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。     

韩国国立古宫博物馆世宗朝自击漏复原(英文)

自动时报漏刻(自击宫漏)是宫中都工匠护军蒋英实奉世宗大王(李祹,1397—1450年;1418—1450年在位)之命于1433年制造的。从1434年7月1日开始它成为国家的标准计时仪器。对民众报时的午正、人定和罢漏就是根据这套计时仪器报的。它安装在景福宫的报漏阁里,因此后称报漏阁漏.景福宫是国家天文台"简仪台"所在地。它能够通过操控声音和视觉信号发生系统依朝鲜时代的二元化时制——即十二时辰和五更点法——自动报时。系统自动发出报时声同时显示指示,报出十二时、百刻,以及五更时刻。世宗大王创制的报漏阁自击漏成为模型在朝鲜(1392—1910年)经历过3次复制或修复——1433年的初创,1536年的再创以及1618年的重创。初创之后574年,2004年为了纪念韩国国立古宫博物馆在首尔开馆,文化财厅,博物馆与建国大学校和自击漏硏究会签订了自击漏复原计划,到2007年11月展示了复原的自击漏。复原计划是按照《世宗实录.报漏阁记》中的记载以及原器物的一些残余部分——包括1536年和1618年仪器的现存部分——进行的。用了一年半的时间复制漏器和自击装置。文章从机械学和功能方面的细节系统地描述了复原的过程,包括根据当时的教范《漏筹通义》的记载刻制十一支箭.《漏筹通义》是根据授时历和经过汉阳(当时朝鲜首都)地方时校正的《七政算内篇》编纂的。自击漏包括4个主要部分:(1)漏器部,通过安排三级播水壶,用于两个受水壶递水的计时壶来计时;(2)方木机构,通过在相应的时间落下相应的小铜丸将水平面转换到以数字显示的二元报时时刻标示信号;(3)铁丸放出机构,由复杂的杠杆系统操纵的机构放大动力报时机来操作。(4)视听觉报时部,由两个次一级结构组成。一个是十二时辰报时机部,包括一个钟和木制的小雕像系统,以不同次数的敲钟声和相应的木制的十二支神小雕像举出的时辰牌来报时。另一个是更点机,包括一面鼓、一面锣、以及小雕像,小雕像在不同的更点敲击出相应次数的锣鼓声以报更点。我们对已经失传几个世纪的铁丸作动人形机构的详细复制表明,蒋英实受到了阿拉伯铁丸利用报时法的启发,发明了丸落下时刻标时法(通过落丸来标示时刻的机械装置),并通过改进13世纪阿拉伯时计师al-Jazari的仪器来实现将动力传到对人形机构的推动中。另一方面,苏颂的《新仪象法要》,《元史》中描述的郭守敬的大明殿灯漏以及顺帝的宫漏可能影响了世宗朝的宫廷学者。总的来说,这次复原源于对当时的文献记载和遗物的重建,中国-阿拉伯钟表技术对我们也很有帮助。全部系统现在运行良好。我们的复原将有助于重建古代东亚、甚至阿拉伯的机械水钟。     

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.     

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.