Encountering soviet geography: oral histories of British geographical studies of the USSR and Eastern Europe 1945-1991

This paper considers the history of British geographical studies of the USSR and Eastern Europe 1945-1991, presenting material from a research project which has included thirty-two oral history interviews. Oral history is an especially fruitful research methodology in this context due to the distinct issues of formality and informality involved in researching the Soviet bloc. After discussing the nature of the subdiscipline and the Cold War context, including the role of the British state in shaping the field, the paper considers the role of formal academic meetings and exchanges, and the place of unofficial spaces of encounter in the formation of an intellectual culture. The paper concludes by reflecting on the merits of oral history in studies of the production of geographical knowledge

Non-bisphosphonate inhibitors of isoprenoid biosynthesis identified via computer-aided drug design.

The relaxed complex scheme, a virtual-screening methodology that accounts for protein receptor flexibility, was used to identify a low-micromolar, non-bisphosphonate inhibitor of farnesyl diphosphate synthase. Serendipitously, we also found that several predicted farnesyl diphosphate synthase inhibitors were low-micromolar inhibitors of undecaprenyl diphosphate synthase. These results are of interest because farnesyl diphosphate synthase inhibitors are being pursued as both anti-infective and anticancer agents, and undecaprenyl diphosphate synthase inhibitors are antibacterial drug leads

A finite element based formulation for sensitivity studies of piezoelectric systems

Sensitivity Analysis is a branch of numerical analysis which aims to quantify the affects that variability in the parameters of a numerical model have on the model output. A finite element based sensitivity analysis formulation for piezoelectric media is developed here and implemented to simulate the operational and sensitivity characteristics of a piezoelectric based distributed mode actuator (DMA). The work acts as a starting point for robustness analysis in the DMA technology

Multi-omic Profiling Reveals Dynamics of the Phased Progression of Pluripotency

Pluripotency is highly dynamic and progresses through a continuum of pluripotent stem cell states. The two states that bookend the pluripotency continuum, naive and primed, are well characterized, but our understanding of the intermediate states and transitions between them remains incomplete. Here, we dissect the dynamics of pluripotent state transitions underlying pre- to post-implantation epiblast differentiation. Through comprehensive mapping of the proteome, phosphoproteome, transcriptome, and epigenome of embryonic stem cells transitioning from naive to primed pluripotency, we find that rapid, acute, and widespread changes to the phosphoproteome precede ordered changes to the epigenome, transcriptome, and proteome. Reconstruction of the kinase-substrate networks reveals signaling cascades, dynamics, and crosstalk. Distinct waves of global proteomic changes mark discrete phases of pluripotency, with cell-state-specific surface markers tracking pluripotent state transitions. Our data provide new insights into multi-layered control of the phased progression of pluripotency and a foundation for modeling mechanisms regulating pluripotent state transitions (www.steamcellatlas.org)

Genomic analysis of serogroup Y Neisseria meningitidis isolates reveals extensive similarities between carriage and disease-associated organisms

Background. Neisseria meningitidis is a frequent colonizer of the human nasopharynx with asymptomatic carriage providing the reservoir for invasive, disease-causing strains. Serogroup Y (MenY) strains are a major cause of meningococcal disease. High resolution genetic analyses of carriage and disease isolates can establish epidemiological relationships and identify potential virulence factors. Methods. Whole genome sequence data were obtained from UK MenY carriage isolates from 1997-2010 (n=99). Sequences were compared to those from MenY invasive isolates from 2010 and 2011 (n=73) using a gene-by-gene approach. Results. Comparisons across 1,605 core genes resolved 91% of isolates into one of eight clusters containing closely related disease and carriage isolates. Six clusters contained carried meningococci isolated in 1997-2001 suggesting temporal stability. One cluster of isolates, predominately sharing the designation Y: P1.5-1,10-1: F4-1: ST-1655 (cc23), was resolved into a sub-cluster with 86% carriage isolates and a second with 90% invasive isolates. These subclusters were defined by specific allelic differences in five core genes encoding glycerate kinase (glxK), valine-pyruvate transaminase (avtA), superoxide dismutase (sodB) and two hypothetical proteins. Conclusions. High resolution genetic analyses detected long-term temporal stability and temporally-overlapping carriage and disease populations for MenY clones but also evidence of a disease-associated clone

Can oral infection be a risk factor for Alzheimer’s disease?

Alzheimer’s disease (AD) is a scourge of longevity that will drain enormous resources from public health budgets in the future. Currently, there is no diagnostic biomarker and/or treatment for this most common form of dementia in humans. AD can be of early familial-onset or sporadic with a late-onset. Apart from the two main hallmarks, amyloid-beta and neurofibrillary tangles, inflammation is a characteristic feature of AD neuropathology. Inflammation may be caused by a local central nervous system insult and/or by peripheral infections. Numerous microorganisms are suspected in AD brains ranging from bacteria (mainly oral and non-oral Treponema species), viruses (Herpes simplex type I) and yeasts (Candida species). A causal relationship between periodontal pathogens/non-oral Treponema species of bacteria has been proposed via the amyloid-beta and inflammatory links. Periodontitis constitutes a peripheral oral infection that can provide the brain with intact bacteria and virulence factors and inflammatory mediators due to daily, transient bacteraemias. If and when genetic risk factors meet environmental risk factors in the brain, disease is expressed, in which neurocognition may be impacted, leading to the development of dementia. To achieve the goal of finding a diagnostic biomarker and possible prophylactic treatment for AD, there is an initial need to solve the etiological puzzle contributing to its pathogenesis. This review therefore addresses oral infection as the plausible aetiology of late onset AD (LOAD)

Variant signal peptides of vaccine antigen, FHbp, impair processing affecting surface localization and antibody-mediated killing in most meningococcal isolates

© Copyright © 2019 da Silva, Karlyshev, Oldfield, Wooldridge, Bayliss, Ryan and Griffin. Meningococcal lipoprotein, Factor H binding protein (FHbp), is the sole antigen of the Trumenba vaccine (Pfizer) and one of four antigens of the Bexsero vaccine (GSK) targeting Neisseria meningitidis serogroup B isolates. Lipidation of FHbp is assumed to occur for all isolates. We show in the majority of a collection of United Kingdom isolates (1742/1895) non-synonymous single nucleotide polymorphisms (SNPs) in the signal peptide (SP) of FHbp. A single SNP, common to all, alters a polar amino acid that abolishes processing: lipidation and SP cleavage. Whilst some of the FHbp precursor is retained in the cytoplasm due to reduced binding to SecA, remarkably some is translocated and further surface-localized by Slam. Thus we show Slam is not lipoprotein-specific. In a panel of isolates tested, the overall reduced surface localization of the precursor FHbp, compared to isolates with an intact SP, corresponded with decreased susceptibility to antibody-mediated killing. Our findings shed new light on the canonical pathway for lipoprotein processing and translocation of important relevance for lipoprotein-based vaccines in development and in particular for Trumenba