Twaweza Independent Evaluation Overview of Case Studies

As the independent evaluator, CIE is charged with four primary goals: 1) verification of Twaweza’s outputs; 2) identification of outcomes/effects; 3) analysis of the relation between outputs and outcomes/effects; and 4) review of the appropriateness of Twaweza’s theory of change. A secondary goal is to contribute to Twaweza’s learning and communications processes by making rigorous analyses which invite probing questions and discussions available on a regular basis to the Learning & Communications Team. This is often referred to as ‘formative evaluation’, although that concept trivializes the depth of interaction and supported questioning that Twaweza is committed to. These analyses and discussions will focus on ‘what is working well’, on ‘what needs re-positioning or re-calibrating’, and on ‘what is just not working at all.

Status of water hyacinth infestation and control in River Kagera

During a regional workshop held in Mukono, Uganda (May 2001) by scientists and technocrats from Kenya, Tanzania and Uganda, working on water hyacinth management under the Lake Victoria Environmental Management Project (LVEMP), it was resolved that a survey of River Kagera be made to study the status of water hyacinth infestation and biological control in the river. Reports at the Mukono Workshop indicated that although Tanzania and Uganda had made serious effort to introduced biological control weevils (Neochefina eichhorniae and Neochetina brucht) on the weed in River Kagera, the level of establishment of biological control in the river was doubtful. Large quantities of water hyacinth biomass drifted down River Kagera into Lake Victoria daily. Similar reports of apparent inability of biological control weevils to fully establish and have effect on water hyacinth in River Nile, especially the Upper Victoria Nile, were also made by Uganda, and large quantities of weed biomass continuously drifted down the Upper Victoria Nile into Lake Kyoga. This was in spite of the successful control of the weed in Lake Victoria between 1998 and 200

ROLE OF CHEMOKINE-CHEMOKINE RECEPTORS IN THE PATHOGENESIS OF SEVERE PLASMODIUM FALCIPARUM MALARIA IN CHILDREN: IMPLICATIONS FOR MALARIA-HIV INTERACTION

Molecular determinants of malaria pathogenesis are largely undefined. Chemokines and chemokine receptors, regulate immune responses, may thus determine malaria severity. Further, by regulating HIV pathogenesis, they may constitute a crucial link in malaria-HIV interaction. Understanding biologic mechanisms underlying malaria-HIV interaction has important public health utility in designing rational therapeutic and preventive strategies. Malaria could potentially modulate HIV-1 infection through alteration in expression of CD4 and chemokine receptors, required for cellular entry. This study has determined circulating levels and transcriptional profiles of β-chemokines (MIP-1α, MIP-1β, and RANTES) in ex vivo peripheral blood mononuclear cells (PBMCs) of children with varying degrees of malaria severity. Additional in vitro experiments assessed the effects of stimulation of PBMCs with crude hemozoin (Hz) or synthetic hemozoin (sHz) on CD4, β-chemokine and chemokine receptor (CCR5 and CXCR4) protein expression and transcript formation. Plasma MIP-1α and MIP-1β levels were significantly elevated in mild and severe malaria, while RANTES levels decreased with increasing disease severity. β-chemokine gene expression closely matched circulating β-chemokine profile, illustrating that PBMCs are a primary source for β-chemokine production during malaria. Healthy children with a history of severe malaria had lower baseline RANTES production than children with a history of mild malaria, suggesting inherent differences in RANTES production. In vitro experiments in PBMCs from healthy malaria-naïve donors showed that Hz and sHz promote a similar pattern of β-chemokine protein secretion and transcript expression. FACS analysis showed that Hz and sHz induced similar patterns of cellular surface expression of CD4, CCR5 and CXCR4 on PBMCs. Hz or sHz-exerted differential effects on CD14+ and CD3+ subsets, and this modulatory effect part to transcriptional regulation based on gene expression profiles obtained for respective antigens. Additional studies showed that HIV-1 replicates differently in monoctye-derived macrophages (MDMs) stimulated with either Hz or sHz. sHz enhanced HIV-1 replication while Hz had an inhibitory effect. Results presented here demonstrate a distinct profile of β-chemokine expression in children with severe malaria, which is promoted by P. falciparum derived hemozoin. Further, Hz modulates expression of surface antigens required for HIV-1 entry, defining a possible mechanism for HIV-malaria interaction

Selected Computing Research Papers Volume 7 June 2018

Contents Critical Evaluation of Arabic Sentimental Analysis and Their Accuracy on Microblogs (Maha Al-Sakran) Evaluating Current Research on Psychometric Factors Affecting Teachers in ICT Integration (Daniel Otieno Aoko) A Critical Analysis of Current Measures for Preventing Use of Fraudulent Resources in Cloud Computing (Grant Bulman) An Analytical Assessment of Modern Human Robot Interaction Systems (Dominic Button) Critical Evaluation of Current Power Management Methods Used in Mobile Devices (One Lekula) A Critical Evaluation of Current Face Recognition Systems Research Aimed at Improving Accuracy for Class Attendance (Gladys B. Mogotsi) Usability of E-commerce Website Based on Perceived Homepage Visual Aesthetics (Mercy Ochiel) An Overview Investigation of Reducing the Impact of DDOS Attacks on Cloud Computing within Organisations (Jabed Rahman) Critical Analysis of Online Verification Techniques in Internet Banking Transactions (Fredrick Tshane

Neprilysin inhibition for pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled, proof-of-concept trial

This is the peer reviewed version of the following article: Hobbs AJ, Moyes AJ, Baliga RS, et al. Neprilysin inhibition for pulmonary arterial hypertension: a randomized, double‐blind, placebo‐controlled, proof‐of‐concept trial. Br J Pharmacol. 2019. https://doi.org/10.1111/bph.14621, which has been published in final form at https://doi.org/10.1111/bph.14621. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived VersionsThis work was supported by a British Heart Foundation Project Grant (PG/11/88/28992) and the National Institutes for Health Research, Comprehensive Biomedical Research Centre award to UC

The Neuropathology of Fatal Cerebral Malaria in Malawian Children

We examined the brains of 50 Malawian children who satisfied the clinical definition of cerebral malaria (CM) during life; 37 children had sequestration of infected red blood cells (iRBCs) and no other cause of death, and 13 had a nonmalarial cause of death with no cerebral sequestration. For comparison, 18 patients with coma and no parasitemia were included. We subdivided the 37 CM cases into two groups based on the cerebral microvasculature pathology: iRBC sequestration only (CM1) or sequestration with intravascular and perivascular pathology (CM2). We characterized and quantified the axonal and myelin damage, blood-brain barrier (BBB) disruption, and cellular immune responses and correlated these changes with iRBC sequestration and microvascular pathology. Axonal and myelin damage was associated with ring hemorrhages and vascular thrombosis in the cerebral and cerebellar white matter and brainstem of the CM2 cases. Diffuse axonal and myelin damage were present in CM1 and CM2 cases in areas of prominent iRBC sequestration. Disruption of the BBB was associated with ring hemorrhages and vascular thrombosis in CM2 cases and with sequestration in both CM1 and CM2 groups. Monocytes with phagocytosed hemozoin accumulated within microvessels containing iRBCs in CM2 cases but were not present in the adjacent neuropil. These findings are consistent with a link between iRBC sequestration and intravascular and perivascular pathology in fatal pediatric CM, resulting in myelin damage, axonal injury, and breakdown of the BBB

Uterine Epithelial Cell Regulation of DC-SIGN Expression Inhibits Transmitted/Founder HIV-1 Trans Infection by Immature Dendritic Cells

Sexual transmission accounts for the majority of HIV-1 infections. In over 75% of cases, infection is initiated by a single variant (transmitted/founder virus). However, the determinants of virus selection during transmission are unknown. Host cell-cell interactions in the mucosa may be critical in regulating susceptibility to infection. We hypothesized in this study that specific immune modulators secreted by uterine epithelial cells modulate susceptibility of dendritic cells (DC) to infection with HIV-1.Here we report that uterine epithelial cell secretions (i.e. conditioned medium, CM) decreased DC-SIGN expression on immature dendritic cells via a transforming growth factor beta (TGF-β) mechanism. Further, CM inhibited dendritic cell-mediated trans infection of HIV-1 expressing envelope proteins of prototypic reference. Similarly, CM inhibited trans infection of HIV-1 constructs expressing envelopes of transmitted/founder viruses, variants that are selected during sexual transmission. In contrast, whereas recombinant TGF- β1 inhibited trans infection of prototypic reference HIV-1 by dendritic cells, TGF-β1 had a minimal effect on trans infection of transmitted/founder variants irrespective of the reporter system used to measure trans infection.Our results provide the first direct evidence for uterine epithelial cell regulation of dendritic cell transmission of infection with reference and transmitted/founder HIV-1 variants. These findings have immediate implications for designing strategies to prevent sexual transmission of HIV-1

Changes in the levels of cytokines, chemokines and malaria-specific antibodies in response to Plasmodium falciparum infection in children living in sympatry in Mali

<p>Abstract</p> <p>Background</p> <p>The Fulani are known to be less susceptible to <it>Plasmodium falciparum </it>malaria as reflected by lower parasitaemia and fewer clinical symptoms than other sympatric ethnic groups. So far most studies in these groups have been performed on adults, which is why little is known about these responses in children. This study was designed to provide more information on this gap.</p> <p>Methods</p> <p>Circulating inflammatory factors and antibody levels in children from the Fulani and Dogon ethnic groups were measured. The inflammatory cytokines; interleukin (IL)-1beta, IL-6, IL-8, IL-10, IL-12p70, tumor necrosis factor (TNF) and the chemokines; regulated on activation normal T cell expressed and secreted (RANTES), monokine-induced by IFN-gamma (MIG), monocyte chemotactic protein (MCP)-1 and IFN-gamma-inducible protein (IP)-10 were measured by cytometric bead arrays. The levels of interferon (IFN)-alpha, IFN-gamma and malaria-specific antibodies; immunoglobulin (Ig) G, IgM and IgG subclasses (IgG1-IgG4) were measured by ELISA.</p> <p>Results</p> <p>The results revealed that the Fulani children had higher levels of all tested cytokines compared to the Dogon, in particular IFN-gamma, a cytokine known to be involved in parasite clearance. Out of all the tested chemokines, only MCP-1 was increased in the Fulani compared to the Dogon. When dividing the children into infected and uninfected individuals, infected Dogon had significantly lower levels of RANTES compared to their uninfected peers, and significantly higher levels of MIG and IP-10 as well as MCP-1, although the latter did not reach statistical significance. In contrast, such patterns were not seen in the infected Fulani children and their chemokine levels remained unchanged upon infection compared to uninfected counterparts. Furthermore, the Fulani also had higher titres of malaria-specific IgG and IgM as well as IgG1-3 subclasses compared to the Dogon.</p> <p>Conclusions</p> <p>Taken together, this study demonstrates, in accordance with previous work, that Fulani children mount a stronger inflammatory and antibody response against <it>P. falciparum </it>parasites compared to the Dogon and that these differences are evident already at an early age. The inflammatory responses in the Fulani were not influenced by an active infection which could explain why less clinical symptoms are seen in this group.</p

Synthetic Plasmodium-Like Hemozoin Activates the Immune Response: A Morphology - Function Study

Increasing evidence points to an important role for hemozoin (HZ), the malaria pigment, in the immunopathology related to this infection. However, there is no consensus as to whether HZ exerts its immunostimulatory activity in absence of other parasite or host components. Contamination of native HZ preparations and the lack of a unified protocol to produce crystals that mimic those of Plasmodium HZ (PHZ) are major technical limitants when performing functional studies with HZ. In fact, the most commonly used methods generate a heterogeneous nanocrystalline material. Thus, it is likely that such aggregates do not resemble to PHZ and differ in their inflammatory properties. To address this issue, the present study was designed to establish whether synthetic HZ (sHZ) crystals produced by different methods vary in their morphology and in their ability to activate immune responses. We report a new method of HZ synthesis (the precise aqueous acid-catalyzed method) that yields homogeneous sHZ crystals (Plasmodium-like HZ) which are very similar to PHZ in their size and physicochemical properties. Importantly, these crystals are devoid of protein and DNA contamination. Of interest, structure-function studies revealed that the size and shape of the synthetic crystals influences their ability to activate inflammatory responses (e.g. nitric oxide, chemokine and cytokine mRNA) in vitro and in vivo. In summary, our data confirm that sHZ possesses immunostimulatory properties and underline the importance of verifying by electron microscopy both the morphology and homogeneity of the synthetic crystals to ensure that they closely resemble those of the parasite. Periodic quality control experiments and unification of the method of HZ synthesis are key steps to unravel the role of HZ in malaria immunopathology

Phylogenetic classification of Cordyceps and the clavicipitaceous fungi

Cordyceps, comprising over 400 species, was historically classified in the Clavicipitaceae, based on cylindrical asci, thickened ascus apices and filiform ascospores, which often disarticulate into part-spores. Cordyceps was characterized by the production of well-developed often stipitate stromata and an ecology as a pathogen of arthropods and Elaphomyces with infrageneric classifications emphasizing arrangement of perithecia, ascospore morphology and host affiliation. To refine the classification of Cordyceps and the Clavicipitaceae, the phylogenetic relationships of 162 taxa were estimated based on analyses consisting of five to seven loci, including the nuclear ribosomal small and large subunits (nrSSU and nrLSU), the elongation factor 1α (tef1), the largest and the second largest subunits of RNA polymerase II (rpb1 and rpb2), β-tubulin (tub), and mitochondrial ATP6 (atp6). Our results strongly support the existence of three clavicipitaceous clades and reject the monophyly of both Cordyceps and Clavicipitaceae. Most diagnostic characters used in current classifications of Cordyceps (e.g., arrangement of perithecia, ascospore fragmentation, etc.) were not supported as being phylogenetically informative; the characters that were most consistent with the phylogeny were texture, pigmentation and morphology of stromata. Therefore, we revise the taxonomy of Cordyceps and the Clavicipitaceae to be consistent with the multi-gene phylogeny. The family Cordycipitaceae is validated based on the type of Cordyceps, C. militaris, and includes most Cordyceps species that possess brightly coloured, fleshy stromata. The new family Ophiocordycipitaceae is proposed based on Ophiocordyceps Petch, which we emend. The majority of species in this family produce darkly pigmented, tough to pliant stromata that often possess aperithecial apices. The new genus Elaphocordyceps is proposed for a subclade of the Ophiocordycipitaceae, which includes all species of Cordyceps that parasitize the fungal genus Elaphomyces and some closely related species that parasitize arthropods. The family Clavicipitaceae s. s. is emended and includes the core clade of grass symbionts (e.g., Balansia, Claviceps, Epichloë, etc.), and the entomopathogenic genus Hypocrella and relatives. In addition, the new genus Metacordyceps is proposed for Cordyceps species that are closely related to the grass symbionts in the Clavicipitaceae s. s. Metacordyceps includes teleomorphs linked to Metarhizium and other closely related anamorphs. Two new species are described, and lists of accepted names for species in Cordyceps, Elaphocordyceps, Metacordyceps and Ophiocordyceps are provided