Identification of the active site of legumain links it to caspases, clostripain and gingipains in a new clan of cysteine endopeptidases

AbstractWe show by site-directed mutagenesis that the catalytic residues of mammalian legumain, a recently discovered lysosomal asparaginycysteine endopeptidase, form a catalytic dyad in the motif His-Gly-spacer-Ala-Cys. We note that the same motif is present in the caspases, aspartate-specific endopeptidases central to the process of apoptosis in animal cells, and also in the families of clostripain and gingipain which are arginyl/lysyl endopeptidases of pathogenic bacteria. We propose that the four families have similar protein folds, are evolutionarily related in clan CD, and have common characteristics including substrate specificities dominated by the interactions of the S1 subsite

Are you a SCEPTIC? SoCial mEdia Precision and uTility in Conferences

We analysed Twitter feeds at an emergency medicine scientific conference to determine the (1) accuracy of disseminated educational messages and the (2) use in providing rapid feedback to speakers. Most speakers were happy for key messages to be tweeted, and the majority of tweets (34/37) represented these accurately. It is important that speakers and conference organisers consider Twitter use and its potential benefits and disadvantages

Predicting prostate cancer progression:protocol for a retrospective cohort study to identify prognostic factors for prostate cancer outcomes using routine primary care data

Graphic representation of publication bias using funnel plots of all included studies. (DOCX 1318 kb

Predicting prostate cancer progression:protocol for a retrospective cohort study to identify prognostic factors for prostate cancer outcomes using routine primary care data

IntroductionProstate cancer is the most common cancer in men in the UK, with nearly 40 000 diagnosed in 2014; and it is the second most common cause of male cancer-related mortality. The clinical conundrum is that most men live with prostate cancer rather than die from it, while existing treatments have significant associated morbidity. Recent studies have shown very low mortality rates (1% after a median of 10-year follow-up) and no treatment-related reductions in mortality, in men with localised prostate cancer. This study will identify prognostic factors associated with prostate cancer progression to help differentiate aggressive from more indolent tumours in men with localised disease at diagnosis, and so inform the decision to adopt conservative (active surveillance) or radical (surgery or radiotherapy) management strategies.Methods and analysisThe Clinical Practice Research Datalink (CPRD) contains 57 318 men who were diagnosed with prostate cancer between 1 January 1987 and 31 December 2016. These men will be linked to the Office for National Statistics (ONS) and the National Cancer Registration and Analysis Service registry databases for mortality, TNM stage, Gleason grade and treatment data. Men with a diagnosis date prior to 1 January 1987 and men with lymph node or distant metastases at diagnosis will be excluded. A priori determined prognostic factors potentially associated with prostate cancer mortality, the end point of cancer progression, will be measured at baseline, and the participants followed through to development of cancer progression, death or the end of the follow-up period (31 December 2016). Cox proportional hazards regression will be used to estimate crude and mutually adjusted HRs. Mortality risk will be predicted using flexible parametric survival models that can accurately fit the shape of the hazard function.Ethics and disseminationThis study protocol has approval from the Independent Scientific Advisory Committee for the UK Medicines and Healthcare products Regulatory Agency Database Research (protocol 17_041). The findings will be presented in peer-reviewed journals and local CPRD researcher meetings.</jats:sec

Vibronic coupling explains the ultrafast carotenoid-to-bacteriochlorophyll energy transfer in natural and artificial light harvesters

The initial energy transfer in photosynthesis occurs between the light-harvesting pigments and on ultrafast timescales. We analyze the carotenoid to bacteriochlorophyll energy transfer in LH2 Marichromatium purpuratum as well as in an artificial light-harvesting dyad system by using transient grating and two-dimensional electronic spectroscopy with 10 fs time resolution. We find that F\"orster-type models reproduce the experimentally observed 60 fs transfer times, but overestimate coupling constants, which leads to a disagreement with both linear absorption and electronic 2D-spectra. We show that a vibronic model, which treats carotenoid vibrations on both electronic ground and excited state as part of the system's Hamiltonian, reproduces all measured quantities. Importantly, the vibronic model presented here can explain the fast energy transfer rates with only moderate coupling constants, which are in agreement with structure based calculations. Counterintuitively, the vibrational levels on the carotenoid electronic ground state play a central role in the excited state population transfer to bacteriochlorophyll as the resonance between the donor-acceptor energy gap and vibrational ground state energies is the physical basis of the ultrafast energy transfer rates in these systems

The Relationship Between Fractures and DXA Measures of BMD in the Distal Femur of Children and Adolescents With Cerebral Palsy or Muscular Dystrophy

Children with limited or no ability to ambulate frequently sustain fragility fractures. Joint contractures, scoliosis, hip dysplasia, and metallic implants often prevent reliable measures of bone mineral density (BMD) in the proximal femur and lumbar spine, where BMD is commonly measured. Further, the relevance of lumbar spine BMD to fracture risk in this population is questionable. In an effort to obtain bone density measures that are both technically feasible and clinically relevant, a technique was developed involving dual-energy X-ray absorptiometry (DXA) measures of the distal femur projected in the lateral plane. The purpose of this study is to test the hypothesis that these new measures of BMD correlate with fractures in children with limited or no ability to ambulate. The relationship between distal femur BMD Z-scores and fracture history was assessed in a cross-sectional study of 619 children aged 6 to 18 years with muscular dystrophy or moderate to severe cerebral palsy compiled from eight centers. There was a strong correlation between fracture history and BMD Z-scores in the distal femur; 35% to 42% of those with BMD Z-scores less than −5 had fractured compared with 13% to 15% of those with BMD Z-scores greater than −1. Risk ratios were 1.06 to 1.15 (95% confidence interval 1.04–1.22), meaning a 6% to 15% increased risk of fracture with each 1.0 decrease in BMD Z-score. In clinical practice, DXA measure of BMD in the distal femur is the technique of choice for the assessment of children with impaired mobility. © 2010 American Society for Bone and Mineral Researc

Mechanistic role of a disease-associated genetic variant within the ADAM33 asthma susceptibility gene

<p>Abstract</p> <p>Background</p> <p>ADAM33 has been identified as an asthma-associated gene in an out-bred population. Genetic studies suggested that the functional role of this metalloprotease was in airway remodeling. However, the mechanistic roles of the disease-associated SNPs have yet to be elucidated especially in the context of the pathophysiology of asthma. One disease-associated SNP, BC+1, which resides in intron BC toward the 5' end of ADAM33, is highly associated with the disease.</p> <p>Methods</p> <p>The region surrounding this genetic variant was cloned into a model system to determine if there is a regulatory element within this intron that influences transcription.</p> <p>Results</p> <p>The BC+1 protective allele did not impose any affect on the transcription of the reporter gene. However, the at-risk allele enforced such a repressive affect on the promoter that no protein product from the reporter gene was detected. These results indicated that there exists within intron BC a regulatory element that acts as a repressor for gene expression. Moreover, since SNP BC+1 is a common genetic variant, this region may interact with other undefined regulatory elements within ADAM33 to provide a rheostat effect, which modulates pre-mRNA processing. Thus, SNP BC+1 may have an important role in the modulation of ADAM33 gene expression.</p> <p>Conclusion</p> <p>These data provide for the first time a functional role for a disease-associated SNP in ADAM33 and begin to shed light on the deregulation of this gene in the pathophysiology of asthma.</p

Bioinformatic characterisation of the effector repertoire of the strawberry pathogen Phytophthora cactorum

The oomycete pathogen Phytophthora cactorum causes crown rot, a major disease of cultivated strawberry. We report the draft genome of P. cactorum isolate 10300, isolated from symptomatic Fragaria x ananassa tissue. Our analysis revealed that there are a large number of genes encoding putative secreted effectors in the genome, including nearly 200 RxLR domain containing effectors, 77 Crinklers (CRN) grouped into 38 families, and numerous apoplastic effectors, such as phytotoxins (PcF proteins) and necrosis inducing proteins. As in other Phytophthora species, the genomic environment of many RxLR and CRN genes differed from core eukaryotic genes, a hallmark of the two-speed genome. We found genes homologous to known Phytophthora infestans avirulence genes including Avr1, Avr3b, Avr4, Avrblb1 and AvrSmira2 indicating effector sequence conservation between Phytophthora species of clade 1a and clade 1c. The reported P. cactorum genome sequence and associated annotations represent a comprehensive resource for avirulence gene discovery in other Phytophthora species from clade 1 and, will facilitate effector informed breeding strategies in other crops