Restricted access Contributions to sequence stratigraphy from analogue and numerical experiments

The sequence stratigraphic model, although no longer focused on eustasy and accommodation, has been until recently based largely on observation and interpretation of outcrop and subsurface data. This approach may be restrictive if the current model places limits on what is observed and how observations are interpreted. To make progress in our understanding of strata, the sequence stratigraphic model and method should be tested against and fully incorporate theoretical and experimental results that provide new knowledge of (1) autogenesis, (2) intrinsic stratigraphic responses, (3) alluvial grade, and (4) scales appropriate to single depositional systems evolving with relative sea-level changes. More extensive inclusion of analogue and numerical experimental results could lead to significant modification and refinement of existing sequence stratigraphic models

Can sediment supply variations create sequences? Insights from stratigraphic forward modelling

Classic sequence stratigraphy suggests depositional sequences can form due to changes in accommodation and due to changes in sediment supply. Accommodation‐dominated sequences are problematic to define rigorously, but are commonly interpreted from outcrop and subsurface data. In contrast, supply‐dominated sequences are much less commonly identified. We employ numerical stratigraphic forward modelling to compare stratal geometries forced by cyclic changes in relative sea level with stratal geometries forced by sediment discharge and water discharge changes. Our quantitative results suggest that both relative sea‐level oscillations and variations in sediment/water discharge ratio are able to form sequence‐bounding unconformities independently, confirming previous qualitative sequences definitions. In some of the experiments, the two types of sequence share several characteristics, such as an absence of coastal‐plain topset deposits and stratal offlap, something typically interpreted as the result of falling relative sea level. However, the stratal geometries differ when variations in amplitude and frequency of relative sea‐level change, sediment/water discharge ratio, transport diffusion coefficient and initial bathymetry are applied. We propose that the supply‐dominated sequences could be recognised in outcrop or in the subsurface if the observations of stratal offlap and the absence of coastal‐plain topset can be made without any strong evidence of relative sea‐level fall (e.g. descending shoreline trajectory). These quantitative results suggest that both supply‐dominated and accommodation‐dominated sequences are likely to occur in the ancient record, as a consequence of multiple, possibly complex, controls

Alteration of the unfolded protein response modifies neurodegeneration in a mouse model of Marinesco–Sjögren syndrome

Endoplasmic reticulum (ER) stress has been linked to the onset and progression of many diseases. SIL1 is an adenine nucleotide exchange factor of the essential ER lumen chaperone HSPA5/BiP that senses ER stress and is involved in protein folding. Mutations in the Sil1 gene have been associated with Marinesco–Sjögren syndrome, hallmarks of which include ataxia and cerebellar atrophy. We have previously shown that loss of SIL1 function in mouse results in ER stress, ubiquitylated protein inclusions, and degeneration of specific Purkinje cells in the cerebellum. Here, we report that overexpression of HYOU1/ORP150, an exchange factor that works in parallel to SIL1, prevents ER stress and rescues neurodegeneration in Sil1−/− mice, whereas decreasing expression of HYOU1 exacerbates these phenotypes. In addition, loss of DNAJC3/p58IPK, a co-chaperone that promotes ATP hydrolysis by BiP, ameliorates ER stress and neurodegeneration in Sil1−/− mice. These findings suggest that alterations in the nucleotide exchange cycle of BiP cause ER stress and neurodegeneration in Sil1-deficient mice. Our results present the first evidence of important genetic modifiers of Marinesco–Sjögren syndrome, and provide additional pathways for therapeutic intervention for this, and other ER stress-induced, diseases

Collecting Comet Samples by ER-2 Aircraft: Cosmic Dust Collection During the Draconid Meteor Shower in October 2012

Many tons of dust grains, including samples of asteroids and comets, fall from space into the Earth's atmosphere each day. NASA periodically collects some of these particles from the Earth's stratosphere using sticky collectors mounted on NASA's high-flying aircraft. Sometimes, especially when the Earth experiences a known meteor shower, a special opportunity is presented to associate cosmic dust particles with a known source. NASA JSC's Cosmic Dust Collection Program has made special attempts to collect dust from particular meteor showers and asteroid families when flights can be planned well in advance. However, it has rarely been possible to make collections on very short notice. In 2012, the Draconid meteor shower presented that opportunity. The Draconid meteor shower, originating from Comet 21P/Giacobini-Zinner, has produced both outbursts and storms several times during the last century, but the 2012 event was not predicted to be much of a show. Because of these predictions, the Cosmic Dust team had not targeted a stratospheric collection effort for the Draconids, despite the fact that they have one of the slowest atmospheric entry velocities (23 km/s) of any comet shower, and thus offer significant possibilities of successful dust capture. However, radar measurements obtained by the Canadian Meteor Orbit Radar during the 2012 Draconids shower indicated a meteor storm did occur October 8 with a peak at 16:38 (+/-5 min) UTC for a total duration of approximately 2 hours

A study of the relationships between oligonucleotide properties and hybridization signal intensities from NimbleGen microarray datasets

Well-defined relationships between oligonucleotide properties and hybridization signal intensities (HSI) can aid chip design, data normalization and true biological knowledge discovery. We clarify these relationships using the data from two microarray experiments containing over three million probes from 48 high-density chips. We find that melting temperature (Tm) has the most significant effect on HSI while length for the long oligonucleotides studied has very little effect. Analysis of positional effect using a linear model provides evidence that the protruding ends of probes contribute more than tethered ends to HSI, which is further validated by specifically designed match fragment sliding and extension experiments. The impact of sequence similarity (SeqS) on HSI is not significant in comparison with other oligonucleotide properties. Using regression and regression tree analysis, we prioritize these oligonucleotide properties based on their effects on HSI. The implications of our discoveries for the design of unbiased oligonucleotides are discussed. We propose that isothermal probes designed by varying the length is a viable strategy to reduce sequence bias, though imposing selection constraints on other oligonucleotide properties is also essential

Transmission of Aerosolized Seasonal H1N1 Influenza A to Ferrets

Influenza virus is a major cause of morbidity and mortality worldwide, yet little quantitative understanding of transmission is available to guide evidence-based public health practice. Recent studies of influenza non-contact transmission between ferrets and guinea pigs have provided insights into the relative transmission efficiencies of pandemic and seasonal strains, but the infecting dose and subsequent contagion has not been quantified for most strains. In order to measure the aerosol infectious dose for 50% (aID50) of seronegative ferrets, seasonal influenza virus was nebulized into an exposure chamber with controlled airflow limiting inhalation to airborne particles less than 5 µm diameter. Airborne virus was collected by liquid impinger and Teflon filters during nebulization of varying doses of aerosolized virus. Since culturable virus was accurately captured on filters only up to 20 minutes, airborne viral RNA collected during 1-hour exposures was quantified by two assays, a high-throughput RT-PCR/mass spectrometry assay detecting 6 genome segments (Ibis T5000™ Biosensor system) and a standard real time RT-qPCR assay. Using the more sensitive T5000 assay, the aID50 for A/New Caledonia/20/99 (H1N1) was approximately 4 infectious virus particles under the exposure conditions used. Although seroconversion and sustained levels of viral RNA in upper airway secretions suggested established mucosal infection, viral cultures were almost always negative. Thus after inhalation, this seasonal H1N1 virus may replicate less efficiently than H3N2 virus after mucosal deposition and exhibit less contagion after aerosol exposure

Quality indicators for multiple sclerosis

Determining whether persons with multiple sclerosis (MS) receive appropriate, comprehensive healthcare requires tools for measuring quality. The objective of this study was to develop quality indicators for the care of persons with MS. We used a modified version of the RAND/UCLA Appropriateness Method in a two-stage process to identify relevant MS care domains and to assess the validity of indicators within high-ranking care domains. Based on a literature review, interviews with persons with MS, and discussions with MS providers, 25 MS symptom domains and 14 general health domains of MS care were identified. A multidisciplinary panel of 15 stakeholders of MS care, including 4 persons with MS, rated these 39 domains in a two-round modified Delphi process. The research team performed an expanded literature review for 26 highly ranked domains to draft 86 MS care indicators. Through another two-round modified Delphi process, a second panel of 18 stakeholders rated these indicators using a nine-point response scale. Indicators with a median rating in the highest tertile were considered valid. Among the most highly rated MS care domains were appropriateness and timeliness of the diagnostic work-up, bladder dysfunction, cognition dysfunction, depression, disease-modifying agent usage, fatigue, integration of care, and spasticity. Of the 86 preliminary indicators, 76 were rated highly enough to meet predetermined thresholds for validity. Following a widely accepted methodology, we developed a comprehensive set of quality indicators for MS care that can be used to assess quality of care and guide the design of interventions to improve care among persons with MS

Avian Influenza Virus Glycoproteins Restrict Virus Replication and Spread through Human Airway Epithelium at Temperatures of the Proximal Airways

Transmission of avian influenza viruses from bird to human is a rare event even though avian influenza viruses infect the ciliated epithelium of human airways in vitro and ex vivo. Using an in vitro model of human ciliated airway epithelium (HAE), we demonstrate that while human and avian influenza viruses efficiently infect at temperatures of the human distal airways (37°C), avian, but not human, influenza viruses are restricted for infection at the cooler temperatures of the human proximal airways (32°C). These data support the hypothesis that avian influenza viruses, ordinarily adapted to the temperature of the avian enteric tract (40°C), rarely infect humans, in part due to differences in host airway regional temperatures. Previously, a critical residue at position 627 in the avian influenza virus polymerase subunit, PB2, was identified as conferring temperature-dependency in mammalian cells. Here, we use reverse genetics to show that avianization of residue 627 attenuates a human virus, but does not account for the different infection between 32°C and 37°C. To determine the mechanism of temperature restriction of avian influenza viruses in HAE at 32°C, we generated recombinant human influenza viruses in either the A/Victoria/3/75 (H3N2) or A/PR/8/34 (H1N1) genetic background that contained avian or avian-like glycoproteins. Two of these viruses, A/Victoria/3/75 with L226Q and S228G mutations in hemagglutinin (HA) and neuraminidase (NA) from A/Chick/Italy/1347/99 and A/PR/8/34 containing the H7 and N1 from A/Chick/Italy/1347/99, exhibited temperature restriction approaching that of wholly avian influenza viruses. These data suggest that influenza viruses bearing avian or avian-like surface glycoproteins have a reduced capacity to establish productive infection at the temperature of the human proximal airways. This temperature restriction may limit zoonotic transmission of avian influenza viruses and suggests that adaptation of avian influenza viruses to efficient infection at 32°C may represent a critical evolutionary step enabling human-to-human transmission

Protection of Mice against Lethal Challenge with 2009 H1N1 Influenza A Virus by 1918-Like and Classical Swine H1N1 Based Vaccines

The recent 2009 pandemic H1N1 virus infection in humans has resulted in nearly 5,000 deaths worldwide. Early epidemiological findings indicated a low level of infection in the older population (>65 years) with the pandemic virus, and a greater susceptibility in people younger than 35 years of age, a phenomenon correlated with the presence of cross-reactive immunity in the older population. It is unclear what virus(es) might be responsible for this apparent cross-protection against the 2009 pandemic H1N1 virus. We describe a mouse lethal challenge model for the 2009 pandemic H1N1 strain, used together with a panel of inactivated H1N1 virus vaccines and hemagglutinin (HA) monoclonal antibodies to dissect the possible humoral antigenic determinants of pre-existing immunity against this virus in the human population. By hemagglutinination inhibition (HI) assays and vaccination/challenge studies, we demonstrate that the 2009 pandemic H1N1 virus is antigenically similar to human H1N1 viruses that circulated from 1918–1943 and to classical swine H1N1 viruses. Antibodies elicited against 1918-like or classical swine H1N1 vaccines completely protect C57B/6 mice from lethal challenge with the influenza A/Netherlands/602/2009 virus isolate. In contrast, contemporary H1N1 vaccines afforded only partial protection. Passive immunization with cross-reactive monoclonal antibodies (mAbs) raised against either 1918 or A/California/04/2009 HA proteins offered full protection from death. Analysis of mAb antibody escape mutants, generated by selection of 2009 H1N1 virus with these mAbs, indicate that antigenic site Sa is one of the conserved cross-protective epitopes. Our findings in mice agree with serological data showing high prevalence of 2009 H1N1 cross-reactive antibodies only in the older population, indicating that prior infection with 1918-like viruses or vaccination against the 1976 swine H1N1 virus in the USA are likely to provide protection against the 2009 pandemic H1N1 virus. This data provides a mechanistic basis for the protection seen in the older population, and emphasizes a rationale for including vaccination of the younger, naïve population. Our results also support the notion that pigs can act as an animal reservoir where influenza virus HAs become antigenically frozen for long periods of time, facilitating the generation of human pandemic viruses