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Machine learning in Alzheimer's disease genetics.
Traditional statistical approaches have advanced our understanding of the genetics of complex diseases, yet are limited to linear additive models. Here we applied machine learning (ML) to genome-wide data from 41,686 individuals in the largest European consortium on Alzheimer's disease (AD) to investigate the effectiveness of various ML algorithms in replicating known findings, discovering novel loci, and predicting individuals at risk. We utilised Gradient Boosting Machines (GBMs), biological pathway-informed Neural Networks (NNs), and Model-based Multifactor Dimensionality Reduction (MB-MDR) models. ML approaches successfully captured all genome-wide significant genetic variants identified in the training set and 22% of associations from larger meta-analyses. They highlight 6 novel loci which replicate in an external dataset, including variants which map to ARHGAP25, LY6H, COG7, SOD1 and ZNF597. They further identify novel association in AP4E1, refining the genetic landscape of the known SPPL2A locus. Our results demonstrate that machine learning methods can achieve predictive performance comparable to classical approaches in genetic epidemiology and have the potential to uncover novel loci that remain undetected by traditional GWAS. These insights provide a complementary avenue for advancing the understanding of AD genetics.
Amyloid-β disrupts APP-regulated protein aggregation and dissociation from recycling endosomal membranes.
Secretory proteins aggregate into non-soluble dense-core granules in recycling endosome-like compartments prior to regulated release. By contrast, aberrantly processed, secreted amyloid-β (Aβ) peptides derived from amyloid precursor protein (APP) form pathological extracellular amyloidogenic aggregations in late-stage Alzheimer's disease (AD). By examining living Drosophila prostate-like secondary cells, we show that both APP and Aβ peptides affect normal biogenesis of dense-core granules. These cells generate dense-core granules and secreted nanovesicles called Rab11-exosomes via evolutionarily conserved mechanisms within highly enlarged secretory compartments with recycling endosomal identity. The fly APP homologue, APP-like (APPL), associates with these vesicles and the compartmental limiting membrane, from where its extracellular domain modulates protein aggregation. Proteolytic release of this domain permits mini-aggregates to coalesce into a large central dense-core granule. Mutant Aβ expression disrupts this process and compartment motility, and increases aberrant lysosomal targeting, mirroring previously unexplained early-stage pathological events in AD. It also promotes cell-to-cell propagation of these endolysosomal defects, again phenocopying changes observed in AD. Our data therefore demonstrate physiological roles for APP in membrane-dependent protein aggregation, involving molecular mechanisms, which when disrupted by Aβ peptides, trigger Alzheimer's disease-relevant pathologies.
The dual ubiquitin binding mode of SPRTN secures rapid spatiotemporal proteolysis of DNA-protein crosslinks.
DNA-protein crosslinks (DPCs) are endogenous and chemotherapy-induced genotoxic DNA lesions and, if not repaired, lead to embryonic lethality, neurodegeneration, premature ageing, and cancer. DPCs are heavily polyubiquitinated, and the SPRTN protease and 26S proteasome emerged as two central enzymes for DPC proteolysis. The proteasome recognizes its substrates by their ubiquitination status. How SPRTN protease, an essential enzyme for DPC proteolysis, achieves specificity for DPCs is still not entirely clear. We found that the N-terminal SPRTN catalytic region (SprT) possesses a ubiquitin-binding domain that we named the Ubiquitin Interface of SprT Domain (USD). Using multiple biochemical, biophysical, and structural approaches, we reveal that USD binds ubiquitin chains in an avidity manner. SPRTN binding to ubiquitin chains via USD leads to ∼67-fold higher activation of SPRTN proteolysis towards polyubiquitinated DPCs than the unmodified DPCs. In contrast, the constitutive components of the replisome during unperturbed or translesional DNA synthesis, namely proliferating cell nuclear antigen (PCNA) or monoUb-PCNA, respectively, were poorly degraded, if at all, by SPRTN. This study reveals that the poly-ubiquitination of DPCs serves as the key signal for SPRTN's rapid proteolysis and determines its substrate specificity towards DPCs, rather than the replisome.
Synthesis and Inhibitory Assessment of ACE2 Inhibitors for SARS-CoV-2: An In Silico and In Vitro Study.
The angiotensin-converting enzyme 2 (ACE2) is pivotal as the cellular receptor for SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus responsible for COVID-19. This study presents a novel synthetic route for four analogues of MLN-4760, a known inhibitor of ACE2, guided by in silico docking predictions. These synthetic advances enabled in vitro pIC50 assays confirming the inhibitory potency of the synthesized analogues. Lastly, this route was applied to the synthesis of novel 18F-labeled ACE2 inhibitors for PET imaging applications.
Cost-effectiveness of pramipexole in addition to mood stabilisers for patients with treatment-resistant bipolar depression: Economic evaluation of the PAX-BD randomised controlled trial.
BACKGROUND: People with bipolar disorders (BD) frequently experience depressive symptoms that do not respond to available treatment options. The resulting burden for people with BD and society is substantial. This study sought to explore the cost-effectiveness of pramipexole in combination with mood stabilisers for people with treatment-resistant bipolar disorder (TRBD). METHODS: We calculated mean incremental cost ratios (ICER) of pramipexole compared to placebo over 12 and 48 weeks from health and social care (NHS + PSS) and societal perspectives for 36 participants with TRBD. Quality-adjusted life years (QALY) were captured with the EQ-5D-5L as the primary outcome measure. We used capability well-being measures (ICECAP-A, OxCAP-MH) to assess the robustness of the results and multiple imputation and bootstrapping to address missing data and small sample size. RESULTS: We found that pramipexole is more effective and cost-saving from the NHS + PSS perspective. The probability of being cost-effective at £30,000/QALY gained was 70 % (12 weeks) and 90 % (48 weeks). From the societal perspective, pramipexole was more effective but also more expensive with lower probability of cost-effectiveness (33 % at 12 weeks and 47 % at 48 weeks). Uncertainty around the mean ICERs was substantial due to the small sample size. LIMITATIONS: The PAX-BD trial was conducted during the COVID-19 pandemic and terminated early, resulting in a limited generalizability of resource use outside the pandemic context and a small sample size. CONCLUSIONS: Pramipexole is a cost-effective treatment option for TRBD from the NHS + PSS perspective, with statistically significant increases in health-related quality of life and capability well-being over extended periods.
Interleukin-6, C-Reactive Protein, and Vascular Recurrence After Stroke With and Without Atherosclerosis.
BACKGROUND: Uncertainty remains whether inflammation is implicated in poststroke recurrence in patients without atherosclerosis. We evaluated the contribution of atherosclerosis status to the association between inflammatory markers and major adverse cardiovascular events (MACE) poststroke. METHODS: We performed an individual-participant data meta-analysis of 11 prospective cohorts (12 countries, 1995-2017). Studies included patients with ischemic stroke/transient ischemic attack and measured IL (interleukin)-6/hsCRP (high-sensitivity C-reactive protein) postevent. We analyzed the association between IL-6/hsCRP and recurrent stroke/MACE using multivariable Cox regression analyses (conditional logistic regression for 1 study). Analyses were stratified by the presence/absence of atherosclerosis (definition: prior history of coronary disease, peripheral artery disease, or large artery atherosclerotic stroke) and adjusted for cardiovascular risk factors/preventative medication. RESULTS: Overall 10 148 patients (3448 [34.0%] had atherosclerosis) with 21 177 years of follow-up were included (1707 MACE outcomes/1353 recurrent strokes). In patients with atherosclerosis, IL-6 was independently associated with MACE (risk ratio [RR], 1.22 [95% CI, 1.08-1.37]; per logeunit increase) and recurrent stroke (RR, 1.23 [95% CI, 1.08-1.41]). Compared with patients in the bottom quarter, those in the top quarter of IL-6 levels had double the risk of MACE (RR, 2.05 [95% CI, 1.37-3.08]) and stroke (RR, 1.97 [95% CI, 1.28-3.05]). IL-6 was also associated with MACE (RR, 1.11 [95% CI, 1.01-1.23]) but not stroke (RR, 1.08 [95% CI, 0.98-1.20]; per logeunit) in patients without atherosclerosis. However, there was no evidence of statistical interaction between IL-6 levels and atherosclerosis status for either outcome (Pinteraction=0.25 and 0.13 for MACE/recurrent stroke, respectively). hsCRP was associated with MACE in patients with (RR, 1.12 [95% CI, 1.05-1.21]; per logeunit) and without atherosclerosis (RR, 1.07 [95% CI, 1.01-1.14]; Pinteraction=0.28). No association with recurrent stroke was observed for hsCRP with (RR, 1.06 [95% CI, 0.98-1.14]) or without atherosclerosis (RR, 0.97 [95% CI, 0.91-1.04]; Pinteraction=0.18). CONCLUSIONS: IL-6/hsCRP were associated with poststroke recurrence irrespective of atherosclerosis. These data support the inclusion of patients in trials of anti-inflammatory therapies after stroke with elevated IL-6 or hsCRP, including those without prior atherosclerotic events.
A Phase 3 Trial of Inebilizumab in Generalized Myasthenia Gravis.
BACKGROUND: Autoimmune generalized myasthenia gravis is a disease that manifests with fluctuating muscle weakness. Inebilizumab is a monoclonal antibody that depletes CD19+ B cells, which are central to disease pathogenesis. METHODS: In this phase 3, double-blind, randomized, placebo-controlled trial, we enrolled participants with myasthenia gravis who had anti-acetylcholine receptor antibodies or anti-muscle-specific kinase antibodies. Participants were randomly assigned, in a 1:1 ratio, to receive intravenous inebilizumab (300 mg administered on days 1 and 15 for all, and additionally on day 183 for participants who were acetylcholine receptor antibody-positive) or matching placebo for 52 weeks (in participants who were acetylcholine receptor antibody-positive) or 26 weeks (in those who were muscle-specific kinase antibody-positive). Glucocorticoid therapy was tapered, starting at week 4, to a target of 5 mg per day by week 24. The primary end point was the change from baseline in the score on the Myasthenia Gravis Activities of Daily Living scale (MG-ADL; scores range from 0 to 24, with higher scores indicating greater disease activity) at week 26 in the combined acetylcholine receptor antibody-positive and muscle-specific kinase antibody-positive trial populations. A key secondary end point was the change from baseline in the score on the Quantitative Myasthenia Gravis scale (QMG; scores range from 0 to 39, with higher scores indicating greater disease activity) at week 26 in the combined population. Safety was assessed. RESULTS: A total of 238 participants underwent randomization (119 per group). Participants who received inebilizumab had a greater reduction in the MG-ADL score than those who received placebo (least-squares mean change, -4.2 vs. -2.2; adjusted difference, -1.9; 95% confidence interval [CI], -2.9 to -1.0; P<0.001) at week 26. Participants who received inebilizumab had a greater reduction in the QMG score than those who received placebo (least-squares mean change, -4.8 vs. -2.3; adjusted difference, -2.5; 95% CI, -3.8 to -1.2; P<0.001). The most common adverse events with inebilizumab were headache, cough, nasopharyngitis, infusion-related reactions, and urinary tract infections. Inebilizumab was not associated with a higher incidence of serious adverse events. CONCLUSIONS: In participants with acetylcholine receptor antibody-positive or muscle-specific kinase antibody-positive generalized myasthenia gravis, inebilizumab improved function and reduced disease severity. (Funded by Amgen; MINT ClinicalTrial.gov number, NCT04524273.).
Absolute neutrophil count and adverse drug reaction monitoring during clozapine treatment: consensus guidelines from a global Delphi panel.
Despite its superior effectiveness for treatment-resistant schizophrenia, clozapine has a high burden of adverse drug reactions (ADRs), which require monitoring and treatment. This global Delphi study has established consensus guidelines for absolute neutrophil count (ANC) thresholds for consideration of clozapine cessation and provided monitoring protocols for ADR management. Recommendations include lowering ANC cessation thresholds to 1·0 × 109 cells per L (0·5 × 109 cells per L for Duffy antigen receptor for chemokines-null individuals) and discontinuing routine ANC monitoring after 2 years. Comprehensive ADR monitoring every 3 months should address the metabolic syndrome, constipation, gastro-oesophageal reflux, sialorrhea, nocturnal enuresis, tachycardia, sleep apnoea, sedation, and other ADRs. Consumer representatives underscored the need for shared decision-making, streamlined monitoring, and accessible patient education. Although barriers persist, these findings support updating global policies to reduce burden on patients, enhance adherence, and optimise clinical outcomes. Incorporating evidence-based guidelines into practice could transform clozapine care, balancing safety with practicality to improve the lives of those with treatment-resistant schizophrenia.
An atlas of trait associations with resting-state and task-evoked human brain functional organizations in the UK Biobank.
Functional magnetic resonance imaging (fMRI) has been widely used to identify brain regions linked to critical functions, such as language and vision, and to detect tumors, strokes, brain injuries, and diseases. It is now known that large sample sizes are necessary for fMRI studies to detect small effect sizes and produce reproducible results. Here we report a systematic association analysis of 647 traits with imaging features extracted from resting-state and task-evoked fMRI data of more than 40,000 UK Biobank participants. We used a parcellation-based approach to generate 64,620 functional connectivity measures to reveal fine-grained details about cerebral cortex functional organizations. The difference between functional organizations at rest and during task was examined, and we have prioritized important brain regions and networks associated with a variety of human traits and clinical outcomes. For example, depression was most strongly associated with decreased connectivity in the somatomotor network. We have made our results publicly available and developed a browser framework to facilitate the exploration of brain function-trait association results (http://fmriatlas.org/).
Evaluating functional brain organization in individuals and identifying contributions to network overlap.
Individual differences in the spatial organization of resting-state networks have received increased attention in recent years. Measures of individual-specific spatial organization of brain networks and overlapping network organization have been linked to important behavioral and clinical traits and are therefore potential biomarker targets for personalized psychiatry approaches. To better understand individual-specific spatial brain organization, this paper addressed three key goals. First, we determined whether it is possible to reliably estimate weighted (non-binarized) resting-state network maps using data from only a single individual, while also maintaining maximum spatial correspondence across individuals. Second, we determined the degree of spatial overlap between distinct networks, using test-retest and twin data. Third, we systematically tested multiple hypotheses (spatial mixing, temporal switching, and coupling) as candidate explanations for why networks overlap spatially. To estimate weighted network organization, we adopt the Probabilistic Functional Modes (PROFUMO) algorithm, which implements a Bayesian framework with hemodynamic and connectivity priors to supplement optimization for spatial sparsity/independence. Our findings showed that replicable individual-specific estimates of weighted resting-state networks can be derived using high-quality fMRI data within individual subjects. Network organization estimates using only data from each individual subject closely resembled group-informed network estimates (which was not explicitly modeled in our individual-specific analyses), suggesting that cross-subject correspondence was largely maintained. Furthermore, our results confirmed the presence of spatial overlap in network organization, which was replicable across sessions within individuals and in monozygotic twin pairs. Intriguingly, our findings provide evidence that overlap between 2-network pairs is indicative of coupling. These results suggest that regions of network overlap concurrently process information from both contributing networks, potentially pointing to the role of overlapping network organization in the integration of information across multiple brain systems.