In Silico Screening of Some Active Phytochemicals to Identify Promising Inhibitors Against SARS-CoV-2 Targets.

BACKGROUND: There are very few small-molecule drug candidates developed against SARS-CoV-2 that have been revealed since the epidemic began in November 2019. The typical medicinal chemistry discovery approach requires more than a decade of the year of painstaking research and development and a significant financial guarantee, which is not feasible in the challenge of the current epidemic. OBJECTIVE: This current study proposes to find and identify the most effective and promising phytomolecules against SARS-CoV-2 in six essential proteins (3CL protease, Main protease, Papain- Like protease, N-protein RNA binding domain, RNA-dependent RNA polymerase, and Spike receptor binding domain target through in silico screening of 63 phytomolecules from six different Ayurveda medicinal plants. METHODS: The phytomolecules and SARS-CoV-2 proteins were taken from public domain databases such as PubChem and RCSB Protein Data Bank. For in silico screening, the molecular interactions, binding energy, and ADMET properties were investigated. RESULTS: The structure-based molecular docking reveals some molecules' greater affinity towards the target than the co-crystal ligand. Our results show that tannic acid, cyanidin-3-rutinoside, zeaxanthin, and carbolactone are phytomolecules capable of inhibiting SARS-CoV-2 target proteins in the least energy conformations. Tannic acid had the least binding energy of -8.8 kcal/mol, which is better than the binding energy of its corresponding co-crystal ligand (-7.5 kcal/mol) against 3 CL protease. Also, it has shown the least binding energy of -9.9 kcal/mol with a more significant number of conventional hydrogen bond interactions against the RdRp target. Cyanidin-3-rutinoside showed binding energy values of -8.8 and -7.6 kcal/mol against Main protease and Papain-like protease, respectively. Zeaxanthin was the top candidate in the N protein RBD with a binding score of - 8.4 kcal/mol, which is slightly better when compared to a co-crystal ligand (-8.2 kcal/mol). In the spike, carbolactone was the suitable candidate with the binding energy of -7.2 kcal/mol and formed a conventional hydrogen bond and two hydrophobic interactions. The best binding affinity-scored phytomolecules were selected for the MD simulations studies. CONCLUSION: The present in silico screening study suggested that active phytomolecules from medicinal plants could inhibit SARS-CoV-2 targets. The elite docked compounds with drug-like properties have a harmless ADMET profile, which may help to develop promising COVID-19 inhibitors.

Super-resolution laser probing of integrated circuits using algorithmic methods.

Laser probing remains invaluable to the semiconductor industry for isolating and diagnosing defects in silicon transistors in integrated circuits during electrical stress tests. However, continuous device miniaturization below the 20 nm technology node has crammed multiple transistors within the focal spot of the laser beam, resulting in signal crosstalk, poor beam positioning accuracy and degraded fault isolation capabilities. The challenge is analogous to focusing attention to a single speaker in a crowd despite the multiple simultaneous conversations in the background. Through algorithms introduced in this patented work, consisting of cross-correlations, clustering, and our previously developed combinational logic analysis, we achieved beam positioning accuracy to better than 10 nm, extracted electrooptic waveforms from a node of a group of transistors (~18 times beyond the optical resolution limit), and applied this to isolate and identify an actual fault on a defective device. While problems associated with probing with shorter wavelength lasers continue to be addressed, our approach enhances and enables the continued probing of ICs using sub-bandgap photon energies without hardware modification to existing technology at semiconductor technology nodes below 10 nm.

Quantifying T2-FLAIR Mismatch Using Geographically Weighted Regression and Predicting Molecular Status in Lower-Grade Gliomas.

BACKGROUND AND PURPOSE: The T2-FLAIR mismatch sign is a validated imaging sign of isocitrate dehydrogenase-mutant 1p/19q noncodeleted gliomas. It is identified by radiologists through visual inspection of preoperative MR imaging scans and has been shown to identify isocitrate dehydrogenase-mutant 1p/19q noncodeleted gliomas with a high positive predictive value. We have developed an approach to quantify the T2-FLAIR mismatch signature and use it to predict the molecular status of lower-grade gliomas. MATERIALS AND METHODS: We used multiparametric MR imaging scans and segmentation labels of 108 preoperative lower-grade glioma tumors from The Cancer Imaging Archive. Clinical information and T2-FLAIR mismatch sign labels were obtained from supplementary material of relevant publications. We adopted an objective analytic approach to estimate this sign through a geographically weighted regression and used the residuals for each case to construct a probability density function (serving as a residual signature). These functions were then analyzed using an appropriate statistical framework. RESULTS: We observed statistically significant (P value = .05) differences between the averages of residual signatures for an isocitrate dehydrogenase-mutant 1p/19q noncodeleted class of tumors versus other categories. Our classifier predicts these cases with area under the curve of 0.98 and high specificity and sensitivity. It also predicts the T2-FLAIR mismatch sign within these cases with an under the curve of 0.93. CONCLUSIONS: On the basis of this retrospective study, we show that geographically weighted regression-based residual signatures are highly informative of the T2-FLAIR mismatch sign and can identify isocitrate dehydrogenase-mutation and 1p/19q codeletion status with high predictive power. The utility of the proposed quantification of the T2-FLAIR mismatch sign can be potentially validated through a prospective multi-institutional study.

Syndrome Evaluation System for Simultaneous Detection Pathogens Causing Acute Encephalitic Syndrome in India, Part-1: Development and Standardization of the Assay.

A large number of organisms are known to cause acute encephalitic syndrome (AES). A number of diagnostic tests have to be performed in order to arrive at a probable pathogen causing AES thus making it a very time consuming, laborious and expensive. The problem is further compounded by the lack of availability of sufficient volume of Cerebrospinal fluid (CSF). Thus, there is an urgent need of a diagnostic tool for the simultaneous detection of all probable pathogens responsible for causing AES. Here we report the development of a novel diagnostic method, Syndrome Evaluation System (SES) for the simultaneous detection of 22 pathogens including RNA and DNA Viruses, bacteria, fungi, and parasite all endemic to India and Southeast Asia in a single sample using a novel multiplexing strategy. Syndrome Evaluation System (SES) involves isolation of nucleic acid, multiplex amplification of the DNA, and cDNA followed by identification of the amplified product by sequence specific hybridization on SES platform with the final read out being a visually recordable colored signal. The total time required to carry out this diagnostic procedure is 7 h. The SES was standardized using the commercially available vaccines, panels and cell culture grown quantified viruses/bacteria/fungi. The limit of detection (LOD) of SES ranged between 0.1 and 50 viral particles per ml of CSF and 100 to 200 bacterial cells or 5 parasites per ml of CSF, along with 100% specificity. Precision studies carried out as per the Clinical Laboratory Improvement Amendments (CLIA) guidelines, using two concentrations of each pathogen one the LOD and the other double the LOD, clearly demonstrated, that inter/intra assay variability was within the limits prescribed by the guidelines. SES is a rapid molecular diagnostic tool for simultaneous identification of 22 etiological agents of AES encountered both in sporadic and outbreak settings.

Teratoma Arising from Hepato Duodenal Ligament in the Newborn with Transection of Portal Vein, Hepatic Artery and Common Bile Duct: A Surgical Challenge.

A 7-day-old neonate presented with a large intra-abdominal mass adherent to the hilum of the liver encasing the portal triad. During excision, the portal vein, hepatic artery, and common bile duct were injured. The repair was done promptly and needed massive blood transfusion. Histopathology revealed immature teratoma Grade III. Survival in neonate following total transection of portal triad is rare and has not been reported.

Hemangioendothelioma of palate: A case report with review of literature.

Hemangioendothelioma commonly occurs in the superficial or deep soft tissue of the extremities, lungs, liver, bone and lymph nodes, with oral cavity being a rare location. It is usually benign but can show variable grades of malignancy. According to the histological presentation, hemangioendothelioma has been classified as epithelioid, Kaposiform, hobnail (Dabska-Retiform), epithelioid sarcoma like and composite. We present a case of ulcerated swelling of palate clinically diagnosed as pyogenic granuloma which presented a diagnostically challenging histological picture. We discuss the differential diagnoses obtained from various oral pathologists and general pathologists and substantiate the diagnosis of hemangioendothelioma based on its clinical behavior, histological features and immunohistochemical findings. In addition, we attempt to highlight the diagnostic dilemma that such cases can pose to the attending pathologists.

Multiple apocrine hidrocystomas: a case report.

Hidrocystomas are rare cystic lesions that form benign tumours of the sweat glands. In this report, a clinical case of multiple apocrine hidrocystomas on both the upper and lower eyelids, and on both the malar regions has been discussed. These lesions are less likely than the eccrine lesions to occur at the periorbital region.

A clinical study on the management of inguinal hernias in children on the general surgical practice.

BACKGROUND: Inguinal and scrotal swellings are frequently encountered in the surgical practice, especially in children. It is also important to study the factors which are associated with inguinal hernia, especially in children, for its effective management. OBJECTIVE: To study the factors which are associated with inguinal hernia in children. SETTING AND DESIGN: A prospective hospital based study was undertaken in the Department of Surgery for a period of one year between 2001 to 2002. Children who were aged one day to 12 years were selected for the study. Out of 960 children who were admitted to the surgical ward, 50 children had inguinal hernia and they constituted the sample. METHODOLOGY: The details regarding the clinical history and the examination details were collected by using a predesigned proforma. The data which was thus collected was analyzed by using the appropriate statistical tests. RESULTS: The inguinal hernia in the study group was common in the 1-5 years age group. 90% of the study group was males; a swelling in the inguinal region was the commonest symptom. 70% of the study group was term deliveries; the swelling of the inguinal hernia was elastic in consistency in 35 cases. The swelling of the inguinal hernia was irreducible in two cases. The testis was palpable in 48 cases; a cough impulse was seen and felt in 48 cases. Tenderness of the swelling was present in 2 cases. CONCLUSIONS: Inguinal hernia is a common congenital condition in children. Difficulties are commonly encountered by the surgeons to identify and to confirm the presence of inguinal hernia. This study will help in a better management of hernia in the paediatric age group by understanding the features of inguinal hernia.

Development of a high-performance liquid chromatographic method for determination of letrozole in wistar rat serum and its application in pharmacokinetic studies.

A fast, sensitive, and specific reversed-phase high-performance liquid chromatographic (RP-HPLC) method for the determination of letrozole in Wistar rat serum was developed. In this method, liquid-liquid extraction of letrozole was achieved using diethyl ether as the extracting solvent. The analysis was carried out on a reversed-phase C18 (250 mm × 4.6 mm, 5 µm) column with an isocratic mobile phase of methanol-water (70:30,v/v), at a flow rate of 1.0 mL min(-1). Detection was carried out at 239 nm with a UV-visible spectrophoto-metric detector. The method was shown to be selective and linear over the concentration range of 0.15-100 µg mL(-1). The intra-day and inter-day precision studies showed good reproducibility with coefficients of variation less than 11% for the analyte. The relative errors of intra- and inter-day accuracy were within -11.52 to -2.26%. The limit of quantification was evaluated to be 0.15 µg mL(-1). The method was successfully applied for the pharmacokinetic study of letrozole after oral administration of 10 mg kg(-1) of letrozole in six healthy Wistar rats.

Prevalence of prehypertension and hypertension among urban and rural school going children.

This school based cross sectional study was done to estimate the prevalence of prehypertension and hypertension among apparently healthy school children in urban and rural Mysore. Prevalence of prehypertension and hypertension was 2.9% and 2.8% in urban children and 2.8% and 2% in rural children with no statistically significant difference between them.

Acute gastric volvulus: Late-onset ischemic consequences and their management.

We report three infants who presented with acute gastric volvulus and recovered initially after de-torsion, but later presented with sequelae due to ischemia of gastroesophageal junction, stomach and gastroduodenal junction. The first two infants could not be fed orally or by gastrostomy tube because of microgastria and stricture of the lower esophagus and gastroduodenal junction, and were managed on jejunostomy feeds, while the third child was managed on gastrostomy feeds till the gastric substitution surgery. The first case was treated nonsurgically with repeated dilatations, but ultimately succumbed to sepsis and malnutrition. In the second child, attempted dilatation resulted in esophageal perforation and she was reconstructed using ileocecal segment as a substitute for stomach and lower esophagus, and has done well. The third child was managed surgically by the Hunt Lawrence J pouch as stomach substitute and has also done well.

Clinical and endoscopic spectrum of upper gastrointestinal manifestations in HIV patients.

BACKGROUND: Human Immunodeficiency Virus (HIV) infected patient frequently report upper gastrointestinal (GI) symptoms; however their prevalence and diagnostic approach is not well known. OBJECTIVE: The objective of this study was to study clinical, endoscopic and histopathological changes in HIV infected patients with upper GI symptoms and their correlation with CD4 count. MATERIALS AND METHODS: We evaluated 50 HIV infected patients who presented to M.S. Ramaiah hospital with upper GI symptoms. All patients answered questionnaire assessing upper GI symptoms and underwent upper GI endoscopy. Mucosal biopsy was taken wherever mucosal abnormality seen. RESULTS: In our study, the mean age of patients was 40.98 yrs, of which 80% were males. Vomiting (36%), epigastric pain (36%), weight loss (34%) and anorexia (34%) were the predominant symptoms. Esophagogastroduodenoscopy (EGD) findings revealed--Oesophageal candidiasis in 28.0%, esophagitis in 22.0%, gastritis in 20.0%, duodenitis in 14%, normal upper GI mucosa in 18 % patients. Oesophageal candidiasis was the most common finding on histopathological examination and the mean CD4 count was 157.92 cells/µl. CONCLUSION: Vomiting, epigastric pain, weight loss and anorexia were most frequent symptoms. Oral candidiasis was the most common oral lesion. Oesophageal candidiasis, oesophagitis and oesophageal ulcers were the common findings on EGD. Patient with CD4 count less than 200 cells/µl had more frequent upper GI mucosal involvement than in patients with CD4 count more than 200. Majority of the patients with GI symptoms had upper GI mucosal changes and opportunistic infections. Thus endoscopic and histopathological evaluation is advisable for the early diagnosis and treatment of upper GI complications in patients with HIV infection.

In-vitro anti- inflammatory activity of aqueous extract of leaves of Plectranthus amboinicus (Lour.) Spreng.

Aqueous extract of leaves of Plectranthus amboinicus (lour.) Spreng, which is traditionally used in the treatment of cough and cold was screened for its anti- inflammatory activity by HRBC membrane stabilisation model. Aqueous extract (500 mcg/ml) showed significant anti-inflammatory activity as compared to that of hydrocortisone sodium.

Popliteal A-V Fistula with Pseudo-aneurysm: A Complication Following Total Knee Arthroplasty.

Arthroscopy and total knee replacement (TKR) are the two orthopedic procedures in which instruments are routinely placed near the posterior capsule of the knee. A review of the literature demonstrated that the four commonest reported problems following TKR are thrombosis, arterial transection, A-V fistula, and aneurysm formation. Reports on popliteal artery injury with severe patient morbidity following arthroscopy and TKR have been described in the literature. Despite the uncommon occurrence of these injuries, the outcome can be devastating, leading to further surgery, including vascular repair or possibly even amputation of the affected limb. We present a rare case of popliteal A-V fistula following TKR and discuss the probable etiology and the management.

Evaluation of the protective efficacy of Asteracantha longifolia on acetaminophen-induced liver damage in rats.

The effect of oral administration of methanolic extract of Asteracantha longifolia (AL) seeds on acetaminophen (APAP)-induced acute liver damage in rats was investigated. The activities of marker enzymes (aspartate transaminase, alanine transaminase, alkaline phosphatase, lactate dehydrogenase, and gamma glutamyl transferase) and bilirubin level in serum and the levels of cholesterol, triglycerides, and free fatty acids in both serum and liver were found to be increased when rats were challenged with APAP. This was also associated with a significant reduction of serum and tissue phospholipids. Pretreatment with AL extract prior to the administration of APAP prevented these alterations as evidenced by liver histopathology. Results indicated that the extract could offer protection against APAP-induced liver damage, suggesting its hepatoprotective activity.

Synthesis and biological evaluation of 2,3-diarylpyrazines and quinoxalines as selective COX-2 inhibitors.

Several 2,3-diaryl pyrazines and quinoxalines with 4-sulfamoyl (SO(2)NH(2))/methylsulfonyl (SO(2)Me)-phenyl pharmacophores have been synthesized and evaluated for the cyclooxygenase (COX-1/COX-2) inhibitory activity. Smaller groups such as methoxy, methyl and fluoro when substituted at/around position-4 of the adjacent phenyl ring, have great impact on the selective COX-2 inhibitory activity of the series. Many potential compounds were obtained from a brief structure-activity relationship (SAR) study. Two of these, compounds 11 and 25 exhibited excellent in vivo activity in the established animal model of inflammation. Since compound 25 possessed an amenable sulfonamide group, two of its prodrugs 48 and 49 were also synthesized. Both of them have excellent in vivo potential, and represent a new class of COX-2 inhibitor.