High-resolution mapping of quantitative trait loci in outbred mice

Screening the whole genome of a cross between two inbred animal strains has proved to be a powerful method for detecting genetic loci underlying quantitative behavioural traits, but the level of resolution offered by quantitative trait loci (QTL) mapping is still too coarse to permit molecular cloning of the genetic determinants. To achieve high-resolution mapping, we used an outbred stock of mice for which the entire genealogy is known. The heterogeneous stock (HS) was established 30 years ago from an eight-way cross of C57BL/6, BALB/c, RIII, AKR, DBA/2, I, A/J and C3H inbred mouse strains. At the time of the experiment reported here, the HS mice were at generation 58, theoretically offering at least a 30-fold increase in resolution for QTL mapping compared with a backcross or an F2 intercross. Using the HS mice we have mapped a QTL influencing a psychological trait in mice to a 0.8-cM interval on chromosome 1. This method allows simultaneous fine mapping of multiple QTLs, as shown by our report of a second QTL on chromosome 12. The high resolution possible with this approach makes QTLs accessible to positional cloning.     

A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell receptor

Multiple sclerosis (MS) is a complex chronic neurologic disease with a suspected autoimmune pathogenesis. Although there is evidence that the development of MS is determined by both environmental influences and genes, these factors are largely undefined, except for major histocompatibility (MHC) genes. Linkage analyses and association studies have shown that susceptibility to MS is associated with genes in the human histocompatibility leukocyte antigens (HLA) class II region, but the contribution of these genes to MS disease development less compared with their contribution to disorders such as insulin-dependent diabetes mellitus. Due to the strong linkage disequilibrium in the MHC class II region, it has not been possible to determine which gene(s) is responsible for the genetic predisposition. In transgenic mice, we have expressed three human components involved in T-cell recognition of an MS-relevant autoantigen presented by the HLA-DR2 molecule: DRA*0101/DRB1*1501 (HLA-DR2), an MHC class II candidate MS susceptibility genes found in individuals of European descent; a T-cell receptor (TCR) from an MS-patient-derived T-cell clone specific for the HLA-DR2 bound immunodominant myelin basic protein (MBP) 4102 peptide; and the human CD4 coreceptor. The amino acid sequence of the MBP 84-102 peptide is the same in both human and mouse MBP. Following administration of the MBP peptide, together with adjuvant and pertussis toxin, transgenic mice developed focal CNS inflammation and demyelination that led to clinical manifestations and disease courses resembling those seen in MS. Spontaneous disease was observed in 4% of mice. When DR2 and TCR double-transgenic mice were backcrossed twice to Rag2 (for recombination-activating gene 2)-deficient mice, the incidence of spontaneous disease increased, demonstrating that T cells specific for the HLA-DR2 bound MBP peptide are sufficient and necessary for development of disease. Our study provides evidence that HLA-DR2 can mediate both induced and spontaneous disease resembling MS by presenting an MBP self-peptide to T cells.     

Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia

Autosomal dominant hereditary spastic paraplegia (AD-HSP) is a genetically heterogeneous neurodegenerative disorder characterized by progressive spasticity of the lower limbs. Among the four loci causing AD-HSP identified so far, the SPG4 locus at chromosome 2p2-1p22 has been shown to account for 40-50% of all AD-HSP families. Using a positional cloning strategy based on obtaining sequence of the entire SPG4 interval, we identified a candidate gene encoding a new member of the AAA protein family, which we named spastin. Sequence analysis of this gene in seven SPG4-linked pedigrees revealed several DNA modifications, including missense, nonsense and splice-site mutations. Both SPG4 and its mouse orthologue were shown to be expressed early and ubiquitously in fetal and adult tissues. The sequence homologies and putative subcellular localization of spastin suggest that this ATPase is involved in the assembly or function of nuclear protein complexes.     

低价货之殇

这是一个完整的链条:深被价格刺激的成熟顾客、在街头游荡的出货人和隐藏在网络背后的网商、一些视出货人为救星的遭受囤货苦难的经销商,还有彷徨的公司。而在这个链条之外的,还有两个强势的团体:以系统的名义出低价货的组织,和大部分渴望拥有健康市场的经销商。在这个专题里,我们采访了出货人,采访了网商,采访了反对低价货的高级经销商,也采访了提供低价货的经销商,我们了解到了出货人的生存状态和存在的必要、网商的运作手段和渴望合作的心态、高级经销商对低价市场的反对与无奈、供货经销商的酸楚。     

桥台背跳车病害预防及补救对策

桥头跳车问题一直是困扰桥梁工程技术人员的难题之一，本文通过分析公路桥台背不平顺的成因，介绍了目前常用的公路桥台背跳车病害处理的技术预防及补救措施。     

质子微光束探测元素

由牛津大学设计的一种引人注目的新仪器,能在样品放大的同时,分析其元素组成。设想有一种仪器,同时具有质谱测定仪的分析能力和电子显微镜的成像能力。在显微镜放大的细节中,不仅能显示出物体的形状,同时还能测定并标志出它的构成。如何使用这样一种装置呢?如何才能弄清具有阿尔茨海默病(即老年痴呆症)特点的神经细胞紊乱的组成?或者测量出能够吸收多少重金属细菌?或者找出一位艺术家(例如伦勃朗)怎样使用颜料?