107,561 research outputs found
Transcriptional control of epithelial to mesenchymal transition by regulatory factors and epigenetic mechanisms
No full textThe World Health Organization (WHO) states cancer to be a leading cause of death worldwide accounting for 7.6 million deaths (around 13% of all deaths) and is projected rising to over 11 million in 2030. This is an alarming call to researchers for putting more effort into the analysis of the underlying patho-mechanisms. In a very simplified manner, cancer represents the destruction of healthy tissues and organs by uncontrolled cell proliferation and subsequent formation of a tumor. One key feature of solid tumors that marks the mostly deadly feature of the disease is the acquisition of the potential to invade into the surrounding tissue and form secondary tumors at distant sites, a process called ‘metastasis’. To gain migratory and invasive properties, cancer cells undergo epithelial to mesenchymal transition (EMT) where epithelial cells lose epithelial properties, e.g. their polarized organization and cell-cell junctions, and thus undergo changes in cytoskeleton organization and cell shape and acquire mesenchymal characteristics. Importantly, besides the formation of metastatic lesions, EMT is also involved during development as well as wound healing.
To gain insights into the complex process of EMT and to identify new potential markers for ongoing metastasis, we established different in vitro EMT model systems. Global expression profiling during TGF-β-induced EMT revealed genome-wide transcriptome reprogramming during EMT and identified Krupple-like factor 4 (Klf4) and the SRY-Related HMG-Box Gene4 (Sox4) as one of the key transcription factors that were modulated and may possibly contribute to transcriptional changes during EMT.
We investigated the role of Klf4 and Sox4 during EMT by employing two different in vitro systems of EMT, using normal murine mammary gland (NMuMG) and Polyoma middle T- breast cancer (Py2T) cells, which undergo a progressive EMT upon transforming growth factor (TGF-β) treatment. We further validated the role of Sox4 in breast cancer carcinogenesis in vivo by orthotropic injection of Sox4-depleted cells into the mammary fat pad of nude mice. In addition, we also investigated whether such TGF-β-induced EMT accompanies epigenetic reprogramming and revealed how Polycomb group (PcG) complex-mediated H3K27me3 modification modulates transcription of key genes underlying this process, thereby regulating EMT.
Klf4 is a zinc-finger protein, known to be abnormally expressed in various cancers. It can act as a tumor suppressor or as an oncogene in context dependent manner in different carcinomas. Klf4 is downregulated during TGF-β-induced EMT. Our data reveal a tumor suppressor role for Klf4 in breast carcinogenesis. Klf4 is essential for the maintenance of an epithelial phenotype during EMT, and forced expression of Klf4 leads to blockage of epithelial differentiation. Furthermore, Klf4 is inhibitory to EMT-driven cell migration and also behaves as a survival factor during TGF-β-induced EMT. Genome-wide location analysis by next generation ChIP-seq analysis revealed that Klf4 directly occupies the promoter of many key EMT genes such as N-cadherin, Vimentin, β-catenin and Mapk8. Moreover, one of these Klf4 targets, Mapk8, encoding Jnk1, is upregulated during EMT and a double-knockdown of Klf4 and Jnk1 is able to overcome Klf4 knockdown-induced EMT, migration and apoptosis. These observations underscore a role of Klf4 during EMT by targeting and regulating crucial EMT genes.
Sox4 is also known to be deregulated in many cancers. Sox4 is upregulated during TGF-β-induced EMT. We show that Sox4 is required for maintaining mesenchymal identity and depletion of Sox4 prevents TGF-β-induced EMT. Sox4 reduction further impairs the migratory capacity of cells. Moreover, Sox4 provides a survival advantage to cells during breast carcinogenesis. In addition, Sox4 contributes towards TGF-β-induced tumorigenicity and metastatic spread. Gene expression profiling after Sox4 depletion in complementation with Chromatin immunoprecipitation analysis revealed many key EMT genes such as Spred1, Edn1, Palld, Cyr61, Ereg, Areg and Yap1 which are directly targeted by Sox4 for transcriptional regulation. Furthermore, Sox4 also controls many genes which are shown to regulate various other features of EMT as well as cancer development such as angiogenesis, adhesion, migration, morphogenesis, cell cycle and cytoskeleton re-modeling. Ezh2, a catalytic subunit of the Polycomb Repressive Complex 2 (PRC2), has been also found to be transcriptionally regulated by Sox4. To delineate the role of Ezh2 during EMT, a loss of function approach has been used to demonstrate that Ezh2 is required for proper acquisition of EMT and EMT-driven processes such as migration and apoptosis. Taken together, our data provides a role of Sox4 during EMT via transcriptional regulation of key genes, including the Polycomb component, Ezh2.
We also studied the role of two prominent epigenetic modifications- DNA methylation and histone 3 lysine 27 tri-methylation (H3K27me3) during TGF-β-induced EMT in a mammary epithelial cell line. Our data revealed no evidence of a reprogramming of DNA methylation during this process. To assess the role of H3K27me3 during EMT, we performed chromatin immunoprecipitation using H3K27me3-specific antibodies followed by next-generation sequencing (ChIP-seq) on 6 different stages of EMT progression. This analysis revealed that many key EMT genes are regulated by H3K27me3 mark including Mcam, Pdgfrb and Itga5 which are repressed by this mark in epithelial cells and loose it during EMT as they get activated conversely, Cdh1, Ocln and Cdx2 gain this mark during EMT and get repressed in mesenchymal cells. We further illustrated that the coordinated activities of Ezh1 and Ezh2 are required for H3K27me3-mediated repression of the gene expression and their co-depletion de-represses target genes and blocks EMT. This study provides novel insights into the important regulatory role of the Polycomb machinery during EMT.
In summary, our findings demonstrate how transcription factors, such as Klf4 and Sox4 and the epigenetic machinery, such as PcG proteins, regulate EMT by directly contributing to the transcriptional reprogramming underlying this process
The mobile commerce technologies: Generations, standards and protocols
No full textMobile Commerce has staged a remarkable come-back. Driven by the technological innovations in the field of telecommunications, it is showing signs of a healthy recovery. The collapse of the dot-com boom in 2001/2002 had dealt a severe blow not only to Electronic Commerce but also to Mobile Commerce, which was just about developing at that time. In addition to a general lack of customer demand for mobile, location-based, services, it suffered heavily under the technical deficiencies of end-devices, slow data transmission and unripe technological standards. These factors in turn had a negative impact on the customer acceptance of mobile services and whatever little demand was available, was rendered useless. Many of the environmental conditions have changed since then. Technology innovations have reduced many barriers to acceptance. Increasing globalization has led to more mobility and therefore to greater demand for mobile, ubiquitios services that can be consumed anytime, anywher. This paper examines different telecommunication technologies regarding their suitablilty and deficiencies. It provides an overview over the historical development of mobile technologies while pointing towards the expected future scenario. --Mobile Commerce,M-Commerce,UMTS,WLAN,3G
Letter, [Author unclear] to Paulina T. Merritt
No full textHandwritten letter to Paulina Merritt from an unknown author, October 1, 1876.
Nonlinear functionally graded metamaterials for hydrogen storage and enhanced sustainability under extreme environments
No full textFunctionally graded materials can exhibit remarkable tolerance towards extreme hot or cold environments and chemical surface degradation. This article exploits such properties of functionally graded materials to propose a new class of transversely curved metamaterial architectures with high specific stiffness for operations under extreme surrounding conditions. We envisage the next-generation concept design of hydrogen storage tanks with functionally graded metamaterial core for aerospace and automotive applications. Based on such innovative lattice metamaterial based design of hydrogen storage tanks it is possible to enhance the storage capability in terms of internal pressure and resistance to external loads and impacts. Most importantly the proposed concept would lead to a breakthrough in developing load-bearing energy storage devices. For the metamaterial core, hexagonal bending-dominated unit cell architecture with transversely curved connecting beam-like geometries would ensure the dual functionality of high specific stiffness and energy absorption capability which are mutually exclusive in traditional lattice metamaterials. The functionally graded beams, a periodic network of which constitutes the lattice, are modeled here using 3D degenerated shell elements in a finite element framework. Geometric nonlinearity using Green–Lagrange strain tensor is considered for an accurate analysis. The beam-level nonlinear deformation physics is integrated with the unit cell mechanics following a semi-analytical framework to obtain the effective in-plane and out-of-plane elastic moduli of the metamaterials. The numerical results show that the curved beam lattice metamaterials have significantly enhanced in-plane elastic properties than straight lattices along with a reduced disparity among the in-plane and out-of-plane elastic moduli.<br/
Handwritten biographical information on Paulina T. McClung Merritt
No full textA handwritten biography of Paulina T. McClung Merritt by an unknown author, 1892.
Heterogeneous and tissue-specific regulation of effector T cell responses by IFN-gamma during Plasmodium berghei ANKA infection.
No full textIFN-γ and T cells are both required for the development of experimental cerebral malaria during Plasmodium berghei ANKA infection. Surprisingly, however, the role of IFN-γ in shaping the effector CD4(+) and CD8(+) T cell response during this infection has not been examined in detail. To address this, we have compared the effector T cell responses in wild-type and IFN-γ(-/-) mice during P. berghei ANKA infection. The expansion of splenic CD4(+) and CD8(+) T cells during P. berghei ANKA infection was unaffected by the absence of IFN-γ, but the contraction phase of the T cell response was significantly attenuated. Splenic T cell activation and effector function were essentially normal in IFN-γ(-/-) mice; however, the migration to, and accumulation of, effector CD4(+) and CD8(+) T cells in the lung, liver, and brain was altered in IFN-γ(-/-) mice. Interestingly, activation and accumulation of T cells in various nonlymphoid organs was differently affected by lack of IFN-γ, suggesting that IFN-γ influences T cell effector function to varying levels in different anatomical locations. Importantly, control of splenic T cell numbers during P. berghei ANKA infection depended on active IFN-γ-dependent environmental signals--leading to T cell apoptosis--rather than upon intrinsic alterations in T cell programming. To our knowledge, this is the first study to fully investigate the role of IFN-γ in modulating T cell function during P. berghei ANKA infection and reveals that IFN-γ is required for efficient contraction of the pool of activated T cells
India's National Innovation System: Key elements and corporate perspectives
No full textIn recent years India has emerged as a major destination for corporate research and development (R&D), especially for multinational corporations. India's domestic institutions like Indian Space Research Organisation (ISRO), Defence Research and Development Organisation (DRDO), and the Centre for Development of Advanced Computing (C-DAC) have set prestigious milestones of international standards. Not surprisingly, at Governmental levels a number of international cooperation agreements in the field of science and technology have been signed with India. After years of self-imposed seclusion, principally motivated by post-colonial India's insistence on the development of indigenous technology, India finally seems to have joined the global mainstream of innovation. India is in the process of emerging as a major R&D hub for both large and medium-sized multinational companies in various industries. This development is mainly owing to the availability of skilled labor produced in world-class elite institutions. Cost advantages, e.g. in the form of low wages are still present but receding due to substantial wage hikes often ranging between 15 and 25% per annum. The striking finding is however about market-driven factors. Of late, India's market potential, in the meantime ranked as 3rd largest worldwide by the Global Competitiveness Report 2007-08, has emerged as a crucial driver. Rising income levels of India's billion-plus population are creating unique market opportunities for firms, both domestic and foreign. In India the Government has historically played a major and in most cases a singularly positive role in the formation of its innovation system. India, ever since its independence from British rule, has invested much time, resources and efforts in creating a knowledge society and building institutions of research and higher institutions. Despite explosive population growth literacy rate in India grew from 18.3% in 1950-51 to 64.8% in 2001 thanks to concerted Government efforts; female literacy rose from a mere 8.9% to 53.7% in the same period. Moreover the quality of education in India is generally ranked as very good. According to the Global Competitiveness Report 2007-08 the quality of mathematics and science education in India is ranked as 11th best in the world, much ahead of 29th placed Japan, 36th placed Germany, 45th placed United States and 46th placed United Kingdom. Nevertheless, India is faced with major challenges related to infrastructure and bureaucratic hurdles. The quality of education, notwithstanding such excellent rankings as stated above, in many institutions does not reach the standards required for (cutting-edge) R&D efforts. Moreover, a booming economy is leading to shortage of qualified and experienced skilled labor - which result in inflationary wage growth and high attrition rates, which generally lay in a double-digit range. With the Government maintaining a pro-active role many of these problems may however be expected to get resolved to a manageable extent. In its Eleventh Five Year Plan (2007-12) the Government has announced massive investments in infrastructure and education sectors to enhance both the quantity and the quality. Industrial firms in India have recognized their chances and are investing heavily in R&D capacities. India is also a beneficiary of global mobility and exchange of talents, technology and resources as much as the world, especially the developed Western countries, have profited from India's export of brain power. In sum all these developments raise hopes for a further improvement in the conditions of Indi's National Innovation System. --National Innovation System,India,Offshoring,Globalization,Research and Development
Dispelling the Myths Behind First-author Citation Counts
No full textWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
Hybrid Numerical Analysis of a high-speed non-volatile Suspended Gate Silicon Nanodot Memory
No full textWe present a hybrid numerical analysis of a high-speed and non-volatile suspended gate silicon nanodot memory (SGSNM) which co-integrates a nano-electromechanical (NEM) control gate with a MOSFET as a readout element and silicon nanodots as a floating gate. A hybrid NEM-MOS circuit simulation is developed by taking account of the pull-in/pull-out operation of the suspended gate and electron tunnelling processes through the tunnel oxide layer as behavioural models. The signals for programming, erasing and reading are successfully achieved at circuit level simulation. The programming and erasing times are found as short as 2.5 nsec for a SGSNM with a 1-?m-long suspended gate, which is a summation of the mechanical pull-in/pull-out times and the tunnel charging/discharging times
Pelevin’s Trinity in the novel “t”: author – protagonist – reader
No full textThe article attempts to interpret Pelevin's artistic strategy in the novel "T" by exploring its subject organization and addressing the key problems of the author, the protagonist, and the reader as they are seen by the researcher. The article analyzes the peculiarities of constructing the narrative reality in the novel "T", and goes on to discuss Pelevin's philosophic models of the development of the humankind, and the emergence of his new anthropology
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