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De novo protein fold families expand the designable ligand binding site space

PLoS Computational Biology 2021年第11期17卷 e1009620-e1009620页

作者： Pan, Xingjie Kortemme, Tanja Department of Bioengineering and Therapeutic Sciences University of California San Francisco San FranciscoCA United States UC Berkeley-UCSF Graduate Program in Bioengineering University of California San Francisco San FranciscoCA United States University of California San Francisco San FranciscoCA United States Chan Zuckerberg Biohub San FranciscoCA United States

A major challenge in designing proteins de novo to bind user-defined ligands with high affinity is finding backbones structures into which a new binding site geometry can be engineered with high precision. Recent advances in methods to generate protein fold families de novo have expanded the space of accessible protein structures, but it is not clear to what extend de novo proteins with diverse geometries also expand the space of designable ligand binding functions. We constructed a library of 25,806 high-quality ligand binding sites and developed a fast protocol to place ("match") these binding sites into both naturally occurring and de novo protein families with two fold topologies: Rossman and NTF2. Each matching step involves engineering new binding site residues into each protein "scaffold", which is distinct from the problem of comparing already existing binding pockets. 5,896 and 7,475 binding sites could be matched to the Rossmann and NTF2 fold families, respectively. De novo designed Rossman and NTF2 protein families can support 1,791 and 678 binding sites that cannot be matched to naturally existing structures with the same topologies, respectively. While the number of protein residues in ligand binding sites is the major determinant of matching success, ligand size and primary sequence separation of binding site residues also play important roles. The number of matched binding sites are power law functions of the number of members in a fold family. Our results suggest that de novo sampling of geometric variations on diverse fold topologies can significantly expand the space of designable ligand binding sites for a wealth of possible new protein functions. © 2021 Pan, Kortemme. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

关键词： Topology

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Author Correction: Miniscope3D: optimized single-shot miniature 3D fluorescence microscopy

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Light, science & applications 2023年第1期12卷 93页

作者： Kyrollos Yanny Nick Antipa William Liberti Sam Dehaeck Kristina Monakhova Fanglin Linda Liu Konlin Shen Ren Ng Laura Waller UCB/UCSF Joint Graduate Program in Bioengineering University of California Berkeley CA 94720 USA. kyrollosyanny@***. Department of Electrical Engineering & Computer Sciences University of California Berkeley CA 94720 USA. naantipa@***. Department of Electrical Engineering & Computer Sciences University of California Berkeley CA 94720 USA. TIPs Department Université libre de Bruxelles (ULB) 1050 Brussels Belgium. UCB/UCSF Joint Graduate Program in Bioengineering University of California Berkeley CA 94720 USA.

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A complete allosteric map of a GTPase switch in its native cellular network

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Cell Systems 2023年第3期14卷 237-246.e7页

作者： Mathy, Christopher J.P. Mishra, Parul Flynn, Julia M. Perica, Tina Mavor, David Bolon, Daniel N.A. Kortemme, Tanja Department of Bioengineering and Therapeutic Sciences University of California San Francisco San Francisco 94158 CA United States Quantitative Biosciences Institute University of California San Francisco San Francisco 94158 CA United States The UC Berkeley-UCSF Graduate Program in Bioengineering University of California San Francisco San Francisco 94158 CA United States Department of Biochemistry and Molecular Biotechnology University of Massachusetts Medical School Worcester 01605 MA United States Chan Zuckerberg Biohub San Francisco 94158 CA United States School of Life Sciences University of Hyderabad Telangana Hyderabad India

Allosteric regulation is central to protein function in cellular networks. A fundamental open question is whether cellular regulation of allosteric proteins occurs only at a few defined positions or at many sites distributed throughout the structure. Here, we probe the regulation of GTPases—protein switches that control signaling through regulated conformational cycling—at residue-level resolution by deep mutagenesis in the native biological network. For the GTPase Gsp1/Ran, we find that 28% of the 4,315 assayed mutations show pronounced gain-of-function responses. Twenty of the sixty positions enriched for gain-of-function mutations are outside the canonical GTPase active site switch regions. Kinetic analysis shows that these distal sites are allosterically coupled to the active site. We conclude that the GTPase switch mechanism is broadly sensitive to cellular allosteric regulation. Our systematic discovery of new regulatory sites provides a functional map to interrogate and target GTPases controlling many essential biological processes. © 2023 The Authors

关键词： allostery cellular regulation Gsp1 GTPases mutational scanning protein networks Ran

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Fourier diffuserscope: Single-shot 3d fourier light field microscopy with a diffuser

arXiv

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arXiv 2020年

作者： Liu, Fanglin Linda Grace, K.U.O. Antipa, Nick Yanny, Kyrollos Waller, Laura Electrical Engineering and Computer Sciences University of California Berkeley94709 United States UCB/UCSF Joint Graduate Program in Bioengineering University of California BerkeleyCA94709 United States

Light field microscopy (LFM) uses a microlens array (MLA) near the sensor plane of a microscope to achieve single-shot 3D imaging of a sample, without any moving parts. Unfortunately, the 3D capability of LFM comes with a significant loss of lateral resolution at the focal plane, which is highly undesirable in microscopy. Placing the MLA near the pupil plane of the microscope, rather than the image plane, can mitigate the artifacts near focus and provide an efficient shift-invariant model at the expense of field-of-view. Here, we show that our Fourier DiffuserScope achieves significantly better performance than Fourier LFM. Fourier DiffuserScope uses a diffuser in the pupil plane to encode depth information, then reconstructs volumetric information computationally by solving a sparsity-constrained inverse problem. Our diffuser consists of randomly placed microlenses with varying focal lengths. We show that by randomizing the microlens positions, a larger lateral field-of-view can be achieved compared to a conventional MLA;furthermore, by adding diversity to the focal lengths, the axial depth range is increased. To predict system performance based on diffuser parameters, we for the first time establish a theoretical framework as a design guideline, followed by numerical simulations to verify. Under both theoretical and numerical analysis, we demonstrate that our diffuser design provides more uniform resolution over a larger volume, both laterally and axially, outperforming the MLA used in LFM. We build an experiment system with an optimized lens set and achieve 3 volume. Copyright © 2020, The Authors. All rights reserved.

关键词： Microlenses

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Spectral DiffuserCam: lensless snapshot hyperspectral imaging with a spectral filter array

arXiv

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arXiv 2020年

作者： Monakhova, Kristina Yanny, Kyrollos Aggarwal, Neerja Waller, Laura Department of Electrical Engineering & Computer Sciences University of California BerkeleyCA94720 United States UCB/UCSF Joint Graduate Program in Bioengineering University of California BerkeleyCA94720 United States

Hyperspectral imaging is useful for applications ranging from medical diagnostics to crop monitoring;however, traditional scanning hyperspectral imagers are prohibitively slow and expensive for widespread adoption. Snapshot techniques exist but are often confined to bulky bench-top setups or have low spatio-spectral resolution. In this paper, we propose a novel, compact, and inexpensive computational camera for snapshot hyperspectral imaging. Our system consists of a repeated spectral filter array placed directly on the image sensor and a diffuser placed close to the sensor. Each point in the world maps to a unique pseudorandom pattern on the spectral filter array, which encodes multiplexed spatio-spectral information. A sparsity-constrained inverse problem solver then recovers the hyperspectral volume with good spatio-spectral resolution. By using a spectral filter array, our hyperspectral imaging framework is flexible and can be designed with contiguous or non-contiguous spectral filters that can be chosen for a given application. We provide theory for system design, demonstrate a prototype device, and present experimental results with high spatio-spectral resolution. © 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreement Copyright © 2020, The Authors. All rights reserved.

关键词： Spectroscopy

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Osteocyte dysfunction promotes osteoarthritis through MMP13-dependent suppression of subchondral bone homeostasis

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Bone Research 2019年第4期7卷 354-370页

作者： Courtney MMazur Jonathon JWoo Cristal SYee Aaron JFields Claire Acevedo Karsyn NBailey Serra Kaya Tristan WFowler Jeffrey CLotz Alexis Dang Alfred CKuo Thomas PVail Tamara Alliston Department of Orthopaedic Surgery University of CaliforniaSan FranciscoCA 94143USA UC Berkeley-UCSF Graduate Program in Bioengineering San FranciscoCA 94143USA Department of Mechanical Engineering University of UtahSalt Lake CityUT 84112USA San Francisco Veterans Affairs Medical Center San FranciscoCA 94121USA

Osteoarthritis(OA),long considered a primary disorder of articular cartilage,is commonly associated with subchondral bone ***,the cellular mechanisms responsible for changes to subchondral bone in OA,and the extent to which these changes are drivers of or a secondary reaction to cartilage degeneration,remain *** knee joints from human patients with end-stage OA,we found evidence of profound defects in osteocyte *** of osteocyte perilacunar/canalicular remodeling(PLR)was most severe in the medial compartment of OA subchondral bone,with lower protease expression,diminished canalicular networks,and disorganized and hypermineralized extracellular *** a step toward evaluating the causality of PLR suppression in OA,we ablated the PLR enzyme MMP13 in osteocytes while leaving chondrocytic MMP13 intact,using Cre recombinase driven by the 9.6-kb DMP1 *** only did osteocytic MMP13 deficiency suppress PLR in cortical and subchondral bone,but it also compromised *** in the absence of injury,osteocytic MMP13 deficiency was sufficient to reduce cartilage proteoglycan content,change chondrocyte production of collagen II,aggrecan,and MMP13,and increase the incidence of cartilage lesions,consistent with early ***,in humans and mice,defects in PLR coincide with cartilage ***-derived MMP13 emerges as a critical regulator of cartilage homeostasis,likely via its effects on ***,these findings implicate osteocytes in bone-cartilage crosstalk in the joint and suggest a causal role for suppressed perilacunar/canalicular remodeling in osteoarthritis.

关键词： MMP13 homeostasis likely

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Accessible and accurate cytometry analysis of adherent cells using fluorescence microscopes

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Scientific Reports 2025年第1期15卷 1-9页

作者： Daniel Foyt Yiming Kuang Klaus Yserentant Bo Huang Samma Rehem UCSF-UC Berkeley Joint Graduate Program in Bioengineering University of California San Francisco San Francisco CA 94143 USA Department of Pharmaceutical Chemistry University of California San Francisco San Francisco CA 94143 USA Department of Biochemistry and Biophysics University of California San Francisco San Francisco CA 94143 USA Chan Zuckerberg Biohub San Francisco San Francisco CA 94158 USA Barnard College of Columbia University New York City NY 10027 USA

We have developed a method along with a Python-based analysis tool to capture images and produce flow-cytometry-like data for adherent cell culture utilizing simple accessible microscopes. Leveraging the recently developed generalist algorithms for cell segmentation, our approach efficiently quantifies single-cell fluorescence signals. We demonstrated the utility of this method by screening a set of 88 prime editing conditions using the integration of mNeonGreen211as a reporter.

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A metabolite specific 3D stack-of-spiral bSSFP sequence for improved lactate imaging in hyperpolarized [1-13C]pyruvate studies on a 3T clinical scanner

arXiv

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arXiv 2020年

作者： Tang, Shuyu Bok, Robert Qin, Hecong Reed, Galen VanCriekinge, Mark Santos, Romelyn Delos Overall, William Santos, Juan Gordon, Jeremy Wang, Zhen Jane Vigneron, Daniel B. Larson, Peder E.Z. UC Berkeley-UCSF Graduate Program in Bioengineering University of California San Francisco University of California Berkeley United States Department of Radiology and Biomedical Imaging University of California - San Francisco San FranciscoCA United States HeartVista Los AltosCA United States

Purpose: The balanced steady-state free precession sequence has been previously explored to improve the efficient use of non-recoverable hyperpolarized 13C magnetization, but suffers from poor spectral selectivity and long acquisition time. The purpose of this study was to develop a novel metabolite-specific 3D bSSFP ("MS-3DSSFP") sequence with stack-of-spiral readouts for improved lactate imaging in hyperpolarized [1-13C]pyruvate studies on a clinical 3T scanner. Methods: Simulations were performed to evaluate the spectral response of the MS-3DSSFP sequence. Thermal 13C phantom experiments were performed to validate the MS-3DSSFP sequence. In vivo hyperpolarized [1-13C]pyruvate studies were performed to compare the MS-3DSSFP sequence with metabolite specific gradient echo ("MS-GRE") sequences for lactate imaging. Results: Simulations, phantom and in vivo studies demonstrate that the MS-3DSSFP sequence achieved spectrally selective excitation on lactate while minimally perturbing other metabolites. Compared with MS-GRE sequences, the MS-3DSSFP sequence showed approximately a 2.5-fold SNR improvement for lactate imaging in rat kidneys, prostate tumors in a mouse model and human kidneys. Conclusions: Improved lactate imaging using the MS-3DSSFP sequence in hyperpolarized [1-13C]pyruvate studies was demonstrated in animals and humans. The MS-3DSSFP sequence could be applied for other clinical applications such as in the brain or adapted for imaging other metabolites such as pyruvate and bicarbonate. Copyright © 2020, The Authors. All rights reserved.

关键词： Magnetic resonance imaging

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Resistive-pulse sensing tumor-derived exosome detection device 22

Resistive-pulse sensing tumor-derived exosome detection devi...

引用

22nd International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2018

作者： Carey, Thomas R. Yu, Connie W. Hall, Jennifer Sohn, Lydia L. UC Berkeley UCSF Graduate Program in Bioengineering United States UC Berkeley Bioengineering United States UC Berkeley Molecular and Cell Biology United States UC Berkeley Mechanical Engineering United States

ISBN: (纸本)9781510897571

We present the theory, design, and proof-of-concept demonstration of a tumor-derived exosome detection platform that enables non-invasive, cost-effective, point-of-care cancer screening. Our platform detects exosomes displaying a specific surface antigen by electronically measuring through node-pore sensing the effective size increase that occurs when exosomes bind to colloids functionalized with specific antibodies. We have demonstrated that our platform can differentially detect exosomes derived from A549 cells (a non-small cell lung cancer cell line) and BEAS-2B cells (a non-malignant bronchial epithelial cell line). Copyright © (2018) by Chemical and Biological Microsystems Society. All rights reserved.

关键词： Tumors

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A Regional bolus tracking and Real-time B1 Calibration method for Hyperpolarized 13C MRI

arXiv

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arXiv 2020年

作者： Tang, Shuyu Milshteyn, Eugene Reed, Galen Gordon, Jeremy Bok, Robert Zhu, Xucheng Zhu, Zihan Vigneron, Daniel B. Larson, Peder E.Z. UC Berkeley-UCSF Graduate Program in Bioengineering University of California San Francisco United States University of California Berkeley United States Department of Radiology and Biomedical Imaging University of California - San Francisco San FranciscoCA United States HeartVista Los AltosCA United States

Purpose: Acquisition timing and B1 calibration are two key factors that affect the quality and accuracy of hyperpolarized 13C MRI. The goal of this project was to develop a new approach using regional bolus tracking to trigger Bloch-Siegert B1 mapping and real-time B1 calibration based on regional B1 measurements, followed by dynamic imaging of hyperpolarized 13C metabolites in ***: The proposed approach was implemented on a system which allows real-time data processing and real-time control on the sequence. Real-time center frequency calibration upon the bolus arrival was also added. The feasibility of applying the proposed framework for in vivo hyperpolarized 13C imaging was tested on healthy rats, tumor-bearing mice and a healthy volunteer on a clinical 3T scanner following hyperpolarized [1-13C]pyruvate injection. Multichannel receive coils were used in the human ***: Automatic acquisition timing based on either regional bolus peak or bolus arrival was achieved with the proposed framework. Reduced blurring artifacts in real-time reconstructed images were observed with real-time center frequency calibration. Real-time computed B1 scaling factors agreed with real-time acquired B1 maps. Flip angle correction using B1 maps results in a more consistent quantification of metabolic activity (i.e, pyruvate-to-lactate conversion, kPL). Experiment recordings are provided to demonstrate the real-time actions during the ***: The proposed method was successfully demonstrated on animals and a human volunteer, and is anticipated to improve the efficient use of the hyperpolarized signal as well as the accuracy and robustness of hyperpolarized 13C imaging. Copyright © 2020, The Authors. All rights reserved.

关键词： Mapping

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