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241.
Pandey UB Nie Z Batlevi Y McCray BA Ritson GP Nedelsky NB Schwartz SL DiProspero NA Knight MA Schuldiner O Padmanabhan R Hild M Berry DL Garza D Hubbert CC Yao TP Baehrecke EH Taylor JP 《Nature》2007,447(7146):859-863
A prominent feature of late-onset neurodegenerative diseases is accumulation of misfolded protein in vulnerable neurons. When levels of misfolded protein overwhelm degradative pathways, the result is cellular toxicity and neurodegeneration. Cellular mechanisms for degrading misfolded protein include the ubiquitin-proteasome system (UPS), the main non-lysosomal degradative pathway for ubiquitinated proteins, and autophagy, a lysosome-mediated degradative pathway. The UPS and autophagy have long been viewed as complementary degradation systems with no point of intersection. This view has been challenged by two observations suggesting an apparent interaction: impairment of the UPS induces autophagy in vitro, and conditional knockout of autophagy in the mouse brain leads to neurodegeneration with ubiquitin-positive pathology. It is not known whether autophagy is strictly a parallel degradation system, or whether it is a compensatory degradation system when the UPS is impaired; furthermore, if there is a compensatory interaction between these systems, the molecular link is not known. Here we show that autophagy acts as a compensatory degradation system when the UPS is impaired in Drosophila melanogaster, and that histone deacetylase 6 (HDAC6), a microtubule-associated deacetylase that interacts with polyubiquitinated proteins, is an essential mechanistic link in this compensatory interaction. We found that compensatory autophagy was induced in response to mutations affecting the proteasome and in response to UPS impairment in a fly model of the neurodegenerative disease spinobulbar muscular atrophy. Autophagy compensated for impaired UPS function in an HDAC6-dependent manner. Furthermore, expression of HDAC6 was sufficient to rescue degeneration associated with UPS dysfunction in vivo in an autophagy-dependent manner. This study suggests that impairment of autophagy (for example, associated with ageing or genetic variation) might predispose to neurodegeneration. Morover, these findings suggest that it may be possible to intervene in neurodegeneration by augmenting HDAC6 to enhance autophagy. 相似文献
242.
243.
The upper atmospheres of the four Solar System giant planets exhibit high temperatures that cannot be explained by the absorption of sunlight. In the case of Saturn the temperatures predicted by models of solar heating are approximately 200 K, compared to temperatures of approximately 400 K observed independently in the polar regions and at 30 degrees latitude. This unexplained 'energy crisis' represents a major gap in our understanding of these planets' atmospheres. An important candidate for the source of the missing energy is the magnetosphere, which injects energy mostly in the polar regions of the planet. This polar energy input is believed to be sufficient to explain the observed temperatures, provided that it is efficiently redistributed globally by winds, a process that is not well understood. Here we show, using a numerical model, that the net effect of the winds driven by the polar energy inputs is not to heat but to cool the low-latitude thermosphere. This surprising result allows us to rule out known polar energy inputs as the solution to the energy crisis at Saturn. There is either an unknown--and large--source of polar energy, or, more probably, some other process heats low latitudes directly. 相似文献
244.
245.
Most bony fishes rely on suction mechanisms to capture and transport prey. Once captured, prey are carried by water movement inside the oral cavity to a second set of jaws in the throat, the pharyngeal jaws, which manipulate the prey and assist in swallowing. Moray eels display much less effective suction-feeding abilities. Given this reduction in a feeding mechanism that is widespread and highly conserved in aquatic vertebrates, it is not known how moray eels swallow large fish and cephalopods. Here we show that the moray eel (Muraena retifera) overcomes reduced suction capacity by launching raptorial pharyngeal jaws out of its throat and into its oral cavity, where the jaws grasp the struggling prey animal and transport it back to the throat and into the oesophagus. This is the first described case of a vertebrate using a second set of jaws to both restrain and transport prey, and is the only alternative to the hydraulic prey transport reported in teleost fishes. The extreme mobility of the moray pharyngeal jaws is made possible by elongation of the muscles that control the jaws, coupled with reduction of adjacent gill-arch structures. The discovery that pharyngeal jaws can reach up from behind the skull to grasp prey in the oral jaws reveals a major innovation that may have contributed to the success of moray eels as apex predators hunting within the complex matrix of coral reefs. This alternative prey transport mode is mechanically similar to the ratcheting mechanisms used in snakes--a group of terrestrial vertebrates that share striking morphological, behavioural and ecological convergence with moray eels. 相似文献
246.
Chan CS Guzman JN Ilijic E Mercer JN Rick C Tkatch T Meredith GE Surmeier DJ 《Nature》2007,447(7148):1081-1086
Why dopamine-containing neurons of the brain's substantia nigra pars compacta die in Parkinson's disease has been an enduring mystery. Our studies suggest that the unusual reliance of these neurons on L-type Ca(v)1.3 Ca2+ channels to drive their maintained, rhythmic pacemaking renders them vulnerable to stressors thought to contribute to disease progression. The reliance on these channels increases with age, as juvenile dopamine-containing neurons in the substantia nigra pars compacta use pacemaking mechanisms common to neurons not affected in Parkinson's disease. These mechanisms remain latent in adulthood, and blocking Ca(v)1.3 Ca2+ channels in adult neurons induces a reversion to the juvenile form of pacemaking. Such blocking ('rejuvenation') protects these neurons in both in vitro and in vivo models of Parkinson's disease, pointing to a new strategy that could slow or stop the progression of the disease. 相似文献
247.
A new approach to the research of the distribution of prime-triplets is developed.It differs from the
usual methods(involving the sieve method)for this kind of research,and basing on Chebyshev inequality and
on the computation of average concentration of all the related subset.It leads to the proofs of following Lemma
2and Theorem2(Lemma1and Theorem1in Reference1had been proved by means of this new method):
Lemma2 Among all the prime-triplet-subsets there exists at least one such subset which is an infinite set.
Theorem2 All the prime-triplet-subsets or infinitely many such subsets are infinite sets.
Formulas for estimating the amount of such infinite sets are provided in this paper. 相似文献
248.
Endophenotypes are heritable quantitative traits that are associated with disease liability, can be measured in both affected
and unaffected individuals, and provide much greater power to localize and identify risk genes for mental illness than does
affection status alone. Traditionally, endophenotypic markers for psychiatric illnesses include in vivo neuroanatomic and functional magnetic resonance imaging measurements and indices of neurocognitive abilities. However, neurocognitive
and neuroimaging measures are by no means the only classes of endophenotypes that could be useful for identifying genes for
mental illness. Given the advantages of endophenotype-based strategies for elucidating the genetic underpinnings of psychiatric
disorders, it would seem prudent to develop a wide range of putative endophenotypes. In order for a measure to be considered
a valid endophenotype, it must meet a number of criteria. Specifically, the trait must (1) have moderate to high heritability,
(2) be associated with the illness, (3) be independent of clinical state, and (4) impairment must co-segregate with the illness
within a family, with non-affected family members showing impairment relative to the general population. While each of these
criteria is critical, the heritability and co-segregation requirements are really what differentiate an endophenotype from
a simple biomarker. At this time, one requires an experimental design that includes families to demonstrate both heritability
and co-segregation. The assertion that novel endophenotypes can not be fully established without family data does not preclude
work in unrelated individuals, rather that unrelated samples will only be able to nominate potential candidate endophenotypes
that subsequently need to be confirmed in family-based experiments. 相似文献
249.
Young DA Wright AP Roberts JL Warner RC Young NW Greenbaum JS Schroeder DM Holt JW Sugden DE Blankenship DD van Ommen TD Siegert MJ 《Nature》2011,474(7349):72-75
The first Cenozoic ice sheets initiated in Antarctica from the Gamburtsev Subglacial Mountains and other highlands as a result of rapid global cooling ~34 million years ago. In the subsequent 20 million years, at a time of declining atmospheric carbon dioxide concentrations and an evolving Antarctic circumpolar current, sedimentary sequence interpretation and numerical modelling suggest that cyclical periods of ice-sheet expansion to the continental margin, followed by retreat to the subglacial highlands, occurred up to thirty times. These fluctuations were paced by orbital changes and were a major influence on global sea levels. Ice-sheet models show that the nature of such oscillations is critically dependent on the pattern and extent of Antarctic topographic lowlands. Here we show that the basal topography of the Aurora Subglacial Basin of East Antarctica, at present overlain by 2-4.5?km of ice, is characterized by a series of well-defined topographic channels within a mountain block landscape. The identification of this fjord landscape, based on new data from ice-penetrating radar, provides an improved understanding of the topography of the Aurora Subglacial Basin and its surroundings, and reveals a complex surface sculpted by a succession of ice-sheet configurations substantially different from today's. At different stages during its fluctuations, the edge of the East Antarctic Ice Sheet lay pinned along the margins of the Aurora Subglacial Basin, the upland boundaries of which are currently above sea level and the deepest parts of which are more than 1?km below sea level. Although the timing of the channel incision remains uncertain, our results suggest that the fjord landscape was carved by at least two iceflow regimes of different scales and directions, each of which would have over-deepened existing topographic depressions, reversing valley floor slopes. 相似文献
250.
Robert C. Scharff 《Foundations of Science》2011,16(2-3):227-243
Interest the Erklären?CVerstehen debate is usually interpreted as primarily epistemological. By raising the possibility that there are fundamentally different methods for fundamentally different types of science, the debate puts into play all the standard issues??that is, issues concerning scientific explanation and justification, the unity and diversity of scientific disciplines, the reality of their subject matter, the accessibility of various subject matters to research, and so on. In this paper, however, I do not focus on any of these specific issues. I start instead from the fact that the very existence of the debate itself is an issue; in fact, it poses a philosophical problem that almost everyone but the hardest line logical empiricists has come to realize cannot be resolved epistemologically. In my view, however, that it cannot be resolved ontologically, either. I think the problem is at bottom hermeneutical, and its resolution requires that we focus first, not on the objects of science or the methods of studying them, but on the character of the philosophical orientation assumed by those who would try to resolve it. In this paper, I explain why I think this is so by analyzing (1) Dilthey??s contribution to the original debate, (2) Husserl??s reaction to Dilthey, and (3) Heidegger??s critical evaluation of both. This line of philosophical development??this movement of self-understanding from critiques of objectivism to hermeneutical phenomenology??is of course already a central feature of much work in continental philosophy of science. In my conclusion, however, I argue for the less well-established??even if apparently approved??idea that it ought to be a central feature of technoscience studies as well. 相似文献