Mutations in hepatitis C virus E2 located outside the CD81 binding sites lead to escape from broadly neutralizing antibodies but compromise virus infectivity.

Broadly neutralizing antibodies are commonly present in the sera of patients with chronic hepatitis C virus (HCV) infection. To elucidate possible mechanisms of virus escape from these antibodies, retrovirus particles pseudotyped with HCV glycoproteins (HCVpp) isolated from sequential samples collected over a 26-year period from a chronically infected patient, H, were used to characterize the neutralization potential and binding affinity of a panel of anti-HCV E2 human monoclonal antibodies (HMAbs). Moreover, AP33, a neutralizing murine monoclonal antibody (MAb) to a linear epitope in E2, was also tested against selected variants. The HMAbs used were previously shown to broadly neutralize HCV and to recognize a cluster of highly immunogenic overlapping epitopes, designated domain B, containing residues that are also critical for binding of viral E2 glycoprotein to CD81, a receptor essential for virus entry. Escape variants were observed at different time points with some of the HMAbs. Other HMAbs neutralized all variants except for the isolate 02.E10, obtained in 2002, which was also resistant to MAb AP33. The 02.E10 HCVpp that have reduced binding affinities for all antibodies and for CD81 also showed reduced infectivity. Comparison of the 02.E10 nucleotide sequence with that of the strain H-derived consensus variant, H77c, revealed the former to have two mutations in E2, S501N and V506A, located outside the known CD81 binding sites. Substitution A506V in 02.E10 HCVpp restored binding to CD81, but its antibody neutralization sensitivity was only partially restored. Double substitutions comprising N501S and A506V synergistically restored 02.E10 HCVpp infectivity. Other mutations that are not part of the antibody binding epitope in the context of N501S and A506V were able to completely restore neutralization sensitivity. These findings showed that some nonlinear overlapping epitopes are more essential than others for viral fitness and consequently are more invariant during earlier years of chronic infection. Further, the ability of the 02.E10 consensus variant to escape neutralization by the tested antibodies could be a new mechanism of virus escape from immune containment. Mutations that are outside receptor binding sites resulted in structural changes leading to complete escape from domain B neutralizing antibodies, while simultaneously compromising viral fitness by reducing binding to CD81

On Minisuperspace Models of S-branes

In this note we reconsider the minisuperspace toy models for rolling and bouncing tachyons. We show that the theories require to choose boundary conditions at infinity since particles in an exponentially unbounded potential fall to infinity in finite world-sheet time. Using standard techniques from operator theory, we determine the possible boundary conditions and we compute the corresponding energy spectra and minisuperspace 3-point functions. Based on this analysis we argue in particular that world-sheet models of S-branes possess a discrete spectrum of conformal weights containing both positive and negative values. Finally, some suggestions are made for possible relations with previous studies of the minisuperspace theory.Comment: 24 pages, 3 figure

Anisotropy in Bianchi-type brane cosmologies

The behavior near the initial singular state of the anisotropy parameter of the arbitrary type, homogeneous and anisotropic Bianchi models is considered in the framework of the brane world cosmological models. The matter content on the brane is assumed to be an isotropic perfect cosmological fluid, obeying a barotropic equation of state. To obtain the value of the anisotropy parameter at an arbitrary moment an evolution equation is derived, describing the dynamics of the anisotropy as a function of the volume scale factor of the Universe. The general solution of this equation can be obtained in an exact analytical form for the Bianchi I and V types and in a closed form for all other homogeneous and anisotropic geometries. The study of the values of the anisotropy in the limit of small times shows that for all Bianchi type space-times filled with a non-zero pressure cosmological fluid, obeying a linear barotropic equation of state, the initial singular state on the brane is isotropic. This result is obtained by assuming that in the limit of small times the asymptotic behavior of the scale factors is of Kasner-type. For brane worlds filled with dust, the initial values of the anisotropy coincide in both brane world and standard four-dimensional general relativistic cosmologies.Comment: 12 pages, no figures, to appear in Class. Quantum Gra

Did tool-use evolve with enhanced physical cognitive abilities?

The use and manufacture of tools have been considered to be cognitively demanding and thus a possible driving factor in the evolution of intelligence. In this study, we tested the hypothesis that enhanced physical cognitive abilities evolved in conjunction with the use of tools, by comparing the performance of naturally tool-using and non-tool-using species in a suite of physical and general learning tasks. We predicted that the habitually tool-using species, New Caledonian crows and Galápagos woodpecker finches, should outperform their non-tool-using relatives, the small tree finches and the carrion crows in a physical problem but not in general learning tasks. We only found a divergence in the predicted direction for corvids. That only one of our comparisons supports the predictions under this hypothesis might be attributable to different complexities of tool-use in the two tool-using species. A critical evaluation is offered of the conceptual and methodological problems inherent in comparative studies on tool-related cognitive abilities

A Halomethane thermochemical network from iPEPICO experiments and quantum chemical calculations

Internal energy selected halomethane cations CH3Cl+, CH2Cl2+, CHCl3+, CH3F+, CH2F2+, CHClF2+ and CBrClF2+ were prepared by vacuum ultraviolet photoionization, and their lowest energy dissociation channel studied using imaging photoelectron photoion coincidence spectroscopy (iPEPICO). This channel involves hydrogen atom loss for CH3F+, CH2F2+ and CH3Cl+, chlorine atom loss for CH2Cl2+, CHCl3+ and CHClF2+, and bromine atom loss for CBrClF2+. Accurate 0 K appearance energies, in conjunction with ab initio isodesmic and halogen exchange reaction energies, establish a thermochemical network, which is optimized to update and confirm the enthalpies of formation of the sample molecules and their dissociative photoionization products. The ground electronic states of CHCl3+, CHClF2+ and CBrClF2+ do not confirm to the deep well assumption, and the experimental breakdown curve deviates from the deep well model at low energies. Breakdown curve analysis of such shallow well systems supplies a satisfactorily succinct route to the adiabatic ionization energy of the parent molecule, particularly if the threshold photoelectron spectrum is not resolved and a purely computational route is unfeasible. The ionization energies have been found to be 11.47 ± 0.01 eV, 12.30 ± 0.02 eV and 11.23 ± 0.03 eV for CHCl3, CHClF2 and CBrClF2, respectively. The updated 0 K enthalpies of formation, ∆fHo0K(g) for the ions CH2F+, CHF2+, CHCl2+, CCl3+, CCl2F+ and CClF2+ have been derived to be 844.4 ± 2.1, 601.6 ± 2.7, 890.3 ± 2.2, 849.8 ± 3.2, 701.2 ± 3.3 and 552.2 ± 3.4 kJ mol–1, respectively. The ∆fHo0K(g) values for the neutrals CCl4, CBrClF2, CClF3, CCl2F2 and CCl3F and have been determined to be –94.0 ± 3.2, –446.6 ± 2.7, –702.1 ± 3.5, –487.8 ± 3.4 and –285.2 ± 3.2 kJ mol–1, respectively

The Possibly Remnant Massive Outflow in G5.89-0.39: I - Observations and Initial MHD Simulations

We have obtained maps of the large scale outflow associated with the UCHII regionG5.89-0.39 in CO and 13CO (J=3-2), SiO (J=8-7,J=5-4), SO2 (13(2,12)-13(1,13)) and H13CO+(J=4-3). From these maps we have been able to determine the mass (3.3 M_sun), momentum (96 M_sun km/s), energy (3.5x10^{46} erg), mechanical luminosity (141 L_sun), and mass loss rate (~1x10^{-3}M_sun/yr) in the large scale outflow. The observationally derived parameters were used toguide 3D magnetohydrodynamic models of the jet entrained outflow. Through the combination of observations and simulations, we suggest that the large scale outflowmay be inclined by approximately 45 deg to the line of sight, and that the jet entraining the observed molecular outflow may have been active for as little as 1000 years, half the kinematic age of the outflow.Comment: 27 Pages, 9 Figures, Accepted to ApJ. For full (High) resolution figures, please see http://www.ism.ucalgary.ca/~pamela/papers/index.htm

Slowing and cooling molecules and neutral atoms by time-varying electric field gradients

A method of slowing, accelerating, cooling, and bunching molecules and neutral atoms using time-varying electric field gradients is demonstrated with cesium atoms in a fountain. The effects are measured and found to be in agreement with calculation. Time-varying electric field gradient slowing and cooling is applicable to atoms that have large dipole polarizabilities, including atoms that are not amenable to laser slowing and cooling, to Rydberg atoms, and to molecules, especially polar molecules with large electric dipole moments. The possible applications of this method include slowing and cooling thermal beams of atoms and molecules, launching cold atoms from a trap into a fountain, and measuring atomic dipole polarizabilities.Comment: 13 pages, 10 figures. Scheduled for publication in Nov. 1 Phys. Rev.

Courage in decision-making:A mixed-methods study of COVID-19 vaccine uptake in women of reproductive age in the UK

COVID-19 vaccination rates are lower in women of reproductive age (WRA), including preg-nant/postpartum women despite their poorer COVID-19-related outcomes. We evaluated vac-cination experiences of 3,568 UK WRA, including 1,983 women (55.6%) experiencing a pandemic pregnancy, recruited through the ZOE COVID Symptom Study app. Two staggered online ques-tionnaires (Oct-Dec 2021: 3,453 responders; Aug-Sept 2022: 2,129 responders) assessed reproductive status, COVID-19 status, vaccination, and attitudes for/against vaccination. Descriptive analyses included vaccination type(s), timing relative to age-based eligibility and reproductive status, vaccination delay (first vaccination >28 days from eligibility), and rationale, with content analysis of free-text comments. Most responders (3,392/3,453, 98.2%) were vaccinated by Dec 2021, motivated by: altruism, vaccination supportiveness in general, low-risk, and COVID-19 concerns. Few declined vaccination (by Sept/2022: 20/2,129, 1.0%), citing: risks (pregnancy-specific and longer-term), pre-existing immunity, and personal/philosophical reasons. Few women de-layed vaccination, although pregnant/postpartum women (vs. other WRA), received vaccination later (median 3 vs. 0 days after eligibility, p<0.0001). Despite high uptake, concerns included: adverse effects; misinformation (including from healthcare providers); ever-changing govern-ment advice; and complex decision-making. In summary, most women in this large WRA cohort were promptly vaccinated, including pregnant/post-partum women. Altruism and community benefit superseded personal benefit as reasons for vaccination. Nevertheless, responders expe-rienced angst, and received vaccine-related misinformation and discouragement. These findings should inform vaccination strategies in WRA