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Chung, K.

Publications and source records attributed to Chung, K..

6 recordsLinked to original sources

Predicting One-Year Outcome in First Episode Psychosis using Machine Learning

Lay SummaryO_ST_ABSEvidence before this studyC_ST_ABSOur knowledge of factors which predict outcome in first episode psychosis (FEP) is incomplete. Poor premorbid adjustment, history of developmental disorder, symptom severity at baseline and duration of untreated psychosis are the most replicated predictors of poor clinical, functional, cognitive, and biological outcomes. Yet, such group level differences are not always replicated in individuals, nor can observational results be clearly equated with causation. Advanced machine learning techniques have potential to revolutionise medicine by looking at causation and the prediction of individual patient outcome. Within psychiatry, Koutsouleris et al employed machine learning to predict 4- and 52-week functional outcome in FEP to a 75% and 73.8% test-fold balanced accuracy on repeated nested internal cross-validation. The authors suggest that before employing a machine learning model \"into real-world care, replication is needed in external first episode samples\".\n\nAdded value of this studyWe believe our study to be the first externally validated evidence, in a temporally and geographically independent cohort, for predictive modelling in FEP at an individual patient level. Our results demonstrate the ability to predict both symptom remission and functioning (in employment, education or training (EET)) at one-year. The performance of our EET model was particularly robust, with an ability to accurately predict the one-year EET outcome in more than 85% of patients. Regularised regression results in sparse models which are uniquely interpretable and identify meaningful predictors of recovery including specific individual PANSS items, and social support. This builds on existing studies of group-level differences and the elegant work of Koutsouleris et al.\n\nImplications of all the available evidenceWe have demonstrated the externally validated ability to accurately predict one-year symptomatic and functional status in individual patients with FEP. External validation in a plausibly related temporally and geographically distinct population assesses model transportability to an untested situation rather than simply reproducibility alone. We propose that our results represent important and exciting progress in unlocking the potential of predictive modelling in psychiatric illness. The next step prior to implementation into routine clinical practice would be to establish whether, by the accurate identification of individuals who will have poor outcomes, we can meaningful intervene to improve their prognosis.\n\nAbstractO_ST_ABSBackgroundC_ST_ABSEarly illness course correlates with long-term outcome in psychosis. Accurate prediction could allow more focused intervention. Earlier intervention corresponds to significantly better symptomatic and functional outcomes.\n\nWe use routinely collected baseline demographic and clinical characteristics to predict employment, education or training (EET) status, and symptom remission in patients with first episode psychosis (FEP) at 1 year.\n\nMethods83 FEP patients were recruited from National Health Service (NHS) Glasgow between 2011 and 2014 to a 24-month prospective cohort study with regular assessment of demographic and psychometric measures. An external independent cohort of 79 FEP patients were recruited from NHS Glasgow and Edinburgh during a 12-month study between 2006 and 2009.\n\nElastic net regularised logistic regression models were built to predict binary EET status, period and point remission outcomes at 1 year on 83 Glasgow patients (training dataset). Models were externally validated on an independent dataset of 79 patients from Glasgow and Edinburgh (validation dataset). Only baseline predictors shared across both cohorts were made available for model training and validation.\n\nOutcomesAfter excluding participants with missing outcomes, models were built on the training dataset for EET status, period and point remission outcomes and externally validated on the validation dataset. Models predicted EET status, period and point remission with ROC area under curve (AUC) performances of 0.876 (95%CI: 0.864, 0.887), 0.630 (95%CI: 0.612, 0.647) and 0.652 (95%CI: 0.635, 0.670) respectively. Positive predictors of EET included baseline EET and living with spouse/children. Negative predictors included higher PANSS suspiciousness, hostility and delusions scores. Positive predictors for symptom remission included living with spouse/children, and affective symptoms on the Positive and Negative Syndrome Scale (PANSS). Negative predictors of remission included passive social withdrawal symptoms on PANSS.\n\nInterpretationUsing advanced statistical machine learning techniques, we provide the first externally validated evidence for the ability to predict 1-year EET status and symptom remission in FEP patients.\n\nFundingThe authors acknowledge financial support from NHS Research Scotland, the Chief Scientist Office, the Wellcome Trust, and the Scottish Mental Health Research Network.

neuroscience

Initial Characterization of the Two ClpP Paralogs of Chlamydia trachomatis Suggests Unique Functionality for Each

Chlamydia is an obligate intracellular bacterium that differentiates between two distinct functional and morphological forms during its developmental cycle: elementary bodies (EBs) and reticulate bodies (RBs). EBs are non-dividing, small electron dense forms that infect host cells. RBs are larger, non-infectious replicative forms that develop within a membrane-bound vesicle, termed an inclusion. Given the unique properties of each developmental form of this bacterium, we hypothesized that the Clp protease system plays an integral role in proteomic turnover by degrading specific proteins from one developmental form or the other. Chlamydia has five uncharacterized clp genes: clpX, clpC, two clpP paralogs, and clpB. In other bacteria, ClpC and ClpX are ATPases that unfold and feed proteins into the ClpP protease to be degraded, and ClpB is a deaggregase. Here, we focused on characterizing the ClpP paralogs. Transcriptional analyses and immunoblotting determined these genes are expressed mid-cycle. Bioinformatic analyses of these proteins identified key residues important for activity. Over-expression of inactive clpP mutants in Chlamydia suggested independent function of each ClpP paralog. To further probe these differences, we determined interactions between the ClpP proteins using bacterial two-hybrid assays and native gel analysis of recombinant proteins. Homotypic interactions of the ClpP proteins, but not heterotypic interactions between the ClpP paralogs, were detected. Interestingly, ClpP2, but not ClpP1, protease activity was detected in vitro. This activity was stimulated by antibiotics known to activate ClpP, which also blocked chlamydial growth. Our data suggest the chlamydial ClpP paralogs likely serve distinct and critical roles in this important pathogen.\n\nImportanceChlamydia trachomatis is the leading cause of preventable infectious blindness and of bacterial sexually transmitted infections worldwide. Chlamydiae are developmentally regulated, obligate intracellular pathogens that alternate between two functional and morphologic forms with distinct repertoires of proteins. We hypothesize that protein degradation is a critical aspect to the developmental cycle. A key system involved in protein turnover in bacteria is the Clp protease system. Here, we characterized the two chlamydial ClpP paralogs by examining their expression in Chlamydia, their ability to oligomerize, and their proteolytic activity. This work will help understand the evolutionarily diverse Clp proteases in the context of intracellular organisms, which may aid in the study of other clinically relevant intracellular bacteria.

microbiology

DNMT1 in Six2 progenitor cells is essential for transposable element silencing and kidney development

Cytosine methylation (5mC) plays a key role in maintaining progenitor cell self-renewal and differentiation. Here, we analyzed the role of 5mC in kidney development by genome-wide methylation, expression profiling, and by systematic genetic targeting of DNA methyltransferases (Dnmt) and Ten-eleven translocation methylcytosine hydroxylases (Tet).\n\nIn mice, nephrons differentiate from Six2+ progenitor cells, therefore we created animals with genetic deletion of Dnmt1, 3a, 3b, Tet1, and Tet2 in the Six2+ population (Six2Cre/Dnmt1flox/flox, Six2Cre/Dnmt3aflox/flox, Six2Cre/Dnmt3bflox/flox, Six2Cre/Tet2flox/flox and Tet1-/-). Animals with conditional deletion of Dnmt3a, 3b, Tet1 and Tet2 showed no significant structural or functional renal abnormalities. On the other hand, Six2Cre/Dnmt1flox/flox mice died within 24hrs of birth. Dnmt1 knock-out animals had small kidneys and significantly reduced nephron number. Genome-wide methylation analysis indicated marked loss of methylation mostly on transposable elements. RNA sequencing detected endogenous retroviral (ERV) gene transcripts and early embryonic genes. Increase in levels of interferon (and RIG-I signaling) and apoptosis (Trp53) in response to ERV activity likely contributed to the phenotype development. Once epithelial differentiation was established, loss of Dnmt1, 3a, 3b, Tet1 or Tet2 in glomerular epithelial cells did not lead to functional or structural differences at baseline or following toxic glomerular injury.\n\nGenome-wide cytosine methylation and gene expression profiling showed that Dnmt1-mediated DNA methylation is essential for kidney development by preventing regression of progenitor cells into a primitive undifferentiated state and demethylation of transposable elements.\n\nSignificanceCytosine methylation of regulatory regions (promoters and enhancers) has been proposed to play a key role in establishing gene expression and thereby cellular phenotype. DNMT1 is the key enzyme responsible for maintaining methylation patterns during DNA replication. While the role of Dnmt1 has been described in multiple organs, here we identified a novel, critically important mechanism how Dnmt1 controls tissue progenitors. The greatest methylation difference in Dnmt1 knock-out mice was observed on transposable elements (TE), which resulted in increase of endogenous retroviruses and cell death. We believe that release of TE was a critically overlooked component of phenotype development in previous studies that our comprehensive genome wide methylation analysis allowed us to identify.\n\nCompeting interestsThe Susztak lab receives research support from Biogen, Boehringer Ingelheim, Celgene, GSK, Merck, Regeneron and ONO Pharma for work not related to this manuscript.

developmental biology

Exploring Mechanisms of Inhibition of Amyloid Seeding of Transthyretin

Amyloid deposition of the hormone transporter transthyretin causes familial and sporadic amyloidoses. The current treatment for familial cases is gene-therapy by liver transplantation. However, this procedure is often insufficient to stop subsequent cardiac deposition. Our recent work has shown that preformed amyloid fibrils present in the heart by the time of surgery can template or seed further polymerization of native transthyretin. No drugs have been approved to stop or slow this seeding process; the only treatment option is heart transplantation. Here we explore two potential inhibitory mechanisms. Of clinical significance, we found that tetramer stabilization does not hinder amyloid seeding. In contrast, binding of the peptide inhibitor TabFH2 to ex-vivo fibrils efficiently inhibits amyloid seeding in a tissue-independent manner. Our findings point to inhibition of amyloid seeding by peptide inhibitors as a potential therapeutic approach to be further explored.

biochemistry

NINJA-Associated ERF19 Negatively Regulates Arabidopsis Pattern-Triggered Immunity

Recognition of microbe-associated molecular patterns (MAMPs) derived from invading pathogens by plant pattern recognition receptors (PRRs) initiates defense responses known as pattern-triggered immunity (PTI). Transcription factors (TFs) orchestrate the onset of PTI through complex signaling networks. Here, we characterize the function of ERF19, a member of the Arabidopsis thaliana ethylene response factor (ERF) family. ERF19 was found to act as a negative regulator of PTI against Botrytis cinerea and Pseudomonas syringae pv. tomato DC3000 (Pst). Notably, overexpression of ERF19 increased plant susceptibility to these pathogens and repressed MAMP-induced PTI outputs. In contrast, expression of the chimeric dominant repressor ERF19-SRDX boosted PTI activation, conferred increased resistance to B. cinerea, and enhanced elf18-triggered immunity against Pst. Consistent with a negative role of ERF19 in PTI, MAMP-mediated growth inhibition was respectively weakened or augmented in lines overexpressing ERF19 or expressing ERF19-SRDX. Moreover, we demonstrate that the transcriptional repressor Novel INteractor of JAZ (NINJA) associates with and represses the function of ERF19. Our work reveals ERF19 as a key player in a buffering mechanism to avoid defects imposed by over-activation of PTI and a potential role for NINJA in fine-tuning ERF19-mediated regulation.

plant biology

3D Mapping Reveals Network-specific Amyloid Progression and Subcortical Susceptibility.

Alzheimers disease is a progressive, neurodegenerative condition for which there is no cure. Prominent hypotheses posit that accumulation of beta-amyloid (A{beta}) peptides drives the neurodegeneration that underlies memory loss, however the spatial origins of the lesions remain elusive. Using SWITCH, we created a spatiotemporal map of A{beta} deposition in a mouse model of amyloidosis. We report that structures connected by the fornix show primary susceptibility to A{beta} accumulation and demonstrate that aggregates develop in increasingly complex networks with age. Notably, the densest early A{beta} aggregates occur in the mammillary body coincident with electrophysiological alterations. In later stages, the fornix itself also develops overt A{beta} burden. Finally, we confirm A{beta} in the mammillary body of postmortem patient specimens. Together, our data suggest that subcortical memory structures are particularly vulnerable to A{beta} deposition and that functional alterations within and physical propagation from these regions may underlie the affliction of increasingly complex networks.\n\nAuthor ContributionsRGC, KC, L-HT, ID conceived of the work and planned the experiments.\n\nRGC, HC, JW, LAW, CGY, FA, SMB performed experiments and analyzed data.\n\nHC built the custom microscope.\n\nRGC, L-HT, KC, ID wrote the manuscript.

neuroscience