Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

<p>To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges.p>

PS1-10afx at z = 1.388: Pan-STARRS1 Discovery of a New Type of Superluminous Supernova

We present the Pan-STARRS1 discovery of PS1-10afx, a unique hydrogen-deficient superluminous supernova (SLSN) at redshift z = 1.388. The light curve peaked at z P1 = 21.7 mag, making PS1-10afx comparable to the most luminous known SNe, with Mu = -22.3 mag. Our extensive optical and near-infrared observations indicate that the bolometric light curve of PS1-10afx rose on the unusually fast timescale of ~12 days to the extraordinary peak luminosity of 4.1 × 1044 erg s-1 (M bol = -22.8 mag) and subsequently faded rapidly. Equally important, the spectral energy distribution is unusually red for an SLSN, with a color temperature of ~6800 K near maximum light, in contrast to previous hydrogen-poor SLSNe, which are bright in the ultraviolet (UV). The spectra more closely resemble those of a normal SN Ic than any known SLSN, with a photospheric velocity of ~11, 000 km s-1 and evidence for line blanketing in the rest-frame UV. Despite the fast rise, these parameters imply a very large emitting radius (gsim 5 × 1015 cm). We demonstrate that no existing theoretical model can satisfactorily explain this combination of properties: (1) a nickel-powered light curve cannot match the combination of high peak luminosity with the fast timescale; (2) models powered by the spindown energy of a rapidly rotating magnetar predict significantly hotter and faster ejecta; and (3) models invoking shock breakout through a dense circumstellar medium cannot explain the observed spectra or color evolution. The host galaxy is well detected in pre-explosion imaging with a luminosity near L*, a star formation rate of ~15 M ⊙ yr-1, and is fairly massive (~2 × 1010 M ⊙), with a stellar population age of ~108 yr, also in contrast to the young dwarf hosts of known hydrogen-poor SLSNe. PS1-10afx is distinct from known examples of SLSNe in its spectra, colors, light-curve shape, and host galaxy properties, suggesting that it resulted from a different channel than other hydrogen-poor SLSNe.

Total eclipse of the heart: the AM CVn Gaia14aae/ASSASN-14cn

We report the discovery and characterization of a deeply eclipsing AM CVn-system, Gaia14aae (=ASSASN-14cn). Gaia14aae was identified independently by the All-Sky Automated Survey for Supernovae (ASAS-SN; Shappee et al.) and by the Gaia Science Alerts project, during two separate outbursts. A third outburst is seen in archival Pan-STARRS-1 (PS1; Schlafly et al.; Tonry et al.; Magnier et al.) and ASAS-SN data. Spectroscopy reveals a hot, hydrogen-deficient spectrum with clear double-peaked emission lines, consistent with an accreting double-degenerate classification. We use follow-up photometry to constrain the orbital parameters of the system. We find an orbital period of 49.71 min, which places Gaia14aae at the long period extremum of the outbursting AM CVn period distribution. Gaia14aae is dominated by the light from its accreting white dwarf (WD). Assuming an orbital inclination of 90° for the binary system, the contact phases of the WD lead to lower limits of 0.78 and 0.015 M⊙ on the masses of the accretor and donor, respectively, and a lower limit on the mass ratio of 0.019. Gaia14aae is only the third eclipsing AM CVn star known, and the first in which the WD is totally eclipsed. Using a helium WD model, we estimate the accretor's effective temperature to be 12 900 ± 200 K. The three outburst events occurred within four months of each other, while no other outburst activity is seen in the previous 8 yr of Catalina Real-time Transient Survey (CRTS; Drake et al.), Pan-STARRS-1 and ASAS-SN data. This suggests that these events might be rebrightenings of the first outburst rather than individual events.

Temporal Narrowing of Neutrons Produced by High-Intensity Short-Pulse Lasers

The production of neutron beams having short temporal duration is studied using ultraintense laser pulses. Laser-accelerated protons are spectrally filtered using a laser-triggered microlens to produce a short duration neutron pulse via nuclear reactions induced in a converter material (LiF). This produces a similar to 3 ns duration neutron pulse with 10(4) n/MeV/sr/shot at 0.56 m from the laser-irradiated proton source. The large spatial separation between the neutron production and the proton source allows for shielding from the copious and undesirable radiation resulting from the laser-plasma interaction. This neutron pulse compares favorably to the duration of conventional accelerator sources and should scale up with, present and future, higher energy laser facilities to produce brighter and shorter neutron beams for ultrafast probing of dense materials.

Larval development of the pedunculate barnacles Octolasmis angulata Aurivillius 1894 and Octolasmis cor Aurivillius 1892 (Cirripedia: Thoracica: Poecilasmatidae) from the gills of the mud crab, Scylla tranquebarica Fabricius, 1798

<p>Detailed studies of larval development of Octolasmis angulata and Octolasmis cor are pivotal in understanding the larval morphological evolution as well as enhancing the functional ecology. Six planktotrophic naupliar stages and one non-feeding cyprid stage are documented in details for the first time for the two species of Octolasmis. Morphologically, the larvae of O. angulata and O. cor are similar in body size, setation patterns on the naupliar appendages, labrum, dorsal setae-pores, frontal horns, cyprid carapace, fronto-lateral gland pores, and lattice organs. Numbers of peculiarities were observed on the gnathobases of the antennae and mandible throughout the naupliar life-cycle. The setation pattern on the naupliar appendages are classified based on the segmentation on the naupliar appendages. The nauplius VI of both species undergoes a conspicuous change before metamorphosis into cyprid stage. The cyprid structures begin to form and modify beneath the naupliar body towards the end of stage VI. This study emphasises the importance of the pedunculate barnacle larval developmental studies not only to comprehend the larval morphological evolution but also to fill in the gaps in understanding the modification of the naupliar structures to adapt into the cyprid life-style.p>

Parasite neuropeptide biology:Seeding rational drug target selection?

<p>The rationale for identifying drug targets within helminth neuromuscular signalling systems is based on the premise that adequate nerve and muscle function is essential for many of the key behavioural determinants of helminth parasitism, including sensory perception/host location, invasion, locomotion/orientation, attachment, feeding and reproduction. This premise is validated by the tendency of current anthelmintics to act on classical neurotransmitter-gated ion channels present on helminth nerve and/or muscle, yielding therapeutic endpoints associated with paralysis and/or death. Supplementary to classical neurotransmitters, helminth nervous systems are peptide-rich and encompass associated biosynthetic and signal transduction components - putative drug targets that remain to be exploited by anthelmintic chemotherapy. At this time, no neuropeptide system-targeting lead compounds have been reported, and given that our basic knowledge of neuropeptide biology in parasitic helminths remains inadequate, the short-term prospects for such drugs remain poor. Here, we review current knowledge of neuropeptide signalling in Nematoda and Platyhelminthes, and highlight a suite of 19 protein families that yield deleterious phenotypes in helminth reverse genetics screens. We suggest that orthologues of some of these peptidergic signalling components represent appealing therapeutic targets in parasitic helminths.p>

A feasibility study of auricular therapy and self-administered acupressure for insomnia following cancer treatment

Introduction: Many cancer patients experience sleeping difficulties which can persist several years after the completion of cancer treatment. Previous research suggests that acupuncture, and variants of acupuncture (acupressure, auricular therapy) may be effective treatment options for sleep disturbance. However, current evidence is limited for cancer patients.

Methods: Feasibility study with 3 arms. Seven cancer patients with insomnia randomised to receive either auricular therapy (attaching semen vaccariae seeds to ear acupoints) (n=4), self-acupressure (n=1) or no treatment (n=2). Participants assigned to receive auricular therapy or self-acupressure stimulated the acupoints each night an hour before retiring to bed. The duration of participant involvement was 5 weeks. Subjective sleep quality was measured at baseline and post-treatment using the Pittsburgh Sleep Quality Index (PSQI). The impact of treatment on concerns of importance to the participants themselves was measured using the Measure Yourself Concerns and Wellbeing (MYCaW). Each participant also completed a treatment log book.

Results: All participants completed their treatment. All auricular therapy and self-acupressure participants recorded clinically significant improvements in global PSQI scores. In the auricular therapy arm mean global PSQI reduced from 12.5 at baseline to 8 following completion of treatment. In the self-acupressure arm PSQI reduced from 15 to 11. While in the no treatment arm the mean PSQI score was 14.5 at both baseline and follow up.

Conclusions: Despite the limited sample size, both auricular therapy and self-acupressure may represent potentially effective treatments for cancer patients with insomnia. The positive findings suggest further research is warranted into both treatment modalities.

Inlet recirculation in automotive turbocharger centrifugal compressors

As the designers of modern automotive turbochargers strive to increase map width and lower the mass flow rate at which compressor surge occurs, the recirculating flows at the impeller inlet are becoming a much more relevant aerodynamic feature. Compressors with relatively large map widths tend to have very large recirculating regions at the inlet when operating close to surge; these regions greatly affect the expected performance of the compressor.

This study analyses the inlet recirculation region numerically using several modern automotive turbocharger centrifugal compressors. Using 3D Computational Fluid Dynamics (CFD) and a single passage model, the point at which the recirculating flow begins to develop and the rate at which it grows are investigated. All numerical modelling has been validated using measurements taken from hot gas stand tests for all compressor stages. The paper improves upon an existing correlation between the rate of development of the recirculating region and the compressor stage, which is supported by results from the numerical analysis.

An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes

<p>Defects in primary cilium biogenesis underlie the ciliopathies, a growing group of genetic disorders. We describe a whole-genome siRNA-based reverse genetics screen for defects in biogenesis and/or maintenance of the primary cilium, obtaining a global resource. We identify 112 candidate ciliogenesis and ciliopathy genes, including 44 components of the ubiquitin-proteasome system, 12 G-protein-coupled receptors, and 3 pre-mRNA processing factors (PRPF6, PRPF8 and PRPF31) mutated in autosomal dominant retinitis pigmentosa. The PRPFs localize to the connecting cilium, and PRPF8- and PRPF31-mutated cells have ciliary defects. Combining the screen with exome sequencing data identified recessive mutations in PIBF1, also known as CEP90, and C21orf2, also known as LRRC76, as causes of the ciliopathies Joubert and Jeune syndromes. Biochemical approaches place C21orf2 within key ciliopathy-associated protein modules, offering an explanation for the skeletal and retinal involvement observed in individuals with C21orf2 variants. Our global, unbiased approaches provide insights into ciliogenesis complexity and identify roles for unanticipated pathways in human genetic disease.p>

2D Monolayer MoS2–Carbon Interoverlapped Superstructure: Engineering Ideal Atomic Interface for Lithium Ion Storage: Engineering Ideal Atomic Interface for Lithium Ion Storage

<p>A novel strategy for the controlled synthesis of 2D MoS&lt;inf>2&lt;/inf>/C hybrid nanosheets consisting of the alternative layer-by-layer interoverlapped single-layer MoS&lt;inf>2&lt;/inf> and mesoporous carbon (m-C) is demonstrated. Such special hybrid nanosheets with a maximized MoS&lt;inf>2&lt;/inf>/m-C interface contact show very good performance for lithium-ion batteries in terms of high reversible capacity, excellent rate capability, and outstanding cycling stability.p>

Orange Zinc Germanate with Metallic Ge-Ge Bonds as a Chromophore-Like Center for Visible-Light-Driven Water Splitting

<p>The efficiency of solar-energy-conversion devices depends on the absorption region and intensity of the photon collectors. Organic chromophores, which have been widely stabilized on inorganic semiconductors for light trapping, are limited by the interface between the chromophore and semiconductor. Herein we report a novel orange zinc germanate (Zn-Ge-O) with a chromophore-like structure, by which the absorption region can be dramatically expanded. Structural characterizations and theoretical calculations together reveal that the origin of visible-light response can be attributed to the unusual metallic Ge-Ge bonds which act in a similar way to organic chromophores. Benefiting from the enhanced light harvest, the orange Zn-Ge-O demonstrates superior capacity for solar-driven hydrogen production.p>

Abrupt Climate Changes: Climate and Biogeochemical consequences

Hosted in a wide depression within the Berici Hills (Venetian Plain), outside the maximum extent reached by LGM glaciers, Lake Fimon preserves an almost continuous archive of landscape and climate changes from the penultimate glacial maximum onwards. The stratigraphic succession deposited at the lake bottom has been investigated in three deep cores by means of pollen analysis, petrographic composition, magnetic susceptibility, LOI, and geochronology. Tephra layers have been identified and are currently under study.
Pollen data provide the first continuous vegetation record in northern Italy for the last 150 ky. Terrestrial vegetation varied from interglacial warm-temperate broad leaved to oceanic mixed forests, from boreal conifer forests to open forest-steppes of colder climate. Phases of major forest expansion and reduction have been correlated to isotopic events described in ice (NGRIP), stalagmite (Antro del Corchia) and marine records. Persistent afforestation recorded in northern Italy even during cold phases of the full pleniglacial is consistent with mesoscale paleoclimate simulations suggesting that a sharp rainfall gradient across the Alps enabled the survival of woody species in the southern alpine foreland.
Integrating litho- and biostratigraphical data, we identified sedimentation regìmes, accumulation rates, sediment sources and supply both for the Lake Fimon cores and the adjacent Venetian Plain, allowing a direct comparison with major glacial advances in the Alpine area, deglaciation pulses, and glacio-eustatic displacements of the northern Adriatic shoreline.

Performance of sustainable SCC mixes with mineral additions for use in precast concrete industry

The aim of this research was to study the impact that different mineral powders have on the properties of self-compacting concrete (SCC) in order to obtain relations that make it possible to optimize their dosages for being used in precast concrete applications. Different combinations and contents of cement, mineral additions (active and inert), superplasticizers, and aggregates are considered. A new approach for determining the saturation point of superplasticizers is introduced. The fresh state performance was assessed by means of the following tests: slump flow, V-funnel, and J-ring. Concrete compressive strength values at different ages up to 56 days have been retained as representative of the materials’ performance in its hardened state. All these properties have been correlated with SCC proportioning. As a result, a number of recommendations for the precast concrete industry arise to design more stable SCC mixes with a reduced carbon footprint.