries, natural bonding orbital (NBO), NLO analysis, electronic properties, and absorption spectra of all mentioned compounds. The computed values of λmax, 364, 360, and 361 nm for Q3, Q4, and Q5 show good agreement of their experimental values: 349, 347, and 323 nm, respectively. The designed compounds (Q3D1-Q5D1) exhibited a smaller energy gap with a maximum redshift than the reference molecules (Q3-Q5), which govern their promising NLO behavior. The NBO evaluation revealed that the extended hyperconjugation stabilizes these systems and caused a promising NLO response. The dipole polarizabilities and hyperpolarizability (ß) values of Q3D1-Q3D3, Q4D1-Q1D2, and Q5D1 exceed those of the reference Q3, Q4, and Q5 molecules. These data suggest that the NLO active compounds, Q3D1-Q3D3, Q4D1-Q1D2, and Q5D1, may find their place in future hi-tech optical devices.

Diagnostic Accuracy of Nucleic Acid Amplification-Based Assays for Clostridium perfringens-Associated Diseases: a Systematic Review and Meta-analysis.

Timely and accurate methods for detecting Clostridium perfringens-associated diseases (CPAD) are crucial to improve patient care. A number of studies have evaluated the accuracy of nucleic acid amplification tests (NAAT) in detecting CPAD, but decisive results about their effectiveness have not been reported. We conducted a meta-analysis to evaluate the diagnostic performance of NAAT for detecting C. perfringens in clinical diarrheal samples. Five databases including PubMed, Embase, Scopus, Web of Science, and the Cochrane library were systematically probed for studies published before 6 December 2019. From 2,632 citations, we identified five eligible studies comprising 817 samples. Three studies (n = 695 samples) compared NAAT with a microbiological culture while the other three studies (n = 322 samples) compared NAAT with an immunoassay. NAAT revealed higher diagnostic accuracy against immunoassay (sensitivity, 0.53 [95% confidence interval [CI], 0.35 to 0.7]; specificity, 0.97 [95% CI, 0.95 to 0.99]; positive likelihood ratio [PLR], 23.2 [95% CI, 3.49 to 153.98]; negative likelihood ratio [NLR], 0.25 [95% CI, 0 to 245.28]; diagnostic odds ratio [DOR], 74.11 [95% CI, 2.11 to 2,593.7]) than microbiological culture (sensitivity, 0.31 [95% CI, 0.22 to 0.41]; specificity, 0.95 [95% CI, 0.93 to 0.97]; PLR, 11.56 [95% CI, 3.87 to 34.6]; NLR, 0.57 [95% CI, 0.27 to 1.21]; DOR, 18.1 [95% CI, 4.83 to 67.8]). NAAT pooled specificity was consistently ≥95% against that of applied reference standards. A meta-regression and subgroup analysis of sample condition, gene target, study design, and reference standards could not explain the heterogeneity (P > 0.05) in the diagnostic efficiency. The analysis has demonstrated that the diagnostic accuracy of NAAT is relatively insufficient to replace traditional reference standards as a single diagnostic test. NAAT can be applied in combination with microbiological culture because of the advantage of time to result and in scenarios where traditional tests are not feasible. Further investigations in this direction with larger sample sizes are still warranted to support our findings.

The anti-cancer effects of Tualang honey in modulating breast carcinogenesis: an experimental animal study.

BACKGROUND: Honey has been shown to have anti-cancer effects, but the mechanism behind these effects is not fully understood. We investigated the role of Malaysian jungle Tualang honey (TH) in modulating the hematological parameters, estrogen, estrogen receptors (ER1) and pro and anti-apoptotic proteins expression in induced breast cancer in rats. METHODS: Fifty nulliparous female Sprague-Dawley rats were used and grouped as follows: Group 0 (healthy normal rats control), Group 1 (negative control; untreated rats), Groups 2, 3 and 4 received daily doses of 0.2, 1.0 and 2.0 g/kg body weight of TH, respectively. The rats in groups 1, 2, 3, 4 were induced with 80 mg/kg of 1-methyl-1-nitrosourea (MNU). TH treatment in groups 2, 3 and 4 was started one week prior to tumor induction and continued for 120 days. RESULTS: The TH-treated rats had tumors of different physical attributes compared to untreated negative control rats; the tumor progression (mean 75.3 days versus 51.5 days); the incidence (mean 76.6% versus 100%); the multiplicity (mean 2.5 versus 4 tumor masses per rat); the size of tumor mass (mean 0.41 cm versus 1.47 cm [p < 0.05]) and the weight of the tumor mass (mean 1.22 g versus 3.23 g; [p < 0.05]). Histological examinations revealed that cancers treated with TH were mainly of grades I and II compared with the non-treated control, in which the majority were of grade III (p < 0.05). TH treatment was found to modulate hematological parameters such as Hb, RBCs, PCV, MCV, RDW, MCHC, polymorphs and lymphocytes values. TH treatment groups were found to have a lower anti-apoptotic proteins (E2, ESR1 and Bcl-xL) expression and a higher pro-apoptotic proteins (Apaf-1 and Caspase-9) expression at serum and on cancer tissue level (p < 0.05). CONCLUSION: Tualang Honey alleviates breast carcinogenesis through modulation of hematologic, estrogenic and apoptotic activities in this experimental breast cancer animal model. Tualang Honey may be used as a natural 'cancer-alleviating' agent or as a supplement to chemotherapeutic agents.

Influence of benzothiophene acceptor moieties on the non-linear optical properties of pyreno-based chromophores: first-principles DFT framework.

Herein, a series of heterocyclic organic compounds (PYFD1-PYFD7) are designed with different acceptor moieties at the terminal position of a reference compound (PYFR) for nonlinear optical (NLO) active materials. The optoelectronic characteristics of the designed chromophores were investigated using density functional theory (DFT) calculations with the M06/6-311G(d,p) functional. Frontier molecular orbital (FMO) analysis revealed a significant decrease in the energy of the band gaps (2.340-2.602 eV) for the derivatives as compared to the PYFR reference compound (3.12 eV). An efficient transfer of charge from the highest occupied molecular orbital (HOMO) to the lowest unoccupied molecular orbital (LUMO) was seen, which was further corroborated by the density of states (DOS) and transition density matrix (TDM) heat maps. The results of the global reactivity parameters (GRPs) indicated that all derivatives exhibited greater softness (σ = 0.384-0.427 eV) and lower hardness (η = 0.394-1.302 eV) as compared to PYFR, indicating a higher level of polarizability in the derivatives. Moreover, all of the derivatives showed significant findings in terms of nonlinear optical (NLO) results as compared to the reference chromophore. PYFD2 showed the most effective NLO response (α = 1.861 × 10-22 and ßtot = 2.376 × 10-28 esu), including a lowered band gap of 2.340 eV, the maximum softness value of 0.4273 eV, and the lowest hardness value of 1.170 eV as compared to other chromophores. The incorporation of different acceptors and thiophene as a π-spacer in this structural alteration significantly contributed to achieving remarkable NLO responses. Therefore, our findings may motivate experimentalists to synthesize these designed NLO active materials for the current advanced technological applications.

Vanillin-Isatin Hybrid-Induced MARK4 Inhibition As a Promising Therapeutic Strategy against Hepatocellular Carcinoma.

Microtubule affinity-regulating kinase 4 (MARK4) is a serine-threonine kinase that phosphorylates microtubule-associated proteins (MAPs) and increases the microtubule dynamics. Due to its direct involvement in initiation, cell division, progression, and cancer metastasis, MARK4 is considered a potential therapeutic target. Here, we designed, synthesized, and characterized vanillin-isatin hybrids and evaluated their MARK4 inhibitory potential. All of the compounds strongly bind to MARK4 and interact closely with the active site residues. Finally, the compound VI-9 was selected for further investigation due to its high binding affinity and strong MARK4 inhibitory potential. Tau-phosphorylation assay has further confirmed that VI-9 significantly reduced the activity of MARK4. Compared with vanillin, VI-9 showed a better binding affinity and MARK4 inhibitory potential. Cell viability assays on human hepatocellular carcinoma (HCC) cell lines C3A and SNU-475 revealed that VI-9 inhibited their growth and proliferation. In addition, these compounds were nontoxic (up to 200 µM) for noncancerous (HEK-293) cells. Interestingly, VI-9 induces apoptosis and decreases the metastatic potential of the C3A and SNU-475 cell lines. The present work opens a newer avenue for vanillin-isatin hybrids and their derivatives in developing MARK4-targeted anticancer therapies.

Nanozyme-based sensing of dopamine using cobalt-doped hydroxyapatite nanocomposite from waste bones.

Dopamine is one of the most important neurotransmitters and plays a crucial role in various neurological, renal, and cardiovascular systems. However, the abnormal levels of dopamine mainly point to Parkinson's, Alzheimer's, cardiovascular diseases, etc. Hydroxyapatite (HAp), owing to its catalytic nature, nanoporous structure, easy synthesis, and biocompatibility, is a promising matrix material. These characteristics make HAp a material of choice for doping metals such as cobalt. The synthesized cobalt-doped hydroxyapatite (Co-HAp) was used as a colorimetric sensing platform for dopamine. The successful synthesis of the platform was confirmed by characterization with FTIR, SEM, EDX, XRD, TGA, etc. The platform demonstrated intrinsic peroxidase-like activity in the presence of H2O2, resulting in the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB). The proposed sensor detected dopamine in a linear range of 0.9-35 µM, a limit of detection of 0.51 µM, limit of quantification of 1.7 µM, and an R2 of 0.993. The optimization of the proposed sensor was done with different parameters, such as the amount of mimic enzyme, H2O2, pH, TMB concentration, and time. The proposed sensor showed the best response at 5 mg of the mimic enzyme, pH 5, 12 mM TMB, and 8 mM H2O2, with a short response time of only 2 min. The fabricated platform was successfully applied to detect dopamine in physiological solutions.

Deciphering the electrochemical sensing capability of novel Ga12As12 nanocluster towards chemical warfare phosgene gas: insights from DFT.

The applications of 3D inorganic nanomaterials in environmental and agriculture monitoring have been exploited continuously; however, the utilization of semiconductor nanoclusters, especially for detecting warfare agents, has not been fully investigated yet. To fill this gap, the molecular modelling of novel inorganic semiconductor nanocluster Ga12As12 as a sensor for phosgene gas (highly toxic for living things and the environment) is accomplished employing benchmark DFT and TD-DFT investigations. Computational tools have been applied to explore different adsorption sites and the potential sensing capability of the Ga12As12 nanoclusters. The calculated adsorption energy (-21.34 ± 2.7 kcal mol-1) for ten selected complexes, namely, Pgn-Cl@4m-ring (MS1), Pgn-Cl@6m-ring (MS2), Pgn-Cl@XY66 (MS3), Pgn-O@4m-ring (MS4), Pgn-O@XY66 (MS5), Pgn-O@XY64 (MS6), Pgn-O@Y (MS7), Pgn-planar@Y (MS8), Pgn-planar@X (MS9), and Pgn-planar@4m-ring (MS10), manifest the remarkable and excessive adsorption response of the studied nanoclusters. The explored molecular electronic properties, such as interaction distance (3.05 ± 0.5 Å), energy gap (∼2.17 eV), softness (∼0.46 eV), hardness (1.10 ± 0.01 eV), electrophilicity index (10.27 ± 0.45 eV), electrical conductivity (∼1.98 × 109), and recovery time (∼3 × 10-12 s-1) values, ascertain the elevated reactivity and an imperishable sensitivity of the Ga12As12 nanocluster, particularly for its complex MS8. QTAIM analysis exhibits the presence of a strong electrostatic bond (positive ∇2ρ(r) values), electron delocalization (ELF < 0.5), and a strong chemical bond (because of high all-electron density values). In addition, NBO analysis explores the lone pair electron delocalization of phosgene to the nanocluster stabilized by intermolecular charge transfer (ICT) and different kinds of non-covalent interactions. Also, the green region existence expressed by NCI analysis (between the nanocluster and adsorbate) stipulate the energetic and dominant interactions. Furthermore, the UV-Vis, thermodynamic analysis, and density of state (DOS) demonstrate the maximum absorbance (562.11 nm) and least excitation energy (2.21 eV) by the complex MS8, the spontaneity of the interaction process, and the significant changes in HOMO and LUMO energies, respectively. Thus, the Ga12As12 nanocluster has proven to be a promising influential sensing material to monitor phosgene gas in the real world, and this study will emphasize the informative knowledge for experimental researchers to use Ga12As12 as a sensor for the warfare agent (phosgene).

Recent Approaches for Downplaying Antibiotic Resistance: Molecular Mechanisms.

Antimicrobial resistance (AMR) is a ubiquitous public health menace. AMR emergence causes complications in treating infections contributing to an upsurge in the mortality rate. The epidemic of AMR in sync with a high utilization rate of antimicrobial drugs signifies an alarming situation for the fleet recovery of both animals and humans. The emergence of resistant species calls for new treatments and therapeutics. Current records propose that health drug dependency, veterinary medicine, agricultural application, and vaccination reluctance are the primary etymology of AMR gene emergence and spread. Recently, several encouraging avenues have been presented to contest resistance, such as antivirulent therapy, passive immunization, antimicrobial peptides, vaccines, phage therapy, and botanical and liposomal nanoparticles. Most of these therapies are used as cutting-edge methodologies to downplay antibacterial drugs to subdue the resistance pressure, which is a featured motive of discussion in this review article. AMR can fade away through the potential use of current cutting-edge therapeutics, advancement in antimicrobial susceptibility testing, new diagnostic testing, prompt clinical response, and probing of new pharmacodynamic properties of antimicrobials. It also needs to promote future research on contemporary methods to maintain host homeostasis after infections caused by AMR. Referable to the microbial ability to break resistance, there is a great ultimatum for using not only appropriate and advanced antimicrobial drugs but also other neoteric diverse cutting-edge therapeutics.

Influence of azacycle donor moieties on the photovoltaic properties of benzo[c][1,2,5]thiadiazole based organic systems: a DFT study.

Fullerene free organic chromophores are widely utilized to improve the efficacy of photovoltaic materials. Herein, we designed D-π-A-π-D form chromophores (TAZD1-TAZD5) via end-capped redistribution of donor moieties by keeping the same π-bridge and central acceptor unit for organic solar cells (OSCs). To analyze the photovoltaic characteristics of these derivatives, DFT estimations were accomplished at B3LYP/6-311 G (d,p) functional. Different investigations like frontier molecular orbital (FMO), absorption spectra (UV-Vis), density of states (DOS), binding energy (Eb), open circuit voltage (Voc), and transition density matrix (TDMs) were performed to examine the optical, photophysical and electronic characteristics of afore-mentioned chromophores. A suitable band gap (∆E = 2.723-2.659 eV) with larger bathochromic shift (λmax = 554.218-543.261 nm in acetonitrile) was seen in TAZD1-TAZD5. An effective charge transference from donor to acceptor via spacer was observed by FMO analysis which further supported by DOS and TDM. Further, lower binding energy values also supported the higher exciton dissociation and greater CT in TAZD1-TAZD5. Among all the designed chromophores, TAZD5 exhibited the narrowest Egap (2.659 eV) and maximum red-shifted absorption in solvent as well as gas phase i.e. 554.218 nm and 533.219 nm, respectively which perhaps as a result of the phenothiazine-based donor group (MPT). In a nutshell, all the tailored chromophores can be considered as efficient compounds for promising OSCs with a good Voc response, interestingly, TAZD5 is found to be excellent chromophores as compared to all these designed compounds.

Foliar application of silicon-based nanoparticles improve the adaptability of maize (Zea mays L.) in cadmium contaminated soils.

Heavy metals (HMs) especially cadmium (Cd) absorbed by the roots of crop plants like maize have emerged as one of the most serious threats by causing stunted plant growth along with disturbing the photosynthetic machinery and nutrient homeostasis process. A trial was conducted for inducing Cd stress tolerance in maize by exogenous application of silicon nanoparticles (SiNPs) using five doses of SiNPs (0, 100, 200, 300, and 400 ppm) and three levels of Cd (0, 15, and 30 ppm) for maize hybrid (SF-9515). The response variables included morphological traits and biochemical parameters of maize. The results indicated that Cd level of 30 ppm remained the most drastic for maize plants by recording the minimum traits such as shoot length (39.35 cm), shoot fresh weight (9.52 g) and shoot dry weight (3.20 g), leaf pigments such as chlorophyll a (0.55 mg/g FW), chlorophyll b (0.27 mg/g FW), total contents (0.84 mg/g FW), and carotenoid contents (0.19 µg/g FW). Additionally, the same Cd level disrupted biochemical traits such as TSP (4.85 mg/g FW), TP (252.94 nmol/g FW), TSAA (18.92 µmol g-1 FW), TSS (0.85 mg/g FW), and antioxidant activities such as POD (99.39 min-1 g-1 FW), CAT (81.58 min-1 g-1 FW), APX (2.04 min-1 g-1 FW), and SOD (172.79 min-1 g-1 FW). However, a higher level of Cd resulted in greater root length (87.63 cm), root fresh weight (16.43 g), and root dry weight (6.14 g) along with higher Cd concentration in the root (2.52 µg/g-1) and shoot (0.48 µg/g-1). The silicon nanoparticles (Si NPs) treatment significantly increased all measured attributes of maize. The highest value was noted of all the parameters such as chlorophyll a (0.91 mg/g FW), chlorophyll b (0.57 mg/g FW), total chlorophyll contents (1.48 mg/g FW), total carotenoid contents (0.40 µg/g FW), TSP (6.12 mg/g FW), TP (384.56 nmol/g FW), TSAA (24.64 µmol g-1 FW), TSS (1.87 mg/g FW), POD (166.10 min-1 g-1 FW), CAT (149.54 min-1 g-1 FW), APX (3.49 min-1 g-1 FW), and SOD (225.57 min-1 g-1 FW). Based on recorded findings, it might be inferred that higher levels of Cd tend to drastically reduce morpho-physiological traits of maize and foliage-applied silver nanoparticles hold the potential to ameliorate the adverse effect of Cd stress on maize.

Dose optimization of silicon for boosting arbuscular mycorrhizal fungi colonization and cadmium stress mitigation in maize (Zea mays L.).

The foliar applied silicon (Si) has the potential to ameliorate heavy metals, especially cadmium (Cd) toxicity; however, Si dose optimization is strategically important for boosting the growth of soil microbes and Cd stress mitigation. Thus, the current research was performed to assess the Si-induced physiochemical and antioxidant trait alterations along with Vesicular Arbuscular Mycorrhiza (VAM) status in maize roots under Cd stress. The trial included foliar Si application at the rate of 0, 5, 10, 15, and 20 ppm while Cd stress (at the rate of 20 ppm) was induced after full germination of maize seed. The response variables included various physiochemical traits such as leaf pigments, protein, and sugar contents along with VAM alterations under induced Cd stress. The results revealed that exogenous application of Si in higher doses remained effective in improving the leaf pigments, proline, soluble sugar, total proteins, and all free amino acids. Additionally, the same treatment remained unmatched in terms of antioxidant activity compared to lower doses of foliar-applied Si. Moreover, VAM was recorded to be at peak under 20 ppm Si treatment. Thus, these encouraging findings may serve as a baseline to develop Si foliar application as a biologically viable mitigation strategy for maize grown in Cd toxicity soils. Overall, the exogenous application of Si helpful for reducing the uptake of Cd in maize and also improving the mycorrhizal association as well as the philological mechanism and antioxidant activities in plant under cadmium stress conditions. Also, future studies must test more doses concerning to varying Cd stress levels along with determining the most responsive crop stage for Si foliar application.

Theoretical Perspective toward Designing of 5-Methylbenzo [1,2-b:3,4-b':6,5-b″] trithiophene-Based Nonlinear Optical Compounds with Extended Acceptors.

A series of benzotrithiophene-based compounds (DCTM1-DCTM6) having D1-π1-D2-π2-A configuration were designed using a reference molecule (DCTMR) via incorporating pyrrole rings (n = 1-5) as the π-spacer (π2). Quantum chemical calculations were performed to determine the impact of the pyrrole ring on the nonlinear optical (NLO) behavior of the above-mentioned chromophores. The optoelectronic properties of the compounds were determined at the MW1PW91/6-311G(d,p) functional. Among all of the derivatives, DCTM5 exhibited the least highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) band gap (Eg) 0.968 eV with a high softness of 0.562 eV-1, and hence possessed the highest polarizability. Interestingly, transition density matrix (TDM) findings demonstrated that DCTM5 with an effective diagonal charge transmission proportion at the acceptor group supports the frontier molecular orbital (FMO) results. Additionally, the exciton binding energy values for DCTM1-DCTM6 were found to be less than that for DCTMR and thus, the effective charge transfer was examined in the derivatives. All of the derivatives exhibited effective NLO outcomes with the highest magnitude of linear polarizability ⟨α⟩, and first (ßtot) and second (γtot) hyperpolarizabilities relative to the parent compound. Nevertheless, the highest ßtot and γtot were obtained for DTCM1 and DTCM6, 7.0440 × 10-27 and 22.260 × 10-34 esu, respectively. Hence, through this structural tailoring with a pyrrole spacer, effective NLO materials can be obtained for optoelectronic applications.

Synthesis and Antioxidant Studies of 2,4-Dioxothiazolidine-5-acetic Acid Based Organic Salts: SC-XRD and DFT Approach.

In the current study, two organic salts (1 and 2) are synthesized, and then crystalline structures are characterized by FTIR, UV spectroscopy, and X-ray crystallographic studies. The organic salts 1 and 2 are optimized at the M06/6-311G(d,p)level of theory and further utilized for analysis of natural bond orbitals (NBOs), natural population, frontier molecular orbitals (FMOs), and global reactivity parameters, which confirmed the stability of the studied compounds and charge transfer phenomenon in the studied compounds. The studies further revealed that 1 and 2 are more stable than 3. The lowest energy merged monomer-coformer conformations were docked as flexible ligands with rigid fungal proteins and DNA receptors. The stagnant binding of the monomer through two H bonds with protein was observed for ligands 1 and 3 while different pattern was found with 2. The coformers formed a single H bond with the active site in 2 and 3 and a single pi-arene H interaction in 1. The two-point ligand-receptor interactions hooked the monomer between DNA base pairs for partial intercalation; pi stacking with additive hydrogen bonding with the base pair led to a strong benzimidazole interaction in 1 and 2, whereas ethylene diamine formed weak H bonding. Thus, the molecular docking predicted that the coformer exhibited DNA intercalation reinforced by its salt formation with benzimidazole 1 and methyl benzimidazole 2. Antioxidant studies depicted that 3 has a higher IC50 value than that of 2,4-D and also the largest value among the studied compounds, whereas 2 showed the lowest value among the studied compounds.

mRNA Vaccine Designing Using Chikungunya Virus E Glycoprotein through Immunoinformatics-Guided Approaches.

Chikungunya virus is an alphavirus transmitted by mosquitos that develops into chikungunya fever and joint pain in humans. This virus' name originated from a Makonde term used to describe an illness that changes the joints and refers to the posture of afflicted patients who are affected by excruciating joint pain. There is currently no commercially available drug or vaccine for chikungunya virus infection and the treatment is performed by symptom reduction. Herein, we have developed a computationally constructed mRNA vaccine construct featuring envelope glycoprotein as the target molecule to aid in the treatment process. We have utilized the reverse vaccinology approach to determine epitopes that would generate adaptive immune reactions. The resulting T and B lymphocytes epitopes were screened by various immunoinformatic tools and a peptide vaccine construct was designed. It was validated by proceeding to docking and MD simulation studies. The following design was then back-translated in nucleotide sequence and codons were optimized according to the expression host system (H. sapiens). Various sequences, including 3' and 5' UTR regions, Kozak sequence, poly (A) tail, etc., were introduced into the sequence for the construction of the final mRNA vaccine construct. The secondary structure was generated for validation of the mRNA vaccine construct sequence. Additionally, in silico cloning was also performed to design a vector for proceeding towards in vitro experimentation. The proposed designed vaccine construct may proceed with experimental testing for further efficacy verification and the final development of a vaccine against chikungunya virus infection.

Clinical Relevance of Xpert MRSA/SA in Guiding Therapeutic Decisions for Staphylococcal Infections: A Diagnostic Test Accuracy Analysis.

INTRODUCTION: Rapid identification of the causal organism and antibiotic resistance is crucial for guiding targeted therapy in patients with suspected staphylococcal infection. A meta-analysis was carried out to evaluate the diagnostic relevance of Xpert™ MRSA/SA (Xpert) from clinical samples of various origins for limiting the use of unnecessary empirical methicillin-resistant Staphylococcus aureus (MRSA) therapy. METHODS: Five databases, including the Cochrane Library, Scopus, PubMed, Web of Science, and Embase, were comprehensively inspected from inception to October 12, 2021. The pooled summary estimates were evaluated using a bivariate random-effects model. RESULTS: Our inclusion criteria were met by 49 publications containing 68 datasets out of 735 citations. A total of 21 studies (n = 4996) examined the accuracy of Xpert in detecting methicillin-sensitive S. aureus (MSSA), while 47 studies (n = 45,430) examined the accuracy of Xpert in detecting MRSA. As compared to MRSA, Xpert's diagnostic performance for MSSA detection was markedly higher [sensitivity: 0.97 (0.96-0.98), specificity: 0.97 (0.97-0.98), area under curve (AUC): 0.99 (0.99-1.0)]. Xpert's pooled sensitivity and specificity differed marginally across sample types, including screening of colonization, lower respiratory tract (LRT), osteoarticular, and bloodstream samples. Notably, the Xpert pooled specificity was consistently ≥ 92% against microbiological culture across all sample types. The diagnostic efficiency heterogeneity was not explained by a meta-regression and subgroup analysis of research design, sample conditions, and sampling methods (P > 0.05). CONCLUSION: Our findings suggest that Xpert could be used as the favoured screening test for the early detection of staphylococcal infection in a variety of sample types, with the goal of guiding therapeutic decisions.

Therapeutic Implications of Caffeic Acid in Cancer and Neurological Diseases.

Caffeic acid (CA) is found abundantly in fruits, vegetables, tea, coffee, oils, and more. CA and its derivatives have been used for many centuries due to their natural healing and medicinal properties. CA possesses various biological and pharmacological activities, including antioxidant, anti-inflammatory, anticancer, and neuroprotective effects. The potential therapeutic effects of CA are mediated via repression and inhibition of transcription and growth factors. CA possesses potential anticancer and neuroprotective effects in human cell cultures and animal models. However, the biomolecular interactions and pathways of CA have been described highlighting the target binding proteins and signaling molecules. The current review focuses on CA's chemical, physical, and pharmacological properties, including antioxidant, anti-inflammatory, anticancer, and neuroprotective effects. We further described CA's characteristics and therapeutic potential and its future directions.