A two-stage mechanism of viral RNA compaction revealed by single molecule fluorescence

Long RNAs often exist as multiple conformers in equilibrium. For the genomes of single-stranded RNA viruses, one of these conformers must include a compacted state allowing the RNA to be confined within the virion. We have used single molecule fluorescence correlation spectroscopy to monitor the conformations of viral genomes and sub-fragments in the absence and presence of coat proteins. Cognate RNA-coat protein interactions in two model viruses cause a rapid collapse in the hydrodynamic radii of their respective RNAs. This is caused by protein binding at multiple sites on the RNA that facilitate additional protein-protein contacts. The collapsed species recruit further coat proteins to complete capsid assembly with great efficiency and fidelity. The specificity in RNA-coat protein interactions seen at single-molecule concentrations reflects the packaging selectivity seen for such viruses in vivo. This contrasts with many in vitro reassembly measurements performed at much higher concentrations. RNA compaction by coat protein or polycation binding are distinct processes, implying that defined RNA-coat protein contacts are required for assembly

Comparing antiviral strategies against COVID-19 via multiscale within-host modelling

Within-host models of COVID-19 infection dynamics enable the merits of different forms of antiviral therapy to be assessed in individual patients. A stochastic agent-based model of COVID-19 intracellular dynamics is introduced here, that incorporates essential steps of the viral life cycle targeted by treatment options. Integration of model predictions with an intercellular ODE model of within-host infection dynamics, fitted to patient data, generates a generic profile of disease progression in patients that have recovered in the absence of treatment. This is contrasted with the profiles obtained after variation of model parameters pertinent to the immune response, such as effector cell and antibody proliferation rates, mimicking disease progression in immunocompromised patients. These profiles are then compared with disease progression in the presence of antiviral and convalescent plasma therapy against COVID-19 infections. The model reveals that using both therapies in combination can be very effective in reducing the length of infection, but these synergistic effects decline with a delayed treatment start. Conversely, early treatment with either therapy alone can actually increase the duration of infection, with infectious virions still present after the decline of other markers of infection. This suggests that usage of these treatments should remain carefully controlled in a clinical environment

Using rhythm for rehabilitation: evaluation of a novel haptic device

This project explored how new and novel approaches to stroke rehabilitation could improve physical function and the confidence of stroke survivors to remain active and engaged in the community. The innovation trialed was a ‘Haptic bracelet/cueing device’, developed at The Open University. An overview of the Haptic device, its development and role in stroke rehabilitation can be viewed at: https://www.youtube.com/watch?v=S4ZxN6H6XGk The Haptic bracelets provide a physical (embodied) beat that someone can walk to as an alternative to existing audio cuing ways of working. The haptic device provides a non-invasive, relatively cheap way of facilitating people after stroke to continue to maintain or even improve their mobility after intensive rehabilitation has finished. This research explored the impact of the haptic device to gains in mobility. The project had two key aims: 1. To develop a usable and practical prototype of a haptic device to restore gait symmetry after stroke. 2. To investigate the feasibility and acceptability of the prototype in stroke patients. Summary of findings and recommendations When introduced to the Haptic Bracelets participants hoped the product would provide them with: • More confidence and make them feel safer when walking. • Greater ability to take bigger strides rather than little steps. • A way to combat the silly mistakes participants reported making due to tiredness. • Reduced pain (knees, hips) The physiotherapists saw potential for the Haptic devices as part of post stroke rehabilitation, but expressed concern about their lack of access to mobile technologies when out in community practice settings. There were also concerns about use with some stroke survivors because of issues of cognition; and the sensation from the Haptic beat. In the Haptic gait testing • All the participants demonstrated good mobility performance prior to the study (high score on the Rivermead mobility scale) • 4/7* (57.1%) participants who were the most asymmetrical at baseline improved their gait symmetry whilst wearing the haptic device • 3/7* (42%) participant’s gait symmetry continued to improve in the post off condition. • All the participants walked quicker in post-op condition. However, gait speed varied between participants when they were wearing the haptic bracelets. • Participants were had had their strokes between 3-10 years ago, but there was still an indication that the Haptic bracelets were having some impact on mobility. • Syncing of the Haptic device and more mobile Inertial Measurement Unit (IMU) to the fixed gait laboratory (gold standard) system has improved the potential for more community based rehabilitation and commercialisation of the Haptic bracelets. • Post Haptic interviews identified that there were mixed participant feelings about the bracelets. However, some did express positive experiences from testing the Haptic bracelets, including a carry over effect after the devices were removed. Recommendations As this was a pilot study more work is now required to explore the: • use of the Haptic bracelets in community rehabilitation settings • feasibility of the using Haptic bracelets in community settings, particularly looking at staff access to new technologies • potential for the Haptic bracelets to be used in the home as part of ongoing rehabilitation • benefits of Haptic bracelets in the context of longer term stroke rehabilitation • future design needs to improve the look, size and ease of application • cost benefits of using Haptic bracelets as part of an overall program of stroke rehabilitation

The Role of Wine in Modulating Inflammatory Processes: A Review

Several epidemiological studies associated the consumption of wine with the reduction of the risk factors for cardiovascular disease and certain cancers, as well as for diabetes. These conditions are characterized by inflammatory mechanisms in addition to other biological mechanisms. Acute and chronic inflammation is mediated by a plethora of biomarkers production and pathway activation. Since the health promoting properties of wine in different pathological conditions may include the reduction of inflammation, the aim of this paper was to collect and review the in vitro, in vivo, and human studies performed to evaluate the effects of wine on different models of inflammation. Although great variability in wine intake, period of consumption, and content of phenolic compounds was observed, data from both human and animal studies showed a positive modulation of inflammatory biomarkers (cytokines, coagulation parameters) and oxidative stress (mainly malondialdehyde) involved in cardiovascular function. In addition, some convincing evidence was obtained in different models suggesting a positive modulation of risk factors for gastric and intestinal inflammation. Contradictory results were obtained for metabolic syndrome and type 2 diabetes. To date, no significant paper has been published in the area of immune function. Integrating in vivo data and in vitro studies, the NF-\u3baB pathway has been identified as a critical target for the protective properties of a moderate wine consumptio

Mechanisms of viral capsid assembly around a polymer

Capsids of many viruses assemble around nucleic acids or other polymers. Understanding how the properties of the packaged polymer affect the assembly process could promote biomedical efforts to prevent viral assembly or nanomaterials applications that exploit assembly. To this end, we simulate on a lattice the dynamical assembly of closed, hollow shells composed of several hundred to 1000 subunits, around a flexible polymer. We find that assembly is most efficient at an optimum polymer length that scales with the surface area of the capsid; significantly longer than optimal polymers often lead to partial-capsids with unpackaged polymer `tails' or a competition between multiple partial-capsids attached to a single polymer. These predictions can be tested with bulk experiments in which capsid proteins assemble around homopolymeric RNA or synthetic polyelectrolytes. We also find that the polymer can increase the net rate of subunit accretion to a growing capsid both by stabilizing the addition of new subunits and by enhancing the incoming flux of subunits; the effects of these processes may be distinguishable with experiments that monitor the assembly of individual capsids.Comment: 7 figure

Asymmetric Genome Organization in an RNA Virus Revealed via Graph-Theoretical Analysis of Tomographic Data

Cryo-electron microscopy permits 3-D structures of viral pathogens to be determined in remarkable detail. In particular, the protein containers encapsulating viral genomes have been determined to high resolution using symmetry averaging techniques that exploit the icosahedral architecture seen in many viruses. By contrast, structure determination of asymmetric components remains a challenge, and novel analysis methods are required to reveal such features and characterize their functional roles during infection. Motivated by the important, cooperative roles of viral genomes in the assembly of single-stranded RNA viruses, we have developed a new analysis method that reveals the asymmetric structural organization of viral genomes in proximity to the capsid in such viruses. The method uses geometric constraints on genome organization, formulated based on knowledge of icosahedrally-averaged reconstructions and the roles of the RNA-capsid protein contacts, to analyse cryo-electron tomographic data. We apply this method to the low-resolution tomographic data of a model virus and infer the unique asymmetric organization of its genome in contact with the protein shell of the capsid. This opens unprecedented opportunities to analyse viral genomes, revealing conserved structural features and mechanisms that can be targeted in antiviral drug desig

Till death (or an intruder) do us part: intrasexual-competition in a monogamous Primate

Polygynous animals are often highly dimorphic, and show large sex-differences in the degree of intra-sexual competition and aggression, which is associated with biased operational sex ratios (OSR). For socially monogamous, sexually monomorphic species, this relationship is less clear. Among mammals, pair-living has sometimes been assumed to imply equal OSR and low frequency, low intensity intra-sexual competition; even when high rates of intra-sexual competition and selection, in both sexes, have been theoretically predicted and described for various taxa. Owl monkeys are one of a few socially monogamous primates. Using long-term demographic and morphological data from 18 groups, we show that male and female owl monkeys experience intense intra-sexual competition and aggression from solitary floaters. Pair-mates are regularly replaced by intruding floaters (27 female and 23 male replacements in 149 group-years), with negative effects on the reproductive success of both partners. Individuals with only one partner during their life produced 25% more offspring per decade of tenure than those with two or more partners. The termination of the pair-bond is initiated by the floater, and sometimes has fatal consequences for the expelled adult. The existence of floaters and the sporadic, but intense aggression between them and residents suggest that it can be misleading to assume an equal OSR in socially monogamous species based solely on group composition. Instead, we suggest that sexual selection models must assume not equal, but flexible, context-specific, OSR in monogamous species.Wenner-Gren Foundation, L.S.B. Leakey Foundation, the National Geographic Society, National Science Foundation (BCS- 0621020), the University of Pennsylvania Research Foundation and the Zoological Society of San Diego, German Science Foundation (HU 1746-2/1

Frequency of reported pain in adult males with muscular dystrophy

Introduction The purpose of this study was to present and compare pain between adult males with Duchenne (DMD), Becker’s (BMD), Limb-Girdle (LGMD) Facioscapulohumeral (FSHD) forms of Muscular Dystrophy (MD), and healthy controls (CTRL), using three different methods of assessment. Methods Pain was assessed using 1) a whole body visual analogue scale (VAS) of pain, 2) a generalised body map and 3) a localised body map. Results All types of MD reported more VAS pain than CTRL, with 97% of all MD participants reporting pain; however, no differences were reported between types of MD. The generalised body map approach identified more frequent pain in the shoulders of FSHD (93%) than other groups (13–43%), hips of DMD (87%) and LGMD (75%) than other groups (0–29%), and legs of all MD (64–78%) than CTRL (25%). The localised body map approach identified common areas of frequent pain across types of MD, posterior distal leg and distal back, as well as condition specific regions of frequent pain, for example posterior trapezius in FSHD, and anterior hip pain in DMD and LGMD. Conclusions Using a single pain value (VAS), increased pain was reported by adults with MD compared to CTRL, with no clear differences between different MD groups, suggesting pain is symptomatic of MD. The use of the generalised body map approach, and to an even greater extent the localised body map approach, identified specific areas of frequent pain relevant to each individual condition. These results indicate that whist the commonly used generalised approach can be used to identify broad anatomical regions, the localised approach provides a more comprehensive understanding of pain, reflective of clinical assessment, and should be utilised in future research

Assessing maternal anxiety in pregnancy with the State-Trait Anxiety Inventory (STAI): Issues of validity, location and participation

The State Trait Anxiety Inventory (STAI) has been widely used in research with pregnant women. However, few studies have examined its validity for this group. In this paper the content validity of the STAI, the impact of location and consequences for further participation of higher STAI scores are investigated for 215 pregnant women who completed the STAI at hospital or community based clinics. The study participants answered the open ended question, 'How do you feel about your pregnancy?' and whether or not they would be willing to take part in further research. Results indicated that STAI state scores reflected the nature of women's spontaneous comments regarding their pregnancy, with lower anxiety related to more 'positive' comments. The state scores were also found to be sensitive to the risk level associated with the clinic where the inventory was completed; higher scores related to high-risk localities. Women with the highest levels of state or trait anxiety were also less likely to wish to take part in further research. The study concludes that the STAI does reflect the anxiety-related experiences of pregnant women and that its use with pregnant women is appropriate in this respect; however, we recommend that future research notes the issue of potential recruitment biases. 2010 Society for Reproductive and Infant Psychology.CIHR28pub183

Immunochemical investigation of allergenic residues in experimental and commercially-available wines fined with egg white proteins

Proteinaceous egg whites are widely used as a fining agent during the production of red wines. Residues of egg white in the final wine could present a risk for individuals allergic to eggs. This study investigated the presence of allergenic residues in both red and white wines fined with egg whites. Experimental and commercially available wines fined with egg whites, with or without subsequent bentonite fining, were studied. Unfined wines were used as negative controls. The physicochemical characteristics of each wine were determined to assess their possible role in enhancing or hindering the elimination of allergenic residues from wine. The amount of egg white protein residues was investigated both by a specifically developed/validated ELISA test and by immunoblotting. Both immunochemical tests used the same anti-total egg white protein antibody and were highly sensitive to the allergen. No egg white protein was detected in the wines studied in either immunochemical test, irrespective of the physicochemical characteristics of the wine, the type and dosage of the fining agent and the oenological process used. The risk of adverse reactions in egg-allergic individuals should therefore be considered negligible, but the exemption from labelling should be allowed only when the absence of residues is confirmed by analytical controls. \ua9 2014 Elsevier Ltd. All rights reserved