The findings that amyotrophic lateral sclerosis (ALS) patients almost universally display pathological mislocalization of the RNA-binding protein TDP-43 and that mutations in its gene cause familial ...ALS have nominated altered RNA metabolism as a disease mechanism. However, the RNAs regulated by TDP-43 in motor neurons and their connection to neuropathy remain to be identified. Here we report transcripts whose abundances in human motor neurons are sensitive to TDP-43 depletion. Notably, expression of STMN2, which encodes a microtubule regulator, declined after TDP-43 knockdown and TDP-43 mislocalization as well as in patient-specific motor neurons and postmortem patient spinal cord. STMN2 loss upon reduced TDP-43 function was due to altered splicing, which is functionally important, as we show STMN2 is necessary for normal axonal outgrowth and regeneration. Notably, post-translational stabilization of STMN2 rescued neurite outgrowth and axon regeneration deficits induced by TDP-43 depletion. We propose that restoring STMN2 expression warrants examination as a therapeutic strategy for ALS.
Upon recognition of pathogen virulence effectors, plant nucleotide-binding leucine-rich repeat (NLR) proteins induce defense responses including localized host cell death. In an effort to understand ...the molecular mechanisms leading to this response, we examined the Arabidopsis thaliana NLR protein RECOGNITION OF PERONOSPORA PARASITICA1 (RPP1), which recognizes the Hyaloperonospora arabidopsidis effector ARABIDOPSIS THALIANA RECOGNIZED1 (ATR1). Expression of the N-terminus of RPP1, including the Toll/interleukin-1 receptor (TIR) domain ("N-TIR"), elicited an effector-independent cell death response, and we used allelic variation in TIR domain sequences to define the key residues that contribute to this phenotype. Further biochemical characterization indicated that cell death induction was correlated with N-TIR domain self-association. In addition, we demonstrated that the nucleotide-binding (NB)-ARC1 region of RPP1 self-associates and plays a critical role in cell death activation, likely by facilitating TIR:TIR interactions. Structural homology modeling of the NB subdomain allowed us to identify a putative oligomerization interface that was shown to influence NB-ARC1 self-association. Significantly, full-length RPP1 exhibited effector-dependent oligomerization and, although mutations at the NB-ARC1 oligomerization interface eliminated cell death induction, RPP1 self-association was unaffected, suggesting that additional regions contribute to oligomerization. Indeed, the leucine-rich repeat domain of RPP1 also self-associates, indicating that multiple interaction interfaces exist within activated RPP1 oligomers. Finally, we observed numerous intramolecular interactions that likely function to negatively regulate RPP1, and present a model describing the transition to an active NLR protein.
Scientists disagree about the nature of biodiversity change. While there is evidence for widespread declines from population surveys, assemblage surveys reveal a mix of declines and increases. These ...conflicting conclusions may be caused by the use of different metrics: assemblage metrics may average out drastic changes in individual populations. Alternatively, differences may arise from data sources: populations monitored individually, versus whole‐assemblage monitoring. To test these hypotheses, we estimated population change metrics using assemblage data. For a set of 23 241 populations, 16 009 species, in 158 assemblages, we detected significantly accelerating extinction and colonisation rates, with both rates being approximately balanced. Most populations (85%) did not show significant trends in abundance, and those that did were balanced between winners (8%) and losers (7%). Thus, population metrics estimated with assemblage data are commensurate with assemblage metrics and reveal sustained and increasing species turnover.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor nervous system. We show using multielectrode array and patch-clamp recordings that hyperexcitability detected by ...clinical neurophysiological studies of ALS patients is recapitulated in induced pluripotent stem cell-derived motor neurons from ALS patients harboring superoxide dismutase 1 (SOD1), C9orf72, and fused-in-sarcoma mutations. Motor neurons produced from a genetically corrected but otherwise isogenic SOD1(+/+) stem cell line do not display the hyperexcitability phenotype. SOD1(A4V/+) ALS patient-derived motor neurons have reduced delayed-rectifier potassium current amplitudes relative to control-derived motor neurons, a deficit that may underlie their hyperexcitability. The Kv7 channel activator retigabine both blocks the hyperexcitability and improves motor neuron survival in vitro when tested in SOD1 mutant ALS cases. Therefore, electrophysiological characterization of human stem cell-derived neurons can reveal disease-related mechanisms and identify therapeutic candidates.
Double detonations in double white dwarf (WD) binaries undergoing unstable mass transfer have emerged in recent years as one of the most promising Type Ia supernova (SN Ia) progenitor scenarios. One ...potential outcome of this "dynamically driven double-degenerate double-detonation" (D6) scenario is that the companion WD survives the explosion and is flung away with a velocity equal to its >1000 km s−1 pre-SN orbital velocity. We perform a search for these hypervelocity runaway WDs using Gaia's second data release. In this paper, we discuss seven candidates followed up with ground-based instruments. Three sources are likely to be some of the fastest known stars in the Milky Way, with total Galactocentric velocities between 1000 and 3000 km s−1, and are consistent with having previously been companion WDs in pre-SN Ia systems. However, although the radial velocity of one of the stars is >1000 km s−1, the radial velocities of the other two stars are puzzlingly consistent with 0. The combined five-parameter astrometric solutions from Gaia and radial velocities from follow-up spectra yield tentative 6D confirmation of the D6 scenario. The past position of one of these stars places it within a faint, old SN remnant, further strengthening the interpretation of these candidates as hypervelocity runaways from binary systems that underwent SNe Ia.
SARM1 (sterile alpha and TIR motif containing 1) is responsible for depletion of nicotinamide adenine dinucleotide in its oxidized form (NAD
) during Wallerian degeneration associated with ...neuropathies. Plant nucleotide-binding leucine-rich repeat (NLR) immune receptors recognize pathogen effector proteins and trigger localized cell death to restrict pathogen infection. Both processes depend on closely related Toll/interleukin-1 receptor (TIR) domains in these proteins, which, as we show, feature self-association-dependent NAD
cleavage activity associated with cell death signaling. We further show that SARM1 SAM (sterile alpha motif) domains form an octamer essential for axon degeneration that contributes to TIR domain enzymatic activity. The crystal structures of ribose and NADP
(the oxidized form of nicotinamide adenine dinucleotide phosphate) complexes of SARM1 and plant NLR RUN1 TIR domains, respectively, reveal a conserved substrate binding site. NAD
cleavage by TIR domains is therefore a conserved feature of animal and plant cell death signaling pathways.
Combining biological components, such as cells and tissues, with soft robotics can enable the fabrication of biological machines with the ability to sense, process signals, and produce force. An ...intuitive demonstration of a biological machine is one that can produce motion in response to controllable external signaling. Whereas cardiac cell-driven biological actuators have been demonstrated, the requirements of these machines to respond to stimuli and exhibit controlled movement merit the use of skeletal muscle, the primary generator of actuation in animals, as a contractile power source. Here, we report the development of 3D printed hydrogel “bio-bots” with an asymmetric physical design and powered by the actuation of an engineered mammalian skeletal muscle strip to result in net locomotion of the bio-bot. Geometric design and material properties of the hydrogel bio-bots were optimized using stereolithographic 3D printing, and the effect of collagen I and fibrin extracellular matrix proteins and insulin-like growth factor 1 on the force production of engineered skeletal muscle was characterized. Electrical stimulation triggered contraction of cells in the muscle strip and net locomotion of the bio-bot with a maximum velocity of ∼156 μm s ⁻¹, which is over 1.5 body lengths per min. Modeling and simulation were used to understand both the effect of different design parameters on the bio-bot and the mechanism of motion. This demonstration advances the goal of realizing forward-engineered integrated cellular machines and systems, which can have a myriad array of applications in drug screening, programmable tissue engineering, drug delivery, and biomimetic machine design.
ABSTRACT Despite decades of intense efforts, many fundamental aspects of Type Ia supernovae (SNe Ia) remain elusive. One of the major open questions is whether the mass of an exploding white dwarf ...(WD) is close to the Chandrasekhar limit. Here, we report the detection of strong K-shell emission from stable Fe-peak elements in the Suzaku X-ray spectrum of the Type Ia supernova remnant (SNR) 3C 397. The high Ni/Fe and Mn/Fe mass ratios (0.11-0.24 and 0.018-0.033, respectively) in the hot plasma component that dominates the K-shell emission lines indicate a degree of neutronization in the supernova ejecta that can only be achieved by electron capture in the dense cores of exploding WDs with a near-Chandrasekhar mass. This suggests a single-degenerate origin for 3C 397, since Chandrasekhar mass progenitors are expected naturally if the WD accretes mass slowly from a companion. Together with other results supporting the double-degenerate scenario, our work adds to the mounting evidence that both progenitor channels make a significant contribution to the SN Ia rate in star-forming galaxies.
Abstract
Particle acceleration to suprathermal energies in strong astrophysical shock waves is a widespread phenomenon, generally explained by diffusive shock acceleration. Such shocks can also ...amplify the upstream magnetic field considerably beyond simple compression. The complex plasma physics processes involved are often parameterized by assuming that shocks put some fraction
ϵ
e
of their energy into fast particles and another fraction
ϵ
B
into the magnetic field. Modelers of shocks in supernovae, supernova remnants (SNRs), and gamma-ray bursters, among other locations, often assume typical values for these fractions, presumed to remain constant in time. However, it is rare that enough properties of a source are independently constrained that values of the epsilons can be inferred directly. SNRs can provide such circumstances. Here we summarize results from global fits to spatially integrated emission in six young SNRs, finding 10
−4
≲
ϵ
e
≲ 0.05 and 0.001 ≲
ϵ
B
≲ 0.1. These large variations might be put down to the differing ages and environments of these SNRs, so we conduct a detailed analysis of a single remnant, that of Kepler’s supernova. Both epsilons can be determined at seven different locations around the shock, and we find even larger ranges for both epsilons, as well as for their ratio (thus independent of the shock energy itself). We conclude that unknown factors have a large influence on the efficiency of both processes. Shock obliquity, upstream neutral fraction, or other possibilities need to be explored, while calculations assuming fixed values of the epsilons should be regarded as provisional.
Abstract
We present measurements of the expansion of Kepler’s Supernova Remnant (SNR) over three epochs of Chandra X-ray observations from 2000, 2006, and 2014. As the remnant of a historical ...supernova (observed in 1604 CE), Kepler’s SNR presents the rare opportunity to study the dynamical evolution of such an object in real time. Measurements of the asymmetry in the forward shock velocity can also provide insight into the nature of the explosion and density of the circumstellar material. By combining data from 2014 with previous epochs in 2000 and 2006, we can observe the proper motion of filaments along the outer rim of the SNR. Prior studies of Kepler’s SNR have shown proper motion differences up to a factor of 3 between the northern and southern regions around the remnant. With the longer time baseline we use here, we find results that are consistent with previous studies, but with smaller uncertainties. Additionally, by adding a third epoch of observations, we search for any systemic change in the velocity in the form of a deceleration of the blast wave, as was recently reported in Tycho’s SNR. We find little to no conclusive evidence of such deceleration, and conclude that Kepler’s SNR is encountering circumstellar material that is roughly constant in density, though substantially varied around the periphery.
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