Progeny Transfer Effects of Chitosan-Coated Cobalt Ferrite Nanoparticles.

Cobalt ferrite nanoparticles (CFNs) are promising materials for their enticing properties for different biomedical applications, including magnetic resonance imaging (MRI) contrast, drug carriers, biosensors, and many more. In our previous study, a chitosan-coated CFN (CCN) nanocomplex demonstrated potential as an MRI contrast dye by improving the biocompatibility of CFN. In this study, we report the progeny transfer effects of CCN following a single intravenous injection of CCN (20, 40, or 60 mg/kg) in pregnant albino Wistar rats. Biochemical and histological observation reveals that CCN is tolerated with respect to maternal organ functions (e.g., liver, kidney). Atomic absorption spectroscopy results showed that CCN or CCN-leached iron could cross the placental barrier and deposit in the fetus. Furthermore, this deposition accelerated lipid peroxidation in the placenta and fetus.

Advances in Computational and Bioinformatics Tools and Databases for Designing and Developing a Multi-Epitope-Based Peptide Vaccine.

A vaccine is defined as a biologic preparation that trains the immune system, boosts immunity, and protects against a deadly microbial infection. They have been used for centuries to combat a variety of contagious illnesses by means of subsiding the disease burden as well as eradicating the disease. Since infectious disease pandemics are a recurring global threat, vaccination has emerged as one of the most promising tools to save millions of lives and reduce infection rates. The World Health Organization reports that immunization protects three million individuals annually. Currently, multi-epitope-based peptide vaccines are a unique concept in vaccine formulation. Epitope-based peptide vaccines utilize small fragments of proteins or peptides (parts of the pathogen), called epitopes, that trigger an adequate immune response against a particular pathogen. However, conventional vaccine designing and development techniques are too cumbersome, expensive, and time-consuming. With the recent advancement in bioinformatics, immunoinformatics, and vaccinomics discipline, vaccine science has entered a new era accompanying a modern, impressive, and more realistic paradigm in designing and developing next-generation strong immunogens. In silico designing and developing a safe and novel vaccine construct involves knowledge of reverse vaccinology, various vaccine databases, and high throughput techniques. The computational tools and techniques directly associated with vaccine research are extremely effective, economical, precise, robust, and safe for human use. Many vaccine candidates have entered clinical trials instantly and are available prior to schedule. In light of this, the present article provides researchers with up-to-date information on various approaches, protocols, and databases regarding the computational designing and development of potent multi-epitope-based peptide vaccines that can assist researchers in tailoring vaccines more rapidly and cost-effectively.

In Silico Identification and Analysis of Potentially Bioactive Antiviral Phytochemicals against SARS-CoV-2: A Molecular Docking and Dynamics Simulation Approach.

SARS-CoV-2, a deadly coronavirus sparked COVID-19 pandemic around the globe. With an increased mutation rate, this infectious agent is highly transmissible inducing an escalated rate of infections and death everywhere. Hence, the discovery of a viable antiviral therapy option is urgent. Computational approaches have offered a revolutionary framework to identify novel antimicrobial treatment regimens and allow a quicker, cost-effective, and productive conversion into the health center by evaluating preliminary and safety investigations. The primary purpose of this research was to find plausible plant-derived antiviral small molecules to halt the viral entrance into individuals by clogging the adherence of Spike protein with human ACE2 receptor and to suppress their genome replication by obstructing the activity of Nsp3 (Nonstructural protein 3) and 3CLpro (main protease). An in-house library of 1163 phytochemicals were selected from the NPASS and PubChem databases for downstream analysis. Preliminary analysis with SwissADME and pkCSM revealed 149 finest small molecules from the large dataset. Virtual screening using the molecular docking scoring and the MM-GBSA data analysis revealed that three candidate ligands CHEMBL503 (Lovastatin), CHEMBL490355 (Sulfuretin), and CHEMBL4216332 (Grayanoside A) successfully formed docked complex within the active site of human ACE2 receptor, Nsp3, and 3CLpro, respectively. Dual method molecular dynamics (MD) simulation and post-MD MM-GBSA further confirmed efficient binding and stable interaction between the ligands and target proteins. Furthermore, biological activity spectra and molecular target analysis revealed that all three preselected phytochemicals were biologically active and safe for human use. Throughout the adopted methodology, all three therapeutic candidates significantly outperformed the control drugs (Molnupiravir and Paxlovid). Finally, our research implies that these SARS-CoV-2 protein antagonists might be viable therapeutic options. At the same time, enough wet lab evaluations would be needed to ensure the therapeutic potency of the recommended drug candidates for SARS-CoV-2.

Racial Disparities Affecting Postoperative Outcomes After Brain Tumor Resection.

OBJECTIVE: To investigate racial disparities in 30-day postoperative outcomes of craniotomy for glioma resection. METHODS: 2006-2019 American College of Surgeons' National Surgical Quality Improvement Program files were queried for all patients who underwent a craniotomy for a supratentorial glioma resection. Racial disparities in preoperative variables were studied between the demographic cohorts of Asian, African Americans, Hispanics, and Caucasian. Fisher exact tests were used to examine association of preoperative variables with race. Multivariable logistic regression models, adjusted for all preoperative variables associated with race, were used to determine the odds ratios of postoperative outcomes for each demographic cohort in comparison with Caucasian patients. RESULTS: A total of 12,544 patients were identified: 4% Asian, 5% African American, 7% Hispanic, and 85% Caucasian. African American patients had significantly higher adjusted odds than Caucasian patients of major adverse cardiovascular events (adjusted odds ratio [aOR]: 1.827, 95% confidence interval [CI]: 1.155-2.891, P = 0.01), pulmonary events (aOR: 1.683, 95% CI: 1.145-2.473, P = 0.008), and urinary tract infection (aOR: 2.016, 95% CI: 1.221-3.327, P = 0.006). Asian patients had significantly higher odds than Caucasian patients of requiring a transfusion (aOR: 2.094, 95% CI: 1.343-3.266, P = 0.001). All demographic cohorts had higher odds of having an extended length of stay than Caucasian patients. CONCLUSIONS: African American patients who undergo a craniotomy for glioma resection have almost twice the odds of Caucasian patients of having a postoperative major cardiovascular complication, pulmonary complication, or urinary tract infection. All minority groups have higher odds of an extended length of stay as compared with Caucasian patients.

Enhancement of placental inflammation by Dibutyl Phthalate.

Recent studies suggest that women with high exposures to dibutyl phthalate (DBP) are at increased risk for preterm birth, a condition associated with aberrant inflammation in the placenta often caused by subclinical infections. Placental inflammation is also a risk factor for neurodevelopmental disorders whose risk may also be enhanced by DBP. It is unclear, however, if DBP enhances placental inflammation. Therefore, we studied the effects of DBP on the production of biomarkers of placental inflammation and neurodevelopment under basal conditions and a setting of mild infection. Placental explant cultures established from women undergoing elective caesarean delivery were treated with DBP with and without co-stimulation by 107 CFU/mL heat-killed E. coli for 24 h at 37 °C. Conditioned medium was harvested and concentrations of IL-1ß, TNF-α, IL-10, HO-1 and BDNF, a biomarker for neurodevelopment, were quantified. DBP significantly enhanced IL-6 production in basal cultures but had no significant on the other biomarkers quantified. Both TNF-α and IL-1ß production was enhanced by DBP for cultures co-stimulated with E. coli. Although marginal enhancement of IL-6, and IL-10 were observed for bacteria co-treated cultures, results were either non-monotonic or only approached statistical significance. HO-1 production tended to be reduced at the highest concentration of DBP tested and BDNF production was reduced by DBP in a dose-dependent manner for bacteria-stimulated cultures. These results suggest that DBP enhances basal IL-6 production but has little or no effect on other biomarkers studied. However, DBP enhances IL-1ß and TNF-α production but reduces BDNF production by bacteria-stimulated cultures.

Designing an effective therapeutic siRNA to silence RdRp gene of SARS-CoV-2.

The devastating outbreak of COVID-19 has spread all over the world and has become a global health concern. There is no specific therapeutics to encounter the COVID-19. Small interfering RNA (siRNA)-based therapy is an efficient strategy to control human viral infections employing post-transcriptional gene silencing (PTGS) through neutralizing target complementary mRNA. RNA-dependent RNA polymerase (RdRp) encoded by the viral RdRp gene as a part of the replication-transcription complex can be adopted as an acceptable target for controlling SARS-CoV-2 mediated infection. Therefore, in the current study, accessible siRNA designing tools, including significant algorithms and parameters, were rationally used to design the candidate siRNAs against SARS-COV-2 encoded RdRp. The designed siRNA molecules possessed adequate nucleotide-based and other features for potent gene silencing. The targets of the designed siRNAs revealed no significant matches within the whole human genome, ruling out any possibilities for off-target silencing by the siRNAs. Characterization with different potential parameters of efficacy allowed selecting the finest siRNA among all the designed siRNA molecules. Further, validation assessment and target site accessibility prediction also rationalized the suitability of this siRNA molecule. Molecular docking study between the selected siRNA molecule and component of RNA interference (RNAi) pathway gave an excellent outcome. Molecular dynamics of two complexes: siRNA and argonaute complex, guide RNA, and target protein complex, have shown structural stability of these proteins. Therefore, the designed siRNA molecule might act as an effective therapeutic agent against the SARS-CoV-2 at the genome level and can prevent further outbreaks of COVID-19 in humans.

Women with high plasma levels of PBDE-47 are at increased risk of preterm birth.

OBJECTIVES: Nearly 100% of North American women have detectable levels of flame retardants such as polybrominated diphenyl ethers (PBDEs) in their plasma. These molecules have structural homology to thyroid hormones and may function as endocrine disruptors. Thyroid dysfunction has previously been associated with increased risk for preterm birth. Therefore, we conducted a multi-center, case-cohort study to evaluate if high plasma concentrations of a common PBDE congener in the first trimester increases the risk of preterm birth and its subtypes. METHODS: Pregnant women were recruited at the onset of initiation of prenatal care at Kaiser-Permanente Southern California (KPSC)-West Los Angeles and KPSC-San Diego medical centers. Plasma samples from women whose pregnancies ended preterm and random subset of those delivering at term were assayed for PBDE-47 and thyroid-stimulating hormone (TSH) by immunoassay. Quartile cutoffs were calculated for the patients at term and used to determine if women with exposures in the 4th quartile are at increased risk for preterm birth using logistic regression. RESULTS: We found that high concentrations of PBDE-47 in the first trimester significantly increased the odds of both indicated (adjusted odds ratio, adjOR=2.35, 95% confidence interval [CI]: 1.31, 4.21) and spontaneous (adjOR=1.76, 95% CI: 1.02, 3.03) preterm birth. Regardless of pregnancy outcome, TSH concentrations did not differ between women with high and low concentrations of PBDE-47. CONCLUSIONS: These results suggest that high plasma concentrations of PBDE-47 in the first trimester, increases the risk of indicated and spontaneous preterm birth.

Luteolin and abyssinone II as potential inhibitors of SARS-CoV-2: an in silico molecular modeling approach in battling the COVID-19 outbreak.

BACKGROUND: At present, the entire world is in a war against COVID-19 pandemic which has gradually led us toward a more compromised "new normal" life. SARS-CoV-2, the pathogenic microorganism liable for the recent COVID-19 outbreak, is extremely contagious in nature resulting in an unusual number of infections and death globally. The lack of clinically proven therapeutic intervention for COVID-19 has dragged the world's healthcare system into the biggest challenge. Therefore, development of an efficient treatment scheme is now in great demand. Screening of different biologically active plant-based natural compounds could be a useful strategy for combating this pandemic. In the present research, a collection of 43 flavonoids of 7 different classes with previously recorded antiviral activity was evaluated via computational and bioinformatics tools for their impeding capacity against SARS-CoV-2. In silico drug likeness, pharmacophore and Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) profile analysis of the finest ligands were carried out using DataWarrior, DruLiTo and admetSAR programs, respectively. Molecular docking was executed by AutoDock Vina, while molecular dynamics simulation of the target protein-ligand bound complexes was done using nanoscalable molecular dynamics and visual molecular dynamics software package. Finally, the molecular target analysis of the selected ligands within Homo sapiens was conducted with SwissTargetPredcition web server. RESULTS: Out of the forty-three flavonoids, luteolin and abyssinone II were found to develop successful docked complex within the binding sites of target proteins in terms of lowest binding free energy and inhibition constant. The root mean square deviation and root mean square fluctuation values of the docked complex displayed stable interaction and efficient binding between the ligands and target proteins. Both of the flavonoids were found to be safe for human use and possessed good drug likeness properties and target accuracy. CONCLUSIONS: Conclusively, the current study proposes that luteolin and abyssinone II might act as potential therapeutic candidates for SARS-CoV-2 infection. In vivo and in vitro experiments, however, should be taken under consideration to determine the efficiency and to demonstrate the mechanism of action.

Current Therapeutic Strategies of Xeroderma Pigmentosum.

Xeroderma pigmentosum (XP) is an autosomal recessive genetic disease caused by a defect in the DNA repair system, exhibiting skin cancer on sun exposure. As it is an incurable disease, therapeutic strategies of this disease are critical. This review article takes an attempt to explore the current therapeutic advancements in XP. Different approaches including sun avoidance; surgical removal of cancerous lesions; laser and photodynamic therapy; use of retinoid, 5-fluorouracil, imiquimod, photolyase, and antioxidant; interferon therapy and gene therapy are chosen by doctors and patients to lessen the adverse effects of this disease. Among these options, sun avoidance, use of 5-fluorouracil and imiquimod, and interferon therapy are effective. However, some approaches including laser and photodynamic therapy, and the use of retinoids are effective against skin cancer having severe side effects. Furthermore, surgical removal of cancerous lesions and use of antioxidants are considered to be effective against this disease; however, efficacies of these are not experimentally determined. In addition, some approaches including oral vismodegib, immunotherapy, nicotinamide, acetohexamide, glimepiride-restricted diet are found to be effective to minimize the complications secondary to defects in the nucleotide excision repair (NER) system and also enhance the NER, which are under experimental level yet. Besides these, gene therapy, including the introduction of missing genes and genome edition, may be a promising approach to combat this disease, which is also not well established now. In the near future, these approaches may be effective tools to manage XP.

Synthesis of Biogenic Silver Nanoparticles Using Caesalpinia digyna and Investigation of Their Antimicrobial Activity and In Vivo Biocompatibility.

Among metallic nanoparticles, silver nanoparticles (AgNPs) have a wide spectrum of medical applications. Herein, biogenic silver nanoparticles (bAgNPs) were prepared from extracts of Caesalpinia digyna leaf as a reducing agent at different pH values (i.e., 5, 7, 8, and 10). The as-synthesized bAgNPs were characterized using UV-vis and Fourier transform infrared (FTIR) spectroscopies, scanning transmission electron microscopy, powder X-ray diffraction analysis, dynamic light scattering, and ζ-potential analysis. The sizes of bAgNPs prepared at pH 5, 7, 8, and 10 were 45.4, 11.3, 11.4, and 40.8 nm, respectively, and all of the nanoparticles were negatively charged. The antimicrobial activity of the as-prepared bAgNPs was investigated against Bacillus subtilis, Escherichia coli DH5α, E. coli K12, enteropathogenic E. coli (EPEC), and Salmonella typhi. The bAgNPs prepared at pH 8 showed the highest antibacterial propensity against all of the bacterial strains as exhibited in the zone of inhibition (ZOI) as well as the CellTox green assay, which can be due to their relatively small size, stability, and higher surface area-to-volume ratio. The bAgNPs synthesized at pH 8 showed the highest ZOI against B. subtilis, which was ∼25 mm in diameter. The lipid peroxidation assay demonstrated the formation of the malondialdehyde-thiobarbituric acid (MDA-TBA) adduct while treating the bacteria with bAgNPs due to the oxidation of fatty acids present in the membrane. The highest amount of MDA-TBA adduct was observed when Gram-positive B. subtilis was exposed to bAgNPs. On the contrary, rats treated with bAgNPs demonstrated no significant toxicity in terms of hematological and biochemical parameters. The bAgNPs also showed excellent compatibility with human red blood cells. Overall, bAgNPs synthesized at pH 8 have superior antimicrobial activity and excellent biocompatibility and, therefore, can be used as potential antibacterial agents.

Structure to function analysis with antigenic characterization of a hypothetical protein,HPAG1_0576 from Helicobacter pylori HPAG1.

Helicobacter pylori, a unique gastric pathogen causing chronic inflammation in the gastric mucosa with a possibility to develop gastric cancer has one-third of its proteins still uncharacterized. In this study, a hypothetical protein (HP) namely HPAG1_0576 from H. pylori HPAG1 was chosen for detailed computational analysis of its structural, functional and epitopic properties. The primary, secondary and 3D structure/model of the selected HP was constructed. Then refinement and structure validation were done, which indicated a good quality of the newly constructed model. ProFunc and STRING suggested that HPAG1_0576 shares 98% identity with a carcinogenic factor, TNF-α inducing protein (Tip-α ) of H. pylori. IEDB immunoinformatics tool predicted VLMLQACTCPNTSQRNS from position 19-35 as most potential B-cell linear epitope and SFLKSKQL from position 5-12 as most potent conformational epitope. Alternatively, FALVRARGF and FLCGLGVLM were predicted as most immunogenic CD8+ and CD4+ T-cell epitopes respectively. At the same time findings of IFN epitope tool suggests that, HPAG1_0576 had a great potential to evoke interferon-gamma (IFN-γ) mediated immune response. However, this experiment is a primary approach for in silico vaccine designing from a HP, findings of this study will provide significant insights in further investigations and will assist in identifying new drug targets/vaccine candidates.

tRNA diversification among uncultured archeon clones.

Whole genome sequences (DNA sequences) of four uncultured archeon clones (1B6:CR626858.1, 4B7:CR626856.1, 22i07:JQ768096.1 and 19c08:JQ768095.1) were collected from NCBI BioSample database for the construction of digital data on tRNA. tRNAscan-SE 2.0 and ENDMEMO tools were used to identify and sketch tRNA structure as well as calculate Guanine-Cytosine (GC) percentage respectively. Eight true/functional tRNAs were identified from above 4 sequences which showed cove score greater than 20% with no variable loop. The tRNAs from the uncultured archeon clones were classified as Ala, Arg, Ile, Thr, Pro and Val type tRNA with cove score ranging from 34.22%-79.03%. The range of GC content was found 42.89%-56.91%; while tRNA contributed GC content ranging from 52%-64.86% to the total GC content in these sequences. The data fabricated in this study could be very useful for studying the diversity of tRNA among prokaryotes.

Genomics dataset on unclassified published organism (patent US 7547531).

Nucleotide (DNA) sequence analysis provides important clues regarding the characteristics and taxonomic position of an organism. With the intention that, DNA sequence analysis is very crucial to learn about hierarchical classification of that particular organism. This dataset (patent US 7547531) is chosen to simplify all the complex raw data buried in undisclosed DNA sequences which help to open doors for new collaborations. In this data, a total of 48 unidentified DNA sequences from patent US 7547531 were selected and their complete sequences were retrieved from NCBI BioSample database. Quick response (QR) code of those DNA sequences was constructed by DNA BarID tool. QR code is useful for the identification and comparison of isolates with other organisms. AT/GC content of the DNA sequences was determined using ENDMEMO GC Content Calculator, which indicates their stability at different temperature. The highest GC content was observed in GP445188 (62.5%) which was followed by GP445198 (61.8%) and GP445189 (59.44%), while lowest was in GP445178 (24.39%). In addition, New England BioLabs (NEB) database was used to identify cleavage code indicating the 5, 3 and blunt end and enzyme code indicating the methylation site of the DNA sequences was also shown. These data will be helpful for the construction of the organisms' hierarchical classification, determination of their phylogenetic and taxonomic position and revelation of their molecular characteristics.

Halogen-directed drug design for Alzheimer's disease: a combined density functional and molecular docking study.

A series of halogen-directed donepezil drugs has been designed to inhibit acetyl cholinesterase (AChE). Density Functional theory (DFT) has been employed to optimize the chair as well as boat conformers of the parent drug and modified ligands at B3LYP/MidiX and B3LYP/6-311G + (d,p) level of theories. Charge distribution, dipole moment, enthalpy, free energy and molecular orbitals of these ligands are also investigated to understand how the halogen-directed modifications impact the ligand structure and govern the non-bonding interactions with the receptors. Molecular docking calculation has been performed to understand the similarities and differences between the binding modes of unmodified and halogenated chair-formed ligands. Molecular docking indicated donepezil and modified ligands had non-covalent interactions with hydrophobic gorges and anionic subsites of AChE. The -CF3-directed ligand possessed the most negative binding affinity. Non-covalent interactions within the ligand-receptor systems were found to be mostly hydrophobic and π- stacking type. F, Cl and -CF3 containing ligands emerge as effective and selective AChE inhibitors, which can strongly interact with the two active sites of AChE. In addition, we have also investigated selected pharmacokinetic parameters of the parent and modified ligands.