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Background: An ongoing global public health concern is the emerging COVID-19 pandemic triggered by acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Mpro, a main protease of SARSCoV- 2, has been established as a potential drug target because of its direct role in viral replication and ability to infiltrate the multiple host pathways. Objective: This research aims to classify new therapeutic drug candidates who may be repositioned for COVID-19 therapeutics. Methods: We have taken similar drug compounds of Dexamethasone and targeted the main protease of SARS-CoV-2 (Mpro) along with the key molecules involved in the 'cytokine storm.' Further, we did MD simulations and calculated the molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) on the active site of the main protease of SARS-CoV-2 (Mpro) and TNF-α, IL-6, & IL-1β to explore the binding affinity and stability. Results: Based on our study outcome, Triamcinolone emerged as the most promising inhibitor of the main protease of SARS-CoV-2 (Mpro) and the cytokine storm molecules, i.e., TNF-α, IL-6, and IL-1β. Conclusion: This research investigates the repositioning of COVID-19 drugs as a new therapeutic application.

Chronic inflammation is a major factor in tumor growth and progression. Cancer cells secrete C-X-C chemokine ligand 8 (CXCL8) along with its receptor C-X-C chemokine receptor 1 (CXCR1) and chemokine receptor 2 (CXCR2). It plays a significant role in the activation and trafficking of inflammatory mediators, tumor proliferation and interferes in breast cancer development by controlling cell adhesion, proliferation, migration, and metastasis. This axis also plays a significant role in driving different cancers and melanomas, including breast cancer progression, by controlling stem cell masses. Few small-molecule CXCR1/2 inhibitors and CXCL8 releasing inhibitors have been identified in the past two decades that bind these receptors in their inactive forms and blocks their signaling as well as the biological activities associated with inflammation. Inhibitors of certain inflammatory molecules are projected to be more efficient in different inflammatory diseases. Preclinical trials indicate that patients may be benefitted from combined treatment with targeted drugs, chemotherapies, and immunotherapies. Thus, targeting the CXCL8-CXCR1/2 signaling axis in breast cancer could be a promising approach for its therapeutics. This review examines the roles of the CXCL8-CXCR1/2 signaling axis and how it is implicated in the tumor microenvironment in breast cancer. In addition, we also discuss the potential role of the CXCL8-CXCR1/2 axis in targeted therapeutics for breast cancer.

Breast cancer is recognized globally as one of the leading causes of malignant morbidity. It is a heterogeneous disease that accounts for 30 percent of all women diagnosed with cancer. To bring an anti-cancer drug from the bench to the bedside is an expensive and time-consuming process. The drug repurposing approach targets new enemies (new diseases) with old weapons (known drugs). The present study identified an FDA-approved drug targeting the γ-secretase complex involved in the Notch signaling pathway in breast cancer stem cells (BCSCs). A literature survey and in-silico study identified Venetoclax as a γ-secretase inhibitor (GSI) from 1615 FDA-approved drug compounds. In-silico docking potential of Venetoclax was better than the standard γ-secretase inhibitor RO4929097. Also, the molecular dynamics simulations of 200 ns confirmed the stability of the Venetoclax-γ-secretase complex. These findings suggest that the use of Venetoclax represents a potential γ-secretase inhibitor in breast cancer stem cells. Eventually, the in vitro and clinical evaluation will be needed to confirm the potential chemopreventive and treatment effects of Venetoclax against breast cancer and breast cancer stem cells. Venetoclax appeared as the most promising drug of the 1615 FDA-approved drugs. Our in-silico findings suggest that Venetoclax may act as a γ-secretase inhibitor against the Notch signaling pathway in breast cancer stem cells.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has taken over the world, and more than 38 lakh deaths had been reported till now due to this infectious disease. It has been declared a global pandemic by the world health organization. SARS-CoV-2 causes coronavirus disease of 2019 (COVID-19), and the major problem called “Cytokine storm” is reported, which may lead to death among the COVID-19 patients. This study aimed to review the Cytokine storm and its mechanism along with few immunomodulatory therapies for SARSCoV- 2 infection suppression effectively. Methods: The recently published works of literature were selected and reviewed based on the subject of this study. The databases, including Pubmed, ScienceDirect, Scopus, and Google Scholar, were searched extensively. Results: The review of the literature showed that an uncontrolled immune response causes excess inflammation. Evidence from recent trials has demonstrated that cytokine storms can be an important factor in the COVID-19 severity, leading to multiple organ failure and death. Conclusion: This study reviewed immunomodulatory therapies and strategies for SARS-CoV-2 infected patients to suppress the immune response. Ultimately, the cytokine storm can prove to be a boon and reduce the significant death tolls to SARS-CoV-2 infection.

The Coronavirus Disease 2019 (COVID-19), also known as a novel coronavirus (2019-n- CoV), reportedly originated from Wuhan City, Hubei Province, China. Coronavirus Disease 2019 rapidly spread all over the world within a short period. On January 30, 2020, the World Health Organization (WHO) declared it a global epidemic. COVID-19 is a Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) evolves to respiratory, hepatic, gastrointestinal, and neurological complications, and eventually death. SARS-CoV and the Middle East Respiratory Syndrome coronavirus (MERS-CoV) genome sequences similar identity with 2019-nCoV or Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). However, few amino acid sequences of 2019-nCoV differ from SARS-CoV and MERS-CoV. COVID-19 shares about 90% amino acid sequence similarity with SARS-CoV. Effective prevention methods should be taken in order to control this pandemic situation. To date, there are no effective treatments available to treat COVID-19. This review provides information regarding COVID-19 history, epidemiology, pathogenesis and molecular diagnosis. Also, we focus on the development of vaccines in the management of this COVID-19 pandemic and limiting the spread of the virus.

Cancer stem cells (CSCs) are indispensable for development, progression, drug resistance, and tumor metastasis. Current cancer-directed interventions target targeting rapidly dividing cancer cells and slow dividing CSCs, which are the root cause of cancer origin and recurrence. The most promising targets include several self-renewal pathways involved in the maintenance and renewal of CSCs, such as the Wnt/β-Catenin, Sonic Hedgehog, Notch, Hippo, Autophagy, and Ferroptosis. In view of safety, natural compounds are coming to the front line of treatment modalities for modifying various signaling pathways simultaneously involved in maintaining CSCs. Therefore, targeting CSCs with natural compounds is a promising approach to treating various types of cancers. In view of this, here we provide a comprehensive update on the current status of natural compounds that effectively tune key self-renewal pathways of CSCs. In addition, we highlighted surface expression markers in several types of cancer. We also emphasize how natural compounds target these self-renewal pathways to reduce therapy resistance and cancer recurrence properties of CSCs, hence providing valuable cancer therapeutic strategies. The inclusion of nutraceuticals is believed to enhance the therapeutic efficacy of current cancer-directed interventions significantly.

At the end of December 2019, in Wuhan, China, a rapidly spreading unknown virus was reported to have caused coronavirus disease of 2019 (COVID-19). Origin linked to Wuhan’s wholesale food market where live animals are sold. This disease is caused by SARS Coronavirus-2 (SARS-CoV-2), which is closely related to the Severe Acute Respiratory Coronavirus (SARS-CoV) and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). This virus shares a high sequence identity with bat-derived SARS-like Coronavirus, which indicating its zoonotic origin. The virus spread globally, provoking widespread attention and panic. This Coronavirus is highly pathogenic and causes mild to severe respiratory disorders. Later, it was declared a global pandemic by the World Health Organization (WHO) due to its highly infectious nature and worldwide mortality rate. This virus is a single-stranded, positive-sense RNA genome, and its genome length about 26 to 32 kb that infects a broad range of vertebrates. The researchers worldwide focus on establishing treatment strategies on drug and vaccine development to prevent this COVID-19 pandemic. A drug repurposing approach has been used to identify a rapid treatment for the people affected by COVID-19, which could be cost-effective and bypass some Food and Drug Association (FDA) regulations to move quickly in phase-3 trials. However, there is no promising therapeutic option available yet. This book chapter addresses current information about the COVID-19 disease, including its origins, impacts, and the novel potential drug candidates that can help treat the COVID-19.

The complexes of Co(II), Ni(II), Cu(II) and Zn(II) metal ions has been synthesized through template method by the condensation of succinic acid dihydrazide with 5-chloroisatin in alcoholic medium. Complexes were characterized by C H N analysis, molar conductance, thermal analysis, magnetic susceptibility, mass spectrometry, FTIR, EPR, 1H NMR, UV–Visible spectroscopy. These studies suggest an octahedral geometry for all the complexes. The compounds were found active against B. subtilis and S. aureus and P. aeruginosa and E. coli bacteria. The Zn(II) complex showed significant anticancer activity against Squamous Cell Carcinoma cells tested by the MTT assay method. Molecular docking studies with EGFR tyrosine kinase were also carried out. All these results show that some of the synthesized compounds have remarkable antibacterial and anticancer property.

Immunological memory is critical for host immunity and decisive for individual to respond exponentially to previously encountered infection. Both T and B cell memory are known to orchestrate immunological memory with their central and effector memory arms contributing in prolonged immunity/defence mechanisms of host. While central memory helps in maintaining prolonged immunity for a particular infection, effector memory helps in keeping local/seasonal infection in control. In addition to this, generation of long-lived plasma cells is pivotal for generating neutralizing antibodies which can enhance recall and B cell memory to control re-infection. In view of this, scaling up memory response is one of the major objectives for the expected outcome of vaccination. In this line, this review deals with the significance of memory cells, molecular pathways of their development, maintenance, epigenetic regulation and negative regulation in various infections. We have also highlighted the significance of both T and B cell memory responses in the vaccination approaches against range of infections which is not fully explored so far.[Box: see text].

Fibromyalgia (FM) or Fibromyalgia Syndrome (FMS) is a neurodegenerative disorder causing musculoskeletal pain, tenderness, stiffness, fatigue, and sleep disorder in the body. It is one of the most common chronic pain conditions, affecting about 6% of the world population. Being refractory, till date, no specific treatment of this disease is available. Accumulating evidences over the last few decades indicate that proinflammatory macrophages, cytokines, & chemokines as the key players in this disease. Recent findings suggest activation of Microglial cells and associated pro-inflammatory signals as one of the major causes of chronic pain in patients suffering from fibromyalgia. Increased density of iNOs/CD68+ M1 effector macrophages has been associated with neuropathic pain models. In light of this, depletion of these pro-inflammatory macrophages has been shown to reduce sensitivity to neuropathic pain. On the other hand, modulating pattern of AGEs (Advanced Glycation End-Products) can also contribute to inactivation of macrophages. These findings strongly suggest that macrophages are critical in both inflammatory and neuropathic pain. Therefore, this chapter highlights the impact of macrophage plasticity in various immunopathological aspects of fibromyalgia.

Introduction Drug repurposing is the need of the hour considering the medical emergency caused by the COVID-19 pandemic. Recently, cytokine storm by the host immune system has been linked with high viral load, loss of lung function, acute respiratory distress syndrome (ARDS), multiple organ failure, and subsequent fatal outcome. Objective This study aimed to identify potential FDA approved drugs that can be repurposed for COVID-19 treatment using an in-silico analysis. Methods In this study, virtual screening of selected FDA approved drugs was performed by targeting the main protease (Mpro) of SARS-CoV-2 and the key molecules involved in the ‘Cytokine storm’ in COVID-19 patients. Based on our preliminary screening supported by extensive literature search, we selected FDA approved drugs to target the SARS-CoV-2 main protease (Mpro) and the key players of cytokine storm, TNF-α, IL-6, and IL-1β. These compounds were examined based on systematic docking studies and further validated using a combination of molecular dynamics simulations and molecular mechanic/generalized/Born/Poisson-Boltzmann surface area (MM/G/P/BSA) free energy calculations. Results Based on the findings, Rifampicin and Letermovir appeared as the most promising drug showing a very good binding affinity with the main protease of SARS-CoV-2 and TNF-α, IL-6, and IL-1β. However, it is pertinent to mention here that our findings need further validation by in vitro analysis and clinical trials. Conclusion This study provides an insight into the drug repurposing approach in which several FDA approved drugs were examined to inhibit COVID-19 infection by targeting the main protease of SARS-COV-2 and the cytokine storm. Graphic abstract Supplementary Information The online version contains supplementary material available at 10.1007/s43440-021-00228-0.

Hyper activation of macrophages contributes to acute respiratory distress syndrome, respiratory failure, and subsequent death of COVID-19 cases. Given this, tempering macrophage plasticity is paramount and the highest priority for the management of COVID-19 cases. In this context we here propose that either exchange or in situ re-programming of derailed Th17+ alveolar macrophages/ Slan+ DC with Th1 programmed counterpart would potentially mitigate or abolish pulmonary fibrosis. This approach is also anticipated to afford antiviral immune response and promote recovery in the patients and hold tremendous potential for managing severely infected patients by both curbing viruses and enhancing post-treatment recovery.

COVID-19 pandemic, a novel coronavirus disease is caused by severe acute respiratory syndrome corona virus, SARS-CoV-2. It was first reported in Wuhan, China and has now expanded to more than 190 countries across the world. Till date, there is no specific medication available to prevent or target SARS CoV-2 infection. Very recently, the crystal structure of COVID- 19 main protease (Mpro) was revealed by Liu et al. (2020). SARS-CoV-2 main protease (Mpro) is a key enzyme that plays a crucial role in viral replication and transcription. Thus, Mpro could be a promising target to inhibit SARS-CoV-2 infection. Natural compounds due to their structural diversity and safety are considered as an excellent source of antiviral drugs. In this study, we selected Herbacetin, Rhoifolin, Pectolinarin, Apigenin, Luteolin, Amentoflavone, Daidzein, Puerarin, Epigallocatechin, Gallocatechin gallate, Resveratrol, Maslinic acid, Piperine and Ganomycin B to target the SARS-CoV-2 main protease (Mpro) using in silico tools. These compounds were examined based on ADME, drug likeness, docking studies, MD simulations using CABS-flex 2.0, and prediction of major toxicity parameters (hepatotoxicity & cytotoxicity) to check the safety aspects of the selected compounds. We also investigated the similarity of these compounds, if any, with FDA approved drugs using Swiss similarity. The docking results were found in the order of Amentoflavone (-9.13 kcal/mol), Ritonavir (-8.52 kcal/mol), Lopinavir (-8.5 kcal/mol), Puerarin (-7.97 kcal/mol), Maslinic acid (-7.97 kcal/mol), Piperine (-7.65 kcal/mol), Gallocatechin gallate (-7.59 kcal/mol), Luteolin (-7.58 kcal/mol), Apigenin (-7.42 kcal/mol), Resveratrol (-7.41 kcal/mol), Herbacetin (-7.4 kcal/mol), Daidzein (-7.32 kcal/mol), Rhoifolin (-6.71 kcal/mol), Ganomycin B (-6.46 kcal/mol), Epigallocatechin (-6.13 kcal/mol), and Pectolinarin (-5.88 kcal/mol). Among these selected natural compounds, Amentoflavone and Puerarin were the two top leads which showed the lowest binding energies. Interestingly, Amentoflavone showed highest binding affinity among all the selected compounds. Our promising findings based on in-silico studies warrants further clinical trial in order to use these compounds as potential inhibitors of SARS-CoV-2 protease.

The ongoing Coronavirus disease 2019 (COVID-19) outbreak has led to global epidemics with high morbidity and mortality. However, there are no efficacious therapeutic options available for the treatment of COVID-19. Considering this medical emergency, drug repurposing is the need of the hour. Therefore, this study aimed to determine possible COVID-19 drug candidates using virtual screening of selected FDA approved drugs by targeting the main protease (Mpro) of novel coronavirus (SARS-CoV-2). In this study, first, we have done an extensive literature search to find out the marketed FDA approved drug compounds available for human therapeutic applications having anti-viral and anti-bacterial properties. The preliminary reports paved the way for further studies that revealed some of the drugs approved to treat other viral or bacterial infections may be a promising drug candidate and can be repurposed for the treatment of COVID-19. Using a computer-aided drug designing approach, novel candidates for drug repurposing were identified. Based on our preliminary screening supported by previous works of literature, we selected Rifampicin, Ciclesonide, Reserpine, Loperamide, Elvitegravir, Brivudine, Pentoxifylline, Eugenol, Isoniazid, Tinidazole, Diethylcarbamazine, and Vancomycin to target the SARS-CoV-2 main protease (Mpro). These compounds were examined based on docking studies using Autodock 4.2 Autodock 4.2., visualization of the docked results using Pymol version 1.7.4.5 Edu and prediction of two main toxicity aspects hepatotoxicity and cytotoxicity to check the safety of the hit compounds. Selected drugs were ranked for potential efficacy against COVID-19 based on their binding energy. The docking results were found in the order of Rifampicin (-11.16), Ciclesonide (-8.77), Reserpine (-7.76), Loperamide (-7.63), Elvitegravir (-6.58), Brivudine (-6.06), Pentoxifylline (-5.64), Eugenol (-4.78), Isoniazid (-4.71), Tinidazole (-4.51), Diethylcarbamazine (-4.66), Vancomycin (-4.11). ). In the current study, Rifampicin appeared as the most promising drug showing a very good binding energy. Based on our preliminary insights from in silico studies, we propose that Rifampicin may be repurposed for the treatment of COVID-19 however it is pertinent to mention here that our findings need further validation by in vitro studies and clinical trials. In summary, the findings of this study suggest Rifampicin might be a promising drug for targeting the COVID-19 protease.

Host plays an important role in influencing virulence of a pathogen and efficacy of a biopesticide. The present study was aimed to characterize the possible factors present in Spodoptera litura that influenced pathogenecity of orally ingested S. marcescens strains, differing in their virulence. Fifth instar larvae of S. litura responded differently as challenged by two Serratia marcescens strains, SEN (virulent strain, LC50 7.02 103 cfu/ml) and ICC-4 (non-virulent strain, LC50 1.19 1012 cfu/ml). Considerable increase in activity of lytic enzymes protease and phospholipase was recorded in the gut and hemolymph of larvae fed on diet supplemented with S. marcescens strain ICC-4 as compared to the larvae treated with S. marcescens strain SEN. However, a significant up-regulation of antioxidative enzymes SOD (in foregut and midgut), CAT (in the midgut) and GST (in the foregut and hemolymph) was recorded in larvae fed on diet treated with the virulent S. marcescens strain SEN in comparison to larvae fed on diet treated with the non-virulent S. marcescens strain ICC-4. Activity of defense related enzymes lysozyme and phenoloxidase activity were also higher in the hemolymph of larvae fed with diet treated with S. marcescens strain SEN as compared to hemolymph of S. marcescens strain ICC-4 treated larvae. More number of over-expressed proteins was observed in the gut and hemolymph of S. marcescens strains ICC-4 and SEN treated larvae, respectively. Identification of the selected differentially expressed proteins indicated induction of proteins involved in insect innate immune response (Immunoglobulin I-set domain, Apolipophorin III, leucine rich repeat and Titin) in S. marcescens strain SEN treated larvae. Over-expression of two proteins, actin related protein and mt DNA helicase, were noted in S. marcescens treated larvae with very high levels observed in the non-virulent strain. Up-regulation of homeobox protein was noted only in S. marcescens strain ICC-4 challenged larvae. This study indicated that ingestion of non-virulent S. marcescens strain ICC-4 induced strong immune response in insect gut while there was weak response to the virulent S. marcescens strain SEN which probably resulted in difference in their virulence.

Introduction: Severe acute respiratory syndrome coronavirus identified as the root cause of the Coronavirus disease 2019 (COVID-19) has spread all over the world. The pandemic situation caused by SARS-CoV-2 currently challenging the world. Given that the COVID-19 disease has no vaccine or therapeutic drugs to prevent the infection. In contrast, the key protease (Mpro) of SARS CoV-2 is involved in replication and proliferation of the virus and hence represents a crucial drug for the inhibition of COVID-19. Recent development shows the antiviral and anti-cancerous potential of natural products in the drug development process against various diseases which resulted in the screening of such agents to combat emergent mutants of SARS-CoV-2. Herein, we have applied a bioinformatics approach including molecular docking and a combination of molecular dynamics simulations and Poisson-Boltzmann surface area (MM/G/P/BSA) free energy calculations to identify the inhibitory potency of candidates against SARS-CoV2 main protease. Methods: In-Silico molecular docking analysis was performed for all selected anti-cancerous natural compounds with the potential drug target, PDB Id: 6W63 COVID-19 main protease in complex with a noncovalent inhibitor X77 using molecular docking and a combination of molecular dynamics simulations and Poisson-Boltzmann surface area (MM/G/P/BSA) free energy calculations. Absorption, Distribution, Metabolism, and Excretion (ADME) property as well as Lipinski's rule of five was also predicted for all the selected compounds. Among the 20 natural compounds, four natural metabolites namely, amentoflavone, guggulsterone, puerarin, and piperine were found to have strong interaction with Mpro of COVID-19. During MD simulations, all four natural compounds bound to Mpro at 50ns and MM/G/P/BSA free energy calculations showed that all four shortlisted ligands have stable and favorable energies causing strong binding with the binding site of Mpro protein. Conclusion: Although the anti-cancerous natural compounds show high binding affinity with the active site of SARS-CoV-2 main protease. Among these Amentoflavone and Guggulsterone were the top two leads showing the lowest binding energy and satisfying our studied parameters. Guggulsterone of Indian traditional ayurvedic medical plant Commiphoramukul was found to be the most suitable based on comprehensive pharmacokinetic parameters, drug-likeness, and docking analysis. Therefore, we propose anti-cancerous natural compound Guggulsterone may further be validated as potential inhibitors of COVID-19 main protease Mpro. Citation Format: Amaresh Mishra, Yamini Pathak, Gourav Choudhir, Anuj Kumar, Surabhi Kirti Mishra, Vishwas Tripathi. Anticancer natural compounds as potential inhibitors of novel coronavirus (COVID19) main protease: An in-silico study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 712.

Objective: To explore natural compounds as potential inhibitors against main protease (Mpro) of SARS-CoV-2. Methods: In the current study, systematic molecular docking analysis was conducted using AutoDock 4.2 to determine the binding affinities and interactions between natural compounds and Mpro. Selected natural compounds were further validated using a combination of molecular dynamic (MD) simulations and molecular mechanic Poisson-Boltzmann surface area (MM/PBSA) free energy calculations. Results: Out of twenty natural compounds, four natural metabolites namely, amentoflavone, guggulsterone, puerarin, and piperine were found to have strong interaction with Mpro of SARS-CoV-2 based on docking analysis. During MD simulations, all four natural compounds bound to Mpro at 50 ns and MM/G/P/BSA free energy calculations showed that all four shortlisted ligands had stable and favorable energies with strong binding to Mpro protein. Conclusions: Guggulsterone is a potential inhibitor of COVID- 19 main protease Mpro. Further in vitro and pre-clinical studies are needed.

Autoimmune disease management presents a significant challenge to medical science. Environmental factors potentially increase the risk of developing inflammatory and autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, and lupus. Among various environmental stresses, cigarette smoke and hypoxia have both been reported to lead to an enhanced risk of inflammatory and autoimmune diseases. In this review, we shed light on all reported mechanisms whereby cigarette smoke and a hypoxic environment can induce inflammatory and autoimmune diseases and discuss how hypoxic conditions influence the cigarette smoke-induced threat of inflammatory and autoimmune disease development. Cigarette smoke and hypoxia both lead to increased oxidative stress and production of reactive oxygen species and other free radicals, which have various effects including the generation of autoreactive pro-inflammatory T cells and autoantibodies, reductions in T regulatory (Treg) cell activity, and enhanced expression of pro-inflammatory mediators [e.g., interleukin-6 (IL-6), interleukin-4 (IL-4) and interleukin-8 (IL-8)]. Accordingly, smoking and hypoxic environments may synergistically act as potent environmental risk factors for inflammatory and autoimmune diseases. To our knowledge, no studies have reported the direct association of cigarette smoke and hypoxic environments with the risk of developing inflammatory and autoimmune diseases. Future studies exploring the risk of autoimmune disease development in smokers at high altitudes, particularly military personnel and mountaineers who are not acclimatized to high-altitude regions, are required to obtain a better understanding of disease risk as well as its management.

Two Serratia marcescens strains, SEN and ICC-4, isolated from diseased insect cadavers were observed to differ considerably in their virulence towards Spodoptera litura. The present study was aimed to characterize the possible virulence factors present in the virulent Serratia marcescens strain SEN. Both the S. marcescens strains were evaluated for the presence of various lytic enzymes such as chitinase, lipase, protease and phospholipase. The virulent S. marcescens strain SEN was observed to possess considerably higher activity of chitinase and protease enzymes; activity of phospholipase enzyme was also higher. Although, all the three toxin genes shlA, phlA and swr could be detected in both the S. marcescens strains, there was a higher expression of these genes in the virulent strain SEN. S. marcescens strain ICC-4 showed greater reduction in overall growth yield in the post-exponential phase in the presence of midgut juice and hemolymph of S. litura larvae, as compared to S. marcescens strain SEN. Proliferation of the S. marcescens strain SEN was also considerably higher in foregut, midgut and hemolymph of S. litura larvae, as compared to strain ICC-4. Peritrophic membrane treated with broth culture of the S. marcescens strain SEN showed higher damage as compared to strain ICC-4. The peritrophic membrane of larvae fed on diet treated with the virulent strain showed considerable damage while the peritrophic membrane of larvae fed on diet treated with the non-virulent strain showed no damage. This is the first report documenting the fate of ingested S. marcescens in S. litura gut and the relative expression of toxin genes from two S. marcescens strains differing in their virulence towards S. litura.

Pulse step modulation (PSM)-based high-voltage power supplies have played a significant role in fusion research. In many cases, multisecondary transformers are used for generation of tens of kilovolt range outputs with fast (microsecond-order) transient response. In this scheme, large numbers of isolated voltage sources are connected in series to generate the output. Isolated voltage sources can be achieved by a large number of separate transformers or by a single unit of multisecondary transformer. Naturally, a transformer having numbers of secondary windings (40) on a single core is the preferred solution for PSM topology due to its space and cost consideration. For design and simulation analysis of such a power supply, the model of a multisecondary transformer poses special problem to any circuit analysis software. While many simulation software packages provide transformer models with limited number (3-6) of secondary windings, they still fail to predict the actual observed results from a manufactured unit. This paper discusses the difficulties in modeling, step by step with representative schemes of multisecondary transformer, and advantages/disadvantages of each scheme with simulation results. Finally, a model using flux-coupled cores as basic building blocks is proposed; this model is able to simulate actual transformers very close to its observed parameters in test and actual usage.

Background: Quinic acid (QA), a natural compound found in fruits, for example in apple, berries, and coffee beans, is a neutraceutical chiral compound used to synthesize new pharmaceutically important chemical compounds. Platinum-based drugs such as cisplatin are widely used in the therapy, including oral cancer, one of the most prevalent cancer. Due to their severe side effects and acquired resistance to the treatment, phytotherapies are being explored to find out strong anticancer compounds that can alone and synergistically prevent and cure cancer without side effects. Objective: This study aimed to find out the mechanism behind the anticancer property of QA, a natural compound alone and synergistically with cisplatin in oral cancer cells (squamous cell carcinoma-4 [SCC-4]). Materials and Methods: Oral cancer cells were treated with QA alone and synergistically with cisplatin. MTT assay was performed to investigate the cytotoxic effect of QA and QA + cisplatin combination. Apoptotic effects of QA and QA + cisplatin combination were analyzed using DAPI and real-time-polymerase chain reaction for the expression of apoptotic marker genes. Effect of QA and QA + cisplatin combination was assessed by flow cytometry and immunoblotting technique. Results: Our result shows that QA promotes apoptosis in oral cancer cells by downregulating the expression of anti-apoptotic genes and attenuating the expression of cyclin D1 and Akt signaling pathway. Moreover, QA shows synergistic effect with cisplatin in these cells. Conclusion: QA inhibits cell proliferation and promotes apoptosis in oral cancer cells (SCC-4) alone and with cisplatin. Abbreviations used: QA: Quinic acid; CDK: Cyclin-dependent kinase; SCC-4: Squamous cell carcinoma-4; FBS: Fetal bovine serum.

Chemokine receptor expression by human trophoblast and other placental cells have important implications for understanding the regulation of placental growth, development, and their role in maternofetal HIV transmission. CXCR7, now a deorphanized G protein coupled receptor that has been recently shown to bind to the ligands ITAC and CXCL12 has been proposed to act as a co-receptor for HIV-1, HIV-2, and SIV strains. The differential expression of CXCR7 in the human placenta is not yet reported. The expression of CXCR7 was studied in 45 different human placental tissues, of which 20 were from early placental tissues (8–10 week old) obtained from medically terminated pregnancies and 25 were placenta from normal term deliveries. Immunohistochemistry and RT-PCR analysis revealed a greater expression of CXCR7 in term human placenta as compared to the early stage. This was further confirmed by real-time PCR. Our study reveals, for the first time, the differential expression of CXCR7 in early (8–10 weeks) and term human placenta. The precise role of CXCR7 in the human placenta needs to be determined. HIV vertical transmission is reported to occur mainly during the end stages of pregnancy. Our finding of increased CXCR7 expression in the term human placenta therefore warrants future studies to assess its role in the vertical transmission of HIV-1.

CXCL12 acts as a physiological ligand for the chemokine receptor CXCR7. Chemokine receptor expression by human trophoblast and other placental cells have important implications for understanding the regulation of placental growth and development. We had previously reported the differential expression of CXCR7 in different stages of the human placenta suggesting its possible role in regulation of placental growth and development. In this study, we determined the expression of CXCR7 in human choriocarcinoma JAR cells at the mRNA level and protein level and the downstream signaling pathway mediated by CXCL12-CXCR7 interaction. We observed that binding of CXCL12 to CXCR7 activates the ERK and Akt cell-survival pathways in JAR cells. Inhibition of the ERK and Akt pathways using specific inhibitors (Wortmanin & PD98509) led to the activation of the p38 pathway. Our findings suggest a possible role of CXCR7 in activating the cell survival pathways ERK and Akt in human choriocarcinoma JAR cells.

Pelvic endometriosis is a chronic inflammatory disease with an immunological background. Yet there is paucity of contemporary research exploring both the angiogenic cytokines, leptin and IL-8 for a possible role in its pathophysiology.To compare levels of both leptin and IL-8 in peritoneal fluid (PF) in women with endometriosis vs. fertile controls and correlate with disease stage, type and symptoms.PF from 58 women with endometriosis and 28 women undergoing tubal ligation was collected at laparoscopy and leptin and IL-8 levels were measured using ELISA. Results showed significantly higher levels of both cytokines in women with endometriosis. Significantly higher leptin and IL-8 levels were demonstrated in patients with early peritoneal (ASRM stage I and II) and advancing disease (ASRM stage III and IV), respectively. Levels of leptin/IL-8 were significantly lower in patients with endometrioma (4.8 ng/mL/32 pg/mL) vs. implants (13.0 ng/mL/68 pg/mL). There was no correlation of infertility or chronic pelvic pain with these levels.Both leptin and IL-8 levels are raised in PF of women with endometriosis reflecting inflammation and dysregulated immunomodulation. Higher levels of leptin were seen in early stages; IL-8 seems to stimulate the disease in a dose-dependent manner.

Pulse Step Modulation based High voltage power supply has played significant role in fusion research. Multi-Secondary transformers are invariably used for generation of tens of kV range outputs with fast (µS order) transient response. In this scheme, large numbers of isolated voltage sources are connected in series to generate the output. Isolated voltage sources can be achieved by large number of separate transformers or by single unit of multi-secondary transformer. Naturally, a transformer having numbers of secondary windings (∼40) on single core is the preferred solution due to its space and cost consideration. For design and simulation analysis of such a power supply, the model of a multi-secondary transformer poses special problem to any circuit analysis software. While many simulation softwares provide transformer models with limited number (3–6) of secondary windings, they still fail to predict the actual observed results from a manufactured unit. This paper discusses the difficulties in modelling, step by step with representative schemes of multi-secondary transformer, advantages/disadvantages of each scheme with simulation results. Finally, a model using flux coupled cores as basic building block is proposed, this model is able to simulate actual transformers very close to its observed parameters in test and actual usage.

Chemokine receptors CXCR7 and CXCR4 bind to the same ligand stromal cell derived factor-1alpha (SDF-1α/CXCL12). We assessed the downstream signaling pathways mediated by CXCL12-CXCR7 interaction in Jurkat T cells. All experiments were carried out after functionally blocking the CXCR4 receptor. CXCL12, on binding CXCR7, induced phosphorylation of extra cellular regulated protein kinases (ERK 1/2) and Akt. Selective inhibition of each signal demonstrated that phosphorylated ERK 1/2 is essential for chemotaxis and survival of T cells whereas activation of Akt promotes only cell survival. Another interesting finding of this study is that CXCL12-CXCR7 interaction under normal physiological conditions does not activate the p38 pathway. Furthermore, we observed that the CXCL12 signaling via CXCR7 is Giα independent. Our findings suggest that CXCR7 promotes cell survival and does not induce cell death in T cells. The CXCL12 signaling via CXCR7 may be crucial in determining the fate of the activated T cells.

Bacillus anthracis makes highly stable, heat-resistant spores which remain viable for decades. Effect of various stress conditions on sporulation in B. anthracis was studied in nutrient-deprived and sporulation medium adjusted to various pH and temperatures. The results revealed that sporulation efficiency was dependent on conditions prevailing during sporulation. Sporulation occurred earlier in culture sporulating at alkaline pH or in PBS than control. Spores formed in PBS were highly sensitive towards spore denaturants whereas, those formed at 45 degrees C were highly resistant. The decimal reduction time (D-10 time) of the spores formed at 45 degrees C by wet heat, 2 M HCl, 2 M NaOH and 2 M H(2)O(2) was higher than the respective D-10 time for the spores formed in PBS. The dipicolinic acid (DPA) content and germination efficiency was highest in spores formed at 45 degrees C. Since DPA is related to spore sensitivity towards heat and chemicals, the increased DPA content of spores prepared at 45 degrees C may be responsible for increased resistance to wet heat and other denaturants. The size of spores formed at 45 degrees C was smallest amongst all. The study reveals that temperature, pH and nutrient availability during sporulation affect properties of B. anthracis spores.

Regulated High Voltage Power Supplies (RHVPS) are commonly used in high-energy particle accelerators. RHVPS is a modular power supply in which kV level modules (40 or 80#) are cascaded to generate desired level of voltage/power [1]. One of the most challenging tasks involved is to provide input power to number of rectifier modules with required isolation (inter-winding and winding to ground). This is accomplished by deploying multi-secondary (large numbers, say 40 secondaries) transformers. This RHVPS concept was realized for the first time in the country with development of oil filled multi-secondary transformer. A pair of 3.3MVA, 11kV/ (940Vx40) has been successfully demonstrated, isolation of 6kVDC (inter-winding) and 160kVDC (all secondary to ground) tested. The next generation power supplies are unitized with indoor installations. This has created the demand for dry type multi-secondary transformers in compliance with safety regulations. This paper presents manufacturing issues and testing of the prototype resin cast coil. On the manufactured prototype, inter-winding isolation is tested up to 6kVDC and 125kVDC with respect to ground.

This paper presents operational experience of integrated control of the arc-filament and High-voltage power supply of Steady State Tokamak (SST)-1 NBI system using Versa Module Europa (VME) system on prototype Ion source. The control algorithm is implemented on the VxWorks operating system using 'C' language. This paper also describes the operating sequence and controls on power supply system. Discharge and Filament power supplies are controlled in such a way so that necessary discharge current can be available in Ion Source. The discharge current is controlled by manipulating the filament current. Close loop control is implemented on each filament power supply with feedback from Discharge Current to control the overall discharge inside the ion source. Necessary actions for shut OFF and subsequent Turn ON are also taken during breakdowns between the Grids of the ion source. Total numbers of breakdowns are also monitored. Shot is terminated, if the breakdown count is higher than the set value. This control system can be programmed to restart High-voltage power supply within 5mS after breakdown occurs. This control system is capable to handle the all types of dynamics in the system. This paper also presents results of experiment.

This article describes the control system for a 5MW ion source of the NBI (neutral beam injector) for steady-state superconducting tokamak-1 (SST-1). The system uses both hardware and software solutions. It comprises a DAS (data acquisition system) and a control system. The DAS is used to read the voltage and current signals from eight filament heater power supplies and 24 discharge power supplies. The control system is used to adjust the filament heater current in order to achieve an effective control on the discharge current in the plasma box. The system consists of a VME (Verse Module Eurocard) system and C application program running on a VxWorks™ real-time operating system. A PID (proportional, integral, and differential) algorithm is used to control the filament heater current. Experiments using this system have shown that the discharge current can be controlled within 1% accuracy for a PID loop time of 20ms. Response of the control system to the pressure variation of the gas in the chamber has also...