Shortened primary cilium length and dysregulated Sonic hedgehog signaling in Niemann-Pick C1 disease

The Niemann-Pick type C1 (NPC1) disease is a neurodegenerative lysosomal storage disorder due to mutations in the NPC1 gene, encoding a transmembrane protein related to the Sonic hedgehog receptor, Patched, and involved in intracellular trafficking of cholesterol. We have recently found that the proliferation of cerebellar granule neuron precursors is significantly reduced in Npc1-/- mice due to the downregulation of Shh expression. This finding prompted us to analyze the formation of the primary cilium, a non-motile organelle that is specialized for Shh signal transduction and responsible, when defective, for several human genetic disorders. In this study, we show that the expression and subcellular localization of Shh effectors and ciliary proteins are severely disturbed in Npc1-deficient mice. The dysregulation of Shh signaling is associated with a shortening of the primary cilium length and with a reduction of the fraction of ciliated cells in Npc1-deficient mouse brains and the human fibroblasts of NPC1 patients. These defects are prevented by treatment with 2-hydroxypropyl-β-cyclodextrin, a promising therapy currently under clinical investigation. Our findings indicate that defective Shh signaling is responsible for abnormal morphogenesis of the cerebellum of Npc1-deficient mice and show, for the first time, that the formation of the primary cilium is altered in NPC1 disease

Embryonic origin and genetic basis of cave associated phenotypes in the isopod crustacean Asellus aquaticus.

Characteristics common to animals living in subterranean environments include the reduction or absence of eyes, lessened pigmentation and enhanced sensory systems. How these characteristics have evolved is poorly understood for the majority of cave dwelling species. In order to understand the evolution of these changes, this study uses an invertebrate model system, the freshwater isopod crustacean, Asellus aquaticus, to examine whether adult differences between cave and surface dwelling individuals first appear during embryonic development. We hypothesized that antennal elaboration, as well as eye reduction and pigment loss, would be apparent during embryonic development. We found that differences in pigmentation, eye formation, and number of segments of antenna II were all present by the end of embryonic development. In addition, we found that cave and surface hatchlings do not significantly differ in the relative size of antenna II and the duration of embryonic development. To investigate whether the regions responsible for eye and pigment differences could be genetically linked to differences in article number, we genotyped F2 hybrids for the four previously mapped genomic regions associated with eye and pigment differences and phenotyped these F2 hybrids for antenna II article number. We found that the region previously known to be responsible for both presence versus absence of pigment and eye size also was significantly associated with article number. Future experiments will address whether pleiotropy and/or genetic linkage play a role in the evolution of cave characteristics in Asellus aquaticus

Junior Recital

List of performers and performances

Convocation

List of performers and performances

Wednesday Convocation

Program listing performers and works performe

AMI observations of Lynds Dark Nebulae: further evidence for anomalous cm-wave emission

Observations at 14.2 to 17.9 GHz made with the AMI Small Array towards fourteen Lynds Dark Nebulae with a resolution of 2' are reported. These sources are selected from the SCUBA observations of Visser et al. (2001) as small angular diameter clouds well matched to the synthesized beam of the AMI Small Array. Comparison of the AMI observations with radio observations at lower frequencies with matched uv-plane coverage is made, in order to search for any anomalous excess emission which can be attributed to spinning dust. Possible emission from spinning dust is identified as a source within a 2' radius of the Scuba position of the Lynds dark nebula, exhibiting an excess with respect to lower frequency radio emission. We find five sources which show a possible spinning dust component in their spectra. These sources have rising spectral indices in the frequency range 14.2--17.9 GHz. Of these five one has already been reported, L1111, we report one new definite detection, L675, and three new probable detections (L944, L1103 and L1246). The relative certainty of these detections is assessed on the basis of three criteria: the extent of the emission, the coincidence of the emission with the Scuba position and the likelihood of alternative explanations for the excess. Extended microwave emission makes the likelihood of the anomalous emission arising as a consequence of a radio counterpart to a protostar or a proto-planetary disk unlikely. We use a 2' radius in order to be consistent with the IRAS identifications of dark nebulae (Parker 1988), and our third criterion is used in the case of L1103 where a high flux density at 850 microns relative to the FIR data suggests a more complicated emission spectrum.Comment: submitted MNRA

Obesity and gambling: neurocognitive and clinical associations.

OBJECTIVE: Research on health correlates in gamblers has found an association between gambling and obesity. The neurocognitive underpinnings of impulsivity may be useful targets for understanding and ultimately treating individuals with both gambling and obesity problems. METHOD: 207 non-treatment seeking young adults (18-29 years) with subsyndromal gambling disorder were recruited from the community. Subjects were grouped according to weight ('normal weight' BMI<25, 'overweight' BMI≥25; or 'obese' BMI≥30). Measures relating to gambling behaviour and objective computerized neurocognitive measures were collected. RESULTS: Of the 207 subjects, 22 (10.6%) were obese and 49 (23.7%) were overweight. The obese gamblers consumed more nicotine (packs per day equivalent) and reported losing more money per week to gambling. Obese gamblers exhibited significant impairments in terms of reaction times for go trials on the stop-signal test (SST), quality of decision making and risk adjustment on the Cambridge Gamble Test (CGT), and sustained attention on the rapid visual information processing task (RVP). CONCLUSION: Obesity was associated with decision making and sustained attention impairments in gamblers, along with greater monetary loss due to gambling. Future work should use longitudinal designs to examine the temporal relationship between these deficits, weight, other impulsive behaviour, and functional impairment.This research was supported by a Center for Excellence in Gambling Research grant by the National Center for Responsible Gaming to Dr. Grant.This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1111/acps.1235

第806回 千葉医学会・第10回 歯科口腔外科例会 20.

Niemann-Pick type C1 (NPC1) disease is a lysosomal storage disorder caused by defective intracellular trafficking of exogenous cholesterol. Purkinje cell (PC) degeneration is the main sign of cerebellar dysfunction in both NPC1 patients and animal models. It has been recently shown that a significant decrease in Sonic hedgehog (Shh) expression reduces the proliferative potential of granule neuron precursors in the developing cerebellum of Npc1 (-/-) mice. Pursuing the hypothesis that this developmental defect translates into functional impairments, we have assayed Npc1-deficient pups belonging to the milder mutant mouse strain Npc1 (nmf164) for sensorimotor development from postnatal day (PN) 3 to PN21. Npc1 (nmf164) / Npc1 (nmf164) pups displayed a 2.5-day delay in the acquisition of complex motor abilities compared to wild-type (wt) littermates, in agreement with the significant disorganization of cerebellar cortex cytoarchitecture observed between PN11 and PN15. Compared to wt, Npc1 (nmf164) homozygous mice exhibited a poorer morphological differentiation of Bergmann glia (BG), as indicated by thicker radial shafts and less elaborate reticular pattern of lateral processes. Also BG functional development was defective, as indicated by the significant reduction in GLAST and Glutamine synthetase expression. A reduced VGluT2 and GAD65 expression also indicated an overall derangement of the glutamatergic/GABAergic stimulation that PCs receive by climbing/parallel fibers and basket/stellate cells, respectively. Lastly, Npc1-deficiency also affected oligodendrocyte differentiation as indicated by the strong reduction of myelin basic protein. Two sequential 2-hydroxypropyl-β-cyclodextrin administrations at PN4 and PN7 counteract these defects, partially preventing functional impairment of BG and fully restoring the normal patterns of glutamatergic/GABAergic stimulation to PCs.These findings indicate that in Npc1 (nmf164) homozygous mice the derangement of synaptic connectivity and dysmyelination during cerebellar morphogenesis largely anticipate motor deficits that are typically observed during adulthood

Hubble Space Telescope NICMOS Polarization Measurements of OMC-1

We present 2micron polarization measurements of positions in the BN region of the Orion Molecular Cloud (OMC-1) made with NICMOS Camera 2 (0.2'' resolution) on HST. Our results are as follows: BN is sim 29% polarized by dichroic absorption and appears to be the illuminating source for most of the nebulosity to its north and up to sim 5'' to its south. Although the stars are probably all polarized by dichroic absorption, there are a number of compact, but non-point-source, objects that could be polarized by a combination of both dichroic absorption and local scattering of star light. We identify several candidate YSOs, including an approximately edge-on bipolar YSO 8.7'' east of BN, and a deeply-embedded variable star. Additional strongly polarized sources are IRc2-B, IRc2-D, and IRc7, all of which are obviously self-luminous at mid-infrared wavelengths and may be YSOs. None of these is a reflection nebula illuminated by a star located near radio source I, as was previously suggested. Other IRc sources are clearly reflection nebulae: IRc3 appears to be illuminated by IRc2-B or a combination of the IRc2 sources, and IRc4 and IRc5 appear to be illuminated by an unseen star in the vicinity of radio source I, or by Star n or IRc2-A. Trends in the magnetic field direction are inferred from the polarization of the 26 stars that are bright enough to be seen as NICMOS point sources. The most polarized star has a polarization position angle different from its neighbors by sim 40^o, but in agreement with the grain alignment inferred from millimeter polarization measurements of the cold dust cloud in the southern part of OMC-1.Comment: 41 pages, 8 figures, 4 tables, to appear in The Astrophysical Journa

Oral immunization with pBsVP6-transgenic alfalfa protects mice against rotavirus infection

AbstractA critical factor in edible plant-derived vaccine development is adequate expression of the exogenous antigens in transgenic plants. We synthesized a codon-optimized gene (sVP6) encoding the VP6 protein of human group A rotavirus and inserted it into the alfalfa genome using agrobacterium-mediated transformation. As much as 0.28% of the total soluble protein of the pBsVP6-transgenic alfalfa was sVP6. Female BALB/c mice were gavaged weekly with 10 mg of transgenic alfalfa extract containing 24 μg of sVP6 protein and 10 μg of CpG-rich oligodeoxynucleotides as mucosal adjuvant. Immunized mice developed high titers of anti-VP6 serum IgG and mucosal IgA. Offspring of immunized dams developed less severe diarrhea after challenge with simian rotavirus SA-11, indicating that antibodies generated in the dams provided passive heterotypic protection to the pups. These results suggest that oral immunization with pBsVP6-transgenic alfalfa provides a potential means of protecting children and young animals from severe acute rotavirus-induced diarrhea