Structures of complement component C3 provide insights into the function and evolution of immunity

The mammalian complement system is a phylogenetically ancient cascade system that has a major role in innate and adaptive immunity. Activation of component C3 (1,641 residues) is central to the three complement pathways and results in inflammation and elimination of self and non-self targets. Here we present crystal structures of native C3 and its final major proteolytic fragment C3c. The structures reveal thirteen domains, nine of which were unpredicted, and suggest that the proteins of the alpha2-macroglobulin family evolved from a core of eight homologous domains. A double mechanism prevents hydrolysis of the thioester group, essential for covalent attachment of activated C3 to target surfaces. Marked conformational changes in the alpha-chain, including movement of a critical interaction site through a ring formed by the domains of the beta-chain, indicate an unprecedented, conformation-dependent mechanism of activation, regulation and biological function of C3.     

Structural mechanism of plant aquaporin gating

Plants counteract fluctuations in water supply by regulating all aquaporins in the cell plasma membrane. Channel closure results either from the dephosphorylation of two conserved serine residues under conditions of drought stress, or from the protonation of a conserved histidine residue following a drop in cytoplasmic pH due to anoxia during flooding. Here we report the X-ray structure of the spinach plasma membrane aquaporin SoPIP2;1 in its closed conformation at 2.1 A resolution and in its open conformation at 3.9 A resolution, and molecular dynamics simulations of the initial events governing gating. In the closed conformation loop D caps the channel from the cytoplasm and thereby occludes the pore. In the open conformation loop D is displaced up to 16 A and this movement opens a hydrophobic gate blocking the channel entrance from the cytoplasm. These results reveal a molecular gating mechanism which appears conserved throughout all plant plasma membrane aquaporins.     

RNA sequencing of pancreatic circulating tumour cells implicates WNT signalling in metastasis

Circulating tumour cells (CTCs) shed into blood from primary cancers include putative precursors that initiate distal metastases. Although these cells are extraordinarily rare, they may identify cellular pathways contributing to the blood-borne dissemination of cancer. Here, we adapted a microfluidic device for efficient capture of CTCs from an endogenous mouse pancreatic cancer model and subjected CTCs to single-molecule RNA sequencing, identifying Wnt2 as a candidate gene enriched in CTCs. Expression of WNT2 in pancreatic cancer cells suppresses anoikis, enhances anchorage-independent sphere formation, and increases metastatic propensity in vivo. This effect is correlated with fibronectin upregulation and suppressed by inhibition of MAP3K7 (also known as TAK1) kinase. In humans, formation of non-adherent tumour spheres by pancreatic cancer cells is associated with upregulation of multiple WNT genes, and pancreatic CTCs revealed enrichment for WNT signalling in 5 out of 11 cases. Thus, molecular analysis of CTCs may identify candidate therapeutic targets to prevent the distal spread of cancer.     

顽拗型种子贮藏和脱水过程中碳水化合物、脂肪和蛋白质的生化变化

顽拗型种子通常不能干燥到较低含水量或贮藏较长时间而不受伤害。导致这一问题的生化机制因属不同甚至同一属中的种不同而异。笔者测定了栎属、槭属和七叶树属顽拗型种子在室温下贮藏或干燥过程中的生化变化。虽然贮藏脂肪组成的变化是不确定的，但膜脂肪和蛋白质的结构以及蔗糖含量发生了变化。用两份白橡树种子在室温下贮藏12d的实验表明，脱水样品的蔗糖含量发生很大变化，而保持水分的样品中蔗糖含量变化很小。因此，保持水分种子的蔗糖用于正常的生长和发育，而干燥种子的蔗糖则用作糖保护剂。尽管如此，蔗糖的存在也许能保护干燥橡实的细胞膜不致破裂，但蔗糖不能保持橡实的生活力。     

Subendothelial retention of atherogenic lipoproteins in early atherosclerosis

Complications of atherosclerosis are the most common cause of death in Western societies. Among the many risk factors identified by epidemiological studies, only elevated levels of lipoproteins containing apolipoprotein (apo) B can drive the development of atherosclerosis in humans and experimental animals even in the absence of other risk factors. However, the mechanisms that lead to atherosclerosis are still poorly understood. We tested the hypothesis that the subendothelial retention of atherogenic apoB-containing lipoproteins is the initiating event in atherogenesis. The extracellular matrix of the subendothelium, particularly proteoglycans, is thought to play a major role in the retention of atherogenic lipoproteins. The interaction between atherogenic lipoproteins and proteoglycans involves an ionic interaction between basic amino acids in apoB100 and negatively charged sulphate groups on the proteoglycans. Here we present direct experimental evidence that the atherogenicity of apoB-containing low-density lipoproteins (LDL) is linked to their affinity for artery wall proteoglycans. Mice expressing proteoglycan-binding-defective LDL developed significantly less atherosclerosis than mice expressing wild-type control LDL. We conclude that subendothelial retention of apoB100-containing lipoprotein is an early step in atherogenesis.     

Ultrafast precessional magnetization reversal by picosecond magnetic field pulse shaping

Since the invention of the first magnetic memory disk in 1954, much effort has been put into enhancing the speed, bit density and reliability of magnetic memory devices. In the case of magnetic random access memory (MRAM) devices, fast coherent magnetization rotation by precession of the entire memory cell is desired, because reversal by domain-wall motion is much too slow. In principle, the fundamental limit of the switching speed via precession is given by half of the precession period. However, under-critically damped systems exhibit severe ringing and simulations show that, as a consequence, undesired back-switching of magnetic elements of an MRAM can easily be initiated by subsequent write pulses, threatening data integrity. We present a method to reverse the magnetization in under-critically damped systems by coherent rotation of the magnetization while avoiding any ringing. This is achieved by applying specifically shaped magnetic field pulses that match the intrinsic properties of the magnetic elements. We demonstrate, by probing all three magnetization components, that reliable precessional reversal in lithographically structured micrometre-sized elliptical permalloy elements is possible at switching times of about 200 ps, which is ten times faster than the natural damping time constant.     

A collisional family of icy objects in the Kuiper belt

The small bodies in the Solar System are thought to have been highly affected by collisions and erosion. In the asteroid belt, direct evidence of the effects of large collisions can be seen in the existence of separate families of asteroids--a family consists of many asteroids with similar orbits and, frequently, similar surface properties, with each family being the remnant of a single catastrophic impact. In the region beyond Neptune, in contrast, no collisionally created families have hitherto been found. The third largest known Kuiper belt object, 2003 EL61, however, is thought to have experienced a giant impact that created its multiple satellite system, stripped away much of an overlying ice mantle, and left it with a rapid rotation. Here we report the discovery of a family of Kuiper belt objects with surface properties and orbits that are nearly identical to those of 2003 EL61. This family appears to be fragments of the ejected ice mantle of 2003 EL61.     

The problem of grounding natural modality in Kant's account of empirical laws of nature

One of the central problems of Kant's account of the empirical laws of nature is: What grounds their necessity? In this article I discuss the three most important lines of interpretation and suggest a novel version of one of them. While the first interpretation takes the transcendental principles as the only sources of the empirical laws' necessity, the second interpretation takes the systematicity of the laws to guarantee their necessity. It is shown that both views involve serious problems. The third interpretation, the “causal powers interpretation”, locates the source of the laws' necessity in the properties of natural objects. Although the second and third interpretations seem incompatible, I analyse why Kant held both views and I argue that they can be reconciled, because the metaphysical grounding project of the laws' necessity is accounted for by Kant's causal powers account, while his best system account explains our epistemic access to the empirical laws. If, however, causal powers are supposed to fulfil the grounding function for the laws' natural modality, then I suggest that a novel reading of the causal powers interpretation should be formulated along the lines of a genuine dispositionalist conception of the laws of nature.     

Human mesenchymal stem cells induce E-cadherin degradation in breast carcinoma spheroids by activating ADAM10

Mesenchymal stem cells (MSCs) have been shown to communicate with tumor cells. We analyzed the effect of human MSCs (hMSCs) on breast cancer cells in three-dimensional cultures. By using GFP expression and immunohistochemistry, we show that hMSCs invade 3D breast cancer cell aggregates. hMSCs caused breast cancer spheroids to become disorganized which was accompanied by a disruption of cell–cell adhesion, E-cadherin cleavage, and nuclear translocation of E-cadherin, but not by epithelial/mesenchymal transition or by an increase in ERK1/2 activity. In addition, hMSCs enhanced the motility of breast cancer cells. Inhibition of ADAM10 (a disintegrin and metalloprotease 10), known to cleave E-cadherin, prevented both hMSC-mediated E-cadherin cleavage and enhanced migration. Our data suggest that hMSCs interfere with cell–cell adhesion and enhance migration of breast cancer cells by activating ADAM10.