Recursos de colección

Caltech Authors (155.447 recursos)

Repository of works by Caltech published authors.

Group = Heritage Medical Research Institute

Mostrando recursos 1 - 18 de 18

  1. Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models

    Cekanaviciute, Egle; Yoo, Bryan B.; Runia, Tessel F.; Debelius, Justine W.; Singh, Sneha; Nelson, Charlotte A.; Kanner, Rachel; Bencosme, Yadira; Lee, Yun Kyung; Hauser, Stephen L.; Crabtree-Hartman, Elizabeth; Katz Sand, Ilana; Gacias, Mar; Zhu, Yungjiao; Casaccia, Patrizia; Cree, Bruce A. C.; Knight, Rob; Mazmanian, Sarkis K.; Baranzini, Sergio E.
    The gut microbiota regulates T cell functions throughout the body. We hypothesized that intestinal bacteria impact the pathogenesis of multiple sclerosis (MS), an autoimmune disorder of the CNS and thus analyzed the microbiomes of 71 MS patients not undergoing treatment and 71 healthy controls. Although no major shifts in microbial community structure were found, we identified specific bacterial taxa that were significantly associated with MS. Akkermansia muciniphila and Acinetobacter calcoaceticus, both increased in MS patients, induced proinflammatory responses in human peripheral blood mononuclear cells and in monocolonized mice. In contrast, Parabacteroides distasonis, which was reduced in MS patients, stimulated antiinflammatory...

  2. Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models

    Cekanaviciute, Egle; Yoo, Bryan B.; Runia, Tessel F.; Debelius, Justine W.; Singh, Sneha; Nelson, Charlotte A.; Kanner, Rachel; Bencosme, Yadira; Lee, Yun Kyung; Hauser, Stephen L.; Crabtree-Hartman, Elizabeth; Katz Sand, Ilana; Gacias, Mar; Zhu, Yungjiao; Casaccia, Patrizia; Cree, Bruce A. C.; Knight, Rob; Mazmanian, Sarkis K.; Baranzini, Sergio E.
    The gut microbiota regulates T cell functions throughout the body. We hypothesized that intestinal bacteria impact the pathogenesis of multiple sclerosis (MS), an autoimmune disorder of the CNS and thus analyzed the microbiomes of 71 MS patients not undergoing treatment and 71 healthy controls. Although no major shifts in microbial community structure were found, we identified specific bacterial taxa that were significantly associated with MS. Akkermansia muciniphila and Acinetobacter calcoaceticus, both increased in MS patients, induced proinflammatory responses in human peripheral blood mononuclear cells and in monocolonized mice. In contrast, Parabacteroides distasonis, which was reduced in MS patients, stimulated antiinflammatory...

  3. Localization of Microscale Devices In Vivo using Addressable Transmitters Operated as Magnetic Spins

    Monge, Manuel; Lee-Gosselin, Audrey; Shapiro, Mikhail G.; Emami, Azita
    The function of miniature wireless medical devices, such as capsule endoscopes, biosensors and drug-delivery systems, depends critically on their location inside the body. However, existing electromagnetic, acoustic and imaging-based methods for localizing and communicating with such devices suffer from limitations arising from physical tissue properties or from the performance of the imaging modality. Here, we embody the principles of nuclear magnetic resonance in a silicon integrated-circuit approach for microscale device localization. Analogous to the behaviour of nuclear spins, the engineered miniaturized radio frequency transmitters encode their location in space by shifting their output frequency in proportion to the local magnetic...

  4. Preparation of biogenic gas vesicle nanostructures for use as contrast agents for ultrasound and MRI

    Lakshmanan, Anupama; Lu, George J.; Farhadi, Arash; Nety, Suchita P.; Kunth, Martin; Lee-Gosselin, Audrey; Maresca, David; Bourdeau, Raymond W.; Yin, Melissa; Yan, Judy; Witte, Christopher; Malounda, Dina; Foster, F. Stuart; Schröder, Leif; Shapiro, Mikhail G.
    Gas vesicles (GVs) are a unique class of gas-filled protein nanostructures that are detectable at subnanomolar concentrations and whose physical properties allow them to serve as highly sensitive imaging agents for ultrasound and MRI. Here we provide a protocol for isolating GVs from native and heterologous host organisms, functionalizing these nanostructures with moieties for targeting and fluorescence, characterizing their biophysical properties and imaging them using ultrasound and MRI. GVs can be isolated from natural cyanobacterial and haloarchaeal host organisms or from Escherichia coli expressing a heterologous GV gene cluster and purified using buoyancy-assisted techniques. They can then be modified by...

  5. Going Deeper: Biomolecular Tools for Acoustic and Magnetic Imaging and Control of Cellular Function

    Piraner, Dan I.; Farhadi, Arash; Davis, Hunter C.; Wu, Di; Maresca, David; Szablowski, Jerzy O.; Shapiro, Mikhail G.
    Most cellular phenomena of interest to mammalian biology occur within the context of living tissues and organisms. However, today’s most advanced tools for observing and manipulating cellular function, based on fluorescent or light-controlled proteins, work best in cultured cells, transparent model species, or small, surgically accessed anatomical regions. Their reach into deep tissues and larger animals is limited by photon scattering. To overcome this limitation, we must design biochemical tools that interface with more penetrant forms of energy. For example, sound waves and magnetic fields easily permeate most biological tissues, allowing the formation of images and delivery of energy for...

  6. Quantitative analysis of a III-V tapered horn-shaped metal-clad nano-cavity as an on-chip light source

    Koo, Sukmo; Siddique, Radwanul Hasan; Choo, Hyuck
    A horn-shaped metal-clad InGaAsP nano-cavity with sloped sidewalls is proposed as a platform for nanoscale light sources. The nano-cavity’s physical dimensions are 350 × 350 × 350 nm^3, and its mode volume is 0.5 (λ_0/n)^3. In our numerical simulations and quantitative analysis, we have shown that the sloped sidewalls reduce metallic absorption and improve resonant mode confinement; and adjusting their slope from 0 to 16° increased the Q factor from 150 to 900 and laser modulation 3dB bandwidth from 4.3 to 36 GHz. The lasing threshold current was expected to be 35 μA at 16°. In a simulated feasibility study,...

  7. Characterizing Single Polymeric and Protein Nanoparticles with Surface Plasmon Resonance Imaging Measurements

    Maley, Adam M.; Lu, George J.; Shapiro, Mikhail G.; Corn, Robert M.
    Near-infrared surface plasmon resonance imaging (SPRI) microscopy is used to detect and characterize the adsorption of single polymeric and protein nanoparticles (PPNPs) onto chemically modified gold thin films in real time. The single-nanoparticle SPRI responses, Δ%R_(NP), from several hundred adsorbed nanoparticles are collected in a single SPRI adsorption measurement. Analysis of Δ%R_(NP) frequency distribution histograms is used to provide information on the size, material content, and interparticle interactions of the PPNPs. Examples include the measurement of log-normal Δ%R_(NP) distributions for mixtures of polystyrene nanoparticles, the quantitation of bioaffinity uptake into and aggregation of porous NIPAm-based (N-isopropylacrylamide) hydrogel nanoparticles specifically engineered...

  8. The microbiome activates CD4 T-cell-mediated immunity to compensate for increased intestinal permeability

    Edelblum, Karen L.; Sharon, Gil; Singh, Gurminder; Odenwald, Matthew A.; Sailer, Anne; Cao, Severine; Ravens, Sarina; Thomsen, Irene; El Bissati, Kamal; McLeod, Rima; Dong, Chen; Gurbuxani, Sandeep; Prinz, Immo; Mazmanian, Sarkis K.; Turner, Jerrold R.
    Background & Aims: Despite a prominent association, chronic intestinal barrier loss is insufficient to induce disease in human subjects or experimental animals. We hypothesized that compensatory mucosal immune activation might protect individuals with increased intestinal permeability from disease. We used a model in which intestinal barrier loss is triggered by intestinal epithelial-specific expression of constitutively active myosin light chain kinase (CA-MLCK). Here we asked whether constitutive tight junction barrier loss impacts susceptibility to enteric pathogens. Methods: Acute or chronic Toxoplasma gondii or Salmonella typhimurium infection was assessed in CA-MLCK transgenic or wild-type mice. Germ-free mice or those lacking specific immune...

  9. Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems

    Chan, Ken Y.; Jang, Min J.; Yoo, Bryan B.; Greenbaum, Alon; Ravi, Namita; Wu, Wei-Li; Sanchez-Guardado, Luis; Lois, Carlos; Mazmanian, Sarkis K.; Deverman, Benjamin E.; Gradinaru, Viviana
    Adeno-associated viruses (AAVs) are commonly used for in vivo gene transfer. Nevertheless, AAVs that provide efficient transduction across specific organs or cell populations are needed. Here, we describe AAV-PHP.eB and AAV-PHP.S, capsids that efficiently transduce the central and peripheral nervous systems, respectively. In the adult mouse, intravenous administration of 1 × 1011 vector genomes (vg) of AAV-PHP.eB transduced 69% of cortical and 55% of striatal neurons, while 1 × 1012 vg of AAV-PHP.S transduced 82% of dorsal root ganglion neurons, as well as cardiac and enteric neurons. The efficiency of these vectors facilitates robust cotransduction and stochastic, multicolor labeling for...

  10. The Enteric Network: Interactions between the Immune and Nervous Systems of the Gut

    Yoo, Bryan B.; Mazmanian, Sarkis K.
    Interactions between the nervous and immune systems enable the gut to respond to the variety of dietary products that it absorbs, the broad spectrum of pathogens that it encounters, and the diverse microbiome that it harbors. The enteric nervous system (ENS) senses and reacts to the dynamic ecosystem of the gastrointestinal (GI) tract by translating chemical cues from the environment into neuronal impulses that propagate throughout the gut and into other organs in the body, including the central nervous system (CNS). This review will describe the current understanding of the anatomy and physiology of the GI tract by focusing on...

  11. Dorsal Raphe Dopamine Neurons Modulate Arousal and Promote Wakefulness by Salient Stimuli

    Cho, Jounhong Ryan; Treweek, Jennifer B.; Robinson, J. Elliott; Xiao, Cheng; Bremner, Lindsay R.; Greenbaum, Alon; Gradinaru, Viviana
    Ventral midbrain dopamine (DA) is unambiguously involved in motivation and behavioral arousal, yet the contributions of other DA populations to these processes are poorly understood. Here, we demonstrate that the dorsal raphe nucleus DA neurons are critical modulators of behavioral arousal and sleep-wake patterning. Using simultaneous fiber photometry and polysomnography, we observed time-delineated dorsal raphe nucleus dopaminergic (DRNDA) activity upon exposure to arousal-evoking salient cues, irrespective of their hedonic valence. We also observed broader fluctuations of DRNDA activity across sleep-wake cycles with highest activity during wakefulness. Both endogenous DRNDA activity and optogenetically driven DRNDA activity were associated with waking from...

  12. 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...

  13. Simple, Large-Scale Fabrication of Uniform Raman-Enhancing Substrate with Enhancement Saturation

    Yang, Daejong; Cho, Hyunjun; Koo, Sukmo; Vaidyanathan, Sagar R.; Woo, Kelly; Yoon, Youngzoon; Choo, Hyuck
    It is well-known that gold nanoparticle (AuNP) clusters generate strong surface-enhanced Raman scattering (SERS). In order to produce spatially uniform Raman-enhancing substrates at a large scale, we synthesized vertically perforated three-dimensional (3D) AuNP stacks. The 3D stacks were fabricated by first hydrothermally synthesizing ZnO nanowires perpendicular to silicon wafers followed by repetitively performing liquid-phase deposition of AuNPs on the tops and side surfaces of the nanowires. During the deposition process, the nanowires were shown to gradually dissolve away, leaving hollow vestiges or perforations surrounded by stacks of AuNPs. Simulation studies and experimental measurements reveal these nanoscale perforations serve as light...

  14. 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....

  15. 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...

  16. 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...

  17. 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...

  18. Cholinergic Mesopontine Signals Govern Locomotion and Reward through Dissociable Midbrain Pathways

    Xiao, Cheng; Cho, Jounhong Ryan; Zhou, Chunyi; Treweek, Jennifer B.; Chan, Ken; McKinney, Sheri L.; Yang, Bin; Gradinaru, Viviana
    The mesopontine tegmentum, including the pedunculopontine and laterodorsal tegmental nuclei (PPN and LDT), provides major cholinergic inputs to midbrain and regulates locomotion and reward. To delineate the underlying projection-specific circuit mechanisms, we employed optogenetics to control mesopontine cholinergic neurons at somata and at divergent projections within distinct midbrain areas. Bidirectional manipulation of PPN cholinergic cell bodies exerted opposing effects on locomotor behavior and reinforcement learning. These motor and reward effects were separable via limiting photostimulation to PPN cholinergic terminals in the ventral substantia nigra pars compacta (vSNc) or to the ventral tegmental area (VTA), respectively. LDT cholinergic neurons also form...

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