Multiple regression analysis of a comprehensive transcriptomic data assembly elucidates mechanically- and biochemically-driven responses to focused ultrasound blood-brain barrier disruption - additional non-FUS controls. Multiple regression analysis of a comprehensive transcriptomic data assembly elucidates mechanically- and biochemically-driven responses to focused ultrasound blood-brain barrier disruption - additional non-FUS controls

Focused ultrasound (FUS) blood brain barrier disruption (BBBD) permits the noninvasive, targeted, and repeatable delivery of drugs to the brain. FUS BBBD also elicits secondary responses capable of augmenting immunotherapies, clearing amyloid-β and hyperphosphorylated tau, and driving neurogenesis. Leveraging these secondary effects will benefit from an understanding of how they correlate to the magnitude of FUS BBBD and are differentially affected by the mechanical and biochemical stimuli imparted during FUS BBBD. Microbubble activation (MBA) and contrast enhancement (CE) differentially predicted expression of 1,124 genes 6 h or 24 h later. While there existed overlap in the transcripts correlated with MBA vs CE, MBA was principally predictive of expression of genes associated with endothelial reactivity while CE chiefly predicted sterile inflammation gene sets. Over-representation analysis identified transcripts not previously linked to BBBD, including actin filament organization, which is likely important for BBB recovery. Transcripts and pathways associated with neurogenesis, microglial activation, and amyloid-β clearance were significantly correlated to BBBD metrics. This submission includes non-FUS controls to supplement other studies analyzed within the work (GSE152171, GSE141728). Overall design: We aggregated 75 murine transcriptomes in a multiple regression framework to identify genes expressed in proportion to biochemical (i.e. contrast MR image enhancement (CE)) or mechanical (i.e. harmonic acoustic emissions from MB-activation (MBA)) stimuli associated with FUS BBBD. Models were constructed to control for potential confounders, such as sex, anesthesia, and sequencing batch. This upload includes controls unused in previous work (GSE152171, GSE141728) but utilized in the correlation analysis described herein.

聚焦超声（Focused ultrasound, FUS）介导的血脑屏障开放（blood brain barrier disruption, BBBD）可实现无创、靶向且可重复地向脑部递送药物。FUS BBBD还可引发次级应答，该应答能够增强免疫治疗、清除β淀粉样蛋白（amyloid-β）与过度磷酸化tau蛋白，并促进神经发生。若要利用这些次级效应，需先明确其与FUS BBBD强度的关联，以及其如何受FUS BBBD过程中施加的机械与生化刺激的差异化调控。微泡激活（Microbubble activation, MBA）与对比增强（contrast enhancement, CE）可分别预测6小时或24小时后1124个基因的表达水平。尽管与MBA和CE相关的转录本存在部分重叠，但MBA主要预测与内皮反应性相关的基因表达，而CE则主要预测无菌炎症基因集的表达。富集分析（over-representation analysis）鉴定出此前未被报道与BBBD相关的转录本，其中包括肌动蛋白丝组织相关通路，该过程可能对血脑屏障恢复至关重要。与神经发生、小胶质细胞激活及β淀粉样蛋白清除相关的转录本与通路，均与BBBD相关检测指标显著相关。本数据集包含非FUS对照样本，用于补充本研究中分析的其他相关数据集（GSE152171、GSE141728）。研究设计：本研究通过多元回归框架整合75个小鼠转录组数据，以筛选出与FUS BBBD相关的生化刺激（即对比磁共振成像增强（CE））或机械刺激（即微泡激活产生的谐波声发射（MBA））呈比例表达的基因。模型构建过程中控制了潜在混杂因素，包括性别、麻醉方案及测序批次。本次上传的数据包含此前两项研究（GSE152171、GSE141728）中未被使用，但在本研究所述的相关性分析中得到应用的对照样本。