Structural basis for the subunit assembly of the anaphase-promoting complex

The anaphase-promoting complex or cyclosome (APC/C) is an unusually large E3 ubiquitin ligase responsible for regulating defined cell cycle transitions. Information on how its 13 constituent proteins are assembled, and how they interact with co-activators, substrates and regulatory proteins is limited. Here, we describe a recombinant expression system that allows the reconstitution of holo APC/C and its sub-complexes that, when combined with electron microscopy, mass spectrometry and docking of crystallographic and homology-derived coordinates, provides a precise definition of the organization and structure of all essential APC/C subunits, resulting in a pseudo-atomic model for 70% of the APC/C. A lattice-like appearance of the APC/C is generated by multiple repeat motifs of most APC/C subunits. Three conserved tetratricopeptide repeat (TPR) subunits (Cdc16, Cdc23 and Cdc27) share related superhelical homo-dimeric architectures that assemble to generate a quasi-symmetrical structure. Our structure explains how this TPR sub-complex, together with additional scaffolding subunits (Apc1, Apc4 and Apc5), coordinate the juxtaposition of the catalytic and substrate recognition module (Apc2, Apc11 and Apc10 (also known as Doc1)), and TPR-phosphorylation sites, relative to co-activator, regulatory proteins and substrates.     

Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation

Excessive inflammation and tumour-necrosis factor (TNF) synthesis cause morbidity and mortality in diverse human diseases including endotoxaemia, sepsis, rheumatoid arthritis and inflammatory bowel disease. Highly conserved, endogenous mechanisms normally regulate the magnitude of innate immune responses and prevent excessive inflammation. The nervous system, through the vagus nerve, can inhibit significantly and rapidly the release of macrophage TNF, and attenuate systemic inflammatory responses. This physiological mechanism, termed the 'cholinergic anti-inflammatory pathway' has major implications in immunology and in therapeutics; however, the identity of the essential macrophage acetylcholine-mediated (cholinergic) receptor that responds to vagus nerve signals was previously unknown. Here we report that the nicotinic acetylcholine receptor alpha7 subunit is required for acetylcholine inhibition of macrophage TNF release. Electrical stimulation of the vagus nerve inhibits TNF synthesis in wild-type mice, but fails to inhibit TNF synthesis in alpha7-deficient mice. Thus, the nicotinic acetylcholine receptor alpha7 subunit is essential for inhibiting cytokine synthesis by the cholinergic anti-inflammatory pathway.     

Upper intestinal lipids trigger a gut-brain-liver axis to regulate glucose production

Energy and glucose homeostasis are regulated by food intake and liver glucose production, respectively. The upper intestine has a critical role in nutrient digestion and absorption. However, studies indicate that upper intestinal lipids inhibit food intake as well in rodents and humans by the activation of an intestine-brain axis. In parallel, a brain-liver axis has recently been proposed to detect blood lipids to inhibit glucose production in rodents. Thus, we tested the hypothesis that upper intestinal lipids activate an intestine-brain-liver neural axis to regulate glucose homeostasis. Here we demonstrate that direct administration of lipids into the upper intestine increased upper intestinal long-chain fatty acyl-coenzyme A (LCFA-CoA) levels and suppressed glucose production. Co-infusion of the acyl-CoA synthase inhibitor triacsin C or the anaesthetic tetracaine with duodenal lipids abolished the inhibition of glucose production, indicating that upper intestinal LCFA-CoAs regulate glucose production in the preabsorptive state. Subdiaphragmatic vagotomy or gut vagal deafferentation interrupts the neural connection between the gut and the brain, and blocks the ability of upper intestinal lipids to inhibit glucose production. Direct administration of the N-methyl-d-aspartate ion channel blocker MK-801 into the fourth ventricle or the nucleus of the solitary tract where gut sensory fibres terminate abolished the upper-intestinal-lipid-induced inhibition of glucose production. Finally, hepatic vagotomy negated the inhibitory effects of upper intestinal lipids on glucose production. These findings indicate that upper intestinal lipids activate an intestine-brain-liver neural axis to inhibit glucose production, and thereby reveal a previously unappreciated pathway that regulates glucose homeostasis.     

Recent Antarctic Peninsula warming relative to Holocene climate and ice-shelf history

Rapid warming over the past 50?years on the Antarctic Peninsula is associated with the collapse of a number of ice shelves and accelerating glacier mass loss. In contrast, warming has been comparatively modest over West Antarctica and significant changes have not been observed over most of East Antarctica, suggesting that the ice-core palaeoclimate records available from these areas may not be representative of the climate history of the Antarctic Peninsula. Here we show that the Antarctic Peninsula experienced an early-Holocene warm period followed by stable temperatures, from about 9,200 to 2,500?years ago, that were similar to modern-day levels. Our temperature estimates are based on an ice-core record of deuterium variations from James Ross Island, off the northeastern tip of the Antarctic Peninsula. We find that the late-Holocene development of ice shelves near James Ross Island was coincident with pronounced cooling from 2,500 to 600?years ago. This cooling was part of a millennial-scale climate excursion with opposing anomalies on the eastern and western sides of the Antarctic Peninsula. Although warming of the northeastern Antarctic Peninsula began around 600 years ago, the high rate of warming over the past century is unusual (but not unprecedented) in the context of natural climate variability over the past two millennia. The connection shown here between past temperature and ice-shelf stability suggests that warming for several centuries rendered ice shelves on the northeastern Antarctic Peninsula vulnerable to collapse. Continued warming to temperatures that now exceed the stable conditions of most of the Holocene epoch is likely to cause ice-shelf instability to encroach farther southward along the Antarctic Peninsula.     

Nectar-sugar concentrations and flower visitors in the western Great Basin

v\:* {behavior:url(#default#VML);} o\:* {behavior:url(#default#VML);} w\:* {behavior:url(#default#VML);} .shape {behavior:url(#default#VML);} Normal 0 false false false EN-US X-NONE X-NONE MicrosoftInternetExplorer4 st1\:*{behavior:url(#ieooui) } /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;} Nectar - sugar concentrations and major flower visitors were determined for 15 species of plants in the Eagle Lake area of Northeastern California. Sugar concentrations for 12 of these are reported for the first time, with means ranging from a low of 10 percent in Mentzelia laevicaulis to a high of 63 percent in Ranunculus uncinatus. The utilization of the various nectar concentrations varied with the type of flower visitor as well as with the habitat and distributional ranges of the plant and/or animal. Hummingbirds and hawkmoths were not observed visiting the flowers they typically visit in other areas (e.g. Aquilegia and Ipomopsis, or Oenothera ), but here preferred more concentrated nectar ( Cirsium spp., with mean   of 57 percent sugar). Specialization in nectar use is reported at the generic and specific level in Hymenoptera and Lepidoptera; solitary bees, as a whole, used slightly less concentrated nectar ( mean = 38 percent sugar) than butterflies ( mean = 44 percent sugar).        

斯蒂芬·杰伊·古尔德(1941～2002)

斯蒂芬·杰伊·古尔德 (ＳｔｅｐｈｅｎＪａｙＧｏｕｌｄ ,见上图 )是哈佛大学生物进化论科学家 ,他的研究、演讲以及大量科学散文作品给古生物学研究领域注入了新的内涵。 2 0 0 2年 5月 2 0日 ,他在曼哈顿的家中去世 ,癌症夺去了他的生命 ,享年 60岁。古尔德博士可以说是 2 0世纪最有影响的进化生物学家之一 ,也可以说是自查尔斯·达尔文 (ＣｈａｒｌｅｓＤａｒｗｉｎ)以来最知名的生物学家。他引发了多场争论 ,时而迫使科学家们重新考虑已成定论的有关进化模式和进化过程的观点。他最有名的理论之一是与奈尔斯·埃尔德雷奇(ＮｉｌｅｓＥ…     

Parthenogenetic reptiles: New subjects for laboratory research

Summary Problems preventing establishment of laboratory colonies of parthenogenetic lizards have been solved. Now, productive colonies of these lizards, which have remarkably little genetic variation, can be readily established and used not only for research on parthenogenesis but also for many kinds of experiments for which reptile systems are desirable. Research colonies can provide valuable specimens while reducing the exploitation of natural populations.We thank José P. O. Rosado and George W. Foley for technical assistance and Richard G. Zweifel for specimens, ideas and support.