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Specific targeting of brain endothelial cells using enhancer AAV vectors

Neuron 2025年第10期113卷 1562-1578.e6页

作者： Eric Velazquez-Rivera Oyshi Dey Nayoon S. Kim Wenhao Cao Qiao Ye Pan Gao Andy Thai Jason K. Nguyen Hai Zhang Jonathan T. Ting M. Gopi Bing Ren Todd C. Holmes Xiangmin Xu Department of Anatomy and Neurobiology School of Medicine University of California Irvine Irvine CA 92697 USA Department of Computer Science University of California Irvine Irvine CA 92697 USA Human Cell Types Program Allen Institute for Brain Science Seattle WA 98109 USA Department of Cellular and Molecular Medicine School of Medicine University of California San Diego La Jolla CA 92093 USA Center for Neural Circuit Mapping (CNCM) University of California Irvine Irvine CA 92697 USA Department of Physiology and Biophysics School of Medicine University of California Irvine Irvine CA 92697 USA Department of Biomedical Engineering University of California Irvine Irvine CA 92697 USA Department of Microbiology and Molecular Genetics University of California Irvine Irvine CA 92697 USA

Brain endothelial cells (BECs) in brain vasculature are critical structural and functional components of the blood brain barrier (BBB). Adeno-associated virus (AAV) capsids have previously been genetically engineered to confer specificity to endothelial cells, but these capsids show limited endothelial cell specificity that varies by delivery conditions. We developed a set of new BEC-enhancer AAV vectors that specifically target BECs based on the cis-regulatory elements identified from single-cell epigenetic datasets. Ex vivo and in vivo characterization of BEC-enhancer AAVs in wild-type, Ai9 reporter, and Alzheimer's disease model mouse brains show their utility for high transduction selectivity of the BECs with little off-target transduction in the liver. Our BEC-enhancer AAVs target the brain vasculature by systemic administration and can be minimally invasive in terms of the route of administration. They are useful new tools for delivering genetic payloads specifically to BECs for normal and diseased brain studies.

关键词： enhancer AAV endothelial cells gene therapy Alzheimer's recombinase genetic access

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Unzipping Kinetics of Double-Stranded DNA in a Nanopore

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Physical Review Letters 2003年第23期90卷 238101-238101页

作者： Alexis F. Sauer-Budge Jacqueline A. Nyamwanda David K. Lubensky Daniel Branton Biophysics Program Harvard University Cambridge Massachusetts 02138 USA Department of Molecular & Cellular Biology Harvard University Cambridge Massachusetts 02138 USA Bell Labs Lucent Technologies 700 Mountain Avenue Murray Hill New Jersey 07974 USA

We studied the unzipping of single molecules of double-stranded DNA by pulling one of their two strands through a narrow protein pore. Polymerase chain reaction analysis yielded the first direct proof of DNA unzipping in such a system. The time to unzip each molecule was inferred from the ionic current signature of DNA traversal. The distribution of times to unzip under various experimental conditions fit a simple kinetic model. Using this model, we estimated the enthalpy barriers to unzipping and the effective charge of a nucleotide in the pore, which was considerably smaller than previously assumed.

关键词： .dsDNA strands enthalpy nanopore double-stranded strand separation Unzipping effective charge protein pore

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Recurrent computations for visual pattern completion

arXiv

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arXiv 2017年

作者： Tang, Hanlin Schrimpf, Martin Lotter, Bill Moerman, Charlotte Paredes, Ana Caro, Josue Ortega Hardesty, Walter Cox, David Kreiman, Gabriel Program in Biophysics Harvard University Program in Software Engineering Augsburg University Technische Universitat Munchen Ludwig-Maximilians-Universitat Munchen Molecular and Cellular Biology Harvard University Children's Hospital Harvard Medical School

Making inferences from partial information constitutes a critical aspect of cognition. During visual perception, pattern completion enables recognition of poorly visible or occluded objects. We combined psychophysics, physiology and computational models to test the hypothesis that pattern completion is implemented by recurrent computations and present three pieces of evidence that are consistent with this hypothesis. First, subjects robustly recognized objects even when rendered Copyright © 2017, The Authors. All rights reserved.

关键词： Physiological models

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A lateral resolution metric for static single molecule localization microscopy images from time-resolved pair correlation functions

arXiv

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arXiv 2022年

作者： Shaw, Thomas R. Fazekas, Frank J. Kim, Sumin Flanagan-Natoli, Jennifer C. Sumrall, Emily R. Veatch, S.L. Program in Biophysics University of Michigan Ann ArborMI United States Program in Applied Physics University of Michigan Ann ArborMI United States Program in Cellular and Molecular Biology University of Michigan Ann ArborMI United States

Single molecule localization microscopy (SMLM) permits the visualization of cellular structures an order of magnitude smaller than the diffraction limit of visible light, and an accurate, objective evaluation of the resolution of an SMLM dataset is an essential aspect of the image processing and analysis pipeline. Here we present a simple method that uses the pair autocorrelation function evaluated both in space and time to measure the time-interval dependent point-spread function of SMLM images of static samples. Using this approach, we demonstrate that experimentally obtained images typically have effective point spread functions that are broader than expected from the localization precision alone, due to additional uncertainty arising from drift and drift correction algorithms. This resolution metric reports on how precisely one can measure pairwise distances between labeled objects and is complementary to the commonly used Fourier Ring Correlation metric that also considers spatial sampling. The method is demonstrated on simulated localizations, DNA origami rulers, and cellular structures labelled by dye-conjugated antibodies or fluorescent fusion proteins. © 2022, CC BY.

关键词： cellular automata

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Computational Methods for Single-Particle Cryo-EM

arXiv

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arXiv 2020年

作者： Singer, Amit Sigworth, Fred J. Department of Mathematics and Program in Applied and Computational Mathematics Princeton University PrincetonNJ08544 United States Departments of Cellular and Molecular Physiology Biomedical Engineering and Molecular Biophysics and Biochemistry Yale University New HavenCT06520 United States

Single-particle electron cryomicroscopy (cryo-EM) is an increasingly popular technique for elucidating the three-dimensional structure of proteins and other biologically significant complexes at near-atomic resolution. It is an imaging method that does not require crystallization and can capture molecules in their native states. In single-particle cryo-EM, the three-dimensional molecular structure needs to be determined from many noisy two-dimensional tomographic projections of individual molecules, whose orientations and positions are unknown. The high level of noise and the unknown pose parameters are two key elements that make reconstruction a challenging computational problem. Even more challenging is the inference of structural variability and flexible motions when the individual molecules being imaged are in different conformational states. This review discusses computational methods for structure determination by single-particle cryo-EM and their guiding principles from statistical inference, machine learning, and signal processing that also play a significant role in many other data science applications. Copyright © 2020, The Authors. All rights reserved.

关键词： Molecules

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Automated Measurements of Key Morphological Features of Human Embryos for IVF

arXiv

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arXiv 2020年

作者： Leahy, B.D. Jang, W.-D. Yang, H.Y. Struyven, R. Wei, D. Sun, Z. Lee, K.R. Royston, C. Cam, L. Kalma, Y. Azem, F. Ben-Yosef, D. Pfister, H. Needleman, D. School of Engineering and Applied Sciences Department of Molecular and Cellular Biology Harvard Graduate Program in Biophysics Harvard University CambridgeMA United States Tel Aviv Sourasky Medical Center Tel Aviv Israel

A major challenge in clinical In-Vitro Fertilization (IVF) is selecting the highest quality embryo to transfer to the patient in the hopes of achieving a pregnancy. Time-lapse microscopy provides clinicians with a wealth of information for selecting embryos. However, the resulting movies of embryos are currently analyzed manually, which is time consuming and subjective. Here, we automate feature extraction of time-lapse microscopy of human embryos with a machine-learning pipeline of five convolutional neural networks (CNNs). Our pipeline consists of (1) semantic segmentation of the regions of the embryo, (2) regression predictions of fragment severity, (3) classification of the developmental stage, and object instance segmentation of (4) cells and (5) pronuclei. Our approach greatly speeds up the measurement of quantitative, biologically relevant features that may aid in embryo selection. Copyright © 2020, The Authors. All rights reserved.

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A 20 YEAR CLINICAL AND LABORATORY STUDY OF FAMILIAL B-CHRONIC LYMPHOCYTIC-LEUKEMIA IN A SINGLE KINDRED

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LEUKEMIA & LYMPHOMA 1991年第5-6期3卷 331-&页

作者： CAPORASO, NE WHITEHOUSE, J BERTIN, P AMOS, C PAPADOPOULOS, N MULLER, J WHANGPENG, J TUCKER, MA FLEISHER, TA MARTI, GE [a] Family Studies Section Epidemiology and Biostatistics Program NCI NIH 439E Executive Plaza North Bethesda Maryland USA[b] Laboratory of Cellular and Molecular Biology Division of Biochemistry and Biophysics CBER FDA NIH Bdg 29 Rm 502 Bethesda Maryland USA[c] Clinical Chemistry CPD CC NIH Bethesda Maryland USA[d] Division of Virology CBER FDA Bethesda Maryland USA[e] Cytogenetic Oncology Medicine Branch NCI Bethesda Maryland USA[f] Immunology Service CPD CC NIH Bethesda Maryland USA

Four siblings and a parent in a single kindred had documented blood and marrow lymphocytosis during the past 18 to 20 years consistent with chronic lymphocytic leukemia (CLL). Of the four siblings, one developed a spontaneous remission; one died secondary to subepiglotitis with sepsis; one died with prolymphocytoid transformation and one remains alive with splenomegalic CLL. Lymphadenopathy and splenomegaly were variable as was the clinical response to chemotherapy. Bone marrow morphology was initially nodular but progessed to diffuse patterns in both deceased siblings. Blood lymphocyte morphology was extremely variable as were cell doubling times and cytogenetic studies. ABO and HLA typing revealed no evidence of linkage. Immunophenotypic analysis of the B lymphocytes demonstrated a CD19 +, CD20-, CD5 +, Leu8-, Kappa + and a CD19 +, CD20 +, CD5 +, Leu8 +, Kappa + monoclonal lymphocytosis in two affected members. An unaffected sibling showed a CD4 lymphocytosis. V_HV and V_HII gene sequences were previously described in this kindred (PNAS 84: 8563, '87). We speculate that a CD5 B cell and CD4 T cell lymphocytosis may arise early in this disease followed by the development of a pleomorphic, monoclonal lymphocytosis. The subsequent oligomorphic, monoclonal lymphocytosis shows genotypic, immunophenotypic and some morphological heterogeneity consistent with ongoing differentiation. The longitudinal investigation of familial CLL offers a unique opportunity to study the sequence of events related to the natural history of B-CLL.

关键词： FAMILY STUDIES B-CLL LYMPHOCYTIC LEUKEMIA SINGLE KINDRED CLL

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A mean shift algorithm for drift correction in localization microscopy

引用

Biophysical Reports 2021年第1期1卷 100008页

作者： Fazekas, Frank J. Shaw, Thomas R. Kim, Sumin Bogucki, Ryan A. Veatch, Sarah L. Program in Biophysics University of Michigan Ann Arbor MI United States Program in Applied Physics University of Michigan Ann Arbor MI United States Cellular and Molecular Biology Graduate Program University of Michigan Ann Arbor MI United States

Single-molecule localization microscopy techniques transcend the diffraction limit of visible light by localizing isolated emitters sampled stochastically. This time-lapse imaging necessitates long acquisition times, over which sample drift can become large relative to the localization precision. Here, we present an efficient and robust method for estimating drift, using a simple peak-finding algorithm based on mean shifts that is effective for single-molecule localization microscopy in two or three dimensions. © 2021 The Author(s)

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Electrochemical coupling in the voltage-dependent phosphatase Ci-VSP (vol 6, pg 369, 2010)

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NATURE CHEMICAL BIOLOGY 2010年第10期6卷 782-782页

作者： Kohout, Susy C. Bell, Sarah C. Liu, Lijun Xu, Qiang Minor, Daniel L., Jr. Isacoff, Ehud Y. Department of Molecular and Cell Biology University of California Berkeley California USA Chemical Biology Graduate Program University of California Berkeley California USA Cardiovascular Research Institute University of California San Francisco California USA Department of Biochemistry and Biophysics University of California San Francisco California USA Department of Cellular and Molecular Pharmacology University of California San Francisco California USA California Institute for Quantitative Biosciences University of California San Francisco California USA Physical Biosciences Division Lawrence Berkeley National Laboratory Berkeley California USA Helen Wills Neuroscience Institute University of California Berkeley California USA Material Science Division Lawrence Berkeley National Laboratory Berkeley California USA.

In the voltage-sensing phosphatase Ci-VSP, a voltage-sensing domain (VSD) controls a lipid phosphatase domain (PD). The mechanism by which the domains are allosterically coupled is not well understood. Using an in vivo assay, we found that the interdomain linker that connects the VSD to the PD is essential for coupling the full-length protein. Biochemical assays showed that the linker is also needed for activity in the isolated PD. We also identified a late step of VSD motion in the full-length protein that depends on the linker. Notably, we found that this VSD motion requires PI(4,5)P₂, a substrate of Ci-VSP. These results suggest that the voltage-driven motion of the VSD turns the enzyme on by rearranging the linker into an activated conformation, and that this activated conformation is stabilized by PI(4,5)P₂. We propose that Ci-VSP activity is self-limited because its decrease of PI(4,5)P₂ levels decouples the VSD from the enzyme.

关键词： Biophysical chemistry Electrophysiology Enzyme mechanisms Ion channels

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G-Quadruplex(G4) Motifs in the Maize(Zea mays L.) Genome Are Enriched at Specific Locations in Thousands of Genes Coupled to Energy Status,Hypoxia,Low Sugar,and Nutrient Deprivation

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Journal of Genetics and Genomics 2014年第12期41卷 627-647页

作者： Carson M.Andorf Mykhailo Kopylov Drena Dobbs Karen E.Koch M.Elizabeth Stroupe Carolyn J.Lawrence Hank W.Bass USDA-ARS Corn Insects and Crop Genetics Research Unit Iowa State University Department of Computer Science Iowa State University Institute of Molecular Biophysics Florida State University Department of Genetics Development and Cell BiologyIowa State University Plant Molecular and Cellular Biology Program Horticultural Sciences DepartmentGenetics InstituteUniversity of Florida Department of Biological Science Florida State University Department of Agronomy Iowa State University

The G-quadruplex （G4） elements comprise a class of nucleic acid structures formed by stacking of guanine base quartets in a quadruple helix. This （34 DNA can form within or across single-stranded DNA molecules and is mutually exclusive with duplex B-form DNA. The reversibility and structural diversity of G4s make them highly versatile genetic structures, as demonstrated by their roles in various functions including telomere metabolism, genome maintenance, immunoglobulin gene diversification, transcription, and translation. Sequence motifs capable of forming G4 DNA are typically located in telomere repeat DNA and other non-telomeric genomic loci. To investigate their potential roles in a large-genome model plant species, we computationaily identified 149,988 non-telomeric G4 motifs in maize （Zea mays L., B73 AGPv2）, 29% of which were in non-repetitive genomic regions. G4 motif hotspots exhibited non-random enrichment in genes at two locations on the antisense strand, one in the 5~ UTR and the other at the 5~ end of the first intron. Several genic G4 motifs were shown to adopt sequence-specific and potassium-dependent G4 DNA structures in vitro. The G4 motifs were prevalent in key regulatory genes associated with hypoxia （group VII ERFs）, oxidative stress （D J-1/GATasel）, and energy status （AMPK/ SnRK） pathways. They also showed statistical enrichment for genes in metabolic pathways that function in glycolysis, sugar degradation, inositol metabolism, and base excision repair. Collectively, the maize G4 motifs may represent conditional regulatory elements that can aid in energy status gene responses. Such a network of elements could provide a mechanistic basis for linking energy status signals to gene regulation in maize, a model genetic system and major world crop species for feed, food, and fuel.

关键词： Maize G-quadruplex G4 Hypoxia Sucrose synthase

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