Klavsenschneider9584

Heterogeneous transcriptional start site usage by HIV-1 produces 5'-capped RNAs beginning with one, two, or three 5'-guanosines (Cap1G, Cap2G, or Cap3G, respectively) that are either selected for packaging as genomes (Cap1G) or retained in cells as translatable messenger RNAs (mRNAs) (Cap2G and Cap3G). To understand how 5'-guanosine number influences fate, we probed the structures of capped HIV-1 leader RNAs by deuterium-edited nuclear magnetic resonance. The Cap1G transcript adopts a dimeric multihairpin structure that sequesters the cap, inhibits interactions with eukaryotic translation initiation factor 4E, and resists decapping. The Cap2G and Cap3G transcripts adopt an alternate structure with an elongated central helix, exposed splice donor residues, and an accessible cap. Extensive remodeling, achieved at the energetic cost of a G-C base pair, explains how a single 5'-guanosine modifies the function of a ~9-kilobase HIV-1 transcript. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.Venus has a thick atmosphere that rotates 60 times as fast as the surface, a phenomenon known as super-rotation. We use data obtained from the orbiting Akatsuki spacecraft to investigate how the super-rotation is maintained in the cloud layer, where the rotation speed is highest. A thermally induced latitudinal-vertical circulation acts to homogenize the distribution of the angular momentum around the rotational axis. Maintaining the super-rotation requires this to be counteracted by atmospheric waves and turbulence. Among those effects, thermal tides transport the angular momentum, which maintains the rotation peak, near the cloud top at low latitudes. Other planetary-scale waves and large-scale turbulence act in the opposite direction. We suggest that hydrodynamic instabilities adjust the angular-momentum distribution at mid-latitudes. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.Plasmonic skyrmions are an optical manifestation of topological defects in a continuous vector field. Identifying them requires characterization of the vector structure of the electromagnetic near field on thin metal films. Here we introduce time-resolved vector microscopy that creates movies of the electric field vectors of surface plasmons with subfemtosecond time steps and a 10-nanometer spatial scale. We image complete time sequences of propagating surface plasmons as well as plasmonic skyrmions, resolving all vector components of the electric field and their time dynamics, thus demonstrating dynamic spin-momentum coupling as well as the time-varying skyrmion number. The ability to image linear optical effects in the spin and phase structures of light in the single-nanometer range will allow for entirely novel microscopy and metrology applications. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.Protein quality control is essential for the proper function of cells and the organisms that they make up. The resulting loss of proteostasis, the processes by which the health of the cell's proteins is monitored and maintained at homeostasis, is associated with a wide range of age-related human diseases. Here, we highlight how the integrated stress response (ISR), a central signaling network that responds to proteostasis defects by tuning protein synthesis rates, impedes the formation of long-term memory. In addition, we address how dysregulated ISR signaling contributes to the pathogenesis of complex diseases, including cognitive disorders, neurodegeneration, cancer, diabetes, and metabolic disorders. The development of tools through which the ISR can be modulated promises to uncover new avenues to diminish pathologies resulting from it for clinical benefit. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.Misfolded luminal endoplasmic reticulum (ER) proteins undergo ER-associated degradation (ERAD-L) They are retrotranslocated into the cytosol, polyubiquitinated, and degraded by the proteasome. ERAD-L is mediated by the Hrd1 complex (composed of Hrd1, Hrd3, Der1, Usa1, and Yos9), but the mechanism of retrotranslocation remains mysterious. Here, we report a structure of the active Hrd1 complex, as determined by cryo-electron microscopy analysis of two subcomplexes. Hrd3 and Yos9 jointly create a luminal binding site that recognizes glycosylated substrates. Hrd1 and the rhomboid-like Der1 protein form two "half-channels" with cytosolic and luminal cavities, respectively, and lateral gates facing one another in a thinned membrane region. These structures, along with crosslinking and molecular dynamics simulation results, suggest how a polypeptide loop of an ERAD-L substrate moves through the ER membrane. Ku-0059436 Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.Baseline lung function, quantified as forced expiratory volume in the first second of exhalation (FEV1), is a standard diagnostic criterion used by clinicians to identify and classify lung diseases. Using whole genome sequencing data from the National Heart, Lung, and Blood Institute TOPMed project, we identified a novel genetic association with FEV1 on chromosome 12 in 867 African American children with asthma (p = 1.26 × 10-8, β = 0.302). Conditional analysis within 1 Mb of the tag signal (rs73429450) yielded one major and two other weaker independent signals within this peak. We explored statistical and functional evidence for all variants in linkage disequilibrium with the three independent signals and yielded 9 variants as the most likely candidates responsible for the association with FEV1 Hi-C data and eQTL analysis demonstrated that these variants physically interacted with KITLG (aka SCF) and their minor alleles were associated with increased expression of KITLG gene in nasal epithelial cells. Gene-by-air-pollution interaction analysis found that the candidate variant rs58475486 interacted with past-year SO2 exposure (p = 0.