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AbstractNeurodegenerative disorders are illnesses that are responsible for neuronal cell death and resulting in lifelong cognitive problems. Due to their unclear mechanism, there are no effective drugs available for the treatment. For a long time, herbal drugs have been used as a role model in the field of the drug discovery process. Withania somnifera(Ashwagandha) in the Indian medicinal system (Ayurveda) is used for several neuronal disorders like insomnia and memory loss for decades. This study aims to identify active components of W. somnifera(WS) as potential inhibitors for the treatment of neurodegenerative diseases (ND). To fulfill this objective, Network pharmacology approach, gene ontology, pharmacokinetics analysis, molecular docking, and molecular dynamics simulation (MDS) studies were performed. A total of 77 active components in WS, 175 predicted neurodegenerative targets of WS, and 8085 ND-related targets were identified from different databases. The network analysis showed that the top ten targets APP, EGFR, MAPK1, ESR1, HSPA4, PRKCD, MAPK3, ABL1, JUN, and GSK3B were found as significant target related to ND. On the basis of gene ontology and topology analysis results, APP was found as a significant target related to Alzheimer’s disease pathways. Molecular docking results found that Anahygrine, Cuscohygrine, Isopelletierine, and Nicotine showed the best binding affinities −5.55, −4.73, −4.04, and −4.11 Kcal/mol. Further, MDS results suggested that Isopelletierine and Nicotine could be used as potential inhibitors against APP protein and could be useful for the treatment of Alzheimer’s disease.Communicated by Ramaswamy H. Sarma

ABSTRACTThis paper presents the full scale experimental as well as software analysis investigation of Gerber frames subjected to elastic lateral torsional buckling (LTB). To understand the elastic buckling load, three experiments were undertaken and recorded the buckling modes. To predict the elastic LTB resistance, shell finite element (FE) solution was conducted. A comparison is made among the experimental elastic buckling load and results obtained by FE model for Gerber frames. A good agreement is observed between experimental and finite element analysis.

AbstractComputational approaches have been helpful in high throughput screening of drug libraries and designing ligands against receptors. Alzheimer's disease is a complex neurological disorder, which causes dementia. In this disease neurons are damaged due to formation of Amyloid-beta plaques and neurofibrillary tangles, which along with some other factors contributes to disease development and progression. The objective of this study was to predict tertiary structures of five G-protein coulped neurotransmitter receptors; CHRM5, CYSLTR2, DRD5, GALR1 and HTR2C, that are upregulated in Alzheimer’s disease, and to screen potential inhibitors for against these receptors. In this study, Comparative modelling, molecular docking, MMGBSA analysis, ADMET screening and molecular dynamics simulation were performed. Tertiary structures of the five GPCRs were predicted and further subjected to molecular docking against natural compounds. Pharmacokinetic studies of natural compounds were also conducted for assessing drug-likeness properties. Molecular dynamics simulations were performed to investigate the structural stability and binding affinities of each complex. Finally, the results suggested that ZINC04098704, ZINC31170017, ZINC05998597, ZINC67911229, and ZINC67910690 had better binding affinity with CHRM5, CYSLTR2, DRD5, GALR1, and HTR2C (5-HT2C) proteins, respectively.Communicated by Ramaswamy H. Sarma

Post-traumatic stress disorder (PTSD), previously known as battle fatigue syndrome or shell shock, is a severe mental disturbance condition that is normally triggered by the experience of some frightening/scary events or trauma where a person undergoes some serious physical or mental harm or threatened. PTSD is a long-life effect of the continuous occurrence of traumatic conditions, leading to the production of feelings of helplessness, intense fear, and horror in the person. There are various examples of events that can cause PTSD, such as physical, mental, or sexual assault at home or working place by others, unexpected death of a loved one, an accidental event, war, or some kind of natural disaster. Treatment of PTSD includes the removal or reduction of these emotional feelings or symptoms with the aim to improve the daily life functioning of a person. Problems which are needed to be considered in case of PTSD like ongoing trauma, abusive or bad relationships. Various drugs which are used for the treatment of PTSD include selective serotonin reuptake inhibitors (SSRIs) (citalopram, fluvoxamine, fluoxetine, etc.); tricyclic antidepressants (amitriptyline and isocarboxazid); mood stabilizers (Divalproex and lamotrigine); atypical antipsychotics (aripiprazole and quetiapine), etc. In this review, we have covered the different risk factors, case studies related to various treatment options with different age group of peoples with PTSD and their effects on them. We have also covered the symptoms and associated disorders which can play a key role in the development of PTSD.

The goal of this study is to analyse the IPO listing returns in National Stock Exchange (NSE) and provide insights for retail investors study has considered a sample of 463 IPOs listed in NSE from January 2000 to August 2018. Mean listing return has been found to be 20.10% which is abnormally high as compared to mean market return which is 0.24. Out of 463 IPOs 66.74% IPOs gave positive listing returns which means these IPOs were underpriced. But we cannot generalise that all IPOs are underpriced because 33.26% IPOs were overpriced and gave negative listing returns. This study provides a base for retail investor to formulate investment strategy. This study shows that by subscribing for all IPOs (over a period of 18 years) and selling them on listing day, a retail investor could have earned about 99% more returns as compared to market return and savings bank account return.

Precision medicine is promising for treating human diseases, as it focuses on tailoring drugs to a patient’s genes, environment, and lifestyle. The need for personalized medicines has opened the doors for turning nucleic acids into therapeutics. Although gene therapy has the potential to treat and cure genetic and acquired diseases, it needs to overcome certain obstacles before creating the overall prescription drugs. Recent advancement in the life science has helped to understand the effective manipulation and delivery of genome-engineering tools better. The use of sequence-specific nucleases allows genetic changes in human cells to be easily made with higher efficiency and precision than before. Nanotechnology has made rapid advancement in the field of drug delivery, but the delivery of nucleic acids presents unique challenges. Also, designing efficient and short time-consuming genome-editing tools with negligible off-target effects are in high demand for precision medicine. In the fourth annual Biopharmaceutical Research and Development Symposium (BRDS) held at the University of Nebraska Medical Center (UNMC) on September 7–8, 2017, we covered different facets of developing tools for precision medicine for therapeutic and diagnosis of genetic disorders.

Gemcitabine (GEM), a first-line chemotherapy for pancreatic cancer undergoes rapid metabolism and develops chemoresistance after repeated administration. We previously demonstrated that the combination of GEM and miR-205 provides an effective therapeutic strategy to sensitize GEM-resistant pancreatic cancer cells. Since epidermal growth factor receptor (EGFR) is overexpressed in pancreatic cancer cells, in this study, we aimed to deliver mixed micelles containing GEM and miR-205 decorated with EGFR-targeting cetuximab (C225) monoclonal antibody for targeted therapy. Cetuximab C225 was conjugated to malemido-poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol (C225–PEG-PCD) to prepare mixed micelles with mPEG-b-PCC-g-GEM-g-DC-g-TEPA for targeted codelivery of GEM and miR-205. This mixed micelle formulation showed a significant enhancement in EGFR-mediated cellular uptake in GEM-resistant MIA PaCa-2Rcells. Further, an enhanced tumor accumulation of C225-micelles conjugated with near-infrared fluorescent Cy7.5 dye and Dy677-labeled miR-205 in orthotopic pancreatic tumor bearing NSG mice was evident after systemic administration. In addition, inhibition of tumor growth was also observed with increased apoptosis and reduced EMT after treatment with C225-micelles containing GEM and miR-205. Therefore, we believe that the targeted delivery of GEM and miR-205 in combination could be a novel strategy for treating advanced pancreatic cancer.

The completion of human genome project, decrease in the sequencing cost, and correlation of genome sequencing data with specific diseases led to the exponential rise in the nucleic acid-based therapeutic approaches. In the third annual Biopharmaceutical Research and Development Symposium (BRDS) held at the Center for Drug Discovery and Lozier Center for Pharmacy Sciences and Education at the University of Nebraska Medical Center (UNMC), we highlighted the remarkable features of the nucleic acid-based nanomedicines, their significance, NIH funding opportunities on nanomedicines and gene therapy research, challenges and opportunities in the clinical translation of nucleic acids into therapeutics, and the role of intellectual property (IP) in drug discovery and development.

The availability of therapeutic substances at colonic regions is always challenging for researchers. In this work, we aimed to evaluate the colon-targeting ability of mesalazine and probiotic biomass using Opuntia ficusindica polysaccharide. The present work will explore the application of novel plant polysaccharides as a rate-controlling polymer for colon drug delivery. Opuntia ficusindicapolysaccharide was extracted and evaluated for the in-vitro toxicity study on HT-29 cell lines. Drug-loaded macroparticles were prepared and compressed into the tablet. In-vitro drug release was determined in simulated gastric fluid. Disease models were developed in Sprague Dawley rats to determine the efficacy of prepared formulation in the presence of probiotic biomass. Colon targeting efficiency of 99mTc-pertechnetate labeled mesalazine was monitored in human volunteers. Investigation of the polysaccharide's in-vitrotoxicity revealed that the polysaccharide was safe for colon applications. Drug release data increased (p < 0.05) in the presence of rat cecal material at 6 h. The study also revealed that drug release from the different batches was directly proportional to polysaccharide concentration. In-vivo animal study confirms the better prevention of the disease in the presence of probiotic mass and drug. Gamma scintigraphy further supports the minimal drug release from the radiolabeled formulation in the upper gastrointestinal tract (GIT), despite the fact that it started drug release after 360 min, which was then disseminated during the subsequent 720–960 min in the colon. The study shows that Opuntia ficusindicapolysaccharide can be used to deliver mesalazine to the colon.

The introduction of foreign direct investments (FDI) in the Indian telecom sector has resulted in increased competition among the telecom service providers. Accordingly, the service providers have changed their attention from profit earning to customer satisfaction. Instead of getting new customers, the service providers have become interested in retaining their existing customers. They have realised that satisfied customers improved an organisation's image in the market. Thus, the main research objective of the study is to discuss the service quality of a public sector unit (PSU) having important service attributes. This study was conducted in three stages. In the first stage, the important telecom dimensions were identified. In the second stage, these attributes were prioritised using experts' choice and fuzzy extent analysis. In the third stage, the model was tested on the PSU customers using factor analysis and regression. The results showed that grievance handling was given the highest priority compared to the other quality attributes. This research is useful for telecom service providers, especially those who focused on service quality. To the best of our knowledge, the quality of mobile, wireline and broadband services has been rarely investigated using analytic hierarchy process (AHP) and fuzzy extent analysis.

A 474-bp ds-DNA linker-A containing all bio-parts was designed to construct tightly inducible expression vector, pNB1, for Escherichia coli . The cymR repressor expressed constitutively under pGapA promoter binds cumate operator, thus repressing the expression of target gene under T7 promoter. The potential of pNB1 was evaluated by comparing the fluorescence of green fluorescence proteins (GFP) in pNB1 and other expression system induced with cumate and isopropyl β- d -1-thiogalactopyranoside (IPTG), respectively. Compared to IPTG, cumate was found to be less toxic to bacterial cells with 2.5-fold increment in GFP expression. In addition, pNB1 was efficient in expressing GFP at low temperature. [ABSTRACT FROM AUTHOR]

Glycosyltransferase (GT) can convert flavonoids, alkaloids, and terpenoids into glycosylated forms. An oleandomycin glycosyltransferase, “OleD” GT from Streptomyces antibioticus was exploited for the glycosylation of amentoflavone. The OleD was functionally expressed in Escherichia coli BL21 (DE3) and purified enzyme was employed as the biocatalyst for the glycosylation of amentoflavone via the transfer of glucose moiety from UDP (uridine diphosphate)-glucose. As a result, amentoflavone monoglycoside was evident in HPLC and LC–ESI-MS spectrometry with an exact mass of 701. In addition, the reaction conditions were optimized with the highest conversion up to 85% at 30 min. [ABSTRACT FROM AUTHOR]

The growth of technology has caused to raise the demand of quality telecom services as a significant factor. Evaluation of telecom service quality has become a tactical issue; one that is critical to improve the quality level. This study identifies the significant factors that impacts on the success of telecom service in the Indian telecom market. Two questionnaires were used to identify these factors. One of questionnaire was based on analytical hierarchical process (AHP) methodology. These factors were discovered with the help of literature survey and then AHP method with fuzzy was applied for prioritising. Our research provides the direction to the managers who are involved in telecom operation, how can they judge their telecom service quality and improvement thereof to retain their prospective customers. Our proposed model provides implications for future research on telecom service quality.

Tumor endothelial marker 8 (TEM8) is a cell surface receptor that is highly expressed in a variety of human tumors and promotes tumor angiogenesis and cell growth. Antibodies targeting TEM8 block tumor angiogenesis in a manner distinct from the VEGF receptor pathway. Development of a TEM8 imaging agent could aid in patient selection for specific antiangiogenic therapies and for response monitoring. In these studies, L2, a therapeutic anti-TEM8 monoclonal IgG antibody (L2mAb), was labeled with 89Zr and evaluated in vitro and in vivo in TEM8 expressing cells and mouse xenografts (NCI-H460, DLD-1) as a potential TEM8 immuno-PET imaging agent. 89Zr-df–L2mAb was synthesized using a desferioxamine–L2mAb conjugate (df–L2mAb); 125I-L2mAb was labeled directly. In vitro binding studies were performed using human derived cell lines with high, moderate, and low/undetectable TEM8 expression. 89Zr-df–L2mAb in vitro autoradiography studies and CD31 IHC staining were performed with cryosections from human tumor xenografts (NCI-H460, DLD-1, MKN-45, U87-MG, T-47D, and A-431). Confirmatory TEM8 Western blots were performed with the same tumor types and cells. 89Zr-df–L2mAb biodistribution and PET imaging studies were performed in NCI-H460 and DLD-1 xenografts in nude mice. 125I-L2mAb and 89Zr-df–L2mAb exhibited specific and high affinity binding to TEM8 that was consistent with TEM8 expression levels. In NCI-H460 and DLD-1 mouse xenografts nontarget tissue uptake of 89Zr-df–L2mAb was similar; the liver and spleen exhibited the highest uptake at all time points. 89Zr-L2mAb was highly retained in NCI-H460 tumors with <10% losses from day 1 to day 3 with the highest tumor to muscle ratios (T:M) occurring at day 3. DLD-1 tumors exhibited similar pharmacokinetics, but tumor uptake and T:M ratios were reduced ∼2-fold in comparison to NCI-H460 at all time points. NCI-H460 and DLD-1 tumors were easily visualized in PET imaging studies despite low in vitro TEM8 expression in DLD-1 cells indicating that in vivo expression might be higher in DLD-1 tumors. From in vitro autoradiography studies 89Zr-df–L2mAb specific binding was found in 6 tumor types (U87-MG, NCI-H460, T-47D MKN-45, A-431, and DLD-1) which highly correlated to vessel density (CD31 IHC). Westerns blots confirmed the presence of TEM8 in the 6 tumor types but found undetectable TEM8 levels in DLD-1 and MKN-45 cells. This data would indicate that TEM8 is associated with the tumor vasculature rather than the tumor tissue, thus explaining the increased TEM8 expression in DLD-1 tumors compared to DLD-1 cell cultures. 89Zr-df–L2mAb specifically targeted TEM8 in vitro and in vivo although the in vitro expression was not necessarily predictive of in vivo expression which seemed to be associated with the tumor vasculature. In mouse models, 89Zr-df–L2mAb tumor uptakes and T:M ratios were sufficient for visualization during PET imaging. These results would suggest that a TEM8 targeted PET imaging agent, such as 89Zr-df–L2mAb, may have potential clinical, diagnostic, and prognostic applications by providing a quantitative measure of tumor angiogenesis and patient selection for future TEM8 directed therapies.

Blocking tumor angiogenesis is an important goal of cancer therapy, but clinically approved anti-angiogenic agents suffer from limited efficacy and adverse side effects, fueling the need to identify alternative angiogenesis regulators. Tumor endothelial marker 8 (TEM8) is a highly conserved cell surface receptor overexpressed on human tumor vasculature. Genetic disruption of Tem8in mice revealed that TEM8 is important for promoting tumor angiogenesis and tumor growth but dispensable for normal development and wound healing. The induction of TEM8 in cultured endothelial cells by nutrient or growth factor deprivation suggests that TEM8 may be part of a survival response pathway that is activated by tumor microenvironmental stress. In preclinical studies, antibodies targeted against the extracellular domain of TEM8 inhibited tumor angiogenesis and blocked the growth of multiple human tumor xenografts. Anti-TEM8 antibodies augmented the activity of other anti-angiogenic agents, vascular targeting agents and conventional chemotherapeutic agents and displayed no detectable toxicity. Thus, anti-TEM8 antibodies provide a promising new tool for selective blockade of neovascularization associated with cancer and possibly other angiogenesis-dependent diseases.

Right ventricular function affects the outcome in valvular heart disease but less is known about the relation between indices of dysfunction and outcome. Seventy patients undergoing mitral valve replacement between April 2007 and April 2008 for predominant rheumatic mitral stenosis were included in the study. Two groups were formed based on right ventricular systolic pressure (RVSP), 41 mmHg (group II, n=54). Right ventricle (RV) function indices were studied by echocardiography. RVSP reduced significantly in group II (P=0.0001) but not in group I. Brain natriuretic peptide (BNP) was raised in all cases and reduced significantly postoperatively. Tricuspid annular plane excursion, myocardial performance index, RV descent and tricuspid valve annular shortening (TV shortening) conformed to RV dysfunction in both groups, and did not change significantly postoperatively. Regression analysis for outcome revealed TV shortening as the only significant factor (P=0.03). Receiver operating characteristic of TV shortening and adverse outcome showed worse outcome with TV shortening of <11%. RV dysfunction was observed in all cases irrespective of RVSP. TV shortening of <11% was associated with adverse outcome. Postoperative fall in BNP levels may indicate a trend towards recovery.

The outcome of multivessel off-pump coronary artery bypass grafting in cases of severe left ventricular dysfunction was studied in 58 consecutive patients with ejection fraction =35% who were followed up for a median of 15 months. Patients with ejection fractions =25% (group 1) had the largest left ventricular dimensions preoperatively, with gradual increases during follow-up; those with ejection fractions of 26%-35% (group 2) had smaller preoperative ventricular dimensions, with left ventricular regression postoperatively. There was more improvement in ejection fraction in group 2 than group 1 (33% vs. 10%). Mitral regurgitation improved from moderate to mild in group 2; whereas in group 1, mild mitral regurgitation progressed to moderate or severe during follow-up. Ejection fraction was a predictor of more frequent use of intraaortic balloon pumping, longer duration of inotropic use, a higher mean pulmonary artery-to-systemic arterial pressure ratio, and increased postoperative drainage.

Cytochrome P450 enzymes protect the body from foreign substances through a mechanism that involves oxidation of those substances into more readily excretable polar compounds. It has been shown that some naphthoflavones function as substrates of certain P450 enzymes (CYP1A1 and CYP1B1) and with appropriate structural changes may become inhibitors. Moreover, propargyl ether derivatives of adamantane have been shown to function as selective inactivators of some P450 enzymes (CYP2B1 and CYP2B5). In an attempt to improve the potency and selectivity of inhibition, we have designed and synthesized a series of naphthoflavone propargyl ethers. We report here the synthesis, X-ray crystal structures, and inhibition data (IC50of EROD inhibition in CYP1A1 and CYP1B1 enzymes) of α-naphthoflavone 2′-propargyl ether, β-naphthoflavone 2′-propargyl ether, α-naphthoflavone 4′-propargyl ether, and β-naphthoflavone 4′-propargyl ether. Crystallographic data: α-naphthoflavone 2′-propargyl ether, $$P\bar 1$$, a=7.775(1) Å, b=8.062(1) Å, c=13.110(1) Å, α=84.32(1)°, β=75.42(1)°, γ=86.56(1)°, V=790.8(2) Å3; β-naphthoflavone 2′-propargyl ether, $$P\bar 1$$, a=7.605(2) Å, b=7.793(1) Å, c=14.167(2) Å, α=77.06(1)°, β=75.41(1)°, γ=89.54(1)°, V=790.9(2) Å3; α-naphthoflavone 4′-propargyl ether, P21/n, a=14.595(2) Å, b=4.708(1) Å, c=24.745(6) Å, β=106.31(2)°, V=1631.8(7) Å3; β-naphthoflavone 4′-propargyl ether, P1, a=4.8871(5) Å, b= 7.9597(7) Å, c=21.788(3) Å, α=81.771(9)°, β=89.918(10)°, γ=72.223(8)°, V= 797.9(2) Å3.Cytochrome P450 enzymes protect the body from foreign substances through a mechanism that involves oxidation of those substances into more readily excretable polar compounds. It has been shown that some naphthoflavones function as substrates of certain P450 enzymes (CYP1A1 and CYP1B1) and with appropriate structural changes may become inhibitors. Moreover, propargyl ether derivatives of adamantane have been shown to function as selective inactivators of some P450 enzymes (CYP2B1 and CYP2B5). In an attempt to improve the potency and selectivity of inhibition, we have designed and synthesized a series of naphthoflavone propargyl ethers. We report here the synthesis, X-ray crystal structures, and inhibition data (IC50of EROD inhibition in CYP1A1 and CYP1B1 enzymes) of α-naphthoflavone 2′-propargyl ether, β-naphthoflavone 2′-propargyl ether, α-naphthoflavone 4′-propargyl ether, and β-naphthoflavone 4′-propargyl ether. Crystallographic data: α-naphthoflavone 2′-propargyl ether, $$P\bar 1$$, a=7.775(1) Å, b=8.062(1) Å, c=13.110(1) Å, α=84.32(1)°, β=75.42(1)°, γ=86.56(1)°, V=790.8(2) Å3; β-naphthoflavone 2′-propargyl ether, $$P\bar 1$$, a=7.605(2) Å, b=7.793(1) Å, c=14.167(2) Å, α=77.06(1)°, β=75.41(1)°, γ=89.54(1)°, V=790.9(2) Å3; α-naphthoflavone 4′-propargyl ether, P21/n, a=14.595(2) Å, b=4.708(1) Å, c=24.745(6) Å, β=106.31(2)°, V=1631.8(7) Å3; β-naphthoflavone 4′-propargyl ether, P1, a=4.8871(5) Å, b= 7.9597(7) Å, c=21.788(3) Å, α=81.771(9)°, β=89.918(10)°, γ=72.223(8)°, V= 797.9(2) Å3.