Protein oxidation and 20S proteasome-dependent proteolysis in mammalian cells

The generation of reactive oxygen species is an inevitable aspect of aerobic life. In addition to being exposed to free radicals in the environment, aerobic organisms must also deal with oxygen radicals generated as byproducts of a number of physiological mechanisms - for example, by the mitochondrial and endoplasmic reticulum electron transport chains, and by cells of the immune system. Although most organisms are equipped with several lines of defense against oxidative stress, these defensive mechanisms are not 100% effective, and oxidatively modified forms of proteins accumulate during aging, and in many pathological conditions.?Oxidatively modified proteins can form large aggregates due to covalent cross-linking or increased surface hydrophobicity. Unless repaired or removed from cells, these oxidized proteins are often toxic and can threaten cell viability. Mammalian cells exhibit only limited direct repair mechanisms, and oxidatively damaged proteins appear to undergo selective proteolysis, primarily by the major cytosolic proteinase, the proteasome. Interestingly, it appears that the 20S 'core' proteasome conducts the recognition and elimination of oxidized proteins in an ATP-independent and ubiquitin-independent pathway. Received 31 May 2001; accepted 26 June 2001     

佯谬消失

什么东西都不能从黑洞里逃脱。可是斯蒂芬·霍金出色地证明：黑洞并非真正是黑的，相反，它们因热而发光。那末这种热能怎么可能从那条单向通道里往外流源呢？答案全然同它所解释的现象一样奇特：黑洞辐射的热量不是用从黑洞流出来的通常能量来偿付，而是由流入黑洞的负能量来补偿。这难道是个数学花招？不对。负能量是确实存在的。问题在于：相当大的负能量的生成和利用会损害一些最神圣的自然法则，比如说热力学第二定律。梦想制造众动机或作逆时间旅行这些反常的非自然情景是容易的。对于物理学家来说，这些都是吓人的观念。但是大自然似…     

Microstructure-based multiphysics modeling for semiconductor integration and packaging

Semiconductor technology and packaging is advancing rapidly toward system integration where the packaging is co-designed and co-manufactured along with the wafer fabrication. However, materials issues, in par- ticular the mesoscale microstructure, have to date been excluded from the integrated product design cycle of electronic packaging due to the myriad of materials used and the complex nature of the material phenomena that require a multiphysics approach to describe. In the context of the materials genome initiative, we present an overview of a series of studies that aim to establish the linkages between the material microstructure and its responses by considering the multiple perspectives of the various mul- tiphysics fields. The microstructure was predicted using thermodynamic calculations, sharp interface kinetic models, phase field, and phase field crystal modeling techniques. Based on the predicted mesoscale microstruc- ture, linear elastic mechanical analyses and electromigra- tion simulations on the ultrafine interconnects were performed. The microstructural index extracted by a method based on singular value decomposition exhibits a monotonous decrease with an increase in the interconnect size. An artificial neural network-based fitting revealed a nonlinear relationship between the microstructure index and the average yon Mises stress in the ultrafine interconnects. Future work to address the randomness of microstructure and the resulting scatter in the reliability is discussed in this study.     

Characterization of a contact zone between two subspecies of the big brown bat ( Eptesicus fuscus ) in Nebraska

Two subspecies of the big brown bat ( Eptesicus fuscus ) are reported to occur in Nebraska. The eastern race, E. f. fuscus , is reportedly bigger and darker than its western counterpart E. f. pallidus . Where these 2 subspecies come in contact is the subject of debate. We used external, cranial, and colorimetric data to investigate geographic variation among populations of E. fuscus in Nebraska to determine the location of the zone of contact between E. f. fuscus and E. f. pallidus . We discovered significant variation in external, cranial, and colorimetric data, suggesting that E. fuscus is represented by 2 subspecies in Nebraska. Our results showed that E. f. pallidus is smaller, possesses lighter pelage, and is restricted to the northern and western parts of Nebraska, whereas E. f. fuscus is larger, possesses darker pelage, and occurs in southern and southeastern parts of the state. Populations located between these regions represent intergrades of the 2 subspecies. We suggest that the subspecific boundary represents a broad zone of integration running in a northeast to southwest direction and may reflect the position of temperature and precipitation clines.     

The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein.

One of the neuropathological hallmarks of Alzheimer's disease is the neurofibrillary tangle, which contains paired helical filaments (PHFs) composed of the microtubule-associated protein tau. Tau is hyperphosphorylated in PHFs, and phosphorylation of tau abolishes its ability to bind microtubules and promote microtubule assembly. Restoring the function of phosphorylated tau might prevent or reverse PHF formation in Alzheimer's disease. Phosphorylation on a serine or threonine that precedes proline (pS/T-P) alters the rate of prolyl isomerization and creates a binding site for the WW domain of the prolyl isomerase Pin1. Pin1 specifically isomerizes pS/T-P bonds and regulates the function of mitotic phosphoproteins. Here we show that Pin1 binds to only one pT-P motif in tau and copurifies with PHFs, resulting in depletion of soluble Pin1 in the brains of Alzheimer's disease patients. Pin1 can restore the ability of phosphorylated tau to bind microtubules and promote microtubule assembly in vitro. As depletion of Pin1 induces mitotic arrest and apoptotic cell death, sequestration of Pin1 into PHFs may contribute to neuronal death. These findings provide a new insight into the pathogenesis of Alzheimer's disease.     

The rapid formation of a large rotating disk galaxy three billion years after the Big Bang

Observations and theoretical simulations have established a framework for galaxy formation and evolution in the young Universe. Galaxies formed as baryonic gas cooled at the centres of collapsing dark-matter haloes; mergers of haloes and galaxies then led to the hierarchical build-up of galaxy mass. It remains unclear, however, over what timescales galaxies were assembled and when and how bulges and disks--the primary components of present-day galaxies--were formed. It is also puzzling that the most massive galaxies were more abundant and were forming stars more rapidly at early epochs than expected from models. Here we report high-angular-resolution observations of a representative luminous star-forming galaxy when the Universe was only 20% of its current age. A large and massive rotating protodisk is channelling gas towards a growing central stellar bulge hosting an accreting massive black hole. The high surface densities of gas, the high rate of star formation and the moderately young stellar ages suggest rapid assembly, fragmentation and conversion to stars of an initially very gas-rich protodisk, with no obvious evidence for a major merger.     

Visual Models in Analogical Problem Solving

Visual analogy is believed to be important in human problem solving. Yet, there are few computational models of visual analogy. In this paper, we present a preliminary computational model of visual analogy in problem solving. The model is instantiated in a computer program, called Galatea, which uses a language for representing and transferring visual information called Privlan. We describe how the computational model can account for a small slice of a cognitive-historical analysis of Maxwell’s reasoning about electromagnetism.     

Antibiotic resistance in microbes

The treatment of infectious disease is compromised by the development of antibiotic-resistant strains of microbial pathogens. A variety of biochemical processes are involved that may keep antibiotics out of the cell, alter the target of the drug, or disable the antibiotic. Studies have shown that resistance determinants arise by either of two genetic mechanisms: mutation and acquisition. Antibiotic resistance genes can be disseminated among bacterial populations by several processes, but principally by conjugation. Thus the overall problem of antibiotic resistance is one of genetic ecology and a better understanding of the contributing parameters is necessary to devise rational approaches to reduce the development and spread of antibiotic resistance and so avoid a critical situation in therapy--a return to a pre-antibiotic era.     

High temperatures in the Late Cretaceous Arctic Ocean

To understand the climate dynamics of the warm, equable greenhouse world of the Late Cretaceous period, it is important to determine polar palaeotemperatures. The early palaeoceanographic history of the Arctic Ocean has, however, remained largely unknown, because the sea floor and underlying deposits are usually inaccessible beneath a cover of floating ice. A shallow piston core taken from a drifting ice island in 1970 fortuitously retrieved unconsolidated Upper Cretaceous organic-rich sediment from Alpha ridge, a submarine elevated feature of probable oceanic origin. A lack of carbonate in the sediments from this core has prevented the use of traditional oxygen-isotope palaeothermometry. Here we determine Arctic palaeotemperatures from these Upper Cretaceous deposits using TEX86, a new palaeothermometer that is based on the composition of membrane lipids derived from a ubiquitous component of marine plankton, Crenarchaeota. From these analyses we infer an average sea surface temperature of approximately 15 degrees C for the Arctic Ocean about 70 million years ago. This calibration point implies an Equator-to-pole gradient in sea surface temperatures of approximately 15 degrees C during this interval and, by extrapolation, we suggest that polar waters were generally warmer than 20 degrees C during the middle Cretaceous (approximately 90 million years ago).