Natural Products Chemistry of Leads Acting on MRSA, HCV, Malaria, and Depression Disorders

Nature has proven to be an endless source of abundant diversity of chemical entities with varying biological activities. The World Health Organization (WHO) estimates that 80% of the world\u27s population depends on traditional medicine for treating their everyday health problems. According to Gordon Cragg, former director of the natural products branch of the NCI, ″Nature has produced wonderfully complex molecules that no synthetic chemist could ever dream up.″ Moreover, he emphasized that over 60% of cancer therapeutics have been derived from nature whether directly through isolation or indirectly through semi-synthesis. Various examples have been reported such as extracts from Catharanthus roseus (Rosy Periwinkle) used for treatment of Hodgkin\u27s disease and leukemia, digitalis from Digitalis purpurea (foxglove) for treatment of heart disease, galantamine from Galanthus caucasicus (snowdrops) for treatment of Alzheimer\u27s disease, and paclitaxel from the bark of the Pacific yew tree to treat cancer. During the course of these studies, we researched the potential of natural products to provide drugs for treatment of human and plant diseases for which no adequate therapy exists. For instance, methicillin-resistant Staphylococcus aureus (MRSA) is a destructive pathogen with a high patient mortality rate. Over 50% of the Staph. aureus infections around the world are caused by MRSA. In the first chapter, we will address the bioassay-guided isolation and characterization of a series of anti-MRSA active glycosides that exhibit a high degree of selectivity for MRSA from the leaves of the comAmerican sycamore, Platanus occidentalis. The isolated metabolites; E,E-platanoside [kaempferol 3-O-α-L-(2\u27\u27,3\u27\u27-di-E-pcoumaroyl)rhamnoside, IC50 2.0 µg/mL], E,Z-platanoside [kaempferol 3-O-α-L-(2\u27\u27-E-pcoumaroyl-3\u27\u27-Z-p-coumaroyl)rhamnoside, IC50 0.8 µg/mL], Z,E-platanoside [kaempferol 3-O-αL-(2\u27\u27-Z-p-coumaroyl-3\u27\u27-E-p-coumaroyl)rhamnoside, IC50 0.7 µg/mL], and Z,Z-platanoside [kaempferol 3-O-α-L-(2\u27\u27,3\u27\u27-di-Z-p-coumaroyl)rhamnoside, IC50 0.4 µg/mL] have been shown to prevent growth of MRSA on surfaces and systemically. The in vitro anti-MRSA activity of these metabolites indicated that changing the configuration of the double bond in the p-comaroyl units greatly affects the MRSA activity. This, in turn, encouraged us to establish economic methods to transform the less active E,Eplatanoside to the more active Z, Z-platanoside. Light-mediated isomerization in platanosides provides a precise, noninvasive, and “green” approach for controlling MRSA activity. In the second chapter, the development of a simple “green” chemistry approach is described that uses light induced photoisomerization for transforming the thermodynamically stable E,E-platanoside to the Z,E-, E,Z- and Z,Z-platanosides. This provided support for the light mediated photoisomerization over the enzymatic control theory for the biosynthesis formation of the Zisomers. American sycamore is significant to the forest products industry due to its use as pulpwood for making paper and fiberboard, and sawlogs for manufacturing butcher\u27s blocks, furniture, interior trim, boxes, and flooring. Historically, American sycamore has held, and continues to hold, good potential as a dedicated biofuels crop grown on short rotations in plantations. However, the growth and productivity of sycamore plantations is hampered by bacterial leaf scorch disease (BLS) caused by Xylella fastidiosa. Strains of this bacterium are the major cause of various plant diseases such as phony peach disease (PPD), plum leaf scald (PLS), and Pierce\u27s disease (PD) of grapes, citrus variegated chlorosis (CVC), and leaf scorch of almond, oleander, and pear. The isolated anti-MRSA metabolites are found in greater concentrations in healthy sycamore trees versus diseased trees suggesting an ecological link between tree health and glycoside content. The third chapter describes this ecological link and presents data that demonstrates the ability of the metabolites to inhibit X. fastidiosa at nanomolar concentrations (MIC ≤ 17-67 nM). The presence of these metabolites in sycamore has the potential to be a useful analytical tool for selecting disease-resistant strains. Depression is the most comdisease of the central nervous system affecting approximately 17% of Americans each year. According to the National Institute of Mental Health (NIMH), every year about 40 million American adults suffer from anxiety disorders that frequently co-occur with other psychiatric illnesses like depression. Recently, our group reported the isolation of several marine indole alkaloids and evaluated their biological activity in the forced swim (FST) and locomotor activity tests, revealing their potential to become new antidepressant drug leads. Among the isolated compounds, 5-bromo-N,N-dimethyltryptamine was found to display a high sedative effect in the locomotor activity test. Owing to the limited amounts of this compound obtained from isolation, a synthetic approach was adopted to prepare 5-bromo-N,N-dimethyltryptamine and its derivatives to study the structure activity relationships (SAR) and complete the dose-response experiments. In the fourth chapter, the synthesis is described of a series of 2-(5-halo-1H-indol-3-yl)-N,N-dimethylethanamines, as is the evaluation of their in vivo antidepressant and sedative activities using the FST and locomotor activity tests. Of the synthetically prepared compounds, 2-(1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide, 2- (5-chloro-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide, 2-(1H-indol-3-yl)-N,Ndimethylethanamine, 2-(5-chloro-1H-indol-3-yl)-N,N-dimethylethanamine, and 2-(5-iodo-1Hindol-3-yl)-N,N-dimethylethanamine have been shown to possess antidepressant-like action. Dose response studies were completed for the active compounds. Manzamine A is an alkaloid that contains a unique multi-heterocyclic ring system coupled to a β-carboline moiety. Manzamine A shopotent in vitro antimalarial activity against P. falciparum D6 and W2 (0.017-0.020 µM), but its toxicity hindered its development as a drug lead. Malaria, a major tropical infectious disease caused primarily by the protozoan parasite Plasmodium falciparum, is responsible for the death of more than 1.12 million individuals every year. Recently, Ihara reported that the π-delocalized lipophilic cationic (DLC) structures of various β-carboline natural products, display reasonable antimalarial activity against P. falciparum with low cytotoxicity against mammalian cells. The fifth chapter describes the synthesis of mono- and di-methylated quaternary carbolinium cations of manzamine A and evaluations of their in vitro antimalarial and antimicrobial activities, cytotoxicity, and also their potential for glycogen synthase kinase (GSK-3β) inhibition using molecular docking studies. Among the analogs, 2-N-methylmanzamine A exhibited antimalarial activity (IC50 0.7 – 1.0 µM), but was less potent than manzamine A. However, the compound was significantly less cytotoxic to mammalian kidney fibroblasts with a selectivity index in the same range as manzamine A. One of the most serious threats to humans is hepatitis C virus (HCV) infections affecting approximately 4 million individuals in the United States, and 200-300 million individuals worldwide, causing over 8,000 deaths each year. HCV can progress to severe liver disorders such as fibrosis, cirrhosis, and hepatocellular carcinoma. A rare Latin American plant extract provided through collaboration with the National Cancer Institute (NCI) repository (No. 77951) shopotent anti-HCV activity. Diplostephium rhododendroides (family Asteraceae) is only found between Ecuador and Colombia and has not been subjected to phytochemical screening. The last chapter describes the isolation and identification from this rare plant of anti-HCV oleanane-triterpenes complex glycosides with m/z of 1700-1800. The isolated rhododendrosaponins I-III have shown exceptional activity (EC50 0.2 µg/mL) against HCV and warrant further evaluations

Community engagement and civic participation in education: The role of education in advancing social capital among rural communities. A case study of USAID funded program to basic education in Egypt; the new schools program (NSP)- 2000-2008

This thesis examines e the role of civic participation in education in building the capacities of rural communities and advancing behaviors of democracy through the formation of a culture of social capital among them

Impact of Change in Exchange Rate on Foreign Direct Investment: Evidence from Somalia

The purpose of this study is to examine the influence of exchange rate on foreign direct investment in Somali. The study used location theory to analyze the data by applying multiple regression models under OLS method. The results show that the overall model is significant. There is a negative and significant relationship found between exchange rate and FDI, while, a positive and significant relationship is observed between inflation and domestic investment on FDI, and a negative but insignificant relationship is observed between lack of government and FDI.The strength of this research lies in its time limit. The scope of this research was for the less than 50 years ending and including the year 2010. It is not known whether the results would hold if a longer period would have been researched upon. Further it is not possible to tell whether the same findings will hold for the period after 2010. There is need for the government to retain tight monetary and fiscal policies in order to stable exchange rate in the Somalia. Central bank should promote monetary authorities at managing exchange rate effectively to attract foreign direct investors. while utilization location theory, this study contribute significant to the literature by adding new variable to the model lack of government. Keywords- exchange rate, foreign direct investment and Somalia

Assessing the Financial Accountability of the Somali Federal Government Organizations

Building robust financial accountability system is an essential step in making the Federal government of Somalia (FGS) a more effective institution that is able to deliver basic public services to the people of Somalia. The purpose of this study is to assess the financial accountability in the FGS. The study collected data from six federal institutions employing questionnaires. Seventy civil servants participated in the study. The Data were analyzed using descriptive statistics of mean and standard deviation. The study found that the system of financial accountability in the FGS is improving. The study recommends to the FGS to upgrade internal controls and financial reporting systems, publish significant budget information in a regular and timely manner to the public; promote public participation in the budget process and strength the auditor general to carry out its functions effectively. Keywords: Accountability, Financial matters, Federal government, Somali

Service Quality Provided by Higher Education Institutions in Somalia and Its Impact on Student Satisfaction

This study attempts to examine the relationship between service quality dimensions (tangibility, reliability, responsiveness, assurance and empathy) and students’ satisfaction. Furthermore, this study is also examining critical factors in service quality dimensions (tangibility, responsiveness, reliability, assurance and empathy) that contribute most to the satisfaction of the students. The study employed both purposive and stratified sampling technique by using a set of questionnaire that was distributed 120 undergraduate students in three of the universities in Mogadishu (SIMAD, MUQDISHO and BANADIR). However the study found that there is a positive significant relationship between service quality dimensions and students’ satisfaction. The study also found that Empathy has significant relationship with student’s satisfaction in the students’ perception of service quality rendered by their universities. Finally the study concludes that assessing level of satisfaction and continuous improvements of the quality of services that universities of Mogadishu provide to their students will help management and other staff of these universities to reach organizational success. Keywords: Service quality, Student satisfaction, higher education, tangibility, reliability, responsiveness, assurance, empathy, Mogadishu

New insights into the pathogenesis of adenomyosis: Is the dislocation of the endometrial fragments into the myometrium evident in adenomyosis uteri?

Introduction Adenomyosis (AM) is a prevalent disease among women in the reproductive-age. It is histopathologically defined by the ectopic presence of endometrial tissue deep in the underlying myometrium. Although the disease pathogenesis is so far unclear, a translocation of fragments of the basal endometrium into the myometrium, through micro-dehiscences in the inner myometrium, is the most widely accepted theory. These micro-dehiscences are caused by a uterine hyperperistalsis. The latter induces a tissue micro-trauma at the endometrial myometrial junctional zone (EMJZ) in AM-uteri. In our study, possible microscopic and ultra-microscopic evidence of micro- trauma and corresponding tissue-translocation in the EMJZ was investigated. Materials and methods Uterine wall biopsies were collected from clinically and histopathologically diagnosed AM (n=18) and non-AM (n=14) patients, to study any structural difference in favour of a micro-trauma at EMJZ. The biopsies were examined with Transmission Electron Microscopy (TEM), Van Gieson stain (for extra cellular collagen fibres) and immune-labelled for markers of: myofibroblasts (ASMA, collagen I), mature smooth muscle (desmin), Transforming Growth Factor beta receptor 1 (TGFβR1), TGFβR2, TGFβR3, cell-cell contact (E-cadherin) and hematopoietic cells (CD45, CD68). Results The EMJZ in AM-uteri showed both microscopic as well as ultra-microscopic changes as following: (1) A disarray of the smooth muscle fibres in the inner myometrium of AM-uteri was evident, compared to the parallel arrangement in non-AM uteri. (2) A disruption of the smooth interface between the endometrium and myometrium in AM was clearly seen, but lacked in non-AM. Nevertheless, neither cell disruption nor translocation of fragments of the basal endometrial glands into the stroma in AM-uteri was seen. (3) Interestingly, uterine pale cells were described in the basal endometrial glands in both AM and non-AM-uteri. However, only in the AM group were these cells migrating into the stroma, through ultra-microruptures of the glandular basement membrane at different locations. (4) As a consequence of tissue trauma, both ASMA-immunolabeled stromal cells in the endometrium as well as collagen I immunolabeling in the inner myometrium were significantly higher in AM uteri than in non-AM uteri. Conclusion The different morphological changes at the EMJZ support the theory of occurrence of a micro-trauma in AM-uteri being part of the pathogenesis of the disease. However, there is no evidence of a translocation of the basal endometrium in AM uteri. Moreover, the migrating uterine pale cells in AM-uteri demand an in-depth in-vitro characterization to elucidate if they are involved in the disease pathogenesis.Einleitung Die Adenomyoseis Erkrankung betrifft häufig Frauen im gebärfähigem Alter. Mikroskopisch zeichnet lässt sich die Erkrankung durch das Vorkommen von ektopen endometrialen Drüsen und Stromazellen tief im Myometrium aus. Obwohl die Pathogenese der Adenomyose bis heute nicht geklärt wurde, ist wohl von einer Translokation von Fragmenten des basalen Endometriums durch Mikro-Dehiszenz im inneren Myometrium auszugehen. Als ursächlich wird eine mögliche uterine Hyperperistaltik diskutiert. Die Mikro-Dehiszenzen werden mikroskopisch im Bereich der Übergangzone zwischen dem basalen Endometrium und dem inneren Myometrium verortet. In der vorliegenden Studie wurden betroffene und nicht betroffenen uterine Gewebe, mikroskopisch und ultramikroskopisch, auf Mikro-Traumata und Translokationen des basalen Endometriums hin untersucht und immunhistochemisch charakterisiert. Methodik Zweiunddreißig Patientinnen wurden in die Studie eingeschlossen, davon waren 18 klinisch und histopathologisch von AM betroffen, 14 wiesen klinisch und histopathologisch keine AM auf. Die uterinen Proben wurden mittels Transmissions-Elektronenmikroskopie charakterisiert. Weiterhin wurden folgende Nachweise Immunhistochemisch angefertigt: van Gieson-Färbung (extrazelluläre Kollagenfaserfärbung), Myofibroblasten (ASMA, Kollagen I), glatte Muskulatur (Desmin), Transforming Growth Factor Beta Rezeptor 1, 2 und 3 (TGFβR1, R2 und R3), Zellkontakte (ECadherin) und Immunzellen (CD45, CD68). Ergebnisse Sowohl mikroskopisch als auch ultra-mikroskopisch zeigten sich mehrere Veränderungen in den AM-Uteri: 1. Es zeigte sich eine unkoordinierte Anordnung der glatten Muskelfasern im inneren Myometrium der AM-Kohorte. Die Anordnung der myometrialen glatten Muskelzellen der Kontrollgruppe war hingegen in paralleler Orientierung zu den basalen endometrialen Drüsen. 2. Der Übergang Endometrium/Myometrium in AM-Uteri war äußert unregelmäßig, hingegen glatt in den Kontrollproben. Es ließ sich allerdings keine Dislokation einzelner Zellen darstellen, diese blieben immer im Verband, auch waren die Zell-Zellkontakte nicht gestört. 3. Die sogenannten Pale-Zellen in den basalen endometrialen Drüsen konnte sowohl in AM-Uteri als auch in der Kontrollgruppe nachgewiesen werden. In AM-Uteri stellte sich eine Migration der Pale Zellen ins Stroma dar, die an mehreren Stellen eine Ultra-Mikroruptur der basalen Membran in endometrialen Drüsen verursachten. 4. Als Mikrotraumatisierungsfolge, zeigten sich sowohl die ASMA-Expression im basalen Endometrium als auch die Kollagen-Expression im inneren Myometrium in der AM-Gruppe signifikant gegenüber den Kontrollproben erhöht. Schlussfolgerung Mehrere morphologisch-histologische Veränderungen bestärken die Theorie, dass es in der Endo-Myometrialen Übergangszone zu einer Mikrotraumatisierung kommt, die möglicherweise ursächlich an der Pathogenese der Adenomyosis uteri zu sein scheint. Dabei bleibt aber der Zellverbund intakt. Hingegen scheint der Nachweis von migrierenden Pale Zellen insbesondere in Patientinnen mit Adenomyosis uteri die These zu stärken, dass Gründerzellen mit an der Pathogenese der Adenomyosis beteiligt sein könnten. Um diese Hypothese zu bestätigen bedarf es jedoch weiterer in vivo und vitro Charakterisierung der Pale Zellen

Low speed aerodynamic characteristics of non-slender delta wing at low angles of attack

Low-speed wind tunnel experiments are conducted to study the aerodynamic performance of a half-span delta wing with 45° leading-edge sweep at subsonic flow regime. The experiments are carried out at a Reynolds number of 8.37 × 105, a free-stream Mach number of 0.1 and angles of attack up to 25°, in steps of 5°. The test model was designed with thirty-two pressure taps fixed on its surfaces (sixteen on each side). Multi-tube manometers were connected to these taps using long tubes to enable recording the pressure readings. Surface pressure distributions and aerodynamic characteristics were calculated at different span-wise locations along the non-dimensional chord-wise distance. Results exhibited that most lift on the studied wing is generated in the region close to the leading edge for all the studied incidence angles. Additional lift is created in the region close to the root chord rather than the tip chord, whereas drag forces increases from tip to root. This can be attributed to the formation of trailing edge vortexes due to the flow separation at the wing leading edge that produces more drag, hence suppressing lift. The study showed also that angle of attack increases the drag coefficient from tip to root, especially at high angle of attack, indicating unfavourable behaviour for manoeuvring. Moreover, the angle of attack increased the pitching moment coefficient up to 10° before it drops sharply until it reaches the tip of the wing model.Peer Reviewe

The Elements of Environment incubator for Competitive Research projects in Egyptian Universities: A prospective study

The study aimed to reach elements of the environment incubator for university research projects, and identify the nature of the research projects at universities. To achieve this, a Delphi research method was used to identify the views of experts in the elements of the environment incubator for research projects at Egyptian universities, in three successive rounds. The study ended to provide future vision for the elements of the environment incubator for research projects in Egyptian universities in the light of the views of experts

Impact of Agricultural Water Management Activities on Rural Poverty Alleviation with Reference to Gash Scheme, Sudan (2013)

     Poverty alleviation is an essential issue for development process, and it considered as one of UN Millennium Development Goals (MDGs), there is worldwide agreement on the role of poverty alleviation as target of development policies and strategies, particularly for country like Sudan, which has high poverty incidence in rural and urban areas. This study aimed at investigating the impact of agricultural water management activities on alleviate rural poverty in Sudan: with reference to Gash scheme, Kassala State. The research depended on primary data collected by means of a questionnaire, which is distributed to a sample contained 240 respondents in the study area, half of them are members of Water User Associations (WUAs)  and the other half are not members (control group). Also  the study measured the level of  income and expenditure poverty  and the differences between means for some variables  among  the two groups of the study. The logistic regression model has  been adopted for predicting either some of the respondents can escape poverty line according to some basic  characteristics or not. The results suggested that the income and expenditure poverty indices have declined among the members of WUAs than non-members. The results revealed that there is significant differences between means of the two groups of study in favor of WUAs members, in term of household income, total revenues of the farm, household educational years and the total costs of the farming. The results of binary logistic regression model showed that households headed by member of water user associations are 3.8  times more likely to be above the poverty line than those headed by non members of theses associations and the household headed by literate persons are 1.3 more likely  have a chance to escape poverty line than those households headed by illiterate persons