The respiratory syncytial virus nucleoprotein–RNA complex forms a left-handed helical nucleocapsid

Respiratory Syncytial Virus (RSV) is an important human pathogen. Its nucleocapsid (NC), which comprises the negative sense RNA viral genome coated by the viral nucleoprotein N, is a critical assembly that serves as template for both mRNA synthesis and genome replication. We have previously described the X-ray structure of a nucleocapsid-like structure: a decameric ring formed of N-RNA that mimics one turn of the helical NC. In the absence of experimental data we had hypothesized that the NC helix would be right-handed, as the N-N contacts in the ring appeared to more easily adapt to that conformation. We now unambiguously show that the RSV NC is a left-handed helix. We further show that the contacts in the ring can be distorted to maintain key N-N protein interactions in a left-handed helix, and discuss the implications of the resulting atomic model of the helical NC for viral replication and transcription

Characterization of a Structural Intermediate of Flavivirus Membrane Fusion

Viral membrane fusion proceeds through a sequence of steps that are driven by triggered conformational changes of viral envelope glycoproteins, so-called fusion proteins. Although high-resolution structural snapshots of viral fusion proteins in their prefusion and postfusion conformations are available, it has been difficult to define intermediate structures of the fusion pathway because of their transient nature. Flaviviruses possess a class II viral fusion protein (E) mediating fusion at acidic pH that is converted from a dimer to a trimer with a hairpin-like structure during the fusion process. Here we show for tick-borne encephalitis virus that exposure of virions to alkaline instead of acidic pH traps the particles in an intermediate conformation in which the E dimers dissociate and interact with target membranes via the fusion peptide without proceeding to the merger of the membranes. Further treatment to low pH, however, leads to fusion, suggesting that these monomers correspond to an as-yet-elusive intermediate required to convert the prefusion dimer into the postfusion trimer. Thus, the use of nonphysiological conditions allows a dissection of the flavivirus fusion process and the identification of two separate steps, in which membrane insertion of multiple copies of E monomers precedes the formation of hairpin-like trimers. This sequence of events provides important new insights for understanding the dynamic process of viral membrane fusion

Central ions and lateral asparagine/glutamine zippers stabilize the post-fusion hairpin conformation of the SARS coronavirus spike glycoprotein

AbstractThe coronavirus spike glycoprotein is a class I membrane fusion protein with two characteristic heptad repeat regions (HR1 and HR2) in its ectodomain. Here, we report the X-ray structure of a previously characterized HR1/HR2 complex of the severe acute respiratory syndrome coronavirus spike protein. As expected, the HR1 and HR2 segments are organized in antiparallel orientations within a rod-like molecule. The HR1 helices form an exceptionally long (120 Å) internal coiled coil stabilized by hydrophobic and polar interactions. A striking arrangement of conserved asparagine and glutamine residues of HR1 propagates from two central chloride ions, providing hydrogen-bonding “zippers” that strongly constrain the path of the HR2 main chain, forcing it to adopt an extended conformation at either end of a short HR2 α-helix

Self-trapping in an array of coupled 1D Bose gases

We study the transverse expansion of arrays of ultracold $^{87}$Rb atoms weakly confined in tubes created by a 2D optical lattice, and observe that transverse expansion is delayed because of mutual atom interactions. A mean-field model of a coupled array shows that atoms become localized within a roughly square fort-like self-trapping barrier with time-evolving edges. But the observed dynamics is poorly described by the mean-field model. Theoretical introduction of random phase fluctuations among tubes improves the agreement with experiment, but does not correctly predict the density at which the atoms start to expand with larger lattice depths. Our results suggest a new type of self-trapping, where quantum correlations suppress tunneling even when there are no density gradients

Association between speech reception threshold in noise and multimorbidity: The UK Biobank Study

Objective. To investigate the association between hearing function, as approached with the functional auditory capacity, and multimorbidity. Study Design. Cross-sectional study. Setting. The UK Biobank was established from 2006 to 2010 in the United Kingdom. This cross-sectional analysis included 165,524 participants who provided baseline information on hearing function. Methods. Functional auditory capacity was measured with a digit triplet test. Three categories were defined according to the speech reception threshold in noise (SRTn): normal (SRTn < −5.5 dB signal-to-noise ratio [SNR]), insufficient (SRTn ≥ −5.5 to ≤ −3.5 dB SNR) and poor hearing function (SRTn > −3.5 dB SNR). To define multimorbidity, 9 chronic diseases were considered, including chronic obstructive pulmonary disease, dementia, Parkinson's disease, stroke, cancer, depression, osteoarthritis, coronary heart disease, and diabetes; multimorbidity was defined as the coexistence of 2 or more in the same individual. Analyses were conducted using logistic models adjusted for relevant confounders. Results. Among the study participants, 54.5% were women, and the mean (range) age was 56.7 (39-72) years. The prevalence of insufficient and poor hearing function and multimorbidity was 13% and 13.2%, respectively. In comparison with having a normal SRTn, the odds ratio (95% confidence interval) of multimorbidity associated with insufficient SRTn was 1.13 (1.08- 1.18), and with poor SRTn was 1.25 (1.14-1.37). Conclusion. Insufficient and poor hearing function was associated with multimorbidity. This association suggests common biological pathways for many of the considered morbiditiesThis work was supported by Instituto de Salud Carlos III through the FIS project 20/01040 (Instituto de Salud Carlos III, State Secretary of R + D + I), and co‐funded by a European Regional Development Fund, “A way of shaping Europe.” Ellen A. Struijk holds a Ramón y Cajal contract (RYC‐ 2021‐031146‐I) from the Ministry of Science, Innovation and Universities and FEDER/FS

Dermal-Type Macrophages Expressing CD209/DC-SIGN Show Inherent Resistance to Dengue Virus Growth

Mosquito-transmitted pathogens are a major challenge to humans due to ever-increasing distribution of the vector worldwide. Dengue virus causes morbidity and mortality, and no anti-viral treatment or vaccine are currently available. The virus is injected into the skin when an infected mosquito probes for blood. Among the skin immunocytes, dendritic cells and macrophages are equipped with pathogen-sensing receptors. Our work has shown that dermal macrophages bind the dengue virus envelope protein. We demonstrate that monocyte-derived dermal macrophages are resistant to infection and present evidence that this is due to sequestration of the virus into fusion-incompetent intracellular vesicles. This identifies skin macrophages as the first innate immune cell potentially capable of protecting the human host from infection by dengue virus shortly after a mosquito bite. These findings have important implications for better understanding the early infection events of dengue virus and of other skin-penetrating pathogens

Assessing the internal uppermost crustal structure of the central pyrenees by gravity-constrained cross sections

The Pyrenees constitutes an exceptional example of an Alpine orogenic belt characterized by basement thrust sheets involving Paleozoic rocks and Mesozoic and Cenozoic cover units detached on the Triassic evaporites, the main décollement level. This work is located in the Central Pyrenees, where gravity data help to better constrain the internal architecture of the upper crust of the southern half of the Axial Zone and the northern part of the South Pyrenean Zone, a key area to understand the orogenic evolution of the chain. Previous and new gravity, petrophysical and geological data have been used to obtain the Bouguer and residual anomaly maps of the study area and six serial gravity-constrained cross sections perpendicular to the main structural trend. The residual anomaly map shows a good correlation between basement units involved in thrust sheets of the study area and gravity highs whereas negative anomalies are interpreted to correspond with Mesozoic/Cenozoic basins, Triassic evaporites, Late Variscan igneous bodies, and Ordovician gneisses. The six gravity-constrained cross sections highlight strong along-strike variations on the gravity signal due to lateral differences of the superficial and subsurface occurrence of Triassic evaporites, different geometry at depth of the Late Variscan igneous bodies outcropping in the study area, and geometric lateral variations of the basement thrust sheets and their relationship with the Mesozoic-Cenozoic units.This work was funded by projects CGL2017-84901-C2-2-P funded by MCIN/AEI/10.13039/501100011033 and “ERDF A way of making Europe”, PID2020-114273GB-C22 funded by MCIN/AEI/10.13039/501100011033 from the Spanish Ministry of Science and Innovation, and "Severo Ochoa” extraordinary grants for excellence IGME-CSIC (AECEX2021).Peer reviewe

H1N1 2009 Pandemic Influenza Virus: Resistance of the I223R Neuraminidase Mutant Explained by Kinetic and Structural Analysis

Two classes of antiviral drugs, neuraminidase inhibitors and adamantanes, are approved for prophylaxis and therapy against influenza virus infections. A major concern is that antiviral resistant viruses emerge and spread in the human population. The 2009 pandemic H1N1 virus is already resistant to adamantanes. Recently, a novel neuraminidase inhibitor resistance mutation I223R was identified in the neuraminidase of this subtype. To understand the resistance mechanism of this mutation, the enzymatic properties of the I223R mutant, together with the most frequently observed resistance mutation, H275Y, and the double mutant I223R/H275Y were compared. Relative to wild type, KMvalues for MUNANA increased only 2-fold for the single I223R mutant and up to 8-fold for the double mutant. Oseltamivir inhibition constants (KI) increased 48-fold in the single I223R mutant and 7500-fold in the double mutant. In both cases the change was largely accounted for by an increased dissociation rate constant for oseltamivir, but the inhibition constants for zanamivir were less increased. We have used X-ray crystallography to better understand the effect of mutation I223R on drug binding. We find that there is shrinkage of a hydrophobic pocket in the active site as a result of the I223R change. Furthermore, R223 interacts with S247 which changes the rotamer it adopts and, consequently, binding of the pentoxyl substituent of oseltamivir is not as favorable as in the wild type. However, the polar glycerol substituent present in zanamivir, which mimics the natural substrate, is accommodate