Taking aim at a moving target: designing drugs to inhibit drug-resistant HIV-1 reverse transcriptases

HIV undergoes rapid genetic variation; this variation is caused primarily by the enormous number of viruses produced daily in an infected individual. Because of this variation, HIV presents a moving target for drug and vaccine development. The variation within individuals has led to the generation of diverse HIV-1 subtypes, which further complicates the development of effective drugs and vaccines. In general, it is more difficult to hit a moving target than a stationary target. Two broad strategies for hitting a moving target (in this case, HIV replication) are to understand the movement and to aim at the portions that move the least. In the case of anti-HIV drug development, the first option can be addressed by understanding the mechanism(s) of drug resistance and developing drugs that effectively inhibit mutant viruses. The second can be addressed by designing drugs that interact with portions of the viral machinery that are evolutionarily conserved, such as enzyme active sites.     

Recovery after damage to motor cortical areas

Until recently, the neural bases underlying recovery of function after damage to the cerebral cortex were largely unknown. Recent results from neuroanatomical and neurophysiological studies in animal models have demonstrated that after cortical damage, long-term and widespread structural and functional alterations take place in the spared cortical tissue. These presumably adaptive changes may play an important role in functional recovery.     

Characterization of a Mouse Gene (Fbxw6) That Encodes a Homologue of Caenorhabditis elegans SEL-10

The SCF complex is a type of ubiquitin ligase that consists of the invariable components SKP1, CUL1, and RBX1 as well as a variable component, known as an F-box protein, that is the main determinant of substrate specificity. The Caenorhabditis elegans F-box- and WD40-repeat-containing protein SEL-10 functionally and physically associates with LIN-12 and SEL-12, orthologues of mammalian Notch and presenilin, respectively. We have now identified a gene (which we call Fbxw6) that encodes a mouse homologue (F-box–WD40 repeat protein 6, or FBW6) of SEL-10 and is expressed mainly in brain, heart, and testis. Co-immunoprecipitation analysis showed that FBW6 interacts with SKP1 and CUL1, indicating that these three proteins form an SCF complex. Comparison of the genomic organization of Fbxw6, which is located on mouse chromosome 3.3E3, with that of mouse Fbxw1, Fbxw2, and Fbxw4 showed only a low level of similarity, indicating that these genes diverged relatively early and thereafter evolved independently.     

Circling,deafness, and yellow coat displayed by yellow submarine (ysb) and light coat and circling (lcc) mice with mutations on chromosome 3

We describe here two mouse mutants, yellow submarine (Ysb) and light coat and circling (Lcc). Ysb arose as the result of insertions of a transgene, pAA2, into the genome. Lcc is an independent, radiation-induced mutation. Both mutants are characterized by recessive circling behavior and deafness, associated with a non-segregating, semi-dominant yellow coat color. Complementation tests showed that Ysb and Lcc are allelic. We attribute the yellow coat in Ysb and Lcc mice to the absence of black awl overhairs, increased agouti zigzag underhairs, and the presence of agouti awls with long subapical yellow pigment. Chromosomal mapping and genomic characterization showed the Ysb and Lcc mutations involve complex chromosomal rearrangements in overlapping regions of mouse chromosome 3, A2/A3-B/C and B-E1, respectively. Ysb and Lcc show for the first time, to our knowledge, the presence of genes in the B-C region of chromosome 3 important for balance and hearing and the pigmentation and specification of coat hair.     

Neural control of human motor development

It has been possible to expand considerably our understanding of human motor development by making a detailed analysis of various types of movement and muscular activation patterns during different stages of development. Alterations in development subsequent to the appearance of brain lesions have enabled valuable information to be collected about the underlying neural mechanisms, in addition to new information concerning the pathophysiology of cerebral palsy. Studies on the development of the corticospinal system indicate that plastic changes can take place after perinatal brain damage.     

Conceptual issues related to the role of the superior colliculus in the control of gaze

Various conceptual issues have been brought into focus by recent experiments studying the role of the superior colliculus in the control of coordinated movements of the eyes and head, the interaction of saccadic and vergence movements, and cognitive processes influencing the initiation and execution of saccades.     

Chemosensory behavior: the path from stimulus to response

In the past year, candidates have been identified for two long-sought classes of molecules, insect odorant receptors and mammalian taste receptors. In addition, genes directing receptor gene expression and the development of specific chemosensory neurons have been described in Drosophila melanogaster and Caenorhabditis elegans. Finally, recent physiological experiments have provided new insights into the mechanisms by which chemosensory information is processed.     

经济增加值指标在医院经营管理评价中的应用

2010年,国家国有资产管理委员会引入经济增加值,作为对央企高管绩效考核的重要指标。借鉴央企改革,论述经济增加值指标较传统指标在管理中的优胜之处,并讨论经济增加值指标在医院价值评价、财务管理和绩效管理方面的应用可能。     

Dead cells don't dance: insights from live-cell imaging in plants

Live-cell imaging has yielded surprising pictures of subcellular structures and dynamics in living plant cells. Recent studies illustrate the power of live-cell observation for revealing new biological phenomena and for generating new questions about plant cell structure and function.     

Nucleotide Sequence, Genomic Organization, and Chromosomal Localization of Genes Encoding the Human NMDA Receptor Subunits NR3A and NR3B

The N-methyl-D-aspartate (NMDA) receptors are glutamate-regulated ion channels that are critically involved in important physiological and pathological functions of the mammalian central nervous system. We have identified and characterized the gene encoding the human NMDA receptor subunit NR3A (GRIN3A), as well as the gene (GRIN3B) encoding an entirely novel subunit that we named NR3B, as it is most closely related to NR3A (57.4% identity). GRIN3A localizes to chromosome 9q34, in the region 13-34, and consists of nine coding exons. The deduced protein contains 1115 amino acids and shows 92.7% identity to rat NR3A. GRIN3B localizes to chromosome 19p13.3 and contains, as does the mouse NR3B gene (Grin3b), eight coding exons. The deduced proteins of human and mouse NR3B contain 901 and 900 amino acid residues, respectively (81.6% identity). In situ hybridization shows a widespread distribution of Grin3b mRNA in the brain of the adult rat.     

Physical mapping of the mouse tilted locus identifies an association between human deafness loci DFNA6/14 and vestibular system development

The tilted (tlt) mouse carries a recessive mutation causing vestibular dysfunction. The defect in tlt homozygous mice is limited to the utricle and saccule of the inner ear, which completely lack otoconia. Genetic mapping of tlt placed it in a region orthologous with human 4p16.3-p15 that contains two loci, DFNA6 and DFNA14, responsible for autosomal dominant, nonsyndromic hereditary hearing impairment. To identify a possible relationship between tlt in mice and DFNA6 and DFNA14 in humans, we have refined the mouse genetic map, assembled a BAC contig spanning the tlt locus, and developed a comprehensive comparative map between mouse and human. We have determined the position of tlt relative to 17 mouse chromosome 5 genes with orthologous loci in the human 4p16.3-p15 region. This analysis identified an inversion between the mouse and human genomes that places tlt and DFNA6/14 in close proximity.     

Neurobiology: Paper alert

A selection of interesting papers that were published in the two months before our press date in major journals most likely to report significant results in neurobiology.     

Bridging the gap - from ion channels to networks and behaviour

A major challenge for current research in neuroscience is to understand the intrinsic operation of the functional modules of the central nervous system, such as those formed by cortical columns and the neuronal networks controlling motor behaviour. Most vertebrate experimental models used in network analyses involve developing nervous systems, which are in rapid transition with regard to their cellular properties and the expression of different ion channels. Recent advances in our understanding of the cellular and circuit properties of motor networks are making it possible to decipher the mechanisms involved in vertebrate motor pattern generation.     

Mental imaging of motor activity in humans

Motor imagery corresponds to a subliminal activation of the motor system, a system that appears to be involved not only in producing movements, but also in imagining actions, recognising tools and learning by observation, as well as in understanding the behaviour of other people. Recent advances in the field include the use of techniques for mapping brain activity and probing cortical excitability, as well as observation of brain lesioned patients during imaging tasks; these advances provide new insights into the covert aspects of motor activity.     

Neurobiology of sexual behavior

Recent advances in the neurobiology of sexual behavior have helped to refine our understanding of the neuroanatomical, neuroendocrine and neurochemical systems that modulate responses to sexual stimulation. Both appetitive and consummatory sexual behaviors have been studied in several laboratory species and in humans using traditional and novel behavioral paradigms. New knowledge has emerged concerning the role of hypothalamic, limbic and brainstem structures, neuropeptides, brain monoamines and nitric oxide in the control of partner preference, sexual desire, erection, copulation, ejaculation, orgasm and sexual satiety. Brain imaging of visually evoked sexual arousal in humans has also been examined.     

Plant cell-size control: growing by ploidy?

The size of plant cells is determined by genetic, structural and physical factors as well as by internal and external signals. Our knowledge of the molecular mechanisms of these controls is still rudimentary. Recent studies indicate that ploidy level exerts an important control on cell size. By increasing ploidy, endoreduplication may allow cells to reach extraordinary sizes. This process is widespread in plants and may provide a means to manipulate the cell volume.