A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease

Vaccinations with amyloid-beta peptide (A beta) can dramatically reduce amyloid deposition in a transgenic mouse model of Alzheimer's disease. To determine if the vaccinations had deleterious or beneficial functional consequences, we tested eight months of A beta vaccination in a different transgenic model for Alzheimer's disease in which mice develop learning deficits as amyloid accumulates. Here we show that vaccination with A beta protects transgenic mice from the learning and age-related memory deficits that normally occur in this mouse model for Alzheimer's disease. During testing for potential deleterious effects of the vaccine, all mice performed superbly on the radial-arm water-maze test of working memory. Later, at an age when untreated transgenic mice show memory deficits, the A beta-vaccinated transgenic mice showed cognitive performance superior to that of the control transgenic mice and, ultimately, performed as well as nontransgenic mice. The A beta-vaccinated mice also had a partial reduction in amyloid burden at the end of the study. This therapeutic approach may thus prevent and, possibly, treat Alzheimer's dementia.     

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.     

Enzyme–substrate relationships in the ubiquitin system: approaches for identifying substrates of ubiquitin ligases

Protein ubiquitylation is an important post-translational modification, regulating aspects of virtually every biochemical pathway in eukaryotic cells. Hundreds of enzymes participate in the conjugation and deconjugation of ubiquitin, as well as the recognition, signaling functions, and degradation of ubiquitylated proteins. Regulation of ubiquitylation is most commonly at the level of recognition of substrates by E3 ubiquitin ligases. Characterization of the network of E3–substrate relationships is a major goal and challenge in the field, as this expected to yield fundamental biological insights and opportunities for drug development. There has been remarkable success in identifying substrates for some E3 ligases, in many instances using the standard protein–protein interaction techniques (e.g., two-hybrid screens and co-immunoprecipitations paired with mass spectrometry). However, some E3s have remained refractory to characterization, while others have simply not yet been studied due to the sheer number and diversity of E3s. This review will discuss the range of tools and techniques that can be used for substrate profiling of E3 ligases.     

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。     

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.     

Type I IFN-mediated regulation of IL-1 production in inflammatory disorders

Although contributing to inflammatory responses and to the development of certain autoimmune pathologies, type I interferons (IFNs) are used for the treatment of viral, malignant, and even inflammatory diseases. Interleukin-1 (IL-1) is a strongly pyrogenic cytokine and its importance in the development of several inflammatory diseases is clearly established. While the therapeutic use of IL-1 blocking agents is particularly successful in the treatment of innate-driven inflammatory disorders, IFN treatment has mostly been appreciated in the management of multiple sclerosis. Interestingly, type I IFNs exert multifaceted immunomodulatory effects, including the reduction of IL-1 production, an outcome that could contribute to its efficacy in the treatment of inflammatory diseases. In this review, we summarize the current knowledge on IL-1 and IFN effects in different inflammatory disorders, the influence of IFNs on IL-1 production, and discuss possible therapeutic avenues based on these observations.     

Genetic variation in Mon1a affects protein trafficking and modifies macrophage iron loading in mice

We undertook a quantitative trait locus (QTL) analysis in mice to identify modifier genes that might influence the severity of human iron disorders. We identified a strong QTL on mouse chromosome 9 that differentially affected macrophage iron burden in C57BL/10J and SWR/J mice. A C57BL/10J missense allele of an evolutionarily conserved gene, Mon1a, cosegregated with the QTL in congenic mouse lines. We present evidence that Mon1a is involved in trafficking of ferroportin, the major mammalian iron exporter, to the surface of iron-recycling macrophages. Differences in amounts of surface ferroportin correlate with differences in cellular iron content. Mon1a is also important for trafficking of cell-surface and secreted molecules unrelated to iron metabolism, suggesting that it has a fundamental role in the mammalian secretory apparatus.     

Variation in interleukin 7 receptor alpha chain (IL7R) influences risk of multiple sclerosis

Multiple sclerosis is a chronic, often disabling, disease of the central nervous system affecting more than 1 in 1,000 people in most western countries. The inflammatory lesions typical of multiple sclerosis show autoimmune features and depend partly on genetic factors. Of these genetic factors, only the HLA gene complex has been repeatedly confirmed to be associated with multiple sclerosis, despite considerable efforts. Polymorphisms in a number of non-HLA genes have been reported to be associated with multiple sclerosis, but so far confirmation has been difficult. Here, we report compelling evidence that polymorphisms in IL7R, which encodes the interleukin 7 receptor alpha chain (IL7Ralpha), indeed contribute to the non-HLA genetic risk in multiple sclerosis, demonstrating a role for this pathway in the pathophysiology of this disease. In addition, we report altered expression of the genes encoding IL7Ralpha and its ligand, IL7, in the cerebrospinal fluid compartment of individuals with multiple sclerosis.     

Viral immune modulators perturb the human molecular network by common and unique strategies

Viruses must enter host cells to replicate, assemble and propagate. Because of the restricted size of their genomes, viruses have had to evolve efficient ways of exploiting host cell processes to promote their own life cycles and also to escape host immune defence mechanisms. Many viral open reading frames (viORFs) with immune-modulating functions essential for productive viral growth have been identified across a range of viral classes. However, there has been no comprehensive study to identify the host factors with which these viORFs interact for a global perspective of viral perturbation strategies. Here we show that different viral perturbation patterns of the host molecular defence network can be deduced from a mass-spectrometry-based host-factor survey in a defined human cellular system by using 70 innate immune-modulating viORFs from 30 viral species. The 579 host proteins targeted by the viORFs mapped to an unexpectedly large number of signalling pathways and cellular processes, suggesting yet unknown mechanisms of antiviral immunity. We further experimentally verified the targets heterogeneous nuclear ribonucleoprotein?U, phosphatidylinositol-3-OH kinase, the WNK (with-no-lysine) kinase family and USP19 (ubiquitin-specific peptidase 19) as vulnerable nodes in the host cellular defence system. Evaluation of the impact of viral immune modulators on the host molecular network revealed perturbation strategies used by individual viruses and by viral classes. Our data are also valuable for the design of broad and specific antiviral therapies.