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Characterisation of the UK anthrax vaccine and human immunogenicity
Get PDFThe manufacture of the UK Anthrax vaccine (AVP) focuses on the production of Protective Antigen (PA) from the Bacillus anthracis Sterne strain. Although used for decades, several of AVP’s fundamental properties are poorly understood, including its exact composition, the extent to which proteins other than PA may contribute to protection, and whether the degree of protection varies between individuals.
This study involved three innovative investigations. Firstly, the composition of AVP was analysed using liquid chromatography tandem mass-spectrometry (LC-MS/MS), requiring the development of a novel desorption method for releasing B. anthracis proteins from the vaccine’s aluminium-containing adjuvant. Secondly, computational MHC-binding predictions using NetMHCIIpan were made for the eight most abundant proteins of AVP, for the commonest HLA alleles in multiple ethnic groups, and for multiple B. anthracis strains. Thirdly, antibody levels and toxin neutralising antibody (TNA) levels were measured in sera from AVP human vaccinees for both PA and Lethal Factor (LF).
It was demonstrated that AVP is composed of at least 138 B. anthracis proteins, including PA (65%), LF (8%) and Edema Factor (EF) (3%), using LC-MS/MS. NetMHCIIpan predicted that peptides from all eight abundant proteins are likely to be presented to T cells, a pre-requisite for protection; however, the number of such peptides varied considerably between different HLA alleles.
These analyses highlight two important properties of the AVP vaccine that have not been established previously. Firstly, the effectiveness of AVP within humans may not depend on PA alone; there is compelling evidence to suggest that LF has a protective role, with computational predictions suggesting that additional proteins may be important for individuals with specific HLA allele combinations. Secondly, in spite of differences in the sequences of key antigenic proteins from different B. anthracis strains, these are unlikely to affect the cross-strain protection afforded by AVP
Infant Spontaneous Motor Tempo
Get PDFSpontaneous Motor Tempo (SMT) is influenced by individual differences in
age and body size. We present the first data documenting the SMT of infants
from five- to 37-months-of-age using a simple drumming task. As in late
childhood and adulthood, we predicted that infant SMT would slow across the
first years of life. However, we find that older infants drum more quickly than
younger infants. Further, studies of adults suggest larger bodies prefer slower
rhythms. This relationship may be the product of biomechanical resonance,
or, effects may be driven by rhythmic experience, such as of locomotion. We
used infants, whose body size is dissociated from their predominant
experience of locomotion as their parent often carries them, to test this
argument. We reveal that infant SMT is predicted by parent, but not own, body
size, supporting a passive experience-based argument, and propose that
early rhythm may be set by repetitive vestibular stimulation when carried by
the caregiver
Does ownership structure affect performance? Evidence from Chinese mutual funds
Get PDFThis paper examines the impact of ownership structure on Chinese mutual fund performance and market share. We focus on two dimensions of ownership structure, namely the background of the owners and the degree of ownership concentration. Using a hand-collected dataset comprising 731 observations for 94 fund management companies over the period from 2005 to 2015, we provide evidence with panel estimation shows that the government ownership ratio and government-controlled companies have a positive effect on funds’ performance. On the other hand, foreign ownership has a negative impact on performance and market share. Having a higher ownership concentration is more likely to increase the company’s market share, whereas government-controlled companies experience a negative impact on their market share
The skeletal remains of the euryhaline sclerorhynchid batoid †Onchopristis (Elasmobranchii, Batoidea) from the ‘mid’ Cretaceous and its palaeontological implications
Get PDFWe present the first known cranial remains of the fossil batoid †Onchopristis numidus. Based on two exceptionally well-preserved specimens collected from the “Kem Kem Beds” (Albian-Cenomanian), South-East of Morocco, an almost complete description of the rostral and cranial portions of the genus †Onchopristis is provided, along with new observations regarding the addition and arrangement of the rostral denticles series for this genus. The comparison between the rostrum length of the specimens of †Onchopristis numidus with those of extant pristids revealed a relatively large batoid species with an estimated total length between two to four meters. Overall, the cranial morphology of †Onchopristis resembles that of other sclerorhynchoids. Its robust hypertrophied rostrum with the characteristic wood-like mineralisation covering the inner layer of tessellate cartilage at the centre of the rostrum, in addition to the thick lateral layers of densely porous cartilage on the sides of the rostral cartilages, resembles that observed in †Ischyrhiza and †Shizorhiza, and differentiates †Onchopristis from other sclerorhynchoids species (e.g. †Micropristis, †Sclerorhynchus and †Libanopristis). Based on these rostral features, a phylogenetic analysis to establish the phylogenetic position of †Onchopristis within sclerorhynchoids is carried out, which results suggest a new taxonomic arrangement for the sclerorhynchoids
Correlative light and electron microscopy suggests that mutant huntingtin dysregulates the endolysosomal pathway in presymptomatic Huntington’s disease
Get PDFHuntington’s disease (HD) is a late onset, inherited neurodegenerative disorder for which early pathogenic events remain poorly understood. Here we show that mutant exon 1 HTT proteins are recruited to a subset of cytoplasmic aggregates in the cell bodies of neurons in brain sections from presymptomatic HD, but not wild-type, mice. This occurred in a disease stage and polyglutamine-length dependent manner. We successfully adapted a high-resolution correlative light and electron microscopy methodology, originally developed for mammalian and yeast cells, to allow us to correlate light microscopy and electron microscopy images on the same brain section within an accuracy of 100 nm. Using this approach, we identified these recruitment sites as single membrane bound, vesicle-rich endolysosomal organelles, specifically as (1) multivesicular bodies (MVBs), or amphisomes and (2) autolysosomes or residual bodies. The organelles were often found in close-proximity to phagophore-like structures. Immunogold labeling localized mutant HTT to non-fibrillar, electron lucent structures within the lumen of these organelles. In presymptomatic HD, the recruitment organelles were predominantly MVBs/amphisomes, whereas in late-stage HD, there were more autolysosomes or residual bodies. Electron tomograms indicated the fusion of small vesicles with the vacuole within the lumen, suggesting that MVBs develop into residual bodies. We found that markers of MVB-related exocytosis were depleted in presymptomatic mice and throughout the disease course. This suggests that endolysosomal homeostasis has moved away from exocytosis toward lysosome fusion and degradation, in response to the need to clear the chronically aggregating mutant HTT protein, and that this occurs at an early stage in HD pathogenesis
Whole genome mapping and identification of single nucleotide polymorphisms of four Bangladeshi individuals and their functional significance
Get PDFObjective: The major objective of the study was to sequence the whole genome of four Bangladeshi individuals and
identify variants that are known to be associated with functional changes or disease states. We also carried out an
ontology analysis to identify the functions and pathways most likely to be afected by these variants.
Results: We identifed around 900,000 common variants and close to 5 million unique ones in all four of the indi‑
viduals. This included over 11,500 variants that caused nonsynonymous changes in proteins. Heart function associ‑
ated pathways were heavily implicated by the ontology analysis; corroborating previous studies that claimed the
Bangladeshi population as highly susceptible to heart disorders. Two variants were found that have been previously
identifed as pathogenic factors in familial hypercholesteremia and structural disorders of the heart. Other pathogenic
variants we found were associated with pseudoxanthoma elasticum, cancer progression, polyagglutinable erythro‑
cyte syndrome, preeclampsia, and other
PG-Keys: keys for property graphs
Get PDFWe report on a community effort between industry and academia to shape the future of property graph constraints. The standardization for a property graph query language is currently underway through the ISO Graph Query Language (GQL) project. Our position is that this project should pay close attention to schemas and constraints, and should focus next on key constraints. The main purposes of keys are enforcing data integrity and allowing the referencing and identifying of objects. Motivated by use cases from our industry partners, we argue that key constraints should be able to have different modes, which are combinations of basic restriction that require the key to be exclusive, mandatory, and singleton. Moreover, keys should be applicable to nodes, edges, and properties since these all can represent valid real-life entities. Our result is PG-Keys, a flexible and powerful framework for defining key constraints, which fulfills the above goals. PG-Keys is a design by the Linked Data Benchmark Council's Property Graph Schema Working Group, consisting of members from industry, academia, and ISO GQL standards group, intending to bring the best of all worlds to property graph practitioners. PG-Keys aims to guide the evolution of the standardization efforts towards making systems more useful, powerful, and expressive
Can confidential research be reproducible: consent, ethics, prison interviews and the open research agenda
No full textA presentation given at the ESRC DTP conference on 29th January 2021, reflecting on the Open Research agenda and some ethical questions it raises in relation to interviews conducted in prison
The decline of magic: Britain in the Enlightenment
No full textBook synopsis: In early modern Britain, belief in prophecies, omens, ghosts, apparitions and fairies was commonplace. Among both educated and ordinary people the absolute existence of a spiritual world was taken for granted. Yet in the eighteenth century such certainties were swept away. Credit for this great change is usually given to science – and in particular to the scientists of the Royal Society. But is this justified?
Michael Hunter argues that those pioneering the change in attitude were not scientists but freethinkers. While some scientists defended the reality of supernatural phenomena, these sceptical humanists drew on ancient authors to mount a critique both of orthodox religion and, by extension, of magic and other forms of superstition. Even if the religious heterodoxy of such men tarnished their reputation and postponed the general acceptance of anti-magical views, slowly change did come about. When it did, this owed less to the testing of magic than to the growth of confidence in a stable world in which magic no longer had a place
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