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PUMA-mediated apoptosis in fibroblast-like synoviocytes does not require p53
Xin You, David L Boyle, Deepa Hammaker, Gary S Firestein
Arthritis Research & Therapy , 2006, DOI: 10.1186/ar2052
Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial hyperplasia and invasion into cartilage and bone. Inadequate apoptosis of fibroblast-like synoviocytes (FLS) could contribute to this process by increasing the accumulation of cells in the intimal lining [1]. As a result of the aggressive nature of rheumatoid synovium and the relatively low level of apoptosis, interventions designed to increase programmed cell death of synoviocytes have been considered in treating RA. Several genes have been evaluated as potential gene therapy targets, including Fas [2], TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) [3], p53 [4], and PUMA (p53 up-regulated modulator of apoptosis) [5]. The latter is an especially interesting target because it rapidly induces apoptosis in cultured synoviocytes [5]. PUMA is a Bcl-2 homology 3 (BH3)-only pro-apoptotic Bcl-2 family member recently identified as a principal mediator of p53-dependent apoptosis [6]. The in vivo effects on apoptosis observed in PUMA-/- mice are similar to those in p53-/- animals, suggesting that PUMA can serve as an effector of p53 function [7,8]. However, our previous studies showed that p53 is only a weak inducer of PUMA in FLS, which could account for the variable pro-apoptotic effect of p53 in this cell lineage, with no significant apoptosis induced by p53 overexpression in some studies [9,10].The mechanism of PUMA-mediated apoptosis has been extensively evaluated. PUMA expression leads to apoptosis by displacing p53 from Bcl-XL and allowing p53 to increase mitochondrial permeability [6]. The need for functional p53 raises significant concerns about the utility of PUMA as a therapeutic target in RA because deficient p53 expression or function in the rheumatoid synovial intimal lining has been described [11-14]. To address this issue, we determined whether PUMA requires functional p53 in cultured FLS. These studies show that PUMA-induced apoptosis can occur despite defe
Regulation of the JNK pathway by TGF-beta activated kinase 1 in rheumatoid arthritis synoviocytes
Deepa R Hammaker, David L Boyle, Tomoyuki Inoue, Gary S Firestein
Arthritis Research & Therapy , 2007, DOI: 10.1186/ar2215
Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial lining hyperplasia and sublining infiltration of inflammatory cells [1]. Fibroblast-like synoviocytes (FLSs) play a crucial role in joint damage as well as the propagation of inflammation [2]. In response to potent pro-inflammatory cytokines such as IL-1β, FLSs produce large amounts of matrix metalloproteinases (MMP), which are key drivers of matrix destruction [3-5]. MMP production is, in turn, regulated by several signal transduction pathways, including the mitogen-activated protein kinases (MAPKs) [6,7].All three MAPK families have been implicated in RA, including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 [8-10]. JNK plays an especially important role in extracellular matrix turnover because it is activated in RA synovium, regulates MMP gene expression in cultured FLSs, and mediates joint destruction in rat adjuvant arthritis [11-16]. JNK is phosphorylated by upstream MAPK kinases (MAPKKs), which are dual specific enzymes that phosphorylate threonine and tyrosine residues [17]. Two MAPKKs (or mitogen-activated protein kinases [MEKs]), MKK4 and MKK7, form a complex with JNK [18], although only the latter is required for cytokine-mediated engagement of this pathway in FLSs [19].Multiple upstream MAPKK kinases (MAP3Ks) that activate the MAPKKs and the JNK cascade have been identified in RA. For instance, MEK kinase (MEKK)1, MEKK2, and transforming growth factor-β activated kinase (TAK)1 are the most abundant in inflamed synovium as well as cultured FLSs [20]. Of these MAP3Ks, MEKK2 initially appeared to be the most important in RA because it forms a functional complex with JNK. In the present study, TAK1 functioned as the dominant MAP3K for JNK activation in IL-1-stimulated FLSs. These results were unexpected because several groups have shown that MEKK1, MEKK2 and MEKK3 are indispensable for JNK activation. For instance, MEKK1 is the predom
Regulation of Peripheral Inflammation by Spinal p38 MAP Kinase in Rats
David L Boyle,Toni L Jones,Deepa Hammaker,Camille I Svensson,Sanna Rosengren,Salvatore Albani,Linda Sorkin,Gary S Firestein
PLOS Medicine , 2006, DOI: 10.1371/journal.pmed.0030338
Abstract: Background Somatic afferent input to the spinal cord from a peripheral inflammatory site can modulate the peripheral response. However, the intracellular signaling mechanisms in the spinal cord that regulate this linkage have not been defined. Previous studies suggest spinal cord p38 mitogen-activated protein (MAP) kinase and cytokines participate in nociceptive behavior. We therefore determined whether these pathways also regulate peripheral inflammation in rat adjuvant arthritis, which is a model of rheumatoid arthritis. Methods and Findings Selective blockade of spinal cord p38 MAP kinase by administering the p38 inhibitor SB203580 via intrathecal (IT) catheters in rats with adjuvant arthritis markedly suppressed paw swelling, inhibited synovial inflammation, and decreased radiographic evidence of joint destruction. The same dose of SB203580 delivered systemically had no effect, indicating that the effect was mediated by local concentrations in the neural compartment. Evaluation of articular gene expression by quantitative real-time PCR showed that spinal p38 inhibition markedly decreased synovial interleukin-1 and ?6 and matrix metalloproteinase (MMP3) gene expression. Activation of p38 required tumor necrosis factor α (TNFα) in the nervous system because IT etanercept (a TNF inhibitor) given during adjuvant arthritis blocked spinal p38 phosphorylation and reduced clinical signs of adjuvant arthritis. Conclusions These data suggest that peripheral inflammation is sensed by the central nervous system (CNS), which subsequently activates stress-induced kinases in the spinal cord via a TNFα-dependent mechanism. Intracellular p38 MAP kinase signaling processes this information and profoundly modulates somatic inflammatory responses. Characterization of this mechanism could have clinical and basic research implications by supporting development of new treatments for arthritis and clarifying how the CNS regulates peripheral immune responses.
Differential Roles of MAPK Kinases MKK3 and MKK6 in Osteoclastogenesis and Bone Loss
David L. Boyle, Deepa Hammaker, Meghan Edgar, Mario M. Zaiss, Stefan Teufel, Jean Pierre David, Georg Schett, Gary S. Firestein
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0084818
Abstract: Bone mass is maintained by osteoclasts that resorb bone and osteoblasts that promote matrix deposition and mineralization. Bone homeostasis is altered in chronic inflammation as well as in post-menopausal loss of estrogen, which favors osteoclast activity that leads to osteoporosis. The MAPK p38α is a key regulator of bone loss and p38 inhibitors preserve bone mass by inhibiting osteoclastogenesis. p38 function is regulated by two upstream MAPK kinases, namely MKK3 and MKK6. The goal of this study was to assess the effect of MKK3- or MKK6-deficiency on osteoclastogenesis in vitro and on bone loss in ovariectomy-induced osteoporosis in mice. We demonstrated that MKK3 but not MKK6, regulates osteoclast differentiation from bone marrow cells in vitro. Expression of NFATc1, a master transcription factor in osteoclastogenesis, is decreased in cells lacking MKK3 but not MKK6. Expression of osteoclast-specific genes Cathepsin K, osteoclast-associated receptor and MMP9, was inhibited in MKK3?/? cells. The effect of MKK-deficiency on ovariectomy-induced bone loss was then evaluated in female WT, MKK3?/? and MKK6?/? mice by micro-CT analysis. Bone loss was partially inhibited in MKK3?/? as well as MKK6?/? mice, despite normal osteoclastogenesis in MKK6?/? cells. This correlated with the lower osteoclast numbers in the MKK-deficient ovariectomized mice. These studies suggest that MKK3 and MKK6 differentially regulate bone loss due to estrogen withdrawal. MKK3 directly mediates osteoclastogenesis while MKK6 likely contributes to pro-inflammatory cytokine production that promotes osteoclast formation.
Suitable Site Selection of Decentralised Treatment Plants Using Multicriteria Approach in GIS  [PDF]
K. Deepa, M. Krishnaveni
Journal of Geographic Information System (JGIS) , 2012, DOI: 10.4236/jgis.2012.43030
Abstract: Metropolitan cities like Chennai facing rapid urbanisation. This results in informal extension of cities in peri-urban and rural areas. Once the city expands the problem arising is the water supply and sewage treatment system. In the present work an attempt is made in site suitable selection of Decentralised treatment plants (DCTP) with appropriate waste water treatment technologies using GIS techniques. Multicriteria analysis were performed by the combination of Analytical Hierarchy Process (AHP). Six thematic maps were considered such as population density map, landuse map, slope map, soil map, cost map and technology. Different classes were identified for each thematic maps. Using Analytical Hierarchy Principle (AHP) [1] (Saaty, 2000), a paired comparison matrix was prepared for criteria classes and individual class weights and map scores were worked out. These weights were applied in linear summation equation to obtain a unified weight map containing due weights of all input variables. Finally all the weighted maps were reclassified to arrive the best suitable site location of decentralised treatment plants.
Analyzing the Impact of Different Factors on Software Cost Estimation in Today’s Scenario  [PDF]
Deepa Gangwani, Saurabh Mukherjee
Journal of Software Engineering and Applications (JSEA) , 2015, DOI: 10.4236/jsea.2015.85025
Abstract: Software cost estimation is a main concern of the software industry. However, the fact is also that in today’s scenario, software industries are more interested in other issues like new technologies in the market, shorter development time, skill shortage etc. They are actually deviating from critical issues to routine issues. Today, people expect high quality products at very low costs and same is the goal of software engineering. An accuracy in software cost estimation has a direct impact on company’s reputation and also affects the software investment decisions. Accurate cost estimation can minimize the unnecessary costs and increase the productivity and efficiency of the company. The objective of this paper is to identify the existing methods of software cost estimation prevailing in the market and analyzing some of the important factors impacting the software cost estimation process. In order to achieve the objective, a survey was conducted to find out:

Nature of projects that companies prefer.

Impact of training on employees in software cost estimation.

How many people review the estimated cost?

How much risk buffer the company keeps for future prospects?

ELMAN Neural Network with Modified Grey Wolf Optimizer for Enhanced Wind Speed Forecasting  [PDF]
M. Madhiarasan, S. N. Deepa
Circuits and Systems (CS) , 2016, DOI: 10.4236/cs.2016.710255
Abstract: The scope of this paper is to forecast wind speed. Wind speed, temperature, wind direction, relative humidity, precipitation of water content and air pressure are the main factors make the wind speed forecasting as a complex problem and neural network performance is mainly influenced by proper hidden layer neuron units. This paper proposes new criteria for appropriate hidden layer neuron unit’s determination and attempts a novel hybrid method in order to achieve enhanced wind speed forecasting. This paper proposes the following two main innovative contributions 1) both either over fitting or under fitting issues are avoided by means of the proposed new criteria based hidden layer neuron unit’s estimation. 2) ELMAN neural network is optimized through Modified Grey Wolf Optimizer (MGWO). The proposed hybrid method (ELMAN-MGWO) performance, effectiveness is confirmed by means of the comparison between Grey Wolf Optimizer (GWO), Adaptive Gbest-guided Gravitational Search Algorithm (GGSA), Artificial Bee Colony (ABC), Ant Colony Optimization (ACO), Cuckoo Search (CS), Particle Swarm Optimization (PSO), Evolution Strategy (ES), Genetic Algorithm (GA) algorithms, meanwhile proposed new criteria effectiveness and precise are verified comparison with other existing selection criteria. Three real-time wind data sets are utilized in order to analysis the performance of the proposed approach. Simulation results demonstrate that the proposed hybrid method (ELMAN-MGWO) achieve the mean square error AVG ± STD of 4.1379e-11 ± 1.0567e-15, 6.3073e-11 ± 3.5708e-15 and 7.5840e-11 ± 1.1613e-14 respectively for evaluation on three real-time data sets. Hence, the proposed hybrid method is superior, precise, enhance wind speed forecasting than that of other existing methods and robust.
Political Solution As Garnered By The National Dailies During The Ethnic Crisis In Srilanka- Frame Analysis
Deepa Viswam
Golden Research Thoughts , 2013, DOI: 10.9780/22315063
Abstract: Tamil United Liberation front Chief V.Anadasangaree vehemently opposed the unitary label within unitedSrilanka. He expressed concern over media reports about the possibility of the All Parties Representative conferences(APRC) coming forward with package of proposals with unitary label. He warned that such a proposal would onlystrengthen the LTTE's call for separation and give oxygen to the dying organization and kill hopes of those who haveplaced their faith in (APRC).A political solution with the unitary label where the state is not willing to recognize the othercommunities as those with legitimate grounds of power sharing is a defeat for people like who have been changing theTamil community to forget separation and come into path of a united srilanka. Any solution under unitary constitution willbe half baked one. It will give room for further agitation in the future fuelled by the remnants of the LTTE. The resultwould be a disruption of the hard earned peace and the country back square back one, into another cycle of violence. “Nopolitical solution will be acceptable to the LTTE, other than a kingdom for Prabhakaran………….fair and just politicalsolution will convince the Tamil people not only in the country but around the world that there is no need for tyranny andterror of LTTE”. He advocated the Indian Model as an ideal solution for the ethnic crisis, the Indian constitution does notsay federal or unitary but has managed to hold the country together for 60 years.(sep,13,07,The Hindu).The editor –inchiefof the Hindu N.Ram during the annual meeting of the srilanka –India friendship society said democratic governancewas the need of the hour in the east and went on to ask if the government was ready to demonstrate the political will andtake reasonable risks in its quest to resolve the ethnic question.“There are huge gaps in the development status of provinces. For instance, while the western province accountsfor 50% of the country's GDP the share of the eastern province is more 2.5 percent. That is why we say the issue is notfederalism but democracy and equality. President, Tamil United Liberation Front (TULF), V.Anandasangree also wantedthe Srilankan government to find out possible solution to ethnic problems the weakening of the Liberation Tigers of TamilEelam National party(UNP) openly acknowledged federalism as the option to solve the problem and the leftists alwayssupported it. Mr.anandasangree said though the people had been liberated from LTTE control they were going throughenormous is possible hardship. He also urged leaders and people of Tamilnadu
Feature Extraction for Collaborative Filtering: A Genetic Programming Approach
Deepa Anand
International Journal of Computer Science Issues , 2012,
Abstract: Collaborative filtering systems offer customized recommendations to users by exploiting the interrelationships between users and items. Users are assessed for their similarity in tastes and items preferred by similar users are offered as recommendations. However scalability and scarcity of data are the two major bottlenecks to effective recommendations. With web based RS typically having users in order of millions, timely recommendations pose a major challenge. Sparsity of ratings data also affects the quality of suggestions. To alleviate these problems we propose a genetic programming approach to feature extraction by employing GP to convert from user-item space to user-feature preference space where the feature space is much smaller than the item space. The advantage of this approach lies in the reduction of sparse high dimensional preference information into a compact and dense low dimensional preference data. The features are constructed using GP and the individuals are evolved to generate the most discriminative set of features. We compare our approach to content based feature extraction approach and demonstrate the effectiveness of the GP approach in generating the optimal feature set.
Are Mesenchymal Cells Indeed Pluripotent Stem Cells or Just Stromal Cells? OCT-4 and VSELs Biology Has Led to Better Understanding
Deepa Bhartiya
Stem Cells International , 2013, DOI: 10.1155/2013/547501
Abstract: Stem cells have excited researchers because of their potential to regenerate. However, which stem cells will be the best candidate for regenerative medicine remains an enigma. Compared to pluripotent stem cells with associated risks of immune rejection and teratoma formation, adult stem cells especially the mesenchymal stem cells (MSCs) are hyped to be a suitable alternate since they also exhibit pluripotent properties. This review shows that there is a subpopulation of pluripotent very small embryonic-like stem cells (VSELs) among MSCs culture. The two populations differ from each other in expression pattern of OCT-4. VSELs exhibit nuclear OCT-4A, whereas the MSCs have cytoplasmic OCT-4B, similar to our earlier findings in testis and ovary. Pluripotent VSELs with nuclear OCT-4A exist in various adult body organs, and the immediate progenitors express cytoplasmic OCT-4B which is eventually lost as the cell differentiates further. To conclude it is essential to discriminate between nuclear and cytoplasmic OCT-4 expression and also to acknowledge the presence of VSELs. 1. Introduction Stem cells represent a novel cell type in the body which has the potential to regenerate any worn out tissue and maintain tissue homeostasis. Stem cells can be multiplied in large numbers in vitro and may serve to replace the damaged cells for regeneration rather than the existing means of managing diseases by treating the damaged cells with drugs. Stem cells are broadly classified based on their source into embryonic (hESCs) and adult (ASCs) stem cells. Embryonic stem cells are pluripotent in nature and can be differentiated into 200 odd cell types in the body belonging to the three germ layers, namely, ectoderm, endoderm, and mesoderm. On the other hand adult stem cells are isolated from adult body tissues and are multi- to unipotent in nature. Since the initial isolation of hES cell lines [1], there has been a divide amongst the embryonic and adult stem cell biologists. It has been the endeavor of the adult stem cell biologists to demonstrate that ASCs are equally good compared to hES cells, and thus hES cell research is not required (because of associated ethics since spare human embryos are used and manipulated). In January 2013, hES cell biologists were greatly relieved, when US Supreme Court refused to hear a case that could have prohibited government funding for hES cells [2]. Various approaches have been used to demonstrate that ASCs can replace hES cells. In particular with the ability to reprogram adult somatic cells to pluripotent state by iPS technology, the
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