Holistic process development to mitigate proteolysis of a subunit rotavirus vaccine candidate produced in Pichia pastoris by means of an acid pH pulse during fed‐batch fermentation

To meet the challenges of global health, vaccine design and development must be reconsidered to achieve cost of goods as low as 15¢ per dose. A new recombinant protein‐based rotavirus vaccine candidate derived from non‐replicative viral subunits fused to a P2 tetanus toxoid CD4(+) T cell epitope is currently under clinical development. We have sought to simplify the existing manufacturing process to meet these aims. To this end, we have taken a holistic process development approach to reduce process complexity and costs while producing a product with the required characteristics. We have changed expression system from Escherichia coli to Pichia pastoris, to produce a secreted product, thereby reducing the number of purification steps. However, the presence of proteases poses challenges to product quality. To understand the effect of fermentation parameters on product quality small‐scale fermentations were carried out. Media pH and fermentation duration had the greatest impact on the proportion of full‐length product. A novel acidic pH pulse strategy was used to minimize proteolysis, and this combined with an early harvest time significantly increased the proportion of full‐length material (60–75%). An improved downstream process using a combination of CIEX and AIEX to further reduce proteases, resulted in maintaining product quality (95% yield)

Electrical Detection of DC Spin Current Propagation Through an Epitaxial Antiferromagnetic NiO Layer

This is the author accepted manuscript. The final version is available from IEEE via the DOI in this recordA method for detecting dc spin current propagation through an epitaxial antiferromagnetic (AFM) NiO layer is presented. Spin current is generated by spin pumping from an adjoining ferromagnetic (FM) layer and detected in a non-magnetic metallic layer by the inverse spin Hall effect. Comparison is made with a YIG/Pt bilayer, where only the Pt layer is electrically conducting, but for which spin Hall magnetoresistance makes an additional contribution to the measured signal. The signal obtained from the multilayered stack containing the AFM NiO layer is found to contain additional contributions due to anisotropic magnetoresistance. By exciting the sample with out-of-plane rf magnetic field and making measurements with a static field applied at different orientations within the plane of the sample, a signal associated with the dc spin current may be identified.Engineering and Physical Sciences Research Council (EPSRC

Revisions to the derivation of the Australian and New Zealand guidelines for toxicants in fresh and marine waters

The Australian and New Zealand Guidelines for Fresh and Marine Water Quality are a key document in the Australian National Water Quality Management Strategy. These guidelines released in 2000 are currently being reviewed and updated. The revision is being co-ordinated by the Australian Department of Sustainability, Environment, Water, Population and Communities, while technical matters are dealt with by a series of Working Groups. The revision will be evolutionary in nature reflecting the latest scientific developments and a range of stakeholder desires. Key changes will be: increasing the types and sources of data that can be used; working collaboratively with industry to permit the use of commercial-in-confidence data; increasing the minimum data requirements; including a measure of the uncertainty of the trigger value; improving the software used to calculate trigger values; increasing the rigour of site-specific trigger values; improving the method for assessing the reliability of the trigger values; and providing guidance of measures of toxicity and toxicological endpoints that may, in the near future, be appropriate for trigger value derivation. These changes will markedly improve the number and quality of the trigger values that can be derived and will increase end-users’ ability to understand and implement the guidelines in a scientifically rigorous manner

Criminal and Noncriminal Psychopathy: The Devil is in the Detail

Brooks, NS ORCiD: 0000-0003-1784-099XPsychopathy is prevalent and problematic in criminal populations, but is also found to be present in noncriminal populations. In 1992, Robert Hare declared that psychopaths may also “be found in the boardroom”, which has since been followed by an interest in the issue of noncriminal, or even successful, psychopathy. In this chapter, the paradox of criminal and noncriminal psychopathy is discussed with specific attention given to the similarities and differences that account for psychopathic personality across contexts. That psychopathy is a condition typified by a constellation of traits and behaviours requires wider research across diverse populations, and thus the streams of research related to criminal and noncriminal psychopathy are presented and the implications of these contrasting streams are explored

Sex differences in the relative contribution of social and clinical factors to the Health Utilities Index Mark 2 measure of health-related quality of life in older home care clients

Abstract Background The heterogeneity evident among home care clients highlights the need for greater understanding of the clinical and social determinants of multi-dimensional health-related quality of life (HRQL) indices and of potential sex-differences in these determinants. We examined the relative contribution of social and clinical factors to HRQL among older home care clients and explored whether any of the observed associations varied by sex. Methods The Canadian-US sample included 514 clients. Self-reported HRQL was measured during in-home interviews (2002-04) using the Health Utilities Index Mark 2 (HUI2). Data on clients' sociodemographic, health and clinical characteristics were obtained with the Minimum Data Set for Home Care. The relative associations between clients' characteristics and HUI2 scores were examined using multivariable linear regression models. Results Women had a significantly lower mean HUI2 score than men (0.48, 95%CI 0.46-0.50 vs. 0.52, 0.49-0.55). Clients with distressed caregivers and poor self-rated health exhibited significantly lower HRQL scores after adjustment for a comprehensive list of clinical conditions. Several other factors remained statistically significant (arthritis, psychiatric illness, bladder incontinence, urinary tract infection) or clinically important (reported loneliness, congestive heart failure, pressure ulcers) correlates of lower HUI2 scores in adjusted analyses. These associations generally did not vary significantly by sex. Conclusion For females and males, HRQL scores were negatively associated with conditions predictive or indicative of disability and with markers of psychosocial stress. Despite sex differences in the prevalence of social and clinical factors likely to affect HRQL, few varied significantly by sex in their relative impact on HUI2 scores. Further exploration of differences in the relative importance of clinical and psychosocial well-being (e.g., loneliness) to HRQL among female and male clients may help guide the development of sex-specific strategies for risk screening and care management

Predicting Spatial Patterns of Plant Recruitment Using Animal-Displacement Kernels

For plants dispersed by frugivores, spatial patterns of recruitment are primarily influenced by the spatial arrangement and characteristics of parent plants, the digestive characteristics, feeding behaviour and movement patterns of animal dispersers, and the structure of the habitat matrix. We used an individual-based, spatially-explicit framework to characterize seed dispersal and seedling fate in an endangered, insular plant-disperser system: the endemic shrub Daphne rodriguezii and its exclusive disperser, the endemic lizard Podarcis lilfordi. Plant recruitment kernels were chiefly determined by the disperser's patterns of space utilization (i.e. the lizard's displacement kernels), the position of the various plant individuals in relation to them, and habitat structure (vegetation cover vs. bare soil). In contrast to our expectations, seed gut-passage rate and its effects on germination, and lizard speed-of-movement, habitat choice and activity rhythm were of minor importance. Predicted plant recruitment kernels were strongly anisotropic and fine-grained, preventing their description using one-dimensional, frequency-distance curves. We found a general trade-off between recruitment probability and dispersal distance; however, optimal recruitment sites were not necessarily associated to sites of maximal adult-plant density. Conservation efforts aimed at enhancing the regeneration of endangered plant-disperser systems may gain in efficacy by manipulating the spatial distribution of dispersers (e.g. through the creation of refuges and feeding sites) to create areas favourable to plant recruitment

Correlating corneal arcus with atherosclerosis in familial hypercholesterolemia

Abstract Background A relationship between corneal arcus and atherosclerosis has long been suspected but is controversial. The homozygous familial hypercholesterolemia patients in this study present a unique opportunity to assess this issue. They have both advanced atherosclerosis and corneal arcus. Methods This is a cross-sectional study of 17 patients homozygous for familial hypercholesterolemia presenting to the Clinical Center of the National Institutes of Health. Plasma lipoproteins, circumferential extent of arcus, thoracic aorta and coronary calcific atherosclerosis score, and Achilles tendon width were measured at the National Institutes of Health. Results Patients with corneal arcus had higher scores for calcific atherosclerosis (mean 2865 compared to 412), cholesterol-year score (mean 11830 mg-yr/dl compared to 5707 mg-yr/dl), and Achilles tendon width (mean 2.54 cm compared to 1.41 cm) than those without. Corneal arcus and Achilles tendon width were strongly correlated and predictive of each other. Although corneal arcus was correlated with calcific atherosclerosis (r = 0.67; p = 0.004), it was not as highly correlated as was the Achilles tendon width (r = 0.855; p Conclusion Corneal arcus reflects widespread tissue lipid deposition and is correlated with both calcific atherosclerosis and xanthomatosis in these patients. Patients with more severe arcus tend to have more severe calcific atherosclerosis. Corneal arcus is not as good an indicator of calcific atherosclerosis as Achilles tendon thickness, but its presence suggests increased atherosclerosis in these hypercholesterolemic patients.</p