发表机构
imec（imec）
机构由 AI 辅助整理，请以论文原文为准。AI 中文总结
本研究提出锚定引导对齐与概率速度建模方法，利用固态纳米孔实现DNA分子条形码的高精度定位，显著降低定位误差并支持高密度信息读出。
AI 中文摘要
通过固态纳米孔的快速且不均匀的易位限制了小分子标签的检测及其沿分子载体的精确定位。在本工作中，我们报道了使用薄平面膜中的固态纳米孔，对沿双链DNA支架的核苷酸基分子标签进行检测和定位的性能。对于难以单独分辨的小标签，我们引入了一种锚定策略，其中易于检测的 bulky 标签作为参考点来对齐多次易位事件，从而实现基于群体的较小分子特征的检测和定位。测量的锚点位置约束了易位速度的概率模型，为每个事件识别最可能的速度分布，并实现非线性轨迹“解扭曲”以改进多事件对齐。一种互补的基于窗口的证据聚合程序累积了跨事件的微弱但一致的标签特征，使得能够检测被噪声单独掩盖的特征。这些方法能够稳健地恢复约28个核苷酸的单哑铃标签（DB1），并在对多个事件进行平均时，将DB3标签的平均定位误差降低至低至10个碱基对，DB1标签的平均定位误差降低至40个碱基对。更强的分数化DNA相关电流阻断（作为较小孔几何形状的代理）还与跨膜基纳米孔制造技术的改进检测和更低定位误差相关。总体而言，锚定引导的对齐提供了一条在不通过受控易位方法牺牲通量的情况下实现更高密度分子信息读出的途径。
英文摘要
Fast and nonuniform translocation through solid-state nanopores limits both the detection of small molecular labels and their precise localization along molecular carriers. In this work we report the detection and localization performance of nucleotide-based molecular labels along double-stranded DNA scaffolds using solid-state nanopores in thin planar membranes. For small labels that are challenging to resolve individually, we introduce an anchoring strategy where readily detectable bulky labels serve as reference points to align multiple translocation events, enabling population-based detection and localization of smaller molecular features. The measured anchor positions constrain a probabilistic model of translocation velocity, identifying the most probable velocity profile for each event and enabling nonlinear trace "unwarping" for improved multi-event alignment. A complementary window-based evidence aggregation procedure accumulates weak but consistent label signatures across events, enabling detection of features that are individually masked by noise. These approaches enable robust recovery of single-dumbbell labels (DB1) on the order of 28 nucleotides and reduce mean localization errors to as low as 10 base pairs for DB3 labels and 40 base pairs for DB1 labels when averaging over multiple events. Stronger fractional DNA-associated current blockades, used as proxy for smaller pore geometries, are additionally associated with improved detection and lower localization error across membrane-based nanopore fabrication techniques. Overall, anchor-guided alignment provides a route to higher-density molecular information readout without compromising throughput via controlled translocation approaches.
Comments40 pages, 6 figures
