62 research outputs found
Collaborative work with Somaliland stakeholders to increase evidence based decision making in FGM/C
The Population Council collaborated with partners Orchid Project and Somaliland Family Health Association to pilot a new approach to disseminating research findings in order to increase the impact of evidence-based decisionmaking in program, policy, and investments in female genital mutilation/cutting (FGM/C). This brief reports on a recent workshop that utilized an open space approach to encourage review of recent key evidence on FGM/C in Somaliland; explore UNICEF’s six elements of abandonment and their relevance to the Somaliland context; link research with decisionmaking; and develop action plans. Participants identified six key themes for further reflection: behavioral/social change, medicalization, policy, child rights, further research, and the role of NGOs and community-based organizations. After the discussions on the last day of the workshop, participants developed draft action plans to link the research to their current work on policy and programming for FGM/C
Effects of Allosteric Mutations on Dihydrofolate Reductase
Dihydrofolate reductase (DHFR) is an essential enzyme necessary in the synthesis of DNA precursors. DHFR acquires resistance to numerous known anti-folates and this has led to the continuous need to discover novel and selective DHFR inhibitors. Allosteric mutations on Bacillus stearothermophilus (Bs.) DHFR were previously found to alter inhibitor binding and specificity. In this work, we investigate how these mutations affect the conformational motions of DHFR associated with inhibitor binding. Two distal allosteric mutations, isoleucine at position 86 to alanine (I86A) and tyrosine at position 127 to alanine (Y127A) were separately introduced to C73A/S131C, a previously modified wild type DHFR to give C73A/I86A/S131C and C73A/Y127A/S131C DHFRs. The modified C73A/S131C DHFR contains a site for attachment of fluorescent label, N- [2-(l-maleimidyl) ethyl]-7-(diethyl amino) coumarin-3-carboxamide (MDCC). Development of C73A/S131Cmdcc DHFR allowed for a method to study two native conformations of DHFR that could otherwise not be studied by intrinsic fluorescence alone. Stopped-flow instrumentation together with fluorescence is used to study the kinetics of protein structural motions. This approach allowed us to examine the conformational changes associated with methotrexate (MTX) and pyrimethamine (PYR) binding, for the mutants and compare them to C73A/S131C DHFR. Intrinsic tryptophan fluorescence of the three DHFR constructs (C73A/S131C, 186A, Y127A) revealed a different conformational change upon PYR binding to one conformer compared to MTX binding. To study the second conformer, MDCC is covalently attached to the cysteine at position 131 on the DHFR (C73A/S131Cmdcc» I86Amdcc? Y127Amdcc) and all three enzymes show a conformational change, different from that observed by intrinsic fluorescence upon inhibitor binding that are inhibitor specific. This study provides insight on the conformational changes associated with inhibitor binding. How the conformational changes are inhibitor specific. As well as how the mutants’ (I86A and Y127A) affect the conformational changes compared to C73A/S131C. Understanding what happens during inhibitor binding and the role of allosteric mutations on ligand binding specificity can inform design and repurposing of selective DHFR drug compounds
A diagnostic assessment of the health system’s response to female genital mutilation/cutting management and prevention in Kenya
Female genital mutilation/cutting (FGM/C) is a cultural practice associated with health consequences and rights violations. In Kenya, health sector–led FGM/C-related interventions are anchored in the legal and policy instruments and guidelines adapted from global/regional frameworks, as well as interventional tools approved by the World Health Organization. Despite the existence of the instruments, guidelines, and tools that should direct a robust health system response to FGM/C, the practice persists and quality of care of services for women and girls with FGM/C-related complications has not been ascertained. Evidence on whether the health sector implements relevant FGM/C-related legal and policy frameworks to address the practice and its related impacts is also lacking. To address these gaps, a diagnostic assessment of the health sector’s response to FGM/C management and prevention was conducted. Findings of the assessment, noted in this working paper, underscore the need for investments to strengthen the health sector’s response to FGM/C by developing appropriate tools and guidelines that inform the prevention, management, and quality of care for women with FGM/C, including integration of interventions at all levels of the health sector
Tracing change in female genital mutilation/cutting: Shifting norms and practices among communities in Narok and Kisii counties, Kenya
In Kenya, there has been a steady and marked decline in the prevalence of female genital mutilation/cutting (FGM/C) but there is great variance in the prevalence of FGM/C across the country, with prevalence remaining high among certain ethnic groups such as Somali, Samburu, Kisii, and the Maasai. The objectives of this study were: 1) to explore whether and how unprogrammed factors or programmed FGM/C interventions (alternative rites of passage, legal and policy measures, religious-oriented approaches, promotion of girls’ education, intergenerational dialogues, use of rescue centers, and other undocumented approaches) influence community values deliberation in Narok and Kisii counties; 2) to assess what changes in FGM/C norms and practices have occurred in Narok and Kisii counties, and identify factors motivating these changes; and 3) to identify barriers to FGM/C abandonment in these key “hot spots,” and assess how, in light of empirical findings and theoretical models of behavior, intervention efforts might be optimized and coordinated to accelerate abandonment. The study clearly shows that norms and practices of FGM/C are not static even in these study areas. While there might not be widespread abandonment yet, people are reassessing norms and traditions in light of the current social climate. These changes may provide a useful starting point for intervention programs that seek to create dialogue and critical reflection on the practice of FGM/C in an effort to accelerate its abandonment
Tracing change in female genital mutilation/cutting: Shifting norms and practices among communities in Narok and Kisii counties, Kenya—Brief
This policy brief summarizes key findings from a study that examined whether there are shifts in norms and practices related to FGM/C among communities in Narok (predominantly inhabited by Maasai) and Kisii (predominantly inhabited by Abagusii) counties in Kenya. Although Kisii and Narok are FGM/C hotspots, practicing communities in these counties are reassessing norms and traditions in light of the current social and legal climate. These changes may provide a useful starting point for intervention programs that seek to create dialogue and critical reflection on the practice of FGM/C in an effort to accelerate its abandonment. Programmatic recommendations include: engaging community members in values deliberation to facilitate community-wide abandonment, addressing human rights issues and gender norms, allocating sufficient resources to local grassroots organizations, and a long-term commitment to ensure successful and sustainable change
Three Toxoplasma gondii dense granule proteins are required for induction of Lewis rat macrophage pyroptosis
Upon invasion of Lewis rat macrophages, Toxoplasma rapidly induces programmed cell death (pyroptosis), which prevents Toxoplasma replication, possibly explaining the resistance of the Lewis rat to Toxoplasma Using a chemical mutagenesis screen, we identified Toxoplasma mutants that no longer induced pyroptosis. Whole-genome sequencing led to the identification of three Toxoplasma parasitophorous vacuole-localized dense granule proteins, GRA35, GRA42, and GRA43, that are individually required for induction of Lewis rat macrophage pyroptosis. Macrophage infection with Δgra35, Δgra42, and Δgra43 parasites led to greatly reduced cell death rates and enhanced parasite replication. Lewis rat macrophages infected with parasites containing a single, double, or triple deletion of these GRAs showed similar levels of cell viability, suggesting that the three GRAs function in the same pathway. Deletion of GRA42 or GRA43 resulted in GRA35 (and other GRAs) being retained inside the parasitophorous vacuole instead of being localized to the parasitophorous vacuole membrane. Despite having greatly enhanced replication in Lewis rat macrophages in vitro, Δgra35, Δgra42, and Δgra43 parasites did not establish a chronic infection in Lewis rats. Toxoplasma did not induce F344 rat macrophage pyroptosis, but F344 rats infected with Δgra35, Δgra42, and Δgra43 parasites had reduced cyst numbers. Thus, these GRAs determined parasite in vivo fitness in F344 rats. Overall, our data suggest that these three Toxoplasma dense granule proteins play a critical role in establishing a chronic infection in vivo, independently of their role in mediating macrophage pyroptosis, likely due to their importance in regulating protein localization to the parasitophorous vacuole membrane.IMPORTANCE Inflammasomes are major components of the innate immune system and are responsible for detecting various microbial and environmental danger signals. Upon invasion of Lewis rat macrophages, the parasite rapidly activates the NLRP1 inflammasome, resulting in pyroptosis and elimination of the parasite's replication niche. The work reported here revealed that Toxoplasma GRA35, GRA42, and GRA43 are required for induction of Lewis rat macrophage pyroptosis. GRA42 and GRA43 mediate the correct localization of other GRAs, including GRA35, to the parasitophorous vacuole membrane. These three GRAs were also found to be important for parasite in vivo fitness in a Toxoplasma-susceptible rat strain, independently of their role in NLRP1 inflammasome activation, suggesting that they perform other important functions. Thus, this study identified three GRAs that mediate the induction of Lewis rat macrophage pyroptosis and are required for pathogenesis of the parasite
LACTB is a tumour suppressor that modulates lipid metabolism and cell state
Post-mitotic, differentiated cells exhibit a variety of characteristics that contrast with those of actively growing neoplastic cells, such as the expression of cell-cycle inhibitors and differentiation factors. We hypothesized that the gene expression profiles of these differentiated cells could reveal the identities of genes that may function as tumour suppressors. Here we show, using in vitro and in vivo studies in mice and humans, that the mitochondrial protein LACTB potently inhibits the proliferation of breast cancer cells. Its mechanism of action involves alteration of mitochondrial lipid metabolism and differentiation of breast cancer cells. This is achieved, at least in part, through reduction of the levels of mitochondrial phosphatidylserine decarboxylase, which is involved in the synthesis of mitochondrial phosphatidylethanolamine. These observations uncover a novel mitochondrial tumour suppressor and demonstrate a connection between mitochondrial lipid metabolism and the differentiation program of breast cancer cells, thereby revealing a previously undescribed mechanism of tumour suppression
LACTB is a tumour suppressor that modulates lipid metabolism and cell state
Post-mitotic, differentiated cells exhibit a variety of characteristics that contrast with those of actively growing neoplastic cells, such as the expression of cell-cycle inhibitors and differentiation factors. We hypothesized that the gene expression profiles of these differentiated cells could reveal the identities of genes that may function as tumour suppressors. Here we show, using in vitro and in vivo studies in mice and humans, that the mitochondrial protein LACTB potently inhibits the proliferation of breast cancer cells. Its mechanism of action involves alteration of mitochondrial lipid metabolism and differentiation of breast cancer cells. This is achieved, at least in part, through reduction of the levels of mitochondrial phosphatidylserine decarboxylase, which is involved in the synthesis of mitochondrial phosphatidylethanolamine. These observations uncover a novel mitochondrial tumour suppressor and demonstrate a connection between mitochondrial lipid metabolism and the differentiation program of breast cancer cells, thereby revealing a previously undescribed mechanism of tumour suppression
Attitudes et comportements envers l'argent et le temps chez les Atetela (République démocratique du Congo) : rôle des facteurs socioculturels dans le développement
Thèse de doctorat en sociologie -- UCL, 199
Nematode community structure and distribution along the Kenyan continental shelf
Meiofauna communities were analysed from samples collected at four stations on the Kenyan continental shelf (Shimoni, Kwale, Mombasa and Kilifi) during the maiden cruise of the RV Mtafiti, 12–21 December 2015. Nematodes were identified to genus level, and their distribution and composition were mainly influenced by grain size distribution, a finding similar to studies in other areas with a similar grain size distribution (iso-communities). The southern stations (Shimoni and Kwale) had coarser sediments than the northern stations (Mombasa and Kilifi). The family Chromadoridae was dominant at Shimoni, while Cyatholaimidae dominated at Kwale. Mombasa was dominated by Chromadoridae, Cyatholaimidae and Oxystominidae, and Kilifi by Xyalidae. The dominant genera portrayed a trend similar to that observed in the families, in that the dominant genera were members of the dominant families. Spilophorella was dominant at Shimoni, and Paracanthonchus, Paracyatholaimus, Desmodora, Microlaimus and Draconema were dominant at Kwale and Mombasa. Microlaimus, Daptonema and Terschellingia represented the highest abundances at Kilifi. All stations were dominated by epistratum feeders. Selective deposit feeders were the second-most-dominant feeding guild at Mombasa and Kwale, whereas non-selective feeders had the second-highest abundance at Kilifi. The diversity index was highest at Mombasa and lowest at Shimoni, whereas dominance was highest at Shimoni and lowest at Mombasa
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