Neuroimaging-Based Classification of PTSD Using Data-Driven Computational Approaches:A Multisite Big Data Study from the ENIGMA-PGC PTSD Consortium

BACKGROUND: Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. However, current machine learning studies limited to small homogeneous samples, different methodologies, and different imaging collection protocols, limit the ability to directly compare and generalize their results. Here we aimed to classify individuals with PTSD versus controls and assess the generalizability using a large heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group.METHODS: We analyzed brain MRI data from 3,477 structural-MRI; 2,495 resting state-fMRI; and 1,952 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification performance. Third, we assessed the generalizability and reproducibility of both models using leave-one-site-out cross-validation procedure for each modality.RESULTS: We found lower performance in classifying PTSD vs. controls with data from over 20 sites (60% test AUC for s-MRI, 59% for rs-fMRI and 56% for d-MRI), as compared to other studies run on single-site data. The performance increased when classifying PTSD from HC without trauma history in each modality (75% AUC). The classification performance remained intact when applying the DVAE framework, which reduced the number of features. Finally, we found that the DVAE framework achieved better generalization to unseen datasets compared with the traditional machine learning frameworks, albeit performance was slightly above chance.CONCLUSION: These results have the potential to provide a baseline classification performance for PTSD when using large scale neuroimaging datasets. Our findings show that the control group used can heavily affect classification performance. The DVAE framework provided better generalizability for the multi-site data. This may be more significant in clinical practice since the neuroimaging-based diagnostic DVAE classification models are much less site-specific, rendering them more generalizable.</p

From old organisms to new molecules: integrative biology and therapeutic targets in accelerated human ageing

Understanding the basic biology of human ageing is a key milestone in attempting to ameliorate the deleterious consequences of old age. This is an urgent research priority given the global demographic shift towards an ageing population. Although some molecular pathways that have been proposed to contribute to ageing have been discovered using classical biochemistry and genetics, the complex, polygenic and stochastic nature of ageing is such that the process as a whole is not immediately amenable to biochemical analysis. Thus, attempts have been made to elucidate the causes of monogenic progeroid disorders that recapitulate some, if not all, features of normal ageing in the hope that this may contribute to our understanding of normal human ageing. Two canonical progeroid disorders are Werner’s syndrome and Hutchinson-Gilford progeroid syndrome (also known as progeria). Because such disorders are essentially phenocopies of ageing, rather than ageing itself, advances made in understanding their pathogenesis must always be contextualised within theories proposed to help explain how the normal process operates. One such possible ageing mechanism is described by the cell senescence hypothesis of ageing. Here, we discuss this hypothesis and demonstrate that it provides a plausible explanation for many of the ageing phenotypes seen in Werner’s syndrome and Hutchinson-Gilford progeriod syndrome. The recent exciting advances made in potential therapies for these two syndromes are also reviewed

Moral economy versus political economy: provincializing Polanyi

This theoretically focused chapter by John Holmwood adopts a strategy of conceptual ‘provincializing’ and thereby reveals race as a lacuna in Polanyian and neo-Polanyian scholarship. Alongside its wide-ranging theoretical engagement, including innovative postcolonial reflections, Holmwood’s discussion is extraordinarily timely, engaging with US ‘race relations’ and the current ‘asylum crisis’ in large parts of Europe, as well as with wider currents of marketization. Racism is thereby analysed in both its deeper historical and current socioeconomic contexts

Reversals of fortune: path dependency, problem solving, and temporal cases

Historical reversals highlight a basic methodological problem: is it possible to treat two successive periods both as independent cases to compare for causal analysis and as parts of a single historical sequence? I argue that one strategy for doing so, using models of path dependency, imposes serious limits on explanation. An alternative model which treats successive periods as contrasting solutions for recurrent problems offers two advantages. First, it more effectively combines analytical comparisons of different periods with narratives of causal sequences spanning two or more periods. Second, it better integrates scholarly accounts of historical reversals with actors’ own narratives of the past

The (A)BC excinuclease of Escherichia coli has only the UvrB and UvrC subunits in the incision complex.

The uvrA, uvrB, and uvrC genes control excision repair in Escherichia coli. Cells with mutations in any of these three genes cannot repair DNA by nucleotide excision. When the purified gene products--the UvrA, UvrB, and UvrC proteins--are mixed together, an excision nuclease is formed that incises on both sides of the damaged nucleotide in an ATP-dependent reaction; it has been presumed that the excision nuclease was an ABC complex containing all three Uvr proteins. To determine the stoichiometry of the subunits in the enzyme, we conducted hydrodynamic studies with mixtures of the subunits with or without DNA substrate. We found that without DNA the UvrA subunit is a dimer and that when UvrB protein is also present, a (UvrA)2(UvrB)1 complex forms. Without DNA no detectable interaction of either the UvrA or UvrB subunits or the (UvrA)2(UvrB)1 complex with the UvrC subunit occurs. Unexpectedly, with UV-irradiated DNA, the UvrA/UvrB ratio in isolated DNA-protein complexes is variable, and the ratio becomes infinitesimally low as the UvrA concentration in the reaction mixture decreases. Under conditions of saturating UvrB protein approximately one UvrB molecule binds to DNA per damaged site in a reaction that requires catalytic amounts of UvrA subunit. Addition of UvrC protein to purified UvrB-DNA complexes results in rapid incision of the DNA, presumably catalyzed by an excision nuclease containing only UvrB and UvrC subunits