The protease associated (PA) domain in ScpA from Streptococcus pyogenes plays a role in substrate recruitment

Annually, over 18 million disease cases and half a million deaths worldwide are estimated to be caused by Group A Streptococcus. ScpA (or C5a peptidase) is a well characterised member of the cell enveleope protease family, which possess a S8 subtilisin-like catalytic domain and a shared multi-domain architecture. ScpA cleaves complement factors C5a and C3a, impairing the function of these critical anaphylatoxins and disrupts complement-mediated innate immunity. Although the high resolution structure of ScpA is known, the details of how it recognises its substrate are only just emerging. Previous studies have identified a distant exosite on the 2nd fibronectin domain that plays an important role in recruitment via an interaction with the substrate core. Here, using a combination of solution NMR spectroscopy, mutagenesis with functional assays and computational approaches we identify a second exosite within the protease-associated (PA) domain. We propose a model in which the PA domain assists optimal delivery of the substrate's C terminus to the active site for cleavage

Mario Bunge and the Current Revival of Causal Realism

Mario Bunge’s Causality and Modern Science is arguably one of the best treatments of the causal realist tradition ever to have been written, one that defends the place of causality as a category in the conceptual framework of modern science. And yet in the current revival of causal realism in contemporary metaphysics, there is very little awareness of Bunge’s work. This paper seeks to remedy this, by highlighting one particular criticism Bunge levels at the Aristotelian view of causation and illustrating its relevance for contemporary powers-based accounts. Roughly, the Aristotelian view depicts interactions between objects as involving a unidirectional exertion of influence of one object upon another. This idea of unidirectional action is central to the Aristotelian distinction between active and passive powers, and its corresponding distinction between active and passive objects. As Bunge points out, modern physics does not recognise the existence of any unidirectional actions at all; all influence comes in the form of reciprocal action, or interaction. If this is right, all notions deriving from or influenced by the idea of unidirectional actions—such as the concept of mutual manifestation and reciprocal disposition partners—risk being false by the same measure. Bunge drew the conclusion that the Aristotelian view is ontologically inadequate, but still advocated its use as the most useful approximation available in science. He considered, but ultimately rejected the possibility of a modified view of causation built on reciprocal action, because, in his view, it couldn’t account for the productivity of causation. Bunge’s critique of this particular aspect of the Aristotelian view cannot be overlooked in contemporary metaphysics, but it is possible to construe a modified view of causation that takes the reciprocity of interactions seriously without loss of productivity.Peer reviewe

Exploration of Shared Genetic Architecture Between Subcortical Brain Volumes and Anorexia Nervosa

In MRI scans of patients with anorexia nervosa (AN), reductions in brain volume are often apparent. However, it is unknown whether such brain abnormalities are influenced by genetic determinants that partially overlap with those underlying AN. Here, we used a battery of methods (LD score regression, genetic risk scores, sign test, SNP effect concordance analysis, and Mendelian randomization) to investigate the genetic covariation between subcortical brain volumes and risk for AN based on summary measures retrieved from genome-wide association studies of regional brain volumes (ENIGMA consortium, n = 13,170) and genetic risk for AN (PGC-ED consortium, n = 14,477). Genetic correlations ranged from − 0.10 to 0.23 (all p > 0.05). There were some signs of an inverse concordance between greater thalamus volume and risk for AN (permuted p = 0.009, 95% CI: [0.005, 0.017]). A genetic variant in the vicinity of ZW10, a gene involved in cell division, and neurotransmitter and immune system relevant genes, in particular DRD2, was significantly associated with AN only after conditioning on its association with caudate volume (pFDR = 0.025). Another genetic variant linked to LRRC4C, important in axonal and synaptic development, reached significance after conditioning on hippocampal volume (pFDR = 0.021). In this comprehensive set of analyses and based on the largest available sample sizes to date, there was weak evidence for associations between risk for AN and risk for abnormal subcortical brain volumes at a global level (that is, common variant genetic architecture), but suggestive evidence for effects of single genetic markers. Highly powered multimodal brain- and disorder-related genome-wide studies are needed to further dissect the shared genetic influences on brain structure and risk for AN

Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision

In 2012, we published guidelines summarizing and evaluating late 2011 evidence for diagnosis and therapy of urea cycle disorders (UCDs). With 1:35 000 estimated incidence, UCDs cause hyperammonemia of neonatal (~50%) or late onset that can lead to intellectual disability or death, even while effective therapies do exist. In the 7 years that have elapsed since the first guideline was published, abundant novel information has accumulated, experience on newborn screening for some UCDs has widened, a novel hyperammonemia-causing genetic disorder has been reported, glycerol phenylbutyrate has been introduced as a treatment, and novel promising therapeutic avenues (including gene therapy) have been opened. Several factors including the impact of the first edition of these guidelines (frequently read and quoted) may have increased awareness among health professionals and patient families. However, under-recognition and delayed diagnosis of UCDs still appear widespread. It was therefore necessary to revise the original guidelines to ensure an up-to-date frame of reference for professionals and patients as well as for awareness campaigns. This was accomplished by keeping the original spirit of providing a trans-European consensus based on robust evidence (scored with GRADE methodology), involving professionals on UCDs from nine countries in preparing this consensus. We believe this revised guideline, which has been reviewed by several societies that are involved in the management of UCDs, will have a positive impact on the outcomes of patients by establishing common standards, and spreading and harmonizing good practices. It may also promote the identification of knowledge voids to be filled by future research