ANN Based Virtual Classification Model for Discriminating Active and Inactive Withanolide E Analogs against Human Breast Cancer Cell Line MCF-7

Withanolides are a group of natural C-28 steroids built on an ergostane skeleton and classified into two major groups according to their structural skeleton: (a) compounds with a beta-oriented side chain and (b) compounds with an alpha-oriented side chain. Withanolide E represents one of the members of the latter group. Classification of active compounds on the basis of pharmacophore against specific cancer cell line poses a serious concern at the primary stage of virtual screening. To overcome this problem we have developed an artificial neural network based virtual screening model for discriminating active and non-active Withanolide-E-like derivatives or analogs against human breast cancer cell line MCF-7. In the present work, a 2D chemical descriptors ensemble pharmacophore has been modelled on the basis of withanolide E structural featured molecules. The ANN structure activity based classification model could be useful for identification of active withanolide analogs as anticancer leads against MCF-7. This model can be used for predicting possible growth inhibitory concentration (logGI50) against breast cancer cell line MCF-7. The virtual screening tool “CanWithaANN” can be accessed at local network of CIMAP

Weight matrix based identification of terpene synthases conserved motifs in Arabidopsis thaliana proteome

Terpenes comprise the most diverse collection of natural products. Out of more than 30,000 individual terpenoids identified, at least half are synthesized by plants. A relatively small, but quantitatively significant, number of terpenoids are involved in primary plant metabolism. However, the vast majorities are classified as secondary metabolites; compounds not required for plant growth and development but presumed to have an ecological function in communication or defense and are widely used in industrial applications. Terpene hydrocarbon scaffolds are generated by the action of the mechanistically intriguing family of mono-, sesqui-, and diterpene synthases collectively termed as terpene synthases, that catalyze multistep reactions with diphosphorylated substrates of 10 (geranyl diphosphate), 15 (farnesyl diphosphate) or 20 (geranylgeranyl diphosphate) carbons. In the studied work, we performed a computational study on proteome wide identification of terpene synthase motifs in Arabidopsis thaliana proteome on the basis of weight matrix approach. We have developed an optimal weight matrix for the identification of terpene synthase motifs in the plant’s proteome. Weight matrix was constructed by aligning orthologous sequences of known terpene synthases originated from diverse plant species viz., Abies grandis, Nicotiana tobaccum etc. Sequences of detected domains & motifs were retrieved through SwissProtKB/NCBI on the basis of specific conservation IDs of Prosite, Pfam, Interpro, Prodom, COG, TIGR databases, while position specific scoring matrices were made through MEME, MotifSampler, PossuMsearch tools. Weight matrix based search of conserved motifs in the proteome of A. thaliana was done through ESA, Lahead and Simple algorithm based search tools of PossuMsearch biosuite in Linux system. Prediction was first validated by using positive control data set and optimized the method to reach prediction accuracy upto >90%. After tool performance evaluation, prediction was made on whole proteome at specific threshold/score value. Significant results were found in A. thaliana with motif similarity ranges from 80% to 100%. This proteome wide search model paves the path to identify more terpene synthases genes in A. thaliana, as well as in other plant systems

Nuclear Security in Pakistan: Separating Myth From Reality

Pakistan is passing through an extremely delicate phase in its history. Recent instability in Pakistan, including the Taliban's advance into settled areas, prompted the Pakistani military to undertake large-scale military operations in the Swat Valley. As military and Taliban forces fight in the rugged tribal terrain, several Western analysts have raised concerns about the future of nuclear Pakistan

Rough Neighbors: Afghanistan and Pakistan; Strategic Insights: v.2, issue 1 (January 2003)

This article appeared in Strategic Insights (January 2003), v.2 no.1Focus on South Asia over the past fifty years has primarily remained on the India-Pakistan rivalry and tensions over Kashmir. This dimension overshadowed the effect of Pakistan-Afghanistan relations on the security dynamics of the South-Central Asian region. The historical and cultural dimension of the Afghanistan-Pakistan relation has been and will remain critical in the evolving regional dynamics. Since the events of September 11, 2001 the political landscape of the region has transformed dramatically. Pakistan made a strategic about-face over the Taliban, when her decade old forward policy in Afghanistan became counterproductive to her own national security. A year after the historic Bonn Agreement on December 6, 2001, Afghanistan has now embarked on a journey towards peace and reconstruction after being ravaged by war, bloody coups, and displacement of the society. In June 2002, the Loya Jirga endorsed the leadership of President Hamid Karzai. The interim administration and coalition in Kabul however remains fragile and the potential danger for a return to civil war still remains as Afghanistan undergoes a delicate transition period until 2003. For the past year Afghanistan and Pakistan have been enjoying an unprecedented level of cooperative relations. Will both countries remain on track and for how long? Will Afghanistan and Pakistan destabilize each other this decade? What major changes have now taken place and what steps might be taken to sustain this healthy trend in the future of their relations? This essay analyzes the security dynamics of Afghanistan-Pakistan relations in their historical framework and within the context of the ongoing war on terrorism, with an eye to the future of the region

The independence-dependence paradox: stability dilemmas in south

Has a new era of detente and stability emerged in South Asia five years after India and Pakistan first openly tested nuclear weapons? In the process, have India and Pakistan effectively demonstrated the value of nuclear weapons in deterring war? Deterrence optimists claim that fear of the ultimate weapon has restrained the otherwise rough actors who have been at each others' throats more often than any other nuclear neighbors in the nuclear age. Empirical evidance also suggests that the region has been spared from major wars, despite recurrent crises during the past two decades. Deterrence pessimists, however, dispute that nuclear weaons have had a stabilizing impact in the region. Indeed, the advent of nuclear weapons has witnessed increased tensions, a growing arms race, and a half-dozen crises nearing war. The region has come close to full blows at least twice since the open 1998 nuclear weapons tests -- in 1999 and 22001/2002--and thrice earlier in the covert nuclear period--in 1984, 1986-1987, and 1989-1990. In fact, the three most recent crises--in 1990, 1999 and 2001-2002--only avoided escalation into a full-scale war because of intense U.S. diplomacy. In fact, it could be argued that the deterrence equation in South Asia now implicitly depends on U.S. intevention. In essence, India's and Pakistan's nuclear politics involve what might be called the "independence-dependence paradox". These two proud countries have attempted to wean themselves from outside support by using nuclear weapons. But this strategy has ironically served to make them more dependent on other powers who are forced to mitigate the consequences of this arms race. No other country has played a more crucial role than the United States

Prospects for Indian and Pakistani Arms Control and Confidence-Building Measures

The regional dynamic in South Asia is both extravagant and complicated. For centuries various empires have risen, thrived, and fallen, as numerous wars and clashes for control over resources spread across the geography. South Asian history writ large has seen hypothetical borders redrawn several times, leaving in question the viability of state control and perpetuating ethnic tensions. Though the great partition of India in 1947 ought to have politically resolved communal disharmony, the haste of British withdrawal created a geopolitical quagmire that has resulted in an “enduring rivalry” between the nations of India and Pakistan, one that has lasted for more than sixty years

Symptom Burden Among Patients Hospitalized For Heart Failure

Heart failure (HF) is one of the most common reasons for hospitalization and the leading cause of 30-day readmissions. There is great interest in developing strategies to reduce hospital utilization in this large and growing patient population. Aside from classic heart failure symptoms of dyspnea and fatigue, other symptoms reported include decreased appetite, pain and anxiety. These symptoms may be amenable to treatment and patients hospitalized with heart failure may benefit from intensive symptom management in the form of palliative care. There is limited data in the heart failure population about symptom burden both during hospitalization and shortly after hospital discharge, as well as patients\u27 perceptions of palliative care. Therefore, our aim was to evaluate if patients discharged from the hospital after acute decompensated heart failure exhibit a high burden of residual symptoms one week post-discharge. Patients hospitalized for heart failure were enrolled in this prospective cohort study. Patients were interviewed about symptom burden using the Edmonton Symptom Assessment System (ESAS) and Patient Health Questionnaire (PHQ-8) during the hospital admission and 7 to 10 days post- discharge. Patients were also questioned about existing knowledge of palliative care, and then - after a brief, standardized explanation of the goals of palliative care - patients were queried about their interest in receiving palliative care services. Ninety-one patients were enrolled; their mean age was 71.5 years (SD 12.6 years) 51.6% were female and 74.5% had NYHA class III/IV heart failure. Symptoms frequently reported during the baseline interview included decreased wellbeing (94.1%), fatigue (85.9%), shortness of breath (81.2%), anxiety (62.4%) and pain (47.1%). Frequent symptoms reported in the follow- up interview were decreased wellbeing (95.3%), fatigue (88.2%) and shortness of breath (84.7%), anxiety (60.0%) and pain (55.3%). While only 22.4% of patients had heard of `palliative care,\u27 after a standardized explanation, 68.2% were interested in receiving palliative care services while hospitalized. Patients hospitalized for heart failure experience a high burden of symptoms, including not only those usually associated with heart failure such as dyspnea and fatigue, but also anxiety and pain. These symptoms are common during hospitalization and the majority of patients appear to experience troublesome symptoms shortly after discharge as well. Given that patients\u27 symptoms frequently drive health care utilization, integration of palliative care into routine heart failure management is a promising strategy to reduce readmission after heart failure hospitalization

Docking and QSAR Studies of Camptothecin Derivatives as Inhibitor of DNA Topoisomerase-I

Camptothecin (CPT) is a cytotoxic quinoline alkaloid which inhibits the DNA enzyme Topoisomerase-I (Topo-I) and has shown remarkable anticancer activity in preliminary clinical trials. The major limitation is its low solubility and high adverse reaction. In the studied work, we performed molecular docking of CPT derivatives against Topo-I and developed the quantitative structure activity relationship (QSAR) model for anticancer activity screening. For QSAR, we used CPT and other anticancer drugs with its IC50 values. We used a total of forty seven anticancer drugs as training set and eight compounds as test set and thirty derivatives of CPT as query set. Total of fifty two chemical descriptors were used for the quantitative data calculation. Only four showed good correlation with the experimental activity. Forward feed regression method was used for development of multiple linear regression (MLR) QSAR model. Model showed acceptable regression coefficient (r2) 0.89 (i.e., 89% of correlation) and cross validation coefficient (rCV2) 0.86 (i.e., 86 % of prediction accuracy). After drug likeness test, ten compounds namely, MSB3a, MSB3b, MSB19, MSB22L, MSB22M, MSB22O, MSB22R, MSB25D, MSB37G and MSB39D, showed promising predicted anticancer activity and drug likeness properties. Out of ten, only six compounds namely, MSB19, MSB22L, MSBM, MSB22O, MSB22R and MSB37D indicate two times more activity than the parent CPT compound. In molecular docking studies, all the identified active CPT derivatives showed high binding affinity with Topo-I. QSAR study indicates that connectivity index, electron affinity, mol.wt. & ether group count highly contribute to inhibitory activity of CPT derivatives. These results can offer useful references for directing the molecular design of Topo-I inhibitor with improved anticancer activity.
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QSAR studies on Withanolide analogs for anticancer activity

Withanolides are a group of pharmacologically active compounds present in most prodigal amounts in roots and leaves of Withania somnifera (Indian ginseng), one of the most important medicinal plants of Indian systems of medicine. Withanolides are basically steroidal lactones (highly oxygenated C-28 phytochemicals) and similar to ginsenosides activity. Some of the withanolides that have been reported possess immunomodulatory, and anticancer activities. In the present investigation, a quantitative structure activity relationship (QSAR) model based on forward stepwise multiple linear regression (MLR) has been developed against the MCF7, MCF7/BUS, and SK-Br-3 human solid tumor breast cancer cell lines. Relationship correlation coefficient (r2) and cross validation correlation coefficient (r2CV) of QSAR model were 0.77 and 0.73 for MCF7, 0.91 and 0.85 for MCF7/BUS, 0.93 and 0.90 for SK-Br-3 respectively. Developed QSAR model was also evaluated for prediction accuracy through internal, external and randomization validation methods. The QSAR study indicates that chemical descriptors viz., atom count (all atoms), connectivity index (order 2, standard), for MCF7, Connectivity Index (order 0, standard), Dipole Vector X (debye), Molar Refractivity, Shape Index (basic kappa, order 2) for SK-Br-3 and Atom Count (all atoms), Dielectric Energy (kcal/mole), Total Energy (Hartree), Heat of Formation (kcal/mole) for MCF7/BUS are correlate well with the breast cancer activity, Moreover, on the basis of screening for oral bioavailability, in silico ADME and toxicity risk assessment, we concluded that compounds W3, W4, W8 have markedly higher anticancer activity compared to control. These results can offer useful references for directing the molecular design of lead compound(s) based on withanolide or analogous template with improved activity

The Challenges of Nuclear Learning in South Asia

Published as a contributed paper for "Nuclear Learning in South Asia: The Next Decade" (2014).The sustainability of strategic stability in South Asia remains of the highest importance to U.S. national security policy. The South Asian Nuclear Learning project was accordingly conceived to examine the region’s nuclear experiences after the 1998 tests. The end of the first decade (1998-2008) represented a good starting point. Later, the project expanded to further analyze the nuclear learning curve in the next decade, when security environment and technological innovations undertook major shifts. The National Nuclear Security Administration sponsored this research, which involved selected scholars and experts from Pakistan, India and United States. Some of these contributors also helped shape their state’s nuclear decisions in the earlier period following the nuclear tests