Extreme genetic fragility of the HIV-1 capsid

Genetic robustness, or fragility, is defined as the ability, or lack thereof, of a biological entity to maintain function in the face of mutations. Viruses that replicate via RNA intermediates exhibit high mutation rates, and robustness should be particularly advantageous to them. The capsid (CA) domain of the HIV-1 Gag protein is under strong pressure to conserve functional roles in viral assembly, maturation, uncoating, and nuclear import. However, CA is also under strong immunological pressure to diversify. Therefore, it would be particularly advantageous for CA to evolve genetic robustness. To measure the genetic robustness of HIV-1 CA, we generated a library of single amino acid substitution mutants, encompassing almost half the residues in CA. Strikingly, we found HIV-1 CA to be the most genetically fragile protein that has been analyzed using such an approach, with 70% of mutations yielding replication-defective viruses. Although CA participates in several steps in HIV-1 replication, analysis of conditionally (temperature sensitive) and constitutively non-viable mutants revealed that the biological basis for its genetic fragility was primarily the need to coordinate the accurate and efficient assembly of mature virions. All mutations that exist in naturally occurring HIV-1 subtype B populations at a frequency >3%, and were also present in the mutant library, had fitness levels that were >40% of WT. However, a substantial fraction of mutations with high fitness did not occur in natural populations, suggesting another form of selection pressure limiting variation in vivo. Additionally, known protective CTL epitopes occurred preferentially in domains of the HIV-1 CA that were even more genetically fragile than HIV-1 CA as a whole. The extreme genetic fragility of HIV-1 CA may be one reason why cell-mediated immune responses to Gag correlate with better prognosis in HIV-1 infection, and suggests that CA is a good target for therapy and vaccination strategies

Time-dependent failure in load-bearing polymers: a potential hazard in structural applications of polylactides

With their excellent biocompatibility and relatively high mechanical strength, polylactides are attractive candidates for application in load-bearing, resorbable implants. Pre-clinical studies provided a proof of principle for polylactide cages as temporary constructs to facilitate spinal fusion, and several cages already made it to the market. However, also failures have been reported: clinical studies reported considerable amounts of subsidence with lumbar spinal fusion cages, and in an in vivo goat study, polylactide spinal cages failed after only three months of implantation, although mechanical testing had predicted sufficient strength for at least eight months. The failures appear to be related to the long-term performance of polylactides under static loading conditions, a phenomenon which is common to all glassy polymers and finds its origin in stress-activated molecular mobility leading to plastic flow. This paper reviews the mechanical properties and deformation kinetics of amorphous polylactides. Compression tests were performed with various strain rates, and static stress experiments were done to determine time-to failure. Pure PLLA appeared to have a higher yield strength than its co-polymers with d-lactide, but the kinetic behaviour of the polymers was the same: an excellent short-term strength at higher loading rates, but lifetime under static stress is rather poor. As spinal implants need to maintain mechanical integrity for a period of at least six months, this has serious implications for the clinical application of amorphous polylactides in load bearing situations. It is recommended that standards for mechanical testing of implants made of polymers be revised in order to consider this typical time-dependent behaviour

Capture, Reconstruction, and Representation of the Visual Real World for Virtual Reality

We provide an overview of the concerns, current practice, and limitations for capturing, reconstructing, and representing the real world visually within virtual reality. Given that our goals are to capture, transmit, and depict complex real-world phenomena to humans, these challenges cover the opto-electro-mechanical, computational, informational, and perceptual fields. Practically producing a system for real-world VR capture requires navigating a complex design space and pushing the state of the art in each of these areas. As such, we outline several promising directions for future work to improve the quality and flexibility of real-world VR capture systems

Explaining lifelong loyalty: The role of identity fusion and self-shaping group events

Pledging lifelong loyalty to an ingroup can have far-reaching behavioural effects, ranging from ordinary acts of ingroup kindness to extraordinary acts of self-sacrifice. What motivates this important form of group commitment? Here, we propose one especially potent answer to this question–the experience of a visceral sense of oneness with a group (i.e., identity fusion). In a sample of British football fans, a population in which high levels of lifelong loyalty are thought to be common, we first examined the hypothesised relationship between fusion and perceptions of lifelong loyalty to one’s club. We further explored the hypothesis that fusion and lifelong loyalty are not merely a reflection of past time investment in a group, but also reflect a deeper, memory-based process of feeling personally shaped by key group events, both euphoric and dysphoric. We found broad support for these hypotheses. Results suggest that feeling personally self-shaped by club events (e.g., crucial wins and losses), rather than time invested in the club, leads to greater identity fusion to one’s club. In turn, fusion engenders a sense of lifelong club loyalty. We discuss our findings in relation to the growing literature on the experiential origins of intense social cohesion

Localizing FRBs through VLBI with the Algonquin Radio Observatory 10 m Telescope

The Canadian Hydrogen Intensity Mapping Experiment (CHIME)/FRB experiment has detected thousands of fast radio bursts (FRBs) due to its sensitivity and wide field of view; however, its low angular resolution prevents it from localizing events to their host galaxies. Very long baseline interferometry (VLBI), triggered by FRB detections from CHIME/FRB will solve the challenge of localization for non-repeating events. Using a refurbished 10 m radio dish at the Algonquin Radio Observatory located in Ontario Canada, we developed a testbed for a VLBI experiment with a theoretical λ/D ≲ 30 mas. We provide an overview of the 10 m system and describe its refurbishment, the data acquisition, and a procedure for fringe fitting that simultaneously estimates the geometric delay used for localization and the dispersive delay from the ionosphere. Using single pulses from the Crab pulsar, we validate the system and localization procedure, and analyze the clock stability between sites, which is critical for coherently delay referencing an FRB event. We find a localization of ∼200 mas is possible with the performance of the current system (single-baseline). Furthermore, for sources with insufficient signal or restricted wideband to simultaneously measure both geometric and ionospheric delays, we show that the differential ionospheric contribution between the two sites must be measured to a precision of 1 × 10-8 pc cm-3 to provide a reasonable localization from a detection in the 400-800 MHz band. Finally we show detection of an FRB observed simultaneously in the CHIME and the Algonquin 10 m telescope, the first non-repeating FRB in this long baseline. This project serves as a testbed for the forthcoming CHIME/FRB Outriggers project

Архетип свобода у контексті французької політичної теорії та історії

Розглянуто сучасні підходи щодо аналізу політичної ментальності. У межах політологічного аналізу окреслено коло проблем, які потребують вирішення з використанням підходів психології. Зроблено висновок про те, що архетип “свобода” становить важливий елемент політичної ментальності французів.Modern approaches of analysis of political mentality are considered. Within the limits of political science analysis outlined circle of problems which need decision with the use of approaches of psychology. A conclusion is done that archetype freedom makes the important element of political mentality of French’s

Glycogen Synthase Kinase 3 (GSK3) Inhibitor, SB-216763, Promotes Pluripotency in Mouse Embryonic Stem Cells

Canonical Wnt/β-catenin signaling has been suggested to promote self-renewal of pluripotent mouse and human embryonic stem cells. Here, we show that SB-216763, a glycogen synthase kinase-3 (GSK3) inhibitor, can maintain mouse embryonic stem cells (mESCs) in a pluripotent state in the absence of exogenous leukemia inhibitory factor (LIF) when cultured on mouse embryonic fibroblasts (MEFs). MESCs maintained with SB-216763 for one month were morphologically indistinguishable from LIF-treated mESCs and expressed pluripotent-specific genes Oct4, Sox2, and Nanog. Furthermore, Nanog immunostaining was more homogenous in SB-216763-treated colonies compared to LIF. Embryoid bodies (EBs) prepared from these mESCs expressed early-stage markers for all three germ layers, and could efficiently differentiate into cardiac-like cells and MAP2-immunoreactive neurons. To our knowledge, SB-216763 is the first GSK3 inhibitor that can promote self-renewal of mESC co-cultured with MEFs for more than two months

Imaging and Modeling Data from the Hydrogen Epoch of Reionization Array

We analyze data from the Hydrogen Epoch of Reionization Array. This is the third in a series of papers on the closure phase delay-spectrum technique designed to detect the HI 21cm emission from cosmic reionization. We present the details of the data and models employed in the power spectral analysis, and discuss limitations to the process. We compare images and visibility spectra made with HERA data, to parallel quantities generated from sky models based on the GLEAM survey, incorporating the HERA telescope model. We find reasonable agreement between images made from HERA data, with those generated from the models, down to the confusion level. For the visibility spectra, there is broad agreement between model and data across the full band of $\sim 80$MHz. However, models with only GLEAM sources do not reproduce a roughly sinusoidal spectral structure at the tens of percent level seen in the observed visibility spectra on scales $\sim 10$ MHz on 29 m baselines. We find that this structure is likely due to diffuse Galactic emission, predominantly the Galactic plane, filling the far sidelobes of the antenna primary beam. We show that our current knowledge of the frequency dependence of the diffuse sky radio emission, and the primary beam at large zenith angles, is inadequate to provide an accurate reproduction of the diffuse structure in the models. We discuss implications due to this missing structure in the models, including calibration, and in the search for the HI 21cm signal, as well as possible mitigation techniques