Evaluation of vincamine against Acetylcholinesterase enzyme.

The current article deals with the in-silico along with enzyme kinetics approach to search for a prominent AChE enzyme inhibitor among the known natural compounds. The computational tools were involved for this purpose and eventual vincamine, a monoterpenoid indole alkaloid, was selected based on several parameters, including free energy of binding (-10.77 kcal/mol) and ADME parameter. Computationally, it confirmed the interaction between vincamine and AChE at an indistinguishable locus from that of substrate AChI (-3.94 kcal/mol) but with much higher binding energy. Interestingly, amino acid residues Gly120, Gly121, Gly122, Glu202, Trp86, Tyr133, Ser203, Phe297, and His447 of AChE were found to be common in these interactions. Further, these findings were approved with wet lab tests where detailed kinetics was studied. It was found that vincamine inhibited AChE with the inhibition constant Ki (239 µM). The value of  IC50 (239 µM) and KM (0.598 mM) was determined and further confirmed by Dixon, Lineweaver- Burk reciprocal, Hanes, and Eadie- Hofstee plots, respectively. The mode of interaction of the compound was found to be competitive for AChE. Thus, the present computational and enzyme kinetics studies conclude that vincamine can be a promising inhibitor of AChE for the effective management of AD.

Identification of compelling inhibitors of human norovirus 3CL protease to combat gastroenteritis: A structure-based virtual screening and molecular dynamics study.

Human noroviruses (NV) are the most prevalent cause of sporadic and pandemic acute gastroenteritis. NV infections cause substantial morbidity and death globally, especially amongst the aged, immunocompromised individuals, and children. There are presently no authorized NV vaccines, small-molecule therapies, or prophylactics for humans. NV 3 C L protease (3CLP) has been identified as a promising therapeutic target for anti-NV drug development. Herein, we employed a structure-based virtual screening method to screen a library of 700 antiviral compounds against the active site residues of 3CLP. We report three compounds, Sorafenib, YM201636, and LDC4297, that were revealed to have a higher binding energy (BE) value with 3CLP than the control (Dipeptidyl inhibitor 7) following a sequential screening, in-depth molecular docking and visualization, physicochemical and pharmacological property analysis, and molecular dynamics (MD) study. Sorafenib, YM201636, and LDC4297 had BEs of -11.67, -10.34, and -9.78 kcal/mol with 3CLP, respectively, while control had a BE of -6.38 kcal/mol. Furthermore, MD simulations of the two best compounds and control were used to further optimize the interactions, and a 100 ns MD simulation revealed that they form stable complexes with 3CLP. The estimated physicochemical, drug-like, and ADMET properties of these hits suggest that they might be employed as 3CLP inhibitors in the management of gastroenteritis. However, wet lab tests are a prerequisite to optimize them as NV 3CLP inhibitors.

Codon Usage Bias Correlates With Gene Length in Neurodegeneration Associated Genes.

Codon usage analysis is a crucial part of molecular characterization and is used to determine the factors affecting the evolution of a gene. The length of a gene is an important parameter that affects the characteristics of the gene, such as codon usage, compositional parameters, and sometimes, its functions. In the present study, we investigated the association of various parameters related to codon usage with the length of genes. Gene expression is affected by nucleotide disproportion. In sixty genes related to neurodegenerative disorders, the G nucleotide was the most abundant and the T nucleotide was the least. The nucleotide T exhibited a significant association with the length of the gene at both the overall compositional level and the first and second codon positions. Codon usage bias (CUB) of these genes was affected by pyrimidine and keto skews. Gene length was found to be significantly correlated with codon bias in neurodegeneration associated genes. In gene segments with lengths below 1,200 bp and above 2,400 bp, CUB was positively associated with length. Relative synonymous CUB, which is another measure of CUB, showed that codons TTA, GTT, GTC, TCA, GGT, and GGA exhibited a positive association with length, whereas codons GTA, AGC, CGT, CGA, and GGG showed a negative association. GC-ending codons were preferred over AT-ending codons. Overall analysis indicated that the association between CUB and length varies depending on the segment size; however, CUB of 1,200-2,000 bp gene segments appeared not affected by gene length. In synopsis, analysis suggests that length of the genes correlates with various imperative molecular signatures including A/T nucleotide disproportion and codon choices. In the present study we additionally evaluated various molecular features and their correlation with different indices of codon usage, like the Codon Adaptation Index (CAI) and Relative Dynonymous Codon Usage (RSCU) of codons. We also considered the impact of gene fragment size on different molecular features in genes related to neurodegeneration. This analysis will aid our understanding of and in potentially modulating gene expression in cases of defective gene functioning in clinical settings.

Strong Selectional Forces Fine-Tune CpG Content in Genes Involved in Neurological Disorders as Revealed by Codon Usage Patterns.

Neurodegenerative disorders cause irreversible damage to the neurons and adversely affect the quality of life. Protein misfolding and their aggregation in specific parts of the brain, mitochondrial dysfunction, calcium load, proteolytic stress, and oxidative stress are among the causes of neurodegenerative disorders. In addition, altered metabolism has been associated with neurodegeneration as evidenced by reductions in glutamine and alanine in transient global amnesia patients, higher homocysteine-cysteine disulfide, and lower methionine decline in serum urea have been observed in Alzheimer's disease patients. Neurodegeneration thus appears to be a culmination of altered metabolism. The study's objective is to analyze various attributes like composition, physical properties of the protein, and factors like selectional and mutational forces, influencing codon usage preferences in a panel of genes involved directly or indirectly in metabolism and contributing to neurodegeneration. Various parameters, including gene composition, dinucleotide analysis, Relative synonymous codon usage (RSCU), Codon adaptation index (CAI), neutrality and parity plots, and different protein indices, were computed and analyzed to determine the codon usage pattern and factors affecting it. The correlation of intrinsic protein properties such as the grand average of hydropathicity index (GRAVY), isoelectric point, hydrophobicity, and acidic, basic, and neutral amino acid content has been found to influence codon usage. In genes up to 800 amino acids long, the GC3 content was highly variable, while GC12 content was relatively constant. An optimum CpG content is present in genes to maintain a high expression level as required for genes involved in metabolism. Also observed was a low codon usage bias with a higher protein expression level. Compositional parameters and nucleotides at the second position of codons played essential roles in explaining the extent of bias. Overall analysis indicated that the dominance of selection pressure and compositional constraints and mutational forces shape codon usage.

Parents' awareness and knowledge of testicular torsion: A cross-sectional study.

BACKGROUND: Testicular torsion (TT) is one of the most common emergencies in pediatric urology. Family awareness of this condition could lead to early diagnosis and intervention and salvage of the effected testicle. The purpose of this study is to assess parental awareness about TT and their source of knowledge. We also evaluated the response of the parents to their children's scrotal pain. METHODS: A quantitative, observational, cross-sectional study was conducted from March 2017 to September 2017 at our institution. The study target were parents attending the pediatric urology clinic and the comparison group included parents attending the general pediatric clinic in the same period. We distributed a questionnaire and then compared the results in both groups. RESULTS: A total of 200 parents participated in this study (100 parents from each clinic). Nineteen percent of pediatric urology clinic parents were aware and 14% of general pediatric clinic parents were aware about TT with no statistically significant difference observed (P = 0.341). The parents in urology clinic choose doctor as their main source of knowledge (42.1%), while in general pediatric clinic, doctor and through a friend as the main source of knowledge had the same percentage (28.6%). Response of the parents to their children's scrotal pain during working hours in urology and general pediatric clinics was to drive their children to the emergency room immediately with 85% and 82%, respectively. The response of the parents after working hours in both clinics did not show difference, with 83% of parents in pediatric urology clinic and 85% in general pediatric clinic driving their children immediately to the emergency room. CONCLUSION: TT in boys is a common problem we face as pediatric urologists and it may lead to testicular loss if not diagnosed and treated early. We found that the awareness of TT in children is low in our community and it is our responsibility to raise it to improve our children's well-being.

Peptide based therapeutics and their use for the treatment of neurodegenerative and other diseases.

Bioactive peptides are actively involved in different biological functions and importantly contribute to human health, and the use of peptides as therapeutics has a long successful history in disease management. A number of peptides have wide-ranging therapeutic effects, such as antioxidant, antimicrobial, and antithrombotic effects. Neurodegenerative diseases are typically caused by abnormal aggregations of proteins or peptides, and the depositions of these aggregates in or on neurons, disrupt signaling and eventually kill neurons. During recent years, research on short peptides has advanced tremendously. This review offers a brief introduction to peptide based therapeutics and their application in disease management and provides an overview of peptide vaccines, and toxicity related issues. In addition, the importance of peptides in the management of different neurodegenerative diseases and their therapeutic applications is discussed. The present review provides an understanding of peptides and their applications for the management of different diseases, but with focus on neurodegenerative diseases. The role of peptides as anti-cancer, antimicrobial and antidiabetic agents has also been discussed.

The attitude and perception of breast reconstruction by general surgeons in Saudi Arabia.

BACKGROUND AND OBJECTIVES: Post-mastectomy breast reconstruction surgery had always been integral part in the approach to a patient with breast cancer. It is our aim of this study to report in a simplistic manner the variability in the perception and practice by surgeons surrounding breast reconstruction. DESIGN AND SETTINGS: This is a descriptive cross-sectional survey targeting a sample of general surgeons in 6 tertiary hospitals in Saudi Arabia from April 2012 to October 2012. METHODS: A questionnaire adopted from the one designed by Spyrou et al was distributed to our sample of surgeons. It primarily focused on the surgeon's attitude and perception of breast reconstruction surgery after mastectomy. RESULTS: A total of 51 general surgeons were included in the study. Most of them, 24 (47.1%), worked in teaching hospitals. Thirty-six (70.6%) surgeons had a special interest in breast cancer management. Eighteen of them (35.5%) referred their patients for breast reconstruction. We observed that the surgeons of high-referral tendency were generally females (P=.016). More than half (33 [64.7%]), thought that a general surgeon is the one responsible for counseling patients. The majority (47%), disagreed with the notion that breast reconstruction can interfere with host defenses. Yet, (76.5 %) were concerned about masking local recurrence of the cancer, and 21 (41.2%) reported that patients refused such type of surgery. Forty-eight (94.1%) agreed that breast reconstruction has psychological benefits. CONCLUSION: In Saudi Arabia, general surgeons have a high concern about masking local recurrence of the cancer despite the lack of evidence in the published reports. Nevertheless, less than half of the surgeons referred their cases for breast reconstruction. We recommend establishing national efforts to educate on the benefits of breast reconstruction and establish a tumor conference protocol on breast reconstruction including all involved specialties (oncologists and general and plastic surgeons).