Close Cassini flybys of Saturn's ring moons Pan, Daphnis, Atlas, Pandora, and Epimetheus.

Saturn's main ring system is associated with a set of small moons that either are embedded within it or interact with the rings to alter their shape and composition. Five close flybys of the moons Pan, Daphnis, Atlas, Pandora, and Epimetheus were performed between December 2016 and April 2017 during the ring-grazing orbits of the Cassini mission. Data on the moons' morphology, structure, particle environment, and composition were returned, along with images in the ultraviolet and thermal infrared. We find that the optical properties of the moons' surfaces are determined by two competing processes: contamination by a red material formed in Saturn's main ring system and accretion of bright icy particles or water vapor from volcanic plumes originating on the moon Enceladus.

The use of Singapore flaps for vaginal reconstruction in women with vaginal stenosis with obstetric fistula: a surgical technique.

Gynecologic and plastic surgeons collaborate to improve vaginal reconstruction for women with vaginal stenosis and obstetric fistula. As these cases occur typically in low-resource settings, the Singapore flap is a useful technique given its reliability, safety, ease of dissection, and minimal need for additional supplies. The fasciocutaneous flap maintains cutaneous innervation and vasculature and does not require stenting. The surgical collaboration has made it possible to provide functional vaginal reconstruction as a part of the overall care of obstetric fistula patients. The technique shows promise for improving sexual function for women with obstetric fistula and may also enhance healing. TWEETABLE ABSTRACT: Gynecologic & plastic surgeons collaborate to improve vaginal reconstruction for women with obstetric fistula.

Spectral properties of Titan's impact craters imply chemical weathering of its surface.

We examined the spectral properties of a selection of Titan's impact craters that represent a range of degradation states. The most degraded craters have rims and ejecta blankets with spectral characteristics that suggest that they are more enriched in water ice than the rims and ejecta blankets of the freshest craters on Titan. The progression is consistent with the chemical weathering of Titan's surface. We propose an evolutionary sequence such that Titan's craters expose an intimate mixture of water ice and organic materials, and chemical weathering by methane rainfall removes the soluble organic materials, leaving the insoluble organics and water ice behind. These observations support the idea that fluvial processes are active in Titan's equatorial regions.

Dynamic auroral storms on Saturn as observed by the Hubble Space Telescope.

We present observations of significant dynamics within two UV auroral storms observed on Saturn using the Hubble Space Telescope in April/May 2013. Specifically, we discuss bursts of auroral emission observed at the poleward boundary of a solar wind-induced auroral storm, propagating at ∼330% rigid corotation from near ∼01 h LT toward ∼08 h LT. We suggest that these are indicative of ongoing, bursty reconnection of lobe flux in the magnetotail, providing strong evidence that Saturn's auroral storms are caused by large-scale flux closure. We also discuss the later evolution of a similar storm and show that the emission maps to the trailing region of an energetic neutral atom enhancement. We thus identify the auroral form with the upward field-aligned continuity currents flowing into the associated partial ring current.

An observed correlation between plume activity and tidal stresses on Enceladus.

Saturn's moon Enceladus emits a plume of water vapour and micrometre-sized ice particles from a series of warm fissures located near its south pole. This geological activity could be powered or controlled by variations in the tidal stresses experienced by Enceladus as it moves around its slightly eccentric orbit. The specific mechanisms by which these varying stresses are converted into heat, however, are still being debated. Furthermore, it has proved difficult to find a clear correlation between the predicted tidal forces and measured temporal variations in the plume's gas content or the particle flux from individual sources. Here we report that the plume's horizontally integrated brightness is several times greater when Enceladus is near the point in its eccentric orbit where it is furthest from Saturn (apocentre) than it is when near the point of closest approach to the planet (pericentre). More material therefore seems to be escaping from beneath Enceladus' surface at times when geophysical models predict its fissures should be under tension and therefore may be wider open.

Mutational analysis reveals the FUS homolog TAF15 as a candidate gene for familial amyotrophic lateral sclerosis.

FUS, EWS, and TAF15 belong to the TET family of structurally similar DNA/RNA-binding proteins. Mutations in the FUS gene have recently been discovered as a cause of familial amyotrophic lateral sclerosis (FALS). Given the structural and functional similarities between the three genes, we screened TAF15 and EWS in 263 and 94 index FALS cases, respectively. No coding variants were found in EWS, while we identified six novel changes in TAF15. Of these, two 24 bp deletions and a R388H missense variant were also found in healthy controls. A D386N substitution was shown not to segregate with the disease in the affected pedigree. A single A31T and two R395Q changes were identified in FALS cases but not in over 1,100 controls. Interestingly, one of the R395Q FALS cases also harbors a TARDBP mutation (G384R). Altogether, these results suggest that additional studies are needed to determine whether mutations in the TAF15 gene represent a cause of FALS.

Tau levels do not influence human ALS or motor neuron degeneration in the SOD1G93A mouse.

BACKGROUND: The microtubule-associated protein tau is thought to play a pivotal role in neurodegeneration. Mutations in the tau coding gene MAPT are a cause of frontotemporal dementia, and the H1/H1 genotype of MAPT, giving rise to higher tau expression levels, is associated with progressive supranuclear palsy, corticobasal degeneration, and Parkinson disease (PD). Furthermore, tau hyperphosphorylation and aggregation is a hallmark of Alzheimer disease (AD), and reducing endogenous tau has been reported to ameliorate cognitive impairment in a mouse model for AD. Tau hyperphosphorylation and aggregation have also been described in amyotrophic lateral sclerosis (ALS), both in human patients and in the mutant SOD1 mouse model for this disease. However, the precise role of tau in motor neuron degeneration remains uncertain. METHODS: The possible association between ALS and the MAPT H1/H2 polymorphism was studied in 3,540 patients with ALS and 8,753 controls. Furthermore, the role of tau in the SOD1(G93A) mouse model for ALS was studied by deleting Mapt in this model. RESULTS: The MAPT genotype of the H1/H2 polymorphism did not influence ALS susceptibility (odds ratio = 1.08 [95% confidence interval 0.99-1.18], p = 0.08) and did not affect the clinical phenotype. Lowering tau levels in the SOD1(G93A) mouse failed to delay disease onset (p = 0.302) or to increase survival (p = 0.557). CONCLUSION: These findings suggest that the H1/H2 polymorphism in MAPT is not associated with human amyotrophic lateral sclerosis, and that lowering tau levels in the mutant SOD1 mouse does not affect the motor neuron degeneration in these animals.

Non-recurrent SEPT9 duplications cause hereditary neuralgic amyotrophy.

BACKGROUND: Genomic copy number variants have been shown to be responsible for multiple genetic diseases. Recently, a duplication in septin 9 (SEPT9) was shown to be causal for hereditary neuralgic amyotrophy (HNA), an episodic peripheral neuropathy with autosomal dominant inheritance. This duplication was identified in 12 pedigrees that all shared a common founder haplotype. METHODS AND RESULTS: Based on array comparative genomic hybridisation, we identified six additional heterogeneous tandem SEPT9 duplications in patients with HNA that did not possess the founder haplotype. Five of these novel duplications are intragenic and result in larger transcript and protein products, as demonstrated through reverse transcription-PCR and western blotting. One duplication spans the entire SEPT9 gene and does not generate aberrant transcripts and proteins. The breakpoints of all the duplications are unique and contain regions of microhomology ranging from 2 to 9 bp in size. The duplicated regions contain a conserved 645 bp exon within SEPT9 in which HNA-linked missense mutations have been previously identified, suggesting that the region encoded by this exon is important to the pathogenesis of HNA. CONCLUSIONS: Together with the previously identified founder duplication, a total of seven heterogeneous SEPT9 duplications have been identified in this study as a causative factor of HNA. These duplications account for one third of the patients in our cohort, suggesting that duplications of various sizes within the SEPT9 gene are a common cause of HNA.

Analysis of FUS gene mutation in familial amyotrophic lateral sclerosis within an Italian cohort.

OBJECTIVE: Mutations in the FUS gene on chromosome 16 have been recently discovered as a cause of familial amyotrophic lateral sclerosis (FALS). This study determined the frequency and identities of FUS gene mutations in a cohort of Italian patients with FALS. METHODS: We screened all 15 coding exons of FUS for mutations in 94 Italian patients with FALS. RESULTS: We identified 4 distinct missense mutations in 5 patients; 2 were novel. The mutations were not present in 376 healthy Italian controls and thus are likely to be pathogenic. CONCLUSIONS: Our results demonstrate that FUS mutations cause approximately 4% of familial amyotrophic lateral sclerosis cases in the Italian population.

A large-scale international meta-analysis of paraoxonase gene polymorphisms in sporadic ALS.

BACKGROUND: Six candidate gene studies report a genetic association of DNA variants within the paraoxonase locus with sporadic amyotrophic lateral sclerosis (ALS). However, several other large studies, including five genome-wide association studies, have not duplicated this finding. METHODS: We conducted a meta-analysis of 10 published studies and one unpublished study of the paraoxonase locus, encompassing 4,037 ALS cases and 4,609 controls, including genome-wide association data from 2,018 ALS cases and 2,425 controls. RESULTS: The combined fixed effects odds ratio (OR) for rs662 (PON1 Q192R) was 1.09 (95% confidence interval [CI], 1.02-1.16, p = 0.01); the genotypic OR for RR homozygotes at Q192R was 1.25 (95% CI, 1.07-1.45, p = 0.0004); the combined OR for rs854560 (PON1 L55M) was 0.97 (95% CI, 0.86-1.10, p = 0.62); the OR for rs10487132 (PON2) was 1.08 (95% CI, 0.92-1.27, p = 0.35). Although the rs662 polymorphism reached a nominal level of significance, no polymorphism was significant after multiple testing correction. In the subanalysis of samples with genome-wide data from which population outliers were removed, rs662 had an OR of 1.06 (95% CI, 0.97-1.16, p = 0.22). CONCLUSIONS: In contrast to previous positive smaller studies, our genetic meta-analysis showed no significant association of amyotrophic lateral sclerosis (ALS) with the PON locus. This is the largest meta-analysis of a candidate gene in ALS to date and the first ALS meta-analysis to include data from whole genome association studies. The findings reinforce the need for much larger and more collaborative investigations of the genetic determinants of ALS.

Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disorder. Ten percent of cases are inherited; most involve unidentified genes. We report here 13 mutations in the fused in sarcoma/translated in liposarcoma (FUS/TLS) gene on chromosome 16 that were specific for familial ALS. The FUS/TLS protein binds to RNA, functions in diverse processes, and is normally located predominantly in the nucleus. In contrast, the mutant forms of FUS/TLS accumulated in the cytoplasm of neurons, a pathology that is similar to that of the gene TAR DNA-binding protein 43 (TDP43), whose mutations also cause ALS. Neuronal cytoplasmic protein aggregation and defective RNA metabolism thus appear to be common pathogenic mechanisms involved in ALS and possibly in other neurodegenerative disorders.

The identification of liquid ethane in Titan's Ontario Lacus.

Titan was once thought to have global oceans of light hydrocarbons on its surface, but after 40 close flybys of Titan by the Cassini spacecraft, it has become clear that no such oceans exist. There are, however, features similar to terrestrial lakes and seas, and widespread evidence for fluvial erosion, presumably driven by precipitation of liquid methane from Titan's dense, nitrogen-dominated atmosphere. Here we report infrared spectroscopic data, obtained by the Visual and Infrared Mapping Spectrometer (VIMS) on board the Cassini spacecraft, that strongly indicate that ethane, probably in liquid solution with methane, nitrogen and other low-molecular-mass hydrocarbons, is contained within Titan's Ontario Lacus.

Paraoxonase 1 (PON1) organophosphate hydrolysis is not reduced in ALS.

OBJECTIVE: Four recent studies report a genetic association of the paraoxonase locus with sporadic amyotrophic lateral sclerosis (ALS). We tested the hypothesis that this association correlates with functional changes in paraoxonase 1 (PON1, MIM 168820). METHODS: Sera from 140 ALS participants; 153 age-, race-, and sex-matched controls; and 30 matched CSF samples were tested for paraoxonase, diazoxonase, and arylesterase activities. Participants with ALS were genotyped using tagging single nucleotide polymorphisms across the PON locus. Survival data and enzyme activity were correlated with genotype. RESULTS: There was a trend toward increased paraoxonase activity in ALS compared with controls (mean control paraoxonase 701.9 +/- 469.7 U/L, mean ALS 792.5 +/- 574.1 U/L; p = 0.066 after correction) which correlated with increased frequency of the homozygous arginine (RR) variant of PON1(Q192R) (p = 0.004). There was no significant difference in PON1 protein levels, or arylesterase or diazoxonase activities. Organophosphate hydrolysis rates had no effect on ALS survival. CONCLUSIONS: Contrary to expectations, PON1 protein, paraoxonase, diazoxonase, and arylesterase activities were not reduced in amyotrophic lateral sclerosis (ALS). The increase in PON1(R192) frequency in ALS in our study supports previous genetic susceptibility studies. Our findings suggest that the influence of PON1 polymorphisms on ALS susceptibility is not due to reduced organophosphate hydrolysis.

New VAPB deletion variant and exclusion of VAPB mutations in familial ALS.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disorder involving upper and lower motor neurons. The vesicle-associated membrane protein B (VAPB) gene has been genetically linked to ALS in several large Brazilian families in which the disorder is caused by a proline to serine mutation at codon 56 (P56S). No additional mutations have been identified. METHODS: To establish the prevalence of VAPB mutations, we screened 80 familial ALS samples by DNA sequencing. RESULTS: Our study failed to identify any novel VAPB gene mutations but identified a single Brazilian family harboring the P56S mutation. In a second familial ALS case, we identified a three-base pair deletion within exon 5 of the VAPB gene that deleted the serine residue at position 160 (Delta S160). This variant is detected in a normal population at low frequency (0.45%). Analyses of homology alignment and secondary structure predict that this deletion significantly alters the structure of VAPB, although a GFP-Delta S160 VAPB fusion protein demonstrates a wild-type subcellular localization. This contrasts the aberrant localization observed in a GFP-P56S VAPB fusion protein. The allele frequency of Delta S160 in patients with sporadic ALS does not differ significantly from that in the normal population. CONCLUSIONS: Mutations in the VAPB gene are rare and the Delta S160 variant does not contribute to the development of amyotrophic lateral sclerosis.

Quantification of reverse transcriptase in ALS and elimination of a novel retroviral candidate.

BACKGROUND: Retroviral involvement in amyotrophic lateral sclerosis (ALS) has been suspected for several years since the recognition that both murine and human retroviruses can cause ALS-like syndromes. Nonquantitative studies have demonstrated the retroviral enzyme reverse transcriptase (RT) in ALS patients' sera, but the amount and source of RT activity are unknown. We therefore developed a quantitative assay to study RT levels in ALS and examined the possibility that the recently discovered human gammaretrovirus XMRV (xenotropic MuLV-related virus) might be the source of the RT activity. METHODS: A quantitative product-enhanced RT assay was used to measure RT activity levels in serum and CSF. XMRV sequences were sought by PCR analysis of DNA and RNA extracted from blood. RESULTS: Fifty percent of ALS patients' sera contained >6 x 10(-8) RT units/mL as opposed to 7% of control sera (p = 0.008). The levels of RT activity in ALS patients were comparable to the levels observed in patients infected with HIV. RT activity was detected in only 1 of 25 CSF samples tested. XMRV sequences were not found in any of 25 nucleic acid extracts obtained from ALS patients' blood. CONCLUSIONS: These findings further support the concept of retroviral involvement in amyotrophic lateral sclerosis (ALS) and demonstrate that serum is more suitable than CSF for assay of reverse transcriptase (RT) activity in this disease. The levels of serum RT activity detected are comparable to those found in HIV infection. XMRV is not detectable in the blood of ALS patients, and the agent responsible for ALS-associated RT activity therefore remains unidentified.

Optical birefringence study of the ferroelectric phase transition in lithium niobate tantalate mixed crystals: LiNb(1-x)Ta(x)O(3).

The optical birefringence of a complete solid-solution series of lithium niobate-tantalate crystals has been measured as a function of temperature. It is found that, irrespective of composition, the high-temperature paraelectric phase has a birefringence close to +0.063, suggesting that this value arises purely from the oxygen octahedra in the crystal structure. It is also observed that a small addition of lithium niobate to the tantalate produces a crystal that has zero birefringence at room temperature.

SOD1A4V-mediated ALS: absence of a closely linked modifier gene and origination in Asia.

Familial amyotrophic lateral sclerosis (ALS) accounts for 10% of all ALS. Approximately 20% of cases are due to mutations in the Cu/Zn superoxide dismutase gene (SOD1). In North America, SOD1(A4V) is the most common SOD1 mutation. Carriers of the SOD1(A4V) mutation share a common phenotype with rapid disease progression and death on average occurring at 1.4 years (versus 3-5 years with other dominant SOD1 mutations). Previous studies of SOD1(A4V) carriers identified a common haplotype around the SOD1 locus, suggesting a common founder for most SOD1(A4V) patients. In the current study we sequenced the entire common haplotypic region around SOD1 to test the hypothesis that polymorphisms in either previously undescribed coding regions or non-coding regions around SOD1 are responsible for the more aggressive phenotype in SOD1(A4V)-mediated ALS. We narrowed the conserved region around the SOD1 gene in SOD1(A4V) ALS to 2.8Kb and identified five novel SNPs therein. None of these variants was specifically found in all SOD1(A4V) patients. It therefore appears likely that the aggressive nature of the SOD1(A4V) mutation is not a result of a modifying factor within the region around the SOD1 gene. Founder analysis estimates that the A4V mutation occurred 540 generations (approximately 12,000 years) ago (95% CI 480-700). The conserved minimal haplotype is statistically more similar to Asian than European population DNA sets, suggesting that the A4V mutation arose in native Asian-Americans who reached the Americas through the Bering Strait.

Motoneuron-specific NR3B gene: no association with ALS and evidence for a common null allele.

OBJECTIVE: The GRIN3B gene encodes NR3B, a motoneuron-specific member of the NMDA type of ionotropic glutamate receptors. NR3B reduces the Ca(2+)-permeability as well as the overall current of the receptor response and may thereby protect motoneurons against glutamate-mediated excitotoxicity. We tested whether genetic dysfunction of GRIN3B is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). METHODS: We searched for mutations in the GRIN3B coding region (3.1 kb) in 117 individuals with familial ALS and in 46 individuals with sporadic ALS. We genotyped the newly identified GRIN3B null allele and four "tag single nucleotide polymorphisms (SNPs)" at the GRIN3B locus in 342 individuals with sporadic ALS and in 374 matched controls. The GRIN3B null allele frequency was determined in 2,128 individuals from a worldwide panel of 42 populations. We furthermore compared the GRIN3B coding sequence in primates (human-macaque) and rodents (rat-mouse) to evaluate the molecular evolution of GRIN3B. RESULTS: Thirty-two SNPs, including 16 previously unreported SNPs, one 27-bp deletion, a polymorphic CAG repeat, and a 4-bp insertion (insCGTT), were identified. Mutational and case-control studies did not reveal variants that cause or modify disease in ALS. Intriguing is an insCGTT variant that truncates the protein at its amino terminus and results in a GRIN3B null allele. We demonstrated a global distribution of the null allele with allele frequencies ranging between 0 and 0.38, and we delineated a null allele specific haplotype of 9.89 kb. Comparative genomic analysis across four taxa demonstrated accelerated evolution of NR3B in primates. CONCLUSIONS: Our study supports the conclusions that 1) GRIN3B does not seem to be associated with familial or sporadic ALS, 2) the GRIN3B null allele is a common polymorphism, 3) the GRIN3B null allele has arisen once and early in human evolution, and 4) the GRIN3B gene belongs to a group of nervous system-related genes that have been subjected to faster evolution during evolution.

Genetic variability of induction and emergence times for inhalational anaesthetics.

BACKGROUND AND OBJECTIVES: Anaesthetic requirements differ among inbred mouse strains. We tested the genetic influence on induction and arousal times to inhalational anaesthetics in two of these strains. METHODS: Five male C57BL/6J (B6) and five male C3H/HeJ (C3) mice were each exposed to five different concentrations of nitrous oxide (N2O) at five different levels of halothane. Time to sleep and arousal were assessed. Data were analysed by repeated measures of analysis of variance. RESULTS: Halothane, N2O and genetic strain, all were significant independent factors on the time to sleep, while only N2O was a significant independent factor on the time to arousal (P = 0.004). B6 mice took significantly longer to fall asleep compared to the C3 mice controlling for halothane and N2O concentrations (F-ratio = 36, P < 0.0001). The effect of N2O on time to arousal was only significant for the B6 strain (F-ratio = 10, P = 0.005), and not for the C3 strain (F-ratio = 0.8, P = 0.38). CONCLUSIONS: Genetics influences the time to sleep for anaesthetic agents in mice.

Surface composition of Hyperion.

Hyperion, Saturn's eighth largest icy satellite, is a body of irregular shape in a state of chaotic rotation. The surface is segregated into two distinct units. A spatially dominant high-albedo unit having the strong signature of H2O ice contrasts with a unit that is about a factor of four lower in albedo and is found mostly in the bottoms of cup-like craters. Here we report observations of Hyperion's surface in the ultraviolet and near-infrared spectral regions with two optical remote sensing instruments on the Cassini spacecraft at closest approach during a fly-by on 25-26 September 2005. The close fly-by afforded us the opportunity to obtain separate reflectance spectra of the high- and low-albedo surface components. The low-albedo material has spectral similarities and compositional signatures that link it with the surface of Phoebe and a hemisphere-wide superficial coating on Iapetus.