Qatar Foundation Annual Research Forum Volume 2012 Issue 1

Background: Many human diseases lack validated animal models, hampering translational progress in several important disease areas. New and improved models can often be developed by recapitulating phenotypes related to those associated with human diseases. Objectives: Our lab has been interested in generating and characterizing several transgenic (Tg) animal models. These Tg animals were used to explore, on the cellular and molecular levels, the pathological mechanisms underlying several diseases, including immunological, neurodegenerative diseases, viral infections, cardiovascular disease, and cancer. Methods: Transgenes construction, analyzing techniques, and generation of Tg mice are as described in literature. Results: Examples of research projects that utilized animal models in our lab include: - Infectious diseases such as the acquired immunodeficiency syndrome (AIDS), which is caused by the human immunodeficiency virus type 1 (HIV-1). HIV-1 causes disease only in humans and chimpanzees. Thus, a major obstacle to explore the cellular and molecular mechanisms by which HIV-1 acts in vivo and to study how HIV-1 causes disease has been the lack of a small and cheap animal model. However, we have overcome the block to disease induction in rodents by generating Tg mice that express HIV-1 in the same immune cells that are normally infected in AIDS patients. These mice develop a severe AIDS-like disease leading to early death. Several pathological phenotypes, remarkably similar to those observed in HIV-1 infected individuals, were found. These included signs of growth retardation and wasting, atrophy of all lymphoid organs, preferential loss of CD4+ T cells, and interstitial nephritis and pneumonitis. More details will be presented. - Cancers such as leukemia and lymphoma as caused by murine leukemia viruses (MuLV) in inoculated mice. Their proviruses integrate in the vicinity of various genes involved in growth regulation, and act as insertion mutagens. We are using this retroviral insertion mutagenesis approach to identify novel oncogenes involved in T- or B-cell lymphomas induced by various MuLVs. We have succeeded in identifying novel oncogenes responsible for the onset of cancer. Among these oncogenes are members of Notch family, which are now under intense investigation to understand their role in inducing cancer. The details of these studies will be presented. Conclusions: It is likely that these novel Tg models will prove valuable in evaluating new pharmacological drugs, vaccines and disease therapies.

Multiple myeloma (MM) is one of the most common hematological malignancies, but current therapy options are limited to high-dose chemotherapy or high-risk stem-cell transplantation. In a recent kinome-wide RNAi study by Tiedemann and colleagues (2010), the G-protein coupled receptor kinase 6 (GRK6) was identified as a critical kinase required for survival of MM cells. This study also suggests that MM cells, but not other cell types, are dependent on GRK6; and that gene silencing by shRNA or siRNA of GRK6, but not other GRKs, results in decreased survival. At present, the G protein-coupled receptor (GPCR) signaling mediated by GRK6 in MM cells is not well understood. Through gene silencing techniques and expression of either the wild-type or kinase-dead form of GRK6 protein, we determined that a functional GRK6 kinase domain is required for survival of MM cells. These findings helped validate that the GRK6 kinase domain is a potential target for MM, and have spurred the investigation of small molecule kinase inhibitors of GRK6. By screening a cassette of compounds that are known as kinase inhibitors, compounds with moderate potency in preliminary biochemical assays were identified and further evaluated. As part of this effort we identified CX-4945, which is a known potent and selective ATP-competitive small molecule protein kinase CK2 inhibitor (IC₅₀ of 1 nM for recombinant human CK2α) as a moderately potent inhibitor of GRK6 (IC₅₀ on GRK6 = 300-500 nM). Herein we describe the design and synthesis of novel analogs of CX-4945 and key structure activity relationships (SAR) of this chemical series against GRK6 that serve as a platform for further optimization.

Fate Therapeutics (Fate) is pursuing the pharmacological modulation of adult stem cells to enhance tissue regeneration. Fate's lead clinical program, ProHema, consists of pharmacologically-enhanced hematopoietic stem cells (HSCs), designed to improve HSC engraftment and hematopoietic reconstitution during the normal course of a stem cell transplant for the treatment of patients with hematologic malignancies. Fate is currently conducting three clinical phase II trials of ProHema (FT1050‐enhanced umbilical cord blood). In addition, Fate is advancing a human recombinant protein, FT301, engineered for improved pharmacologic properties, and for driving the regeneration of skeletal muscle cells for use in atrophy and dystrophy. FT301 has a novel mode of action that results in the expansion of satellite stem cells. Fate has applied its proprietary induced pluripotent stem cell (iPSC) technology to test the efficacy of FT301 in a human model of Duchenne muscular dystrophy (DMD). We established iPSC lines from patients with DMD, and explored the regenerative capacity of FT301 on myoblasts generated from the DMD-specific iPSCs. Treatment of the iPSC-derived muscle fibers with FT301 induced significant hypertrophy confirming our in vitro and in vivo observed effects of FT301 in inducing productive muscular hypertrophy, and highlighting its possible application in muscular degenerative disorders.

Background: Esophageal adenocarcinoma (EAC) is characterized by a poor response to therapy with less than 10% five-year survival rates. Although Herceptin, a humanized monoclonal anti-ERBB2 antibody, has been successfully used for treatment of ERBB2-positive metastatic breast and gastroesophageal junction adenocarcinoma, a significant proportion of patients either fail to achieve initial response or develop acquired resistance. Clinical trials using Herceptin for the treatment of esophageal and gastroesophageal adenocarcinomas are ongoing in several Western countries. Understanding mechanisms that could hamper the response to Herceptin could influence the therapeutic decision making options and the management of these patients. Methods and Results: Truncated DARPP-32 (t-DARPP) (dopamine and cyclic AMP-regulated phosphoprotein of Mr 32,000), located at the 17q21 region, is a commonly amplified and overexpressed gene in upper gastrointestinal malignancies. The CellTiter cell viability, clonogenic survival, and Annexin V assays results indicated that stable or transient t-DARPP expression in OE19 cells significantly promoted cell survival and blocked apoptosis after treatment with 20 μg/ml Herceptin (p<0.01). The western blot results showed that t-DARPP sustained p-ERBB2 (Y1248) and p-AKT (S473) protein levels in response to Herceptin. Conversely, knockdown of endogenous t-DARPP in OE33 cells significantly decreased cell survival and p-ERBB2 (Y1248) and p-AKT (S473) protein levels in response to Herceptin (p<0.01). Western blot results showed that transient and stable t-DARPP expression without Herceptin increased protein levels of ERBB2, p-ERBB2 (Y1248), and p-AKT (S473). We hypothesized that t-DARPP enhances ERBB2 protein stability, thus blocking ERBB2 receptor steady-state down-regulation. The cycloheximide-based chase assay results showed that stable expression of t-DARPP increased the half-life of ERBB2 protein to 43.6 hours as opposed to 29.6 hours in control cells. We next investigated the effect of t-DARPP on Herceptin binding to ERBB2 receptor. Using co-immunoprecipitation, we have also shown that t-DARPP interacts with ERBB2 protein, hence, interfering with Herceptin binding to ERBB2 receptor, blocking Herceptin-induced down-regulation of downstream signaling. We also developed a Herceptin-resistant OE19 cell model, generated after selection with Herceptin for six months. The acquired resistance cell model demonstrated upregulation of endogenous t-DARPP and recapitulated the signaling events of Herceptin resistance. Conclusions: Our data demonstrate, for the first time, that t-DARPP enhances AKT signaling and is a key contributor to Herceptin resistance in EAC. In addition, t-DARPP mediates resistance to Herceptin through blocking ERBB2 receptor drug accessibility in EAC. The studies using in vivo models are ongoing.

ClpP is a cylindrical tetradecameric serine protease whose activity is regulated by the unfoldase ATP-dependent chaperones ClpX and ClpA of the AAA+ superfamily. The chaperones act to select substrate proteins, unfold them, and then thread them into the ClpP cylinder for degradation. ClpP can only degrade small peptides on its own. Structural and functional studies from my group have elucidated the mechanism of function of the ClpXP chaperone-protease system. These studies highlighted the importance of protein dynamics in this system. More recently, we used ClpP as a target in a high-throughput screen for compounds, which activate the protease and allow it to degrade larger proteins, hence, abolishing the specificity arising from the ATP-dependent chaperones. Our screen resulted in five structurally distinct compounds, which we designate as activators of self-compartmentalizing proteases 1 to 5 (ACP 1 to 5). The compounds are found to stabilize the ClpP double ring structure. The ACP1 chemical structure was considered to have drug-like characteristics and was further optimized to give analogs with bactericidal activity. Hence, the ACPs represent new classes of compounds that can activate ClpP and that can be developed as potential novel antibiotics.

Data converters play a crucial role in interfacing real time analog signals to the digital processing circuitry. Almost every SOC (system-on-chip) silicon design has an analog front/back end, which includes either an ADC (analog-to-digital converter) or a DAC (digital-to-analog converter). There is a wide range of applications that uses data converters spanning from medical systems to industrial control to audio players like the iPod. The resolution and speed of the converter depends on the application. For example, in video processors, the ADC resolution is 8/10 bits and the clock rate is approximately 150 MHz; whereas in digital audio applications, the resolution is much higher at 16/24 bits and the clock rate is about 44 KHz. We will discuss how ADCs are used in touch screen controllers and in high-energy detectors or medical imaging systems.

Background: Superconductivity is the complete loss of electric resistance in some elements and compounds cooled below a transition temperature (Tc). Since its discovery more than 100 years ago, this phenomenon has enriched basic science in ways that nobody could have foreseen. Moreover, superconductors have been used in various applications like power transmission, high magnetic field generation, levitated high-speed trains (MAGLEV), and magnetic resonance imaging (MRI). In a county, like Qatar, seeking to find alternative renewable energy sources, superconductors can be greatly useful in connecting the electric power generated from the renewable energy sources (solar and wind power) with superconducting devices (especially cables) to fulfill the energy saving and sustainability objectives. Objectives and methods: The effective use of superconductors in applications requires a better understanding of the basic phenomena of high-Tc superconductivity. For this purpose, several techniques are used especially photoemission spectroscopy which is considered as the most powerful tool to directly investigate the electronic structure of solids including superconductors. This technique is based on the photoelectric effect where various light sources like synchrotron radiation, lasers and others may be used. We have been using photoemission spectroscopy to investigate the electronic structure of newly discovered superconductors known as iron pnictides since their discovery in Japan in 2008. We have used several facilities like the Institute for Solid State Physics at the University of Tokyo in Japan, Photon Factory in Japan, Hiroshima Synchrotron Radiation Center at Hiroshima University in Japan, and Stanford Synchrotron Radiation Lightsource at Stanford University in USA. Our work was published in refereed scientific journals and presented at many international conferences worldwide and has had important implications on this field from the very early stage. Results and conclusions: In this paper, I will present an introduction about superconductivity and highlight on its various possible applications especially in Qatar. Also I will present an overview of our research on newly discovered iron pnictide superconductors using photoemission spectroscopy and how our results led to a better understanding of high-Tc superconductivity in these compounds.

The need to produce vehicles with improved fuel efficiency and reduced emissions has led the automotive industry to consider the use of "lightweighting" materials in the construction of automotive body and chassis systems. Towards this end, interest has been increasingly focusing on the use of sheet magnesium in the manufacture of panels and structural components by utilizing recent advances in twin-roll casting technology of magnesium. However, challenges in the areas of manufacturing, material processing and modeling need to be resolved in order to fully utilize magnesium alloys. Despite the limited formability of magnesium alloys at room temperature due to its hexagonal close-packed crystalline structure, studies have shown that the formability of magnesium alloys can be significantly improved by processing the material at elevated temperatures and by modifying the microstructure to increase ductility. Such improvements can potentially be achieved by processes such as superplastic forming and warm forming along with sheet manufacturing techniques such as Twin Roll Casting (TRC). In this work we investigate the superplastic behavior of twin-roll cast AZ31B through mechanical testing, microstructure characterization and modeling. The experimental results show that the as-received AZ31B sheet consists of relatively large gains, and while it is brittle at low temperature it is ductile at high temperature with activation energies of the deformation close to that of lattice diffusion. The material analyzed possesses medium strain-rate sensitivity of 0.27 with a relatively modest ductility of about 74%. Based on the experimental results, we use a physically-based constitutive model for deformation. The model integrates the main microstructural features, grain shape and grain orientations, within a self-consistent viscoplasticity theory with internal variables. Simulation of the deformation process at room temperature shows activity of the basal and prismatic systems at the early stages of deformation and increasing activity of pyramidal systems due to twinning. The predicted texture from the model is consistent with the experimental results. With the use of the appropriate model parameters, the stress strain relationship can be described accurately over the range of low strain rates.

The oxyanions of chlorine have seen multiple uses from bleaching to oxidizers in rocket fuel. Concerns over their accumulation in the environment, particularly that of perchlorate, have risen over the past two decades. Both chlorate (ClO₃¯) and chlorite (ClO₂¯) are employed in the generation of chlorine dioxide gas (ClO₂), which has been used in water treatment, disinfections, the pulp bleaching industry, and as an oxidizing agent. The lack of stability of ClO₂ and difficulties associated with its storage require its generation on-demand. Current methods employ harsh and corrosive conditions that require sulfuric acid and produce large amounts of salt and unwanted byproducts. Inspired by nature and how microorganisms isolated from contaminated sites degrade the oxyanions of chlorine, our research group developed catalysts based on manganese, a cheap and earth-abundant metal, for the conversion of chlorite to ClO₂ under ambient temperature and pH in aqueous solution. Two families of catalysts have been shown effective for this reaction, water-soluble manganese porphyrin/heme complexes and manganese compounds supported by simple polypyridyl cage ligands. Several spectroscopic techniques such as UV-vis, EPR, X-ray, mass spectrometry, and ion chromatography have been employed in the characterization of intermediates and products. Study of the reaction kinetics in conjunction with isotope labeling experiments has lead to mechanistic insight on the relevant species involved in catalysis. The prevailing pathway appears to involve an unprecedented homolytic Cl-O bond cleavage of chlorite at the metal site to generate high-valent manganese oxo and solvated chlorine oxide radical. The implication of these mechanistic insights on the reaction chemistry and development of future practical catalysts will be discussed.

Background: Trawl net fisheries are effective fishing activities, but often cause bycacth and discards issues for commercial species of unmarketable small size and endangered species. It is well accepted that codend mesh has size sorting properties for fish and other animals, and the codend selectivity is usually used as one of fisheries management measures to protect small animals. In the ocean, squids are abundant and still prospective fisheries resources, and especially swordtip squid is commercially important because of its good taste and high price in Japan and China. Objectives: Difference in selectivity parameters a, b and p could occur between years. This study objective is to analyze the variation between years and between hauls in selectivity parameters for swordtip squid (Loligo edulis) having a peculiar soft body type. Methods: A total of 23 experimental hauls were carried using trouser trawl onboard the research and training vessel Umitaka-Maru of the Tokyo University of Marine Science and Technology from 2006 to 2011, with 60mm mesh size test codend and 8.3mm mesh size control codend. Mantle length and girth of the swordtip squid caught were measured in cm. Catches were modeled by fitting codend selectivity parameters (a, b and p) in the Share Each LEngth Catch to the Total (SELECT) process and its variation between hauls and between years tested by the Akaike's Information Criterion (AIC) model selection. Results: The model with common logistic parameters a and b in each year and different split parameter p for each haul had a better estimation, confirmed by AIC. There was a variation in the 50% retention length (l50) from 6.04 to 7.11 cm and in the selection range, (S.R.) from 0.62 to 5.05 cm, which resulted in different selection curves annually. Conclusion: The difference in selection curves occurred although the codend used was the same. The fluctuation in S.R. was large compared with the l50, which could result from the small sample size. Others possible reasons are the yearly change in mesh size, catch size, and so on. This result is useful for fisheries managers to consider mesh size regulation for squid resource conservation.

There is an increasing need for improved environmental compliance, while reducing the time and cost of compliance checking (CC). This research offers a new approach for automated environmental CC. The approach utilizes semantic modeling and natural language processing (NLP) techniques. Semantic modeling aims at offering the level of knowledge representation and reasoning that is needed to process applicable environmental regulations and check compliance of construction plans to the rules that are prescribed by those regulations. NLP techniques will facilitate text analysis and processing for achieving human-like extraction and formalization of rules and information. The approach is intended to automatically detect non-compliance instances and provide a rich analysis of the non-compliance such as which regulation was violated, reason for violation, possible consequences of violation. To achieve such deep levels of text processing and automated reasoning, three algorithms are developed and combined into one computational platform: (1) a machine-learning-based text classification algorithm to classify relevant text (in documents such as environmental regulations), (2) a hybrid syntactic-semantic, utilizing grammatical and meaning-descriptive features of the text, information extraction algorithm to facilitate text processing for extraction and formalization of rules and information, and (3) a logic-based algorithm for compliance reasoning. Automated analysis will be facilitated by a semantic model for environmental knowledge representation and reasoning. The algorithms will be implemented in a proof-of-concept prototype software for automated environmental CC, and will be tested and validated using real-life-based test case scenarios. This research will transform the way we conceptualize and formally reason about complex regulatory schemes and associated CC processes, and will advance the research in the areas of deep NLP and deep semantic reasoning. The results of this research will also transform the way construction professionals and government regulators (e.g. environmental protection agencies) check the compliance of construction projects with environmental regulations and green practices. The ultimate goals of this research, in terms of benefits to the society, are: (1) increasing environmental compliance in construction, thereby protecting human health and the environment, (2) promoting compliance with non-regulatory green construction practices, thereby supporting green and sustainable construction, and (3) reducing the time and cost of environmental CC.^{2 2} This material is based upon work supported by the National Science Foundation under Grant No. 1201170. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author and do not necessarily reflect the views of the National Science Foundation.

Clustering is an important data mining technique that groups similar data records. In this research, the problem of clustering categorical (or transactional) data is studied. An algorithm for clustering transactional data, called F-Tree (frequent tree), is proposed, and a new similarity measure function, called PWO (probability of the weights of overlapped items), is introduced. Then, a framework to detect the best similarity value for different datasets is developed. Based on the items' frequencies in transactions, the F-Tree algorithm first generates small but highly pure clusters. It then merges similar clusters using the PWO similarity measure function, which depends on the probability of weights of overlapped items. One advantage of PWO is that it outputs the percentage of similarity between items; this is a clearer and more accurate measure of similarity than other similarity measures. Our experimental evaluation on real categorical datasets such as (Mushrooms, KrVskp, Congressional Voting, Soybean-Large, Soybean-Small, Hepatitis, Zoo, Lenses, and Adult-Stretch) shows that: Firstly, F-Tree is effective in finding rare or interesting clusters, and produces clusters with higher purity than LargeItem, WCD and CLOPE. Secondly, PWO is more effective in measuring the similarity between categorical data than LargeItem and CLOPE. Thirdly, clustering using the similarity measure PWO with pre-defined number of clusters results in separate classes with a good purity of average 80% coverage of real classes. Fourthly, the overlap estimator perfectly estimates the value of the overlap threshold using a small sample of dataset of around 5%. Finally, it is seen that the process of merging pure and small clusters increases the purity of resulted clusters as well as reduces time of clustering better than the process of generating clusters directly from the dataset then refining clusters. Based on the items' frequencies in transactions, The F-Tree algorithm first generates small but highly pure clusters. It then merges similar clusters using the PWO similarity measure function, which depends on the probability of weights of overlapped items. One advantage of PWO is that it outputs the percentage of similarity between items; this is a clearer and more accurate measure of similarity than other similarity measures. Our experimental evaluation on real categorical datasets such as "Mushrooms, KrVskp, Congressional Voting, Soybean-Large, Soybean-Small, Hepatitis, Zoo, Lenses, and Adult-Stretch" shows that: Firstly, F-Tree is effective in finding rare or interesting clusters, and produces clusters with higher purity than LargeItem, WCD and CLOPE. Secondly, PWO is more effective in measuring the similarity between categorical data than LargeItem and CLOPE. Thirdly, Clustering using the similarity measure PWO with pre-defined number of clusters results in separate classes with a good purity of average 80% coverage of real classes. Fourthly, the overlap estimator perfectly estimates the value of the overlap threshold using a small sample of dataset of around 5 percent. Finally, It is seen that the process of merging pure and small clusters increases the purity of resulted clusters as well as reduces time of clustering better than the process of generating clusters directly from the dataset then refining clusters.

I. Background Articulatory modeling is used to incorporate speech production information into automatic speech recognition (ASR) systems. It is believed that solutions to the problems of co-articulation, pronunciation variations, and other speaking style related phenomena rest in how accurately we capture the production process. II. Objective In this work we present a novel approach for speech recognition that incorporates knowledge of the speech production process. We discuss our contribution on going from a purely statistical speech recognizer to one that is motivated by the physical generative process of speech. III. Methods We follow an analysis-by-synthesis approach. Firstly, we attribute a physical meaning to the inner states of the recognition system pertaining to the configurations the human vocal tract takes over time. We utilize a geometric model of the vocal tract, adapt it to our speakers, and derive realistic vocal tract shapes from electromagnetic articulograph (EMA) measurements in the MOCHA database. Secondly, we synthesize speech from the vocal tract configurations using a physiologically-motivated articulatory synthesis model of speech generation. Thirdly, the observation probability of the Hidden Markov Model (HMM), which is used for phone classification, is a function of the distortion between the speech synthesized from the vocal tract configurations and the real speech. The output of each state in the HMM is based on a mixture of density functions. Each density models the distribution of the distortion at the output of each vocal tract configuration. During training, we initialize the model parameters using ground-truth articulatory knowledge. During testing, only the acoustic data is used. IV. Results and conclusion We present phone classification results using our novel dynamic articulatory model and following our adaptation procedure. The table below shows phone error rates (PER) for a female and a male speaker. We use a three-state HMM with different observation densities and initialization techniques. We combine the probabilities of the baseline topology with the new ones. Our novel framework provides a 10.9% relative reduction in phone error rate over our baseline which uses MFCC features. This is achieved using the distortion features with linear discriminant analysis (LDA) and cepstral mean normalization (CMN). We conclude that incorporating articulatory knowledge in the combined statistical framework we devised contributes to lowering the error rates in speech recognition. Features (dimension) Topology Observation Prob / Initialization Female PER Male PER Both PER Improvement Baseline Features MFCC + CMN (13) 3S-128M-HMM Gaussian/VQ 61.6% 55.9% 58.8% Distortion Features (1024) (Prob. Combination with MFCC, α = 0.2) 3S-1024M-HMM Exponential/Flat Sparsity = 21% 57.6% 53.7% 55.7% 5.3% Distortion Features (1024) (Prob. Combination with MFCC, α = 0.2) 3S-1024M-HMM Exponential/EMA Sparsity = 51% 58.3% 53.9% 56.1% 4.6% Adapted Distortion Features (1024) (Prob. Combination with MFCC, α = 0.25) 3S-1024M-HMM Exponential/EMA Sparsity = 51% 58.4% 53.1% 55.7% 5.3% Distortion Features + LDA + CMN (20) (Prob. Combination with MFCC, α = 0.6) 3S-128M-HMM Gaussian/VQ Sparsity = 0% 54.9% 49.8% 52.4% 10.9%

Spermidine/spermine-N1-acetyltransferase (SSAT) is a highly inducible and tightly controlled enzyme that is the rate-limiting step for polyamine catabolism. Because polyamines increase in dividing cells, SSAT has long been a target for cancer drug discovery. We have shown that the ability to enhance SSAT activity is a useful tool for cancer research, perhaps especially so for prostate cancer since the polyamine pathway is particularly active in this organ. SSAT can be induced by small molecules, including the biogenic polyamines themselves, which activate the negative feedback mechanism used to remove excess levels of these polyamines. SSAT activity is known to be affected by many mechanisms and good evidence indicates that translation control is important. We recently found that SSAT translation control involves a stem loop at the beginning of the open reading frame (ORF) and an upstream ORF 5' to the initiating methionine. A nucleolin isoform suppresses translation by binding to and stabilizing a 5' stem loop of SSAT mRNA but this repression is released when increased polyamines activate nucleolin autocatalysis; i.e., this is a negative feedback system. The current study is designed to exploit these exciting results with the overall goal to identify drug candidates with high potency and desirable physical properties to take forward into pre-clinical development. Here we report the development and validation of a luciferase-based reporter system for the identification of compounds that are able to promote the translation of SSAT. The translational de-repression sensor system, which uses HEK293T cells transformed with a construct composed of SSAT mRNA modified to lack uORF function, is mutated to overcome repression and is linked at the 3' end with luciferase. As a proof of principle of the utility of the SSAT translation sensor, we screened 2 libraries, the Redox library consisting of antioxidants (84 compounds) and the FDA Approved Drug library (1,200 compounds). Untreated cells were used as the negative control, and cells treated with 10 µM DENSPM (N1, N11-diethylnorspermine) were the positive control. Twelve compounds were identified from these libraries that activate SSAT translation by at least 35% more than the basal expression. We conclude that an SSAT translational control-based high throughput screening sensor can lead to the identification of novel pharmacophores that are able to prevention and/or treat prostate cancer.

This study examines the practice of arranged marriage with close relatives in Qatar. A survey was conducted on 521 young males and females to identify weather youth attitudes towards marriage selection have changed and to what extent their attitudes are influenced by the traditional standards of the arranged marriage which is associated with kinship system. The study also reviewed many previous studies about marriage in the region, dating back to the last century, and compared them with the results of more recent studies and the current study. The study findings showed that the practice of this form of consanguineous marriage is common in the region, and remains common, in spite of the rapid modernization and urbanization of the region. The perseverance of these practices challenges some of the fundamental assumptions about the correlation between modernization and social change. From a practical standpoint, the perseverance of these consanguineous marriage practices also represents a significant risk to the societies in question, as endogamous marriage practices within a tribe result in high levels of congenital disorders. This study suggests the cultural foundation of these practices, and recommends that programs seeking to remedy these problems take aim at their social and cultural roots.

A web-based application designed for the iPad which focuses on buildings designed for Doha across the decades.  Over the years, some of the greatest architects of their respective eras have designed buildings for Doha. These buildings were preceded by the local vernacular architecture, of which a few notable examples remain. Each of these buildings responds, in its own way, to the local climate and culture. More than any other single artifact, a building represents a culture's values and aspirations, socioeconomic conditions and construction techniques. Buildings project these attributes outward and become a means for a city or a nation to transmit its identity to others. It is not by accident that postcards of buildings are so common; an image of the city as represented by its architecture is disseminated outward across the globe.  These digital postcards represent a curated selection of noteworthy buildings that were designed for Doha. They range in time, location, use, style and built status. These categories allow for different means of sorting the information: into different eras (pre-oil, independence, realignment, or expansion), by architectural language or style (vernacular, modern, postmodern or contemporary); and by its current condition (built, demolished, unrealized or renovated). Part of an ongoing research project on the physical growth of Doha over time, 4dDoha: Buildings is an educational web-based application that focuses on the city's architecture throughout its history. Combining research, graphic design and interaction design, the iPad app allows users to sift through the data via a series of filters, while recording the users' choices on a projected map. Created by Carnegie Mellon School of Architecture faculty Kelly Hutzell and Rami el Samahy with research associates Adam Himes, Spencer Gregson and Kristina Ricco. Generous support provided by Carnegie Mellon Qatar and Qatar Foundation. Concept and software design by over,under, inc.

Background & Objectives: This presentation reports on the findings of a Qatar National Research Fund-sponsored study that is the first of its kind in the Gulf. Through a survey, the study examines the demographics, cost, migration arrangements, and the living and working conditions of low-income migrant workers in Qatar. Although much has been written about the problems and challenges of migrant workers in the Gulf, these quantitative data are the first of their kind in the larger area of migration studies in the Gulf. Our presentation seeks to provide an overview of the findings, with more in-depth discussion of the findings that complement and challenge our ethnographically-derived findings to date. Methods: Utilizing a sampling frame derived from utility records, we constructed a random sample of 1,189 low-income transnational labor migrants in Qatar's worker accommodations and other migrant dwellings. The administered survey explores the problems and challenges labor migrants oftentimes encounter in the Gulf States, with topical sections exploring labor brokerage, wages, housing, health, migrant finances, and living and working conditions in general. Results: The findings suggest that while labor migrants in Qatar face a similar regime of structures, practices, and challenges, there is significant variation within the total population of low-income labor migrants, with nationality and ethnicity playing the most significant role in shaping the migrant experience. For example, basic salaries for low-income workers from the Philippines and Egypt were substantially higher than the lowest earning nationalities. Arab low-income migrants also work fewer days per week, live in slightly less crowded conditions, and, unlike their South Asian counterparts, report no problems with salary withholding. Conclusions: Although our findings generally confirm the conclusions others have produced via small-scale, anecdotal, or non-representative samples in regard to the general characteristics of the population and the challenges they face, we also present several surprising findings that challenge conventional knowledge about labor migration in Qatar and the GCC at large.

This study reports on the development and large-scale validation of the "Assessing Arabic Speaking Students' Attitudes toward Science Survey" (ASSASS). The study is part of a larger project funded by the Qatar Foundation and aimed at identifying factors that impact precollege (grades 3 through 12) Qatari students' interest in, and attitudes toward, science. The development was primarily motivated by the fact that no instruments have been specifically designed and systematically validated for use with Arabic speaking students. Additionally, most extant instruments were developed for use with a specific grade or school level, and many lacked grounding in a robust theoretical framework. ASSASS was grounded in the most recent revision of the theories of reasoned action and planned behavior (TRABP). A 10-member international panel of science educators and education researchers reviewed an initial pool of 74, 5-point Likert scale items for alignment with TRABP. A revised pool of 60 items was piloted with a purposively selected sample of 396 grade 3 through 12 students in Qatar. Survey administration was followed by individual interviews with a 10% random sample of the students to ensure that ASSASS items were comprehensible to, and meaningful from the perspective of, students. Exploratory factor analysis (EFA) of pilot data resulted in the deletion of 14 items, which had poor loadings on an initial six-factor model for the instrument. Next, the resulting 46-item version of ASSASS was administered to a nationally representative sample of 2,778 grade 3 through 12 students in Qatar. Again, survey administration was followed by individual interviews with a 3% randomly selected sample of respondents to help triangulate assertions derived from quantitative data. EFA followed by confirmatory factor analysis (CFA) resulted in a robust model showing a very good fit, with a Root Mean Square Error of Approximation (RMSEA) at .042 (among many other robust statistical indicators). The model included a single global factor ("attitudes toward science") plus four orthogonal residual factors (a sub-set of the six factors identified in the pilot study). These factors were: intention to pursue or engage in science, negative outlook toward science, perceptions of school science, and perceived utility of science.

Infrastructure assets and services, such as water, energy, transport and telecommunications, play a vital role in promoting economic prosperity, political stability and human development. However, throughout the Muslim world, the availability of infrastructure services is poor due to the combination of growing populations, rapid urbanization, and historic underinvestment in infrastructure. These factors as well as the constant need for technological advancements put extreme pressures on public budgets, many of which are already constrained. Huge investment in infrastructure is needed through a consorted effort between the public and private sector. In Qatar alone, the pipeline of infrastructure projects is estimated at over $70 billion up to 2030. Among the most important sources of financing in the Muslim world is Islamic finance. However, data suggests that Islamic finance and capital market activity in infrastructure projects (excluding real estate) has been relatively limited. The objective of this paper is to highlight the importance of Islamic finance in infrastructure projects, to investigate the current state of Islamic infrastructure finance within the Gulf Cooperation Council (GCC) region, and to suggest ways of overcoming the challenges that Islamic and infrastructure finance face. The paper begins with a review of the economic literature on the importance of infrastructure to economic development, poverty alleviation, entrepreneurship and trade. The paper argues that there is a natural theoretical and ideological link between Islamic finance and infrastructure finance. Sources of financing infrastructure projects are then analyzed, and the mechanics of Islamic project financing are explained. The Islamic infrastructure finance market in the Gulf Cooperation Council countries is then surveyed. Case studies of past projects are then presented drawing attention to four areas: (1) structure of Islamic finance products for infrastructure financing; (2) challenges facing the use of Islamic finance; (3) potential development of new products; and (4) implications for policy-makers. The information presented in this research will provide useful lessons for GCC member countries on a subject that is given scarce attention to by academia.

Background: The groundbreaking activities that were enabled and facilitated by an NPRP research grant (Islamic Medical and Scientific Ethics, NPRP No. 08-783-6-017) to build a comprehensive collection of scholarly resources on Islamic bioethics have transformed the original proposal and slowly succeeded in creating a research culture that brought local, regional, and international attention to the project and its resources as an important hub for Islamic bioethics research. These activities include: development of a multilingual collection, which is catalogued, indexed, and maintained by the project team; development of an information retrieval system that enables fast and accurate searching capabilities of the stored bibliographic information; supporting collaborative initiatives with local, regional, and international stakeholders; envisioning further research opportunities that expand the scope of the project beyond bibliographic research into topical research projects and comprehensive reference works, which inspired another three-year research proposal to compile the world's first Encyclopedia of Islamic Bioethics and which has been accepted and awarded at the QNRF's Fifth Cycle in May 2012 (NPRP No. 5-1390-6-043) . These efforts have recently culminated in the successful organization of an international conference on Islamic bioethics, which brought together some of the most prominent experts of Islamic bioethics both in the West and in the Muslim world, which was held in June 2012 in Doha. Objectives: The presentation aims to show the different dimensions of the Islamic bioethics research project with a special focus on the important aspects that ensure smooth and effective transition from one level of the research process to another. More particularly, the presentation seeks to highlight the importance of maintaining a long-term vision, which inspires short-term and periodical objectives. Methods: the presentation will address these dimensions of the project: - Planning and revision - Bibliographic component - Research component - Workflow and team-building component - Dissemination and outreach component Results and Conclusions: The presentation will share the most important results that the project achieved in the first phase as well as preparations for the following phase with a special focus on the challenges that the project team encountered as well as the important lessons gained in the process.

The conflicts between economic growth, social well-being and ecological environment have frequently been highlighted. There is evidence that rehabilitation projects, while generating economic activity and improving the physical environment, also lead to many serious social problems, such as forced eviction and gentrification. Other issues include conflicts involving the cultural role of heritage and loss of social continuity and community neighborhood, exclusion of community participation, property speculation, loss of sense of place, urban sprawl and social exclusion. Thus, there is an urgent need to address the concept of socially sustainable development in the rehabilitation of urban historic districts. The case of Souq Waqif provides a unique opportunity for the topic where there was no previous relevant research. In addition, its urban context and the city are unique considering the architectural components, and environmental, cultural and social context. Lessons learned from studying social sustainability in Doha are expected to add remarkable input to the understanding of the city urban development and the resulting social change. The complexity and the novelty of the research topic required a combination of methods or what the research sources refer to as 'triangulation'. The study evaluated a large amount of literature related to social and cultural values connected directly or indirectly to the built environment, particularly historical districts. Four main stages were done starting from literature review to collecting data, conducting surveys, analyzing them and arriving to solid results and recommendations. Interviews were conducted in three modes; face-to-face (F2F), telephonic, and online. Three main experts on the project participated during the research to reflect on different points studied over a carefully designed questionnaire. The experts represented the project designers, the development management and the academic perspective on the topic. Results were able to identify the strengths and weaknesses in the development of Souq Waqif and the direct and indirect impacts of the project on the overall social life of the space users - whether they are tourists, labourers or business owners. The study has resulted in important messages for planning and social sustainability of similar projects, management recommendations and necessary practices to avoid anticipated decay.

المخاطر في مجال الصناعة البنكية أمر لابد منه تقتضيه طبيعة نشاط البنوك ، و هذا البحث هو استكشاف لعالم المخاطر في الصناعة البنكية قديما و حديثا، بالإضافة إلى اجراء التحليلات المالية و الاحصائية للبنوك المدرجة في السوق المالي القطري في الفترة ما بين 2006-2010 منهج البحث : قائم على لغة الارقام و التحليل و الاستقراء مع الاستعانة بمنهج الوصف و المقارنة . هدف البحث : قياس المخاطر الرئيسية التي تتعرض لها البنوك الاسلامية و التقليدية في قطر من خلال النسب المالية و التحليل بالمخاطر الخاصة و التحليل الاحصائي لمعرفة من أكثر مخاطرة . ومن اهم النتائج التي توصل اليها الباحث : 1-ان البنوك الإسلامية التزمت ببازل 1و2 لانه خيار يفرضه عليها العولمة ولكنها راعت في تطبيقه اختلاف طبيعة البنوك الإسلامية عن التقليدية . 2-إن لمجلس الخدمات الإسلامي و هيئة المحاسبة و المراجعة دورا بارزا في أسلمة بازل 1و2 لتلاءم البنوك الاسلامية و تراعي الاختلافات بينها وبين البنوك التقليدية . 3-التحليل المالي للبنوك الإسلامية و التقليدية يثبت تفوق البنوك الإسلامية في بعض النسب و تفوق البنوك التقليدية في نسب اخرى . 4-التحليل باستخدام معادلة المخاطر الخاصة تدل على تفوق البنوك الإسلامية . 5-التحليل الاحصائي للإنحراف المعياري للعائد على الملكية يظهر أن البنوك الإسلامية مجتمعة أقل خطرا من البنوك التقليدية مجتمعة . 6-التحليل الاحصائي يؤكد أن الحجم مؤثر في مخاطر البنوك الإسلامية و التقليدية . 7- التحليل الاحصائي يدل على ان العوامل المؤثرة في مخاطر البنوك الإسلامية و التقليدية تنقسم إلى قسمين :عوامل مشتركة و عوامل مختلفة لاتفاق كليهما في كونهما وسيطا ماليا و اختلاف كليهما في الطريقة . التوصيات :في ضوء التحليلات التي قام بها الباحث و الاستنتاجات التي تم التوصل اليها يمكن التوصية باجراء المزيد من التحليلات المالية و الاحصائية للبنوك الاسلامية في الدول الخليجية و العربية و الاسلامية لمعرفة مدى أمان البنوك الإسلامية .

Background: While technology comes from outside sources, ideas and concepts are quietly evolved in local Arabian society. With advanced channels of communication and ease of available technological tools, the young minds of Qatari women are ready to adapt to forthcoming challenges. The notion of storytelling in the digital realm among these young Arab women reflects the interplay of traditional culture, Western modernism and changes brought about by media industries. As a result, the way these young minds convey meaning in their moving images is also changing dramatically. These women adopt and use new media as a vehicle to maneuver their interesting and fresh ideas. Their thinking methodology has culminated in pragmatic and dynamic visuals which celebrate, inform or create awareness about issues of their surrounding world. They are creating new visual culture with freedom of expression and forcing themselves to transform into a meaningful workforce for the region. The intuitive context of these animations from these young minds incorporates the challenges of synthesizing multiple "dialect" and "codes" that have traditionally been segregated. This presentation shows how current technological tools embrace a contextual adjective, intangible cultural heritage and design thinking in a classroom setting. The presentation also highlights the pedagogical concerns of media industry in the region, from the dichotomies between intuitive and pragmatic instructional paradigm for the young Arab storytellers. Objectives: * To develop creative responses to the ways in which 3D/2D emerging technologies initiate the imagination for young minds; * To discuss the emotional and communicative aspects of visual narratives within the contextual paradigm; The central research question: Is emerging technology a meaningful factor of initiating a purposeful content creation? Results: The presentation will be showing the following outcomes developed by young Arab women: http://www.muqeemkhan.com/teaching/MIT%20395_12/index.html http://www.muqeemkhan.com/teaching/MIT393_sum_11/index.html http://www.muqeemkhan.com/teaching/MIT393_10/index.html

Statistics shows that more than 80 Qataris under the age of 24, die each year - and a large number are exposed to serious injuries - as a result of excessive speed and also because of reckless driving. This study aims to identify the factors which motivate the young to drive recklessly and practice risky behaviors, comparing the study results with other studies in different societies in order to develop knowledge about young people's risky behaviors, as well to develop intervention programs to change their concepts and attitudes. The study combined quantitative and qualitative analyzes. This included: - analyzing data which related to the traffic accidents - conducting a survey to gather information from 1000 young people - a case study of 50 young people who have frequent traffic violations - interviewing 5 fathers and 5 mothers whose sons practice risky driving - audience interviews (52 individuals) Study results showed that there are many reasons behind reckless driving, such as the age of the driver, parenting styles (the case study showed that the fathers encouraged their sons to drive a car during holidays), families allowing teenagers to drive before getting a driver's license, the young believing that speed and risky driving reinforce the confidence of the driver himself, the passengers' negative role on the young drivers. The study proposes an intervention program to reduce accidents by integrating young people who are applying for a driver's license into a training program.

The purpose of this paper is twofold. First, it highlights the strategic challange and importance of managing knowledge resources in the Gulf. Second, it presents the factors that influence the GCC countries' ability to better transfer, manage and utilize knowledge within the peculiar context of large expatriate workforce. A set of recommendations are addressed to both policy makers and the heads of KM departments in the region. There are numerous lessons to be drawn from this study, which may be taken as guidelines for future initiatives or programs targeted to the development and employment of national human capital. The study confirms that it is pivotal to focus on not only knowledge development but also knowledge management.