A curious concept of CNS clearance
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Rapid brain tumor classification from sparse epigenomic data
Although the intraoperative molecular diagnosis of the approximately 100 known brain tumor entities described to date has been a goal of neuropathology for the past decade, achieving this within a clinically relevant timeframe of under 1 h after biopsy collection remains elusive. Advances in third-generation sequencing have brought this goal closer, but established machine learning techniques rely on computationally intensive methods, making them impractical for live diagnostic workflows in clinical applications. Here we present MethyLYZR, a naive Bayesian framework enabling fully tractable, live classification of cancer epigenomes. For evaluation, we used nanopore sequencing to classify over 200 brain tumor samples, including 10 sequenced in a clinical setting next to the operating room, achieving highly accurate results within 15 min of sequencing. MethyLYZR can be run in parallel with an ongoing nanopore experiment with negligible computational overhead. Therefore, the only limiting factors for even faster time to results are DNA extraction time and the nanopore sequencer’s maximum parallel throughput. Although more evidence from prospective studies is needed, our study suggests the potential applicability of MethyLYZR for live molecular classification of nervous system malignancies using nanopore sequencing not only for the neurosurgical intraoperative use case but also for other oncologic indications and the classification of tumors from cell-free DNA in liquid biopsies.
CNS prophylaxis is (mostly) futile in DLBCL
Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is associated with a poor prognosis, with a median overall survival of approximately five months [1]. The risk for CNS disease has been estimated to be about 5% overall [2], but it is significantly higher in certain high-risk groups [3]. CNS prophylaxis is often administered to patients felt to be at high risk for CNS recurrence. Options for CNS prophylaxis include high-dose methotrexate (HD-MTX) and intrathecal (IT) chemotherapy with methotrexate and/or cytarabine. However, a number of recent retrospective analyses have called into question the efficacy of prophylaxis. Here, we aim to review the literature regarding CNS prophylaxis with HD-MTX or IT chemotherapy in DLBCL. Our review and discussion exclude Burkitt lymphoma and lymphoblastic leukemia/lymphoma, for which standard treatment protocols include CNS prophylaxis. We also exclude double and triple hit lymphoma (DHL, THL) as it is generally accepted that these patients are at a high risk of CNS relapse. Based on the results of several recent studies, we recommend consideration of IT chemotherapy instead of HD-MTX if prophylaxis is desired due to better tolerability. If HD-MTX is desired, it should be done after systemic therapy is completed to avoid treatment delays. We provide an algorithm to guide decision making. However, our review of the literature suggests that CNS prophylaxis by either means has no clear benefit.
Structure and function relationships of mucociliary clearance in human and rat airways
Mucociliary clearance is a vital defense mechanism of the human airways, protecting against harmful particles and infections. When this process fails, it contributes to respiratory diseases like chronic obstructive pulmonary disease (COPD) and asthma. While advances in single-cell transcriptomics have revealed the complexity of airway composition, much of what we know about how airway structure impacts clearance relies on animal studies. This limits our ability to create accurate human-based models of airway diseases. Here we show that the airways in female rats and in humans exhibit species-specific differences in the distribution of ciliated and secretory cells as well as in ciliary beat, resulting in significantly higher clearance effectiveness in humans. We further reveal that standard lab-grown cultures exhibit lower clearance effectiveness compared to human airways, and we identify the underlying structural differences. By combining diverse experiments and physics-based modeling, we establish universal benchmarks to assess human airway function, interpret preclinical models, and better understand disease-specific impairments in mucociliary clearance.
Brain O-GlcNAcylation: Bridging physiological functions, disease mechanisms, and therapeutic applications
O-GlcNAcylation, a dynamic post-translational modification occurring on serine or threonine residues of numerous proteins, plays a pivotal role in various cellular processes, including gene regulation, metabolism, and stress response. Abundant in the brain, O-GlcNAcylation intricately governs neurodevelopment, synaptic assembly, and neuronal functions. Recent investigations have established a correlation between the dysregulation of brain O-GlcNAcylation and a broad spectrum of neurological disorders and injuries, spanning neurodevelopmental, neurodegenerative, and psychiatric conditions, as well as injuries to the central nervous system (CNS). Manipulating O-GlcNAcylation has demonstrated neuroprotective properties against these afflictions. This review delineates the roles and mechanisms of O-GlcNAcylation in the CNS under both physiological and pathological circumstances, with a focus on its neuroprotective effects in neurological disorders and injuries. We discuss the involvement of O-GlcNAcylation in key processes such as neurogenesis, synaptic plasticity, and energy metabolism, as well as its implications in conditions like Alzheimer’s disease, Parkinson’s disease, and ischemic stroke. Additionally, we explore prospective therapeutic approaches for CNS disorders and injuries by targeting O-GlcNAcylation, highlighting recent clinical developments and future research directions. This comprehensive overview aims to provide insights into the potential of O-GlcNAcylation as a therapeutic target and guide future investigations in this promising field.
Informational ecosystems partially explain differences in socioenvironmental conceptual associations between U.S. American racial groups
Social groups represent a collective identity defined by a distinct consensus of concepts (e.g., ideas, values, and goals) whose structural relationship varies between groups. Here we set out to measure how a set of inter-concept semantic associations, comprising what we refer to as a concept graph, covaries between established social groups, based on racial identity, and how this effect is mediated by information ecosystems, contextualized as news sources. Group differences among racial identity (278 Black and 294 white Americans) and informational ecosystems (Left- and Right- leaning news sources) are present in subjective judgments of how the meaning of concepts such as healthcare, police, and voting relate to each other. These racial group differences in concept graphs were partially mediated by the bias of news sources that individuals get their information from. This supports the idea of groups being defined by common conceptual semantic relationships that partially arise from shared information ecosystems.
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