To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening ...strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology.
Mon.Not.Roy.Astron.Soc. 339 (2003) 1223 We examine the hypothesis that there exists a simple scaling between the
observed velocities of jets found in Young Stellar Objects (YSOs) and jets
found in ...Active Galactic Nuclei (AGN). We employ a very simplified physical
model of the jet acceleration process. We use time-dependent, spherically
symmetric wind models in Newtonian and relativistic gravitational fields to ask
whether the energy input rates required to produce the jet velocities observed
in YSOs (of about 2 $\times$ the escape velocity from the central object) can
also produce AGN jet velocities (Lorentz factors of $\gamma \sim$ 10). Such a
scaling would be expected if there is a common production mechanism for such
jets. We demonstrate that such a scaling does exist, provided that the energy
input process takes place sufficiently deep in the gravitational potential
well, enabling physical use to be made of the speed of light as a limiting
velocity, and provided that the energy released in the accretion process is
imparted to a small fraction of the available accreting material.
Recent work on Cygnus X-2 suggests that neutron-star or black-hole binaries
survive highly super-Eddington mass transfer rates without undergoing
common-envelope evolution. We suggest here that the ...accretion flows in such
cases are radiation pressure-dominated versions of the "ADIOS" picture proposed
by Blandford and Begelman (1999), in which almost all the mass is expelled from
large radii in the accretion disk. We estimate the maximum radius from which
mass loss is likely to occur, and show that common-envelope evolution is
probably avoided in any binary in which a main-sequence donor transfers mass on
a thermal timescale to a neutron star or black hole, even though the mass
transfer rate may reach values of 0.001 solar masses per year. This conclusion
probably applies also to donors expanding across the Hertzsprung gap, provided
that their envelopes are radiative. SS433 may be an example of a system in this
state.
Sound localization relies on the neural processing of binaural and monaural spatial cues generated by the physical properties of the head and body. Hearing loss in one ear compromises binaural ...computations, impairing the ability to localize sounds in the horizontal plane. With appropriate training, adult individuals can adapt to this binaural imbalance and largely recover their localization accuracy. However, it remains unclear how long this learning is retained or whether it generalizes to other stimuli.
We trained ferrets to localize broadband noise bursts in quiet conditions and measured their initial head orienting responses and approach-to-target behavior. To evaluate the persistence of auditory spatial learning, we tested the sound localization performance of the animals over repeated periods of monaural earplugging that were interleaved with short or long periods of normal binaural hearing. To explore learning generalization to other stimulus types, we measured the localization accuracy before and after adaptation using different bandwidth stimuli presented against constant or amplitude-modulated background noise.
Retention of learning resulted in a smaller initial deficit when the same ear was occluded on subsequent occasions. Each time, the animals' performance recovered with training to near pre-plug levels of localization accuracy. By contrast, switching the earplug to the contralateral ear resulted in less adaptation, indicating that the capacity to learn a new strategy for localizing sound is more limited if the animals have previously adapted to conductive hearing loss in the opposite ear. Moreover, the degree of adaptation to the training stimulus for individual animals was significantly correlated with the extent to which learning extended to untrained octave band target sounds presented in silence and to broadband targets presented in background noise, suggesting that adaptation and generalization go hand in hand.
Together, these findings provide further evidence for plasticity in the weighting of monaural and binaural cues during adaptation to unilateral conductive hearing loss, and show that the training-dependent recovery in spatial hearing can generalize to more naturalistic listening conditions, so long as the target sounds provide sufficient spatial information.
Viruses are the most abundant biological entities on Earth, known to be crucial components of microbial ecosystems. However, there is little information on the viral community within agricultural ...waste. There are currently ~ 2.7 million dairy cattle in the UK producing 7-8% of their own bodyweight in manure daily, and 28 million tonnes annually. To avoid pollution of UK freshwaters, manure must be stored and spread in accordance with guidelines set by DEFRA. Manures are used as fertiliser, and widely spread over crop fields, yet little is known about their microbial composition. We analysed the virome of agricultural slurry over a 5-month period using short and long-read sequencing.
Hybrid sequencing uncovered more high-quality viral genomes than long or short-reads alone; yielding 7682 vOTUs, 174 of which were complete viral genomes. The slurry virome was highly diverse and dominated by lytic bacteriophage, the majority of which represent novel genera (~ 98%). Despite constant influx and efflux of slurry, the composition and diversity of the slurry virome was extremely stable over time, with 55% of vOTUs detected in all samples over a 5-month period. Functional annotation revealed a diverse and abundant range of auxiliary metabolic genes and novel features present in the community, including the agriculturally relevant virulence factor VapE, which was widely distributed across different phage genera that were predicted to infect several hosts. Furthermore, we identified an abundance of phage-encoded diversity-generating retroelements, which were previously thought to be rare on lytic viral genomes. Additionally, we identified a group of crAssphages, including lineages that were previously thought only to be found in the human gut.
The cattle slurry virome is complex, diverse and dominated by novel genera, many of which are not recovered using long or short-reads alone. Phages were found to encode a wide range of AMGs that are not constrained to particular groups or predicted hosts, including virulence determinants and putative ARGs. The application of agricultural slurry to land may therefore be a driver of bacterial virulence and antimicrobial resistance in the environment. Video abstract.
The upper bound of 50 parts per trillion by volume for Mars methane above 5 km established by the ExoMars Trace Gas Orbiter, substantially lower than the 410 parts per trillion by volume average ...measured overnight by the Curiosity Rover, places a strong constraint on the daytime methane flux at the Gale crater. We propose that these measurements may be largely reconciled by the inhibition of mixing near the surface overnight, whereby methane emitted from the subsurface accumulates within meters of the surface before being mixed below detection limits at dawn. A model of this scenario allows the first precise calculation of microseepage fluxes at Gale to be derived, consistent with a constant 1.5 × 10−10 kg·m−2·sol−1 (5.4 × 10−5 tonnes·km−2·year−1) source at depth. Under this scenario, only 2.7 × 104 km2 of Mars's surface may be emitting methane, unless a fast destruction mechanism exists.
Plain Language Summary
The ExoMars Trace Gas Orbiter and the Curiosity Rover have recorded different amounts of methane in the atmosphere on Mars. The Trace Gas Orbiter measured very little methane (<50 parts per trillion by volume) above 5 km in the sunlit atmosphere, while Curiosity measured substantially more (410 parts per trillion by volume) near the surface at night. In this paper we describe a framework which explains both measurements by suggesting that a small amount of methane seeps out of the ground constantly. During the day, this small amount of methane is rapidly mixed and diluted by vigorous convection, leading to low overall levels within the atmosphere. During the night, convection lessens, allowing methane to build up near the surface. At dawn, convection intensifies and the near‐surface methane is mixed and diluted with much more atmosphere. Using this model and methane concentrations from both approaches, we are able—for the first time—to place a single number on the rate of seepage of methane at Gale crater which we find equivalent to 2.8 kg per Martian day. Future spacecraft measuring methane near the surface of Mars could determine how much methane seeps out of the ground in different locations, providing insight into what processes create that methane in the subsurface.
Key Points
Nighttime SAM‐TLS seasonal cycle enrichment measurements and TGO sunset/sunrise measurements are not in opposition
Microseepage fluxes must be local to Gale, range from 0.82 to 4.6 kg/sol, and are consistent with a constant source at depth
Little of Mars experiences microseepage unless a fast destruction mechanism exists or Gale is very unusual
Clear cell renal cell carcinoma (ccRCC) is the most common form of adult kidney cancer, characterized by the presence of inactivating mutations in the VHL gene in most cases, and by infrequent ...somatic mutations in known cancer genes. To determine further the genetics of ccRCC, we have sequenced 101 cases through 3,544 protein-coding genes. Here we report the identification of inactivating mutations in two genes encoding enzymes involved in histone modification-SETD2, a histone H3 lysine 36 methyltransferase, and JARID1C (also known as KDM5C), a histone H3 lysine 4 demethylase-as well as mutations in the histone H3 lysine 27 demethylase, UTX (KMD6A), that we recently reported. The results highlight the role of mutations in components of the chromatin modification machinery in human cancer. Furthermore, NF2 mutations were found in non-VHL mutated ccRCC, and several other probable cancer genes were identified. These results indicate that substantial genetic heterogeneity exists in a cancer type dominated by mutations in a single gene, and that systematic screens will be key to fully determining the somatic genetic architecture of cancer.
Acute viral infections can have durable functional impacts on the immune system long after recovery, but how they affect homeostatic immune states and responses to future perturbations remain poorly ...understood
. Here we use systems immunology approaches, including longitudinal multimodal single-cell analysis (surface proteins, transcriptome and V(D)J sequences) to comparatively assess baseline immune statuses and responses to influenza vaccination in 33 healthy individuals after recovery from mild, non-hospitalized COVID-19 (mean, 151 days after diagnosis) and 40 age- and sex-matched control individuals who had never had COVID-19. At the baseline and independent of time after COVID-19, recoverees had elevated T cell activation signatures and lower expression of innate immune genes including Toll-like receptors in monocytes. Male individuals who had recovered from COVID-19 had coordinately higher innate, influenza-specific plasmablast, and antibody responses after vaccination compared with healthy male individuals and female individuals who had recovered from COVID-19, in part because male recoverees had monocytes with higher IL-15 responses early after vaccination coupled with elevated prevaccination frequencies of 'virtual memory'-like CD8
T cells poised to produce more IFNγ after IL-15 stimulation. Moreover, the expression of the repressed innate immune genes in monocytes increased by day 1 to day 28 after vaccination in recoverees, therefore moving towards the prevaccination baseline of the healthy control individuals. By contrast, these genes decreased on day 1 and returned to the baseline by day 28 in the control individuals. Our study reveals sex-dimorphic effects of previous mild COVID-19 and suggests that viral infections in humans can establish new immunological set-points that affect future immune responses in an antigen-agnostic manner.
Diffuse intrinsic pontine glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children, with no effective treatment and near 100% fatality. The failure of most therapies can be ...attributed to the delicate location of these tumors and to the selection of therapies on the basis of assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic makeup of this brain cancer, with nearly 80% found to harbor a p.Lys27Met histone H3.3 or p.Lys27Met histone H3.1 alteration. However, DIPGs are still thought of as one disease, with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs, we integrated whole-genome sequencing with methylation, expression and copy number profiling, discovering that DIPGs comprise three molecularly distinct subgroups (H3-K27M, silent and MYCN) and uncovering a new recurrent activating mutation affecting the activin receptor gene ACVR1 in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of the downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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