The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease

The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (Abeta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Abeta-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.     

Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome

Protein-protein interaction analyses have uncovered a ciliary and basal body protein network that, when disrupted, can result in nephronophthisis (NPHP), Leber congenital amaurosis, Senior-L?ken syndrome (SLSN) or Joubert syndrome (JBTS). However, details of the molecular mechanisms underlying these disorders remain poorly understood. RPGRIP1-like protein (RPGRIP1L) is a homolog of RPGRIP1 (RPGR-interacting protein 1), a ciliary protein defective in Leber congenital amaurosis. We show that RPGRIP1L interacts with nephrocystin-4 and that mutations in the gene encoding nephrocystin-4 (NPHP4) that are known to cause SLSN disrupt this interaction. RPGRIP1L is ubiquitously expressed, and its protein product localizes to basal bodies. Therefore, we analyzed RPGRIP1L as a candidate gene for JBTS and identified loss-of-function mutations in three families with typical JBTS, including the characteristic mid-hindbrain malformation. This work identifies RPGRIP1L as a gene responsible for JBTS and establishes a central role for cilia and basal bodies in the pathophysiology of this disorder.     

Gastrointestinal helminths of nine species of Cnemaspis (Squamata: Gekkonidae) from Peninsular Malaysia,one species from Cambodia and Thailand and two species from Vietnam

A total of 12 species of Cnemaspis (N = 104) from Southeast Asia were examined for gastrointestinal helminths. Samples consisted of nine species (n = 86) from Peninsular Malaysia: Cnemaspis affinis (n = 4); Cnemaspis baueri (n = 17); Cnemaspis biocellata (n = 12); Cnemaspis grismeri (n = 8); Cnemaspis kumpoli (n = 11); Cnemaspis limi (n = 9): Cnemaspis monachorum (n = 7); Cnemaspis pemanggilensis (n = 10); Cnemaspis peninsularis (n = 8); one species (n = 5) from Cambodia and Thailand, Cnemaspis chanthaburiensis (n = 5); and two species (n = 13) from Vietnam: Cnemaspis nuicamensis (n = 6) and Cnemaspis tucdupensis (n = 7). The aggregate helminth community consisted of one species of Cestoda, Cylindrotaenia malayi and nine species of Nematoda: Bakeria schadi, Meteterakis singaporensis, Parapharyngodon maplestoni, Maxvachonia sp., Physalopteroides sp., Physalopteridae gen. sp., Riticulariidae gen. sp., Seuratoidea gen. sp., Ascaridoidea gen. sp. Meteterakis singaporensis had the largest number of individuals (457) and greatest prevalence (24%). Twenty-eight new host records are reported.     

AOP event manager in open service gateway 〖WT5"HZ〗Abstract:〖WT5"BZ〗 〖WT5”HZ〗Key words:〖WT5”BZ〗

The Open Service Gateway Initiative (OSGi) has played an important role in ubiquitous environments that support interoperability among embedded devices, such as home appliances and network devices. However, the OSGi does not have a common event mechanism yet, and it is difficult to communicate among services asynchronously. In the present work, a common event manager, AspectOriented Event Manager (AOEM), was designed on an OSGi framework. AOEM supports services to generate and provide notification of events. This paper presents the implementation of AOEM as an OSGi bundle with AspectJ. The experiment on transferring between device service and application service demonstrate that AOEM provides good abstraction of the services and convenience.     

Interleukin-33 stimulates formation of functional osteoclasts from human CD14+ monocytes

Interleukin (IL)-33 is a recently described pro-inflammatory cytokine. Here we demonstrate IL-33 as a regulator of functional osteoclasts (OCs) from human CD14⁺ monocytes. IL-33 stimulates formation of tartrate-resistant acid phosphatase (TRAP)⁺ multinuclear OCs from monocytes. This action was suppressed by anti-ST2 antibody, suggesting that IL-33 acts through its receptor ST2, but not by the receptor activator of NF-κB ligand (RANKL) decoy, osteoprotegerin, or anti-RANKL antibody. IL-33 stimulated activating phosphorylations of signaling molecules in monocytes that are critical for OC development. These included Syk, phospholipase Cγ2, Gab2, MAP kinases, TAK-1, and NF-κB. IL-33 also enhanced expression of OC differentiation factors including TNF-α receptor-associated factor 6 (TRAF6), nuclear factor of activated T cells cytoplasmic 1, c-Fos, c-Src, cathepsin K, and calcitonin receptor. IL-33 eventually induced bone resorption. This study suggests that the osteoclastogenic property of IL-33 is mediated through TRAF6 as well as the immunoreceptor tyrosine-based activation motif-dependent Syk/PLCγ pathway in human CD14⁺ monocytes.     

Multispecies-compatible antitumor effects of a cross-species small-interfering RNA against mammalian target of rapamycin

Successful development of sequence-specific siRNA (small interfering RNA)-based drugs requires an siRNA design that functions consistently in different organisms. Utilizing the CAPSID program previously developed by our group, we here designed siRNAs against mammalian target of rapamycin (mTOR) that are entirely complementary among various species and investigated their multispecies-compatible gene-silencing properties. The mTOR siRNAs markedly reduced mTOR expression at both the mRNA and protein levels in human, mouse, and monkey cell lines. The reduction in mTOR expression resulted in inactivation of both mTOR complex I and II signaling pathways, as confirmed by reduced phosphorylation of p70S6K (70-kDa ribosomal protein S6 kinase), 4EBP1 (eIF4E-binding protein 1), and AKT, and nuclear accumulation of FOXO1 (forkhead box O1), with consequent cell-cycle arrest, proliferation inhibition, and autophagy activation. Moreover, interfering with mTOR activity in vivo using mTOR small-hairpin RNA-expressing recombinant adeno-associated virus led to significant antitumor effects in xenograft and allograft models. Thus, the present study demonstrates that cross-species siRNA successfully silences its target and readily produces multispecies-compatible phenotypic alterations-antitumor effects in the case of mTOR siRNA. Application of cross-species siRNA should greatly facilitate the development of siRNA-based therapeutic agents.     

Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs

Schizophrenia is a complex disorder caused by both genetic and environmental factors. Using 9,087 affected individuals, 12,171 controls and 915,354 imputed SNPs from the Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium (PGC-SCZ), we estimate that 23% (s.e. = 1%) of variation in liability to schizophrenia is captured by SNPs. We show that a substantial proportion of this variation must be the result of common causal variants, that the variance explained by each chromosome is linearly related to its length (r = 0.89, P = 2.6 × 10(-8)), that the genetic basis of schizophrenia is the same in males and females, and that a disproportionate proportion of variation is attributable to a set of 2,725 genes expressed in the central nervous system (CNS; P = 7.6 × 10(-8)). These results are consistent with a polygenic genetic architecture and imply more individual SNP associations will be detected for this disease as sample size increases.     

Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome

IMAGe syndrome (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies) is an undergrowth developmental disorder with life-threatening consequences. An identity-by-descent analysis in a family with IMAGe syndrome identified a 17.2-Mb locus on chromosome 11p15 that segregated in the affected family members. Targeted exon array capture of the disease locus, followed by high-throughput genomic sequencing and validation by dideoxy sequencing, identified missense mutations in the imprinted gene CDKN1C (also known as P57KIP2) in two familial and four unrelated patients. A familial analysis showed an imprinted mode of inheritance in which only maternal transmission of the mutation resulted in IMAGe syndrome. CDKN1C inhibits cell-cycle progression, and we found that targeted expression of IMAGe-associated CDKN1C mutations in Drosophila caused severe eye growth defects compared to wild-type CDKN1C, suggesting a gain-of-function mechanism. All IMAGe-associated mutations clustered in the PCNA-binding domain of CDKN1C and resulted in loss of PCNA binding, distinguishing them from the mutations of CDKN1C that cause Beckwith-Wiedemann syndrome, an overgrowth syndrome.