Beyond Autonomy: Coersion and Morality in Clinical Relationships

International audienc

Appeal No. 0678: Perto Drilling Corp., Inc. v. Division of Mineral Resources Management

Chief\u27s Order 99-15

Quantitative Proteomic Analysis of Simian Primary Hepatocytes Reveals Candidate Molecular Markers for Permissiveness to Relapsing Malaria Plasmodium cynomolgi.

A major obstacle impeding malaria research is the lack of an in vitro system capable of supporting infection through the entire liver stage cycle of the parasite, including that of the dormant forms known as hypnozoites. Primary hepatocytes lose their liver specific functions in long-term in vitro culture. The malaria parasite Plasmodium initiates infection in hepatocyte. This corresponds to the first step of clinically silent infection and development of malaria parasite Plasmodium in the liver. Thus, the liver stage is an ideal target for development of novel antimalarial interventions and vaccines. However, drug discovery against Plasmodium liver stage is severely hampered by the poor understanding of host-parasite interactions during the liver stage infection and development. In this study, tandem mass tag labeling based quantitative proteomic analysis is performed in simian primary hepatocytes cultured in three different systems of susceptibility to Plasmodium infection. The results display potential candidate molecular markers, including asialoglycoprotein receptor, apolipoproteins, squalene synthase, and scavenger receptor B1 (SR-BI) that facilitate productive infection and full development in relapsing Plasmodium species. The identification of these candidate proteins required for constructive infection and development of hepatic malaria liver stages paves the way to explore them as therapeutic targets

Towards an In Vitro Model of Plasmodium Hypnozoites Suitable for Drug Discovery

Contains fulltext : 96475.pdf (publisher's version ) (Open Access)BACKGROUND: Amongst the Plasmodium species in humans, only P. vivax and P. ovale produce latent hepatic stages called hypnozoites, which are responsible for malaria episodes long after a mosquito bite. Relapses contribute to increased morbidity, and complicate malaria elimination programs. A single drug effective against hypnozoites, primaquine, is available, but its deployment is curtailed by its haemolytic potential in glucose-6-phosphate dehydrogenase deficient persons. Novel compounds are thus urgently needed to replace primaquine. Discovery of compounds active against hypnozoites is restricted to the in vivo P. cynomolgi-rhesus monkey model. Slow growing hepatic parasites reminiscent of hypnozoites had been noted in cultured P. vivax-infected hepatoma cells, but similar forms are also observed in vitro by other species including P. falciparum that do not produce hypnozoites. METHODOLOGY: P. falciparum or P. cynomolgi sporozoites were used to infect human or Macaca fascicularis primary hepatocytes, respectively. The susceptibility of the slow and normally growing hepatic forms obtained in vitro to three antimalarial drugs, one active against hepatic forms including hypnozoites and two only against the growing forms, was measured. RESULTS: The non-dividing slow growing P. cynomolgi hepatic forms, observed in vitro in primary hepatocytes from the natural host Macaca fascicularis, can be distinguished from similar forms seen in P. falciparum-infected human primary hepatocytes by the differential action of selected anti-malarial drugs. Whereas atovaquone and pyrimethamine are active on all the dividing hepatic forms observed, the P. cynomolgi slow growing forms are highly resistant to treatment by these drugs, but remain susceptible to primaquine. CONCLUSION: Resistance of the non-dividing P. cynomolgi forms to atovaquone and pyrimethamine, which do not prevent relapses, strongly suggests that these slow growing forms are hypnozoites. This represents a first step towards the development of a practical medium-throughput in vitro screening assay for novel hypnozoiticidal drugs

BMJ Open

In low-income settings with limited access to diagnosis, COVID-19 information is scarce. In September 2020, after the first COVID-19 wave, Mali reported 3086 confirmed cases and 130 deaths. Most reports originated from Bamako, with 1532 cases and 81 deaths (2.42 million inhabitants). This observed prevalence of 0.06% appeared very low. Our objective was to estimate SARS-CoV-2 infection among inhabitants of Bamako, after the first epidemic wave. We assessed demographic, social and living conditions, health behaviours and knowledges associated with SARS-CoV-2 seropositivity. We conducted a cross-sectional multistage household survey during September 2020, in three neighbourhoods of the commune VI (Bamako), where 30% of the cases were reported. We recruited 1526 inhabitants in 3 areas, that is, 306 households, and 1327 serological results (≥1 years), 220 household questionnaires and collected answers for 962 participants (≥12 years). We measured serological status, detecting SARS-CoV-2 spike protein antibodies in blood sampled. We documented housing conditions and individual health behaviours through questionnaires among participants. We estimated the number of SARS-CoV-2 infections and deaths in the population of Bamako using the age and sex distributions. The prevalence of SARS-CoV-2 seropositivity was 16.4% (95% CI 15.1% to 19.1%) after adjusting on the population structure. This suggested that ~400 000 cases and ~2000 deaths could have occurred of which only 0.4% of cases and 5% of deaths were officially reported. Questionnaires analyses suggested strong agreement with washing hands but lower acceptability of movement restrictions (lockdown/curfew), and mask wearing. The first wave of SARS-CoV-2 spread broadly in Bamako. Expected fatalities remained limited largely due to the population age structure and the low prevalence of comorbidities. Improving diagnostic capacities to encourage testing and preventive behaviours, and avoiding the spread of false information remain key pillars, regardless of the developed or developing setting. This study was registered in the registry of the ethics committee of the Faculty of Medicine and Odonto-Stomatology and the Faculty of Pharmacy, Bamako, Mali, under the number: 2020/162/CA/FMOS/FAPH

Differential transmissibility to Anopheles arabiensis of Plasmodium vivax gametocytes in patients with diverse Duffy blood group genotypes

International audienceBackgroundMeasuring risk of malaria transmission is complex, especially in case of Plasmodium vivax. This may be overcome using membrane feeding assays in the field where P. vivax is endemic. However, mosquito-feeding assays are affected by a number of human, parasite and mosquito factors. Here, this study identified the contributions of Duffy blood group status of P. vivax-infected patients as a risk of parasite transmission to mosquitoes.MethodsA membrane feeding assay was conducted on a total of 44 conveniently recruited P. vivax infected patients in Adama city and its surroundings in East Shewa Zone, Oromia region, Ethiopia from October, 2019 to January, 2021. The assay was performed in Adama City administration. Mosquito infection rates were determined by midgut dissections at seven to 8 days post-infection. Duffy genotyping was defined for each of the 44 P. vivax infected patients.ResultsThe infection rate of Anopheles mosquitoes was 32.6% (296/907) with 77.3% proportion of infectious participants (34/44). Infectiousness of participants to Anopheles mosquitoes appeared to be higher among individuals with homozygous Duffy positive blood group (TCT/TCT) than heterozygous (TCT/CCT), but the difference was not statistically significant. The mean oocyst density was significantly higher among mosquitoes fed on blood of participants with FY*B/FY*BES than other genotypes (P = 0.001).ConclusionDuffy antigen polymorphisms appears to contribute to transmissibility difference of P. vivax gametocytes to Anopheles mosquitoes, but further studies are required

Qualitative evidence of the flexoelectric effect in a single multi-wall carbon nanotube by nanorobotic manipulation

International audienceThe flexoelectric effect corresponds to the linear variation of the electric polarization of a<div style=""&gt<font face="arial, helvetica"&gt<span style="font-size: 13px;"&gtmaterial subjected to a strain gradient (i.e. during its mechanical bending). Unlike</span&gt</font&gt</div&gt<div style=""&gt<font face="arial, helvetica"&gt<span style="font-size: 13px;"&gtpiezoelectricity, it also exists in non-centrosymmetric materials. Furthermore, due to the</span&gt</font&gt</div&gt<div style=""&gt<font face="arial, helvetica"&gt<span style="font-size: 13px;"&gtgradient term, its magnitude can increase as the size of the system decreases. Thanks to this</span&gt</font&gt</div&gt<div style=""&gt<font face="arial, helvetica"&gt<span style="font-size: 13px;"&gteffect, nanoscale systems could be used to harvest thermal vibration energy to power a</span&gt</font&gt</div&gt<div style=""&gt<font face="arial, helvetica"&gt<span style="font-size: 13px;"&gtmicrodevice. These could be multi-wall carbon nanotubes since they are known to bend easily</span&gt</font&gt</div&gt<div style=""&gt<font face="arial, helvetica"&gt<span style="font-size: 13px;"&gtin an elastic manner. However, it is very challenging to experimentally measure the</span&gt</font&gt</div&gt<div style=""&gt<font face="arial, helvetica"&gt<span style="font-size: 13px;"&gtflexoelectric behavior of a single multi-wall carbon nanotube due to its small size (less than 50</span&gt</font&gt</div&gt<div style=""&gt<font face="arial, helvetica"&gt<span style="font-size: 13px;"&gtnm in diameter), to the low level of induced charges and to the need to vary the imposed stress.</span&gt</font&gt</div&gt<div style=""&gt<font face="arial, helvetica"&gt<span style="font-size: 13px;"&gtTo progress in this direction, a six-degree-of-freedom robot with a fiber tip is used inside a</span&gt</font&gt</div&gt<div style=""&gt<font face="arial, helvetica"&gt<span style="font-size: 13px;"&gtdual-beam microscope to pick up a few single carbon nanotubes from a tangle and connect them</span&gt</font&gt</div&gt<div style=""&gt<font face="arial, helvetica"&gt<span style="font-size: 13px;"&gtto the fiber tip. After ion-soldering the two tips, each carbon nanotube is dynamically bent</span&gt</font&gt</div&gt<div style=""&gt<font face="arial, helvetica"&gt<span style="font-size: 13px;"&gtseveral times while monitoring the brightness of the bending area and its effective radius of</span&gt</font&gt</div&gt<div style=""&gt<font face="arial, helvetica"&gt<span style="font-size: 13px;"&gtcurvature. This allowed us to demonstrate qualitatively the flexoelectric effect at the level of a</span&gt</font&gt</div&gt<div style=""&gt<font face="arial, helvetica"&gt<span style="font-size: 13px;"&gtsingle MWCNT.</span&gt</font&gt</div&g

Systematic gene expression mapping clusters nuclear receptors according to their function in the brain.

Nuclear receptors (NRs) compose a large family of transcription factors that operate at the interface between genes and environment, acting as sensors and effectors that translate endocrine and metabolic cues into well-defined gene expression programs. We report here on a systematic quantitative and anatomical expression atlas of the 49 NR genes in 104 regions of the adult mouse brain, organized in the interactive MousePat database. MousePat defines NR expression patterns to cellular resolution, a requirement for functional genomic strategies to understand the function of a highly heterogeneous and complex organ such as the brain. Using MousePat data, NR expression patterns can be clustered into anatomical and regulatory networks that delineate the role of NRs in brain functions, like the control of feeding and learning/memory. Mining the MousePat resource will improve the understanding of NR function in the brain and elucidate hierarchical networks that control behavior and whole body homeostasis

Systematic gene expression mapping clusters nuclear receptors according to their function in the brain

Nuclear receptors (NRs) compose a large family of transcription factors that operate at the interface between genes and environment, acting as sensors and effectors that translate endocrine and metabolic cues into well-defined gene expression programs. We report here on a systematic quantitative and anatomical expression atlas of the 49 NR genes in 104 regions of the adult mouse brain, organized in the interactive MousePat database. MousePat defines NR expression patterns to cellular resolution, a requirement for functional genomic strategies to understand the function of a highly heterogeneous and complex organ such as the brain. Using MousePat data, NR expression patterns can be clustered into anatomical and regulatory networks that delineate the role of NRs in brain functions, like the control of feeding and learning/memory. Mining the MousePat resource will improve the understanding of NR function in the brain and elucidate hierarchical networks that control behavior and whole body homeostasis