Homozygotes for Huntington's disease

Careful comparison of symptomatic individuals with normal controls has revealed the primary biochemical abnormality in many human genetic diseases, particularly recessive disorders. This strategy has proved less successful for most human disorders which are not recessive, and where a single copy of the aberrant gene has clinically significant effects even though the normal gene product is present. An alternative approach that eliminates the impediment of a normal protein in affected individuals is to study homozygotes for the mutant allele. For virtually all dominant human disorders in which homozygotes have been described, symptoms have been significantly more severe in the homozygote than in the heterozygote. Thus, these disorders do not conform to the classical definition of dominance which states that homozygotes and heterozygotes for a defect are phenotypically indistinguishable. Instead, they display incomplete dominance, indicating that the normal allele may play a role in ameliorating the disease process. The D4S10 locus, defined by the probe G8 and linked to the gene for Huntington's disease (HD), has permitted us to identify individuals with a high probability of being homozygous for this autosomal dominant neurodegenerative disorder. These homozygotes do not differ in clinical expression or course from typical HD heterozygotes. HD appears to be the first human disease of genetically documented homozygosity that displays complete phenotypic dominance.     

A polymorphic DNA marker genetically linked to Huntington's disease

Family studies show that the Huntington's disease gene is linked to a polymorphic DNA marker that maps to human chromosome 4. The chromosomal localization of the Huntington's disease gene is the first step in using recombinant DNA technology to identify the primary genetic defect in this disorder.     

A highly polymorphic locus very tightly linked to the Huntington's disease gene

The genetic defect in Huntington's disease (HD), an inherited neuropsychiatric disorder of unknown etiology, has not been defined. The discovery of linkage between HD and the DNA marker D4S10(G8) raised the possibility of isolating the disease gene on the basis of its chromosomal location, in addition to providing a limited presymptomatic test for the late onset disorder. But it has been difficult to isolate other DNA markers nearer to the HD gene, and this has hampered attempts to identify the disease locus and limited the applicability and accuracy of predictive testing. Recently, several new DNA markers from the region of the genome near the HD gene have been isolated using a directed cloning strategy. We describe here the characterization of one of these new markers, D4S95, a highly polymorphic locus which displays no recombination with the HD gene in the families tested. The high degree of polymorphism at this locus and its proximity to the HD gene make it extremely useful for predictive testing and as a new starting point for attempts to clone the disease gene.     

伪抛物方程组解的全局存在

研究如下非线性伪抛物方程组柯西问题解的全局存在性,u_t-Δu_t=Δu+u~αv~p,v_t-Δv_t=Δv+u~qv~β,这里p,q≥0,α,β≥0.首先应用压缩映射原理得到解的局部存在性,之后运用上下解方法研究α,β≤1,pq≤(1-α)(1-β)时解的全局存在性.     

Replication of the neurochemical characteristics of Huntington's disease by quinolinic acid

Huntington's disease (HD) is an autosomal dominant neurological disorder characterized by progressive chorea, cognitive impairment and emotional disturbance. The disease usually occurs in midlife and symptoms progress inexorably to mental and physical incapacitation. It has been postulated that an excitotoxin is involved in the pathogenesis of HD. Schwarcz and colleagues have shown that quinolinic acid (QA) can produce axon-sparing lesions similar to those observed in HD. The lesions result in a depletion of neurotransmitters contained within striatal spiny neurones, for example gamma-aminobutyric acid (GABA), while dopamine is unaffected. Recently, we and others have demonstrated that in HD striatum there is a paradoxical 3-5-fold increase in both somatostatin and neuropeptide Y which is attributable to selective preservation of a subclass of striatal aspiny neurones in which these peptides are co-localized. In the present study we demonstrate that lesions due to quinolinic acid closely resemble those of HD as they result in marked depletions of both GABA and substance P, with selective sparing of somatostatin/neuropeptide Y neurones. Lesions produced by kainic acid (KA), ibotenic acid (IA) and N-methyl-D-aspartate (MeAsp) were unlike those produced by QA, as they affected all cell types without sparing somatostatin/neuropeptide Y neurones. These results suggest that QA or a similar compound could be responsible for neuronal degeneration in HD.     

Towards a transgenic model of Huntington's disease in a non-human primate

Non-human primates are valuable for modelling human disorders and for developing therapeutic strategies; however, little work has been reported in establishing transgenic non-human primate models of human diseases. Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor impairment, cognitive deterioration and psychiatric disturbances followed by death within 10-15 years of the onset of the symptoms. HD is caused by the expansion of cytosine-adenine-guanine (CAG, translated into glutamine) trinucleotide repeats in the first exon of the human huntingtin (HTT) gene. Mutant HTT with expanded polyglutamine (polyQ) is widely expressed in the brain and peripheral tissues, but causes selective neurodegeneration that is most prominent in the striatum and cortex of the brain. Although rodent models of HD have been developed, these models do not satisfactorily parallel the brain changes and behavioural features observed in HD patients. Because of the close physiological, neurological and genetic similarities between humans and higher primates, monkeys can serve as very useful models for understanding human physiology and diseases. Here we report our progress in developing a transgenic model of HD in a rhesus macaque that expresses polyglutamine-expanded HTT. Hallmark features of HD, including nuclear inclusions and neuropil aggregates, were observed in the brains of the HD transgenic monkeys. Additionally, the transgenic monkeys showed important clinical features of HD, including dystonia and chorea. A transgenic HD monkey model may open the way to understanding the underlying biology of HD better, and to the development of potential therapies. Moreover, our data suggest that it will be feasible to generate valuable non-human primate models of HD and possibly other human genetic diseases.     

Global mean temperature changes during the last millennium

A synthetic study is made on the global or hemispheric mean temperature series for the last millennium worked out by Mann et al., Jones et al., Crowley and Lowery, and Briffa. The global mean temperature series reconstructed by using proxy data at 30 sites by Wang et al. and simulations from AD 1000 to 2000 by energy balance model are described and compared with the series of others. Wang's series gives greater variability and shows the highest correlation coefficient (0.83) with the simulation results. Uncertainties in the reconstructions and simulations are discussed. The errors in reconstructing a global mean temperature series according to 30 sites as used in the research are estimated. Wang's series indicate that temperature average for the 11th century is higher than the mean of the last millennium. It infers that the Medieval Warm Period predominated to some extent over the globe. However, the 20th century is no doubt the warmest century during the last millennium.     

Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease.

Huntington's disease is an autosomal-dominant progressive neurodegenerative disorder resulting in specific neuronal loss and dysfunction in the striatum and cortex. The disease is universally fatal, with a mean survival following onset of 15-20 years and, at present, there is no effective treatment. The mutation in patients with Huntington's disease is an expanded CAG/polyglutamine repeat in huntingtin, a protein of unknown function with a relative molecular mass of 350,000 (M(r) 350K). The length of the CAG/polyglutamine repeat is inversely correlated with the age of disease onset. The molecular pathways mediating the neuropathology of Huntington's disease are poorly understood. Transgenic mice expressing exon 1 of the human huntingtin gene with an expanded CAG/polyglutamine repeat develop a progressive syndrome with many of the characteristics of human Huntington's disease. Here we demonstrate evidence of caspase-1 activation in the brains of mice and humans with the disease. In this transgenic mouse model of Huntington's disease, expression of a dominant-negative caspase-1 mutant extends survival and delays the appearance of neuronal inclusions, neurotransmitter receptor alterations and onset of symptoms, indicating that caspase-1 is important in the pathogenesis of the disease. In addition, we demonstrate that intracerebroventricular administration of a caspase inhibitor delays disease progression and mortality in the mouse model of Huntington's disease.     

Motor disorder in Huntington's disease begins as a dysfunction in error feedback control

A steady progression of motor dysfunction takes place in Huntington's disease (HD). The origin of this disturbance with relation to the motor control process is not understood. Here we studied reaching movements in asymptomatic HD gene-carriers (AGCs) and subjects with manifest HD. We found that movement jerkiness, which characterizes the smoothness and efficiency of motion, was a sensitive indicator of presymptomatic HD progression. A large fraction of AGCs displayed elevated jerk even when more than seven years remained until predicted disease onset. Movement termination was disturbed much more than initiation and was highly variable from trial to trial. Analysis of this variability revealed that the sensitivity of end-movement jerk to subtle, self-generated early-movement errors was greater in HD subjects than in controls. Additionally, we found that HD corrective responses to externally-generated force pulses were greatly disturbed, indicating that HD subjects display aberrant responses to both external and self-generated errors. Because feedback corrections are driven by error and are delayed such that they predominantly affect movement termination, these findings suggest that a dysfunction in error correction characterizes the motor control deficit in early HD. This dysfunction may be observed years before clinical disease onset and grows worse as the disease progresses.     

Lorenz超混沌系统的全局同步控制

研究了Lorenz超混沌系统的混沌同步问题,利用非线性反馈控制方法,设计了几个实现超混沌同步的控制器,结合李雅普诺夫稳定性理论证明了在混沌同步控制器作用下,驱动和相应混沌系统可以实现全局同步;数值仿真结果表明,所设计的混沌控制器能有效地实现混沌同步,并且具有很强的鲁棒性。     

The tails of ubiquitin precursors are ribosomal proteins whose fusion to ubiquitin facilitates ribosome biogenesis

Three of the four yeast ubiquitin genes encode hybrid proteins which are cleaved to yield ubiquitin and previously unidentified ribosomal proteins. The transient association between ubiquitin and these proteins promotes their incorporation into nascent ribosomes and is required for efficient ribosome biogenesis. These results suggest a novel 'chaperone' function for ubiquitin, in which its covalent association with other proteins promotes the formation of specific cellular structures.