Synergistic effects of GSK3 and p38 MAPK inhibitors on growth of Plasmodium falciparum ex vivo

Pharmacological inhibitors of glycogen synthase kinase 3 (GSK3) and p38 mitogen-activated protein kinase (p38 MAPK), two kinases commonly associated with signaling within cells, have been shown to suppress in vivo or ex vivo growth of plasmodial sp. Here we evaluated antiplasmodial activities ex vivo of four inhibitors against GSK3 [lithium chloride (LiCl),kenpaullone, (2’Z, 3’E)-6-bromoindirubin-3’-oxime (BIO) and SB216763]; and two against p38 MAPK (RWJ67657 and SB202190) individually and in combination preparatory to understanding the role of protein kinases in plasmodial development.The order of decreasing growth-suppressing potencies of the GSK3 inhibitors tested against Plasmodium falciparum 3D7 cultured ex vivo in erythrocytes was BIO (IC50=3.13 μM) > kenpaullone (IC50 = 18.3 μM) > SB216763 (IC50= 27.12 μM)> LiCl (IC50= 25 468 μM). The p38 MAPK inhibitor, RWJ67657, displayed an IC50 of 7.52 μM against 3D7. SB202190 was less effective at inhibiting 3D7 displaying an IC50 of 14.80 μM. When tested in combination, marked synergism was observed for combination of BIO or SB216763 with RWJ67657. In conclusion, GSK3 and MAPK inhibitors showed potent antiplasmodial activities. Synergistic effects observed between BIO or SB216763 and RWJ67657 in inhibiting plasmodial growth may implicate interaction between MAPK and GSK3 pathways and warrant further investigation

The Impact of Equal Employment Opportunity-Affirmative Action in U.S. and New Economic Policy in Malaysia on Employment and Reverse Discrimination

Penggubalan polisi Equal Employment Opportunity-Affirmative Action (EEO-AA) bertujuan memastikan wujud keseimbangan peluang pekerjaan di antara kaum majoriti dan minoriti di Amerika Syarikat. Di Malaysia pula, Dasar Ekonomi Baru (DEB)diwujudkan bagi menyeimbangkan status ekonomi di antara pelbagai etnik. Kajian ini pertamanya bertujuan untuk menganalisis sejauhmana EEO-AA dan DEB dapat mencapai matlamat untuk menyeimbangkan peluang pekerjaan di Amerika Syarikat dan juga status ekonomi antara etnik di Malaysia. Keduanya, untuk menganalisis sama ada EEO-AA dan DEB ini menyebabkan berlakunya “reverse discrimination”. Hasil kajian mendapati EEO-AA hanya memberi impak yang kecil kepada golongan minoriti di Amerika Syarikat. Di Malaysia pula, DEB telah berjaya meningkatkan jumlah partisipasi Bumiputera di dalam pelbagai sektor. Manakala kedua-dua polisi tidak menyebabkan berlakunya “reverse discrimination”

A Profile Analysis of Potential Investors in Ireit Waqf Investment Products

The objective of this study is to provide a profile analysis of potential investors in iREIT as an instrument for waqf asset development. By adopting a survey questionnaire approach, a total of 365 respondents participated in the survey, which assessed information pertaining to the understanding of iREIT as an investment instrument, level of acceptance towards the idea of its introduction in the context of waqf, the medium of promotion and collection that they most prefer, the suitable price, and the unique features that they agreed to have in this hybrid iREIT. The results suggest that majority of the respondents are interested to participate as investors rather than donors, indicating that greater amount of funds can be tapped from the issuance of the iREITs waqf if these preferences of the investors are given priority. Findings of this study would assist in the formulation of an innovative investment structure based on iREIT waqf that is both practical and appealing to the widest pool of investors, and further contribute towards the development of the waqf sector.     Keywords: Waqf, iREITs, investment, profiling, Islamic financ

The barriers and causes of building information modelling usage for interior design industry

Building Information Modeling (BIM) has since developed alongside the improvement in the construction industry, purposely to simulate the design, management, construction and documentation. It facilitates and monitors the construction through visualization and emphasizes on various inputs to virtually design and construct a building using specific software. This study aims to identify and elaborate barriers of BIM usage in interior design industry in Malaysia. This study is initiated with a pilot survey utilising sixteen respondents that has been randomly chosen. Respondents are attached with interior design firms that are registered by Lembaga Arkitek Malaysia (LAM). The research findings are expected to provide significant information to encourage BIM adoption among interior design firms

The Development of a Point of Care Clinical Guidelines Mobile Application Following a User-Centred Design Approach

This paper describes the development of a point of care clinical guidelines mobile application. A user-centred design approach was utilised to inform the design of a smartphone application, this included: Observations; a survey; focus groups and an analysis of popular apps utilised by clinicians in a UK NHS Trust. Usability testing was conducted to inform iterations of the application, which presents clinicians with a variety of integrated tools to aid in decision making and information retrieval. The study found that clinicians use a mixture of technology to retrieve information, which is often inefficient or has poor usability. It also shows that smartphone application development for use in UK hospitals needs to consider the variety of users and their clinical knowledge and work pattern. This study highlights the need for applying user-centred design methods in the design of information presented to clinicians and the need for clinical information delivery that is efficient and easy to use at the bedside

Control of Glycogen Content in Retina: Allosteric Regulation of Glycogen Synthase

Retinal tissue is exceptional because it shows a high level of energy metabolism. Glycogen content represents the only energy reserve in retina, but its levels are limited. Therefore, elucidation of the mechanisms controlling glycogen content in retina will allow us to understand retina response under local energy demands that can occur under normal and pathological conditions. Thus, we studied retina glycogen levels under different experimental conditions and correlated them with glucose-6-phosphate (G-6-P) content and glycogen synthase (GS) activity

Consumer input into research: the Australian Cancer Trials website

<p>Abstract</p> <p>Background</p> <p>The Australian Cancer Trials website (ACTO) was publicly launched in 2010 to help people search for cancer clinical trials recruiting in Australia, provide information about clinical trials and assist with doctor-patient communication about trials. We describe consumer involvement in the design and development of ACTO and report our preliminary patient evaluation of the website.</p> <p>Methods</p> <p>Consumers, led by Cancer Voices NSW, provided the impetus to develop the website. Consumer representative groups were consulted by the research team during the design and development of ACTO which combines a search engine, trial details, general information about trial participation and question prompt lists. Website use was analysed. A patient evaluation questionnaire was completed at one hospital, one week after exposure to the website.</p> <p>Results</p> <p>ACTO's main features and content reflect consumer input. In February 2011, it covered 1, 042 cancer trials. Since ACTO's public launch in November 2010, until the end of February 2011, the website has had 2, 549 new visits and generated 17, 833 page views. In a sub-study of 47 patient users, 89% found the website helpful for learning about clinical trials and all respondents thought patients should have access to ACTO.</p> <p>Conclusions</p> <p>The development of ACTO is an example of consumers working with doctors, researchers and policy makers to improve the information available to people whose lives are affected by cancer and to help them participate in their treatment decisions, including consideration of clinical trial enrolment. Consumer input has ensured that the website is informative, targets consumer priorities and is user-friendly. ACTO serves as a model for other health conditions.</p

Regulation of GSK-3 Activity as A Shared Mechanism in Psychiatric Disorders

Serin/Treonin kinaz ailesinin üyelerinden bir kinaz olarak ilk kez glikojen sentaz’ı inhibe ettiği keşfedilen glikojen sentaz kinaz-3 (GSK-3), günümüzde bilinen 50’den fazla substratı ile birçok hücre içi düzenleyici mekanizmada görev alan geniş etki spektrumlu bir enzim olarak kabul edilmektedir. GSK-3’ün memelilerde GSK-3α ve GSK-3β olmak üzere yapısal olarak yüksek homoloji gösteren iki izoformu bulunmaktadır. Her iki izoform birçok dokuda yaygın dağılım göstermekle beraber, en yüksek oranda beyinde bulunmakta ve genellikle benzer fonksiyonlar göstermektedirler. Diğer protein kinazların aksine GSK-3 uyarılmamış hücrede yapısal olarak aktif yani defosforile halde bulur. Protein kinaz A (PKA), protein kinaz B (PKB;AKT) ve protein kinaz C (PKC) gibi diğer protein kinazlarla fosforilasyona uğrayarak olarak inaktive edilir. Günümüzde artmış GSK-3 aktivitesinin major depresyon, bipolar bozukluk, hiperaktivite bozuklukları gibi hastalıklar ve şizofreni oluşumunda rol oynayabileceğine ilişkin önemli bulgular mevcuttur. Bu nedenle söz konusu psikiyatrik hastalıklarda arttığı gösterilen GSK-3 aktivitesinin azaltılmasının tedavide umut verici bir yaklaşım olabileceği kabul edilebilir. Bu gözden geçirme çalışmasında yukarıda sözü edilen psikiyatrik hastalıkların oluşmasında görev alan GSK-3 aracılı mekanizmalara kısaca değinilerek GSK-3’ün aktivitesinin düzenlenmesinde rol oynadığı gösterilen klinikte kullanılan ilaçlara yer verilmiştir. Anahtar sözcükler: GSK-3, depresyon, bipolar bozukluk, şizofren

Involvment of Cytosolic and Mitochondrial GSK-3β in Mitochondrial Dysfunction and Neuronal Cell Death of MPTP/MPP+-Treated Neurons

Aberrant mitochondrial function appears to play a central role in dopaminergic neuronal loss in Parkinson's disease (PD). 1-methyl-4-phenylpyridinium iodide (MPP+), the active metabolite of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is a selective inhibitor of mitochondrial complex I and is widely used in rodent and cell models to elicit neurochemical alterations associated with PD. Recent findings suggest that Glycogen Synthase Kinase-3β (GSK-3β), a critical activator of neuronal apoptosis, is involved in the dopaminergic cell death. In this study, the role of GSK-3β in modulating MPP+-induced mitochondrial dysfunction and neuronal death was examined in vivo, and in two neuronal cell models namely primary cultured and immortalized neurons. In both cell models, MPTP/MPP+ treatment caused cell death associated with time- and concentration-dependent activation of GSK-3β, evidenced by the increased level of the active form of the kinase, i.e. GSK-3β phosphorylated at tyrosine 216 residue. Using immunocytochemistry and subcellular fractionation techniques, we showed that GSK-3β partially localized within mitochondria in both neuronal cell models. Moreover, MPP+ treatment induced a significant decrease of the specific phospho-Tyr216-GSK-3β labeling in mitochondria concomitantly with an increase into the cytosol. Using two distinct fluorescent probes, we showed that MPP+ induced cell death through the depolarization of mitochondrial membrane potential. Inhibition of GSK-3β activity using well-characterized inhibitors, LiCl and kenpaullone, and RNA interference, prevented MPP+-induced cell death by blocking mitochondrial membrane potential changes and subsequent caspase-9 and -3 activation. These results indicate that GSK-3β is a critical mediator of MPTP/MPP+-induced neurotoxicity through its ability to regulate mitochondrial functions. Inhibition of GSK-3β activity might provide protection against mitochondrial stress-induced cell death

GSK-3β is essential for physiological electric field-directed Golgi polarization and optimal electrotaxis

Endogenous electrical fields (EFs) at corneal and skin wounds send a powerful signal that directs cell migration during wound healing. This signal therefore may serve as a fundamental regulator directing cell polarization and migration. Very little is known of the intracellular and molecular mechanisms that mediate EF-induced cell polarization and migration. Here, we report that Chinese hamster ovary (CHO) cells show robust directional polarization and migration in a physiological EF (0.3–1 V/cm) in both dissociated cell culture and monolayer culture. An EF of 0.6 V/cm completely abolished cell migration into wounds in monolayer culture. An EF of higher strength (≥1 V/cm) is an overriding guidance cue for cell migration. Application of EF induced quick phosphorylation of glycogen synthase kinase 3β (GSK-3β) which reached a peak as early as 3 min in an EF. Inhibition of protein kinase C (PKC) significantly reduced EF-induced directedness of cell migration initially (in 1–2 h). Inhibition of GSK-3β completely abolished EF-induced GA polarization and significantly inhibited the directional cell migration, but at a later time (2–3 h in an EF). Those results suggest that GSK-3β is essential for physiological EF-induced Golgi apparatus (GA) polarization and optimal electrotactic cell migration