172 results on '"Kumar, Shivani"'
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152. ENTANGLEMENT DIVERSION BETWEEN TWO PAIRS OF ENTANGLED COHERENT STATES: FIDELITY AND DECOHERENCE
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PRAKASH, H., primary, CHANDRA, N., additional, PRAKASH, R., additional, and KUMAR, SHIVANI A., additional
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- 2009
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153. Process optimisation of forming large grain poly-silicon on insulator for advanced CMOS applications
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Kumar, Shivani and Kumar, Shivani
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The combination of MILC and high temperature annealing process is very promising for TFT technology in realizing multilevel 3-D structures. However, the key to success of this method is the optimisation of process parameters and hence the grain size. In order to optimise the grain size, it requires a study on process conditions - temperature, time, metal concentration etc., that affect the crystallization process, grain size, grain boundaries and hence the performance of the device. Temperature and annealing time for crystallization are very important process parameters and need to be optimised. In this thesis work, first material characterization of the metal induced laterally crystallized poly-silicon was performed and the effects of electric field, temperature and time were investigated. It was found that rate of crystallization could be remarkably enhanced in the presence of electric field. Also, electric field combined with the MILC leads to lower crystallization temperature and shortens the annealing time. Furthermore, the concept of ramp annealing was proposed and the effect of temperature and time was studied in detail. Also, the temperature and time for MILC was optimised during this study. Finally, TFTs were fabricated and characterised at different MILC annealing temperatures with and without subsequent high temperature with only one extra mask added. It was found that TFT fabricated using optimised temperature and time shows the performance comparable to super TFT (SOI), thus shortens the annealing time to few hours (2-4 hours) with lower thermal budget. It is believed that super TFTs with SOI CMOS performance and good uniformity can be obtained through the reduction in channel dimensions and optimised process conditions.
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- 2001
154. Almost perfect teleportation of entangled coherent states.
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Kumar, Shivani A.
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- 2012
155. NOISE IN SWAPPING BETWEEN TWO PAIRS OF NON-ORTHOGONAL ENTANGLED COHERENT STATES.
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KUMAR, SHIVANI A., PRAKASH, H., CHANDRA, N., and PRAKASH, R.
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COHERENT states , *INFORMATION theory , *PHOTONS , *MATHEMATICAL analysis , *STOCHASTIC processes , *APPLIED mathematics - Abstract
We consider a scheme of swapping between two pairs of non-orthogonal entangled coherent states with our suggested modification [H. Prakash, N. Chandra, R. Prakash and Shivani, Int. J. Mod. Phys. B 23(8) (2009) 2083] and discuss effect of decoherence on fidelity in swapping. We find that for odd photon counts, MAF (minimum of the fidelity for any arbitrary information) decreases with increase in |α|2 for low noise but in case of high noise, it increases, attains a maximum value and then decreases with |α|2. However, for nonzero even photon counts, the case is reversed. For this case, MAF decreases with increase in |α|2 for high noise but in case of low noise, it increases, attains a maximum value and then decreases with |α|2. We discuss the variation of average fidelity with |α|2 and show that it depends appreciably on the information for low values of |α|2 only. [ABSTRACT FROM AUTHOR]
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- 2013
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156. Anti-Aggregation Property of Allicin by In Vitro and Molecular Docking Studies.
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Kumar, Suresh, Kumar, Shivani, and Ram, Heera
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MOLECULAR docking , *AMINO acid residues , *ALZHEIMER'S disease , *MOLECULAR interactions , *GARLIC , *SULFUR compounds - Abstract
Amyloidogenesis is the process in which amyloid beta (Aβ) peptide aggregation results in plaque formation in central nervous system (CNS) are associated with many neurological diseases such as Alzheimer's disease. The peptide aggregation initiated from peptide monomers results in formation of dimers, tetramers, fibrils, and protofibrils. The ability of allicin, a lipid-soluble volatile organosulfur biological compound, present in freshly crushed garlic (Allium sativum L.) to inhibit fibril formation by the Aβ peptide in vitro was investigated in the present study. Inhibition of fibrillogenesis was measured by a Thioflavin T (ThT) fluorescence assay and visualized by transmission electron microscopy (TEM). The molecular interaction between allicin and Aβ peptide was also demonstrated by in silico studies. The results show that allicin strongly inhibited Aβ fibrils by 97% at 300 µM, compared with control (Aβ only) (P <.001). These results were further validated by visual of fibril formation by transmission microscopy and molecular interaction of amyloid peptide with allicin by molecular docking. Aβ forms favourable hydrophobic interaction with Ile32, Met35, Val36, and Val39, and oxygen of allicin forms hydrogen bond with the amino acid residue Lys28. Allicin anti-amyloidogenic property suggests that this naturally occurring compound may have potential to ameliorate and prevent Alzheimer's disease. [ABSTRACT FROM AUTHOR]
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- 2019
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157. Androgen receptor drives polyamine synthesis creating a vulnerability for prostate cancer.
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Kumar R, Jonnatan S, Sanin DE, Vakkala V, Kadam A, Kumar S, Dalrymple SL, Zhao L, Foley J, Holbert CE, Nwafor A, Kittane S, Penner E, Apostolova P, Warner S, Dang CV, Toska E, Thompson EA, Isaacs JT, De Marzo AM, Pearce EL, Stewart TM, Casero RA, Denmeade SR, and Sena LA
- Abstract
Supraphysiological androgen (SPA) treatment can paradoxically restrict growth of castration-resistant prostate cancer with high androgen receptor (AR) activity, which is the basis for use of Bipolar Androgen Therapy (BAT) for patients with this disease. While androgens are widely appreciated to enhance anabolic metabolism, how SPA-mediated metabolic changes alter prostate cancer progression and therapy response is unknown. Here, we report that SPA markedly increased intracellular and secreted polyamines in prostate cancer models. This occurred through AR binding at enhancer sites upstream of the ODC1 promoter to increase abundance of ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine synthesis, and de novo synthesis of polyamines from arginine. SPA-stimulated polyamines enhance prostate cancer fitness, as dCas9-KRAB-mediated inhibition of AR regulation of ODC1 or direct ODC inhibition by difluoromethylornithine (DFMO) increased efficacy of SPA. Mechanistically, this occurred in part due to increased activity of S-adenosylmethionine decarboxylase 1 (AMD1), which was stimulated both by AR and by loss of negative feedback by polyamines, leading to depletion of its substrate S-adenosylmethionine and global protein methylation. These data provided the rationale for a clinical trial testing the safety and efficacy of BAT in combination with DFMO for patients with metastatic castration-resistant prostate cancer. Pharmacodynamic studies of this drug combination in the first five patients on trial indicated that the drug combination resulted in effective polyamine depletion in plasma. Thus, the AR potently stimulates polyamine synthesis, which constitutes a vulnerability in prostate cancer treated with SPA that can be targeted therapeutically.
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- 2024
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158. Transcriptome analysis of Huh7 cells upon Chikungunya virus infection and capsid transfection reveals regulation of distinct cellular and metabolic pathways.
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Gaurav N, Kumar S, Raghavendhar S, Tripathi PK, Gupta S, Arya R, and Patel AK
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- Humans, Capsid metabolism, Virus Replication, Capsid Proteins metabolism, Gene Expression Profiling, Metabolic Networks and Pathways genetics, Chikungunya Fever, Chikungunya virus physiology
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Chikungunya virus (CHIKV) causes persistent arthritis and neurological problems imposing a huge burden globally. The present study aims to understand the interaction mechanism of Chikungunya virus and CHIKV-capsid in Huh7 cells. The RNA-sequencing and qRT-PCR method was used for the transcript and gene profiles of CHIKV virus and CHIKV capsid alone. Transcriptional analysis showed capsid induced 1114 and 956 differentially expressed genes (DEGs) to be upregulated and downregulated respectively, while in virus, 933 genes were upregulated and 956 were downregulated. Total 202 DEGs were common in both capsid and virus; and nine were validated using qRT-PCR. Identified DEGs were found to be associated with metabolic pathways such as Diabetes, cardiac disease, and visual impairment. Further, knock-down study on one of the DEGs (MafA) responsible for insulin regulation showed low viral proteins expression suggesting a reduction in virus-infection. Thus, the study provides insight into the interplay of the virus-host factors assisting virus replication., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2024
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159. Outcomes of Infrainguinal Bypass in Patients with Cannabis vs Opioid Use Disorder.
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Narayanan M, Alnahhal KI, Lingutla R, Irshad A, Iafrati M, Suarez L, Kumar S, and Salehi P
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- Female, Humans, Male, Postoperative Complications epidemiology, Postoperative Complications etiology, Prospective Studies, Retrospective Studies, Treatment Outcome, United States epidemiology, Vascular Surgical Procedures adverse effects, Acute Kidney Injury, Cannabis, Opioid-Related Disorders complications, Opioid-Related Disorders diagnosis, Opioid-Related Disorders epidemiology
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Background: Marijuana and opioids are commonly used illicit drugs in the United States and their use continues to rise. Cannabis use disorder (CUD) and Opioid use disorder (OUD) are associated with adverse effects on public health and postoperative outcomes. However, their impact on vascular surgery, specifically infrainguinal bypass repair (IIB). is not well described in the literature. Therefore, our study aimed to assess perioperative outcomes in patients with CUD and OUD who underwent IIB., Methods: A retrospective analysis of the National Inpatient Sample database for the years 2005 to 2018 was performed. Using the International Classification of Diseases Clinical Modification, Ninth and Tenth revisions, patients who were diagnosed with peripheral artery disease and underwent IIB repair.were identified. Our primary outcome was the comparison of rates of in-hospital complications between the groups, and the secondary outcomes included analysis of total hospital charges and length of stay. A 1:1 propensity score matching (PSM) CUD and OUD patients to their control groups without the disease was conducted using the nearest-neighbor method. The matching was based on select patient demographics and comorbidities included in our analyses., Results: A total of 190,794 patients were identified: 972 patients with CUD and 682 patients with OUD. In the matched cohorts, patients with a diagnosis of CUD had a higher incidence of in-hospital cardiac complications (adjusted Odds Ratio [aOR], 1.76; 95% Confidence Interval [CI], 0.99-3.12) and acute kidney injury (AKI) (aOR, 1.51; CI, 1.09-2.08). Additionally, total hospital charges and mean length of stay were higher in the CUD group (P < 0.001). Those with OUD had a higher incidence of postoperative respiratory complications (aOR, 1.92; CI, 1.23-2.99), sepsis (aOR, 2.39; CI, 1.32-4.34), infection (aOR, 3.55; CI, 1.16-10.84), AKI (aOR, 2.11; CI,1.47-3.04), major amputations (aOR, 1.69; CI, 1.07-2.69), along with higher total charges and mean length of stay (P < 0.001)., Conclusions: Both CUD and OUD have increased incidence of postoperative complications following IIB. The OUD group had generally worse outcomes compared to patients with CUD. Both were associated with a substantial increase in total hospital charges and length of hospital stay. A further prospective study is warranted to provide better insight on the effects of substance use disorders on the procedure's short- and long-term outcomes., (Copyright © 2021 Elsevier Inc. All rights reserved.)
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- 2022
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160. Contrasting roles for G-quadruplexes in regulating human Bcl-2 and virus homologues KSHV KS-Bcl-2 and EBV BHRF1.
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Kumar S, Ramamurthy C, Choudhary D, Sekar A, Patra A, Bhavesh NS, and Vivekanandan P
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- Herpesvirus 4, Human genetics, Humans, Ligands, Promoter Regions, Genetic, Viral Proteins genetics, G-Quadruplexes, Herpesvirus 8, Human genetics
- Abstract
Herpesviruses are known to acquire several genes from their hosts during evolution. We found that a significant proportion of virus homologues encoded by HSV-1, HSV-2, EBV and KSHV and their human counterparts contain G-quadruplex motifs in their promoters. We sought to understand the role of G-quadruplexes in the regulatory regions of viral Bcl-2 homologues encoded by KSHV (KS-Bcl-2) and EBV (BHRF1). We demonstrate that the KSHV KS-Bcl-2 and the EBV BHRF1 promoter G-quadruplex motifs (KSHV-GQ and EBV-GQ) form stable intramolecular G-quadruplexes. Ligand-mediated stabilization of KS-Bcl-2 and BHRF1 promoter G-quadruplexes significantly increased the promoter activity resulting in enhanced transcription of these viral Bcl-2 homologues. Mutations disrupting KSHV-GQ and EBV-GQ inhibit promoter activity and render the KS-Bcl-2 and the BHRF1 promoters non-responsive to G-quadruplex ligand. In contrast, promoter G-quadruplexes of human bcl-2 gene inhibit promoter activity. Further, KS-Bcl-2 and BHRF1 promoter G-quadruplexes augment RTA (a virus-encoded transcription factor)-mediated increase in viral bcl-2 promoter activity. In sum, this work highlights how human herpesviruses have evolved to exploit promoter G-quadruplexes to regulate virus homologues to counter their cellular counterparts., (© 2022. The Author(s).)
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- 2022
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161. Resilience: a mediator of the negative effects of pandemic-related stress on women's mental health in the USA.
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Kumar S, Lee NK, Pinkerton E, Wroblewski KE, Lengyel E, and Tobin M
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- Anxiety epidemiology, Depression epidemiology, Female, Humans, Mental Health, SARS-CoV-2, COVID-19, Pandemics
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The role of resilience in mediating the negative effects of the COVID-19 pandemic on the mental health of US women is poorly understood. We examined socioeconomic factors associated with low resilience in women, the relationship of low resilience with psychiatric morbidity, and the mediating role of resilience in the relationship between pandemic-related stress and other coincident psychiatric morbidities. Using a quota-based sample from a national panel, we conducted a web-based survey of 3200 US women in April 2020. Weighted, multivariate logistic regression was used to model the odds of pandemic-related stress, and coincident depression and anxiety symptoms among those with and without low resilience. Structural equation modeling was used to evaluate resilience as a mediator of the relationship between pandemic-related stress and other coincident psychiatric morbidities. Risk factors for low resilience included younger age, lower household income, lower education, unemployment, East/Southeast Asian race, unmarried/unpartnered status, and higher number of medical comorbidities. Low resilience was significantly associated with greater odds of depression symptoms (OR = 3.78, 95% CI [3.10-4.60]), anxiety symptoms (OR = 4.17, 95% CI [3.40-5.11]), and pandemic-related stress (OR = 2.86, 95% CI [2.26-3.26]). Resilience acted as a partial mediator in the association between pandemic-related stress and anxiety symptoms (proportion mediated = 0.23) and depression symptoms (proportion mediated = 0.28). In the early days of the COVID-19 pandemic, low resilience mediated the association between pandemic-related stress and psychiatric morbidity. Strategies proven to enhance resilience, such as cognitive behavioral therapy, mindfulness-based stress reduction, and addressing socioeconomic factors, may help mitigate mental health outcomes., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)
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- 2022
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162. Variability of gross tumour volume delineation: MRI and CT based tumour and lymph node delineation for lung radiotherapy.
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Kumar S, Holloway L, Boxer M, Yap ML, Chlap P, Moses D, and Vinod S
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- Humans, Lung, Lymph Nodes diagnostic imaging, Magnetic Resonance Imaging methods, Observer Variation, Positron-Emission Tomography methods, Radiotherapy Planning, Computer-Assisted methods, Tumor Burden, Lung Neoplasms diagnostic imaging, Lung Neoplasms radiotherapy, Tomography, X-Ray Computed methods
- Abstract
Purpose: To compare gross tumour volume (GTV) delineation of lung cancer on magnetic resonance imaging (MRI) and positron emission tomography (PET) versus computed tomography (CT) and PET., Methods: Three experienced thoracic radiation oncologists delineated GTVs on twenty-six patients with lung cancer, based on CT registered to PET, T2-weighted MRI registered to PET and T1-weighted MRI registered with PET. All observers underwent education on reviewing T1 and T2 images along with guidance on window and level setup. Interobserver and intermodality variation was performed based on dice similarity coefficient (DSC), Hausdorff distance (HD), and average Hausdorff distance (AvgHD) metrics. To compute interobserver variability (IOV) a simultaneous truth and performance level estimation (STAPLE) volume for each image modality was used as reference volume. For intermodality analysis, each observers CT based primary and nodal GTV was used as reference volume., Results: A mean DSC of 0.9 across all observers for primary GTV (GTVp) and a DSC of >0.7 for nodal GTV (GTVn) was demonstrated for IOV. Mean T2 and T1 GTVp and GTVn were smaller than CT GTVp and GTVn but the difference in volume between modalities was not statistically significant. Significant difference (p < 0.01) for GTVp and GTVn was found between T2 and T1 GTVp and GTVn compared to CT GTVp and GTVn based on DSC metrics. Large variation in volume similarity was noted based on HD of up-to 5.4 cm for observer volumes compared to STAPLE volume., Conclusion: Interobserver variability in GTV delineation was similar for MRI and PET versus CT and PET. The significant difference between MRI compared to CT delineated volumes needs to be further explored., Competing Interests: Conflict of interest The authors whose names are listed immediately below certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (Copyright © 2021 Elsevier B.V. All rights reserved.)
- Published
- 2022
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163. Identification of phytochemicals as potential therapeutic agents that binds to Nsp15 protein target of coronavirus (SARS-CoV-2) that are capable of inhibiting virus replication.
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Kumar S, Kashyap P, Chowdhury S, Kumar S, Panwar A, and Kumar A
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- Molecular Docking Simulation, Molecular Dynamics Simulation, SARS-CoV-2 physiology, Software, Antiviral Agents pharmacology, Endoribonucleases antagonists & inhibitors, Phytochemicals pharmacology, SARS-CoV-2 drug effects, Viral Nonstructural Proteins antagonists & inhibitors, Virus Replication drug effects
- Abstract
Background: Coronavirus disease 2019 (COVID-19) playing havoc across the globe caused 585,727 deaths and 13,616,593 confirmed cases so far as per World Health Organization data released till 17th July 2020. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2) is responsible for causing this pandemic across different continents. It is not only impacting the world economy but also quarantined millions of people in their homes or hospitals., Purpose: At present, there is no Food and Drug Administration-approved drug or vaccine available to treat this disease. Still, people are trying various pre-existing medicines that are known to have anti-viral or anti-parasitic effects. In view of this, the present study aimed to study the binding potential of various phytochemicals present in multiple natural plant extract as a secondary metabolite to non-structural protein 15 (Nsp15) protein, a drug target known to play a crucial role in virulence of coronavirus., Method: Nsp15 protein was selected because it shows 89% similarity to the other SARS-CoV, which caused the earlier outbreak. The assumption is that inhibition of Nsp15 slowdowns the viral replication. Phytochemicals are selected as these are present in various plant parts (seed, flower, roots, etc.), which are used in different food cuisines in different geographical regions across the globe. The molecular docking approach was performed using two different software, i.e., Autodock, and Swissdock, to study the interaction of various phytochemicals with Nsp15 protein. Hydroxychloroquine is used as a positive control as it is used by medical professionals showing some positive effects in dealing with coronavirus., Results: The present study demonstrated the binding potential of approximately 50 phytochemicals with Nsp15 and capable of inhibiting the viral replication, although in vitro and in vivo tests are required to confirm these findings., Conclusions: In conclusion, the present study successfully demonstrated the binding of phytochemicals such as sarsasapogenin, ursonic acid, curcumin, ajmalicine, novobiocin, silymarin and aranotin, piperine, gingerol, rosmarinic acid, and alpha terpinyl acetate to Nsp15 viral protein and they might play a key role in inhibiting SARS-CoV-2 replication., (Copyright © 2020. Published by Elsevier GmbH.)
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- 2021
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164. Improvements in HOMA indices and pancreatic endocrinal tissues in type 2-diabetic rats by DPP-4 inhibition and antioxidant potential of an ethanol fruit extract of Withania coagulans.
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Ram H, Kumar P, Purohit A, Kashyap P, Kumar S, Kumar S, Singh G, Alqarawi AA, Hashem A, Abd-Allah EF, Al-Arjani AF, and Singh BP
- Abstract
Context: Withania coagulans (Stocks) Dunal fruits are used in the therapeutics of several ailments due to possessing of potent phytoconstituents which is also used traditionally for curing the diabetes., Objective: The present study was assessing the amelioration potential of the phytochemicals of an ethanol fruit extract of W. coagulans (Stocks) Dunal in the HOMA (Homeostatic model assessment) indices and pancreatic endocrinal tissues by inhibition of DPP-4 and antioxidants activities., Material and Methods: The identification of phytoconstituents of the test extract was performed by LCMS. Further, assessments of in-vitro, in-vivo and in-silico were achieved by following standard methods. In-vivo studies were conducted on type-2 diabetic rats., Results: The chosen extract inhibited DPP-4 activity by 63.2% in an in vitro assay as well as significantly inhibit serum DPP-4 levels. Accordingly, the administration of the ethanol fruit extract resulted in a significant (P ≤ 0.001) alterations in the lipid profile, antioxidant levels, and HOMA indices. Moreover, pancreatic endocrinal tissues (islet of Langerhans) appeared to have the restoration of normal histoarchitecture as evidenced by increased cellular mass. Molecular docking (Protein-ligands) of identified phytoconstituents with DPP-4 (target enzyme) shown incredibly low binding energy (Kcal/mol) as required for ideal interactions. ADMET analysis of the pharmacokinetics of the identified phytoconstituents indicated an ideal profile as per Lipinski laws., Conclusion: It can be concluded that the phytoconstituents of an ethanol fruit extract of W. coagulans have the potential to inhibit DPP-4 which result in improved glucose homeostasis and restoration of pancreatic endocrinal tissues in type-2 diabetic rats.
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- 2021
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165. Discovery of new phenyl sulfonyl-pyrimidine carboxylate derivatives as the potential multi-target drugs with effective anti-Alzheimer's action: Design, synthesis, crystal structure and in-vitro biological evaluation.
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Manzoor S, Prajapati SK, Majumdar S, Raza MK, Gabr MT, Kumar S, Pal K, Rashid H, Kumar S, Krishnamurthy S, and Hoda N
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- Acetylcholinesterase metabolism, Alzheimer Disease drug therapy, Blood-Brain Barrier drug effects, Butyrylcholinesterase metabolism, Cell Line, Tumor, Cholinesterase Inhibitors chemical synthesis, Cholinesterase Inhibitors metabolism, Cholinesterase Inhibitors pharmacology, Humans, Molecular Docking Simulation, Neuroprotective Agents chemical synthesis, Neuroprotective Agents metabolism, Nootropic Agents chemical synthesis, Nootropic Agents metabolism, Protein Binding, Pyrimidines chemical synthesis, Pyrimidines metabolism, Sulfonamides chemical synthesis, Sulfonamides metabolism, Neuroprotective Agents pharmacology, Nootropic Agents pharmacology, Pyrimidines pharmacology, Sulfonamides pharmacology
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Alzheimer's disease (AD) is multifactorial, progressive neurodegeneration with impaired behavioural and cognitive functions. The multitarget-directed ligand (MTDL) strategies are promising paradigm in drug development, potentially leading to new possible therapy options for complex AD. Herein, a series of novel MTDLs phenylsulfonyl-pyrimidine carboxylate (BS-1 to BS-24) derivatives were designed and synthesized for AD treatment. All the synthesized compounds were validated by
1 HNMR,13 CNMR, HRMS, and BS-19 were structurally validated by X-Ray single diffraction analysis. To evaluate the plausible binding affinity of designed compounds, molecular docking study was performed, and the result revealed their significant interaction with active sites of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The synthesized compounds displayed moderate to excellent in vitro enzyme inhibitory activity against AChE and BuChE at nanomolar (nM) concentration. Among 24 compounds (BS-1 to BS-24), the optimal compounds (BS-10 and BS-22) displayed potential inhibition against AChE; IC50 = 47.33 ± 0.02 nM and 51.36 ± 0.04 nM and moderate inhibition against BuChE; IC50 = 159.43 ± 0.72 nM and 153.3 ± 0.74 nM respectively. In the enzyme kinetics study, the compound BS-10 displayed non-competitive inhibition of AChE with Ki = 8 nM. Respective compounds BS-10 and BS-22 inhibited AChE-induced Aβ1-42 aggregation in thioflavin T-assay at 10 μM and 20 μM, but BS-10 at 10 μM and 20 μM concentrations are found more potent than BS-22. In addition, the aggregation properties were determined by the dynamic light scattering (DLS) and was found that BS-10 and BS-22 could significantly inhibit self-induced as well as AChE-induced Aβ1-42 aggregation. The effect of compounds (BS-10 and BS-22) on the viability of MC65 neuroblastoma cells and their capability to cross the blood-brain barrier (BBB) in PAMPA-BBB were further studied. Further, in silico approach was applied to analyze physicochemical and pharmacokinetics properties of the designed compounds via the SwissADME and PreADMET server. Hence, the novel phenylsulfonyl-pyrimidine carboxylate derivatives can act as promising leads in the development of AChE inhibitors and Aβ disaggregator for the treatment of AD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)- Published
- 2021
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166. Synthesis of novel 4-methylthiocoumarin and comparison with conventional coumarin derivative as a multi-target-directed ligand in Alzheimer's disease.
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Kumar S, Tyagi YK, Kumar M, and Kumar S
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Alzheimer's disease (AD) is a multifactorial disorder characterized by cognitive deficit and memory loss. The pathological feature of the disease involves β-amyloid senile plaques, reduced levels of acetylcholine neurotransmitter, oxidative stress and neurofibrillary tangles formation within the brain of AD patients. The present study aims to screen the inhibitory activity of newly synthesized and existing novel 4-methylthiocoumarin derivative against acetylcholinesterase, butyrylcholinesterase, BACE1, β-amyloid aggregation and oxidative stress involved in the AD pathogenesis. The in vitro assays used in this study were Ellman's assay, FRET assays, Thioflavin T, transmission electron microscopy, circular dichroism, FRAP, and TEAC. Molecular docking and dynamics studies were performed to correlate the results. C3 and C7 (thiocoumarin derivatives) were found to be the most potent inhibitors of acetylcholinesterase (IC
50 -5.63 µM) and butyrylcholinesterase (IC50 -3.40 µM) using Ellman's assays. Enzyme kinetic studies showed that C3 and C7 compounds followed by the mixed mode of inhibition using LB plot. C3 also moderately inhibited the BACE1 using FRET assay. C3 inhibited the fibrillization of β-amyloid peptides in a concentration-dependent manner as observed by Thioflavin T, TEM studies and Circular dichroism data. Molecular modeling studies were performed to understand the probable mode of binding of C3 and C7 in the binding pocket of acetylcholinesterase, butyrylcholinesterase, BACE1 and amyloid β peptides. This indicates the important role of hydrophobic interactions between C3 and acetylcholinesterase. C3 also exhibited significant antioxidant potential by FRAP and TEAC assays. Hence, C3 might serve as a promising lead for developing novel multi target-directed ligand for the treatment of AD., Competing Interests: Conflict of interestOn behalf of all authors, the corresponding author states that there is no conflict of interest., (© King Abdulaziz City for Science and Technology 2020.)- Published
- 2020
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167. Analysis of G-quadruplexes upstream of herpesvirus miRNAs: evidence of G-quadruplex mediated regulation of KSHV miR-K12-1-9,11 cluster and HCMV miR-US33.
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Kumar S, Choudhary D, Patra A, Bhavesh NS, and Vivekanandan P
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- Cell Line, G-Quadruplexes, Gene Expression genetics, HEK293 Cells, Humans, Ligands, Promoter Regions, Genetic genetics, RNA, Viral genetics, Regulatory Sequences, Nucleic Acid genetics, Cytomegalovirus genetics, Herpesvirus 8, Human genetics, MicroRNAs genetics
- Abstract
Background: G-quadruplexes regulate gene expression, recombination, packaging and latency in herpesviruses. Herpesvirus-encoded miRNAs have been linked to important biological functions. The presence and the biological role of G-quadruplexes have not been studied in the regulatory regions of virus miRNA. We hypothesized that herpesvirus-encoded miRNAs are regulated by G-quadruplexes in their promoters., Results: We analyzed the 1 kb regulatory regions of all herpesvirus-encoded miRNAs for the presence of putative quadruplex-forming sequences (PQS). Over two-third (67%) of the regulatory regions of herpesvirus miRNAs had atleast 1 PQS. The 200 bp region of the promoter proximal to herpesvirus miRNA is particularly enriched for PQS. We chose to study the G-quadruplex motifs in the promoters of miR-K12 cluster in Kaposi's sarcoma-associated Herpesvirus (KSHV miR-K12-1-9,11) and the miR-US33 encoded by Human Cytomegalovirus (HCMV miR-US33). Biophysical characterization indicates that the G-quadruplex motifs in the promoters of the KSHV miR-K12 cluster and the HCMV miR-US33 form stable intramolecular G-quadruplexes in vitro. Mutations disrupting the G-quadruplex motif in the promoter of the KSHV miR-K12 cluster significantly inhibits promoter activity, while those disrupting the motif in the promoter of HCMV miR-US33 significantly enhance the promoter activity as compared to that of the respective wild-type promoter. Similarly, the addition of G-quadruplex binding ligands resulted in the modulation of promoter activity of the wild-type promoters (with intact G-quadruplex) but not the mutant promoters (containing quadruplex-disrupting mutations)., Conclusion: Our findings highlight previously unknown mechanisms of regulation of virus-encoded miRNA and also shed light on new roles for G-quadruplexes in herpesvirus biology.
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- 2020
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168. Prion protein transcription is auto-regulated through dynamic interactions with G-quadruplex motifs in its own promoter.
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Pradhan P, Srivastava A, Singh J, Biswas B, Saini A, Siddique I, Kumari P, Khan MA, Mishra A, Yadav PK, Kumar S, Bhavesh NS, Venkatraman P, Vivekanandan P, and Kundu B
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- Cells, Cultured, Feedback, Physiological, Humans, Prion Proteins biosynthesis, Prion Proteins chemistry, Prion Proteins metabolism, G-Quadruplexes, Gene Expression Regulation, Prion Proteins genetics, Promoter Regions, Genetic, Transcription, Genetic
- Abstract
Cellular prion protein (PrP) misfolds into an aberrant and infectious scrapie form (PrP
Sc ) that lead to fatal transmissible spongiform encephalopathies (TSEs). Association of prions with G-quadruplex (GQ) forming nucleic acid motifs has been reported, but implications of these interactions remain elusive. Herein, we show that the promoter region of the human prion gene (PRNP) contains two putative GQ motifs (Q1 and Q2) that assume stable, hybrid, intra-molecular quadruplex structures and bind with high affinity to PrP. Here, we investigate the ability of PrP to bind to the quadruplexes in its own promoter. We used a battery of techniques including SPR, NMR, CD, MD simulations and cell culture-based reporter assays. Our results show that PrP auto-regulates its expression by binding and resolving the GQs present in its own promoter. Furthermore, we map this resolvase-like activity to the N-terminal region (residues 23-89) of PrP. Our findings highlight a positive transcriptional-translational feedback regulation of the PRNP gene by PrP through dynamic unwinding of GQs in its promoter. Taken together, our results shed light on a yet unknown mechanism of regulation of the PRNP gene. This work provides the necessary framework for a plethora of studies on understanding the regulation of PrP levels and its implications in prion pathogenesis., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2019. Published by Elsevier B.V.)- Published
- 2020
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169. Defining the utility of anteroposterior venography in the diagnosis of venous iliofemoral obstruction.
- Author
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Lau I, Png CYM, Eswarappa M, Miller M, Kumar S, Tadros R, Vouyouka A, Marin M, Faries P, and Ting W
- Subjects
- Angioplasty, Balloon instrumentation, Chronic Disease, Collateral Circulation, Female, Femoral Vein physiopathology, Humans, Iliac Vein physiopathology, Male, Middle Aged, Predictive Value of Tests, Regional Blood Flow, Reproducibility of Results, Retrospective Studies, Stents, Treatment Outcome, Ultrasonography, Interventional, Venous Insufficiency physiopathology, Venous Insufficiency therapy, Femoral Vein diagnostic imaging, Iliac Vein diagnostic imaging, Phlebography, Venous Insufficiency diagnostic imaging
- Abstract
Background: Intravascular ultrasound (IVUS) is the current standard for the diagnosis of obstruction in the iliac and femoral veins. However, multiple venographic findings including collaterals, pancaking, and contrast thinning have been suggested to improve the sensitivity of venography. The objective of our study was to further elucidate where and how anteroposterior venography may successfully guide the diagnosis of venous obstruction., Methods: A retrospective review of patients with chronic venous insufficiency who received iliofemoral stenting by a single practitioner at a tertiary medical center between January 2014 and August 2016 was performed. Patients who had records of anteroposterior venography and IVUS were included. Patients who underwent reoperation, did not have complete records of venography and IVUS, or had preoperative acute deep vein thrombosis were excluded. All patients with a greater than 50% luminal area reduction by IVUS underwent balloon angioplasty and stent placement. The locations of stenosis, collaterals, pancaking, and contrast thinning with venography, the locations of stenosis with IVUS, and the location of each stent placed were recorded., Results: There were 107 patients who underwent venous stenting guided by venography and IVUS in this study. Six patients who underwent reoperation, 1 patient who had an acute preoperative deep vein thrombosis, and 14 patients who had incomplete records were excluded. Thus, 86 patients with 77 left lower extremity and 68 right lower extremity studies were available for analysis. The sensitivity by stenosis on venography was 4% in the left common iliac vein (CIV), 44% in the left external iliac vein (EIV), and 44% in the common femoral vein (CFV). The sensitivity by stenosis on venography in the right CIV, EIV, and CFV was 21%, 46%, and 40%, respectively. Combined, pancaking and collaterals had a sensitivity of 97% in the left CIV. IVUS resulted in a change in plan in 2%, 32%, and 48% of patients in the left CIV, EIV, and CFV, and in 26%, 35%, and 48% of patients in the right CIV, EIV, and CFV, respectively., Conclusions: Anteroposterior venography can indirectly diagnose obstruction of the left CIV through the identification of collaterals and pancaking. The combination of low sensitivity and a high rate of change of plan owing to IVUS precludes complete reliance on anteroposterior venography for the diagnosis of lesions in the left EIV and CFV and the right CIV, EIV, and CFV. IVUS must be used to comprehensively identify all venous iliofemoral lesions., (Copyright © 2019 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
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170. Dual Inhibition of DPP-4 and Cholinesterase Enzymes by the Phytoconstituents of the Ethanolic Extract of Prosopis cineraria Pods: Therapeutic Implications for the Treatment of Diabetes-associated Neurological Impairments.
- Author
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Ram H, Jaipal N, Kumar P, Deka P, Kumar S, Kashyap P, Kumar S, Singh BP, Alqarawi AA, Hashem A, Tabassum B, and Abd Allah EF
- Subjects
- Animals, Antioxidants chemistry, Antioxidants pharmacology, Cholinesterase Inhibitors chemistry, Diabetes Mellitus, Experimental drug therapy, Diabetes Mellitus, Experimental enzymology, Diabetes Mellitus, Experimental pathology, Ethanol chemistry, Molecular Docking Simulation, Nervous System Diseases enzymology, Nervous System Diseases etiology, Nervous System Diseases pathology, Pancreas drug effects, Pancreas pathology, Phytochemicals chemistry, Phytochemicals pharmacology, Plant Extracts chemistry, Rats, Cholinesterase Inhibitors pharmacology, Diabetes Mellitus, Experimental complications, Dipeptidyl-Peptidase IV Inhibitors pharmacology, Nervous System Diseases drug therapy, Plant Extracts pharmacology, Prosopis
- Abstract
Background: Insulin resistance causes decreased uptake of glucose which promotes the susceptibility of type 2 associated neurological impairments., Methods: The study was aimed to evaluate the inhibition potential of the ethanolic extract of Prosopis cineraria (EPC) pods against DPP-4 and cholinesterase enzymes by in-vitro, in-vivo and in-silico assessments. The present study consists of in vivo studies on a diabetes-induced rat model by HOMA (Homeostasis model assessment) and related parameters, in vitro studies through the DPP-4 enzyme assay and cholinesterase assays using Ellman's reaction. The in-silico studies were conducted by the molecular docking of Cinerin C with targeted enzymes. The phytochemical characterization of the extract was demonstrated through LCMS studies. The antioxidant studies on the extract were performed by FRAP and TEAC assays., Results: The extract showed 64.8% maximum inhibition of DPP-4, 34.91% inhibition of AChE and 74.35% inhibition of BuChE. The antioxidant capacity of the extract was observed to be 847.81±16.25μM Fe2+ equivalent in the FRAP assay and 0.40 ± 0.08 mmol/l of Trolox equivalent in the TEAC assay. The in vivo study showed competent glycaemic control against significant HOMA IR (1.5), HOMA % β (26.5) and HOMA % S (68.8) as well as pancreatic cell mass proliferation. The insilico analysis also revealed positive interactions of Cinerin C with targeted enzymes (DPP4 and cholinesterase)., Conclusion: It can be concluded that the phytoconstituents of Prosopis cineraria pod extract can be significantly considered in neuropharmacology to resolve insulin resistance-induced neurological complications as it showed inhibition against DPP-4, AChE and BuChE target enzymes., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Published
- 2019
- Full Text
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171. Comparison of four dimensional computed tomography and magnetic resonance imaging in abdominal radiotherapy planning.
- Author
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Oar A, Liney G, Rai R, Deshpande S, Pan L, Johnston M, Jameson M, Kumar S, and Lee M
- Abstract
Background and Purpose: Four-dimensional (4D) computed tomography (CT) is widely used in radiotherapy (RT) planning and remains the current standard for motion evaluation. We assess a 4D magnetic resonance imaging (MRI) sequence in terms of motion and image quality in a phantom, healthy volunteers and patients undergoing RT., Materials and Methods: The 4D-MRI sequence is a prototype T1-weighted 3D gradient echo with radial acquisition with self-gating. The accuracy of the 4D-MRI respiratory sorting based method was assessed using a MRI-CT compatible respiratory simulation phantom. In volunteers, abdominal viscera were evaluated for artefact, noise, structure delineation and overall image quality using a previously published four-point scoring system. In patients undergoing abdominal RT, the tumour (or a surrogate) was utilized to assess the range of motion on both 4D-CT and 4D-MRI. Furthermore, imaging quality was evaluated for both 4D-CT and 4D-MRI., Results: In phantom studies 4D-MRI demonstrated amplitude of motion error of less than 0.2 mm for five, seven and ten bins. 4D-MRI provided excellent image quality for liver, kidney and pancreas. In patients, the median amplitude of motion seen on 4D-CT and 4D-MRI was 11.2 mm (range 2.8-20.3 mm) and 10.1 mm (range 0.7-20.7 mm) respectively. The median difference in amplitude between 4D-CT and 4D-MRI was -0.6 mm (range -3.4-5.2 mm). 4D-MRI demonstrated superior edge detection (median score 3 versus 1) and overall image quality (median score 2 versus 1) compared to 4D-CT., Conclusions: The prototype 4D-MRI sequence demonstrated promising results and may be used in abdominal targeting, motion gating, and towards implementing MRI-based adaptive RT., (© 2018 The Authors. Published by Elsevier B.V. on behalf of European Society of Radiotherapy & Oncology.)
- Published
- 2018
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172. MRI in radiotherapy for lung cancer: A free-breathing protocol at 3T.
- Author
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Kumar S, Rai R, Moses D, Choong C, Holloway L, Vinod SK, and Liney G
- Subjects
- Humans, Radiotherapy Planning, Computer-Assisted methods, Breath Holding, Image Processing, Computer-Assisted methods, Lung Neoplasms diagnostic imaging, Lung Neoplasms radiotherapy, Magnetic Resonance Imaging methods
- Abstract
Imaging plays a significant role in radiation therapy. Improvements in treatment delivery require sophisticated imaging technologies to define tumor volume accurately. Magnetic resonance imaging scans can provide morphological and functional information and are increasingly being used in imaging for radiation therapy; however, for lung cancer, most protocols are based on breath-hold imaging and noncompliance to breath-hold maneuver can lead to significant artifacts. For patients presenting for lung cancer radiation therapy, maintaining a breath hold can be impossible. This paper describes a completely free-breathing lung magnetic resonance imaging protocol for use in radiation therapy for lung cancer., (Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
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