Recursos de colección

Caltech Authors (147.820 recursos)

Repository of works by Caltech published authors.

Group = Heritage Medical Research Institute

Mostrando recursos 1 - 20 de 28

  1. Histone-Binding of DPF2 Mediates Its Repressive Role in Myeloid Differentiation

    Huber, Ferdinand M.; Greenblatt, Sarah M.; Davenport, Andrew M.; Martinez, Concepcion; Xu, Ye; Vu, Ly P.; Nimer, Stephen D.; Hoelz, André
    Double plant homeodomain finger 2 (DPF2) is a highly evolutionarily conserved member of the d4 protein family that is ubiquitously expressed in human tissues and was recently shown to inhibit the myeloid differentiation of hematopoietic stem/progenitor and acute myelogenous leukemia cells. Here, we present the crystal structure of the tandem plant homeodomain finger domain of human DPF2 at 1.6-Å resolution. We show that DPF2 interacts with the acetylated tails of both histones 3 and 4 via bipartite binding pockets on the DPF2 surface. Blocking these interactions through targeted mutagenesis of DPF2 abolishes its recruitment to target chromatin regions as well...

  2. Global Representations of Goal-Directed Behavior in Distinct Cell Types of Mouse Neocortex

    Allen, William E.; Kauvar, Isaac V.; Chen, Michael Z.; Richman, Ethan B.; Yang, Samuel J.; Chan, Ken; Gradinaru, Viviana; Deverman, Benjamin E.; Luo, Liqun; Deisseroth, Karl
    The successful planning and execution of adaptive behaviors in mammals may require long-range coordination of neural networks throughout cerebral cortex. The neuronal implementation of signals that could orchestrate cortex-wide activity remains unclear. Here, we develop and apply methods for cortex-wide Ca^(2+) imaging in mice performing decision-making behavior and identify a global cortical representation of task engagement encoded in the activity dynamics of both single cells and superficial neuropil distributed across the majority of dorsal cortex. The activity of multiple molecularly defined cell types was found to reflect this representation with type-specific dynamics. Focal optogenetic inhibition tiled across cortex revealed a...

  3. Bone CLARITY: Clearing, imaging, and computational analysis of osteoprogenitors within intact bone marrow

    Greenbaum, Alon; Chan, Ken Y.; Dobreva, Tatyana; Brown, David; Balani, Deepak H.; Boyce, Rogely; Kronenberg, Henry M.; McBride, Helen J.; Gradinaru, Viviana
    Bone tissue harbors unique and essential physiological processes, such as hematopoiesis, bone growth, and bone remodeling. To enable visualization of these processes at the cellular level in an intact environment, we developed “Bone CLARITY,” a bone tissue clearing method. We used Bone CLARITY and a custom-built light-sheet fluorescence microscope to detect the endogenous fluorescence of Sox9-tdTomato+ osteoprogenitor cells in the tibia, femur, and vertebral column of adult transgenic mice. To obtain a complete distribution map of these osteoprogenitor cells, we developed a computational pipeline that semiautomatically detects individual Sox9-tdTomato+ cells in their native three-dimensional environment. Our computational method counted all...

  4. Nickel-Catalyzed Asymmetric Reductive Cross-Coupling To Access 1,1-Diarylalkanes

    Poremba, Kelsey E.; Kadunce, Nathaniel T.; Suzuki, Naoyuki; Cherney, Alan H.; Reisman, Sarah E.
    An asymmetric Ni-catalyzed reductive cross-coupling of (hetero)aryl iodides and benzylic chlorides has been developed to prepare enantioenriched 1,1-diarylalkanes. As part of these studies, a new chiral bioxazoline ligand, 4-heptyl-BiOX (L1), was developed in order to obtain products in synthetically useful yield and enantioselectivity. The reaction tolerates a variety of heterocyclic coupling partners, including pyridines, pyrimidines, indoles, and piperidines.

  5. Enantioselective Synthesis of (−)-Acetylapoaranotin

    Wang, Haoxuan; Regan, Clinton J.; Codelli, Julian A.; Romanato, Paola; Puchlopek-Dermenci, Angela L. A.; Reisman, Sarah E.
    The first enantioselective total synthesis of the epipolythiodiketopiperazine (ETP) natural product (−)-acetylapoaranotin (3) is reported. The concise synthesis was enabled by an eight-step synthesis of a key cyclohexadienol-containing amino ester building block. The absolute stereochemistry of both amino ester building blocks used in the synthesis is set through catalytic asymmetric (1,3)-dipolar cycloaddition reactions. The formal syntheses of (−)-emethallicin E and (−)-haemotocin are also achieved through the preparation of a symmetric cyclohexadienol-containing diketopiperazine.

  6. Chemical Synthesis of (+)-Ryanodine and (+)-20-Deoxyspiganthine

    Xu, Chen; Han, Arthur; Virgil, Scott C.; Reisman, Sarah E.
    (+)-Ryanodine is a natural product modulator of ryanodine receptors, important intracellular calcium ion channels that play a critical role in signal transduction leading to muscle movement and synaptic transmission. Chemical derivatization of (+)-ryanodine has demonstrated that certain peripheral structural modifications can alter its pharmacology, and that the pyrrole-2-carboxylate ester is critical for high affinity binding to ryanodine receptors. However, the structural variation of available ryanodine analogues has been limited by the challenge of site-specific functionalization of semisynthetic intermediates, such as (+)-ryanodol. Here we report a synthetic strategy that provides access to (+)-ryanodine and the related natural product (+)-20-deoxyspiganthine in 18...

  7. Powering portable electronics using vocal fold vibrations

    Cho, Hyunjun; Noh, Kyoohyun; Ishikawa, Tomohiro; Yang, Deajong; Sánchez-Sinencio, Edgar; Choo, Hyuck
    Using a multi-stacked array of vibration-driven energy harvesters and a custom-tailored energy-harvesting (EH) circuit, we have achieved stable 3.12-mW power generation at 5.5 Vdc from the acousto-mechanical vibrations of the human vocal folds at 75 dB and demonstrated its use as a practical on-demand power source for portable and wearable electronics. The voltage and power outputs over 3.7 Vdc and 1 mW necessary for charging lithium polymer (LiPo) batteries were accomplished using a 3D-printed packaging platform whose physical design and mechanical properties maximized the vibration transfer and effectively combined 10 or more individual energy harvesters into a compact unified stack....

  8. Molecular Imaging in Synthetic Biology, and Synthetic Biology in Molecular Imaging

    Gilad, Assaf A.; Shapiro, Mikhail G.
    Biomedical synthetic biology is an emerging field in which cells are engineered at the genetic level to carry out novel functions with relevance to biomedical and industrial applications. This approach promises new treatments, imaging tools, and diagnostics for diseases ranging from gastrointestinal inflammatory syndromes to cancer, diabetes, and neurodegeneration. As these cellular technologies undergo pre-clinical and clinical development, it is becoming essential to monitor their location and function in vivo, necessitating appropriate molecular imaging strategies, and therefore, we have created an interest group within the World Molecular Imaging Society focusing on synthetic biology and reporter gene technologies. Here, we highlight...

  9. Nonlinear ultrasound imaging of nanoscale acoustic biomolecules

    Maresca, David; Lakshmanan, Anupama; Lee-Gosselin, Audrey; Melis, Johan M.; Ni, Yu-Li; Bourdeau, Raymond W.; Kochmann, Dennis M.; Shapiro, Mikhail G.
    Ultrasound imaging is widely used to probe the mechanical structure of tissues and visualize blood flow. However, the ability of ultrasound to observe specific molecular and cellular signals is limited. Recently, a unique class of gas-filled protein nanostructures called gas vesicles (GVs) was introduced as nanoscale (∼250 nm) contrast agents for ultrasound, accompanied by the possibilities of genetic engineering, imaging of targets outside the vasculature and monitoring of cellular signals such as gene expression. These possibilities would be aided by methods to discriminate GV-generated ultrasound signals from anatomical background. Here, we show that the nonlinear response of engineered GVs to acoustic...

  10. Molecular basis for protection of ribosomal protein L4 from cellular degradation

    Huber, Ferdinand M.; Hoelz, André
    Eukaryotic ribosome biogenesis requires the nuclear import of ∼80 nascent ribosomal proteins and the elimination of excess amounts by the cellular degradation machinery. Assembly chaperones recognize nascent unassembled ribosomal proteins and transport them together with karyopherins to their nuclear destination. We report the crystal structure of ribosomal protein L4 (RpL4) bound to its dedicated assembly chaperone of L4 (Acl4), revealing extensive interactions sequestering 70 exposed residues of the extended RpL4 loop. The observed molecular recognition fundamentally differs from canonical promiscuous chaperone–substrate interactions. We demonstrate that the eukaryote-specific RpL4 extension harbours overlapping binding sites for Acl4 and the nuclear transport factor...

  11. Biocompatible Multifunctional Black-Silicon for Implantable Intraocular Sensor

    Lee, Jeong Oen; Narasimhan, Vinayak; Du, Juan; Ndjamen, Blaise; Sretavan, David; Choo, Hyuck
    Multifunctional black-silicon (b-Si) integrated on the surface of an implantable intraocular pressure sensor significantly improves sensor performance and reliability in six-month in vivo studies. The antireflective properties of b-Si triples the signal-to-noise ratio and increases the optical readout distance to a clinically viable 12 cm. Tissue growth and inflammation response on the sensor is suppressed demonstrating desirable anti-biofouling properties.

  12. Biocompatible Multifunctional Black-Silicon for Implantable Intraocular Sensor

    Lee, Jeong Oen; Narasimhan, Vinayak; Du, Juan; Ndjamen, Blaise; Sretavan, David; Choo, Hyuck
    Multifunctional black-silicon (b-Si) integrated on the surface of an implantable intraocular pressure sensor significantly improves sensor performance and reliability in six-month in vivo studies. The antireflective properties of b-Si triples the signal-to-noise ratio and increases the optical readout distance to a clinically viable 12 cm. Tissue growth and inflammation response on the sensor is suppressed demonstrating desirable anti-biofouling properties.

  13. Non-invasive imaging using reporter genes altering cellular water permeability

    Mukherjee, Arnab; Wu, Di; Davis, Hunter C.; Shapiro, Mikhail G.
    Non-invasive imaging of gene expression in live, optically opaque animals is important for multiple applications, including monitoring of genetic circuits and tracking of cell-based therapeutics. Magnetic resonance imaging (MRI) could enable such monitoring with high spatiotemporal resolution. However, existing MRI reporter genes based on metalloproteins or chemical exchange probes are limited by their reliance on metals or relatively low sensitivity. Here we introduce a new class of MRI reporters based on the human water channel aquaporin 1. We show that aquaporin overexpression produces contrast in diffusion-weighted MRI by increasing tissue water diffusivity without affecting viability. Low aquaporin levels or mixed...

  14. Mapping the Microscale Origins of MRI Contrast with Subcellular NV Diamond Magnetometry

    Davis, Hunter C.; Ramesh, Pradeep; Bhatnagar, Aadyot; Lee-Gosselin, Audrey; Barry, John F.; Glenn, David R.; Walsworth, Ronald L.; Shapiro, Mikhail G.
    Magnetic resonance imaging (MRI) is a widely used biomedical imaging modality that derives much of its contrast from microscale magnetic field gradients in biological tissues. However, the connection between these sub-voxel field patterns and MRI contrast has not been studied experimentally. Here, we describe a new method to map subcellular magnetic fields in mammalian cells and tissues using nitrogen vacancy diamond magnetometry and connect these maps to voxel-scale MRI contrast, providing insights for in vivo imaging and contrast agent design.

  15. Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease

    Mazmanian, Sarkis K.; Sampson, Timothy R.; Debelius, Justine W.; Thron, Taren; Janssen, Stefan; Shastri, Gauri G.; Ilhan, Esra; Challis, Collin; Schretter, Catherine E.; Rocha, Sandra; Gradinaru, Viviana; Chesselet, Marie-Francoise; Keshavarzian, Ali; Shannon, Kathleen M.; Krajmalnik-Brown, Rosa; Wittung-Stafshede, Pernilla; Knight, Rob
    The intestinal microbiota influence neurodevelopment, modulate behavior, and contribute to neurological disorders. However, a functional link between gut bacteria and neurodegenerative diseases remains unexplored. Synucleinopathies are characterized by aggregation of the protein α-synuclein (αSyn), often resulting in motor dysfunction as exemplified by Parkinson’s disease (PD). Using mice that overexpress αSyn, we report herein that gut microbiota are required for motor deficits, microglia activation, and αSyn pathology. Antibiotic treatment ameliorates, while microbial re-colonization promotes, pathophysiology in adult animals, suggesting that postnatal signaling between the gut and the brain modulates disease. Indeed, oral administration of specific microbial metabolites to germ-free mice promotes...

  16. The Placental Interleukin-6 Signaling Controls Fetal Brain Development and Behavior

    Wu, Wei-Li; Hsiao, Elaine Y.; Yan, Zihao; Mazmanian, Sarkis K.; Patterson, Paul H.
    Epidemiological studies show that maternal immune activation (MIA) during pregnancy is a risk factor for autism. However, mechanisms for how MIA affects brain development and behaviors in offspring remain poorly described. To determine whether placental interleukin-6 (IL-6) signaling is required for mediating MIA on the offspring, we generated mice with restricted deletion of the receptor for IL-6 (IL-6R_) in placental trophoblasts (Cyp19-Cre^(+);Il6ra^(fl/fl)), and tested offspring of Cyp19-Cre^(+);Il6ra^(fl/fl) mothers for immunological, pathological and behavioral abnormalities following induction of MIA. We reveal that MIA results in acute inflammatory responses in the fetal brain. Lack of IL-6 signaling in trophoblasts effectively blocks MIA-induced...

  17. Tunable thermal bioswitches for in vivo control of microbial therapeutics

    Piraner, Dan I.; Abedi, Mohamad H.; Moser, Brittany A.; Lee-Gosselin, Audrey; Shapiro, Mikhail G.
    Temperature is a unique input signal that could be used by engineered microbial therapeutics to sense and respond to host conditions or spatially targeted external triggers such as focused ultrasound. To enable these possibilities, we present two families of tunable, orthogonal, temperature-dependent transcriptional repressors providing switch-like control of bacterial gene expression at thresholds spanning the biomedically relevant range of 32–46°C. We integrate these molecular bioswitches into thermal logic circuits and demonstrate their utility in three in vivo microbial therapy scenarios, including spatially precise activation using focused ultrasound, modulation of activity in response to a host fever, and self-destruction after fecal...

  18. The Central Nervous System and the Gut Microbiome

    Sharon, Gil; Sampson, Timothy R.; Geschwind, Daniel H.; Mazmanian, Sarkis K.
    Neurodevelopment is a complex process governed by both intrinsic and extrinsic signals. While historically studied by researching the brain, inputs from the periphery impact many neurological conditions. Indeed, emerging data suggest communication between the gut and the brain in anxiety, depression, cognition, and autism spectrum disorder (ASD). The development of a healthy, functional brain depends on key pre- and post-natal events that integrate environmental cues, such as molecular signals from the gut. These cues largely originate from the microbiome, the consortium of symbiotic bacteria that reside within all animals. Research over the past few years reveals that the gut microbiome...

  19. Long non-coding RNAs: spatial amplifiers that control nuclear structure and gene expression

    Engreitz, Jesse M.; Ollikainen, Noah; Guttman, Mitchell
    Over the past decade, it has become clear that mammalian genomes encode thousands of long non-coding RNAs (lncRNAs), many of which are now implicated in diverse biological processes. Recent work studying the molecular mechanisms of several key examples — including Xist, which orchestrates X chromosome inactivation — has provided new insights into how lncRNAs can control cellular functions by acting in the nucleus. Here we discuss emerging mechanistic insights into how lncRNAs can regulate gene expression by coordinating regulatory proteins, localizing to target loci and shaping three-dimensional (3D) nuclear organization. We explore these principles to highlight biological challenges in gene...

  20. NMR Hyperpolarization Techniques of Gases

    Barskiy, Danila A.; Coffey, Aaron M; Nikolaou, Panayiotis; Mikhaylov, Dmitry M.; Goodson, Boyd M.; Branca, Rosa T.; Lu, George J.; Shapiro, Mikhail G.; Telkki, Ville-Veikko; Zhivonitko, Vladimir V.; Koptyug, Igor V.; Salnikov, Oleg G.; Kovtunov, Kirill V.; Bukhtiyarov, Valerii I.; Rosen, Matthew S.; Barlow, Michael J.; Safavi, Shahideh; Hall, Ian P.; Schröder, Leif; Chekmenev, Eduard Y.
    Nuclear spin polarization can be significantly increased through the process of hyperpolarization, leading to an increase in the sensitivity of nuclear magnetic resonance (NMR) experiments by 4-8 orders of magnitude. Hyperpolarized gases, unlike liquids and solids, can be more readily separated and purified from the compounds used to mediate the hyperpolarization processes. These pure hyperpolarized gases enabled many novel MRI applications including the visualization of void spaces, imaging of lung function, and remote detection. Additionally, hyperpolarized gases can be dissolved in liquids and can be used as sensitive molecular probes and reporters. This mini-review covers the fundamentals of the preparation...

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