Self-assembly, Self-organization, Nanotechnology and vitalism

International audienceOver the past decades, self-assembly has attracted a lot of research attention and transformed the relations between chemistry, materials science and biology. The paper explores the impact of the current interest in self-assembly techniques on the traditional debate over the nature of life. The first section describes three different research programs of self-assembly in nanotechnology in order to characterize their metaphysical implications: -1- Hybridization ( using the building blocks of living systems for making devices and machines) ; -2- Biomimetics (making artifacts mimicking nature); -3- Integration (a composite of the two previous strategies). The second section focused on the elusive boundary between selfassembly and self-organization tries to map out the various positions adopted by the promoters of self-assembly on the issue of vitalism

Losartan therapy in adults with Marfan syndrome: study protocol of the multi-center randomized controlled COMPARE trial

Contains fulltext : 87305.pdf (publisher's version ) (Open Access

Piperidinols that show anti-tubercular activity as inhibitors of arylamine N-acetyltransferase: an essential enzyme for mycobacterial survival inside macrophages

Latent M. tuberculosis infection presents one of the major obstacles in the global eradication of tuberculosis (TB). Cholesterol plays a critical role in the persistence of M. tuberculosis within the macrophage during latent infection. Catabolism of cholesterol contributes to the pool of propionyl-CoA, a precursor that is incorporated into cell-wall lipids. Arylamine N-acetyltransferase (NAT) is encoded within a gene cluster that is involved in the cholesterol sterol-ring degradation and is essential for intracellular survival. The ability of the NAT from M. tuberculosis (TBNAT) to utilise propionyl-CoA links it to the cholesterol-catabolism pathway. Deleting the nat gene or inhibiting the NAT enzyme prevents intracellular survival and results in depletion of cell-wall lipids. TBNAT has been investigated as a potential target for TB therapies. From a previous high-throughput screen, 3-benzoyl-4-phenyl-1-methylpiperidinol was identified as a selective inhibitor of prokaryotic NAT that exhibited antimycobacterial activity. The compound resulted in time-dependent irreversible inhibition of the NAT activity when tested against NAT from M. marinum (MMNAT). To further evaluate the antimycobacterial activity and the NAT inhibition of this compound, four piperidinol analogues were tested. All five compounds exert potent antimycobacterial activity against M. tuberculosis with MIC values of 2.3-16.9 µM. Treatment of the MMNAT enzyme with this set of inhibitors resulted in an irreversible time-dependent inhibition of NAT activity. Here we investigate the mechanism of NAT inhibition by studying protein-ligand interactions using mass spectrometry in combination with enzyme analysis and structure determination. We propose a covalent mechanism of NAT inhibition that involves the formation of a reactive intermediate and selective cysteine residue modification. These piperidinols present a unique class of antimycobacterial compounds that have a novel mode of action different from known anti-tubercular drugs

Environmental factors associated with the malaria vectors Anopheles gambiae and Anopheles funestus in Kenya

<p>Abstract</p> <p>Background</p> <p>The <it>Anopheles gambiae </it>and <it>Anopheles funestus </it>mosquito species complexes are the primary vectors of <it>Plasmodium falciparum </it>malaria in sub-Saharan Africa. To better understand the environmental factors influencing these species, the abundance, distribution and transmission data from a south-eastern Kenyan study were retrospectively analysed, and the climate, vegetation and elevation data in key locations compared.</p> <p>Methods</p> <p>Thirty villages in Malindi, Kilifi and Kwale Districts with data on <it>An. gambiae sensu strict</it>, <it>Anopheles arabiensis</it> and <it>An. funestus</it> entomological inoculation rates (EIRs), were used as focal points for spatial and environmental analyses. Transmission patterns were examined for spatial autocorrelation using the Moran's <it>I </it>statistic, and for the clustering of high or low EIR values using the Getis-Ord Gi* statistic. Environmental data were derived from remote-sensed satellite sources of precipitation, temperature, specific humidity, Normalized Difference Vegetation Index (NDVI), and elevation. The relationship between transmission and environmental measures was examined using bivariate correlations, and by comparing environmental means between locations of high and low clustering using the Mann-Whitney <it>U </it>test.</p> <p>Results</p> <p>Spatial analyses indicated positive autocorrelation of <it>An. arabiensis </it>and <it>An. funestus </it>transmission, but not of <it>An. gambiae s.s</it>., which was found to be widespread across the study region. The spatial clustering of high EIR values for <it>An. arabiensis </it>was confined to the lowland areas of Malindi, and for <it>An. funestus </it>to the southern districts of Kilifi and Kwale. Overall, <it>An. gambiae s.s</it>. and <it>An. arabiensis </it>had similar spatial and environmental trends, with higher transmission associated with higher precipitation, but lower temperature, humidity and NDVI measures than those locations with lower transmission by these species and/or in locations where transmission by <it>An. funestus </it>was high. Statistical comparisons indicated that precipitation and temperatures were significantly different between the <it>An. arabiensis </it>and <it>An. funestus </it>high and low transmission locations.</p> <p>Conclusion</p> <p>These finding suggest that the abundance, distribution and malaria transmission of different malaria vectors are driven by different environmental factors. A better understanding of the specific ecological parameters of each malaria mosquito species will help define their current distributions, and how they may currently and prospectively be affected by climate change, interventions and other factors.</p

Genomic Footprints of Selective Sweeps from Metabolic Resistance to Pyrethroids in African Malaria Vectors Are Driven by Scale up of Insecticide-Based Vector Control

Insecticide resistance in mosquito populations threatens recent successes in malaria prevention. Elucidating patterns of genetic structure in malaria vectors to predict the speed and direction of the spread of resistance is essential to get ahead of the `resistance curve' and to avert a public health catastrophe. Here, applying a combination of microsatellite analysis, whole genome sequencing and targeted sequencing of a resistance locus, we elucidated the continent-wide population structure of a major African malaria vector, Anopheles funestus. We identified a major selective sweep in a genomic region controlling cytochrome P450-based metabolic resistance conferring high resistance to pyrethroids. This selective sweep occurred since 2002, likely as a direct consequence of scaled up vector control as revealed by whole genome and fine-scale sequencing of pre- and post-intervention populations. Fine-scaled analysis of the pyrethroid resistance locus revealed that a resistanceassociated allele of the cytochrome P450 monooxygenase CYP6P9a has swept through southern Africa to near fixation, in contrast to high polymorphism levels before interventions, conferring high levels of pyrethroid resistance linked to control failure. Population structure analysis revealed a barrier to gene flow between southern Africa and other areas, which may prevent or slow the spread of the southern mechanism of pyrethroid resistance to other regions. By identifying a genetic signature of pyrethroid-based interventions, we have demonstrated the intense selective pressure that control interventions exert on mosquito populations. If this level of selection and spread of resistance continues unabated, our ability to control malaria with current interventions will be compromised

Could a Factor That Does Not Affect Egg Recognition Influence the Decision of Rejection?

Rejection of the parasitic egg is the most important defence of hosts against brood parasites. However, this response is variable among and within species, and egg discrimination is not always followed by egg rejection. Low risk of parasitism and high risk of rejection costs may lead to the acceptance of the parasitic egg even if it has been previously recognized. The main aim of this paper is to answer a relevant question: can a single egg trait provoke the acceptance of an experimental egg previously recognized as foreign? Increased egg mass should hamper the ejection of an egg that has been discriminated because ejection of a heavy egg may imply higher rejection costs for hosts. We have tested this prediction by experimentally parasitizing natural nests of Common Blackbirds (Turdus merula) with non-mimetic model eggs of different mass (heavy, normal-weight, and light) while controlling for potential confounding factors such as egg size and colour. Our results showed that blackbirds more frequently accepted heavy eggs, even when previously recognized. This differential acceptance may be related to insufficient motivation to assume the higher costs that the ejection of a heavy egg could impose.Financial support has been provided by the Consejería Economía, Innovación, Ciencia y Empleo, Junta de Andalucia (research project CVI-6653)

Prevalence and factors associated with alcohol and drug-related disorders in prison: a French national study

BACKGROUND: Most studies measuring substance-use disorders in prisons focus on incoming or on remand prisoners and are generally restricted to drugs. However, there is evidence that substance use initiation or continuation occurs in prison, and that alcohol use is common. The aim of this study is 1) to assess prevalence of both drug and alcohol abuse and dependence (DAD/AAD) in a national randomised cohort of French prisoners, short or long-term sentence 2) to assess the risk factors associated with DAD/AAD in prison. a stratified random strategy was used to select 1) 23 prisons among the different types of prison 2) 998 prisoners. Diagnoses were assessed according to a standardized procedure, each prisoner being assessed by two psychiatrists, one junior, using a structured interview (MINI 5 plus), and one senior, completing the procedure with an open clinical interview. At the end of the interview the clinicians met and agreed on a list of diagnoses. Cloninger's Temperament and Character Inventory (TCI) was also used. RESULTS: More than a third of prisoners presented either AAD or DAD in the last 12 months. Cannabis was the most frequent drug and just under a fifth of prisoners had AAD. AAD and DAD were clearly different for the following: socio-demographic variables, childhood history, imprisonment characteristics, psychiatric comorbidity and Cloninger's TCI. Profiles of AAD in prison are similar to type II alcoholism. CONCLUSION: Regular screening of AAD/DAD in prison, and specific treatment programmes taking into account differences between prisoners with an AAD and prisoners with a DAD should be a public health priority in priso

Polymorphisms in NF-κB Inhibitors and Risk of Epithelial Ovarian Cancer

<p>Abstract</p> <p>Background</p> <p>The nuclear factor-κB (NF-κB) family is a set of transcription factors with key roles in the induction of the inflammatory response and may be the link between inflammation and cancer development. This pathway has been shown to influence ovarian epithelial tissue repair. Inhibitors of κB (IκB) prevent NF-κB activation by sequestering NF-κB proteins in the cytoplasm until IκB proteins are phosphorylated and degraded.</p> <p>Methods</p> <p>We used a case-control study to evaluate the association between single nucleotide polymorphisms (SNPs) in <it>NFKBIA </it>and <it>NFKBIB </it>(the genes encoding IκBα and IκBβ, respectively) and risk of epithelial ovarian cancer. We queried 19 tagSNPs and putative-functional SNPs among 930 epithelial ovarian cancer cases and 1,037 controls from two studies.</p> <p>Results</p> <p>The minor allele for one synonymous SNP in <it>NFKBIA</it>, rs1957106, was associated with decreased risk (p = 0.03).</p> <p>Conclusion</p> <p>Considering the number of single-SNP tests performed and null gene-level results, we conclude that <it>NFKBIA </it>and <it>NFKBIB </it>are not likely to harbor ovarian cancer risk alleles. Due to its biological significance in ovarian cancer, additional genes encoding NF-κB subunits, activating and inhibiting molecules, and signaling molecules warrant interrogation.</p

Pyrethroid Resistance in an Anopheles funestus Population from Uganda

Background: The susceptibility status of Anopheles funestus to insecticides remains largely unknown in most parts of Africa because of the difficulty in rearing field-caught mosquitoes of this malaria vector. Here we report the susceptibility status of the An. funestus population from Tororo district in Uganda and a preliminary haracterisation of the putative resistance mechanisms involved. Methodology/Principal Findings: A new forced egg laying technique used in this study significantly increased the numbers of field-caught females laying eggs and generated more than 4000 F1 adults. WHO bioassays indicated that An. funestus in Tororo is resistant to pyrethroids (62% mortality after 1 h exposure to 0.75% permethrin and 28% mortality to 0.05% deltamethrin). Suspected DDT resistance was also observed with 82% mortality. However this population is fully susceptible to bendiocarb (carbamate), malathion (organophosphate) and dieldrin with 100% mortality observed after exposure to each of these insecticides. Sequencing of a fragment of the sodium channel gene containing the 1014 codon conferring pyrethroid/DDT resistance in An. gambiae did not detect the L1014F kdr mutation but a correlation between haplotypes and resistance phenotype was observed indicating that mutations in other exons may be conferring the knockdown resistance in this species. Biochemical assays suggest that resistance in this population is mediated by metabolic resistance with elevated level of GSTs, P450s and pNPA compared to a susceptible strain of Anopheles gambiae. RT-PCR further confirmed the involvement of P450s with a 12-fold over-expression of CYP6P9b in the Tororo population compared to the fully susceptible laboratory colony FANG. Conclusion: This study represents the first report of pyrethroid/DDT resistance in An. funestus from East Africa. With resistance already reported in southern and West Africa, this indicates that resistance in An. funestus may be more widespread than previously assumed and therefore this should be taken into account for the implementation and management of vector control programs in Africa

An in vitro model to assess the immunosuppressive effect of tick saliva on the mobilization of inflammatory monocyte-derived cells

Tick-borne pathogens cause potent infections. These pathogens benefit from molecules contained in tick saliva that have evolved to modulate host innate and adaptive immune responses. This is called "saliva-activated transmission" and enables tick-borne pathogens to evade host immune responses. Ticks feed on their host for relatively long periods; thus, mechanisms counteracting the inflammation-driven recruitment and activation of innate effector cells at the bite site, are an effective strategy to escape the immune response. Here, we developed an original in vitro model to evaluate and to characterize the immunomodulatory effects of tick saliva that prevent the establishment of a local inflammatory immune response. This model mimics the tick bite and enables the assessment of the effect of saliva on the inflammatory-associated dynamic recruitment of cells from the mononuclear phagocyte system. Using this model, we were able to recapitulate the dual effect of tick saliva on the mobilization of inflammatory monocyte-derived cells, i.e. (i) impaired recruitment of monocytes from the blood to the bite wound; and (ii) poor mobilization of monocyte-derived cells from the skin to the draining lymph node. This simple tool reconstitutes the effect of tick saliva in vivo, which we characterized in the mouse, and should enable the identification of important factors facilitating pathogen infection. Furthermore, this model may be applied to the characterization of any pathogen-derived immunosuppressive molecule affecting the establishment of the inflammatory immune response