P7C3-A20 neuroprotection is independent of Wallerian degeneration in Primary Neuronal Culture

The anti-apoptotic, neuroprotective compound P7C3-A20 reduces neurological deficits when administered to murine in vivo models of traumatic brain injury. P7C3-A20 is thought to exert its activity through small-molecule activation of the enzyme nicotinamide phosphoribosyltransferase (NAMPT). This enzyme converts nicotinamide to nicotinamide mononucleotide (NMN), the precursor to nicotinamide adenine dinucleotide (NAD) synthesis. Alterations to this bioenergetic pathway have been shown to induce Wallerian degeneration of the distal neurite following injury. This study aimed to establish whether P7C3-A20, through induction of NAMPT activity, would affect the rate of Wallerian degeneration. The model systems used were dissociated primary cortical neurons, dissociated superior cervical ganglion neurons, and superior cervical ganglion explants. P7C3-A20 failed to demonstrate any protection against Wallerian degeneration induced by neurite transection or vincristine administration. Furthermore, there was a concentration dependent neurotoxicity. These findings are important in understanding the mechanism by which P7C3-A20 mediates its effects- a key step before moving to human clinical trials.Wellcome Trus

Selective-pivot sampling of radial distribution functions in asymmetric liquid mixtures

We present a Monte Carlo algorithm for selectively sampling radial distribution functions and effective interaction potentials in asymmetric liquid mixtures. We demonstrate its efficiency for hard-sphere mixtures, and for model systems with more general interactions, and compare our simulations with several analytical approximations. For interaction potentials containing a hard-sphere contribution, the algorithm yields the contact value of the radial distribution function.Comment: 5 pages, 5 figure

Void Growth in BCC Metals Simulated with Molecular Dynamics using the Finnis-Sinclair Potential

The process of fracture in ductile metals involves the nucleation, growth, and linking of voids. This process takes place both at the low rates involved in typical engineering applications and at the high rates associated with dynamic fracture processes such as spallation. Here we study the growth of a void in a single crystal at high rates using molecular dynamics (MD) based on Finnis-Sinclair interatomic potentials for the body-centred cubic (bcc) metals V, Nb, Mo, Ta, and W. The use of the Finnis-Sinclair potential enables the study of plasticity associated with void growth at the atomic level at room temperature and strain rates from 10^9/s down to 10^6/s and systems as large as 128 million atoms. The atomistic systems are observed to undergo a transition from twinning at the higher end of this range to dislocation flow at the lower end. We analyze the simulations for the specific mechanisms of plasticity associated with void growth as dislocation loops are punched out to accommodate the growing void. We also analyse the process of nucleation and growth of voids in simulations of nanocrystalline Ta expanding at different strain rates. We comment on differences in the plasticity associated with void growth in the bcc metals compared to earlier studies in face-centred cubic (fcc) metals.Comment: 24 pages, 12 figure

Agents sans frontiers: cross-border aquatic weed biological control in the rivers of southern Mozambique

Biological control is an effective ways of controlling aquatic plants, especially in South Africa. Release of biological control agents has been limited to Mozambique, where water hyacinth (Eichhornia crassipes (Mart.) Solms-Laubach (Pontederiaceae)), water lettuce (Pistia stratiotes L. (Araceae)), red water ferns (Azolla spp. (Azollaceae)) and salvinia (Salvinia molesta DS Mitch. (Salviniaceae)) are significant weeds in the south of the country. In 2009, we assessed the status of these weeds in seven rivers across southern Mozambique and recorded whether any biocontrol agents were present. The weevils Neochetina eichhorniae Warner (Coleoptera: Curculionidae) and N. bruchi Hustache (Coleoptera: Curculionidae) were on water hyacinth, along with the pathogen Acremonium zonatum (Sawada) W. Gams (Hypocreales) and the mite Orthogalumna terebrantis Wallwork (Acarina: Sarcoptiformes: Galumnidae). Pistia stratiotes supported small numbers of the weevil Neohydronomus affinis Hustache (Coleoptera: Curculionidae). The red water fern in the rivers was A. cristata Kaulfuss (Azollaceae) not the more widely recorded A. filiculoides Lam. (Azollaceae), and it supported small numbers of the weevil Stenopelmus rufinasus Gyllenhal (Coleoptera: Curculionidae). No agents were present on S. molesta. Most of these agents are likely to have dispersed from South Africa, and the rivers of southern Mozambique are likely to be benefitting from the transnational dispersal of these agents

P7C3-A20 neuroprotection is independent of Wallerian degeneration in primary neuronal culture

The antiapoptotic, neuroprotective compound P7C3-A20 reduces neurological deficits when administered to murine in-vivo models of traumatic brain injury. P7C3-A20 is thought to exert its activity through small-molecule activation of the enzyme nicotinamide phosphoribosyltransferase. This enzyme converts nicotinamide to nicotinamide mononucleotide, the precursor to nicotinamide adenine dinucleotide synthesis. Alterations to this bioenergetic pathway have been shown to induce Wallerian degeneration (WD) of the distal neurite following injury. This study aimed to establish whether P7C3-A20, through induction of nicotinamide phosphoribosyltransferase activity, would affect the rate of WD. The model systems used were dissociated primary cortical neurons, dissociated superior cervical ganglion neurons and superior cervical ganglion explants. P7C3-A20 failed to show any protection against WD induced by neurite transection or vincristine administration. Furthermore, there was a concentration-dependent neurotoxicity. These findings are important in understanding the mechanism by which P7C3-A20 mediates its effects - a key step before moving to human clinical trials

Two in one: cryptic species discovered in biological control agent populations using molecular data and crossbreeding experiments

There are many examples of cryptic species that have been identified through DNA-barcoding or other genetic techniques. There are, however, very few confirmations of cryptic species being reproductively isolated. This study presents one of the few cases of cryptic species that has been confirmed to be reproductively isolated and therefore true species according to the biological species concept. The cryptic species are of special interest because they were discovered within biological control agent populations. Two geographically isolated populations of Eccritotarsus catarinensis (Carvalho) [Hemiptera: Miridae], a biological control agent for the invasive aquatic macrophyte, water hyacinth, Eichhornia crassipes (Mart.) Solms [Pontederiaceae], in South Africa, were sampled from the native range of the species in South America. Morphological characteristics indicated that both populations were the same species according to the current taxonomy, but subsequent DNA analysis and breeding experiments revealed that the two populations are reproductively isolated. Crossbreeding experiments resulted in very few hybrid offspring when individuals were forced to interbreed with individuals of the other population, and no hybrid offspring were recorded when a choice of mate from either population was offered. The data indicate that the two populations are cryptic species that are reproductively incompatible. Subtle but reliable diagnostic characteristics were then identified to distinguish between the two species which would have been considered intraspecific variation without the data from the genetics and interbreeding experiments. These findings suggest that all consignments of biological control agents from allopatric populations should be screened for cryptic species using genetic techniques and that the importation of multiple consignments of the same species for biological control should be conducted with caution

Room temperature plasmon laser by total internal reflection

Plasmon lasers create and sustain intense and coherent optical fields below light's diffraction limit with the unique ability to drastically enhance light-matter interactions bringing fundamentally new capabilities to bio-sensing, data storage, photolithography and optical communications. However, these important applications require room temperature operation, which remains a major hurdle. Here, we report a room temperature semiconductor plasmon laser with both strong cavity feedback and optical confinement to 1/20th of the wavelength. The strong feedback arises from total internal reflection of surface plasmons, while the confinement enhances the spontaneous emission rate by up to 20 times.Comment: 8 Page, 2 Figure

Choice of geographic unit influences socioeconomic inequalities in breast cancer survival

Socioeconomic differences in age-standardised crude survival for women diagnosed with breast cancer during 1991–1999 in England were influenced by the population of the geographic area used to assign the deprivation index, but not by the choice of index

Complete mitochondrial DNA sequences provide new insights into the Polynesian motif and the peopling of Madagascar

More than a decade of mitochondrial DNA (mtDNA) studies have given the 'Polynesian motif' renowned status as a marker for tracing the late-Holocene expansion of Austronesian speaking populations. Despite considerable research on the Polynesian motif in Oceania, there has been little equivalent work on the western edge of its expansion - leaving major issues unresolved regarding the motif's evolutionary history. This has also led to considerable uncertainty regarding the settlement of Madagascar. In this study, we assess mtDNA variation in 266 individuals from three Malagasy ethnic groups: the Mikea, Vezo, and Merina. Complete mtDNA genome sequencing reveals a new variant of the Polynesian motif in Madagascar; two coding region mutations define a Malagasy-specific sub-branch. This newly defined 'Malagasy motif' occurs at high frequency in all three ethnic groups (13-50%), and its phylogenetic position, geographic distribution, and estimated age all support a recent origin, but without conclusively identifying a specific source region. Nevertheless, the haplotype's limited diversity, similar to those of other mtDNA haplogroups found in our Malagasy groups, best supports a small number of initial settlers arriving to Madagascar through the same migratory process. Finally, the discovery of this lineage provides a set of new polymorphic positions to help localize the Austronesian ancestors of the Malagasy, as well as uncover the origin and evolution of the Polynesian motif itself

Alternative splicing modifies the effect of mutations in COL11A1 and results in recessive type 2 Stickler syndrome with profound hearing loss.

BACKGROUND: Stickler syndromes types 1, 2 and 3 are usually dominant disorders caused by mutations in the genes COL2A1, COL11A1 and COL11A2 that encode the fibrillar collagens types II and XI present in cartilage and vitreous. Rare recessive forms of Stickler syndrome exist that are due to mutations in genes encoding type IX collagen (COL9A1 type 4 Stickler syndrome and COL9A2 type 5 Stickler syndrome). Recently, recessive mutations in the COL11A1 gene have been demonstrated to result in fibrochondrogenesis, a much more severe skeletal dysplasia, which is often lethal. Here we demonstrate that some mutations in COL11A1 are recessive, modified by alternative splicing and result in type 2 Stickler syndrome rather than fibrochondrogenesis. METHODS: Patients referred to the national Stickler syndrome diagnostic service for England, UK were assessed clinically and subsequently sequenced for mutations in COL11A1. Additional in silico and functional studies to assess the effect of sequence variants on pre-mRNA processing and collagen structure were performed. RESULTS: In three different families, heterozygous COL11A1 biallelic null, null/missense or silent/missense mutations, were found. They resulted in a recessive form of type 2 Stickler syndrome characterised by particularly profound hearing loss and are clinically distinct from the recessive types 4 and 5 variants of Stickler syndrome. One mutant allele in each family is capable of synthesising a normal α1(XI) procollagen molecule, via variable pre-mRNA processing. CONCLUSION: This new variant has important implications for molecular diagnosis and counselling families with type 2 Stickler syndrome