Vesivirus 2117 capsids more closely resemble sapovirus and lagovirus particles than other known vesivirus structures

Vesivirus 2117 is an adventitious agent that in 2009, was identified as a contaminant of CHO cells propagated in bioreactors at a pharmaceutical manufacturing plant belonging to Genzyme. The consequent interruption in supply of Fabrazyme and Cerezyme (drugs used to treat Fabry and Gaucher disease respectively), caused significant economic losses. Vesivirus 2117 is a member of the Caliciviridae; a family of small icosahedral viruses encoding a positive sense RNA genome. We have used cryo-electron microscopy and three dimensional image reconstruction to calculate a structure of vesivirus 2117 virus like particles as well as feline calicivirus and a chimeric sapovirus. We present a structural comparison of several members of the Caliciviridae, showing that the distal P domain of vesivirus 2117 is morphologically distinct from that seen in other known vesivirus structures. Furthermore, at intermediate resolutions we found a high level of structural similarity between vesivirus 2117 and Caliciviridae from other genera, such as sapovirus and rabbit haemorrhagic disease virus. Phylogenetic analysis confirms vesivirus 2117 as a vesivirus closely related to canine vesiviruses. We postulate that morphological differences in virion structure seen between vesivirus clades may reflect differences in receptor usage

Phasing of muscle gene expression with fasting-induced recovery growth in Atlantic salmon

Background: Many fish species experience long periods of fasting in nature often associated with seasonal reductions in water temperature and prey availability or spawning migrations. During periods of nutrient restriction, changes in metabolism occur to provide cellular energy via catabolic processes. Muscle is particularly affected by prolonged fasting as myofibrillar proteins act as a major energy source. To investigate the mechanisms of metabolic reorganisation with fasting and refeeding in a saltwater stage of Atlantic salmon (Salmo salar L.) we analysed the expression of genes involved in myogenesis, growth signalling, lipid biosynthesis and myofibrillar protein degradation and synthesis pathways using qPCR. Results: Hierarchical clustering of gene expression data revealed three clusters. The first cluster comprised genes involved in lipid metabolism and triacylglycerol synthesis (ALDOB, DGAT1 and LPL) which had peak expression 3-14d after refeeding. The second cluster comprised ADIPOQ, MLC2, IGF-I and TALDO1, with peak expression 14-32d after refeeding. Cluster III contained genes strongly down regulated as an initial response to feeding and included the ubiquitin ligases MuRF1 and MAFbx, myogenic regulatory factors and some metabolic genes. Conclusion: Early responses to refeeding in fasted salmon included the synthesis of triacylglycerols and activation of the adipogenic differentiation program. Inhibition of MuRF1 and MAFbx respectively may result in decreased degradation and concomitant increased production of myofibrillar proteins. Both of these processes preceded any increase in expression of myogenic regulatory factors and IGF-I. These responses could be a necessary strategy for an animal adapted to long periods of food deprivation whereby energy reserves are replenished prior to the resumption of myogenesis.Publisher PDFPeer reviewe

The Barbados Insulin Matters (BIM) study: Barriers to insulin therapy among a population-based sample of people with type 2 diabetes in the Caribbean island of Barbados.

AIM: The purpose of this study was to document in people with type 2 diabetes (T2DM) in Barbados, attitudes and beliefs that may result in psychological insulin resistance. METHODS: A representative, population-based, sample of 175 eligible people with T2DM 25 years of age and over was surveyed by telephone. The 20-item insulin treatment appraisal scale (ITAS) was administered (score range 20 to 100 for positive to negative perceptions). RESULTS: 117 people participated (67% response rate, 32% male, mean age 66 years, 90% Black, 22% on insulin). Of non-responders, 52 were not contactable and 6 were difficult to communicate with. Negative perceptions about insulin use included - meant a worsening of diabetes (68%), would worry family (63%), feared self-injection (58%), meant a failure in self-management (57%), injections were painful (54%), would be seen as being sicker (46%), increased hypoglycaemia risk (38%), required effort (34%), causes weight gain (27%), causes a deterioration in health (14%), and would have to give up enjoyable activities (10%). Positive perceptions were - helps good glycaemic control (78%), would prevent complications (61%) and improves health (58%). Mean total ITAS score (61.6, SD = 7.7) was lower for those on insulin compared to those not on insulin (53.7 vs. 63.8, p < 0.0001). Sex, age and diabetes diagnosis duration were not significant predictors of ITAS score. CONCLUSIONS: Multiple factors related to patient beliefs and attitudes need to be considered and addressed when initiating insulin in order to minimise psychological insulin resistance and delay. Patients using insulin had less negative perceptions than those not on insulin

Effective Temperatures of a Driven System Near Jamming

Fluctuations in a model of a sheared, zero-temperature foam are studied numerically. Five different quantities that reduce to the true temperature in an equilibrium thermal system are calculated. All five have the same shear-rate dependence, and three have the same value. Near the onset of jamming, the relaxation time is the same function of these three temperatures in the sheared system as of the true temperature in an unsheared system. These results imply that statistical mechanics is useful for the system and provide strong support for the concept of jamming.Comment: 4 pages, 4 postscript figure

LGN Blocks the Ability of NuMA to Bind and Stabilize Microtubules A Mechanism for Mitotic Spindle Assembly Regulation

AbstractLGN is closely related to a Drosophila protein, Partner of inscuteable (Pins), which is required for polarity establishment and asymmetric cell divisions during embryonic development [1–3]. In mammalian cells, LGN binds with high affinity to the C-terminal tail of NuMA, a large nuclear protein that is required for spindle organization, and accumulates at the spindle poles during mitosis [4–9]. LGN also regulates spindle organization, possibly through inhibition of NuMA function [10], but the mechanism of this effect has not yet been understood. Using mammalian cells, frog egg extracts, and in vitro assays, we now show that a small domain within the C terminus of NuMA stabilizes microtubules (MTs), and that LGN blocks stabilization. The nuclear localization signal adjacent to this domain is not involved in stabilization. NuMA can interact directly with MTs, and the MT binding domain on NuMA overlaps by ten amino acid residues with the LGN binding domain. We therefore propose that a simple steric exclusion model can explain the inhibitory effect of LGN on NuMA-dependent mitotic spindle organization

Influence of grain-refiner addition on the morphology of fe-bearing intermetallics in a semi-solid processed Al-Mg-Si alloy

© The Minerals, Metals & Materials Society and ASM International 2013The three-dimensional morphologies of the Fe-bearing intermetallics in a semisolid-processed Al-Mg-Si alloy were examined after extracting the intermetallics. α -AlFeSi and β-AlFeSi are the major Fe-bearing intermetallics. Addition of Al-Ti-B grain refiner typically promotes β-AlFeSi formation. β-AlFeSi was observed with a flat, plate-like morphology with angular edges in the alloy with and without grain refiner, whereas α -AlFeSi was observed as "flower"-like morphology in the alloy with grain refiner. © 2013 The Minerals, Metals & Materials Society and ASM International

Comparative efficacy of a secretory phospholipase A2 inhibitor with conventional anti-inflammatory agents in a rat model of antigen-induced arthritis

INTRODUCTION: Previously, secretory phospholipase A(2 )(sPLA(2)) inhibition has been used as an adjunct to conventional rheumatoid arthritis therapy in human clinical trials without significant improvement of arthritic pathology. In this study, we compared the efficacy of a potent and orally active group IIa secretory phospholipase A(2 )inhibitor (sPLA(2)I) to conventional anti-arthritic agents; infliximab, leflunomide and prednisolone, in a rat model of antigen-induced arthritis. METHODS: Initially, to establish efficacy and dose-response, rats were orally dosed with the sPLA(2)I (1 and 5 mg/kg) two days prior to arthritis induction, and then daily throughout the 14-day study period. In the second trial, rats were orally dosed with the sPLA(2)I (5 and 10 mg/kg/day) beginning two days after the induction of arthritis, at the peak of joint swelling. Separate groups of rats were also dosed with the tumour necrosis factor-alpha (TNF-α) inhibitor infliximab (single 3 mg/kg i.v. injection), leflunomide (10 mg/kg/day, oral) or prednisolone (1 mg/kg/day, oral) at this same time point and used as comparative treatments. RESULTS: In the pathology prevention trial, both 1 and 5 mg/kg dose groups of sPLA(2)I demonstrated a significant reduction in joint swelling and gait disturbances; however, only the higher 5 mg/kg dose resulted in significantly reduced histopathology scores. In the post-induction trial, rats dosed with sPLA(2)I showed a significant improvement in joint swelling and gait scoring, whereas none of the conventional therapeutics achieved a significant decrease in both of these two disease markers. Histopathological scoring at the end-point of the study demonstrated significantly reduced median scores in rats treated with 10 mg/kg sPLA(2)I and leflunomide. CONCLUSIONS: The results from this study suggest a pathogenic role for sPLA(2 )enzymes in this model of arthritis in rats, and the potential clinical utility of sPLA(2 )inhibition as a safer, and more effective, alternative to conventional anti-arthritic therapeutics

Cholinergic and perfusion brain networks in Parkinson disease dementia.

OBJECTIVE: To investigate muscarinic M1/M4 cholinergic networks in Parkinson disease dementia (PDD) and their association with changes in Mini-Mental State Examination (MMSE) after 12 weeks of treatment with donepezil. METHODS: Forty-nine participants (25 PDD and 24 elderly controls) underwent (123)I-QNB and (99m)Tc-exametazime SPECT scanning. We implemented voxel principal components (PC) analysis, producing a series of PC images of patterns of interrelated voxels across individuals. Linear regression analyses derived specific M1/M4 and perfusion spatial covariance patterns (SCPs). RESULTS: We found an M1/M4 SCP of relative decreased binding in basal forebrain, temporal, striatum, insula, and anterior cingulate (F1,47 = 31.9, p < 0.001) in cholinesterase inhibitor-naive patients with PDD, implicating limbic-paralimbic and salience cholinergic networks. The corresponding regional cerebral blood flow SCP showed relative decreased uptake in temporoparietal and prefrontal areas (F1,47 = 177.5, p < 0.001) and nodes of the frontoparietal and default mode networks (DMN). The M1/M4 pattern that correlated with an improvement in MMSE (r = 0.58, p = 0.005) revealed relatively preserved/increased pre/medial/orbitofrontal, parietal, and posterior cingulate areas coinciding with the DMN and frontoparietal networks. CONCLUSION: Dysfunctional limbic-paralimbic and salience cholinergic networks were associated with PDD. Established cholinergic maintenance of the DMN and frontoparietal networks may be prerequisite for cognitive remediation following cholinergic treatment in this condition.Medical Research Council UK [grant number G9817682], and by the National Institute for Health Research (NIHR) Research for Public Benefit, Wellcome Trust (WT088441MA Fellowship funding J-P.T). NIHR Dementia Biomedical Research Unit at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. The NIHR Newcastle Biomedical Research Centre in Ageing and Chronic Disease and Biomedical Research Unit in Lewy Body Dementia based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University.This is the final version of the article. It first appeared from Wolters Kluwer via http://dx.doi.org/10.​1212/​WNL.​000000000000283

Key parameters linking cyber-physical trust anchors with embedded internet of things systems

Integration of the Internet of Things (IoT) in the automotive industry has brought benefits as well as security challenges. Significant benefits include enhanced passenger safety and more comprehensive vehicle performance diagnostics. However, current onboard and remote vehicle diagnostics do not include the ability to detect counterfeit parts. A method is needed to verify authentic parts along the automotive supply chain from manufacture through installation and to coordinate part authentication with a secure database. In this study, we develop an architecture for anti-counterfeiting in automotive supply chains. The core of the architecture consists of a cyber-physical trust anchor and authentication mechanisms connected to blockchain-based tracking processes with cloud storage. The key parameters for linking a cyber-physical trust anchor in embedded IoT include identifiers (i.e., serial numbers, special features, hashes), authentication algorithms, blockchain, and sensors. A use case was provided by a two-year long implementation of simple trust anchors and tracking for a coffee supply chain which suggests a low-cost part authentication strategy could be successfully applied to vehicles. The challenge is authenticating parts not normally connected to main vehicle communication networks. Therefore, we advance the coffee bean model with an acoustical sensor to differentiate between authentic and counterfeit tires onboard the vehicle. The workload of secure supply chain development can be shared with the development of the connected autonomous vehicle networks, as the fleet performance is degraded by vehicles with questionable replacement parts of uncertain reliability