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      A Guide to Signal Processing Algorithms for Nanopore Sensors

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          Abstract

          Nanopore technology holds great promise for a wide range of applications such as biomedical sensing, chemical detection, desalination, and energy conversion. For sensing performed in electrolytes in particular, abundant information about the translocating analytes is hidden in the fluctuating monitoring ionic current contributed from interactions between the analytes and the nanopore. Such ionic currents are inevitably affected by noise; hence, signal processing is an inseparable component of sensing in order to identify the hidden features in the signals and to analyze them. This Guide starts from untangling the signal processing flow and categorizing the various algorithms developed to extracting the useful information. By sorting the algorithms under Machine Learning (ML)-based versus non-ML-based, their underlying architectures and properties are systematically evaluated. For each category, the development tactics and features of the algorithms with implementation examples are discussed by referring to their common signal processing flow graphically summarized in a chart and by highlighting their key issues tabulated for clear comparison. How to get started with building up an ML-based algorithm is subsequently presented. The specific properties of the ML-based algorithms are then discussed in terms of learning strategy, performance evaluation, experimental repeatability and reliability, data preparation, and data utilization strategy. This Guide is concluded by outlining strategies and considerations for prospect algorithms.

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          Highly accurate protein structure prediction with AlphaFold

          Proteins are essential to life, and understanding their structure can facilitate a mechanistic understanding of their function. Through an enormous experimental effort 1 – 4 , the structures of around 100,000 unique proteins have been determined 5 , but this represents a small fraction of the billions of known protein sequences 6 , 7 . Structural coverage is bottlenecked by the months to years of painstaking effort required to determine a single protein structure. Accurate computational approaches are needed to address this gap and to enable large-scale structural bioinformatics. Predicting the three-dimensional structure that a protein will adopt based solely on its amino acid sequence—the structure prediction component of the ‘protein folding problem’ 8 —has been an important open research problem for more than 50 years 9 . Despite recent progress 10 – 14 , existing methods fall far short of atomic accuracy, especially when no homologous structure is available. Here we provide the first computational method that can regularly predict protein structures with atomic accuracy even in cases in which no similar structure is known. We validated an entirely redesigned version of our neural network-based model, AlphaFold, in the challenging 14th Critical Assessment of protein Structure Prediction (CASP14) 15 , demonstrating accuracy competitive with experimental structures in a majority of cases and greatly outperforming other methods. Underpinning the latest version of AlphaFold is a novel machine learning approach that incorporates physical and biological knowledge about protein structure, leveraging multi-sequence alignments, into the design of the deep learning algorithm. AlphaFold predicts protein structures with an accuracy competitive with experimental structures in the majority of cases using a novel deep learning architecture.
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            Deep learning.

            Deep learning allows computational models that are composed of multiple processing layers to learn representations of data with multiple levels of abstraction. These methods have dramatically improved the state-of-the-art in speech recognition, visual object recognition, object detection and many other domains such as drug discovery and genomics. Deep learning discovers intricate structure in large data sets by using the backpropagation algorithm to indicate how a machine should change its internal parameters that are used to compute the representation in each layer from the representation in the previous layer. Deep convolutional nets have brought about breakthroughs in processing images, video, speech and audio, whereas recurrent nets have shone light on sequential data such as text and speech.
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              Long Short-Term Memory

              Learning to store information over extended time intervals by recurrent backpropagation takes a very long time, mostly because of insufficient, decaying error backflow. We briefly review Hochreiter's (1991) analysis of this problem, then address it by introducing a novel, efficient, gradient-based method called long short-term memory (LSTM). Truncating the gradient where this does not do harm, LSTM can learn to bridge minimal time lags in excess of 1000 discrete-time steps by enforcing constant error flow through constant error carousels within special units. Multiplicative gate units learn to open and close access to the constant error flow. LSTM is local in space and time; its computational complexity per time step and weight is O(1). Our experiments with artificial data involve local, distributed, real-valued, and noisy pattern representations. In comparisons with real-time recurrent learning, back propagation through time, recurrent cascade correlation, Elman nets, and neural sequence chunking, LSTM leads to many more successful runs, and learns much faster. LSTM also solves complex, artificial long-time-lag tasks that have never been solved by previous recurrent network algorithms.
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                Author and article information

                Journal
                ACS Sens
                ACS Sens
                se
                ascefj
                ACS Sensors
                American Chemical Society
                2379-3694
                04 October 2021
                22 October 2021
                : 6
                : 10
                : 3536-3555
                Affiliations
                []Division of Solid-State Electronics, Department of Electrical Engineering, Uppsala University , SE-751 03 Uppsala, Sweden
                []Instituto de Ciencias Humanas, Sociales y Ambientales, CONICET Mendoza Technological Scientific Center , Mendoza M5500, Argentina
                Author notes
                Author information
                https://orcid.org/0000-0003-4395-7905
                https://orcid.org/0000-0002-8726-7837
                https://orcid.org/0000-0003-2417-274X
                Article
                10.1021/acssensors.1c01618
                8546757
                34601866
                581d3278-de85-44fb-8dd3-8f2c4599e66c
                © 2021 The Authors. Published by American Chemical Society

                Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 29 July 2021
                : 20 September 2021
                Funding
                Funded by: Stiftelsen Olle Engkvist Byggmästare, doi 10.13039/501100004200;
                Award ID: 194-0646
                Funded by: Vetenskapsrådet, doi 10.13039/501100004359;
                Award ID: 621-2014-6300
                Funded by: Stiftelsen Olle Engkvist Byggmästare, doi 10.13039/501100004200;
                Award ID: 211-0085
                Funded by: Stiftelsen Olle Engkvist Byggmästare, doi 10.13039/501100004200;
                Award ID: 2016/39
                Categories
                Review
                Custom metadata
                se1c01618
                se1c01618

                nanopore sensing,signal processing algorithm,pulse-like signal,spike recognition,feature extraction,analyte identification,machine learning,neural network

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