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An inexpensive microscopy system for microfluidic studies in budding yeast

Translational Medicine of Aging 2019年 3卷 52-56页

作者： Chen, Kenneth L. Ven, Toby N. Crane, Matthew M. Chen, Dexter E. Feng, Yen-Chi Suzuki, Nozomi Russell, Adam E. de Moraes, Diogo Kaeberlein, Matt Department of Pathology School of Medicine University of Washington Seattle WA United States Department of Genome Sciences School of Medicine University of Washington Seattle WA United States Medical Scientist Training Program School of Medicine University of Washington Seattle WA United States

Recently, microfluidic technologies have been developed to allow higher throughput collection of yeast replicative lifespan data. Adoption of these devices has been limited, in part, due to the high cost of the motorized microscopy instrumentation from mainline manufacturers. Inspired by recent development of open source microscopy hardware and software, we developed minimal-cost hardware attachments to provide long-term focus stabilization for lower-cost microscopes and open source software to manage concurrent time-lapse image acquisition from multiple microscopes. We hope that these tools will help spur the wider adoption of microfluidic technologies for the study of aging in yeast. © 2019 KeAi Communications Co., Ltd

关键词： 3D printing Arduino Lifespan Microdissection Microfluidics Microscopy Replicative aging Yeast

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Cooperation among an anonymous group protected Bitcoin during failures of decentralization

arXiv

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arXiv 2022年

作者： Blackburn, Alyssa Huber, Christoph Eliaz, Yossi Shamim, Muhammad S. Weisz, David Seshadri, Goutham Kim, Kevin Hang, Shengqi Aiden, Erez Lieberman The Center for Genome Architecture Baylor College of Medicine HoustonTX77030 United States Department of Molecular and Human Genetics Baylor College of Medicine HoustonTX United States Center for Theoretical Biological Physics Rice University HoustonTX77030 United States Institute for Markets and Strategy WU Vienna University of Economics and Business Vienna Austria Department of Physics University of Houston HoustonTX77204 United States Medical Scientist Training Program Baylor College of Medicine HoustonTX United States Department of Computer Science Rice University HoustonTX77030 United States

Bitcoin is a digital currency designed to rely on a decentralized, trustless network of anonymous agents. Using a pseudonymous-address-linking procedure that achieves >99% sensitivity and >99% specificity, we reveal that between launch (1/3/2009), and when the price reached $1 (2/9/2011), most bitcoin was mined by only sixty-four agents. This was due to the rapid emergence of Pareto distributions in bitcoin income, producing such extensive resource centralization that almost all contemporary bitcoin addresses can be connected to these top agents by a chain of six transactions. Centralization created a social dilemma. Attackers could routinely exploit bitcoin via a "51% attack", making it possible for them to repeatedly spend the same bitcoins. Yet doing so would harm the community. Strikingly, we find that potential attackers always chose to cooperate instead. We model this dilemma using an N-player Centipede game in which anonymous players can choose to exploit, and thereby undermine, an appreciating good. Combining theory and economic experiments, we show that, even when individual payoffs are unchanged, cooperation is more frequent when the game is played by an anonymous group. Although bitcoin was designed to rely on a decentralized, trustless network of anonymous agents, its early success rested instead on cooperation among a small group of altruistic founders. © 2022, CC BY.

关键词： Pareto principle

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Compromised nonsense-mediated RNA decay results in truncated RNA-binding protein production upon DUX4 expression

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Cell Reports 2023年第6期42卷 112642页

作者： Campbell, Amy E. Dyle, Michael C. Albanese, Roberto Matheny, Tyler Sudheendran, Kavitha Cortázar, Michael A. Forman, Thomas Fu, Rui Gillen, Austin E. Caruthers, Marvin H. Floor, Stephen N. Calviello, Lorenzo Jagannathan, Sujatha Department of Biochemistry and Molecular Genetics University of Colorado Anschutz Medical Campus Aurora 80045 CO United States Functional Genomics Research Centre Human Technopole Milan 20157 Italy Computational Biology Research Centre Human Technopole Milan 20157 Italy RNA Bioscience Initiative University of Colorado Anschutz Medical Campus Aurora 80045 CO United States Department of Biochemistry University of Colorado Boulder Boulder 80309 CO United States Department of Craniofacial Biology University of Colorado Anschutz Medical Campus Aurora 80045 CO United States Medical Scientist Training Program University of Colorado Anschutz Medical Campus Aurora 80045 CO United States Department of Cell and Tissue Biology University of California San Francisco San Francisco 94143 CA United States Helen Diller Family Comprehensive Cancer Center University of California San Francisco San Francisco 94143 CA United States

Nonsense-mediated RNA decay (NMD) degrades transcripts carrying premature termination codons. NMD is thought to prevent the synthesis of toxic truncated proteins. However, whether loss of NMD results in widespread production of truncated proteins is unclear. A human genetic disease, facioscapulohumeral muscular dystrophy (FSHD), features acute inhibition of NMD upon expression of the disease-causing transcription factor, DUX4. Using a cell-based model of FSHD, we show production of truncated proteins from physiological NMD targets and find that RNA-binding proteins are enriched for aberrant truncations. The NMD isoform of one RNA-binding protein, SRSF3, is translated to produce a stable truncated protein, which is detected in FSHD patient-derived myotubes. Ectopic expression of truncated SRSF3 confers toxicity, and its downregulation is cytoprotective. Our results delineate the genome-scale impact of NMD loss. This widespread production of potentially deleterious truncated proteins has implications for FSHD biology as well as other genetic diseases where NMD is therapeutically modulated. © 2023 The Author(s)

关键词： CP: Molecular biology DUX4 dystrophy FSHD muscular NMD quality control RNA decay splicing translation

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Proliferative and metastatic roles for Phospholipase D in mouse models of cancer

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Advances in Biological Regulation 2018年 67卷 134-140页

作者： Roth, Eric Frohman, Michael A. The Graduate Program in Molecular and Cellular Pharmacology The Medical Scientist Training Program the Department of Pharmacological Sciences Stony Brook University New York 11794 United States

Phospholipase D (PLD) activity has been proposed to facilitate multiple steps in cancer progression including growth, metabolism, angiogenesis, and mobility. The canonical enzymes PLD1 and PLD2 enact their diverse effects through hydrolyzing the membrane lipid phosphatidylcholine to generate the second messenger and signaling lipid phosphatidic acid (PA). However, the widespread expression of PLD1 and PLD2 in normal tissues and the additional distinct enzymatic mechanisms through which PA can be generated have produced uncertainty regarding the optimal settings in which PLD inhibition might ameliorate cancer. Recent studies in mouse model systems have demonstrated that inhibition or elimination of PLD activity reduces tumor growth and metastasis. One mechanism proposed for this outcome involves proliferative signaling mediated by receptor tyrosine kinases (RTK) and G protein-coupled receptors (GPCR), which is attenuated when downstream PLD signal propagation is suppressed. The reduced proliferative signaling has been reported to be compounded by dysfunctional energetic metabolism in the tumor cells under conditions of nutrient deprivation. Moreover, cancer cells lacking PLD activity display inefficiencies across multiple steps of the metastatic cascade, limiting the tumor's lethal spread. Using PLD isoform knockout mice, recent studies have reported on the net effects of inhibition and ablation in multiple cancer models through examining the role of PLD in the non-tumor cells comprising the stroma and microenvironment. The promising results of such in vivo studies, combined with the apparent low toxicity of highly-specific and potent inhibitors, highlights PLD as an attractive target for therapeutic inhibition in cancer. We discuss here the array of anti-tumor effects produced by PLD inhibition and ablation in cancer models with a focus on animal studies. © 2017 Elsevier Ltd

关键词： Angiogenesis Cancer Lipid signaling Metabolism Metastasis Phospholipase D

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Radio-pathomic estimates of cellular growth kinetics predict survival in recurrent glioblastoma

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CNS Oncology 2024年第1期13卷 2415285页

作者： Oshima, Sonoko Yao, Jingwen Bobholz, Samuel Nagaraj, Raksha Raymond, Catalina Teraishi, Ashley Guenther, Anna-Marie Kim, Asher Sanvito, Francesco Cho, Nicholas S C Eldred, Blaine S Connelly, Jennifer M Nghiemphu, Phioanh L Lai, Albert Salamon, Noriko Cloughesy, Timothy F LaViolette, Peter S Ellingson, Benjamin M UCLA Brain Tumor Imaging Laboratory (BTIL) Center for Computer Vision & Imaging Biomarkers University of California Los Angeles Los Angeles 90024 CA United States Department of Radiological Sciences David Geffen School of Medicine University of California Los Angeles Los Angeles 90024 CA United States Department of Bioengineering Henry Samueli School of Engineering & Applied Science University of California Los Angeles Los Angeles 90024 CA United States Department of Radiology Medical College of Wisconsin Milwaukee 53226 WI United States Medical Scientist Training Program David Geffen School of Medicine University of California Los Angeles Los Angeles 90024 CA United States UCLA Neuro-Oncology Program David Geffen School of Medicine University of California Los Angeles Los Angeles 90024 CA United States Department of Neurology Medical College of Wisconsin Milwaukee 53226 WI United States Department of Neurology David Geffen School of Medicine University of California Los Angeles Los Angeles 90024 CA United States Department of Biophysics Medical College of Wisconsin Milwaukee 53226 WI United States Department of Biomedical Engineering Medical College of Wisconsin Milwaukee 53226 WI United States Department of Psychiatry & Biobehavioral Sciences David Geffen School of Medicine University of California Los Angeles Los Angeles 90024 CA United States Department of Neurosurgery David Geffen School of Medicine University of California Los Angeles Los Angeles 90024 CA United States

Aim: A radio-pathomic machine learning (ML) model has been developed to estimate tumor cell density, cytoplasm density (Cyt) and extracellular fluid density (ECF) from multimodal MR images and autopsy pathology. In this multicenter study, we implemented this model to test its ability to predict survival in patients with recurrent glioblastoma (rGBM) treated with chemotherapy. Methods: Pre- and post-contrast T₁-weighted, FLAIR and ADC images were used to generate radio-pathomic maps for 51 patients with longitudinal pre- and post-treatment scans. Univariate and multivariate Cox regression analyses were used to test the influence of contrast-enhancing tumor volume, total cellularity, mean Cyt and mean ECF at baseline, immediately post-treatment and the pre- and post-treatment rate of change in volume and cellularity on overall survival (OS). Results: Smaller Cyt and larger ECF after treatment were significant predictors of OS, independent of tumor volume and other clinical prognostic factors (HR = 3.23 × 10^-6, p < 0.001 and HR = 2.39 × 10⁵, p < 0.001, respectively). Both post-treatment volumetric growth rate and the rate of change in cellularity were significantly correlated with OS (HR = 1.17, p = 0.003 and HR = 1.14, p = 0.01, respectively). Conclusion: Changes in histological characteristics estimated from a radio-pathomic ML model are a promising tool for evaluating treatment response and predicting outcome in rGBM. © 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

关键词： MRI rad-path radiopathomic mapping recurrent glioblastoma survival tumor growth rate

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A Graduate-Level Interdisciplinary Curriculum in CAR-T Cell Therapy

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Mayo Clinic Proceedings: Innovations, Quality and Outcomes 2020年第2期4卷 203-210页

作者： Sterner, Rosalie M. Hedin, Karen E. Hayden, Richard E. Nowakowski, Grzegorz S. Wyles, Saranya P. Greenberg-Worisek, Alexandra J. Terzic, Andre Kenderian, Saad S. Mayo Clinic Medical Scientist Training Program Mayo Clinic College of Medicine and Science Rochester MN United States Department of Immunology Mayo Clinic Rochester MN United States Otorhinolaryngology Mayo Clinic Scottsdale AZ United States Division of Hematology Department of Medicine Mayo Clinic Rochester MN United States Department of Dermatology Mayo Clinic Rochester MN United States Center for Regenerative Medicine Mayo Clinic Rochester MN United States Department of Cardiology Mayo Clinic Rochester MN United States

Objective: To evaluate the impact of a novel interdisciplinary graduate-level course in chimeric antigenic receptor-T cell therapy on students’ knowledge and interests in translational science. Materials/Participants and Methods: The course ran November 12 to 16, 2018. Students were surveyed before and after the course. The survey included questions regarding background, self-perceived knowledge/confidence in skills, and interests/predicted behaviors. Students were assigned to work in collaborative interdisciplinary teams to develop a research proposal. Results: A total of 25 students taking the course for graduate-level credit were surveyed. Of these, all 25 (100%) completed the surveys. Students came from variable backgrounds and were at different stages of graduate training. After completion of the course, there was a statistically significant increase in self-perceived knowledge of immunotherapy (mean score of 3.6 postcourse vs 2.6 precourse, on a 5-point Likert scale;P<.001), knowledge of the bench to clinic translational process (3.7 postcourse vs 3.0 precourse;P<.001), confidence in critical reading skills (4.3 postcourse vs 4.0 precourse;P=.008), confidence in immunotherapy-focused grant writing skills (3.6 postcourse vs 2.8 precourse;P<.001), and interest in working in interdisciplinary teams (4.8 postcourse vs 4.6 precourse;P=.02). Conclusion: The structure of this innovative and comprehensive course serves as a platform for educational courses in interdisciplinary translational research and helps trainees build knowledge and interest in the fields of chimeric antigenic receptor-T cells, regenerative sciences, and immunotherapy. © 2019 Mayo Foundation for medical Education and Research

关键词： CAR-T cell, chimeric antigenic receptor-T cell CME, continuing medical education FDA, US Food and Drug Administration GMP, good manufacturing practice MCGSBS, Mayo Clinic Graduate School of Biomedical Sciences S, satisfactory

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STING deletion protects against amyloid β-induced Alzheimer's disease pathogenesis

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Alzheimer's & dementia : the journal of the Alzheimer's Association 2025年第5期21卷 e70305页

作者： Jessica M Thanos Olivia C Campbell Maureen N Cowan Katherine R Bruch Katelyn A Moore Hannah E Ennerfelt Nick R Natale Aman Mangalmurti Nagaraj Kerur John R Lukens Department of Neuroscience Center for Brain Immunology and Glia (BIG) University of Virginia Charlottesville Virginia USA. Neuroscience Graduate Program University of Virginia Charlottesville Virginia USA. Brain Immunology and Glia Graduate Training Program University of Virginia Charlottesville Virginia USA. Department of Neurology Massachusetts General Hospital Boston Massachusetts USA. Department of Neurology and Neurological Sciences Stanford University Palo Alto California USA. Department of Ophthalmology and Visual Sciences the Ohio State University Wexner Medical Center Columbus Ohio USA. Ohio State Havener Eye Institute the Ohio State University Wexner Medical Center Columbus Ohio USA. Department of Microbial Infection and Immunity the Ohio State University Wexner Medical Center Columbus Ohio USA.

INTRODUCTION:While immune dysfunction has been increasingly linked to Alzheimer's disease (AD) progression, many major innate immune signaling molecules have yet to be explored in AD pathogenesis using genetic targeting approaches. METHODS:To investigate a role for the key innate immune adaptor molecule, stimulator of interferon genes (STING), in AD, we deleted Sting1 in the 5xFAD mouse model of AD-related amyloidosis and evaluated the effects on pathology, neuroinflammation, gene expression, and cognition. RESULTS:Genetic ablation of STING in 5xFAD mice led to improved control of amyloid beta (Aβ) plaques, alterations in microglial activation status, decreased levels of neuritic dystrophy, and protection against cognitive decline. Moreover, rescue of neurological disease in STING-deficient 5xFAD mice was characterized by reduced expression of type I interferon signaling genes in both microglia and excitatory neurons. DISCUSSION:These findings reveal critical roles for STING in Aβ-driven neurological disease and suggest that STING-targeting therapeutics may offer promising strategies to treat AD. HIGHLIGHTS:Stimulator of interferon genes (STING) deficiency in the 5xFAD mouse model of Alzheimer's disease-related amyloidosis results in decreased amyloid beta (Aβ) deposition and altered microglial activation status. Protection against amyloidosis in STING-deficient 5xFAD mice is associated with decreased expression of genes involved in type I IFN signaling, improved neuronal health, and reduced levels of oxidative stress. Loss of STING in 5xFAD mice leads to improved spatial learning and memory.

关键词： Alzheimer's disease STING amyloid beta amyloidosis innate immunity microglia neurodegenerative disease neuroimmunology

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Development of a Dual-Antigen Targeting CAR-T Therapy Directed Against CD70 and Active Integrin β2 for Acute Myeloid Leukemia

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Blood 2024年 144卷 2037-2037页

作者： Amrik S Kang Haley Johnson Nabeel Razi Nicole Lei Aaron C. Logan Benjamin J Huang Arun P Wiita Department of Laboratory Medicine University of California San Francisco San Francisco CA Medical Scientist Training Program University of California San Francisco San Francisco CA Department of Laboratory Medicine University of California San Francisco San Francisco CA Department of Medicine Division of Hematology and Oncology University of California San Francisco San Francisco CA Department of Pediatrics University of California San Francisco San Francisco CA

Introduction: Acute myeloid leukemia (AML) remains a devastating disease with a great need for new therapies. While CAR-T therapy has achieved remarkable success in B-cell leukemias, lymphomas, and multiple myeloma, successful cellular therapy for AML remains elusive. A major contributing factor is thought to be antigen expression heterogeneity in AML, preventing complete tumor clearance with single antigen-targeting. Additionally, most leading AML targets (e.g. CD33, CD123) are also expressed on normal hematopoietic stem and progenitor cells (HSPCs), resulting in a limited therapeutic window and clinically deleterious hematologic toxicity. Our group previously identified the active conformation of integrin β2 (aITGB2) as an AML-specific target and generated a CAR-T therapy that eliminated AML tumors while sparing normal HSPCs (Mandal et al., Nat Cancer 2023). More recently, our group developed a potent natural ligand-based CAR-T therapy targeting CD70 (Kasap et al., ASH 2023), another antigen expressed on many AML cells but absent on normal HSPCs. Both aITGB2 and CD70 have heterogeneous expression on AML blasts, however, preventing complete tumor clearance. Here, we combine the potent efficacy and low toxicity of these two single-antigen CAR-Ts into a dual-antigen targeting approach capable of eliminating a larger proportion of AML cells, thereby driving deeper remissions while achieving an acceptable therapeutic index. Methods: Primary AML patient samples were co-cultured with the HS-5 stromal cell line in RPMI media with 20% FBS and 25 ng/ml IL-3, SCF, and FLT3L. Primary AML cells were assessed for expression of CD70 and aITGB2 by flow cytometry. CAR constructs were lentivirally transduced into CD3-selected T-cells. For In vitro cytotoxicity assays, luciferase-expressing target cells were co-cultured with CAR-Ts for 24 hours, with leukemia cell killing measured by endpoint luminescence. Results: To first verify the AML-specificity of CD70, we analyzed the TARGET

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Learning deep attribution priors based on prior knowledge

arXiv

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arXiv 2019年

作者： Weinberger, Ethan Janizek, Joseph Lee, Su-In Paul G. Allen School of Computer Science and Engineering University of Washington Medical Scientist Training Program University of Washington

Feature attribution methods are an essential tool for understanding the behavior of complex deep learning models. However, ensuring that models produce meaningful explanations, rather than ones that rely on noise, is not straightforward. Exacerbating this problem is the fact that attribution methods do not provide insight as to why features are assigned their attribution values, leading to explanations that are difficult to interpret. In real-world problems we often have sets of additional information for each feature that are predictive of that feature's importance to the task at hand. Here we propose the deep attribution prior (DAPr) framework to exploit such information to overcome the limitations of attribution methods. Our framework jointly learns a relationship between prior information and feature importance, as well as biases models to have explanations that rely on features predicted to be important. We find that our framework both results in networks that generalize better to out of sample data and admits new methods for interpreting model explanations. Copyright © 2019, The Authors. All rights reserved.

关键词： Deep learning

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A Kinetic Scout Approach Accelerates Targeted Protein Degrader Development

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Angewandte Chemie 2024年第5期137卷

作者： Angela T. Fan Gillian E. Gadbois Hai-Tsang Huang Charu Chaudhry Jiewei Jiang Logan H. Sigua Emily R. Smith Sitong Wu Grace J. Poirier Kara Dunne-Dombrink Pavitra Goyal Andrew J. Tao William R. Sellers Eric S. Fischer Katherine A. Donovan Fleur M. Ferguson Department of Chemistry and Biochemistry University of California San Diego The Broad Institute of Harvard and MIT Department of Medical Oncology Dana-Farber Cancer Institute Harvard Medical School Boston Discovery Technologies Molecular Pharmacology J&J Innovative Medicine Spring House Pennsylvania 19477 United States Medical Scientist Training Program University of California San Diego Department of Cancer Biology Dana-Farber Cancer Institute Boston Department of Biological Chemistry and Molecular Pharmacology Harvard Medical School Boston Skaggs School of Pharmacy and Pharmaceutical Sciences University of California San Diego

Bifunctional molecules such as targeted protein degraders induce proximity to promote gain-of-function pharmacology. These powerful approaches have gained broad traction across academia and the pharmaceutical industry, leading to an intensive focus on strategies that can accelerate their identification and optimization. We and others have previously used chemical proteomics to map degradable target space, and these datasets have been used to develop and train multiparameter models to extend degradability predictions across the proteome. In this study, we now turn our attention to develop generalizable chemistry strategies to accelerate the development of new bifunctional degraders. We implement lysine-targeted reversible-covalent chemistry to rationally tune the binding kinetics at the protein-of-interest across a set of 25 targets. We define an unbiased workflow consisting of global proteomics analysis, IP/MS of ternary complexes and the E-STUB assay, to mechanistically characterize the effects of ligand residence time on targeted protein degradation and formulate hypotheses about the rate-limiting step of degradation for each target. Our key finding is that target residence time is a major determinant of degrader activity, and this can be rapidly and rationally tuned through the synthesis of a minimal number of analogues to accelerate early degrader discovery and optimization.

关键词： Targeted protein degradation PROTACs compound residence time proteomics proteasomal degradation

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