Publications

NMR spectroscopy is a powerful tool for studies of protein dynamics over timescales extending more than twelve orders of magnitude, with motion queried at many of the backbone and sidechain positions in the molecule of interest. NMR experiments can, in principle, provide atomic resolution descriptions of excited conformational states that are sparsely populated and transiently formed-i.e., invisible, and there are examples of such structures in the literature. However, in other cases, the NMR...

In the face of rapidly accumulating genomic data, our ability to predict key mature RNA properties that underlie transcript function and regulation remains limited. Pretrained genomic foundation models offer an avenue to adapt learned RNA representations to biological prediction tasks; however, existing models are trained using strategies borrowed from textual domains that do not leverage biological domain knowledge. Here we introduce Orthrus, a Mamba-based mature RNA foundation model pretrained...

Children with medical complexity (CMC) have chronic conditions with multisystem comorbidities requiring high-intensity, coordinated care. A substantial yet often invisible aspect of this care is the administrative workload borne by parents and caregivers. This 'unseen and undervalued work' encompasses the relentless administrative labour required to secure services, complete forms, manage appointments, advocate across fragmented systems, and coordinate supports frequently without adequate...

The rapid advancement of unmanned aerial vehicles (UAVs) in disaster response and environmental monitoring has underscored the growing importance of real-time object detection within UAV swarm networks. However, the non-independent and identically distributed (non-IID) characteristics of data in UAV networks present significant challenges to model convergence and adaptability. To tackle these challenges, this study introduces a robust federated UAV object detection framework tailored for non-IID...

ImportanceTonsillectomy has long been scrutinized for its potential long-term impacts on health, with conflicting evidence linking it to increased risks of several diseases, such as cancer, psychiatric disorders, and immune dysfunctions.ObjectiveTo comprehensively analyze the effects of tonsillectomy on various disease outcomes.DesignLongitudinal cohort study, 2-sample Mendelian randomization (MR) analysis, and multivariable MR (MVMR) analysis.SettingThe UK Biobank.ParticipantsAll UK Biobank...

Artificial intelligence (AI) is increasingly embedded in clinical environments, raising questions of trust, fairness, empathy, and governance. The ethical terrain surrounding AI in medicine remains unstable despite its rapid adoption. We introduce the "Seven Deadly Sins of AI in Medicine", a conceptual framework of recurring systemic failure modes: (i) Blind Trust, (ii) Overregulation, (iii) Dehumanization, (iv) Misaligned Optimization, (v) Overinforming and False Forecasting, (vi) Misapplied...

Schizophrenia develops in one in every four individuals with a pathogenic 22q11.2 deletion, yet the genetic modifiers influencing the manifestation of schizophrenia in this high-risk group remain incompletely understood. Here, we identify rare tandem repeat expansions (TREs) as significant contributors to schizophrenia risk in this population. Genome sequencing of 438 unrelated individuals with 22q11.2 deletions revealed a marked enrichment of rare genic TREs among those with schizophrenia, with...

CONCLUSION: Using a Delphi method, international experts reached consensus to generate 37 professional practice guidance statements. The consensus statements provide needed guidance for professional engagement and highlight areas for policy development to advance gender equity and equality for healthcare workers in intensive care. The discordant statements highlight areas for future research.

The clinical utility and validity of preimplantation genetic testing for aneuploidies (PGT-A) in IVF practice is often questioned. Some major societies (Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology 2024) have released ambiguous statements about PGT-A, leaving the potential and benefits of embryo selection, enhanced by chromosome profile assessments, indeterminant. The Preimplantation Genetic Diagnosis International...

Obesity is a global health crisis. Currently available treatments, while effective, show several undesirable side effects that hinder their long-term use. Herein, we investigated the anti-obesity potential of 6-benzylaminopurine (BAP), a plant hormone commonly used in agricultural settings to enhance plant development, in obese mice and mammalian cell models. Orally administered BAP induced significant weight loss in diet induced obese male and female CD-1 mice through sex-specific mechanisms...

Host-pathogen interactions are coevolutionary battles often described as arms races, requiring evolutionary change in both partners, functional consequences, and selection driven by the interaction. Plant-pathogen systems provide strong models, especially through effectors and host immune receptors. We investigated the HopZ family of Pseudomonas syringae type III effectors and their recognition by Arabidopsis thaliana receptors ZAR1 and RPM1. Using ancestral reconstruction, we synthesized...

Dysfunction of corticostriatal circuitry is related to the emergence of self-injurious behavior (SIB) in autism spectrum disorder (ASD). Despite mounting interest in circuit-based interventions for severe, refractory SIB, the lack of causal evidence linking modulation of corticostriatal networks to changes in SIB has limited the advancement of effective, targeted therapies. In this study, we demonstrate that electrical stimulation of the nucleus accumbens (NAcc) mitigates SIB and induces...

Molecular glues promote protein-protein interactions by enhancing the surface complementarity between proteins. Those that recruit an E3 ubiquitin ligase to a target can elicit ubiquitination and subsequent destruction of the target protein-a mechanism that underpins the field of targeted protein degradation (TPD). Here we explored whether small-molecule binders to the CTLH E3 ligase subunit GID4 could act as molecular glues. We discovered that CLEO4-88 functions as a molecular glue (EC(50) =...

CONCLUSIONS: Circulating LL-37-ApoB-100 levels are strongly associated with angiographically documented CAD, highlighting LL-37-ApoB-100 as an independent predictor for CAD.

CONCLUSIONS AND RELEVANCE: This study found that RBM20 variants contributed to arrhythmogenic DCM phenotypes but conferred reduced lifetime disease penetrance compared to TTNtvs and milder disease severity alone than P/LP RBM20 variants. Their potential for additive interactions with other damaging variants should be considered in patients with DCM and their families.

CONCLUSION: Our findings demonstrated OAβT as a reflection of systemic changes linked to early AD pathology. Moreover, the influence of medications and systemic aging on OAβT values pointed to the potential avenues for intervention and emphasized the importance of considering systemic factors in AD pathogenesis and treatment.

Implantable neurotechnologies are increasingly used to reduce seizure burden in pediatric epilepsy. Vagus nerve stimulation (VNS), the most common option, is effective for only half of patients, with no means to predict outcome prior to surgery. As a result, many children undergo invasive and costly procedures without benefit. Although T1-weighted magnetic resonance imaging (T1w) is routinely acquired presurgically and may capture structural brain differences relevant to treatment outcome, its...

Wnt-β-catenin signaling begins when Wnt ligands engage the receptors Frizzled (Fzd) and LRP5 or LRP6 (LRP5/6), leading to the recruitment and phosphorylation of the intracellular protein Dishevelled (Dvl), which is necessary for stabilization of the transcriptional coactivator β-catenin. Understanding the mechanisms by which ligand binding to Fzd activates Wnt-β-catenin signaling is crucial for rational ligand design to selectively modulate Wnt responses in the context of diseases and tissue...

Modeling of medical interventions, such as preventive surgeries, on a survival outcome necessitates an accurate and flexible representation of the time-dependent effect of the intervention. We propose using B-splines to model the time-dependent effect of a binary time-dependent covariate on a survival outcome in the presence of correlated competing risks. The proposed B-splines can also help choose the best functional form for the time-dependent effect. Our simulation studies demonstrate that...

Prethermal discrete time crystals are non-equilibrium states of matter with long-range spatiotemporal order and a subharmonic response stabilized by many-body interactions under periodic driving. The robustness of time-crystalline order to perturbations in the drive protocol makes these systems attractive for quantum sensing. Here we exploit the sensitivity of prethermal discrete time crystal order to deviations in its order parameter to implement the frequency-selective detection of...