Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease.

Huntington's disease is an autosomal-dominant progressive neurodegenerative disorder resulting in specific neuronal loss and dysfunction in the striatum and cortex. The disease is universally fatal, with a mean survival following onset of 15-20 years and, at present, there is no effective treatment. The mutation in patients with Huntington's disease is an expanded CAG/polyglutamine repeat in huntingtin, a protein of unknown function with a relative molecular mass of 350,000 (M(r) 350K). The length of the CAG/polyglutamine repeat is inversely correlated with the age of disease onset. The molecular pathways mediating the neuropathology of Huntington's disease are poorly understood. Transgenic mice expressing exon 1 of the human huntingtin gene with an expanded CAG/polyglutamine repeat develop a progressive syndrome with many of the characteristics of human Huntington's disease. Here we demonstrate evidence of caspase-1 activation in the brains of mice and humans with the disease. In this transgenic mouse model of Huntington's disease, expression of a dominant-negative caspase-1 mutant extends survival and delays the appearance of neuronal inclusions, neurotransmitter receptor alterations and onset of symptoms, indicating that caspase-1 is important in the pathogenesis of the disease. In addition, we demonstrate that intracerebroventricular administration of a caspase inhibitor delays disease progression and mortality in the mouse model of Huntington's disease.     

郭守敬的《授时历》和朝鲜的《七政算内篇》

《授时历》被评价为中国历史上最优秀的历法,并且成为明朝《大统历》和朝鲜《七政算内篇》成书的基础。《七政算内篇》是朝鲜世宗时代(1418—1450年)取得的重要天文业绩之一,以《回回历》为基础,与《七政算外篇》一同于1444年编纂成书。《七政算内篇》的历元、天文常数和计算法等基本体系参照《授时历》,应数值则参照了《大统历》的辛巳应数。且把四余添加在推步的项目中,在计算日月食时使用的常数值则参考了元统1384年编纂的《大统历法通轨》,《七政算内篇》汲取了《授时历》和《大统历》的优点。     

Event-horizon-scale structure in the supermassive black hole candidate at the Galactic Centre

The cores of most galaxies are thought to harbour supermassive black holes, which power galactic nuclei by converting the gravitational energy of accreting matter into radiation. Sagittarius A* (Sgr A*), the compact source of radio, infrared and X-ray emission at the centre of the Milky Way, is the closest example of this phenomenon, with an estimated black hole mass that is 4,000,000 times that of the Sun. A long-standing astronomical goal is to resolve structures in the innermost accretion flow surrounding Sgr A*, where strong gravitational fields will distort the appearance of radiation emitted near the black hole. Radio observations at wavelengths of 3.5 mm and 7 mm have detected intrinsic structure in Sgr A*, but the spatial resolution of observations at these wavelengths is limited by interstellar scattering. Here we report observations at a wavelength of 1.3 mm that set a size of 37(+16)(-10) microarcseconds on the intrinsic diameter of Sgr A*. This is less than the expected apparent size of the event horizon of the presumed black hole, suggesting that the bulk of Sgr A* emission may not be centred on the black hole, but arises in the surrounding accretion flow.     

Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart

Understanding cellular response to environmental stress has broad implications for human disease. AMP-activated protein kinase (AMPK) orchestrates the regulation of energy-generating and -consuming pathways, and protects the heart against ischaemic injury and apoptosis. A role for circulating hormones such as adiponectin and leptin in the activation of AMPK has received recent attention. Whether local autocrine and paracrine factors within target organs such as the heart modulate AMPK is unknown. Here we show that macrophage migration inhibitory factor (MIF), an upstream regulator of inflammation, is released in the ischaemic heart, where it stimulates AMPK activation through CD74, promotes glucose uptake and protects the heart during ischaemia-reperfusion injury. Germline deletion of the Mif gene impairs ischaemic AMPK signalling in the mouse heart. Human fibroblasts with a low-activity MIF promoter polymorphism have diminished MIF release and AMPK activation during hypoxia. Thus, MIF modulates the activation of the cardioprotective AMPK pathway during ischaemia, functionally linking inflammation and metabolism in the heart. We anticipate that genetic variation in MIF expression may impact on the response of the human heart to ischaemia by the AMPK pathway, and that diagnostic MIF genotyping might predict risk in patients with coronary artery disease.     

Isotopic homogeneity of iron in the early solar nebula.

The chemical and isotopic homogeneity of the early solar nebula, and the processes producing fractionation during its evolution, are central issues of cosmochemistry. Studies of the relative abundance variations of three or more isotopes of an element can in principle determine if the initial reservoir of material was a homogeneous mixture or if it contained several distinct sources of precursor material. For example, widespread anomalies observed in the oxygen isotopes of meteorites have been interpreted as resulting from the mixing of a solid phase that was enriched in 16O with a gas phase in which 16O was depleted, or as an isotopic 'memory' of Galactic evolution. In either case, these anomalies are regarded as strong evidence that the early solar nebula was not initially homogeneous. Here we present measurements of the relative abundances of three iron isotopes in meteoritic and terrestrial samples. We show that significant variations of iron isotopes exist in both terrestrial and extraterrestrial materials. But when plotted in a three-isotope diagram, all of the data for these Solar System materials fall on a single mass-fractionation line, showing that homogenization of iron isotopes occurred in the solar nebula before both planetesimal accretion and chondrule formation.     

Migration, Ethnicity and Privilege

Representation assumes that those who govern have knowledge of those for whom they govern. It is easy to presume knowledge of the “other”, but as we know this can be based in prejudice, cultural difference, or simply misinformation or simplification. Usually our explorations of this process have focused on populations identified as disadvantaged, disempowered or somehow “non-privileged”. However, the research process outlined here has revealed previously unexplored diversity within a population commonly described as privileged suggesting that good governance requires alertness to presuming to know both the unprivileged and the privileged. The research approach outlined in this paper has used a blend of historical reappraisal and qualitative techniques focusing on a population who have been conceptualized as doubly privileged. This population focus is that of older British; post World War II male migrants in South Australia. These people have been conceptualized as privileged because they are male, and they were part of the preferred ethnic group that Australian politicians and policy makers favoured post WW2. However, review of the historical data and qualitative interviews with some of these men show that the accepted narrative of a homogenous pre-WW2 British origin population is over simplistic. The historical research suggests that the presumption that post WW2 British migrant men were coming into an homogenous, privileging environment in migrating to SA is both ahistorical and crude. Furthermore the belief that post WW2 British migrant men were ethnically homogenous is undermined by the qualitative research, that reveals that their presumed homogeneity is much more fluid and nuanced than dominant conceptualisations have allowed. The impact of core ethnicities that continue to exist and compete in Britain, the social class focus and economic commodification of migrants in the machinations of powerful players in the state of South Australia all confound homogenizing, simplistic knowing of British migrant men in this state. Generically these findings caution social researchers with regard to presuming to know so called “privileged” populations as well as presumed non-privileged groups.     

Fungitoxicity of m-fluorophenylalanine-containing peptides towards Pythium ultimum

The tripeptide L-m-fluorophenylalanyl-L-alanyl-L-alanine was much more fungitoxic towards Pythium ultimum than the dipeptide L-m-fluorophenylalanyl-L-alanine or m-fluorophenylalanine. The fungitoxicity of the tripeptide was reduced by L-alanyl peptides and phenylalanine, but not by other amino acids. In contrast, the fungitoxicity of m-fluorophenylalanine was unaffected by peptides, and was antagonized by several amino acids. These results suggest the effective delivery of m-fluorophenylalanine into the cell by a tripeptide carrier.     

Objective analysis of the topological organization of the primate cortical visual system.

The primate cortical visual system is composed of many structurally and functionally distinct areas, each receiving and sending about 10 projections from and to other cortical areas. The visual cortex is thus served by many cortico-cortical connections to form a network of considerable complexity. Thus the gross organization of this cortical processing system presents a formidable topological problem: although the spatial position of the areas in the brain is reasonably well established, the gross 'processing architecture' defined by the connections, is less well understood. Here I report an optimization approach that gives both qualitative and quantitative insight into the connectional topology of the primate cortical visual system. This approach supports suggestions that the system is divided into a dorsal 'stream' and a ventral 'stream' with limited cross-talk, that these two streams reconverge in the region of the principal sulcus (area 46) and in the superior temporal polysensory areas, that the system is hierarchically organized, and that the majority of the connections are from 'nearest-neighbour' and 'next-door-but-one' areas.     

Molecular and genetic damage in humans from environmental pollution in Poland.

Extreme environmental pollution such as that found in the highly industrialized Silesian region of Poland has been associated with increased risk of cancer and adverse reproductive outcomes. Among the most prevalent carcinogenic and mutagenic air pollutants in Silesia are the polycyclic aromatic hydrocarbons (PAH) which are largely produced by industrial and residential combustion of coal. Molecular epidemiology aims to prevent disease by using biological markers to identify risks well before clinical onset to allow effective intervention. Here, we use a battery of biological markers to measure molecular and genetic damage in peripheral blood samples from residents of Silesia and from persons living in a rural, less polluted area of Poland. The results show that their exposure to environmental pollution is associated with significant increases in carcinogen-DNA adducts (PAH-DNA and aromatic adducts), in sister chromatid exchange including high-frequency cells, and in chromosomal aberrations as well as a doubling in the frequency of ras oncogene overexpression. We found that aromatic adducts on DNA were significantly correlated with chromosomal mutation, providing us with a molecular link between environmental exposure and a genetic alteration relevant to cancer and reproductive risk.