No cold dust within the supernova remnant Cassiopeia A

A large amount (about three solar masses) of cold (18 K) dust in the prototypical type II supernova remnant Cassiopeia A was recently reported. It was concluded that dust production in type II supernovae can explain how the large quantities (10^8 solar masses) of dust observed in the most distant quasars could have been produced within only 700 million years after the Big Bang. Foreground clouds of interstellar material, however, complicate the interpretation of the earlier submillimetre observations of Cas A. Here we report far-infrared and molecular line observations that demonstrate that most of the detected submillimetre emission originates from interstellar dust in a molecular cloud complex located in the line of sight between the Earth and Cas A, and is therefore not associated with the remnant. The argument that type II supernovae produce copious amounts of dust is not supported by the case of Cas A, which previously appeared to provide the best evidence for this possibility.Comment: 13 pages, 3 figure

Multifunctional biophotonic nanostructures inspired by the longtail glasswing butterfly for medical devices

Numerous living organisms possess biophotonic nanostructures that provide colouration and other diverse functions for survival. While such structures have been actively studied and replicated in the laboratory, it remains unclear whether they can be used for biomedical applications. Here, we show a transparent photonic nanostructure inspired by the longtail glasswing butterfly (Chorinea faunus) and demonstrate its use in intraocular pressure (IOP) sensors in vivo. We exploit the phase separation between two immiscible polymers (poly(methyl methacrylate) and polystyrene) to form nanostructured features on top of a Si3_N_4 substrate. The membrane thus formed shows good angle-independent white-light transmission, strong hydrophilicity and anti-biofouling properties, which prevent adhesion of proteins, bacteria and eukaryotic cells. We then developed a microscale implantable IOP sensor using our photonic membrane as an optomechanical sensing element. Finally, we performed in vivo testing on New Zealand white rabbits, which showed that our device reduces the mean IOP measurement variation compared with conventional rebound tonometry without signs of inflammation

Agalsidase beta treatment is associated with improved quality of life in patients with Fabry disease: Findings from the Fabry Registry

Purpose: To evaluate the effect of agalsidase beta on longitudinal health-related quality of life in patients with Fabry disease. Methods: the SF-36 (R) Health Survey was used to measure health-related quality of life in Fabry Registry patients. Seventy-one men and 59 women who were treated with agalsidase beta (median dose: 1.0 mg/kg/2 weeks) and who had baseline and at least 2 yearly posttreatment health-related quality of life measurements were included in these analyses. A repeated measures model was used to analyze change in score from baseline. Results: Men improved in the physical component summary and in all eight scales of the SF-36 after 1 and 2 years and in the mental component summary after 1 year of agalsidase beta treatment (P < 0.05). Women improved in the mental component summary and in six of the eight scales after 1 and/or 2 years of treatment. Patients whose baseline SF-36 scores were below the median showed the greatest improvements. These responses were comparable with or greater than the published effects of various treatments for multiple sclerosis, rheumatoid arthritis, central neuropathic pain, and Gaucher disease. Conclusion: Long-term treatment with agalsidase beta resulted in substantial improvements in health-related quality of life in both men and women; the effect was more pronounced in men. Genet Med 2010:12(11):703 712.Genzyme CorporationGenzymeNatl Univ Hosp, Dept Endocrinol, DK-2100 Copenhagen, DenmarkSan Bassano Hosp, Dept Neurol, Bassano Del Grappa, ItalyUniv Padua, Dept Neurosci, Padua, ItalyUniv Wurzburg, Dept Med, Wurzburg, GermanyColumbia Univ, Dept Pediat, Div Clin Genet, Coll Phys & Surg, New York, NY 10027 USACincinnati Childrens Hosp, Div Human Genet, Cincinnati, OH USAUniversidade Federal de São Paulo, Inatos Metab CREIM, São Paulo, BrazilMassachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USAGenzyme Corp, Dept Biomed Data Sci & Informat, Cambridge, MA USAUniversidade Federal de São Paulo, Inatos Metab CREIM, São Paulo, BrazilWeb of Scienc

Characteristics of Mothers Caring for Children During Episodes of Homelessness

This study provides a description of the physical, psychological, and substance use problems of adult homeless women who are and are not caring for children. We also examined differences in the characteristics of these two groups of women. Interviews were conducted with 148 homeless women from three mid-sized U.S. cities, 24.3% of whom were caring for at least one child. Our results showed that women caring for children were more likely to be sheltered and have health insurance. Homeless women caring for children and solitary homeless women were generally similar in terms of substance abuse problems. However, rates of Borderline Personality Disorder were higher among women caring for children than among solitary homeless women. Our results are somewhat consistent with previous research, with the exception of substance abuse problems and mental health problems, which were shown to be equally problematic for all women, regardless of current caregiving status

Activation of mGlu3 Receptors Stimulates the Production of GDNF in Striatal Neurons

Metabotropic glutamate (mGlu) receptors have been considered potential targets for the therapy of experimental parkinsonism. One hypothetical advantage associated with the use of mGlu receptor ligands is the lack of the adverse effects typically induced by ionotropic glutamate receptor antagonists, such as sedation, ataxia, and severe learning impairment. Low doses of the mGlu2/3 metabotropic glutamate receptor agonist, LY379268 (0.25–3 mg/kg, i.p.) increased glial cell line-derived neurotrophic factor (GDNF) mRNA and protein levels in the mouse brain, as assessed by in situ hybridization, real-time PCR, immunoblotting, and immunohistochemistry. This increase was prominent in the striatum, but was also observed in the cerebral cortex. GDNF mRNA levels peaked at 3 h and declined afterwards, whereas GDNF protein levels progressively increased from 24 to 72 h following LY379268 injection. The action of LY379268 was abrogated by the mGlu2/3 receptor antagonist, LY341495 (1 mg/kg, i.p.), and was lost in mGlu3 receptor knockout mice, but not in mGlu2 receptor knockout mice. In pure cultures of striatal neurons, the increase in GDNF induced by LY379268 required the activation of the mitogen-activated protein kinase and phosphatidylinositol-3-kinase pathways, as shown by the use of specific inhibitors of the two pathways. Both in vivo and in vitro studies led to the conclusion that neurons were the only source of GDNF in response to mGlu3 receptor activation. Remarkably, acute or repeated injections of LY379268 at doses that enhanced striatal GDNF levels (0.25 or 3 mg/kg, i.p.) were highly protective against nigro-striatal damage induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice, as assessed by stereological counting of tyrosine hydroxylase-positive neurons in the pars compacta of the substantia nigra. We speculate that selective mGlu3 receptor agonists or enhancers are potential candidates as neuroprotective agents in Parkinson's disease, and their use might circumvent the limitations associated with the administration of exogenous GDNF

Paired Tumor and Normal Whole Genome Sequencing of Metastatic Olfactory Neuroblastoma

Olfactory neuroblastoma (ONB) is a rare cancer of the sinonasal tract with little molecular characterization. We performed whole genome sequencing (WGS) on paired normal and tumor DNA from a patient with metastatic-ONB to identify the somatic alterations that might be drivers of tumorigenesis and/or metastatic progression.Genomic DNA was isolated from fresh frozen tissue from a metastatic lesion and whole blood, followed by WGS at >30X depth, alignment and mapping, and mutation analyses. Sanger sequencing was used to confirm selected mutations. Sixty-two somatic short nucleotide variants (SNVs) and five deletions were identified inside coding regions, each causing a non-synonymous DNA sequence change. We selected seven SNVs and validated them by Sanger sequencing. In the metastatic ONB samples collected several months prior to WGS, all seven mutations were present. However, in the original surgical resection specimen (prior to evidence of metastatic disease), mutations in KDR, MYC, SIN3B, and NLRC4 genes were not present, suggesting that these were acquired with disease progression and/or as a result of post-treatment effects.This work provides insight into the evolution of ONB cancer cells and provides a window into the more complex factors, including tumor clonality and multiple driver mutations

Common Variants at 9p21 and 8q22 Are Associated with Increased Susceptibility to Optic Nerve Degeneration in Glaucoma

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63–0.75], p = 1.86×10−18), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21–1.43], p = 3.87×10−11). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50–0.67], p = 1.17×10−12) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53–0.72], p = 8.88×10−10). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41–0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54–1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma

Glial Innate Immunity Generated by Non-Aggregated Alpha-Synuclein in Mouse: Differences between Wild-type and Parkinson's Disease-Linked Mutants

Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized pathologically by the presence in the brain of intracellular protein inclusions highly enriched in aggregated alpha-synuclein (alpha-Syn). Although it has been established that progression of the disease is accompanied by sustained activation of microglia, the underlying molecules and factors involved in these immune-triggered mechanisms remain largely unexplored. Lately, accumulating evidence has shown the presence of extracellular alpha-Syn both in its aggregated and monomeric forms in cerebrospinal fluid and blood plasma. However, the effect of extracellular alpha-Syn on cellular activation and immune mediators, as well as the impact of familial PD-linked alpha-Syn mutants on this stimulation, are still largely unknown.Methods and Findings: In this work, we have compared the activation profiles of non-aggregated, extracellular wild-type and PD-linked mutant alpha-Syn variants on primary glial and microglial cell cultures. After stimulation of cells with alpha-Syn, we measured the release of Th1- and Th2-type cytokines as well as IP-10/CXCL10, RANTES/CCL5, MCP-1/CCL2 and MIP-1 alpha/CCL3 chemokines. Contrary to what had been observed using cell lines or for the case of aggregated alpha-Syn, we found strong differences in the immune response generated by wild-type alpha-Syn and the familial PD mutants (A30P, E46K and A53T).Conclusions: These findings might contribute to explain the differences in the onset and progression of this highly debilitating disease, which could be of value in the development of rational approaches towards effective control of immune responses that are associated with PD

Assessing the Association of Mitochondrial Genetic Variation With Primary Open-Angle Glaucoma Using Gene-Set Analyses

PURPOSE: Recent studies indicate that mitochondrial proteins may contribute to the pathogenesis of primary open-angle glaucoma (POAG). In this study, we examined the association between POAG and common variations in gene-encoding mitochondrial proteins. METHODS: We examined genetic data from 3430 POAG cases and 3108 controls derived from the combination of the GLAUGEN and NEIGHBOR studies. We constructed biological-system coherent mitochondrial nuclear-encoded protein gene-sets by intersecting the MitoCarta database with the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. We examined the mitochondrial gene-sets for association with POAG and with normal-tension glaucoma (NTG) and high-tension glaucoma (HTG) subsets using Pathway Analysis by Randomization Incorporating Structure. RESULTS: We identified 22 KEGG pathways with significant mitochondrial protein-encoding gene enrichment, belonging to six general biological classes. Among the pathway classes, mitochondrial lipid metabolism was associated with POAG overall (P = 0.013) and with NTG (P = 0.0006), and mitochondrial carbohydrate metabolism was associated with NTG (P = 0.030). Examining the individual KEGG pathway mitochondrial gene-sets, fatty acid elongation and synthesis and degradation of ketone bodies, both lipid metabolism pathways, were significantly associated with POAG (P = 0.005 and P = 0.002, respectively) and NTG (P = 0.0004 and P < 0.0001, respectively). Butanoate metabolism, a carbohydrate metabolism pathway, was significantly associated with POAG (P = 0.004), NTG (P = 0.001), and HTG (P = 0.010). CONCLUSIONS: We present an effective approach for assessing the contributions of mitochondrial genetic variation to open-angle glaucoma. Our findings support a role for mitochondria in POAG pathogenesis and specifically point to lipid and carbohydrate metabolism pathways as being important