Mycolactone as Analgesic: Subcutaneous Bioavailability Parameters

is the bacillus responsible for Buruli ulcer, an infectious disease and the third most important mycobacterial disease worldwide, after tuberculosis and leprosy. infection is a type of panniculitis beginning mostly with a nodule or an oedema, which can progress to large ulcerative lesions. The lesions are caused by mycolactone, the polyketide toxin of . Mycolactone plays a central role for host colonization as it has immunomodulatory and analgesic effects. On one hand, mycolactone induces analgesia by targeting type-2 angiotensin II receptors (ATR), causing cellular hyperpolarization and neuron desensitization. Indeed, a single subcutaneous injection of mycolactone into the mouse footpad induces a long-lasting hypoesthesia up to 48 h. It was suggested that the long-lasting hypoesthesia may result from the persistence of a significant amount of mycolactone locally following its injection, which could be probably due to its slow elimination from tissues. To verify this hypothesis, we investigated the correlation between hypoesthesia and mycolactone bioavailability directly at the tissue level. Various quantities of mycolactone were then injected in mouse tissue and hypoesthesia was recorded with nociception assays over a period of 48 h. The hypoesthesia was maximal 6 h after the injection of 4 μg mycolactone. The basal state was reached 48 h after injection, which demonstrated the absence of nerve damage. Surprisingly, mycolactone levels decreased strongly during the first hours with a reduction of 70 and 90% after 4 and 10 h, respectively. Also, mycolactone did not diffuse in neighboring skin tissue and only poorly into the bloodstream upon direct injection. Nevertheless, the remaining amount was sufficient to induce hypoesthesia during 24 h. Our results thus demonstrate that intact mycolactone is rapidly eliminated and that very small amounts of mycolactone are sufficient to induce hypoesthesia. Taken together, our study points out that mycolactone ought to be considered as a promising analgesic

A two-phase flow model to simulate mold filling and saturation in Resin Transfer Molding

The final publication is available at Springer via http://dx.doi.org/10.1007/s12289-015-1225-zThis paper addresses the numerical simulation of void formation and transport during mold filling in Resin Transfer Molding (RTM). The saturation equation, based on a two-phase flow model resin/air, is coupled with Darcy s law and mass conservation to simulate the unsaturated filling flow that takes place in a RTM mold when resin is injected through the fiber bed. These equations lead to a system composed of an advection diffusion equation for saturation including capillary effects and an elliptic equation for pressure taking into account the effect of air residual saturation. The model introduces the relative permeability as a function of resin saturation. When capillary effects are omitted, the hyperbolic nature of the saturation equation and its strong coupling with Darcy equation through relative permeability represent a challenging numerical issue. The combination of the constitutive physical laws relating permeability to saturation with the coupled system of the pressure and saturation equations allows predicting the saturation profiles. The model was validated by comparison with experimental data obtained for a fiberglass reinforcement injected in a RTM mold at constant flow rate. The saturation measured as a function of time during the resin impregnation of the fiber bed compared very well with numerical predictions.The authors acknowledge financial support of the Spanish Government (Projects DPI2010-20333 and DPI2013-44903-R-AR), of the National Science and Research Council of Canada (NSERC) and of the Canada Reseach Chair (CRC) program.Gascón Martínez, ML.; García Manrique, JA.; Lebel, F.; Ruiz, E.; Trochu, F. (2016). A two-phase flow model to simulate mold filling and saturation in Resin Transfer Molding. International Journal of Material Forming. 9(2):229-239. doi:10.1007/s12289-015-1225-zS22923992Patel N, Lee LJ (1996) Modeling of void formation and removal in liquid composite molding. Part I: wettability analysis. Polym Compos 17(1):96–103Ruiz E, Achim V, Soukane S, Trochu F, Bréard J (2006) Optimization of injection flow rate to minimize micro/macro-voids formation in resin transfer molded composites. Compos Sci Technol 66(3–4):475–486Trochu F, Ruiz E, Achim V, Soukane S (2006) Advanced numerical simulation of liquid composite molding for process analysis and optimization. Compos A: Appl Sci Manuf 37(6):890–902Park CH, Lee W (2011) Modeling void formation and unsaturated flow in liquid composite molding processes: a survey and review. J Reinf Plast Compos 30(11):957–977Pillai KM (2004) Modeling the unsaturated flow in liquid composite molding processes: a review and some thoughts. 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Ordering process and ferroelectricity in a spinel derived from FeV2O4

The spinel FeV2O4 is known to exhibit peculiar physical properties, which is generally ascribed to the unusual presence of two cations showing a pronounced interplay between spin, orbital and lattice degrees of freedom (Fe2+ and V3+ on the tetrahedral and octahedral sites, respectively). The present work reports on an experimental re-investigation of this material based on a broad combination of techniques, including x-ray diffraction, energy dispersive and M\"ossbauer spectroscopies, as well as magnetization, heat capacity, dielectric and polarization measurements. Special attention was firstly paid to establish the exact cationic composition of the investigated samples, which was found to be Fe1.18V1.82O4. All the physical properties were found to point out a complex ordering process with a structural transition at TS = 138 K, followed by two successive magnetostructural transitions at TN1 = 111 K and TN2 = 56 K. This latter transition marking the appearance of electric polarization, magnetization data were analysed in details to discuss the nature of the magnetic state at T< TN2. An overall interpretation of the sequence of transitions was proposed, taking into account two spin couplings, as well as the Jahn-Teller effects and the mechanism of spin-orbit stabilization. Finally, the origin of ferroelectricity in Fe1.18V1.82O4 is discussed on the basis of recent models.Comment: 26 pages, 9 figures,59 references.Accepted by Physical Review

Evolution and Phylogenetic Analysis of Full-Length VP3 Genes of Eastern Mediterranean Bluetongue Virus Isolates

Bluetongue virus (BTV) is the ‘type’ species of the genus Orbivirus within the family Reoviridae. The BTV genome is composed of ten linear segments of double-stranded RNA (dsRNA), each of which codes for one of ten distinct viral proteins. Previous phylogenetic comparisons have evaluated variations in genome segment 3 (Seg-3) nucleotide sequence as way to identify the geographical origin (different topotypes) of BTV isolates. The full-length nucleotide sequence of genome Seg-3 was determined for thirty BTV isolates recovered in the eastern Mediterranean region, the Balkans and other geographic areas (Spain, India, Malaysia and Africa). These data were compared, based on molecular variability, positive-selection-analysis and maximum-likelihood phylogenetic reconstructions (using appropriate substitution models) to 24 previously published sequences, revealing their evolutionary relationships. These analyses indicate that negative selection is a major force in the evolution of BTV, restricting nucleotide variability, reducing the evolutionary rate of Seg-3 and potentially of other regions of the BTV genome. Phylogenetic analysis of the BTV-4 strains isolated over a relatively long time interval (1979–2000), in a single geographic area (Greece), showed a low level of nucleotide diversity, indicating that the virus can circulate almost unchanged for many years. These analyses also show that the recent incursions into south-eastern Europe were caused by BTV strains belonging to two different major-lineages: representing an ‘eastern’ (BTV-9, -16 and -1) and a ‘western’ (BTV-4) group/topotype. Epidemiological and phylogenetic analyses indicate that these viruses originated from a geographic area to the east and southeast of Greece (including Cyprus and the Middle East), which appears to represent an important ecological niche for the virus that is likely to represent a continuing source of future BTV incursions into Europe

Development and evaluation of real time RT-PCR assays for detection and typing of Bluetongue virus

Bluetongue virus is the type species of the genus Orbivirus, family Reoviridae. Bluetongue viruses (BTV) are transmitted between their vertebrate hosts primarily by biting midges (Culicoides spp.) in which they also replicate. Consequently BTV distribution is dependent on the activity, geographic distribution, and seasonal abundance of Culicoides spp. The virus can also be transmitted vertically in vertebrate hosts, and some strains/serotypes can be transmitted horizontally in the absence of insect vectors. The BTV genome is composed of ten linear segments of double-stranded (ds) RNA, numbered in order of decreasing size (Seg-1 to Seg-10). Genome segment 2 (Seg-2) encodes outer-capsid protein VP2, the most variable BTV protein and the primary target for neutralising antibodies. Consequently VP2 (and Seg-2) determine the identity of the twenty seven serotypes and two additional putative BTV serotypes that have been recognised so far. Current BTV vaccines are serotype specific and typing of outbreak strains is required in order to deploy appropriate vaccines. We report development and evaluation of multiple ‘TaqMan’ fluorescence-probe based quantitative real-time type-specific RT-PCR assays targeting Seg-2 of the 27+1 BTV types. The assays were evaluated using orbivirus isolates from the ‘Orbivirus Reference Collection’ (ORC) held at The Pirbright Institute. The assays are BTV-type specific and can be used for rapid, sensitive and reliable detection / identification (typing) of BTV RNA from samples of infected blood, tissues, homogenised Culicoides, or tissue culture supernatants. None of the assays amplified cDNAs from closely related but heterologous orbiviruses, or from uninfected host animals or cell cultures