Computational Studies and Design of PPARγ and GLUT1 Inhibitors

The peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent transcription factor of the nuclear receptor superfamily that controls the expression of a variety of genes involved in fatty acid metabolism, adipogenesis, and insulin sensitivity. PPARγ is a target for insulin-sensitizing drugs, and it plays a significant function in prostate cancer. PPARγ antagonists have anti-proliferative effects in a broad range of hematopoietic and epithelial cell lines. The ligand binding domain (LBD) of PPARγ is large and has orthosteric and allosteric binding sites. Several PPARγ-ligand co-crystal structures show two bound molecules, one to the orthosteric pocket and a second to the allosteric site. We ran docking studies against the orthosteric and allosteric binding sites to determine the most favorable binding site for PPARγ antagonists. We found that Glide docking performed well in predicting PPARγ antagonist binding affinities, and that the allosteric site of PPARγ was the most favorable binding site for antagonists. We also investigated PPARγ ligand-protein interactions to better define a structural basis for the binding selectivity of PPARγ antagonists. We found that Phe282, Arg288, and Lys367 interact with antagonists more than with agonists and partial agonists. We then identified several potential PPARγ antagonists by virtual screening of the PPARγ allosteric pocket. The glucose transporter 1 (GLUT1) is a uniporter protein that facilitates the transport of glucose across the plasma membranes of mammalian cells. As GLUT1 is overexpressed in numerous tumors, this transporter is a potential target for cancer treatment. GLUT1 works through conformational switching from an outward-open (OOP) to an inward-open (IOP) conformation passing through an occluded conformation. We sought to determine which conformation is favored for ligand binding by molecular docking studies of known GLUT1 inhibitors with the different GLUT1 conformers. Our data revealed that the IOP is the preferred conformation and that residues Phe291, Phe379, Glu380, Trp388, and Trp412 may play important roles in ligand binding to GLUT1. To identify new chemotypes targeting GLUT1, we built a pharmacophore model and searched against an NCI compound database. Sixteen hit molecules with good docking scores were screened for GLUT1 inhibition and anti-proliferative activities. From these, we identified four compounds that inhibited cell viability in an HCT116 colon cancer cell line. We also determined that one of these, NSC295720, inhibited GLUT1 in a biochemical assay

Examining Women’s Perceptions of Maternity Care in Public and Private Sectors of National Guard Hospitals in Saudi Arabia: A Qualitative Study

Every second, a baby is born. The process of birth is a complex one – biologically, medically, and emotionally. In particular, women in labor need both physical and emotional care. They need to be heard, to be comforted, and to be safe. Women’s satisfaction can be used as a legitimate way to measure the quality of maternity care. Moreover, when health systems practice patient-centered care and listen to women’s concerns and what they want out of their care, it can lead to improvements in their satisfaction. Hospitals in Saudi Arabia are considered to be among the best and most technologically advanced in the world. However, the quality of care in terms of how women are cared for is an issue, especially in the public sector. Therefore, to improve the quality of care, Saudi Arabia is planning to privatize the public sector, which comprises 60% of the services. This study was designed to provide baseline information regarding how satisfied women are with their maternity care and garner their perspectives on how patient-centered care should be practiced. Specifically, it compares women’s satisfaction in the public and the private sectors in two of the National Guards hospitals in two cities (Jeddah and Riyadh) in Saudi Arabia. These hospitals are considered to be among the best in the kingdom. The quality of care in these governmental hospitals is high compared to other public hospitals. This dissertation also examined and compared women’s knowledge and willingness to contribute to patient-centered care during labor and delivery. This study shows that private patients tend to be more satisfied with their care compared to public patients, especially regarding privacy and dealing with nurses. Moreover, private patients tend to know more about their health rights and contributed more into their care process with their health providers. These findings serve as a baseline for health administrators, managers, and policymakers to consider as the transition to privatization begins. Stakeholders should focus on Key aspects to improve patients satisfaction. They should focus on improving patients’ privacy, health providers’ bedside manners, and women’s health rights education within the public and the private sector. These improvements should take place while maintaining the doctors\u27 and the hospitals’ reputations for the high quality of services

Molecular Modeling Studies on the Binding Mode of the PD-1/PD-L1 Complex Inhibitors

The programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) is an immune checkpoint (ICP) overexpressed in various types of tumors; thus, it has been considered as an important target for cancer therapy. To determine important residues for ligand binding, we applied molecular docking studies to PD-1/PD-L1 complex inhibitors against the PD-L1 protein. Our data revealed that the residues Tyr56, Asp122, and Lys124 play critical roles in ligand binding to the PD-L1 protein and they could be used to design ligands that are active against the PD-1/PD-L1 complex. The formation of H-bonds with Arg125 of the PD-L1 protein may enhance the potency of the PD-1/PD-L1 binding

Time as Transition: Experiences of Time, Culture and Immigration amongst Syrian Women in the UK

This study contributes to the current literature on time, gender, migration, culture and identity by bringing insights into how time is perceived and experienced by Syrian women who are settled and working in the UK. It is a topic that is little known in the extant literature, and that differs in its dynamics form the western literature. The notion of time has been widely debated but with little reference to its impact on the perceptions and individual experiences of migrant women, who engage with culturally different time structures and different time schedules. The spatial experiences of those women represented by their mobility across cultural boundaries seem to be affecting how migrant women perceive and organise time. Throughout the study, the Heideggerian interpretive phenomenological perspective has been adopted to make sense of and interpret the meanings and experiences provided by the participants of this study. This has been selected to allow space for considering and acknowledging the impact of the personal experience and prior knowledge of both the researcher and the researched subjects. Perceptions of time and time experiences have been found to be much diversified across personal, social and cultural contexts which are marked by spatial or geographical boundaries. Also, time structures and time schedules have been institutionally gendered across the cultures of both countries: Syria and the UK, but with varying degrees. Empirically, this study can help work organisations and agencies interested in working with migrant people to understand the diversity of perceptions and experiences of migrant female workers in the UK to enable them offering the care and services tailored to the needs of those migrants. In doing so, this research is hoped to improve the quality of work and social contributions of migrant women in the UK. Methodologically, this phenomenological inquiry contributes to the field of empirical and socio-political knowledge as well as the understanding of moral, aesthetic, and personal welfare debated in the migration literature. It contributes to the understanding of human experiences in relation to the notion of time, in isolation of any concern to predicting or prescribing any theory

THE MAJLIS METAMORPHOSIS: Virtues of Local Traditional Environmental Design in a Contemporary Context

In the Arabian Gulf countries, the majlis is a central part of the house. The most public space within it, the majlis represents the household’s occupants to society and its social and economic status. As the house reflects culture and civilization, so the family is understood as a micro-level society of individuals raised in its institutions. Hence, the house is a manifestation of family structure, religious beliefs, and individual needs and desires, reflecting the family’s economic, cultural, and social backgrounds and aspirations. The majlis offers a unique space in Arab societies, articulating cultural and social factors that directly impact identity Accordingly, the design of the majlis and meanings associated with its constituents are essential to the discussion about Qatari culture and society from past to present (Rapoport 1969). Since the discovery of oil in Qatar, there has been a noteworthy change in the way that houses have been designed, with a major transformation in the use of house and majlis over the last few generations, including social factors such as family social structure, the role of women, kinship and its relationship with privacy and proximity, and economic factors such as the availability of disposable income. This research explores the evolution of house architecture in Qatar with a focus on the design and social impact of the majlis. The physical and social changes in the period between pre-oil discovery until today have created gaps between the built form, climate, and sociocultural activities. This research attempts to bridge this gap, concentrating on the majlis

Finding Similar Documents Using Different Clustering Techniques

AbstractText clustering is an important application of data mining. It is concerned with grouping similar text documents together. In this paper, several models are built to cluster capstone project documents using three clustering techniques: k-means, k-means fast, and k-medoids. Our datatset is obtained from the library of the College of Computer and Information Sciences, King Saud University, Riyadh. Three similarity measure are tested: cosine similarity, Jaccard similarity, and Correlation Coefficient. The quality of the obtained models is evaluated and compared. The results indicate that the best performance is achieved using k-means and k-medoids combined with cosine similarity. We observe variation in the quality of clustering based on the evaluation measure used. In addition, as the value of k increases, the quality of the resulting cluster improves. Finally, we reveal the categories of graduation projects offered in the Information Technology department for female students

Properties of Pb(Zr,Ti)O3_3 ultrathin films under stress-free and open-circuit electrical boundary conditions

A first-principles-based scheme is developed to simulate properties of (001) PbO-terminated Pb(Zr$_{1-x}$Ti$_{x}$)O$_3$ thin films that are under stress-free and open-circuit boundary conditions. Their low-temperature spontaneous polarization never vanishes down to the minimal thickness, and continuously rotates between the in-plane and directions when varying the Ti composition around x=0.50. Such rotation dramatically enhances piezoelectricity and dielectricity. Furthermore, the order of some phase transitions changes when going from bulk to thin films.Comment: 11 pages, 3 figure

Conformational Studies of Glucose Transporter 1 (GLUT1) as an Anticancer Drug Target

Glucose transporter 1 (GLUT1) is a facilitative glucose transporter overexpressed in various types of tumors; thus, it has been considered as an important target for cancer therapy. GLUT1 works through conformational switching from an outward-open (OOP) to an inward-open (IOP) conformation passing through an occluded conformation. It is critical to determine which conformation is preferred by bound ligands because the success of structure-based drug design depends on the appropriate starting conformation of the target protein. To find out the most favorable GLUT 1 conformation for ligand binding, we ran systemic molecular docking studies for different conformations of GLUT1 using known GLUT1 inhibitors. Our data revealed that the IOP is the preferred conformation and that residues Phe291, Phe379, Glu380, Trp388, and Trp412 may play critical roles in ligand binding to GLUT1. Our data suggests that conformational differences in these five amino acids in the different conformers of GLUT1 may be used to design ligands that inhibit GLUT1