Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms

Caspases mediate essential key proteolytic events in inflammatory cascades and the apoptotic cell death pathway. Human caspases functionally segregate into two distinct subfamilies: those involved in cytokine maturation (caspase-1, -4 and -5) and those involved in cellular apoptosis (caspase-2, -3, -6, -7, -8, -9 and -10). Although caspase-12 is phylogenetically related to the cytokine maturation caspases, in mice it has been proposed as a mediator of apoptosis induced by endoplasmic reticulum stress including amyloid-beta cytotoxicity, suggesting that it might contribute to the pathogenesis of Alzheimer's disease. Here we show that a single nucleotide polymorphism in caspase-12 in humans results in the synthesis of either a truncated protein (Csp12-S) or a full-length caspase proenzyme (Csp12-L). The read-through single nucleotide polymorphism encoding Csp12-L is confined to populations of African descent and confers hypo-responsiveness to lipopolysaccharide-stimulated cytokine production in ex vivo whole blood, but has no significant effect on apoptotic sensitivity. In a preliminary study, we find that the frequency of the Csp12-L allele is increased in African American individuals with severe sepsis. Thus, Csp12-L attenuates the inflammatory and innate immune response to endotoxins and in doing so may constitute a risk factor for developing sepsis.     

Highly effective SNP-based association mapping and management of recessive defects in livestock

The widespread use of elite sires by means of artificial insemination in livestock breeding leads to the frequent emergence of recessive genetic defects, which cause significant economic and animal welfare concerns. Here we show that the availability of genome-wide, high-density SNP panels, combined with the typical structure of livestock populations, markedly accelerates the positional identification of genes and mutations that cause inherited defects. We report the fine-scale mapping of five recessive disorders in cattle and the molecular basis for three of these: congenital muscular dystony (CMD) types 1 and 2 in Belgian Blue cattle and ichthyosis fetalis in Italian Chianina cattle. Identification of these causative mutations has an immediate translation into breeding practice, allowing marker assisted selection against the defects through avoidance of at-risk matings.     

Development of a preventive vaccine for Ebola virus infection in primates

Outbreaks of haemorrhagic fever caused by the Ebola virus are associated with high mortality rates that are a distinguishing feature of this human pathogen. The highest lethality is associated with the Zaire subtype, one of four strains identified to date. Its rapid progression allows little opportunity to develop natural immunity, and there is currently no effective anti-viral therapy. Therefore, vaccination offers a promising intervention to prevent infection and limit spread. Here we describe a highly effective vaccine strategy for Ebola virus infection in non-human primates. A combination of DNA immunization and boosting with adenoviral vectors that encode viral proteins generated cellular and humoral immunity in cynomolgus macaques. Challenge with a lethal dose of the highly pathogenic, wild-type, 1976 Mayinga strain of Ebola Zaire virus resulted in uniform infection in controls, who progressed to a moribund state and death in less than one week. In contrast, all vaccinated animals were asymptomatic for more than six months, with no detectable virus after the initial challenge. These findings demonstrate that it is possible to develop a preventive vaccine against Ebola virus infection in primates.     

The stream–lake ecotone: potential habitat for juvenile endangered June suckers ( Chasmistes liorus )

Potamodromous fish are poorly studied even though they are threatened often by human activities. The June sucker ( Chasmistes liorus ) is an endangered potamodromous species endemic to Utah Lake. Larval June suckers have not been collected from Utah Lake for at least 3 decades. Recruitment appears to be limited by low temperatures and scarce food, resulting in mass starvation of larval June suckers in the stream environment. We compared water temperature, zooplankton food availability, and small fish abundance in the stream and in 3 habitats along the stream&;ndash;lake ecotone (dense emergent vegetation, sparse emergent vegetation, and open lake) to test the hypothesis that all 3 factors would reach a maximum in the dense emergent vegetation of the stream&;ndash;lake ecotone. We used the abundance of fathead minnows in each habitat type as a surrogate for small fish like juvenile June suckers. We found that temperature, food, and fathead minnows reached their maximums in the open lake rather than in vegetated habitats of the stream&;ndash;lake ecotone. The stream had the lowest average temperatures (15.1 &;deg;C) and the lowest zooplankton concentrations (61 ? L &;ndash;1 ) over the growing season. Contrary to expectations, low temperatures (16.9 &;deg;C) and low food abundance (505 ? L &;ndash;1 ) also characterized the densely vegetated habitat, whereas the open lake had the highest temperatures (20.4&;deg; C) and highest concentrations of zooplankton (2353 ? L &;ndash;1 ). Restoration should include a mechanism to transport larval fish through the densely vegetated portion of the stream&;ndash;lake ecotone, which can be hundreds of meters wide, to the warm productive waters of the open lake. The braided planform of the terminal reaches of Hobble Creek should be replaced with shallow riffles to increase mean stream velocity and decrease the transport time of larval June suckers. Los peces potamodromos se han estudiado poco a pesar de que a menudo los amenazan las actividades humanas. El matalote junio ( Chasmistes liorus ) es una especie potamodroma en peligro de extinci&;oacute;n que es end&;eacute;mica del Lago Utah. Hace al menos tres d&;eacute;cadas que no se colectan matalotes larvales del Lago Utah. El reclutamiento parece estar limitado tanto por las temperaturas bajas como por la escasez de alimento, la cual causa una inanici&;oacute;n masiva de matalotes junio larvales en el h&;aacute;bitat fluvial. Comparamos la temperatura del agua, disponibilidad de zooplancton y abundancia de peces peque&;ntilde;os en el arroyo y en tres h&;aacute;bitats a lo largo del ecotono arroyo&;ndash;lago (vegetaci&;oacute;n semisumergida tupida, vegetaci&;oacute;n semisumergida escasa y el lago abierto) para comprobar la hip&;oacute;tesis de que los tres factores alcanzar&;iacute;an su m&;aacute;ximo en la vegetaci&;oacute;n semisumergida tupida del ecotono arroyo&;ndash;lago. Utilizamos la abundancia de la carpita cabezona en cada clase de h&;aacute;bitat como indicador indirecto de peces peque&;ntilde;os como los matalotes junio juveniles. Descubrimos que la temperatura, el alimento y las carpitas cabezonas alcanzaron sus niveles m&;aacute;ximos en el lago abierto y no en los h&;aacute;bitats con vegetaci&;oacute;n del ecotono arroyo&;ndash;lago. El arroyo tuvo las temperaturas promedio m&;aacute;s bajas durante la temporada de crecimiento (15.1 &;deg;C) y concentraciones bajas de zooplancton (61 ? L &;ndash;1 ). Al contrario de lo esperado, el h&;aacute;bitat de vegetaci&;oacute;n tupida tuvo temperaturas bajas (16.9 &;deg;C) y concentraciones bajas de alimento (505 ? L &;ndash;1 ), mientras que el lago abierto tuvo la temperatura m&;aacute;s alta (20.4 &;deg;C) y la mayor concentraci&;oacute;n de zooplancton (2353 ?&;nbsp; L &;ndash;1 ). La restauraci&;oacute;n de esta especie debe incluir alg&;uacute;n mecanismo para transportar los peces larvales a trav&;eacute;s de la parte de vegetaci&;oacute;n tupida del ecotono arroyo&;ndash;lago, la cual puede tener cientos de metros de ancho, a las aguas c&;aacute;lidas y m&;aacute;s productivas del lago abierto. Se debe reemplazar la forma trenzada de los tramos terminales de Hobble Creek con encalladeros para aumentar la velocidad promedio del arroyo y agilizar la traves&;iacute;a de los matalotes junio larvales.     

Supernova SN 2011fe from an exploding carbon-oxygen white dwarf star

Type Ia supernovae have been used empirically as 'standard candles' to demonstrate the acceleration of the expansion of the Universe even though fundamental details, such as the nature of their progenitor systems and how the stars explode, remain a mystery. There is consensus that a white dwarf star explodes after accreting matter in a binary system, but the secondary body could be anything from a main-sequence star to a red giant, or even another white dwarf. This uncertainty stems from the fact that no recent type Ia supernova has been discovered close enough to Earth to detect the stars before explosion. Here we report early observations of supernova SN 2011fe in the galaxy M101 at a distance from Earth of 6.4 megaparsecs. We find that the exploding star was probably a carbon-oxygen white dwarf, and from the lack of an early shock we conclude that the companion was probably a main-sequence star. Early spectroscopy shows high-velocity oxygen that slows rapidly, on a timescale of hours, and extensive mixing of newly synthesized intermediate-mass elements in the outermost layers of the supernova. A companion paper uses pre-explosion images to rule out luminous red giants and most helium stars as companions to the progenitor.     

AtSNX1 defines an endosome for auxin-carrier trafficking in Arabidopsis

Polarized cellular distribution of the phytohormone auxin and its carriers is essential for normal plant growth and development. Polar auxin transport is maintained by a network of auxin influx (AUX) and efflux (PIN) carriers. Both auxin transport and PIN protein cycling between the plasma membrane and endosomes require the activity of the endosomal GNOM; however, intracellular routes taken by these carriers remain largely unknown. Here we show that Arabidopsis thaliana SORTING NEXIN 1 (AtSNX1) is involved in the auxin pathway and that PIN2, but not PIN1 or AUX1, is transported through AtSNX1-containing endosomes. We demonstrate that the snx1-null mutant exhibits multiple auxin-related defects and that loss of function of AtSNX1 severely enhances the phenotype of a weak gnom mutant. In root cells, we further show that AtSNX1 localizes to an endosomal compartment distinct from GNOM-containing endosomes, and that PIN2 accumulates in this compartment after treatment with the phosphatidylinositol-3-OH kinase inhibitor wortmannin or after a gravity stimulus. Our data reveal the existence of a novel endosomal compartment involved in PIN2 endocytic sorting and plant development.