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Obesity alters pathology and treatment response in inflammatory disease

四川生理科学杂志 2022年第3期44卷 446-446页

作者： Sagar P Bapat NOMIS Center for Immunobiology and Microbial Pathogenesis The Salk Institute for Biological Studies La Jolla CA USA Gene Expression Laboratory The Salk Institute for Biological Studies La Jolla CA USA Medical Scientist Training Program University of California San Diego La Jolla CA USA Department of Laboratory Medicine University of California San Francisco San Francisco CA USA Department of Microbiology and Immunology University of California San Francisco San Francisco CA USA Diabetes Center University of California San Francisco San Francisco CA USA Medical Scientist Training Program University of California San Francisco CA USA Division of Pulmonary Critical Care Allergy and Sleep Department of Medicine University of California San Francisco San Francisco CA USA School of Pharmaceutical Sciences Xiamen University Xiamen China Department of Dermatology University of California San Diego La Jolla CA USA Department of Surgery University of California San Francisco San Francisco CA USA Department of Medicine University of California San Francisco San Francisco CA USA Sandler Asthma Basic Research Center University of California San Francisco San Francisco CA USA School of Medicine Wake Forest University Winston–Salem NC USA Department of Dermatology Icahn School of Medicine at Mount Sinai New York NY USA Lung Biology Center Department of Medicine University of California San Francisco San Francisco CA USA Department of Biomedical Science Graduate School Kyungpook National University Kyungpook National University Hospital Daegu South Korea Department of Dermatology University of California San Francisco San Francisco CA USA Department of Pathology University of California San Francisco San Francisco CA USA Department of Internal Medicine Division of Pulmonary Critical Care and Sleep Medicine University of Kentucky Lexington KY USA Pulmonary Critical Care Section Department of Medicine Veterans Affairs San Diego Hea

Decades of work have elucidated cytokine signalling and transcriptional pathways that control T cell differentiation and have led the way to targeted biologic therapies that are effective in a range of autoimmune,allergic and inflammatory *** evidence indicates that obesity and metabolic disease can also influence the immune system1-7,although the mechanisms and effects on immunotherapy outcomes remain largely ***,using two models of atopic dermatitis,we show that lean and obese mice mount markedly different immune *** converted the classical type 2 T helper(TH2)-predominant disease associated with atopic dermatitis to a more severe disease with prominent TH17 *** also observed divergent responses to biologic therapies targeting TH2 cytokines,which robustly protected lean mice but exacerbated disease in obese ***-cell RNA sequencing coupled with genome-wide binding analyses revealed decreased activity of nuclear receptor peroxisome proliferator-activated receptor-γ(PPARγ)in TH2 cells from obese mice relative to lean mice.

关键词： dermatitis inflammatory allergic

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Modeling and mechanical perturbations reveal how spatially regulated anchorage gives rise to spatially distinct mechanics across the mammalian spindle

arXiv

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arXiv 2022年

作者： Suresh, Pooja Galstyan, Vahe Phillips, Rob Dumont, Sophie Biophysics Graduate Program UCSF San FranciscoCA94158 United States Department of Bioengineering and Therapeutic Sciences UCSF San FranciscoCA94158 United States Yerevan0036 Armenia Biochemistry and Molecular Biophysics Option California Institute of Technology PasadenaCA91125 United States Division of Biology and Biological Engineering California Institute of Technology PasadenaCA91125 United States Department of Physics California Institute of Technology PasadenaCA91125 United States Chan Zuckerberg Biohub San FranciscoCA94158 United States Department of Biochemistry and Biophysics UCSF San FranciscoCA94158 United States

During cell division, the spindle generates force to move chromosomes. In mammals, microtubule bundles called kinetochore-fibers (k-fibers) attach to and segregate chromosomes. To do so, k-fibers must be robustly anchored to the dynamic spindle. We previously developed microneedle manipulation to mechanically challenge k-fiber anchorage, and observed spatially distinct response features revealing the presence of heterogeneous anchorage (Suresh et al. 2020). How anchorage is precisely spatially regulated, and what forces are necessary and sufficient to recapitulate the k-fiber’s response to force remain unclear. Here, we develop a coarse-grained k-fiber model and combine with manipulation experiments to infer underlying anchorage using shape analysis. By systematically testing different anchorage schemes, we find that forces solely at k-fiber ends are sufficient to recapitulate unmanipulated k-fiber shapes, but not manipulated ones for which lateral anchorage over a 3 μm length scale near chromosomes is also essential. Such anchorage robustly preserves k-fiber orientation near chromosomes while allowing pivoting around poles. Anchorage over a shorter length scale cannot robustly restrict pivoting near chromosomes, while anchorage throughout the spindle obstructs pivoting at poles. Together, this work reveals how spatially regulated anchorage gives rise to spatially distinct mechanics in the mammalian spindle, which we propose are key for function. © 2022, CC BY.

关键词： Cell proliferation

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Contributors to the Lab on a Chip cell and tissue engineering in microsystems special issue

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Lab on a Chip 2007年第6期7卷 667-671页

作者： Bhatia, sangeeta N. Chen, Christoper Bashir, Rashid Beebe, David J. Desai, Tejal Gottwald, Eric Khademhosseini, Ali Langer, Robert S. Piel, Matthieu Takayama, Shuichi Thorsen, Todd Tien, Joe Voldman, Joel Vunjak-Novakovic, Gordana Wu, Mingming Yu, Hanry Massachusetts Institute of Technology Harvard-MIT Division of Health Sciences and Technology Department of Electrical Engineering and Computer Science United States Laboratory for Multiscale Regenerative Technologies United States Department of Innovation University of Pennsylvania Department of Bioengineering United States Cell Biology and Physiology Program Cell Growth and Cancer Program Tissue Microfabrication Laboratory Department of Electrical and Computer Engineering and Biomedical Engineering Purdue University United States Department of Electronics University of Glasgow United Kingdom Department of Physiology and Bioengineering University of California San Francisco CA United States California Institute for Quantitative Biomedical Research UCSF/UC Berkeley Graduate Group in Bioengineering United States Laboratory of Therapeutic Micro and Nanotechnology Institute for Biological Interfaces Germany 3D-Cell Culture Techniques Group Institute for Biological Interfaces Germany Department of Medicine and Health Sciences and Technology Massachusetts Institute of Technology (MIT) United States Institut Curie UMR 144 IC/CNRS France Biomedical Engineering Department University of Michigan United States Department of Biomedical Engineering Macromolecular Science and Engineering Program United States Sibley School of Mechanical and Aerospace Engineering School of Chemical and Molecular Engineering Cornell University United States National University of Singapore Singapore Institute of Bioengineering and Nanotechnology A STAR Singapore

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Concentric Micromirror Array for High-Speed Optical Dynamic Focusing

Concentric Micromirror Array for High-Speed Optical Dynamic ...

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IEEE/LEOS International Conference on Optical MEMS

作者： Nathan Tessema Ersumo Cem Yalcin Nicolas Pégard Laura Waller Daniel Lopez Rikky Muller San Francisco Graduate Program in Bioengineering University of California Berkeley - University of California USA Departement of Electrical Engineering & Computer Sciences University of California Berkeley USA Department of Applied Physical Sciences University of North Carolina at Chapel Hill Chapel Hill USA Center for Nanoscale Materials Argonne National Laboratory Argonne USA

Optical dynamic focusing has emerged as a speed, complexity and efficiency bottleneck across various applications, which include scanning multi-photon microscopy in biology, maskless lithography and micromachining in material processing, and wavefront correction. Here, we present a 32-ring 23,852-pixel concentric micromirror array capable of performing dynamic focusing for wavelengths of up to 1040 nm with a response rate of up to 8.75 kHz, 30 V drive and a focusing full-width-half-maximum to range ratio of 4.8%.

关键词： Optimized production technology High-speed optical techniques Micromechanical devices Nanophotonics Micromirrors Focusing

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Recovery of the Gut Microbiota after Antibiotics Depends on Host Diet and Environmental Reservoirs

SSRN

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SSRN 2019年

作者： Ng, Katharine M. Aranda-Diaz, Andrés Tropini, Carolina Frankel, Matthew Ryan van Treuren, William W. O’Laughlin, Colleen Merrill, Bryan D. Yu, Feiqiao Brian Pruss, Kali M. Oliveira, Rita Almeida Higginbottom, Steven K. Neff, Norma Fischbach, Michael Xavier, Karina B. Sonnenburg, Justin L. Huang, Kerwyn Casey Department of Bioengineering Stanford University School of Medicine StanfordCA94305 United States Department of Microbiology & Immunology Stanford University School of Medicine StanfordCA94305 United States Chan Zuckerberg Biohub San FranciscoCA94158 United States Instituto Gulbenkian de Ciência Oeiras Portugal Biophysics Graduate Program

That antibiotics alter microbiota composition and increase infection susceptibility is well known, but their generalizable effects on the gut commensal community and dependence on environmental variables remain open questions. Here, we systematically compared antibiotic responses in gnotobiotic and conventional mice across antibiotics, microbiotas, diets, and housing status. We identify remarkable resilience, whereby a humanized microbiota recovers before drug administration ends, with transient oligodominance and taxa-asymmetric reduction in diversity. In general, in vitro sensitivities were not predictive of in vivo responses, underscoring the significance of community context. A fiber-deficient diet exacerbated collapse of the microbiota. We also observed response reprogramming, in which species replacement after ciprofloxacin treatment established resilience to a second treatment, as did transmission through cross-housing. Single-housing drastically disrupted recovery, highlighting the importance of sanitation and environmental reservoirs. Our findings highlight the ability of the commensal microbiota to deterministically adapt to large perturbations, and the translational potential for modulating diet, sanitation, and microbiota composition during antibiotics. © 2019, The Authors. All rights reserved.

关键词： Antibiotics

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Correction to: Toward Automatic Detection of Radiation-Induced Cerebral Microbleeds Using a 3D Deep Residual Network

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Journal of digital imaging 2019年第5期32卷 898页

作者： Yicheng Chen Javier E Villanueva-Meyer Melanie A Morrison Janine M Lupo UCSF-UC Berkeley Graduate Program in Bioengineering San Francisco USA. Department of Radiology and Biomedical Imaging University of California San Francisco San Francisco USA. UCSF-UC Berkeley Graduate Program in Bioengineering San Francisco USA. Janine.Lupo@ucsf.edu. Department of Radiology and Biomedical Imaging University of California San Francisco San Francisco USA. Janine.Lupo@ucsf.edu.

This paper was published inadvertently as open access. It has been corrected online.

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SARS-CoV-2 identified through crystallographic screening and computational docking

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Science Advances 2021年第16期7卷

作者： Schuller, Marion Correy, Galen J. Gahbauer, Stefan Fearon, Daren Wu, Taiasean Díaz, Roberto Efraín Young, Iris D. Martins, Luan Carvalho Smith, Dominique H. Schulze-Gahmen, Ursula Owens, Tristan W. Deshpande, Ishan Merz, Gregory E. Thwin, Aye C. Biel, Justin T. Peters, Jessica K. Moritz, Michelle Herrera, Nadia Kratochvil, Huong T. Aimon, Anthony Bennett, James M. Neto, Jose Brandao Cohen, Aina E. Dias, Alexandre Douangamath, Alice Dunnett, Louise Fedorov, Oleg Ferla, Matteo P. Fuchs, Martin R. Gorrie-Stone, Tyler J. Holton, James M. Johnson, Michael G. Krojer, Tobias Meigs, George Powell, Ailsa J. Rack, Johannes Gregor Matthias Rangel, Victor L. Russi, Silvia Skyner, Rachael E. Smith, Clyde A. Soares, Alexei S. Wierman, Jennifer L. Zhu, Kang O Brien, Peter Jura, Natalia Ashworth, Alan Irwin, John J. Thompson, Michael C. Gestwicki, Jason E. Von Delft, Frank Shoichet, Brian K. Fraser, James S. Ahel, Ivan Sir William Dunn School of Pathology University of Oxford South Parks Road OxfordOX1 3RE United Kingdom Department of Bioengineering and Therapeutic Sciences University of California San Francisco San FranciscoCA94158 United States Department of Pharmaceutical Chemistry University of California San Francisco San FranciscoCA94158 United States Diamond Light Source Ltd. Harwell Science and Innovation Campus DidcotOX11 0DE United Kingdom Institute for Neurodegenerative Disease University of California San Francisco San FranciscoCA94158 United States Chemistry and Chemical Biology Graduate Program University of California San Francisco San FranciscoCA94158 United States Tetrad Graduate Program University of California San Francisco San FranciscoCA94158 United States Coronavirus Research Group Structural Biology Consortium University of California San Francisco San FranciscoCA94158 United States Biochemistry Department Institute for Biological Sciences Federal University of Minas Gerais Belo Horizonte Brazil Helen Diller Family Comprehensive Cancer University of California San Francisco San FranciscoCA94158 United States Centre for Medicines Discovery University of Oxford South Parks Road HeadingtonOX3 7DQ United Kingdom Stanford Synchrotron Radiation Lightsource Slac National Accelerator Center Menlo ParkCA94025 United States Wellcome Centre for Human Genetics University of Oxford Old Road Campus OxfordOX3 7BN United Kingdom National Synchrotron Light Source Ii Brookhaven National Laboratory UptonNY11973 United States Department of Biochemistry and Biophysics University of California San Francisco San FranciscoCA94158 United States Department of Molecular Biophysics and Integrated Bioimaging Lawrence Berkeley National Laboratory BerkeleyCA94720 United States ChemPartner Corporation South San FranciscoCA94080 United States Structural Genomics Consortium University of Oxford Old Road Campus HeadingtonOX3 7DQ United Kingdom School of

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) macrodomain within the nonstructural protein 3 counteracts host-mediated antiviral adenosine diphosphate ribosylation signaling. This enzyme is a promising antiviral target because catalytic mutations render viruses nonpathogenic. Here, we report a massive crystallographic screening and computational docking effort, identifying new chemical matter primarily targeting the active site of the macrodomain. Crystallographic screening of 2533 diverse fragments resulted in 214 unique macrodomain-binders. An additional 60 molecules were selected from docking more than 20 million fragments, of which 20 were crystallographically confirmed. X-ray data collection to ultra-high resolution and at physiological temperature enabled assessment of the conformational heterogeneity around the active site. Several fragment hits were confirmed by solution binding using three biophysical techniques (differential scanning fluorimetry, homogeneous time-resolved fluorescence, and isothermal titration calorimetry). The 234 fragment structures explore a wide range of chemotypes and provide starting points for development of potent SARS-CoV-2 macrodomain inhibitors. © 2021 American Association for the Advancement of Science. All rights reserved.

关键词： Coronavirus

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StimDust: A 1.7 mm3, implantable wireless precision neural stimulator with ultrasonic power and communication

arXiv

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arXiv 2018年

作者： Piech, David K. Johnson, Benjamin C. Shen, Konlin Meraj Ghanbari, M. Li, Ka Yiu Neely, Ryan M. Kay, Joshua E. Carmena, Jose M. Maharbiz, Michel M. Muller, Rikky San Francisco Graduate Program in Bioengineering University of California Berkeley BerkeleyCA94720 United States Department of Electrical Engineering and Computer Sciences University of California Berkeley BerkeleyCA94720 United States Department of Electrical Engineering and Computer Engineering Boise State University BoiseID83725 United States Helen Wills Neuroscience Institute University of California Berkeley BerkeleyCA94720 United States Chan-Zuckerberg Biohub San FranciscoCA94158 United States

Neural stimulation is a powerful technique for modulating physiological functions and for writing information into the nervous system as part of brain-machine interfaces. Current clinically approved neural stimulators require batteries and are many cubic centimeters in size- typically much larger than their intended targets. We present a complete wireless neural stimulation system consisting of a 1.7 mm3 wireless, batteryless, leadless implantable stimulator (the "mote"), an ultrasonic wireless link for power and bi-directional communication, and a hand-held external transceiver. The mote consists of a piezoceramic transducer, an energy storage capacitor, and a stimulator integrated circuit (IC). The IC harvests ultrasonic power with high efficiency, decodes stimulation parameter downlink data, and generates current-controlled stimulation pulses. Stimulation parameters are time-encoded on the fly through the wireless link rather than being programmed and stored on the mote, enabling complex stimulation protocols with high-temporal resolution and closed-loop capability while reducing power consumption and on-chip memory requirements. Uplink data indicates whether the mote is currently stimulating;it is encoded by the mote via backscatter modulation and is demodulated at the external transceiver. We show that the system operates at an acoustic power one fifth the FDA limit for diagnostic ultrasound and is robust to expected real-world acoustic link misalignment. We investigate the performance of the system with motes acutely implanted with a cuff on the sciatic nerve of anesthetized rats and show highly repeatable stimulation across a wide range of physiological responses. Copyright © 2018, The Authors. All rights reserved.

关键词： Electrophysiology

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A micromirror array with annular partitioning for high-speed random-access axial focusing

arXiv

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arXiv 2020年

作者： Ersumo, Nathan Tessema Yalcin, Cem Antipa, Nick Pégard, Nicolas Waller, Laura Lopez, Daniel Muller, Rikky University of California Berkeley - University of California San Francisco Graduate Program in Bioengineering United States Departement of Electrical Engineering & Computer Sciences University of California BerkeleyCA94720 United States Department of Applied Physical Sciences University of North Carolina at Chapel Hill Chapel HillNC27514 United States Chan Zuckerberg Biohub San FranciscoCA94158 United States Physical Measurement Laboratory National Institute of Standards and Technology GaithersburgMD20899 United States

Dynamic axial focusing functionality has recently seen widespread incorporation in microscopy, augmented/virtual reality (AR/VR), adaptive optics, and material processing. Yet the limitations of existing varifocal tools continue to beset the performance capabilities and operating overhead of the optical systems that mobilize such functionality. The varifocal tools that are the least burdensome to drive (ex: liquid crystal, elastomeric or optofluidic lenses) suffer from low (~100 Hz) refresh rates. Conversely, the fastest devices sacrifice either critical capabilities such as dwelling capacity (ex: acoustic gradient lenses or monolithic micromechanical mirrors) or low operating overhead (ex: deformable mirror arrays). Here, we present a general-purpose random-access axial focusing device that bridges these previously conflicting features of high speed, dwelling capacity and lightweight drive by employing low-rigidity micromirrors that exploit the robustness of defocusing phase profiles. Geometrically, the device consists of an 8.2 mm diameter array of piston-motion, 48 μm-pitch micromirror pixels that provide 2π phase shifting for wavelengths shorter than 1 100 nm with 10-90% settling in 64.8 μs (i.e. 15.44 kHz refresh rate). The pixels are electrically partitioned into 32 rings for a driving scheme that enables phase-wrapped operation with circular symmetry and requires less than 30 V/channel. Optical experiments demonstrated the array’s wide focusing range with a measured ability to target 29 distinct, resolvable depth planes. Overall, the features of the proposed array offer the potential for compact, straightforward methods of tackling bottlenecked applications including high-throughput single-cell targeting in neurobiology and the delivery of dense 3D visual information in AR/VR. Copyright © 2020, The Authors. All rights reserved.

关键词： Pixels

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Imaging neurotransmitter transport in live cells with stimulated Raman scattering microscopy

arXiv

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arXiv 2022年

作者： Manifold, Bryce Dorlhiac, Gabriel F. Landry, Markita P. Streets, Aaron Department of Bioengineering University of California Berkeley BerkeleyCA94720 United States Biophysics Graduate Group University of California Berkeley BerkeleyCA94720 United States Department of Chemical and Biomolecular Engineering University of California Berkeley BerkeleyCA94720 United States Innovative Genomics Institute University of California Berkeley BerkeleyCA94720 United States California Institute for Quantitative Biosciences QB3 University of California Berkeley BerkeleyCA94720 United States Chan-Zuckerberg Biohub San FranciscoCA94158 United States UC Berkeley-UC San Francisco Graduate Program in Bioengineering University of California Berkeley BerkeleyCA94720 United States

Chemical neurotransmission is central to neurotypical brain function but also implicated in a variety of psychiatric and neurodegenerative diseases. The release dynamics of neurotransmitters is correlated with but distinct from neuronal electrical signal propagation. It is therefore necessary to track neurotransmitter modulation separately from neuron electrical activity. Here, we present a new approach for imaging deuterated neurotransmitter molecules in the cell-silent window with stimulated Raman scattering (SRS) microscopy. Using SRS microscopy, we perform direct imaging of deuterated dopamine and GABA in PC12 chromaffin cells, and in primary hippocampal neurons, respectively, based on the carbon-deuterium vibrational frequencies. We demonstrate that SRS imaging of these isotopologues directly visualizes intracellular neurotransmitters without changing the neurotransmitters’ chemical identity, and requiring custom synthesis or genetic encoding protocols. We further show that stimulation of neurotransmitter release results in an overall 20-50% intracellular neurotransmitter signal reduction in agreement with comparable neurotransmission dynamics studies, with the ability to observe inter- and intracellular variation in vesicular neurotransmitter release. Taken together, our data suggest that neurotransmitter isotopologues can serve as a commercially-available, biocompatible, and generalizable method to image neurotransmitters with deuterated molecules that are virtually chemically identical to their native counterparts. © 2022, CC BY.

关键词： Stimulated Raman scattering

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