1,450 research outputs found
Transcriptional control of epithelial to mesenchymal transition by regulatory factors and epigenetic mechanisms
Get PDFThe 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
Founder's Day and Thirteenth Convocation and R R Kale Memorial Lecture (Photographs)
No full textThirteenth Convocation of the Institute held on January 15, 2007. Prof. Kirit S. Parikh, Member, Planning Commission, New Delhi was the Chief Guest of the Function. He also delivered the Kale Memorial Lecture, 2006 on "Bridging Divides and Reducing Disparities". Thirty four successful students were awarded their M.A. degree (Economics). Miss Neha Sharma, who secured first rank with an 'A+' grade in the M. A. Examination, held in May 2006, was awarded the Pandurangi Prize. Miss Neha Sharma, who secured first rank with an 'A+' grade in the M. A. Examination, held in May 2006, was awarded the Late Professor M. V. Namjoshi Prize. Miss Aparajita Das was awarded the Late Professor M. V. Namjoshi Prize for securing highest marks in the course B04 : Industry: Organization, Structure and Problems. Miss Madhurima Malladeb and Miss Shivani Rege was jointly awarded R. M. Agnihotri Prize for securing the highest marks in the course A09: Economics of Development
A Benchmark Collection of Hypergraphs
No full text<p>This benchmark currently contains 2191 hypergraph instances that originate from CQs and CSPs instances from various sources. All hypergraphs have been generated and published by W. Fischl, G. Gottlob, D. M. Longo, and R. Pichler (2017) at <a href="http://hyperbench.dbai.tuwien.ac.at">http://hyperbench.dbai.tuwien.ac.at</a> together with different hypergraph properties including various notions of width.</p>
<p>See Johannes K. Fichte, Markus Hecher, Neha Lodha, and Stefan Szeider: An SMT Approach to Fractional Hypertree Width, Proceedings of the 24th International Conference on Principles and Practice of Constraint Programming (CP2018) for details on the original sources of the benchmarks.</p>
Generative modeling for relational databases
No full textThesis: M. Eng. in Computer Science and Engineering, Massachusetts Institute of Technology, Department of Electrical Engineering and Computer Science, 2016.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Cataloged from student-submitted PDF version of thesis.Includes bibliographical references (pages 79-80).The goal of this thesis is to build a system that automatically creates synthetic data for enabling data science endeavors. To meet this goal, we present the Synthetic Data Vault (SDV), a system that builds generative models of relational databases. We are able to sample from the model and create synthetic data, hence the name SDV. When implementing the SDV, we developed an algorithm that computes statistics at the intersection of related database tables. We then use a state-of-the-art multivariate modeling approach to model this data. The SDV iterates through all possible relations, ultimately creating a model for the entire database. Once this model is computed, the same relational information allows the SDV to synthesize data by sampling from any part of the database. After building the SDV, we used it to generate synthetic data for five different publicly available datasets. We then published the datasets and asked data scientists to develop predictive models for them as part of a crowdsourced experiment. On May 18, 2016, preliminary analysis from the ongoing experiment provided evidence that the synthetic data can successfully replace original data for data science. Our analysis indicates that there is no significant difference in the work produced by data scientists who used synthetic data as opposed to real data. We conclude that the SDV is a viable solution for synthetic data generation. Our primary contribution is that we designed and implemented the first generative modeling system for relational databases that demonstratively synthesizes realistic data.by Neha Patki.M. Eng. in Computer Science and Engineerin
Competing bimetallic ratios: Amsterdam, London and bullion arbitrage in the 18th century
Get PDFThis article analyses the stability of bimetallism in the mid-18th century for the case of two large centres that had different legal ratios and only one international market ratio. A new theoretical framework is articulated for the situation of international independence to set legal bimetallic ratios by monetary authorities in different countries. Then, using new data handcollected from archival sources and relevant to the two main bullion markets in the 18th century, Amsterdam and London, this theoretical framework is utilised to identify the regimes that actually prevailed during that period, in which Amsterdam was effectively on the bimetallic standard while London was on the gold standard de facto.Bimetallism, Bimetallic stability, Bullion markets, Arbitrage, Specie-point mechanism, Melting-minting points
Supplemental Material, GSJ_Supplemental_Material - Cell Therapy for Treatment of Intervertebral Disc Degeneration: A Systematic Review
No full textSupplemental Material, GSJ_Supplemental_Material for Cell Therapy for Treatment of Intervertebral Disc Degeneration: A Systematic Review by Dino Samartzis, Niccole M. Germscheid, Michael G. Fehlings, Charles G. Fisher, Marinus de Kleuver, F. Cumhur Öner, S. Tim Yoon, Luiz R. Vialle, Hans-Joerg Meisel, Neha Agarwal, Patrick C. Hsieh, Andrea Skelly, Jong-Beom Park, Darrel Brodke, Jeffrey C. Wang, S. Tim Yoon and Zorica Buser in Global Spine Journal</p
Auditable private ledgers
No full textThesis: M. Eng., Massachusetts Institute of Technology, Department of Electrical Engineering and Computer Science, 2017.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Cataloged from student-submitted PDF version of thesis.Includes bibliographical references (pages 61-64).This thesis describes the design and implementation of Auditable Private Ledgers (APL), a privacy solution for distributed ledgers that lets third parties audit private ledger data. With the use of permissioned blockchains, zero-knowledge proofs, and additively homomorphic commitments, we are able to provide a balance between privacy and regulation. For this work, I implemented the cryptographic tools in Go, helped develop zero-knowledge proofs to provide data authenticity and integrity, and performed an evaluation of this system to measure its performance. Our work shows that the system is reasonable to run between a small number of participants, and that we can efficiently run private sums without revealing fine-grained inputs.by Willy R. Vasquez.M. Eng
Effect of modern and traditional methods of preparation on the composition and flavor profiles of ghee
No full textGhee is a clarified milk-fat product originally from India. Ghee is prepared traditionally by culturing whole milk with lactic acid bacteria, prior to further processing steps. Industrially ghee is made by directly heating cream separated from whole milk. This research focuses on comparing chemical profiles of ghee made from different sources of milk and by different methods of preparation. Raw (non-pasteurized, non-homogenized) organic-grass fed cow milk and regular diet fed cow milk was obtained from Birchwood Farms, PA and Readington Farms, NJ respectively. Bacterial culture typical to ‘Dahi’ or Indian-style yogurt was obtained from Danisco. Ghee samples were made using these materials by three different methods (Direct cream method, Traditional method and Cultured cream method). Fatty acid profiles were elucidated using the FAMEs method using GC-MS. Non-saponifiable matter was analyzed using GC-Ms as well. Headspace volatiles were analyzed to elucidate differences in flavor profiles. Sensory evaluation was carried out on ghee made from grass-fed cow milk to identify whether the methods of preparation had an impact on the aroma profile. The results from all the analyses were compared for the different samples. Non-detectable differences were found in the fatty acid profiles and the non-saponifiable fractions of the different ghee samples. Cholesterol content in each sample was calculated. Method of preparation did not affect the chemical profiles of ghee significantly. Concentration of fatty acids was not affected by the source of milk or the method of preparation. This was analyzed by doing a two-factor ANOVA (Analysis of Variance). However, significant differences were found in their aroma profiles (based on sensory evaluation), instrumental color measurements and headspace volatile profiles. Thus the source of milk or method of preparation did not affect the fatty acid profiles of ghee however, method of preparation influenced the sensory properties and the flavor profiles.M.S.Includes bibliographical referencesby Neha M Bhid
Simulating the impact of climate change and adaptation strategies on farm productivity and income: A bioeconomic analysis
Get PDFThis study applied at the farm level in Tunisia aims at understanding the effects of climate change on agricultural productivity and income in Africa. Possible future climates are presented through different climate scenarios. The latter combines three levels of increasing temperature (1�centigrade (C), 2�C, and 3�C) with two levels of decreasing precipitation (10 and 20 percent) and a doubling of carbon dioxide concentration in the atmosphere (350 to 700 parts per million). The farming system of production is replicated through a bioeconomic model; that is, one that couples a cropping system model and an economic model run sequentially. The study reveals that land productivity and farm income decline under climate change. Depending on the changes in precipitation, farm productivity falls by 15 to 20 percent and farm income 5 to 20 percent when the temperature increases moderately (1�C). As the climate warms up (2�C and 3�C), farm productivity and income are severely affected, by 35 to 55 percent and 45 to 70 percent, respectively. When simple adaptation strategies based on new management techniques for hard wheat are tested - more irrigation and fertilization - compensations for the negative effects of climate change are found to be worthwhile only for a 1�C increase in temperature. However, the success of adaptation strategies highly depends on the availability of more water and lower additional cost to mobilize them at the farm level.adaptation strategies, Bioeconomic modeling, Agriculture, Climate change, farm income, productivity,
After Columbus: Explaining the Global Trade Boom 1500-1800
Get PDFThis paper documents the size and timing of the world inter-continental trade boom following the greate voyages in the 1490s of Columbus, da Gama and their followers. Indeed, a trade boom followed over the subsequent three centuries. But what was its cause? The conventionnal wisdom in the world history literature offers globalization as the answer: it alleges that declining trade barriers falling transport costs and overseas "discovery" explains the boom. In contrast, this paper reports the evidence that confirms unambiguously that there was no commodity price convergence between continents, something that would have emerged had globalization been a force that mattered. Thus, the trade boom must have been caused by some combination of European import demand and foreign export supply from Asia and the Americas. Furthermore, the behavior of the relative price of foreign importables in European cities should tell us which mattered most and when. We offer detailed evidence on the relative prices of such importables in European markets over the five centuries 1350-1850. We then offer a model which is used to decompose the sources of the trade boom 1500-1800.
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