Spatial learning impairments in PLB1Triple knock-in Alzheimer mice are task-specific and age-dependent

We recently generated an advanced mouse model of Alzheimer’s disease (AD) by targeted knock-in of single-copy mutated human amyloid precursor-protein (APP) and tau genes, crossed with a non-symptomatic presenilin (PS1A246E) over-expressing mouse line. These PLB1_Triple mice presented with age-dependent and AD-relevant phenotypes. Homozygous PLB1_Triple mice aged 4–12 months were assessed here in a battery of spatial learning tasks: Exp.1 radial-arm water maze (spatial reference and working memory) Exp.2 open-field water maze (spatial reference memory); Exp.3 home cage observation system with spatial learning (IntelliCage); Exp.4 spontaneous object recognition (SOR; novel object and spatial object shift). A separate test with high-expression transgenic APP mice matching the design of experiment 1 was also performed. Spatial deficits in PLB1_Triple mice were confirmed at 12, but not 4 months in both water maze tasks. PSAPP mice, by contrast, presented with severe yet non-progressive spatial learning deficits already at 4 months. During tests of spatial learning in SOR and IntelliCage, PLB1_Triple mice neither acquired the location of the water-rewarded corner, nor recognize novel or spatially shifted objects at 4 months, indicating these protocols to be more sensitive than the water maze. Collectively and in line with AD symptomatology, PLB1_Triple mice present with a graded and progressive age-dependent loss of spatial memory that can be revealed by the use of a battery of tasks. With the emergence of subtle deficits progressively increasing in severity, PLB1_Triple mice may offer a more patho-physiologically relevant model of dementia than aggressive expression models.     

DNA sequence and analysis of human chromosome 8

The International Human Genome Sequencing Consortium (IHGSC) recently completed a sequence of the human genome. As part of this project, we have focused on chromosome 8. Although some chromosomes exhibit extreme characteristics in terms of length, gene content, repeat content and fraction segmentally duplicated, chromosome 8 is distinctly typical in character, being very close to the genome median in each of these aspects. This work describes a finished sequence and gene catalogue for the chromosome, which represents just over 5% of the euchromatic human genome. A unique feature of the chromosome is a vast region of approximately 15 megabases on distal 8p that appears to have a strikingly high mutation rate, which has accelerated in the hominids relative to other sequenced mammals. This fast-evolving region contains a number of genes related to innate immunity and the nervous system, including loci that appear to be under positive selection--these include the major defensin (DEF) gene cluster and MCPH1, a gene that may have contributed to the evolution of expanded brain size in the great apes. The data from chromosome 8 should allow a better understanding of both normal and disease biology and genome evolution.     

Transduction of endogenous envelope genes by feline leukaemia virus in vitro

Feline leukaemia viruses (FeLV) are exogenous retroviruses that can be detected in most cats with leukaemia, aplastic anaemia, myeloproliferative diseases and fatal immunosuppression. FeLV isolates have been divided into three subgroups, based on the viral envelope-determined properties of interference and host range in vitro. FeLV-A is present in all natural isolates and is generally minimally pathogenic. FeLV-B is found with FeLV-A in isolates from approximately 40% of natural infections and in a higher percentage of cats with lymphoma. Following the fundamental observations of genetic reassortment of avian retroviruses with endogenous viral genes and the origination of lymphomagenic viruses during the ontogeny of AKR mice, we show here that transfection of feline cells with FeLV-A DNA results in its recombination with endogenous FeLV-related sequences to produce viruses with the structural and host range properties of FeLV-B. Thus in vitro propagation of a retrovirus may result in the generation of variants with very different properties.     

Sequence and analysis of chromosome 2 of Dictyostelium discoideum

The genome of the lower eukaryote Dictyostelium discoideum comprises six chromosomes. Here we report the sequence of the largest, chromosome 2, which at 8 megabases (Mb) represents about 25% of the genome. Despite an A + T content of nearly 80%, the chromosome codes for 2,799 predicted protein coding genes and 73 transfer RNA genes. This gene density, about 1 gene per 2.6 kilobases (kb), is surpassed only by Saccharomyces cerevisiae (one per 2 kb) and is similar to that of Schizosaccharomyces pombe (one per 2.5 kb). If we assume that the other chromosomes have a similar gene density, we can expect around 11,000 genes in the D. discoideum genome. A significant number of the genes show higher similarities to genes of vertebrates than to those of other fully sequenced eukaryotes. This analysis strengthens the view that the evolutionary position of D. discoideum is located before the branching of metazoa and fungi but after the divergence of the plant kingdom, placing it close to the base of metazoan evolution.     

Mutations in the gene encoding epsilon-sarcoglycan cause myoclonus-dystonia syndrome

The dystonias are a common clinically and genetically heterogeneous group of movement disorders. More than ten loci for inherited forms of dystonia have been mapped, but only three mutated genes have been identified so far. These are DYT1, encoding torsin A and mutant in the early-onset generalized form, GCH1 (formerly known as DYT5), encoding GTP-cyclohydrolase I and mutant in dominant dopa-responsive dystonia, and TH, encoding tyrosine hydroxylase and mutant in the recessive form of the disease. Myoclonus-dystonia syndrome (MDS; DYT11) is an autosomal dominant disorder characterized by bilateral, alcohol-sensitive myoclonic jerks involving mainly the arms and axial muscles. Dystonia, usually torticollis and/or writer's cramp, occurs in most but not all affected patients and may occasionally be the only symptom of the disease. In addition, patients often show prominent psychiatric abnormalities, including panic attacks and obsessive-compulsive behavior. In most MDS families, the disease is linked to a locus on chromosome 7q21 (refs. 11-13). Using a positional cloning approach, we have identified five different heterozygous loss-of-function mutations in the gene for epsilon-sarcoglycan (SGCE), which we mapped to a refined critical region of about 3.2 Mb. SGCE is expressed in all brain regions examined. Pedigree analysis shows a marked difference in penetrance depending on the parental origin of the disease allele. This is indicative of a maternal imprinting mechanism, which has been demonstrated in the mouse epsilon-sarcoglycan gene.     

Cloning of HTLV-4 and its relation to simian and human immunodeficiency viruses

Although much is now known of the strain variation among the type-1 human immunodeficiency virus (HIV-1), which is the cause of AIDS (acquired immune deficiency syndrome) in the United States, Europe, and Central Africa, much less is yet known about a second group of viruses that have been found in West Africans. One member of this group, named human T-cell lymphotropic virus type 4 (HTLV-4), has been isolated from healthy Senegalese. Another is the virus isolated from West Africans with AIDS-like illness and originally called LAV-2 but now renamed HIV-2. Both these viruses seem to be less closely related to HIV-1 than they are to a virus of healthy African green monkeys, known variously as simian T-cell lymphotropic virus type 3 (STLV-3) or simian immunodeficiency virus (SIV), which in turn is related to viruses isolated from healthy sooty mangabeys and captive macaques with a form of immunodeficiency (to distinguish these viruses they are referred to as STLV-3 (or SIV)agm, STLV-3mac, or STLV-3smm). To clarify the relationship between the various HIVs, STLV-3s and HTLV-4 we are determining and comparing the molecular and biological characteristics of several of them. Following our recent publication of a restriction-site map of STLV-3agm, we now report that the equivalent map of three isolates of HTLV-4 is remarkably similar to it. In addition we present comparative sequence data on the long terminal repeats (LTR) of HTLV-4, STLV-3agm, HIV-1 and HIV-2, together with evidence that cloned HTLV-4 uses the same receptor as HIV-1 and induces some, but not all, of the cytopathic effects attributed to most isolates of HIV-1 and HIV-2.     

Non-uniformity of regional vasomotor activity indicating the existence of 2 different systems in the sympathetic cardiovascular outflow

Summary In rabbits, 2 populations of sympathetic postganlionic fibres innervating the skin, heart, muscle and kidney could be classified by their different spike heights and their different susceptibility to noradrenaline and angiotensin amide. The ability of the 2 populations to respond to physiological stimuli in a highly differentiated manner leads to the assumption that 2 different systems in the cardiovascular sympathetic outflow exist.