Dearomative Indole Cycloaddition Reactions of Aza-Oxyallyl Cationic Intermediates: Modular Access to Pyrroloindolines.

A regioselective dearomative aza-(3 + 2) cycloaddition reaction of substituted indoles with α-halohydroxamates has been developed. This transformation provides rapid access to highly functionalized pyrroloindolines that are represented in large number of bioactive compounds. The natural product, physostigmine, has been concisely synthesized utilizing this method.

Effect of different synbiotic administration methods on growth, carcass characteristics, ileum histomorphometry, and blood biochemistry of Cobb-500 broilers.

Background and Aim: To combat enteric infections and antibiotic resistance in the poultry industry, researchers seek alternatives such as probiotics, prebiotics, and synbiotics as growth promoters. Synbiotics support probiotic growth through the supply of essential nutrients. The study's objectives were to assess the most effective delivery methods for synbiotics and evaluate their growth, histomorphometric, and hematological impacts on Cobb-500 broilers. Materials and Methods: Two studies, independently conducted, employed a completely randomized design. One hundred and eighty viable eggs in the first trial were assigned to three groups: Control (T1), sterile water (T2), and synbiotic in sterile water (T3). On the 21st day of hatching, hatchability, day-old body weights, and ileum samples for histomorphometric analysis were recorded. In the second trial, out of 500 viable eggs, 200 eggs were fed in ovo with synbiotics (PoultryStar® sol, Biomin Singapore Pte Ltd, Singapore) on 17.5 days and 300 were set aside without in ovo injection. The treatments were control (T1), in water synbiotic (T2), in ovo synbiotic (T3), combination of in ovo synbiotic and synbiotic in feed (T4), and synbiotic in feed only (T5). On 21 and 42 days, blood, ileum, and visceral organ samples were collected for laboratory analysis. Data on weight gain, daily feed intake, and water consumption were recorded for 42 days. Results: The initial experiment's results revealed a decrease in hatchability, slight weight increase, and significant intestinal morphological changes with the use of an in ovo synbiotic. Applying synbiotic through various methods in the second trial yielded better growth results, lower blood cholesterol, and significantly longer (p < 0.05) villi on 21 days. Conclusion: Using the in ovo method to administer synbiotics lowered hatchability. Use of synbiotics with any method or in combination enhances growth, ileum structure, dressing yield, feed efficiency, and cholesterol levels in blood. Synbiotics enhance gut health and overall performance in broilers when used through diverse approaches.

Identification of catechin as main protease inhibitor of SARS-CoV-2 Omicron variant using molecular docking, molecular dynamics, PCA, DCCM, MM/GBSA and ADMET profiling.

The Omicron variant of SARS-CoV-2 spreads more rapidly than other variants and can affect even vaccinated individuals. The Omicron variant main protease (Mpro), crucial for viral replication and transcription, is an attractive target for antiviral drug discovery. This research aims to investigate non-toxic flavonoids that follow Lipinski's rule of five (RO5) and inhibit the Omicron variant Mpro. Molecular docking was performed on 35 flavonoids screened by analysing their medicinal values and adherence to RO5. Catechin (2-(3,4-dihydroxyphenol) chroman-3,5,7-triol), a non-toxic natural compound having predicted toxicity class 6 and LD50 value 10,000 mg/kg, exhibited a docking score of -7.1 kcal/mol with Mpro. The Mpro-catechin complex remained stable during 250 ns MD simulations. The post-MD free energy (MM/GBSA) calculations showed a binding energy of -20.5 kcal/mol, indicating strong interactions with the active amino acid residues. These findings suggest that catechin is a promising drug candidate against the Omicron variant.

Identification of potent inhibitors of HDAC2 from herbal products for the treatment of colon cancer: Molecular docking, molecular dynamics simulation, MM/GBSA calculations, DFT studies, and pharmacokinetic analysis.

The histone deacetylase 2 (HDAC2), an enzyme involved in gene regulation, is a potent drug target for the treatment of colon cancer. Phytocompounds having anticancer properties show the ability to interact with HDAC2 enzyme. Among the compounds, docking scores of caffeic acid (CA) and p-coumaric acid (pCA) with HDAC2 showed good binding efficacy of -5.46 kcal/mol and -5.16 kcal/mol, respectively, with small inhibition constants. The higher binding efficacy of CA compared to pCA can be credited to the presence of an extra oxygen atom in the CA molecule, which forms an additional hydrogen bond with Tyr297. The HDAC2 in complex with these molecules was found to be stable by analyzing RMSD, RMSF, Rg, and SASA values obtained through MD simulations. Furthermore, CA and pCA exhibited low MM/GBSA free energies of -16.32 ± 2.62 kcal/mol and -17.01 ± 2.87 kcal/mol, respectively. The HOMO and LUMO energy gaps, dipole moments, global reactivity descriptor values, and MEP surfaces showed the reactivity of the molecules. The favourable physicochemical and pharmacokinetic properties, along with absence of toxicity of the molecules determined using ADMET analysis, suggested both the acids to be regarded as effective drugs in the treatment of colon cancer.

Control of paretic and non-paretic upper extremity during bimanual reaching after stroke.

Most actions of daily life engage the two upper extremities (UEs) in a highly coordinated manner. While it is recognized that bimanual movements are impaired post-stroke, understanding how the paretic and non-paretic UE contributes to this impairment is important for future interventions. We investigated kinetic and kinematics at the shoulder, elbow, and wrist joints in the paretic and non-paretic UE in 8 individuals with chronic stroke and non-dominant UE in 8 healthy controls during unimanual and bimanual tasks. Kinematic analysis revealed little effect of stroke. However, kinetic analysis revealed that during unimanual movements, joint control was impaired during unimanual and bimanual movements in both UEs, although to a lesser extent in the non-paretic than paretic UE. During bimanual movements, joint control did not change in the paretic UE, and it further deteriorated in the non-paretic UE compared with the unimanual movements. Our findings suggest that a single session of bimanual task performance does not improve joint control of the paretic UE and it impairs control of the non-paretic UE, making it more like that of the paretic UE.

Optimization of TAM16, a Benzofuran That Inhibits the Thioesterase Activity of Pks13; Evaluation toward a Preclinical Candidate for a Novel Antituberculosis Clinical Target.

With increasing drug resistance in tuberculosis (TB) patient populations, there is an urgent need for new drugs. Ideally, new agents should work through novel targets so that they are unencumbered by preexisting clinical resistance to current treatments. Benzofuran 1 was identified as a potential lead for TB inhibiting a novel target, the thioesterase domain of Pks13. Although, having promising activity against Mycobacterium tuberculosis, its main liability was inhibition of the hERG cardiac ion channel. This article describes the optimization of the series toward a preclinical candidate. Despite improvements in the hERG liability in vitro, when new compounds were assessed in ex vivo cardiotoxicity models, they still induced cardiac irregularities. Further series development was stopped because of concerns around an insufficient safety window. However, the demonstration of in vivo activity for multiple series members further validates Pks13 as an attractive novel target for antitubercular drugs and supports development of alternative chemotypes.

[Social Determinants of Anemia and Overweight/Obesity among Pregnant Women in Nepal].

OBJECTIVES: To identify the complex factors associated with anemia and overweight/obesity in pregnant Nepali women. METHODS: This study was conducted with 609 pregnant women who visited the Western Regional Hospital in Pokhara, Nepal, for maternal health checkups. We assessed their nutritional status on the basis of their responses to a questionnaire (socio-economic, demographic and health information using the Nepali version of the 14-item Health Literacy Scale), hemoglobin levels and body mass index (BMI). Data were analyzed and adjusted for confounding factors by binomial logistic regression analysis; this aided in identifying factors associated with anemia and overweight/obesity. RESULTS: The significant factor contributing to anemia is a low BMI (p=0.005, aOR=7.930, 95% CI=1.857, 33.870), followed by maternal age in the teens (p=0.000, aOR=3.018, 95% CI=1.852, 4.919). The significant factors contributing to overweight/obesity are household income, excluding the poorest (p=0.004, aOR=2.975, 95% CI=1.404, 6.303), followed by the presence of a nuclear family (p=0.000, aOR =2.156, 95% CI=1.493, 3.112). Functional literacy (p=0.005, aOR=1.045, 95% CI=1.013, 1.077) increases the risk of overweight/obesity, but critical literacy (p=0.009, aOR=0.819, 95% CI=0.705, 0.951) is a factor that buffers its onset. CONCLUSIONS: The association of malnutrition with anemia and overweight/obesity has been confirmed in pregnant Nepali women, indicating the urgent need for new supports and improvements to nutrition. Nutrition education should be designed to take into consideration reproductive generation, as well as families with low health literacy.

Elesclomol alleviates Menkes pathology and mortality by escorting Cu to cuproenzymes in mice.

Loss-of-function mutations in the copper (Cu) transporter ATP7A cause Menkes disease. Menkes is an infantile, fatal, hereditary copper-deficiency disorder that is characterized by progressive neurological injury culminating in death, typically by 3 years of age. Severe copper deficiency leads to multiple pathologies, including impaired energy generation caused by cytochrome c oxidase dysfunction in the mitochondria. Here we report that the small molecule elesclomol escorted copper to the mitochondria and increased cytochrome c oxidase levels in the brain. Through this mechanism, elesclomol prevented detrimental neurodegenerative changes and improved the survival of the mottled-brindled mouse-a murine model of severe Menkes disease. Thus, elesclomol holds promise for the treatment of Menkes and associated disorders of hereditary copper deficiency.

Evaluation of an Antimicrobial Stewardship Program for Wound and Burn Care in Three Hospitals in Nepal.

Antimicrobial stewardship (AMS) programs can decrease non-optimal use of antibiotics in hospital settings. There are limited data on AMS programs in burn and chronic wound centers in low- and middle-income countries (LMIC). A post-prescription review and feedback (PPRF) program was implemented in three hospitals in Nepal with a focus on wound and burn care. A total of 241 baseline and 236 post-intervention patient chart data were collected from three hospitals. There was a significant decrease in utilizing days of therapy per 1000 patient days (DOT/1000 PD) of penicillin (p = 0.02), aminoglycoside (p < 0.001), and cephalosporin (p = 0.04). Increases in DOT/1000 PD at post-intervention were significant for metronidazole (p < 0.001), quinolone (p = 0.01), and other antibiotics (p < 0.001). Changes in use of antibiotics varied across hospitals, e.g., cephalosporin use decreased significantly at Kirtipur Hospital (p < 0.001) and Pokhara Academy of Health Sciences (p = 0.02), but not at Kathmandu Model Hospital (p = 0.59). An independent review conducted by infectious disease specialists at the Henry Ford Health System revealed significant changes in antibiotic prescribing practices both overall and by hospital. There was a decrease in mean number of intravenous antibiotic days between baseline (10.1 (SD 8.8)) and post-intervention (8.8 (SD 6.5)) (t = 3.56; p < 0.001), but no difference for oral antibiotics. Compared to baseline, over the 6-month post-intervention period, we found an increase in justified use of antibiotics (p < 0.001), de-escalation (p < 0.001), accurate documentation (p < 0.001), and adherence to the study antibiotic prescribing guidelines at 72 h (p < 0.001) and after diagnoses (p < 0.001). The evaluation data presented provide evidence that PPRF training and program implementation can contribute to hospital-based antibiotic stewardship for wound and burn care in Nepal.

Predictive multiscale computational model of shoe-floor coefficient of friction.

Understanding the frictional interactions between the shoe and floor during walking is critical to prevention of slips and falls, particularly when contaminants are present. A multiscale finite element model of shoe-floor-contaminant friction was developed that takes into account the surface and material characteristics of the shoe and flooring in microscopic and macroscopic scales. The model calculates shoe-floor coefficient of friction (COF) in boundary lubrication regime where effects of adhesion friction and hydrodynamic pressures are negligible. The validity of model outputs was assessed by comparing model predictions to the experimental results from mechanical COF testing. The multiscale model estimates were linearly related to the experimental results (p < 0.0001). The model predicted 73% of variability in experimentally-measured shoe-floor-contaminant COF. The results demonstrate the potential of multiscale finite element modeling in aiding slip-resistant shoe and flooring design and reducing slip and fall injuries.

Oxidative (3 + 2) Cycloaddition Reactions of Diaza-Oxyallyl Cationic Intermediates and Indoles for the Synthesis of Imidazoloindolines.

An oxidative diaza-(3 + 2) cycloaddition reaction of simple urea derivatives with substituted indoles has been developed. This transformation provides rapid access to highly functionalized imidazoloindolines that are represented in bioactive compounds. The reported method is compatible with a wide variety of functional groups and directly provides unique heterocyclic scaffolds from indoles and a simple urea derivative.

Access to 4-Oxazolidinones: A (3 + 2) Cycloaddition Approach.

The novel reactivity of in situ generated aza-oxyallyl cation intermediates with a variety of carbonyl compounds is reported to construct 4-oxazolidinones motifs with good yields and diastereoselectivities. This simple and efficient (3 + 2) cycloaddition method provides direct access to potential bioactive compounds.