Macromolecular mimicry in protein biosynthesis

Elongation factor Tu (EF-Tu) is a G-protein which, in its active GTP conformation, protects and carries aminoacylated tRNAs (aa-tRNAs) to the ribosome during protein biosynthesis. EF-Tu consists of three structural domains of which the N-terminal domain consists of two special regions (switch I and switch II) which are structurally dependent on the type of the bound nucleotide. Structural studies of the complete functional cycle of EF-Tu reveal that it undergoes rather spectacular conformational changes when activated from the EF-Tu·GDP form to the EF-Tu·GTP form. In its active form, EF-Tu·GTP without much further structural change interacts with aa-tRNAs in the so-called ternary complex. The conformational changes of EF-Tu involve rearrangements of the secondary structures of both the switch I and switch II regions. As the switch II region forms part of the interface between domains 1 and 3, its structural rearrangement results in a very large change of the position of domain 1 relative to domains 2 and 3. The overall shape of the ternary complex is surprisingly similar to the overall shape of elongation factor G (EF-G). Thus, three domains of the protein EF-G seem to mimic the tRNA part of the ternary complex. This macromolecular mimicry has profound implications for the function of the elongation factors on the ribosome

Associations between interarm differences in blood pressure and cardiovascular disease outcomes: protocol for an individual patient data meta-analysis and development of a prognostic algorithm

This is the final version of the article. Available on open access from BMJ Publishing Group via the DOI in this record.There is another record for this publication in ORE: http://hdl.handle.net/10871/32190INTRODUCTION: Individual cohort studies in various populations and study-level meta-analyses have shown interarm differences (IAD) in blood pressure to be associated with increased cardiovascular and all-cause mortality. However, key questions remain, such as follows: (1) What is the additional contribution of IAD to prognostic risk estimation for cardiovascular and all-cause mortality? (2) What is the minimum cut-off value for IAD that defines elevated risk? (3) Is there a prognostic value of IAD and do different methods of IAD measurement impact on the prognostic value of IAD? We aim to address these questions by conducting an individual patient data (IPD) meta-analysis. METHODS AND ANALYSIS: This study will identify prospective cohort studies that measured blood pressure in both arms during recruitment, and invite authors to contribute IPD datasets to this collaboration. All patient data received will be combined into a single dataset. Using one-stage meta-analysis, we will undertake multivariable time-to-event regression modelling, with the aim of developing a new prognostic model for cardiovascular risk estimation that includes IAD. We will explore variations in risk contribution of IAD across predefined population subgroups (eg, hypertensives, diabetics), establish the lower limit of IAD that is associated with additional cardiovascular risk and assess the impact of different methods of IAD measurement on risk prediction. ETHICS AND DISSEMINATION: This study will not include any patient identifiable data. Included datasets will already have ethical approval and consent from their sponsors. Findings will be presented to international conferences and published in peer reviewed journals, and we have a comprehensive dissemination strategy in place with integrated patient and public involvement. PROSPERO REGISTRATION NUMBER: CRD42015031227.National Institute for Health Research (NIHR

Vitamin D and COVID-19 in older age: evidence versus expectations

This is the author accepted manuscript. The final version is available from the Royal College of General Practitioners via the DOI in this recordThe current global pandemic of SARS-CoV-2 coronavirus infection originated in Wuhan, China, during December 2019; over 50 million cases have been diagnosed to date. Older age and comorbidity have proven to be key markers of risk for severity of COVID-19 and mortality,1,2 and residents of care homes have been proven to be at high risk. The Office for National Statistics has recorded 16 111 deaths related to COVID-19 in care home residents in England up to 20 November 2020.3 In the first wave of the pandemic, 46% of all excess deaths in England and Wales up to 7 August occurred in care homes.4 Older age is associated with increasing prevalence of vitamin D deficiency, which can affect up to 40% of care home residents.5 There is considerable overlap between the non-modifiable risk factors for severe SARS-CoV-2 infection and those associated with deficiency of vitamin D. For example, age, ethnicity, diabetes, and chronic pulmonary and cardiac diseases; in addition, there is the observed trend towards greater severity of disease in northern latitudes. While these could imply an association between reduced vitamin D levels and susceptibility to SARS-CoV-2 infection this may simply be an ecological fallacy.6 Therefore, it is important to understand the strength of evidence provided by epidemiological and observational studies of COVID-19, and compare it with what is known from clinical trials of the impact of vitamin D supplementation on acute respiratory infections, including those due to SARS-CoV-2.National Institute for Health Research (NIHR

Strain-relief by single dislocation loops in calcite crystals grown on self-assembled monolayers

Most of our knowledge of dislocation-mediated stress relaxation during epitaxial crystal growth comes from the study of inorganic heterostructures. Here we use Bragg coherent diffraction imaging to investigate a contrasting system, the epitaxial growth of calcite (CaCO3) crystals on organic self-assembled monolayers, where these are widely used as a model for biomineralization processes. The calcite crystals are imaged to simultaneously visualize the crystal morphology and internal strain fields. Our data reveal that each crystal possesses a single dislocation loop that occupies a common position in every crystal. The loops exhibit entirely different geometries to misfit dislocations generated in conventional epitaxial thin films and are suggested to form in response to the stress field, arising from interfacial defects and the nanoscale roughness of the substrate. This work provides unique insight into how self-assembled monolayers control the growth of inorganic crystals and demonstrates important differences as compared with inorganic substrates

Glucosyltransferase phase variation in Streptococcus gordonii modifies adhesion to saliva-coated hydroxyapatite surfaces in a sucrose-independent manner

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72317/1/j.1399-302X.1992.tb00521.x.pd

Randomised controlled trial and health economic evaluation of the impact of diagnostic testing for influenza, respiratory syncytial virus and Streptococcus pneumoniae infection on the management of acute admissions in the elderly and high-risk 18- to 64-year-olds

Please cite the published version which is available via the DOI link in this record.Western industrialised nations face a large increase in the number of older people. People over the age of 60 years account for almost half of the 16.8 million hospital admissions in England from 2009 to 2010. During 2009-10, respiratory infections accounted for approximately 1 in 30 hospital admissions and 1 in 20 of the 51.5 million bed-days.HTA ProgrammeNational Institute for Health Research (NIHR

Towards single particle imaging of human chromosomes at SACLA

Single particle imaging (SPI) is one of the front-page opportunities which were used to motivate the construction of the first x-ray free electron lasers (XFELs). SPI's big advantage is that it avoids radiation damage to biological samples because the diffraction takes place in femtosecond single shots before any atomic motion can take place in the sample, hence before the onset of radiation damage. This is the 'diffract before destruction' theme, destruction being assured from the high x-ray doses used. This article reports our collaboration's first attempt at SPI using the SACLA XFEL facility in June 2015. The report is limited to experience with the instrumentation and examples of data because we have not yet had time to invert them to images.112Ysciescopu

Phosphorylated Dihydroceramides from Common Human Bacteria Are Recovered in Human Tissues

Novel phosphorylated dihydroceramide (PDHC) lipids produced by the periodontal pathogen Porphyromonas gingivalis include phosphoethanolamine (PE DHC) and phosphoglycerol dihydroceramides (PG DHC) lipids. These PDHC lipids mediate cellular effects through Toll-like receptor 2 (TLR2) including promotion of IL-6 secretion from dendritic cells and inhibition of osteoblast differentiation and function in vitro and in vivo. The PE DHC lipids also enhance (TLR2)-dependent murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. The unique non-mammalian structures of these lipids allows for their specific quantification in bacteria and human tissues using multiple reaction monitoring (MRM)-mass spectrometry (MS). Synthesis of these lipids by other common human bacteria and the presence of these lipids in human tissues have not yet been determined. We now report that synthesis of these lipids can be attributed to a small number of intestinal and oral organisms within the Bacteroides, Parabacteroides, Prevotella, Tannerella and Porphyromonas genera. Additionally, the PDHCs are not only present in gingival tissues, but are also present in human blood, vasculature tissues and brain. Finally, the distribution of these TLR2-activating lipids in human tissues varies with both the tissue site and disease status of the tissue suggesting a role for PDHCs in human disease