This work considers a harvested logistic population for which birth rate, carrying capacity and harvesting rate all vary slowly with time. Asymptotic results from earlier work, obtained using a multiscaling technique, are combined to construct approximate expressions for the evolving population for the situation where the population initially survives to a slowly varying limiting state, but then, due to increasing harvesting, is reduced to extinction in finite time. These results are shown to give very good agreement with those obtained from numerical computation.

One of the most promising new targets for trypanocidal drugs to emerge in recent years is the cyclic AMP (cAMP) phosphodiesterase (PDE) activity encoded by TbrPDEB1 and TbrPDEB2. These genes were genetically confirmed as essential, and a highaffinity inhibitor, CpdA, displays potent antitrypanosomal activity. To identify effectors of the elevated cAMP levels resulting from CpdA action and, consequently, potential sites for adaptations giving resistance to PDE inhibitors, resistance to the drug was induced. Selection of mutagenized trypanosomes resulted in resistance to CpdA as well as cross-resistance to membranepermeable cAMP analogues but not to currently used trypanocidal drugs. Resistance was not due to changes in cAMP levels or in PDEB genes. A second approach, a genome-wide RNA interference (RNAi) library screen, returned four genes giving resistance to CpdA upon knockdown. Validation by independent RNAi strategies confirmed resistance to CpdA and suggested a role for the identified cAMP Response Proteins (CARPs) in cAMP action. CARP1 is unique to kinetoplastid parasites and has predicted cyclic nucleotide binding-like domains, and RNAi repression resulted in >100-fold resistance. CARP2 and CARP4 are hypothetical conserved proteins associated with the eukaryotic flagellar proteome or with flagellar function, with an orthologue of CARP4 implicated in human disease. CARP3 is a hypothetical protein, unique to Trypanosoma. CARP1 to CARP4 likely represent components of a novel cAMP signaling pathway in the parasite. As cAMP metabolism is validated as a drug target in Trypanosoma brucei, cAMP effectors highly divergent from the mammalian host, such as CARP1, lend themselves to further pharmacological development

Background: African trypanosomes are capable of both pyrimidine biosynthesis and salvage of preformed pyrimidines from the host, but it is unknown whether either process is essential to the parasite. Methodology/Principal Findings: Pyrimidine requirements for growth were investigated using strictly pyrimidine-free media, with or without single added pyrimidine sources. Growth rates of wild-type bloodstream form Trypanosoma brucei brucei were unchanged in pyrimidine-free medium. The essentiality of the de novo pyrimidine biosynthesis pathway was studied by knocking out the PYR6-5 locus that produces a fusion product of orotate phosphoribosyltransferase (OPRT) and Orotidine Monophosphate Decarboxylase (OMPDCase). The pyrimidine auxotroph was dependent on a suitable extracellular pyrimidine source. Pyrimidine starvation was rapidly lethal and non-reversible, causing incomplete DNA content in new cells. The phenotype could be rescued by addition of uracil; supplementation with uridine, 29deoxyuridine, and cytidine allowed a diminished growth rate and density. PYR6-52/ 2 trypanosomes were more sensitive to pyrimidine antimetabolites and displayed increased uracil transport rates and uridine phosphorylase activity. Pyrimidine auxotrophs were able to infect mice although the infection developed much more slowly than infection with the parental, prototrophic trypanosome line. Conclusions/Significance: Pyrimidine salvage was not an essential function for bloodstream T. b. brucei. However, trypanosomes lacking de novo pyrimidine biosynthesis are completely dependent on an extracellular pyrimidine source, strongly preferring uracil, and display reduced infectivity. As T. brucei are able to salvage sufficient pyrimidines from the host environment, the py

 Cutaneous leishmaniasis (CL) is an endemic parasitic infection in the Mediterranean region, including Libya and 

its Al-jabal Al-gharbi province. We aimed at studying the occupational relevance as well as other epidemiological aspects 

of CL. We investigated 140 CL cases who attended at Gharyan outpatient polyclinic during a period of 6 months in 2009. 

CL infection was clinically diagnosed and confirmed by demonstration of Leishmania parasites on smears from lesions. 

Our findings showed that males were more affected than females (P=0.04), and people above 10-years were more af￾fected than younger ones (P=0.0001). A significant percent of CL cases belonged to Al-Kawasem subprovince 

(P=0.0001). Farm-related activities were the most frequent occupations among CL cases (P=0.04). In addition to farm 

workers, housewives and students are at risk groups since they are engaged at farm activities. Moreover, those who have 

occupations that require staying outdoors for a part of night, e.g., policemen, are also at risk. Compared to children, adult 

CL patients had multiple lesions (P=0.001) that were more prevalent in their upper and lower extremities than the face 

(P=0.0001). We conclude that CL is a major health problem in Al-jabal Al-gharbi province of Libya. The presence of ro￾dents and sandflies makes it a suitable environment for Leishmania to spread in an endemic epidemiological pattern. Be￾ing engaged in farming activities or outdoor occupations increases the risk of infection. Various clinical patterns of CL 

suggest the presence of more than 1 species of Leishmania at Al-jabal Al-gharbi province. We propose that the 2 species 

responsible for CL in this area are L. major and L. tropica. Further investigations to identify the leishmanial species re￾sponsible for CL at Al-jabal Al-gharbi together with adoption of preventive and control programs are needed.

African trypanosomes are capable of both pyrimidine biosynthesis and salvage of preformed pyrimidines from the host. However, uptake of pyrimidines in bloodstream form trypanosomes has not been investigated, making it difficult to judge the relative importance of salvage and synthesis or to design a pyrimidine-based chemotherapy. Detailed characterization of pyrimidine transport activities in bloodstream form Trypanosoma brucei brucei found that these cells express a high-affinity uracil transporter (designated TbU3) that is clearly distinct from the procyclic pyrimidine transporters. This transporter had low affinity for uridine and 2′deoxyuridine and was the sole pyrimidine transporter expressed in these cells. In addition, thymidine was taken up inefficiently through a P1-type nucleoside transporter. Of importance, the anticancer drug 5-fluorouracil was an excellent substrate for TbU3, and several 5-fluoropyrimidine analogs were investigated for uptake and trypanocidal activity; 5F-orotic acid, 5F-2′deoxyuridine displayed activity in the low micromolar range. The metabolism and mode of action of these analogs was determined using metabolomic assessments of T. brucei clonal lines adapted to high levels of these pyrimidine analogs, and of the sensitive parental strains. The analysis showed that 5-fluorouracil is incorporated into a large number of metabolites but likely exerts toxicity through incorporation into RNA. 5F-2′dUrd and 5F-2′dCtd are not incorporated into nucleic acids but act as prodrugs by inhibiting thymidylate synthase as 5F-dUMP. We present the most complete model of pyrimidine salvage in T. brucei to date, supported by genome-wide profiling of the predicted pyrimidine biosynthesis and conversion enzymes.

The aim was to build an educational website to teach preschoolers aged 2-5 years old some skills; related to reading, writing and pronouncing alphabet, numbers, animal names, shapes and other common words. Also, assist parents and teachers by providing digital game-based learning environment to “edutainment” the children. The study illustrated the usability and usefulness of this educational game-based website and provided future insights for researchers and developers to take into account in future work.

This paper proposes an estimation method based on the reflection of the (manifest) explanatory variable to estimate the parameters of a simple linear regression model when both response and explanatory variables are subject to measurement error (ME). The reflection method (RM) uses all observed data points, and does not exclude or ignore part of the data or replace them by their ranks. The RM is straightforward, and easy to implement. We show that the RM is equivalent or asymptotically equivalent to the orthogonal regression (OR) method. Simulation studies show that the RM produces estimators that are nearly asymptotically unbiased and efficient under the assumption that the ratio of the error variances equals one. Moreover, it allows to define the sum of squares of errors uniquely, the same way as in the case of no measurement error. Simulation based numerical comparisons of the RM with the ordinary least square (OLS) and OR methods are also included.

The classic problem for a logistically evolving single species population being harvested involves three parameters: rate constant, carrying capacity and harvesting rate, which are taken to be positive constants. However, in real world situations, these parameters may vary with time. This paper considers the situation where these vary on a time scale much longer than that intrinsic to the population evolution itself. Application of a multiple time scale approach gives approximate explicit closed form expressions for the changing population, that compare favorably with those generated from numerical solutions.