Stalled translation produces incomplete, ribosome-tethered polypeptides that the ribosome-associated quality control (RQC) pathway targets for degradation via the E3 ubiquitin ligase Ltn1. During ...this process, the protein Rqc2 and the large ribosomal subunit elongate stalled polypeptides with carboxy-terminal alanine and threonine residues (CAT tails). Failure to degrade CAT-tailed proteins disrupts global protein homeostasis, as CAT-tailed proteins can aggregate and sequester chaperones. Why cells employ such a potentially toxic process during RQC is unclear. Here, we developed quantitative techniques to assess how CAT tails affect stalled polypeptide degradation in Saccharomyces cerevisiae. We found that CAT tails enhance the efficiency of Ltn1 in targeting structured polypeptides, which are otherwise poor Ltn1 substrates. If Ltn1 fails to ubiquitylate those stalled polypeptides or becomes limiting, CAT tails act as degrons, marking proteins for proteasomal degradation off the ribosome. Thus, CAT tails functionalize the carboxy termini of stalled polypeptides to drive their degradation on and off the ribosome.
Stalled protein synthesis produces defective nascent chains that can harm cells. In response, cells degrade these nascent chains via a process called ribosome-associated quality control (RQC). Here, ...we review the irregularities in the translation process that cause ribosomes to stall as well as how cells use RQC to detect stalled ribosomes, ubiquitylate their tethered nascent chains, and deliver the ubiquitylated nascent chains to the proteasome. We additionally summarize how cells respond to RQC failure.
We derive analytic bounds on the shape of the primordial power spectrum in the context of single-field inflation. In particular, the steepest possible growth has a spectral index of ns−1=4 once ...transients have died down. Its primary implication is that any constraint on the power spectrum at a particular scale can be extrapolated to an upper bound over an extended range of scales. This is important for models which generate relics due to an enhanced amplitude of the primordial scalar perturbations, such as primordial black holes. In order to generate them, the power spectrum needs to grow many orders of magnitude larger than its observed value on CMB scales—typically achieved through a phase of ultra slow-roll inflation—and is thus subject to additional constraints at small scales. We plot all relevant constraints including CMB spectral distortions and gravitational waves sourced by scalar perturbations at second order. We show how this limits the allowed mass of PBHs, especially for the large masses of interest following recent detections by LIGO and prospects for constraining them further with future observations. We show that any transition from approximately constant ε slow-roll inflation to a phase where the power spectrum rapidly rises necessarily implies an intervening dip in power. We also show how to reconstruct a potential that can reproduce an arbitrary time-varying ε, offering a complementary perspective on how ultra slow-roll can be achieved.
The Canadian Earth System Model version 5 (CanESM5) is a global
model developed to simulate historical climate change and variability, to
make centennial-scale projections of future climate, and to ...produce
initialized seasonal and decadal predictions. This paper describes the model
components and their coupling, as well as various aspects of model
development, including tuning, optimization, and a reproducibility strategy.
We also document the stability of the model using a long control simulation,
quantify the model's ability to reproduce large-scale features of the
historical climate, and evaluate the response of the model to external
forcing. CanESM5 is comprised of three-dimensional atmosphere (T63 spectral
resolution equivalent roughly to 2.8∘) and ocean (nominally 1∘) general
circulation models, a sea-ice model, a land surface scheme, and explicit
land and ocean carbon cycle models. The model features relatively coarse
resolution and high throughput, which facilitates the production of large
ensembles. CanESM5 has a notably higher equilibrium climate sensitivity
(5.6 K) than its predecessor, CanESM2 (3.7 K), which we briefly discuss, along
with simulated changes over the historical period. CanESM5 simulations
contribute to the Coupled Model Intercomparison Project phase 6 (CMIP6)
and will be employed for climate science and service applications in Canada.
We show, theoretically, that a heterostructure of monolayer FeTe1−xSex-a superconducting quantum spin Hall material-with a monolayer of FeTe-a bicollinear antiferromagnet-realizes a higher order ...topological superconductor phase characterized by emergent Majorana zero modes pinned to the sample corners. We provide a minimal effective model for this system, analyze the origin of higher order topology, and fully characterize the topological phase diagram. Despite the conventional s-wave pairing, we find a rather surprising emergence of a novel topological nodal superconductor in the phase diagram. Featured by edge-dependent Majorana flat bands, the topological nodal phase is protected by an antiferromagnetic chiral symmetry. We also discuss the experimental feasibility, the estimation of realistic model parameters, and the robustness of the Majorana corner modes against magnetic and potential disorder. Our work provides a new experimentally feasible high-temperature platform for both higher order topology and non-Abelian Majorana physics.
The paper reviews the literature that may assist in forming a multiscale model of corrosion in soils. This model should take into account macro-environmental processes (rainfall, etc.), soils ...processes (water movement, oxygen transport, etc.), processes within the oxides, and the electrochemical activity occurring at the metal surface. The literature reviewed includes traditional corrosion research such as surveys and historical analysis of buried pipelines, scientific exposures of buried metal, results from buried sensors, and laboratory studies aimed to duplicate soil exposures. Also included are wider studies on water and solute movement in soils, and oxygen transport through soils.
Motivated by recent experiments on FeTe_{1-x}Se_{x}, we construct an explicit minimal model of an iron-based superconductor with band inversion at the Z point and nontopological bulk s_{±} pairing. ...While there has been considerable interest in Majorana zero modes localized at vortices in such systems, we find that our model-without any vortices-intrinsically supports 1D helical Majorana modes localized at the hinges between (001) and (100) or (010) surfaces, suggesting that this is a viable platform for observing "higher-order" topological superconductivity. We provide a general theory for these hinge modes and discuss their stability and experimental manifestation. Our work indicates the possible experimental observability of hinge Majorana modes in iron-based topological superconductors.
Premature arrest of protein synthesis within the open reading frame elicits a protective response that degrades the incomplete nascent chain. In this response, arrested 80S ribosomes are split into ...their large and small subunits, allowing assembly of the ribosome quality control complex (RQC), which targets nascent chains for degradation. How the cell recognizes arrested nascent chains among the vast pool of actively translating polypeptides is poorly understood. We systematically examined translation arrest and modification of nascent chains in
to characterize the steps that couple arrest to RQC targeting. We focused our analysis on two poorly understood 80S ribosome-binding proteins previously implicated in the response to failed translation, Asc1 and Hel2, as well as a new component of the pathway, Slh1, that we identified here. We found that premature arrest at ribosome stalling sequences still occurred robustly in the absence of Asc1, Hel2, and Slh1. However, these three factors were required for the RQC to modify the nascent chain. We propose that Asc1, Hel2, and Slh1 target arresting ribosomes and that this targeting event is a precondition for the RQC to engage the incomplete nascent chain and facilitate its degradation.
KCNMA1 -linked channelopathy Bailey, Cole S; Moldenhauer, Hans J; Park, Su Mi ...
The Journal of general physiology,
10/2019, Letnik:
151, Številka:
10
Journal Article
Recenzirano
Odprti dostop
encodes the pore-forming α subunit of the "Big K
" (BK) large conductance calcium and voltage-activated K
channel. BK channels are widely distributed across tissues, including both excitable and ...nonexcitable cells. Expression levels are highest in brain and muscle, where BK channels are critical regulators of neuronal excitability and muscle contractility. A global deletion in mouse (
) is viable but exhibits pathophysiology in many organ systems. Yet despite the important roles in animal models, the consequences of dysfunctional BK channels in humans are not well characterized. Here, we summarize 16 rare
mutations identified in 37 patients dating back to 2005, with an array of clinically defined pathological phenotypes collectively referred to as "
-linked channelopathy." These mutations encompass gain-of-function (GOF) and loss-of-function (LOF) alterations in BK channel activity, as well as several variants of unknown significance (VUS). Human
mutations are primarily associated with neurological conditions, including seizures, movement disorders, developmental delay, and intellectual disability. Due to the recent identification of additional patients, the spectrum of symptoms associated with
mutations has expanded but remains primarily defined by brain and muscle dysfunction. Emerging evidence suggests the functional BK channel alterations produced by different
alleles may associate with semi-distinct patient symptoms, such as paroxysmal nonkinesigenic dyskinesia (PNKD) with GOF and ataxia with LOF. However, due to the de novo origins for the majority of
mutations identified to date and the phenotypic variability exhibited by patients, additional evidence is required to establish causality in most cases. The symptomatic picture developing from patients with
-linked channelopathy highlights the importance of better understanding the roles BK channels play in regulating cell excitability. Establishing causality between
-linked BK channel dysfunction and specific patient symptoms may reveal new treatment approaches with the potential to increase therapeutic efficacy over current standard regimens.
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