Altered expression of Alzheimer's disease-related genes in the cerebellum of autistic patients: a model for disrupted brain connectome and therapy

Autism and Alzheimer''s disease (AD) are, respectively, neurodevelopmental and degenerative diseases with an increasing epidemiological burden. The AD-associated amyloid-β precursor protein-α has been shown to be elevated in severe autism, leading to the ‘anabolic hypothesis'' of its etiology. Here we performed a focused microarray analysis of genes belonging to NOTCH and WNT signaling cascades, as well as genes related to AD and apoptosis pathways in cerebellar samples from autistic individuals, to provide further evidence for pathological relevance of these cascades for autism. By using the limma package from R and false discovery rate, we demonstrated that 31% (116 out of 374) of the genes belonging to these pathways displayed significant changes in expression (corrected P-values <0.05), with mitochondria-related genes being the most downregulated. We also found upregulation of GRIN1, the channel-forming subunit of NMDA glutamate receptors, and MAP3K1, known activator of the JNK and ERK pathways with anti-apoptotic effect. Expression of PSEN2 (presinilin 2) and APBB1 (or F65) were significantly lower when compared with control samples. Based on these results, we propose a model of NMDA glutamate receptor-mediated ERK activation of α-secretase activity and mitochondrial adaptation to apoptosis that may explain the early brain overgrowth and disruption of synaptic plasticity and connectome in autism. Finally, systems pharmacology analyses of the model that integrates all these genes together (NOWADA) highlighted magnesium (Mg²⁺) and rapamycin as most efficient drugs to target this network model in silico. Their potential therapeutic application, in the context of autism, is therefore discussed.     

Synthetic DNA probes for the identification of sibling species in the Anopheles gambiae complex

The cloned DNA sequences pAna1, pAnq1 and pAnm14, which may be used to distinguish between at least five of the six species in the Anopheles gambiae Giles complex of Afrotropical malaria vector mosquitoes, have been sequenced. Each clone was found to possess a series of repeated sequences of 41, 30 and 163 bases respectively. In pAnq1 and pAnm14 the repeats were in direct tandem array, whilst in pAna1 the repetitive sequence was found to be interspersed by 15-17 variable bases. A comparison of a number of copies of each of the repetitive sequences within the three clones enabled the definition of the consensus sequence for each repetitive element. Based on these consensus sequences, three oligonucleotides of 21, 23 and 26 bases were derived from pAna1, pAnq1 and pAnm14 respectively. When tested as probes against DNA dot-blots and squash-blots of mosquito specimens, each oligonucleotide retained the same species-specificity as the original clones from which they were derived. The radioactively labelled oligonucleotides were able to detect as little as 5 ng of target genomic DNA in an overnight autoradiographic exposure. The synthetic DNA probes will form the basis of a simplified system for the field identification of Anopheles gambiae sibling species specimens.     

Microbial modification of host long-distance dispersal capacity

Background  

Dispersal plays a key role in shaping biological and ecological processes such as the distribution of spatially-structured populations or the pace and scale of invasion. Here we have studied the relationship between long-distance dispersal behaviour of a pest-controlling money spider,Erigone atra, and the distribution of maternally acquired endosymbionts within the wider meta-population. This spider persists in heterogeneous environments because of its ability to recolonise areas through active long-distance airborne dispersal using silk as a sail, in a process termed 'ballooning'.     

Phylogenetic interrelationships,taxonomy, and reductive evolution in the Neotropical electric fish genus Hypopygus (Teleostei,Ostariophysi, Gymnotiformes)

A phylogenetic reconstruction of the Neotropical electric fish genus Hypopygus based on 47 parsimony‐informative morphological characters is presented. A series of synapomorphies support the hypothesis of monophyly of Hypopygus, and partially resolve species‐level relationships within the genus. Hypopygus species are recognized here as miniaturized fishes based on two criteria; first, a derived condition of diminutive body size, and; second, the presence of a suite of reductive morphological characters, including partial or total losses, simplifications, and reductions of the anal‐fin rays, scales, cranial bones, and laterosensory canal system. Reductive characters associated with miniaturization comprise 45% of the total number of characters in the phylogenetic reconstruction of the genus. Miniaturization and reductive morphological evolution in Hypopygus are discussed here in the phylogenetic context. A taxonomic revision of Hypopygus is presented, in which five new species are described, two species previously assigned to the genus are redescribed, and a single known species of Stegostenopos is redescribed and included in Hypopygus as a junior synonym. Distribution maps and a key for all eight valid species of Hypopygus are provided, based on the examination of 5014 catalogued museum specimens. © 2011 The Linnean Society of London, Zoological Journal of the Linnean Society, 2011, 163 , 1096–1156.     

Gradient of distribution in Europe of the major CF mutation and of its associated haplotype

Summary In this collaborative European study, a total of 4871 cystic fibrosis (CF) chromosomes and 3539 normal chromosomes have been characterized for the haplotypes defined by the 2 extragenic polymorphic sequences revealed by XV2c and KM19. The association between one of these haplotypes (B haplotype) and the most frequent CF mutation, ΔF508, suggests for the latter a single origin and a subsequent diffusion according to a South East-North West gradient. The linkage disequilibrium data between CF and the B haplotype in different European populations are compatible with a relatively more recent appearance of the mutation in Northern Europe whereas in Southern Europe a longer history of the same mutation would have allowed time for recombination with other haplotypes. This model is also compatible with a selective advantage of carriers but does not account for (1) the excess of B haplotypes observed among both normal and non-ΔF508 CF chromosomes; (2) the correlation between the B haplotype and the severity of the phenotypic effect caused by CF mutations, as measured by pancreatic insufficiency and meconium ileus.     

DNA probes for species identification of mosquitoes in the Anopheles gambiae complex

Abstract. Identification of species within the Anopheles gambiae Giles species complex is essential for the correct evaluation of malaria vector ecology studies and control programmes. The development of DNA probes to distinguish species of the An.gambiae complex is described. Genomic libraries were prepared for four members of the An.gambiae complex. These were screened using radiolabeled DNA from different species of An. gambiae sensu lato and a number of clones selected on the basis of their species specificity. These clones could be divided into two groups, each containing homologous sequences. Sequences homologous to group 1 inserts are highly reiterated in the genomes of Anopheles arabiensis Patton and Anopheles merus Dönitz, present in low copy number in Anopheles melas Theobald, but were not detected in Anopheles gambiae sensu stricto. Studies on the organization of this sequence in the genome of An.arabiensis show that homologous sequences are male specific and interspersed within the chromatin. Sequences homologous to group 2 inserts are highly repeated in the genomes of An.merus and An.melas, but present in low copy number in An.gambiae s.s. and An.arabiensis. Group 2 homologous sequences are not sex-specific in the species tested and appear to be tandemly repeated. When used as hybridization probes, these sequences provide a sensitive means for the identification of species within the Anopheles gambiae complex.     

Use of a male-specific DNA probe to distinguish female mosquitoes of the Anopheles gambiae species complex

Abstract. A method has been developed to distinguish between mated female individuals of the sibling species Anopheles gambiae Giles sensu stricto and Anopheles arabiensis Patton. The DNA probe pAnal, reported by Gale & Crampton (1987a) to be useful for the specific identification of An.arabiensis males, is here shown to be sufficiently sensitive to deduce the species identity of inseminated females from the identity of the sperm contained within the spermatheca.