Analyzing The Interactions Of Kdm5/lid And Sin3 In Drosophila Melanogaster

SIN3, the scaffold protein of a histone modifying complex is conserved from yeast to mammals. Drosophila SIN3 associates with both a histone deactylase RPD3 and a histone demethylase dKDM5/LID. Immunopurification of dKDM5/LID verifies a previously observed interaction with SIN3 and RPD3. Furthermore, deficiency of dKDM5/LID phenocopies deficiency of SIN3 in many cellular and developmental processes. Knockdown of both Sin3A and lid hinder cell proliferation in Drosophila cultured cells and developing flies. Knockdown of these genes also results in a curved wing phenotype implicating a role in wing development. Analysis of underlying gene expression changes upon decreased expression of SIN3, dKDM5/LID or both at a genome wide level determined multiple genes that are commonly regulated by SIN3 and dKDM5/LID. Common gene targets of SIN3 and dKDM5/LID are implicated in processes related to stress tolerance. Additive roles of these proteins seem important in the regulation of cell cycle associated genes. Induction of paraquat mediated oxidative stress found a higher number of genes to be regulated by both SIN3 and dKDM5/LID, with an enrichment of genes involved in cell cycle regulation. Moreover, SIN3 and dKDM5/LID were found to bind the TSS proximal regions of several regulated genes suggesting direct regulation of these targets. Determination of histone modification changes at the transcriptional start sites of target genes upon knockdown of Sin3A or lid reveal changes in histone acetylation levels at some genes with no significant changes in histone methylation levels. This suggests an important role for the histone deacetylase activity of the complex in affecting gene regulation, while, the contribution of the demethylase activity appears to be minimal. It is, however, possible that the role of demethylation is highly context specific and allows for fine tuning of gene regulation under specific conditions or during specific developmental time points. This work emphasizes the important contributions of the histone demethylase dKDM5/LID to regulation of cellular events by the SIN3 complex. Supplementary files included are as follows: * Supplementary Data 1_AG - Excel spreadsheet containing RNAseq differential expression analysis outputs * Supplementary Data 2_AG - Excel spreadsheet containing Gene Ontology analysis dat

The applicability of international humanitarian law to the UN mission in the Democratic Republic of the Congo

The thesis intends to direct attention to the problems caused by the increased legitimization of use of force through peacekeeping mandates. The core of the thesis answers whether peacekeepers can, once authorized to take up arms, be bound by international humanitarian law (IHL), and whether they can be held accountable for grave breaches thereof. The case study of the MONUSCO peacekeeping-mission in the Democratic Republic of the Congo (DRC) offers valuable ground for consideration of the two formerly distinct concepts of peacekeeping and the laws of armed conflict

Computational Approaches For Designing Protein/inhibitor Complexes And Membrane Protein Variants

Drug discovery of small-molecule protein inhibitors is a vast enterprise that involves several scientific disciplines (i.e. genomics, cell biology, x-ray crystallography, chemistry, computer science, statistics), with each discipline focusing on a particular aspect of the process. In this thesis, I use computational and experimental approaches to explore the most fundamental aspect of drug discovery: the molecular interactions of small-molecules inhibitors with proteins. In Part I (Chapters I and II), I describe how computational docking approaches can be used to identify structurally diverse molecules that can inhibit multiple protein targets in the brain. I illustrate this approach using the examples of microtubule-stabilizing agents and inhibitors of cyclooxygenase(COX)-I and 5-lipoxygenase (5-LOX). In Part II (Chapters III and IV), I focus on membrane proteins, which are notoriously difficult to work with due to their low natural abundances, low yields for heterologous over expression, and propensities toward aggregation. I describe a general approach for designing water-soluble variants of membrane proteins, for the purpose of developing cell-free, label-free, detergent-free, solution-phase studies of protein structure and small-molecule binding. I illustrate this approach through the design of a water-soluble variant of the membrane protein Smoothened, wsSMO. This wsSMO stands to serve as a first-step towards developing membrane protein analogs of this important signaling protein and drug target

Settlement rehabilitation of a 35 year old building : case study integrated with analysis and implementation

This paper presents a rehabilitation project concerning the settlement of a 35 year old building. The foundation system of the northwest wing of the building consists of strip footings and slabon-grade. Differential settlement results in significant cracking of the masonry partition walls located on the footing and hence rehabilitation of the footing is required to stabilize the foundation system. Geotechnical and structural investigations are conducted, including site borings and analytical modeling based on one-dimensional consolidation theory that is incorporated into a finite element analysis. The predictive model exhibits that the differential settlement does not cause noticeable distress for the primary structural members, whereas the continued settlement affects use of the building. Site implementation is performed with the pushpile method to terminate the continuous settlement of the foundation

Predictive modeling of rocking-induced settlement in shallow foundations using ensemble machine learning and neural networks

IntroductionThe objective of this study is to develop predictive models for rocking-induced permanent settlement in shallow foundations during earthquake loading using stacking, bagging and boosting ensemble machine learning (ML) and artificial neural network (ANN) models.MethodsThe ML models are developed using supervised learning technique and results obtained from rocking foundation experiments conducted on shaking tables and centrifuges. The overall performance of ML models are evaluated using k-fold cross validation tests and mean absolute percentage error (MAPE) and mean absolute error (MAE) in their predictions.ResultsThe performances of all six nonlinear ML models developed in this study are relatively consistent in terms of prediction accuracy with their average MAPE varying between 0.64 and 0.86 in final k-fold cross validation tests.DiscussionThe overall average MAE in predictions of all nonlinear ML models are smaller than 0.006, implying that the ML models developed in this study have the potential to predict permanent settlement of rocking foundations with reasonable accuracy in practical applications

Multi-scale Eulerian-Lagrangian simulation of a liquid jet in cross-flow under acoustic perturbations

[EN] The design of modern aeronautical propulsion systems is constantly optimized to reduce pollutant emissions while increasing fuel combustion efficiency. In order to get a proper mixing of fuel and air, Liquid Jets Injected in gaseous Crossflows (LJICF) are found in numerous injection devices. However, should combustion instabilities appear in the combustion chamber, the response of the liquid jet and its primary atomization is still largely unknown. Coupling between an unstable combustion and the fuel injection process has not been well understood and can result from multiple basic interactions. The aim of this work is to predict by numerical simulation the effect of an acoustic perturbation of the shearing air flow on the primary breakup of a liquid jet. Being the DNS approach too expensive for the simulation of complex injector geometries, this paper proposes a numerical simulation of a LJICF based on a multiscale approach which can be easily integrated in industrial LES of combustion chambers. This approach results in coupling of two models: a two-fluid model, based on the Navier-Stokes equations for compressible fluids, able to capture the largest scales of the jet atomization and the breakup process of the liquid column; and a dispersed phase approach, used for describing the cloud of droplets created by the atomization of the liquid jet. The coupling of these two approaches is provided by an atomization and re-impact models, which ensure liquid transfer between the two-fluid model and the spray model. The resulting numerical method is meant to capture the main jet body characteristics, the generation of the liquid spray and the formation of a liquid film whenever the spray impacts a solid wall. Three main features of the LJICF can be used to describe, in a steady state flow as well as under the effect of the acoustic perturbation, the jet atomization behavior: the jet trajectory, the jet breakup length and droplets size and distribution. The steady state simulations provide good agreement with ONERA experiments conducted under the same conditions, characterized by a high Weber number (We>150). The multiscale computation gives the good trajectory of the liquid column and a good estimation of the column breakup location, for different liquid to air momentum flux ratios. The analysis of the droplet distribution in space is currently undergoing. A preliminary unsteady simulation was able to capture the oscillation of the jet trajectory, and the unsteady droplets generation responding to the acoustic perturbation.Thuillet, S.; Zuzio, D.; Rouzaud, O.; Gajan, P. (2017). Multi-scale Eulerian-Lagrangian simulation of a liquid jet in cross-flow under acoustic perturbations. En Ilass Europe. 28th european conference on Liquid Atomization and Spray Systems. Editorial Universitat Politècnica de València. 782-789. https://doi.org/10.4995/ILASS2017.2017.4697OCS78278

Centrifuge modeling of rocking-isolated inelastic RC bridge piers

Experimental proof is provided of an unconventional seismic design concept, which is based on deliberately underdesigning shallow foundations to promote intense rocking oscillations and thereby to dramatically improve the seismic resilience of structures. Termed rocking isolation, this new seismic design philosophy is investigated through a series of dynamic centrifuge experiments on properly scaled models of a modern reinforced concrete (RC) bridge pier. The experimental method reproduces the nonlinear and inelastic response of both the soil-footing interface and the structure. To this end, a novel scale model RC (1:50 scale) that simulates reasonably well the elastic response and the failure of prototype RC elements is utilized, along with realistic representation of the soil behavior in a geotechnical centrifuge. A variety of seismic ground motions are considered as excitations. They result in consistent demonstrably beneficial performance of the rocking-isolated pier in comparison with the one designed conventionally. Seismic demand is reduced in terms of both inertial load and deck drift. Furthermore, foundation uplifting has a self-centering potential, whereas soil yielding is shown to provide a particularly effective energy dissipation mechanism, exhibiting significant resistance to cumulative damage. Thanks to such mechanisms, the rocking pier survived, with no signs of structural distress, a deleterious sequence of seismic motions that caused collapse of the conventionally designed pier. © 2014 The Authors Earthquake Engineering & Structural Dynamics Published by John Wiley & Sons Ltd

The role of rooting strategies on the eco-hydrology of semi-arid regions

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Civil and Environmental Engineering, February 2012.Cataloged from PDF version of thesis.Includes bibliographical references (p. 193-205).Arid regions are characterized by high variability in the arrival of rainfall, and species found in these areas have adapted mechanisms to ensure the capture of this scarce resource. In particular, the rooting strategies employed by vegetation can be critical to their survival. However, land surface models currently prescribe rooting profiles as a function of only the plant functional type of interest with no consideration for the soil texture or rainfall regime of the region being modeled. Additionally, these models do not incorporate the ability of vegetation to dynamically alter their rooting strategies in response to transient changes in environmental forcings or competition from other plant species, and therefore tend to underestimate the resilience of these ecosystems. To address the simplicity of the current representation of roots in land surface models, a new dynamic rooting scheme was incorporated into the framework of the distributed ecohydrologic model tRIBS+VEGGIE. The new scheme optimizes the allocation of carbon to the root zone to reduce the perceived stress of the vegetation, so that root profiles evolve based upon local climate and soil conditions. The strength of this scheme lies in its ability to optimize the rooting profile in a computationally-efficient manner, without requiring additional parameterization by the model user. The ability of the new scheme to capture the complex dynamics of natural systems was evaluated by comparisons to hourly-timescale energy flux, soil moisture and vegetation growth observations from the Walnut Gulch Experimental Watershed, Arizona. Very good agreement was found between the model and observations, providing confidence that the improved model is able to capture the multidirectional interactions between climate, soil and vegetation at this site. The power of the new scheme was demonstrated through simulation of observed forms of within-hillslope vegetation patterning and the model's ability to represent competition-colonization dynamics between different plant functional types under non-equilibrium conditions.by Gajan Sivandran.Ph.D

Perspectives on a 6G Architecture

Mobile communications have been undergoing a generational change every ten years. Whilst we are just beginning to roll out 5G networks, significant efforts are planned to standardize 6G that is expected to be commercially introduced by 2030. This paper looks at the use cases for 6G and their impact on the network architecture to meet the anticipated performance requirements. The new architecture is based on integrating various network functions in virtual cloud environments, leveraging the advancement of artificial intelligence in all domains, integrating different sub-networks constituting the 6G system, and on enhanced means of exposing data and services to third parties.Comment: 7 pages, 5 figures, one tabl

Genome-wide studies reveal novel and distinct biological pathways regulated by SIN3 isoforms

Detailed annotation of ChIP-seq peaks for SIN3 187HA (SIN3 187HA ceas) or SIN3 220HA (SIN3 220HA ceas) as determined by the cis-regulatory enrichment annotation (CEAS) system. This table is related to Fig. 2 (XLSX 4014 kb