Mutations causing syndromic autism define an axis of synaptic pathophysiology

Tuberous sclerosis complex and fragile X syndrome are genetic diseases characterized by intellectual disability and autism. Because both syndromes are caused by mutations in genes that regulate protein synthesis in neurons, it has been hypothesized that excessive protein synthesis is one core pathophysiological mechanism of intellectual disability and autism. Using electrophysiological and biochemical assays of neuronal protein synthesis in the hippocampus of Tsc2(+/-) and Fmr1(-/y) mice, here we show that synaptic dysfunction caused by these mutations actually falls at opposite ends of a physiological spectrum. Synaptic, biochemical and cognitive defects in these mutants are corrected by treatments that modulate metabotropic glutamate receptor 5 in opposite directions, and deficits in the mutants disappear when the mice are bred to carry both mutations. Thus, normal synaptic plasticity and cognition occur within an optimal range of metabotropic glutamate-receptor-mediated protein synthesis, and deviations in either direction can lead to shared behavioural impairments.     

吉林省培智学校教师专业化发展的现状调查

20世纪末，国际上教师专业化思潮传入我国，备受我国教育界关注。短短几年，教师专业化已成为我国教育界的一种语境，并成为许多学校和教师的追求。培智学校是我国基础教育的重要组成部分，培智学校教师专业化水平应如何提升直接关系到智力落后儿童的发展问题。本文采用问卷法、访谈法对吉林省培智学校的一线教师进行调查。立足分析吉林省培智学校教师的专业化水平现状，提出了几点提高培智学校教师专业化水平的建议。     

Failure to find holes in the T-cell repertoire

The ability of an animal to respond to a given antigenic peptide depends on its major histocompatibility complex (MHC) type. Some peptides are not immunogenic when combined with a particular form of the MHC-encoded molecule. This non-responsiveness is regulated by immune response (Ir) genes and is thought to arise by one of two distinct mechanisms. Either the MHC-encoded molecules physically fail to interact with the antigen, preventing the activation of T cells with appropriate receptors, or they limit the expressed repertoire of T cell clones so that no T cells are available to be activated by existing complexes of MHC-encoded molecules and antigen. Experimental evidence has been generated to support both mechanisms. However, the relative importance of each has not been clearly established. In this study we started with a peptide that was immunogenic in B10 mice; it was thus known to be able to interact with the MHC molecule, and T cells existed which could recognise the peptide-MHC complex. Based on previous experiments, we then changed only those parts of the peptide that we thought interacted with the T-cell receptor. All the new analogues created were still immunogenic, confirming that the amino-acid substitutions that we had made did not prevent productive interactions with the MHC-encoded molecule. No limitations ('holes') in the T-cell repertoire were found. The experiments demonstrate the vast potential of the T-cell population to recognize many different analogues, each in a unique way, and suggest that constraints on the diversity of the T-cell repertoire may not be a major explanation for Ir gene defects.     

Functional genomic analysis of C. elegans chromosome I by systematic RNA interference

Complete genomic sequence is known for two multicellular eukaryotes, the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster, and it will soon be known for humans. However, biological function has been assigned to only a small proportion of the predicted genes in any animal. Here we have used RNA-mediated interference (RNAi) to target nearly 90% of predicted genes on C. elegans chromosome I by feeding worms with bacteria that express double-stranded RNA. We have assigned function to 13.9% of the genes analysed, increasing the number of sequenced genes with known phenotypes on chromosome I from 70 to 378. Although most genes with sterile or embryonic lethal RNAi phenotypes are involved in basal cell metabolism, many genes giving post-embryonic phenotypes have conserved sequences but unknown function. In addition, conserved genes are significantly more likely to have an RNAi phenotype than are genes with no conservation. We have constructed a reusable library of bacterial clones that will permit unlimited RNAi screens in the future; this should help develop a more complete view of the relationships between the genome, gene function and the environment.     

T-box gene tbx5 is essential for formation of the pectoral limb bud

The T-box genes Tbx4 and Tbx5 have been shown to have key functions in the specification of the identity of the vertebrate forelimb (Tbx5) and hindlimb (Tbx4). Here we show that in zebrafish, Tbx5 has an additional early function that precedes the formation of the limb bud itself. Functional knockdown of zebrafish tbx5 through the use of an antisense oligonucleotide resulted in a failure to initiate fin bud formation, leading to the complete loss of pectoral fins. The function of the tbx5 gene in the development of zebrafish forelimbs seems to involve the directed migration of individual lateral-plate mesodermal cells into the future limb-bud-producing region. The primary defect seen in the tbx5-knockdown phenotype is similar to the primary defects described in known T-box-gene mutants such as the spadetail mutant of zebrafish and the Brachyury mutant of the mouse, which both similarly exhibit an altered migration of mesodermal cells. A common function for many of the T-box genes might therefore be in mediating the proper migration and/or changes in adhesive properties of early embryonic cells.     

Strategy for the mapping of interactive genes using bulked segregant analysis method and Mapmaker/Exp software

A qualitative trait is usually controlled by a single gene, but it may be sometimes controlled by two or even more genes. This phenomenon is called gene interaction. Rapidly searching for linked mo- lecular markers via bulked segregant analysis (BSA) and then constructing regional linkage map with Mapmaker/Exp has become a common approach to mapping single major genes. However, methods and computer programs developed for mapping single major genes cannot be simply applied to interactive genes because the genetic patterns of gene interac- tions are quite different from that of single-gene in- heritance. Up to now, experimental methods for quickly screening molecular markers linked to inter- active genes and statistical methods and corre- sponding computer softwares for simultaneously analyzing the linkage relationships of multiple mo- lecular markers to an interactive gene have not been available. To solve this problem, in this paper, we propose a strategy for mapping interactive genes using BSA and Mapmaker/Exp. We demonstrate that all interactive genes can be mapped by the 'BSA Mapmaker/Exp' strategy using F2 generation (in a few cases, F3 generation is also needed). As BSA and Mapmaker/Exp have been broadly used in gene mapping studies and are well known by many re- searchers, the strategies proposed in this paper will be useful for practical researches.     

An LDL-receptor-related protein mediates Wnt signalling in mice

Wnt genes comprise a large family of secreted polypeptides that are expressed in spatially and tissue-restricted patterns during vertebrate embryonic development. Mutational analysis in mice has shown the importance of Wnts in controlling diverse developmental processes such as patterning of the body axis, central nervous system and limbs, and the regulation of inductive events during organogenesis. Although many components of the Wnt signalling pathway have been identified, little is known about how Wnts and their cognate Frizzled receptors signal to downstream effector molecules. Here we present evidence that a new member of the low-density lipoprotein (LDL)-receptor-related protein family, LRP6 (ref. 3), is critical for Wnt signalling in mice. Embryos homozygous for an insertion mutation in the LRP6 gene exhibit developmental defects that are a striking composite of those caused by mutations in individual Wnt genes. Furthermore, we show a genetic enhancement of a Wnt mutant phenotype in mice lacking one functional copy of LRP6. Together, our results support a broad role for LRP6 in the transduction of several Wnt signals in mammals.     

Dissecting the architecture of a quantitative trait locus in yeast

Most phenotypic diversity in natural populations is characterized by differences in degree rather than in kind. Identification of the actual genes underlying these quantitative traits has proved difficult. As a result, little is known about their genetic architecture. The failures are thought to be due to the different contributions of many underlying genes to the phenotype and the ability of different combinations of genes and environmental factors to produce similar phenotypes. This study combined genome-wide mapping and a new genetic technique named reciprocal-hemizygosity analysis to achieve the complete dissection of a quantitative trait locus (QTL) in Saccharomyces cerevisiae. A QTL architecture was uncovered that was more complex than expected. Functional linkages both in cis and in trans were found between three tightly linked quantitative trait genes that are neither necessary nor sufficient in isolation. This arrangement of alleles explains heterosis (hybrid vigour), the increased fitness of the heterozygote compared with homozygotes. It also demonstrates a deficiency in current approaches to QTL dissection with implications extending to traits in other organisms, including human genetic diseases.     

Global trends of whole-genome duplications revealed by the ciliate Paramecium tetraurelia

The duplication of entire genomes has long been recognized as having great potential for evolutionary novelties, but the mechanisms underlying their resolution through gene loss are poorly understood. Here we show that in the unicellular eukaryote Paramecium tetraurelia, a ciliate, most of the nearly 40,000 genes arose through at least three successive whole-genome duplications. Phylogenetic analysis indicates that the most recent duplication coincides with an explosion of speciation events that gave rise to the P. aurelia complex of 15 sibling species. We observed that gene loss occurs over a long timescale, not as an initial massive event. Genes from the same metabolic pathway or protein complex have common patterns of gene loss, and highly expressed genes are over-retained after all duplications. The conclusion of this analysis is that many genes are maintained after whole-genome duplication not because of functional innovation but because of gene dosage constraints.     

知识产权的国际化与我国的对策

20世纪以来,知识产权走上国际化的道路,保护的客体范围不断扩大,众多的保护知识产权的国际组织成立,双重保护体系基本形成.我国基于改革开放、市场经济建设及国际知识产权保护的推动,作为知识产权三大支柱的商标法、专利法、著作权法先后实施,随着知识产权国际化的趋势,我国知识产权立法不断地修改、完善,知识产权行政执法和司法的保护力度不断加大,使得我国知识产权保护制度与国际上的做法接轨.     

NJK吊鼓式结晶罐强制循环中置机构研究与应用

强制循环真空结晶罐有煮糖时间短、汽耗减少、产品质量改善等优点。传统的强制循环装置为顶置驱动，有许多固有的机械缺点。本文介绍的新型ＮＪＫ结晶罐中置式搅拌器及其主要特点，经中国不同地区糖厂的实际应用，取得显著成效。它适用于不同容量的甲、乙和丙糖罐。安全率达１００％，汽耗降低３０％以上，结晶率与产品质量有所改善。中置机构突出的机构机械性能是振动小、不漏真空、噪音低。     

Predicting disease genes for familial dilated cardiomyopathy based on the codon usage bias

Familial dilated cardiomyopathy （FDC） is a common monogenic disease mostly with autosomal dominant inheritance. Fifteen different loci for autosomal dominant FDC have been mapped; however, only eight FDC genes have been found, and it is still a big challenge to identify additional seven FDC genes in their chromosomal regions. We found that the codon usage frequencies in most of known FDC gene sequences are consistently biased, and significantly different from the average codon usage frequencies of human genes. This unique feature of codon usage was used to develop a novel approach to predicting FDC genes. Leave-oneout cross-validation results demonstrate that this approach can effectively detect FDC genes from numbers of genes in their chromosomal regions. Another advantage of this approach is that it is solely based on DNA sequences and therefore has the ability to identify potential FDC genes whose functions are completely unknown. Further, this approach has been used to analyze the seven FDC loci in which the FDC genes are still unknown. Both the detailed prediction results and the prediction program are available at http：// infosci.hust.edu.cn, which might provide help for relevant experimental researches to find new FDC genes.     

Polymorphism of human Ia antigens generated by reciprocal intergenic exchange between two DR beta loci

Class II molecules encoded by the human major histocompatibility complex (MHC) are involved in regulating T-cell response to antigens. The mechanisms for generating polymorphism in products of the MHC have been studied extensively for both the murine H-2 and the human HLA complex. Such studies indicate that point mutations plus selection have a major role in the generation of polymorphisms of class I and class II MHC genes. However, a non-reciprocal gene conversion mechanism has been proposed to explain several examples of clustered sequence variation in MHC genes. In all these examples, the proposed gene conversion event is unidirectional; that is, one of the two interacting genes acts as sequence donor and the other as sequence recipient. No examples of potential reciprocal genetic exchange (as occurs in the fungal system), in which the two interacting genes act as both donor and recipient of gene fragments, have been found in the MHC system or in other multigene families of higher organisms. We sequenced two different HLA-DR beta complementary DNAs from each of two different cells all expressing the same serologically defined determinant (DR2) but different T-cell-recognized (Dw) specificities (Dw12 and MN2). Sequence comparisons of these four cDNA clones (and two DR beta amino-acid sequences from the DR2-Dw2 subtype) suggest that new coding sequences for DR beta molecules in the DR2 haplotypes are potentially generated by reciprocal intergenic exchange.     

智能车辆规划与控制策略学习方法综述

智能车辆相关技术已实现了长足的发展,并已能够在有限封闭场景中实现自主行驶的基本功能. 然而,实际道路测试结果表明,目前智能车辆技术仍存在较多局限,而智能车辆在复杂城市与越野环境的大规模应用仍面临较多挑战. 作为智能车辆关键技术之一,运动规划与控制技术已基本建立了完整的理论体系并已得到较多工程应用,但传统方法在实际应用中仍存在动态复杂场景理解能力弱、场景适应性差、模型复杂度高、参数调整难度大等缺陷. 由于机器学习方法具备较强的知识表征与模型拟合能力,其已经在智能车辆的感知与导航技术中得到了广泛的应用. 而为了解决传统运动规划与控制技术存在的泛化性与适用性等问题,许多研究者近年来也开始探索基于深度学习、强化学习等机器学习方法的运动规划与控制方法. 本文将对目前基于机器学习的智能车辆规划与控制方法研究现状进行回顾,从规划与控制策略基本架构、基本学习范式以及基于学习的规划与控制方法三方面对现有智能车辆规划与控制策略学习方法进行分析,最后对研究现状与未来发展方向进行总结与展望.      

The highly reduced genome of an enslaved algal nucleus

Chromophyte algae differ fundamentally from plants in possessing chloroplasts that contain chlorophyll c and that have a more complex bounding-membrane topology. Although chromophytes are known to be evolutionary chimaeras of a red alga and a non-photosynthetic host, which gave rise to their exceptional membrane complexity, their cell biology is poorly understood. Cryptomonads are the only chromophytes that still retain the enslaved red algal nucleus as a minute nucleomorph. Here we report complete sequences for all three nucleomorph chromosomes from the cryptomonad Guillardia theta. This tiny 551-kilobase eukaryotic genome is the most gene-dense known, with only 17 diminutive spliceosomal introns and 44 overlapping genes. Marked evolutionary compaction hundreds of millions of years ago eliminated nearly all the nucleomorph genes for metabolic functions, but left 30 for chloroplast-located proteins. To allow expression of these proteins, nucleomorphs retain hundreds of genetic-housekeeping genes. Nucleomorph DNA replication and periplastid protein synthesis require the import of many nuclear gene products across endoplasmic reticulum and periplastid membranes. The chromosomes have centromeres, but possibly only one loop domain, offering a means for studying eukaryotic chromosome replication, segregation and evolution.     

Systematic analysis of genes required for synapse structure and function

Chemical synapses are complex structures that mediate rapid intercellular signalling in the nervous system. Proteomic studies suggest that several hundred proteins will be found at synaptic specializations. Here we describe a systematic screen to identify genes required for the function or development of Caenorhabditis elegans neuromuscular junctions. A total of 185 genes were identified in an RNA interference screen for decreased acetylcholine secretion; 132 of these genes had not previously been implicated in synaptic transmission. Functional profiles for these genes were determined by comparing secretion defects observed after RNA interference under a variety of conditions. Hierarchical clustering identified groups of functionally related genes, including those involved in the synaptic vesicle cycle, neuropeptide signalling and responsiveness to phorbol esters. Twenty-four genes encoded proteins that were localized to presynaptic specializations. Loss-of-function mutations in 12 genes caused defects in presynaptic structure.     

X-chromosome inactivation may explain the difference in viability of XO humans and mice

Only about 1% of human XO conceptuses survive to birth and these usually have the characteristics of Turner's syndrome, with a complex and variable phenotype including short stature, gonadal dysgenesis and anatomical defects. Both the embryonic lethality and Turner's syndrome are thought to be due to monosomy for a gene or genes common to the X and Y chromosomes. These genes would be expected to be expressed in females from both active and inactive X chromosomes to ensure correct dosage of gene product. Two genes with these properties are ZFX and RPS4X, both of which have been proposed to play a role in Turner's syndrome. In contrast to humans, mice that are XO are viable with no prenatal lethality (P. Burgoyne, personal communication) and are anatomically normal and fertile. We have devised a system to analyse whether specific genes on the mouse X chromosome are inactivated, and demonstrate that both Zfx and Rps4X undergo normal X-inactivation in mice. Thus the relative viability of XO mice compared to XO humans may be explained by differences between the two species in the way that dosage compensation of specific genes is achieved.     

Molecular motors

Life implies movement. Most forms of movement in the living world are powered by tiny protein machines known as molecular motors. Among the best known are motors that use sophisticated intramolecular amplification mechanisms to take nanometre steps along protein tracks in the cytoplasm. These motors transport a wide variety of cargo, power cell locomotion, drive cell division and, when combined in large ensembles, allow organisms to move. Motor defects can lead to severe diseases or may even be lethal. Basic principles of motor design and mechanism have now been derived, and an understanding of their complex cellular roles is emerging.