Patents Assigned to Howard Hughes Medical Institute
  • Patent number: 10539772
    Abstract: A method of imaging a live biological specimen includes generating one or more first light sheets; directing the generated one or more first light sheets along respective paths that are parallel with a first illumination axis such that the one or more first light sheets optically interact with at least a portion of the biological specimen in a first image plane; recording, at each of a plurality of first views, images of fluorescence emitted along a first detection axis; generating one or more second light sheets; directing the generated one or more second light sheets along respective paths that are parallel with a second illumination axis such that the one or more second light sheets optically interact with at least a portion of the biological specimen in a second image plane, and recording, at each of a plurality of second views, images of fluorescence emitted along a second detection axis.
    Type: Grant
    Filed: October 8, 2014
    Date of Patent: January 21, 2020
    Assignee: Howard Hughes Medical Institute
    Inventors: Philipp Johannes Keller, Raghav Kumar Chhetri
  • Patent number: 10509026
    Abstract: Genetically encoded calcium indicator (GECI) polypeptides and the nucleic acid molecules encoding such polypeptides are provided. In addition, methods of using such nucleic acids and polypeptides in methods of screening for agonists or antagonists of G-protein coupled receptor (GPCR) or ion channels and methods of monitoring neural activity also are provided.
    Type: Grant
    Filed: April 12, 2018
    Date of Patent: December 17, 2019
    Assignee: Howard Hughes Medical Institute
    Inventors: Loren Looger, Karel Svoboda, Douglas Kim, Rex Kerr
  • Patent number: 10509217
    Abstract: A microscope has a light source for generating a light beam having a wavelength, ?, and beam-forming optics configured for receiving the light beam and generating a Bessel-like beam that is directed into a sample. The beam-forming optics include an excitation objective having an axis oriented in a first direction. Imaging optics are configured for receiving light from a position within the sample that is illuminated by the Bessel-like beam and for imaging the received light on a detector. The imaging optics include a detection objective having an axis oriented in a second direction that is non-parallel to the first direction. A detector is configured for detecting signal light received by the imaging optics, and an aperture mask is positioned.
    Type: Grant
    Filed: December 15, 2017
    Date of Patent: December 17, 2019
    Assignee: Howard Hughes Medical Institute
    Inventor: Robert E. Betzig
  • Patent number: 10495632
    Abstract: The presently-disclosed subject matter includes azetidine-substituted fluorescent compounds, where the compounds may be used as probes, dyes, tags, and the like. The presently-disclosed subject matter also includes kits comprising the same as well as methods for using the same to detect a target substance.
    Type: Grant
    Filed: December 6, 2018
    Date of Patent: December 3, 2019
    Assignee: HOWARD HUGHES MEDICAL INSTITUTE
    Inventors: Luke D. Lavis, Jonathan B. Grimm, Jiji Chen, Timothee Lionnet, Zhengjian Zhang, Andrey Revyakin, Joel Slaughter
  • Patent number: 10407399
    Abstract: The presently-disclosed subject matter relates to analyte-activated photolabile compounds. The compounds include the formula: wherein Z includes a maskable molecule; L is selected from a bond, C, C(O), O, alkyl, (O)alkyl, and alkoxy; R1 is selected from H, halogen, alkyl, and acyl; each R2 is independently selected from H, alkyl, aryl, and acyl, and is optionally substituted with one or more heteroatoms independently selected from COOH and COO(alkyl); and R3 is selected from H, alkyl, aryl, halogen, CN, OH, O(alkyl), O(aryl), SH, S(alkyl), S(aryl), amine, CHO, COOH, COO(alkyl), COO(aryl), PO3H2, and SO3H, and is optionally substituted with one or more heteroatoms independently selected from N, O, and S, halogen, OH, O(alkyl), O(aryl), SH, S(alkyl), S(aryl), amine, NO2, CHO, COO, COOH, COO(alkyl), COO(aryl), C(O)NR2, PO3H2, and/or SO3H. Also provided are methods of detecting calcium and treating a subject with the analyte-activated photolabile compounds.
    Type: Grant
    Filed: September 1, 2016
    Date of Patent: September 10, 2019
    Assignee: HOWARD HUGHES MEDICAL INSTITUTE
    Inventors: Luke D. Lavis, Jonathan B. Grimm, Laurel M. Heckman, Eric R. Schreiter
  • Patent number: 10386302
    Abstract: A live biological specimen is imaged by generating a plurality of light sheets; directing the plurality of light sheets along an illumination axis through the biological specimen such that the light sheets spatially and temporally overlap within the biological specimen along an image plane, and optically interact with the biological specimen within the image plane; and recording, at each of a plurality of views, images of the fluorescence emitted along a detection axis from the biological specimen due to the optical interaction between the light sheets and the biological specimen. The temporal overlap is within a time shift that is less than a resolution time that corresponds to a spatial resolution limit of the microscope.
    Type: Grant
    Filed: February 10, 2016
    Date of Patent: August 20, 2019
    Assignee: Howard Hughes Medical Institute
    Inventor: Philipp Johannes Keller
  • Patent number: 10361060
    Abstract: An automated workpiece processing apparatus including a processing section including a processing module configured for processing a workpiece at a process location, a transport module including a first shuttle stage, a second shuttle stage independent of the first stage, and an end effector connected to at least one of the first and second stages, the end effector being configured to hold and transport the workpiece into and out of the processing module, and having a range of motion, defined by a combination of the first and second stage, extending from a workpiece holding station outside the processing module to the processing location inside the processing module so the end effector defines a processing stage of the processing module, and an automated loading and transport section including a load port module through which workpieces are loaded into the automated loading and transport section, and being communicably connected to the transport module.
    Type: Grant
    Filed: September 1, 2016
    Date of Patent: July 23, 2019
    Assignee: Howard Hughes Medical Institute
    Inventors: John H. Price, Dravida Bock
  • Publication number: 20190219811
    Abstract: A sample is imaged using light-sheet imaging. The light-sheet imaging includes generating light, forming one or more light sheets from the light at one or more positions within the sample along respective illumination directions that are parallel with an illumination axis, and recording images of fluorescence emitted along a detection direction from the sample due to the optical interaction between the one or more light sheets and the sample. One or more properties relating to the light-sheet imaging are measured; the one or more measured properties are analyzed; and one or more operating parameters associated with the light-sheet imaging are adjusted based on the analysis of the one or more measured properties.
    Type: Application
    Filed: June 23, 2017
    Publication date: July 18, 2019
    Applicant: Howard Hughes Medical Institute
    Inventors: Philipp Johannes KELLER, Raghav Kumar CHHETRI, Loïc Alain ROYER
  • Patent number: 10345297
    Abstract: The present disclosure provides, inter alia, genetically encoded recombinant peptide biosensors comprising analyte-binding framework portions and signaling portions, wherein the signaling portions are present within the framework portions at sites or amino acid positions that undergo a conformational change upon interaction of the framework portion with an analyte.
    Type: Grant
    Filed: August 24, 2018
    Date of Patent: July 9, 2019
    Assignees: Howard Hughes Medical Institute, The Brigham & Women's Hospital, Inc.
    Inventors: Jonathan S. Marvin, Loren Looger, Richard T. Lee, Eric Schreiter
  • Patent number: 10295811
    Abstract: A microscope system including: a source of light; a sample objective configured for focusing the light at a focal plane within a sample; a remote focus unit configured for changing a position of the focal plane along an axis perpendicular to the focal plane; one or more optical element configured for directing the focused light to a location within the focal plane; and a detector configured for detecting light emitted from the focal plane within the sample; wherein the one or more optical element is located after the remote focus unit along a beam path of the light from the source to the sample objective, such that the changing the position of the focal plane along the axis is performed before the directing the focused light to the location within the focal plane.
    Type: Grant
    Filed: November 1, 2016
    Date of Patent: May 21, 2019
    Assignee: Howard Hughes Medical Institute
    Inventors: Karel Svoboda, Daniel Flickinger, Nicholas Sofroniew
  • Publication number: 20190125831
    Abstract: As microbial drug-resistance increases, there is a critical need for new classes of compounds to combat infectious diseases. The Ixodes scapularis tick antifreeze glycoprotein, IAFGP, functions as an anti-infective agent against diverse bacteria including methicillin-resistant Staphylococcus aureus. Recombinant IAFGP and a peptide, P1, described herein and derived from this protein, bind to microbes and alter biofilm formation. Transgenic iafgp-expressing flies and mice challenged with bacteria, as well as wild-type animals administered IAFGP or P1, were resistant to infection, septic shock, or biofilm development on implanted biomaterials. Antifreeze protein controls bacterial infection and present new therapeutic strategies to counter pathogens.
    Type: Application
    Filed: September 6, 2018
    Publication date: May 2, 2019
    Applicants: Yale University, Howard Hughes Medical Institute
    Inventors: Erol Fikrig, Martin Heisig, Nabil Abraham, Girish Neelakanta
  • Patent number: 10247672
    Abstract: A method includes: (a) providing spatially-patterned activation radiation to a sample that includes phototransformable labels, where an optical parameter of the spatially-patterned activation radiation varies periodically in space; (b) providing spatially-patterned excitation radiation to the sample, where an optical parameter of the spatially-patterned excitation radiation varies periodically in space, where (a) and (b) create a non-linear fluorescence emission pattern within the sample, the pattern including H modulation harmonics, with H>1. The method includes (c) detecting radiation emitted from the activated and excited labels, (d) storing detected radiation data, and (e) spatially shifting one or both of the spatially-patterned excitation radiation and the spatially-patterned activation radiation with respect to the sample to spatially shift the non-linear fluorescence emission pattern within the sample, and (f) repeating (a)-(e) at least N times, with N>2.
    Type: Grant
    Filed: September 29, 2015
    Date of Patent: April 2, 2019
    Assignee: Howard Hughes Medical Institute
    Inventors: Robert E. Betzig, Dong Li
  • Patent number: 10186397
    Abstract: An automated workpiece processing system including at least one workpiece processing unit, a workpiece holder configured to removably hold a batch of workpieces therein, each workpiece embodying workpiece identifying indicia where the workpiece identifying indicia is a physical representation of a sample held on a respective workpiece, and to interface with the at least one automated workpiece processing unit, and a controller including a memory having a data structure therein that effects, with the workpiece identifying indicia, batch process tracking of each workpiece in the batch of workpieces through the at least one automated workpiece processing unit in a predetermined batch workpiece processing sequence.
    Type: Grant
    Filed: November 11, 2014
    Date of Patent: January 22, 2019
    Assignee: Howard Hughes Medical Institute
    Inventors: John H. Price, Dravida Bock
  • Patent number: 10161932
    Abstract: The presently-disclosed subject matter includes azetidine-substituted fluorescent compounds, where the compounds may be used as probes, dyes, tags, and the like. The presently-disclosed subject matter also includes kits comprising the same as well as methods for using the same to detect a target substance.
    Type: Grant
    Filed: June 5, 2018
    Date of Patent: December 25, 2018
    Assignee: HOWARD HUGHES MEDICAL INSTITUTE
    Inventors: Luke D. Lavis, Jonathan B. Grimm, Jiji Chen, Timothee Lionnet, Zhengjian Zhang, Andrey Revyakin, Joel Slaughter
  • Patent number: 10123985
    Abstract: Provided herein are methods, compositions, and systems for treating mitochondrial disorders (e.g., MERRF, MELAS, Kearns-Sayre syndrome, chronic progressive external ophthalmoplegia, diabetes mellitus and deafness, lactic acidosis, Leber's hereditary optic neuropathy, Wolff-Parkinson-White syndrome, Leigh syndrome, NARP, myoneurogenic gastrointestinal encephalopathy, mitochondrial DNA depletion syndrome) or neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease) by administering aspartate, or an analog or prodrug thereof, or an agent that increases intracellular levels of aspartate. Pharmaceutical compositions and kits for use in treating mitochondrial disorders and neurodegenerative diseases are also described herein. Also provided are methods for treating disease by modulating the redox state of a cell, and methods of treating a proliferative disease by administering a cytosolic aspartate aminotransferase (GOT1) inhibitor.
    Type: Grant
    Filed: June 8, 2016
    Date of Patent: November 13, 2018
    Assignees: Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Howard Hughes Medical Institute
    Inventors: David M. Sabatini, Kivanc Birsoy, Matthew George Vander Heiden, Lucas Bryan Sullivan, Dan Yi Gui
  • Patent number: 10092626
    Abstract: As microbial drug-resistance increases, there is a critical need for new classes of compounds to combat infectious diseases. The Ixodes scapularis tick antifreeze glycoprotein, IAFGP, functions as an anti-infective agent against diverse bacteria including methicillin-resistant Staphylococcus aureus. Recombinant IAFGP and a peptide, PI, described herein and derived from this protein, bind to microbes and alter biofilm formation. Transgenic iafgp-expressing flies and mice challenged with bacteria, as well as wild-type animals administered IAFGP or PI, were resistant to infection, septic shock, or biofilm development on implanted biomaterials. Antifreeze protein controls bacterial infection and present new therapeutic strategies to counter pathogens.
    Type: Grant
    Filed: December 17, 2014
    Date of Patent: October 9, 2018
    Assignees: Yale University, Howard Hughes Medical Institute
    Inventors: Erol Fikrig, Martin Heisig, Nabil Abraham, Girish Neelakanta
  • Patent number: 10067148
    Abstract: The presently-disclosed subject matter includes fluorescent protein-based indicators for detecting ions, small molecule analytes, or combinations thereof. In some embodiments the indicators include a polypeptide, which itself includes a fluorescent polypeptide, a compound-binding polypeptide, and a polypeptide target of the compound-binding polypeptide. In some embodiments the polypeptide includes an EosFP polypeptide, a calmodulin polypeptide, and a M13 polypeptide, or fragments and/or variants thereof. The presently-disclosed subject matter also includes methods for detecting calcium in a sample with embodiments of the present polypeptides. In some embodiments the present indicators experience a permanent shift from green to red fluorescent when exposed to an detecting substance, such as calcium.
    Type: Grant
    Filed: October 27, 2016
    Date of Patent: September 4, 2018
    Assignee: HOWARD HUGHES MEDICAL INSTITUTE
    Inventors: Eric R. Schreiter, Loren L. Looger, Benjamin F. Fosque
  • Patent number: 10060920
    Abstract: The present disclosure provides, inter alia, genetically encoded recombinant peptide biosensors comprising analyte-binding framework portions and signaling portions, wherein the signaling portions are present within the framework portions at sites or amino acid positions that undergo a conformational change upon interaction of the framework portion with an analyte.
    Type: Grant
    Filed: February 26, 2018
    Date of Patent: August 28, 2018
    Assignees: Howard Hughes Medical Institute, The Brigham & Women's Hospital, Inc.
    Inventors: Jonathan S. Marvin, Loren Looger, Richard T. Lee, Eric Schreiter
  • Patent number: 10054518
    Abstract: A microtome includes a blade located at an end of a trough that defines a cavity for holding a liquid; a sample block in which the at least one sample is suspended, the sample block is moveable relative to the blade such that when the sample block is passed across the blade a section is cut from the sample block; a plate that includes a support frame that defines an opening, and a transparent film extending across the opening, the transparent film being transparent to electrons, a grasper being configured to receive and retain the plate, wherein the grasper is moveable relative to the blade; and a pusher section that lacks the sample pusher section.
    Type: Grant
    Filed: November 5, 2014
    Date of Patent: August 21, 2018
    Assignee: Howard Hughes Medical Institute
    Inventors: Harald F. Hess, David Peale, Patrick R. Lee
  • Patent number: 10053492
    Abstract: Protein indicators useful for calcium imaging, in particular, red genetically-encoded calcium indicators (GECIs) disclosed herein rival best-of-class green GECIs in terms of sensitivity for detecting neural activity, and can be monitored in vivo. The presently-disclosed subject matter further includes a method of monitoring cell activity comprising stimulating a cell comprising a red GECI polypeptide; and detecting fluorescence emitted by the cell.
    Type: Grant
    Filed: March 17, 2017
    Date of Patent: August 21, 2018
    Assignee: HOWARD HUGHES MEDICAL INSTITUTE
    Inventors: Douglas S. Kim, Loren L. Looger, Eric R. Schreiter, Karel Svoboda