Aspect génétique de l'abduction des membres ("splayleg") dans les lignées de porcs large white et piétrain et leurs croisements

International audienc

Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome

Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (HIDS) represent the two ends of a clinical spectrum of disease caused by deficiency of mevalonate kinase (MVK), the first committed enzyme of cholesterol biosynthesis. At least 30 patients with MVA and 180 patients with HIDS have been reported worldwide. MVA is characterized by psychomotor retardation, failure to thrive, progressive cerebellar ataxia, dysmorphic features, progressive visual impairment and recurrent febrile crises. The febrile episodes are commonly accompanied by hepatosplenomegaly, lymphadenopathy, abdominal symptoms, arthralgia and skin rashes. Life expectancy is often compromised. In HIDS, only febrile attacks are present, but a subgroup of patients may also develop neurological abnormalities of varying degree such as mental retardation, ataxia, ocular symptoms and epilepsy. A reduced activity of MVK and pathogenic mutations in the MVK gene have been demonstrated as the common genetic basis in both disorders. In MVA, the diagnosis is established by detection of highly elevated levels of mevalonic acid excreted in urine. Increased levels of immunoglobulin D (IgD) and, in most patients of immunoglobulin A (IgA), in combination with enhanced excretion of mevalonic acid provide strong evidence for HIDS. The diagnosis is confirmed by low activity of mevalonate kinase or by demonstration of disease-causing mutations. Genetic counseling should be offered to families at risk. There is no established successful treatment for MVA. Simvastatin, an inhibitor of HMG-CoA reductase, and anakinra have been shown to have beneficial effect in HIDS

New insights into the nature of the Cibacron brilliant red 3B-A – Chitosan interaction

Cibacron brilliant red 3B-A (CBR) has been introduced to determine chitosan (CS) concentrations in solution, and several studies applied it to measure chitosan content in pharmaceutical formulations. So far, studies have relied on the absorbance band shift to 570 nm to determine the extent of the CBR – CS interaction. In this study, we show that CBR forms micro- to nanometer sized aggregates with CS, depending on their charge ratio and that other photophysical changes in CBR are induced by this interaction. We found that, besides the bathochromic band shift, aggregation induces emission at 600 nm and emission quenching at 360 nm. We compared changes CS induced in absorbance and fluorescence emission of CBR with the CS monomer glucosamine and poly(allylamine) hydrochloride, which both contain amino groups, and found that similar but less intense photophysical changes also occur. Furthermore, CS-induced circular dichroism in CBR suggests a twisted, chiral structure of these aggregates that should match with the previously published in silico simulations of the structure of CS in solution. The low linear charge density of CS and its chiral conformation are considered responsible for the enhanced photophysical response of CBR interacting with the polycation

Post-puff respiration measures on smokers of different tar yield cigarettes

The purpose of this study was to determine the effect of different tar yield cigarette brands on the post-puff inhalation/exhalation depth and duration for established smokers of the brands. The study was conducted with 74 established smokers of 1–17 mg Federal Trade Commission (FTC) tar products. The subjects were participating in a five-day inpatient clinical biomarker study during which time they were allowed to smoke their own brand of cigarette whenever they wished. On two separate days, the subjects' breathing pattern was measured using respiratory inductive plethysmography while they smoked one cigarette. This enabled the measurement of the post-puff inhalation volume, exhalation volume, inhalation duration, and exhalation duration for each subject after each puff on two of their own brand of cigarettes

Fluorescence Dequenching Makes Haem-Free Soluble Guanylate Cyclase Detectable in Living Cells

In cardiovascular disease, the protective NO/sGC/cGMP signalling-pathway is impaired due to a decreased pool of NO-sensitive haem-containing sGC accompanied by a reciprocal increase in NO-insensitive haem-free sGC. However, no direct method to detect cellular haem-free sGC other than its activation by the new therapeutic class of haem mimetics, such as BAY 58-2667, is available. Here we show that fluorescence dequenching, based on the interaction of the optical active prosthetic haem group and the attached biarsenical fluorophor FlAsH can be used to detect changes in cellular sGC haem status. The partly overlap of the emission spectrum of haem and FlAsH allows energy transfer from the fluorophore to the haem which reduces the intensity of FlAsH fluorescence. Loss of the prosthetic group, e.g. by oxidative stress or by replacement with the haem mimetic BAY 58-2667, prevented the energy transfer resulting in increased fluorescence. Haem loss was corroborated by an observed decrease in NO-induced sGC activity, reduced sGC protein levels, and an increased effect of BAY 58-2667. The use of a haem-free sGC mutant and a biarsenical dye that was not quenched by haem as controls further validated that the increase in fluorescence was due to the loss of the prosthetic haem group. The present approach is based on the cellular expression of an engineered sGC variant limiting is applicability to recombinant expression systems. Nevertheless, it allows to monitor sGC's redox regulation in living cells and future enhancements might be able to extend this approach to in vivo conditions

Generality of shear thickening in suspensions

Suspensions are of wide interest and form the basis for many smart fluids. For most suspensions, the viscosity decreases with increasing shear rate, i.e. they shear thin. Few are reported to do the opposite, i.e. shear thicken, despite the longstanding expectation that shear thickening is a generic type of suspension behavior. Here we resolve this apparent contradiction. We demonstrate that shear thickening can be masked by a yield stress and can be recovered when the yield stress is decreased below a threshold. We show the generality of this argument and quantify the threshold in rheology experiments where we control yield stresses arising from a variety of sources, such as attractions from particle surface interactions, induced dipoles from applied electric and magnetic fields, as well as confinement of hard particles at high packing fractions. These findings open up possibilities for the design of smart suspensions that combine shear thickening with electro- or magnetorheological response.Comment: 11 pages, 9 figures, accepted for publication in Nature Material

Decision-Making in Research Tasks with Sequential Testing

Background: In a recent controversial essay, published by JPA Ioannidis in PLoS Medicine, it has been argued that in some research fields, most of the published findings are false. Based on theoretical reasoning it can be shown that small effect sizes, error-prone tests, low priors of the tested hypotheses and biases in the evaluation and publication of research findings increase the fraction of false positives. These findings raise concerns about the reliability of research. However, they are based on a very simple scenario of scientific research, where single tests are used to evaluate independent hypotheses. Methodology/Principal Findings: In this study, we present computer simulations and experimental approaches for analyzing more realistic scenarios. In these scenarios, research tasks are solved sequentially, i.e. subsequent tests can be chosen depending on previous results. We investigate simple sequential testing and scenarios where only a selected subset of results can be published and used for future rounds of test choice. Results from computer simulations indicate that for the tasks analyzed in this study, the fraction of false among the positive findings declines over several rounds of testing if the most informative tests are performed. Our experiments show that human subjects frequently perform the most informative tests, leading to a decline of false positives as expected from the simulations. Conclusions/Significance: For the research tasks studied here, findings tend to become more reliable over time. We also find that the performance in those experimental settings where not all performed tests could be published turned out to be surprisingly inefficient. Our results may help optimize existing procedures used in the practice of scientific research and provide guidance for the development of novel forms of scholarly communication.Engineering and Applied SciencesPsycholog

The secreted triose phosphate isomerase of Brugia malayi is required to sustain microfilaria production in vivo

Human lymphatic filariasis is a major tropical disease transmitted through mosquito vectors which take up microfilarial larvae from the blood of infected subjects. Microfilariae are produced by long-lived adult parasites, which also release a suite of excretory-secretory products that have recently been subject to in-depth proteomic analysis. Surprisingly, the most abundant secreted protein of adult Brugia malayi is triose phosphate isomerase (TPI), a glycolytic enzyme usually associated with the cytosol. We now show that while TPI is a prominent target of the antibody response to infection, there is little antibody-mediated inhibition of catalytic activity by polyclonal sera. We generated a panel of twenty-three anti-TPI monoclonal antibodies and found only two were able to block TPI enzymatic activity. Immunisation of jirds with B. malayi TPI, or mice with the homologous protein from the rodent filaria Litomosoides sigmodontis, failed to induce neutralising antibodies or protective immunity. In contrast, passive transfer of neutralising monoclonal antibody to mice prior to implantation with adult B. malayi resulted in 60–70% reductions in microfilarial levels in vivo and both oocyte and microfilarial production by individual adult females. The loss of fecundity was accompanied by reduced IFNγ expression by CD4+ T cells and a higher proportion of macrophages at the site of infection. Thus, enzymatically active TPI plays an important role in the transmission cycle of B. malayi filarial parasites and is identified as a potential target for immunological and pharmacological intervention against filarial infections

QuantiFERON®-TB gold in-tube performance for diagnosing active tuberculosis in children and adults in a high burden setting.

To determine whether QuantiFERON®-TB Gold In-Tube (QFT) can contribute to the diagnosis of active tuberculosis (TB) in children in a high-burden setting and to assess the performance of QFT and tuberculin skin test (TST) in a prospective cohort of TB suspect children compared to adults with confirmed TB in Tanzania. Sensitivity and specificity of QFT and TST for diagnosing active TB as well as indeterminate QFT rates and IFN-γ levels were assessed in 211 TB suspect children in a Tanzanian district hospital and contrasted in 90 adults with confirmed pulmonary TB. Sensitivity of QFT and TST in children with confirmed TB was 19% (5/27) and 6% (2/31) respectively. In adults sensitivity of QFT and TST was 84% (73/87) and 85% (63/74). The QFT indeterminate rate in children and adults was 27% and 3%. Median levels of IFN-γ were lower in children than adults, particularly children <2 years and HIV infected. An indeterminate result was associated with age <2 years but not malnutrition or HIV status. Overall childhood mortality was 19% and associated with an indeterminate QFT result at baseline. QFT and TST showed poor performance and a surprisingly low sensitivity in children. In contrast the performance in Tanzanian adults was good and comparable to performance in high-income countries. Indeterminate results in children were associated with young age and increased mortality. Neither test can be recommended for diagnosing active TB in children with immature or impaired immunity in a high-burden setting