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Tropical cyclone (TC) stalling has been widely perceived to yield a greater threat of flooding. Understanding the effect of stalling and its long‐term trends will enhance adaptation strategies to cyclone‐associated disasters. We show that stalling prolongs western North Pacific TCs to live 24 hr longer and produces 23% greater 24‐hr rainfall accumulations in a more concentrated area, which is more prominent over a 72‐hr rolling period. More importantly, we discover a northward migration of TC stalling (∼0.7°N decade−1) over 1979–2020, bringing increasingly higher flood risks to the highly‐populated East Asian coast. Further diagnoses suggest the role of binary cyclone interactions in TC stalling, whereby the second larger TC slows down the smaller one by weakening the northwestward steering flows. The northward shift of TC stalling can be explained by a similar trend in binary TC cases and environmental fields. Our findings are robust across various best track and precipitation products. Plain Language Summary Tropical cyclone (TC) stalling occurs when the cyclone resides in a small area for long. It is widely perceived to produce increased accumulated rainfall and flood risks in coastal areas nearby. However, little effort has been made to comprehensively quantify the difference in the general properties and hydrological impacts between stalled and non‐stalled TCs, as well as the spatial pattern and the possible causes of TC stalling. This study addresses the above research gaps by focusing on TC stalling over the western North Pacific (WNP) since the satellite era (1979–2020). We discover that stalling enables TCs to live significantly longer and produce greater rainfall accumulations in a more concentrated area, which is more prominent when measuring over a long rolling period (e.g., 72 hr). We highlight a northward migration of TC stalling phenomenon over the past decades, bringing increasingly greater flood risks to the highly‐populated East Asian coast, especially the Pearl River Delta. The plausible physical causes of stalling are discussed and our conclusions are validated across various sources of data. Findings here improve the understanding of TC stalling and stress the need for future adaptations against more frequent stalling events along the East Asian coasts. Key Points Stalling prolongs tropical cyclones (TCs) by 24 hr more and produces 23% greater 24‐hr rolling downpours over a more concentrated area The hydrological impacts of TC stalling are more prominent over a long rolling period (e.g., 72‐hr) A northward shift of TC stalling (∼0.7°N decade−1) brings increasingly greater threats to coastal areas in the western North Pacific

Translating ribosomes slow down or completely stall when they encounter obstacles on mRNAs. Such events can lead to ribosomes colliding with each other and forming complexes of two (disome), three (trisome) or more ribosomes. While these events can activate surveillance pathways, it has been unclear if collisions are common on endogenous mRNAs and whether they are usually detected by these cellular pathways. Recent genome-wide surveys of collisions revealed widespread distribution of disomes and trisomes across endogenous mRNAs in eukaryotic cells. Several studies further hinted that the recognition of collisions and response to them by multiple surveillance pathways depend on the context and duration of the ribosome stalling. This review considers recent efforts in the identification of endogenous ribosome collisions and cellular pathways dedicated to sense their severity. We further discuss the potential role of collided ribosomes in modulating co-translational events and contributing to cellular homeostasis.

Axial compressors have been used in areas such as propulsion and power generation for many decades now. The development of compressors has been accompanied by the identification of gas dynamic instabilities during their operation, such as surge and stall, and the subsequent development of technologies to mitigate such problems. A widely employed lumped model for studying post stall phenomenon, usually referred to as Moore-Greitzer model, involves combining the geometric and operating parameters of the compression system into certain non-dimensional groups. In this paper, a numerical study of the different parameters affecting the surge phenomenon in axial compressors is performed. By unfurling the non-dimensional groups in the Moore-Greitzer model, the significance of the actual geometric and operational variables is identified.

In vitro-transcribed (IVT) mRNAs are modalities that can combat human disease, exemplified by their use as vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). IVT mRNAs are transfected into target cells, where they are translated into recombinant protein, and the biological activity or immunogenicity of the encoded protein exerts an intended therapeutic effect 1 , 2 . Modified ribonucleotides are commonly incorporated into therapeutic IVT mRNAs to decrease their innate immunogenicity 3 – 5 , but their effects on mRNA translation fidelity have not been fully explored. Here we demonstrate that incorporation of N 1 -methylpseudouridine into mRNA results in +1 ribosomal frameshifting in vitro and that cellular immunity in mice and humans to +1 frameshifted products from BNT162b2 vaccine mRNA translation occurs after vaccination. The +1 ribosome frameshifting observed is probably a consequence of N 1 -methylpseudouridine-induced ribosome stalling during IVT mRNA translation, with frameshifting occurring at ribosome slippery sequences. However, we demonstrate that synonymous targeting of such slippery sequences provides an effective strategy to reduce the production of frameshifted products. Overall, these data increase our understanding of how modified ribonucleotides affect the fidelity of mRNA translation, and although there are no adverse outcomes reported from mistranslation of mRNA-based SARS-CoV-2 vaccines in humans, these data highlight potential off-target effects for future mRNA-based therapeutics and demonstrate the requirement for sequence optimization. A study demonstrates that nucleotide modifications in mRNA-based therapeutics can lead to +1 ribosomal frameshifting during translation, yielding products that can trigger immune responses.

Diffuser rotating stall (DRS) occurring in vaned diffusers significantly limits the operating range of industrial pumps, making the suppression of DRS a critical issue. As one countermeasure, it was experimentally demonstrated that a non-axisymmetric diffuser, formed by cutting the leading edge of every other vane, effectively suppresses the DRS in a mixed-flow pump. The authors applied this design to a centrifugal pump and investigated the suppression mechanism experimentally and numerically. In this study, the leading edges of three vanes in the base model’s eight-vane diffuser were cut by 14% in the vane axial direction. This process suppressed the DRS onset flow rate to 8% below the design flow rate. However, the effect of the short vane geometry on DRS suppression remains undiscussed, requiring further study to establish design guidelines. This study focuses on the inlet area ratio AP/AS, defined as the ratio of the inlet area on the pressure side AP to that on the suction side AS of a short vane. The diffuser with three leading edge cuts, which demonstrated the DRS suppression effect, has an AP/AS ratio of 2.61. As a comparison, the test diffuser was designed with an AP/AS ratio of 1/2.61, while maintaining the inlet and outlet vane angles. Experimental measurements show that at an AP/AS ratio of 1/2.61, DRS onsets at 68% of the design flow rate, significantly higher than at an AP/AS ratio of 2.61. To investigate the cause of this phenomenon, an unsteady RANS analysis was performed at the DRS onset flow rate, revealing that the decrease in AP promotes inlet blockage of the backflow generated on the vane suction surface, contributing to the propagation of the stall region.

In order to improve the stall characteristics of civil aircrafts and increase the maximum available lift coefficient, this paper studied two types of aerodynamic combination measures through wind tunnel test--the inner slat gap seal and outer slat modification, as well as the inner slat stall bar and outer slat modification. The test results showed that the combination measures of the inner slat gap seal and outer slat modification can make the horizontal roll stall divergence angle at least 1° greater than the longitudinal stall angle of attack, and the turning roll stall divergence angle is at least 2° later than the longitudinal stall angle of attack. The combination measures of the inner slat stall bar and outer slat modification can make the horizontal roll stall divergence angle about 2° greater than the longitudinal stall angle of attack, and the turning roll stall divergence angle is also about 2° later than the longitudinal stall angle of attack. The test results indicate that the two types of aerodynamic combination schemes can improve the stall characteristics and change the stall type into the longitudinal stall.

In higher eukaryotes, transfer RNAs (tRNAs) with the same anticodon are encoded by multiple nuclear genes, and little is known about how mutations in these genes affect translation and cellular homeostasis. Similarly, the surveillance systems that respond to such defects in higher eukaryotes are not clear. Here, we discover that loss of GTPBP2, a novel binding partner of the ribosome recycling protein Pelota, in mice with a mutation in a tRNA gene that is specifically expressed in the central nervous system causes ribosome stalling and widespread neurodegeneration. Our results not only define GTPBP2 as a ribosome rescue factor but also unmask the disease potential of mutations in nuclear-encoded tRNA genes.

Molecular-motor coordinationThe proteasome is a cytosolic molecular machine that recognizes and degrades unneeded or damaged proteins that have been tagged with ubiquitin. A heterohexameric adenosine triphosphatase motor pulls the substrate into the proteolytic chamber, while at the same time, a protein located at the entrance of this motor removes the ubiquitin. De la Peña et al. trapped the substrate inside the motor by inhibiting removal of ubiquitin. This allowed them to determine cryo–electron microscopy structures in the presence of substrate and adenosine triphosphate (ATP). The findings distinguish three sequential conformational states that show how ATP binding, hydrolysis, and phosphate release are coordinated between the six subunits of the motor to cause the conformational changes that translocate the substrate through the proteasome.Science, this issue p. eaav0725INTRODUCTIONAs the major protease in eukaryotic cells and the final component of the ubiquitin-proteasome system, the 26S proteasome is responsible for protein homeostasis and the regulation of numerous vital processes. Misfolded, damaged, or obsolete regulatory proteins are marked for degradation by the attachment of polyubiquitin chains, which bind to ubiquitin receptors of the proteasome. A heterohexameric ring of AAA+ (ATPases associated with diverse cellular activities) subunits then uses conserved pore loops to engage, mechanically unfold, and translocate protein substrates into a proteolytic core for cleavage while the deubiquitinase Rpn11 removes substrate-attached ubiquitin chains.RATIONALEDespite numerous structural and functional studies, the mechanisms by which adenosine triphosphate (ATP) hydrolysis drives the conformational changes responsible for protein degradation remained elusive. Structures of related homohexameric AAA+ motors, in which bound substrates were stabilized with ATP analogs or hydrolysis-eliminating mutations, revealed snapshots of ATPase subunits in different nucleotide states and spiral-staircase arrangements of pore loops around the substrate. These structures gave rise to “hand-over-hand” translocation models by inferring how individual subunits may progress through various substrate-binding conformations. However, the coordination of ATP-hydrolysis steps and their mechanochemical coupling to propelling substrate were unknown.RESULTSWe present the cryo–electron microscopy (cryo-EM) structures of the actively ATP-hydrolyzing, substrate-engaged 26S proteasome with four distinct motor conformations. Stalling substrate translocation at a defined position by inhibiting deubiquitination led to trapped states in which the substrate-attached ubiquitin remains functionally bound to the Rpn11 deubiquitinase, and the scissile isopeptide bond of ubiquitin is aligned with the substrate-translocation trajectory through the AAA+ motor. Our structures suggest a ubiquitin capture mechanism, in which mechanical pulling on the substrate by the AAA+ motor delivers ubiquitin modifications directly into the Rpn11 catalytic groove and accelerates isopeptide cleavage for efficient, cotranslocational deubiquitination.These structures also show how the substrate polypeptide traverses from the Rpn11 deubiquitinase, through the AAA+ motor, and into the core peptidase. The proteasomal motor thereby adopts staircase arrangements with five substrate-engaged subunits and one disengaged subunit. Four of the substrate-engaged subunits are ATP bound, whereas the subunit at the bottom of the staircase and the disengaged subunit are bound to adenosine diphosphate (ADP).CONCLUSIONOf the four distinct motor states we observed, three apparently represent sequential stages of ATP binding, hydrolysis, and substrate translocation and hence reveal the coordination of individual steps in the ATPase cycle and their mechanochemical coupling with translocation. ATP hydrolysis occurs in the fourth substrate-engaged subunit from the top, concomitantly with exchange of ADP for ATP in the disengaged subunit. The subsequent transition, which is likely triggered by phosphate release from the fourth, posthydrolysis subunit of the staircase, then involves major conformational changes of the entire ATPase hexamer. The bottom ADP-bound subunit is displaced and the previously disengaged subunit binds the substrate at the top of the staircase, while the four engaged subunits move downward as a rigid body and translocate substrate toward the peptidase. Our likely consecutive proteasome conformations, together with previously determined substrate-free structures, suggest a sequential progression of ATPase subunits through the ATP-hydrolysis cycle. We hypothesize that, in general, hexameric AAA+ translocases function by this sequential mechanism.The 26S proteasome is the primary eukaryotic degradation machine and thus is critically involved in numerous cellular processes. The heterohexameric adenosine triphosphatase (ATPase) motor of the proteasome unfolds and translocates targeted protein substrates into the open gate of a proteolytic core while a proteasomal deubiquitinase concomitantly removes substrate-attached ubiquitin chains. However, the mechanisms by which ATP hydrolysis drives the conformational changes responsible for these processes have remained elusive. Here we present the cryo–electron microscopy structures of four distinct conformational states of the actively ATP-hydrolyzing, substrate-engaged 26S proteasome. These structures reveal how mechanical substrate translocation accelerates deubiquitination and how ATP-binding, -hydrolysis, and phosphate-release events are coordinated within the AAA+ (ATPases associated with diverse cellular activities) motor to induce conformational changes and propel the substrate through the central pore.

Remdesivir is the only FDA-approved drug for the treatment of COVID-19 patients. The active form of remdesivir acts as a nucleoside analog and inhibits the RNA-dependent RNA polymerase (RdRp) of coronaviruses including SARS-CoV-2. Remdesivir is incorporated by the RdRp into the growing RNA product and allows for addition of three more nucleotides before RNA synthesis stalls. Here we use synthetic RNA chemistry, biochemistry and cryo-electron microscopy to establish the molecular mechanism of remdesivir-induced RdRp stalling. We show that addition of the fourth nucleotide following remdesivir incorporation into the RNA product is impaired by a barrier to further RNA translocation. This translocation barrier causes retention of the RNA 3ʹ-nucleotide in the substrate-binding site of the RdRp and interferes with entry of the next nucleoside triphosphate, thereby stalling RdRp. In the structure of the remdesivir-stalled state, the 3ʹ-nucleotide of the RNA product is matched and located with the template base in the active center, and this may impair proofreading by the viral 3ʹ-exonuclease. These mechanistic insights should facilitate the quest for improved antivirals that target coronavirus replication. Remdesivir is a nucleoside analog that inhibits the SARS-CoV-2 RNA dependent RNA polymerase (RdRp) and is used as a drug to treat COVID19 patients. Here, the authors provide insights into the mechanism of remdesivir-induced RdRp stalling by determining the cryo-EM structures of SARS-CoV-2 RdRp with bound RNA molecules that contain remdesivir at defined positions and observe that addition of the fourth nucleotide following remdesivir incorporation into the RNA product is impaired by a barrier to further RNA translocation.

Oncoproteins of the MYC family are major drivers of human tumorigenesis. Since a large body of evidence indicates that MYC proteins are transcription factors, studying their function has focused on the biology of their target genes. Detailed studies of MYC-dependent changes in RNA levels have provided contrasting models of the oncogenic activity of MYC proteins through either enhancing or repressing the expression of specific target genes, or as global amplifiers of transcription. In this Review, we first summarize the biochemistry of MYC proteins and what is known (or is unclear) about the MYC target genes. We then discuss recent progress in defining the interactomes of MYC and MYCN and how this information affects central concepts of MYC biology, focusing on mechanisms by which MYC proteins modulate transcription. MYC proteins promote transcription termination upon stalling of RNA polymerase II, and we propose that this mechanism enhances the stress resilience of basal transcription. Furthermore, MYC proteins coordinate transcription elongation with DNA replication and cell cycle progression. Finally, we argue that the mechanism by which MYC proteins regulate the transcription machinery is likely to promote tumorigenesis independently of global or relative changes in the expression of their target genes.The MYC oncoproteins are transcription factors, but the molecular mechanism of their oncogenic activity is unclear. MYC proteins promote transcription termination in stress conditions, which is proposed to increase cellular resilience to stress and to promote tumorigenesis independently of changes in the expression of their target genes.