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Advances in AAV capsid engineering: Integrating rational design, directed evolution and machine learning

Molecular Therapy 2025年第5期33卷 1937-1945页

作者： Nisanov, Alan M. Rivera de Jesús, Julio A. Schaffer, David V. Department of Chemistry University of California Berkeley Berkeley 94720 CA United States Department of Chemical and Biomolecular Engineering University of California Berkeley Berkeley 94720 CA United States Department of Bioengineering University of California Berkeley Berkeley 94720 CA United States Graduate Program in Bioengineering University of California Berkeley San Francisco and University of California Berkeley 94720 CA United States Department of Neurological Surgery University of California San Francisco 94143 CA United States Department of Molecular and Cell Biology University of California Berkeley Berkeley 94720 CA United States

Adeno-associated virus (AAV) has emerged as a highly promising vector for human gene therapy due to its favorable safety profile, versatility, and ability to transduce a wide range of tissues. However, natural AAV serotypes have shortcomings, including suboptimal transduction efficiency, pre-existing immunity, and a lack of tissue specificity, that hinder their therapeutic potential. To address these challenges, significant efforts are being applied to engineer novel AAV capsids. Rational design leverages structural insights to enhance capsid properties, directed evolution enables unbiased selection of superior variants, and machine learning accelerates discovery by computational analysis of high-throughput screening results to enable predictive algorithms. These strategies have yielded novel capsids with improved transduction efficiency, reduced immunogenicity, and enhanced tissue targeting. Future advances that continue to integrate such multi-disciplinary approaches will further drive the clinical translation of AAV-based therapies. © 2025 The Authors

关键词： AAV directed evolution gene therapy high-throughput screening machine learning next generation sequencing NGS rational design

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SKAP binding to microtubules reduces friction at the kinetochore-microtubule interface and increases attachment stability under force

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Current Biology 2025年第8期35卷 1805-1815.e4页

作者： Rosas-Salvans, Miquel Rux, Caleb J. Das, Moumita Dumont, Sophie Department of Bioengineering & Therapeutic Sciences University of California San Francisco San Francisco 94158 CA United States Bioengineering Graduate Program University of California San Francisco UCB San Francisco 94158 CA United States School of Physics and Astronomy Rochester Institute of Technology Rochester 14623 NY United States Department of Biochemistry & Biophysics University of California San Francisco San Francisco 94158 CA United States Chan Zuckerberg Biohub San Francisco 94158 CA United States

The kinetochore links chromosomes to spindle microtubules to drive chromosome segregation at cell division. We recently uncovered that the kinetochore complex Astrin-SKAP, which binds microtubules, reduces rather than increases friction at the mammalian kinetochore-microtubule interface. How it does so is not known. Astrin-SKAP could affect how other kinetochore complexes bind microtubules, reducing their friction along microtubules, or it could itself bind microtubules with similar affinity but lower friction than other attachment factors. Using SKAP mutants unable to bind microtubules, live imaging, and laser ablation, we show that SKAP's microtubule binding is essential for sister kinetochore coordination, force dissipation at the interface, and attachment responsiveness to force changes. Further, we show that SKAP's microtubule binding is essential to prevent chromosome detachment under both spindle forces and microneedle-generated forces. Together, our findings indicate that SKAP's microtubule binding reduces kinetochore friction and increases attachment responsiveness and stability under force. We propose that having complexes with both high and low sliding friction on microtubules, making a mechanically heterogeneous interface, is key to maintaining robust attachments under force and thus accurate segregation. © 2025 The Authors

关键词： Astrin-SKAP attachment dynamics friction interface kinetochore mechanics microtubule robustness spindle

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Interoceptive modulation of emotions

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Current Opinion in Neurobiology 2025年 92卷 103049-103049页

作者： Zsembik, Leo Oldroyd, Poppy Chen, Ritchie Department of Neurological Surgery University of California San Francisco United States Weill Institute for Neurosciences University of California San Francisco United States Neuroscience Graduate Program University of California San Francisco United States Department of Psychiatry and Behavioral Sciences University of California San Francisco United States Department of Bioengineering and Therapeutic Sciences University of California San Francisco United States

The metaphorical use of the heart to represent emotions has been documented since our earliest known writings, which reflects a historical recognition of the deep connection between bodily sensations and emotions. However, it remains an active topic of investigation to determine the degree to which bodily physiology modulates emotion states. Recent advances in the neuroscience of interoception—the process by which we sense, interpret, and integrate internal bodily signals and physiology—are uncovering neurobiological mechanisms by which visceral signals can influence emotions. Here we review interoceptive pathways that relay visceral signals to the brain and discuss how these signals influence emotion states as well as challenges and opportunities to better understand interoceptive modulation of emotions. © 2025 Elsevier Ltd

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Three-Dimensional Free-Breathing Ultrashort Echo Time (UTE) 1H MRI Regional Ventilation: Comparison With Hyperpolarized 129Xe MRI and Pulmonary Function Testing in Healthy Volunteers and People With Cystic Fibrosis

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NMR in Biomedicine 2025年第6期38卷 e70033页

作者： Tan, Fei Eddy, Rachel L. Diamond, Vanessa M. Rayment, Jonathan H. Larson, Peder E. Z. UC Berkeley–UCSF Graduate Program in Bioengineering University of California Berkeley BerkeleyCA United States Department of Radiology and Biomedical Imaging University of California San Francisco San FranciscoCA United States BC Children's Hospital Research Institute Vancouver Canada Centre for Heart Lung Innovation University of British Columbia Vancouver Canada Department of Pediatrics University of British Columbia Vancouver Canada

MRI can provide localized assessment of lung function for monitoring people with lung disease. Hyperpolarized 129Xe MRI directly images pulmonary gas distribution but requires specialized hardware. Conventional 1H MRI acquisitions can also provide functional maps using free-breathing approaches. The purpose of this study is to evaluate regional ventilation derived from 3D ultrashort echo-time (UTE) 1H MRI using Motion-Compensated Low-Rank constrained reconstruction (MoCoLoR), by comparing against 129Xe MRI and pulmonary function testing as reference-standard. The study is retrospective in design. The study included 57 participants (25.4 ± 15.8 years, 35 males and 22 females): 12 healthy volunteers, 20 pediatric, and 25 adult people with cystic fibrosis (CF) scanned between January 2022 and February 2023. Field strength/sequence: 3T;129Xe: 2D multislice spoiled gradient-recalled sequence;UTE 1H: variable-density 3D radial sequence. K-means-based 129Xe ventilation defect percent (VDP), forced expiratory volume in 1 s (FEV1), and lung clearance index (LCI) were evaluated against UTE 1H VDP from a modified k-means method. The correspondence of ventilation defect maps from 129Xe and UTE 1H was also evaluated. Statistical tests included the Pearson correlation coefficient (r) and t tests, with p 129Xe and UTE 1H VDP were significantly correlated (r = 0.64, p = (Formula presented.)). Bland–Altman analysis showed a bias of −0.05 (p = (Formula presented.)) and limits of agreement of (0.07, −0.17). The Dice spatial accuracy of the UTE-based ventilation defect regions using 129Xe as reference was 0.64 ± 0.05. UTE 1H VDP was significantly correlated with FEV1 (r = −0.54, p = (Formula presented.)) and LCI (r = 0.48, p = (Formula presented.)) and was significantly different between healthy and CF participants (p = 0.017), although the correlations and differences were stronger for 129Xe VDP. UTE 1H VDP correlated with 129Xe VDP, FEV1, and LCI, and demonstrated high, consistent Di

关键词： Magnetic resonance imaging

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Robustness tests for biomedical foundation models should tailor to specification

arXiv

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arXiv 2025年

作者： Xian, R. Patrick Baker, Noah R. David, Tom Cui, Qiming Holmgren, A. Jay Bauer, Stefan Sushil, Madhumita Abbasi-Asl, Reza Weill Institute for Neurosciences University of California San Francisco 1651 4th Street San FranciscoCA94158 United States Biological and Medical Informatics Graduate Program University of California San Francisco 550 16th Street 3rd Floor San FranciscoCA94158 United States PRISM Eval 10 Rue de Penthièvre Paris75008 France Department of Bioengineering University of California Berkeley 306 Stanley Hall University Drive BerkeleyCA94720 United States Division of Clinical Informatics and Digital Transformation University of California San Francisco 10 Koret Way San FranciscoCA94117 United States School of Computation Information and Technology Technical University of Munich & Helmholtz AI Arcisstrasse 21 Munich80333 Germany Bakar Computational Health Sciences Institute University of California San Francisco 490 Illinois Street San FranciscoCA94158 United States

Existing regulatory frameworks for biomedical AI include robustness as a key component but lack detailed implementational guidance. The recent rise of biomedical foundation models creates new hurdles in testing and certification given their broad capabilities and susceptibility to complex distribution shifts. To balance test feasibility and effectiveness, we suggest a priority-based, task-oriented approach to tailor robustness evaluation objectives to a predefined specification. We urge concrete policies to adopt a granular categorization of robustness concepts in the specification. Our approach promotes the standardization of risk assessment and monitoring, which guides technical developments and mitigation efforts. © 2025, CC BY-NC-SA.

关键词： Specifications

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Multi-institutional atlas of brain metastases informs spatial modeling for precision imaging and personalized therapy

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Nature Communications 2025年第1期16卷 1-15页

作者： Barrios, Jorge Porter, Evan Capaldi, Dante P. I. Upadhaya, Taman Chen, William C. Perks, Julian R. Apte, Aditya Aristophanous, Michalis LoCastro, Eve Hsu, Dylan Stone, Payton H. Villanueva-Meyer, Javier E. Valdes, Gilmer Jiang, Fei Maddalena, Michael Ballangrud, Ase Prezelski, Kayla Lin, Hui Sun, Jinger Y. Aldin, Muhtada A. K. Chau, Oi Wai Ziemer, Benjamin Seaberg, Maasa Sneed, Penny K. Nakamura, Jean L. Boreta, Lauren C. Fogh, Shannon E. Raleigh, David R. Chew, Jessica Vasudevan, Harish Cha, Soonmee Hess, Christopher Fragoso, Ruben Shultz, David B. Pike, Luke Hervey-Jumper, Shawn L. Tsang, Derek S. Theodosopoulos, Philip Cooke, Daniel Benedict, Stanley H. Sheng, Ke Seuntjens, Jan Coolens, Catherine Deasy, Joe Braunstein, Steve Morin, Olivier Department of Radiation Oncology University of California San Francisco San Francisco CA United States Department of Radiation Oncology University of California Davis Health Sacramento CA United States Department of Radiation Oncology Memorial Sloan Kettering New York NY United States Department of Medical Physics Memorial Sloan Kettering New York NY United States Department of Radiology and Biomedical Imaging University of California San Francisco San Francisco CA United States Department of Neurological Surgery University of California San Francisco San Francisco CA United States Department of Epidemiology and Biostatistics University of California San Francisco San Francisco CA United States Moffit Cancer Center Tampa FL United States Radiation Medicine Program Princess Margaret Cancer Centre University Health Network Toronto ON Canada Department of Medical Biophysics University of Toronto Toronto ON Canada UCSF/UC Berkeley Graduate Program in Bioengineering San Francisco CA United States Department of Pathology University of California San Francisco San Francisco CA United States

Brain metastases are a frequent and debilitating manifestation of advanced cancer. Here, we collect and analyze neuroimaging of 3,065 cancer patients with 13,067 brain metastases, representing an extensive collection for research. We find that metastases predominantly localize to high perfusion areas near the grey-white matter junction, but also identify notable differences depending on the primary cancer histology as well as brain regions which do not conform to this relationship. Lung and breast cancers, in contrast to melanoma, frequently metastasize to the cerebellum, hinting at biological pathways of spread. Additionally, the deep brain structures are relatively spared from metastasis, regardless of primary cancer type. Leveraging this data, we propose a probabilistic brain metastasis risk model to enhance the therapeutic ratio of whole-brain radiotherapy by targeting high risk areas while preserving cortical and subcortical brain regions of functional significance and low metastasis risk, potentially reducing the cognitive side effects of therapy. © The Author(s) 2025.

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BPS2025 - NuMA mechanically reinforces spindle poles independently of dynein through self-interactions

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Biophysical Journal 2025年第3期124卷 376a-376a页

作者： Nathan Cho Sophie Dumont Department of Bioengineering & Therapeutic Sciences University of California San Francisco San Francisco CA USA Tetrad Graduate Program University of California San Francisco San Francisco CA USA Chan Zuckerberg Biohub San Francisco CA USA

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Regulation of vascular smooth muscle cells and mesenchymal stem cells by mechanical strain

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MCB Molecular and Cellular Biomechanics 2006年第1期3卷 21-34页

作者： Kurpinski, Kyle Park, Jennifer Thakar, Rahul G. Li, Song Department of Bioengineering University of California at Berkeley Berkeley CA United States Joint Graduate Program in Bioengineering UC Berkeley Berkeley CA United States Joint Graduate Program in Bioengineering UC San Francisco San Francisco CA United States

Vascular smooth muscle cells (SMCs) populate in the media of the blood vessel, and play an important role in the control of vasoactivity and the remodeling of the vessel wall. Blood vessels are constantly subjected to hemodynamic stresses, and the pulsatile nature of the blood flow results in a cyclic mechanical strain in the vessel walls. Accumulating evidence in the past two decades indicates that mechanical strain regulates vascular SMC phenotype, function and matrix remodeling. Bone marrow mesenchymal stem cell (MSC) is a potential cell source for vascular regeneration therapy, and may be used to generate SMCs to construct tissue-engineered vascular grafts for blood vessel replacements. In this review, we will focus on the effects of mechanical strain on SMCs and MSCs, e.g., cell phenotype, cell morphology, cytoskeleton organization, gene expression, signal transduction and receptor activation. We will compare the responses of SMCs and MSCs to equiaxial strain, uniaxial strain and mechanical strain in three-dimensional culture. Understanding the hemodynamic regulation of SMC and MSC functions will provide a basis for the development of new vascular therapies and for the construction of tissue-engineered vascular, grafts. Copyright © 2006 Tech Science Press.

关键词： Muscle

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Deep learning–guided design of dynamic proteins

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Science 2025年第6749期388卷 eadr7094页

作者： Amy B. Guo Deniz Akpinaroglu Christina A. Stephens Michael Grabe Colin A. Smith Mark J. S. Kelly Tanja Kortemme The UC Berkeley–UCSF Graduate Program in Bioengineering University of California San Francisco San Francisco CA USA. Department of Bioengineering and Therapeutic Sciences University of California San Francisco San Francisco CA USA. Department of Pharmaceutical Chemistry University of California San Francisco San Francisco CA USA. Cardiovascular Research Institute University of California San Francisco San Francisco CA USA. Department of Chemistry Wesleyan University Middletown CT USA. Quantitative Biosciences Institute University of California San Francisco San Francisco CA USA. Chan Zuckerberg Biohub San Francisco CA USA.

Deep learning has advanced the design of static protein structures, but the controlled conformational changes that are hallmarks of natural signaling proteins have remained inaccessible to de novo design. Here, we describe a general deep learning–guided approach for de novo design of dynamic changes between intradomain geometries of proteins, similar to switch mechanisms prevalent in nature, with atomic-level precision. We solve four structures that validate the designed conformations, demonstrate modulation of the conformational landscape by orthosteric ligands and allosteric mutations, and show that physics-based simulations are in agreement with deep-learning predictions and experimental data. Our approach demonstrates that new modes of motion can now be realized through de novo design and provides a framework for constructing biology-inspired, tunable, and controllable protein signaling behavior de novo.

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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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