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Search Results: 1 - 10 of 671 matches for " Siddharth Balachandran "
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Defining Emerging Roles for NF-κB in Antivirus Responses: Revisiting the Interferon-β Enhanceosome Paradigm
Siddharth Balachandran ,Amer A. Beg
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1002165
Interferon Impedes an Early Step of Hepatitis Delta Virus Infection
Ziying Han, Shoko Nogusa, Emmanuelle Nicolas, Siddharth Balachandran, John Taylor
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0022415
Abstract: Hepatitis delta virus (HDV) infects hepatocytes, the major cell type of the liver. Infection of the liver may be either transient or chronic. The prognosis for patients with chronic HDV infection is poor, with a high risk of cirrhosis and hepatocellular carcinoma. The best antiviral therapy is weekly administration for at least one year of high doses of interferon alpha. This efficacy of interferon therapy has been puzzling in that HDV replication in transfected cell lines is reported as insensitive to administration of interferon alpha or gamma. Similarly, this study shows that even when an interferon response was induced by transfection of poly(IC) into a cell line, HDV RNA accumulation was only modestly inhibited. However, when the HDV replication was initiated by infection of primary human hepatocytes, simultaneous addition of interferons alpha or gamma at 600 units/ml, a concentration comparable to that achieved in treated patients, the subsequent HDV RNA accumulation was inhibited by at least 80%. These interferon treatments were shown to produce significant time-dependent increases of host response proteins such as for Stat-1, phosphoStat-1, Mx1/2/3 and PKR, and yet interferon pretreatment of hepatocytes did not confer an increased inhibition of HDV replication over interferon treatment at the time of (or after) infection. These and other data support the interpretation that interferon action against HDV replication can occur and is largely mediated at the level of entry into primary human hepatocytes. Thus in vivo, the success of long-term interferon therapy for chronic HDV, may likewise involve blocking HDV spread by interfering with the initiation of productive infection of na?ve hepatocytes.
TBK1 Protects Vacuolar Integrity during Intracellular Bacterial Infection
Andrea L Radtke,Laura M Delbridge,Siddharth Balachandran,Glen N Barber,Mary X. D O'Riordan
PLOS Pathogens , 2007, DOI: 10.1371/journal.ppat.0030029
Abstract: TANK-binding kinase-1 (TBK1) is an integral component of Type I interferon induction by microbial infection. The importance of TBK1 and Type I interferon in antiviral immunity is well established, but the function of TBK1 in bacterial infection is unclear. Upon infection of murine embryonic fibroblasts with Salmonella enterica serovar Typhimurium (Salmonella), more extensive bacterial proliferation was observed in tbk1?/? than tbk1+/+ cells. TBK1 kinase activity was required for restriction of bacterial infection, but interferon regulatory factor-3 or Type I interferon did not contribute to this TBK1-dependent function. In tbk1?/?cells, Salmonella, enteropathogenic Escherichia coli, and Streptococcus pyogenes escaped from vacuoles into the cytosol where increased replication occurred, which suggests that TBK1 regulates the integrity of pathogen-containing vacuoles. Knockdown of tbk1 in macrophages and epithelial cells also resulted in increased bacterial localization in the cytosol, indicating that the role of TBK1 in maintaining vacuolar integrity is relevant in different cell types. Taken together, these data demonstrate a requirement for TBK1 in control of bacterial infection distinct from its established role in antiviral immunity.
Meta-Analysis Identifies NF-κB as a Therapeutic Target in Renal Cancer
Suraj Peri, Karthik Devarajan, Dong-Hua Yang, Alfred G. Knudson, Siddharth Balachandran
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0076746
Abstract: Objective To determine the expression patterns of NF-κB regulators and target genes in clear cell renal cell carcinoma (ccRCC), their correlation with von Hippel Lindau (VHL) mutational status, and their association with survival outcomes. Methods Meta-analyses were carried out on published ccRCC gene expression datasets by RankProd, a non-parametric statistical method. DEGs with a False Discovery Rate of < 0.05 by this method were considered significant, and intersected with a curated list of NF-κB regulators and targets to determine the nature and extent of NF-κB deregulation in ccRCC. Results A highly-disproportionate fraction (~40%; p < 0.001) of NF-κB regulators and target genes were found to be up-regulated in ccRCC, indicative of elevated NF-κB activity in this cancer. A subset of these genes, comprising a key NF-κB regulator (IKBKB) and established mediators of the NF-κB cell-survival and pro-inflammatory responses (MMP9, PSMB9, and SOD2), correlated with higher relative risk, poorer prognosis, and reduced overall patient survival. Surprisingly, levels of several interferon regulatory factors (IRFs) and interferon target genes were also elevated in ccRCC, indicating that an ‘interferon signature’ may represent a novel feature of this disease. Loss of VHL gene expression correlated strongly with the appearance of NF-κB- and interferon gene signatures in both familial and sporadic cases of ccRCC. As NF-κB controls expression of key interferon signaling nodes, our results suggest a causal link between VHL loss, elevated NF-κB activity, and the appearance of an interferon signature during ccRCC tumorigenesis. Conclusions These findings identify NF-κB and interferon signatures as clinical features of ccRCC, provide strong rationale for the incorporation of NF-κB inhibitors and/or and the exploitation of interferon signaling in the treatment of ccRCC, and supply new NF-κB targets for potential therapeutic intervention in this currently-incurable malignancy.
Role of Infrared Spectroscopy in Coal Analysis—An Investigation  [PDF]
Manoj Balachandran
American Journal of Analytical Chemistry (AJAC) , 2014, DOI: 10.4236/ajac.2014.56044
Abstract: Fourier transform infrared (FT-IR) spectroscopy is a widely used analytical technique for determining the different functional groups of a coal structure. This method, being able to reveal carbo-hydrogenated structures (aromatic and aliphatic) and heteroatomic functions (mainly oxygenated), as well as to detect the presence of minerals, is currently one of the most powerful techniques for coal characterization and thus is of paramount importance in the various utilization procedures of coal (industrial combustion, coke production processes, etc.). FT-IR study shows the presence of aliphatic -CH, -CH2 and -CH3 groups, aliphatic C-O-C stretching associated with -OH and -NH stretching vibrations and HCC rocking. It is conjectured that, the two-stage leaching using HNO3 followed by HF remarkably reduced the ash content as well as the minerals including Al, Si and Ca. The solubilization of samples with buffered EDTA could not eliminate the minerals in coal. The silicate and kaolinite bands showed a systematic lowering on EDTA and carboxylic acid treatment. The fungal leaching was most beneficial for aromatic molecules with different degrees of substitution. The intensity of bands due to carbonyl groups was increased, when treated with fungi, whereas that due to oxygen functional groups showed a reverse trend. The mineral bands due to silicates also decreased in intensity, on post treatment with fungal culture.
Anti-CD70 Immunocytokines for Exploitation of Interferon-γ-Induced RIP1-Dependent Necrosis in Renal Cell Carcinoma
Peirong Chen, Shoko Nogusa, Roshan J. Thapa, Calvin Shaller, Heidi Simmons, Suraj Peri, Gregory P. Adams, Siddharth Balachandran
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0061446
Abstract: Metastatic renal cell carcinoma (RCC) is an incurable disease in clear need of new therapeutic interventions. In early-phase clinical trials, the cytokine IFN-γ showed promise as a biotherapeutic for advanced RCC, but subsequent trials were less promising. These trials, however, focused on the indirect immunomodulatory properties of IFN-γ, and its direct anti-tumor effects, including its ability to kill tumor cells, remains mostly unexploited. We have previously shown that IFN-γ induces RIP1 kinase-dependent necrosis in cells lacking NF-κB survival signaling. RCC cells display basally-elevated NF-κB activity, and inhibiting NF-κB in these cells, for example by using the small-molecule proteasome blocker bortezomib, sensitizes them to RIP1-dependent necrotic death following exposure to IFN-γ. While these observations suggest that IFN-γ-mediated direct tumoricidal activity will have therapeutic benefit in RCC, they cannot be effectively exploited unless IFN-γ is targeted to tumor cells in vivo. Here, we describe the generation and characterization of two novel ‘immunocytokine’ chimeric proteins, in which either human or murine IFN-γ is fused to an antibody targeting the putative metastatic RCC biomarker CD70. These immunocytokines display high levels of species-specific IFN-γ activity and selective binding to CD70 on human RCC cells. Importantly, the IFN-γ immunocytokines function as well as native IFN-γ in inducing RIP1-dependent necrosis in RCC cells, when deployed in the presence of bortezomib. These results provide a foundation for the in vivo exploitation of IFN-γ-driven tumoricidal activity in RCC.
Performance Optimization of a Six-Strand Tundish  [PDF]
Siddharth Gupta, Anupam Dewan
World Journal of Mechanics (WJM) , 2013, DOI: 10.4236/wjm.2013.33018

The aims of the present study are to predict and improve inclusion separation capacity of a six strand tundish by employing flow modifiers (dams and weirs) and to assess the influence of inclusion properties (diameter and density) together with velocity of liquid steel at the inlet gate on the inclusion removal efficiency of a six-strand tundish. Computational solutions of the Reynolds-Averaged Navier-Strokes (RANS) equations together with the energy equation are performed to obtain the steady, three-dimensional velocity and temperature fields using the standard k-ε model of turbulence. These flow fields are then used to predict the inclusion sepapration by numerically solving the inclusion transport equation. To account for the effects of turbulence on particle paths a discrete random walk model is employed. It was observed that with the employment of flow modifiers, the inclusion separation capacity of tundish increases without any large variation in the outlet temperatures. It is shown that inclusion properties and velocity are important parameters in defining the operating conditions of a six-strand tundish.

Cellular Oxidative Stress Response Controls the Antiviral and Apoptotic Programs in Dengue Virus-Infected Dendritic Cells
David Olagnier ,Suraj Peri,Courtney Steel,Nadine van Montfoort,Cindy Chiang,Vladimir Beljanski,Michael Slifker,Zhong He,Carmen N. Nichols,Rongtuan Lin,Siddharth Balachandran,John Hiscott
PLOS Pathogens , 2014, DOI: doi/10.1371/journal.ppat.1004566
Abstract: Dengue virus (DENV) is a re-emerging arthropod borne flavivirus that infects more than 300 million people worldwide, leading to 50,000 deaths annually. Because dendritic cells (DC) in the skin and blood are the first target cells for DENV, we sought to investigate the early molecular events involved in the host response to the virus in primary human monocyte-derived dendritic cells (Mo-DC). Using a genome-wide transcriptome analysis of DENV2-infected human Mo-DC, three major responses were identified within hours of infection - the activation of IRF3/7/STAT1 and NF-κB-driven antiviral and inflammatory networks, as well as the stimulation of an oxidative stress response that included the stimulation of an Nrf2-dependent antioxidant gene transcriptional program. DENV2 infection resulted in the intracellular accumulation of reactive oxygen species (ROS) that was dependent on NADPH-oxidase (NOX). A decrease in ROS levels through chemical or genetic inhibition of the NOX-complex dampened the innate immune responses to DENV infection and facilitated DENV replication; ROS were also essential in driving mitochondrial apoptosis in infected Mo-DC. In addition to stimulating innate immune responses to DENV, increased ROS led to the activation of bystander Mo-DC which up-regulated maturation/activation markers and were less susceptible to viral replication. We have identified a critical role for the transcription factor Nrf2 in limiting both antiviral and cell death responses to the virus by feedback modulation of oxidative stress. Silencing of Nrf2 by RNA interference increased DENV-associated immune and apoptotic responses. Taken together, these data demonstrate that the level of oxidative stress is critical to the control of both antiviral and apoptotic programs in DENV-infected human Mo-DC and highlight the importance of redox homeostasis in the outcome of DENV infection.
Hydro-Geophysical Investigation of Contaminant Distribution at a Closed Landfill in Southwestern Ontario, Canada  [PDF]
Jianwen Yang, Siddharth Dilip Joshi
Journal of Geoscience and Environment Protection (GEP) , 2014, DOI: 10.4236/gep.2014.23002

This paper presents a hydro-geophysical investigation into the landfill leachate distribution and subsurface geology at a closed site in southwestern Ontario, Canada, using geophysical mapping and hydrological modeling approaches. Conductivity mapping was first conducted over the study site using a frequency-domain EM terrain conductivity meter, revealing an anomalous high-con- ductivity zone of about 200 m (S-N) × 80 m (W-E) at the western half of the site. The DC resistivity survey was then carried out at this anomalous zone with eight S-N profiles and three W-E profiles measuring 200m in length using a Wenner-α configuration. Our resistivity survey results indicate that the landfill leachate travels mainly south-east wards over the upper aquifer, with a minor vertical component into the upper weathered portion of the silt/sand aquitard at some locations. No contamination seems to exist in the lower sand aquifer. The geophysical results were later used to develop two conceptualized models for hydrological modeling. Our numerical results predict the leachate distribution at the study site in the future, confirming that the contaminant will occupy the entire upper aquifer and the most of the aquitard in a time of 1000 years, and that the barrier of the aquitard will protect the lower sand aquifer from the leachate pollution. These findings are critical in evaluating the current leachate conditions and the existing compliance monitoring plan for potential implementation at this study site and other sites in elsewhere.

Electroplating: Applications in the Semiconductor Industry  [PDF]
Jivaan Kishore Jhothiraman, Rajesh Balachandran
Advances in Chemical Engineering and Science (ACES) , 2019, DOI: 10.4236/aces.2019.92018
Abstract: There is a lot of research that has been done on electroplating of metals depending on the type of application. In this chapter, the importance of this technique to the semiconductor industry is discussed in detail from an experimental as well as a modeling standpoint. In particular, the effect of solution variables i.e. chloride, accelerator, suppressor on copper electrodeposition is discussed. This knowledge is applied to achieve a defect-free, bottom-up metal/copper fill that eventually, is one of the most critical processes in this billion-dollar industry.
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