Abstract: The present disclosure relates to therapeutic methods and clinically useful molecular switches, for which activity or degradation of a switch-presenting polypeptide can be precisely induced via administration or withdrawal of an FDA-approved drug. Certain aspects of the disclosure relate to an engineered drug-inducible heterodimeric system including a first polypeptide presenting a CRBN polypeptide disrupted for or lacking a DDB1-interacting domain and a second polypeptide presenting a CRBN polypeptide substrate, where binding between the CRBN polypeptide and the CRBN polypeptide substrate are inducible via administration of an FDA-approved thalidomide analog immunomodulatory drug (IMiD). Another aspect of the disclosure relates to a chimeric antigen receptor (CAR) that presents a minimal fragment of the CRBN polypeptide substrate IKZF3 capable of triggering proteasomal degradation of CAR upon administration of an FDA-approved IMiD.

Abstract: Polarization-insensitive metasurfaces using anisotropic nanostructures are disclosed. These anisotropic structures allow for an accurate implementation of phase, group delay, and group delay dispersion, while simultaneously making it possible to realize a polarizationinsensitive, diffraction-limited and achromatic metalens for wavelength, e.g., ?=from about 460 nm to about 700 nm. The approach of polarization-insensitivity can be also applied for other metasurface devices with applications in, e.g., imaging and virtual or augmented reality.

Abstract: The present invention generally relates to systems and methods for imaging or determining nucleic acids, for instance, within cells. In some embodiments, the transcriptome of a cell may be determined. Certain embodiments are directed to determining nucleic acids, such as mRNA, within cells at relatively high resolutions. In some embodiments, a plurality of nucleic acid probes may be applied to a sample, and their binding within the sample determined, e.g., using fluorescence, to determine locations of the nucleic acid probes within the sample. In some embodiments, codewords may be based on the binding of the plurality of nucleic acid probes, and in some cases, the codewords may define an error-correcting code to reduce or prevent misidentification of the nucleic acids. In certain cases, a relatively large number of different targets may be identified using a relatively small number of labels, e.g., by using various combinatorial approaches.

Abstract: The present invention generally relates to systems and methods for imaging or determining nucleic acids, for instance, within cells. In some embodiments, the transcriptome of a cell may be determined. Certain embodiments are directed to determining nucleic acids, such as mRNA, within cells at relatively high resolutions. In some embodiments, a plurality of nucleic acid probes may be applied to a sample, and their binding within the sample determined, e.g., using fluorescence, to determine locations of the nucleic acid probes within the sample. In some embodiments, codewords may be based on the binding of the plurality of nucleic acid probes, and in some cases, the codewords may define an error-correcting code to reduce or prevent misidentification of the nucleic acids. In certain cases, a relatively large number of different targets may be identified using a relatively small number of labels, e.g., by using various combinatorial approaches.

Abstract: The present disclosure provides virus-like particles (VLPs) for delivering prime editors, and systems comprising such prime editor (PE) VLPs. The present disclosure also provides polynucleotides encoding the PE-VLPs described herein, which may be useful for producing said PE-VLPs. Also provided herein are methods for editing the genome of a target cell by introducing the presently described PE-VLPs into the target cell. The present disclosure also provides fusion proteins that make up a component of the PE-VLPs described herein, as well as polynucleotides, vectors, cells, and kits.

Abstract: Nucleic acid molecules, compositions, recombinant AAV (rAAV) particles, kits, and methods are described herein for delivering a base editor (or “nucleobase editor”) to cells, e.g., via AAV vectors. In particular, the disclosure provides compositions, methods, and uses for delivery of adenine base editors and cytosine base editors in a single AAV vector (or genome). Further described herein are improved AAV vectors containing size-minimized regulatory components that enable, e.g., the packaging of base editors. Provided herein are methods and compositions for delivering base editor proteins to a cell or tissue in a single recombinant AAV (rAAV) vector. Contemplated herein are improved methods and compositions for delivering these base editors in vivo, in a single rAAV particle. Further provided herein are base editors and compositions and cells comprising these base editors.

Abstract: The present invention generally relates to systems and methods for imaging or determining nucleic acids, for instance, within cells. In some embodiments, the transcriptome of a cell may be determined. Certain embodiments are directed to determining nucleic acids, such as mRNA, within cells at relatively high resolutions. In some embodiments, a plurality of nucleic acid probes may be applied to a sample, and their binding within the sample determined, e.g., using fluorescence, to determine locations of the nucleic acid probes within the sample. In some embodiments, codewords may be based on the binding of the plurality of nucleic acid probes, and in some cases, the codewords may define an error-correcting code to reduce or prevent misidentification of the nucleic acids. In certain cases, a relatively large number of different targets may be identified using a relatively small number of labels, e.g., by using various combinatorial approaches.

Abstract: An electrochemical apparatus includes an array of pixels disposed on a chip, stimulator circuitry disposed on the chip and configured to provide electrical input signals to cause stimulation of the pixels of the array, and sensor circuitry disposed on the chip and configured to read electrical output signals from the pixels of the array. The stimulator circuitry is configured to provide the input signals to cause stimulation of the pixels individually, and the sensor circuitry is configured to selectively read the output signals from the pixels while the pixels are being stimulated. The sensor circuitry is configured to measure an open-circuit voltage at each of the pixels and a current flow at each of the pixels while the pixels are being stimulated by the stimulator circuitry. The open-circuit voltage may be measured while the current flow is being measured.

Abstract: A compact laser-steering end effector includes a frame, at least two active mirrors, and a pair of actuators. The frame has a greatest dimension in a plane orthogonal to a longitudinal axis of no more than 13 mm, and the mirrors are mounted proximate to the distal end of the frame. The actuators are mounted to the frame and configured to respectively change the tilt of the active mirrors relative to the frame. A pathway is provided through the frame to deliver a laser beam to the mirrors, and wherein the mirrors are positioned and configurable via the actuators to reflect the laser beam off of each mirror en route to an external target.

Abstract: A method is provided for deterministically translocating through a nanopore a target polymer molecule of a nucleic acid polymer molecule or a protein polymer molecule. In the method, an enzyme clamp is reversibly bound to a plurality of sequential polymer subunits of the target polymer molecule. The target polymer molecule and the enzyme clamp are disposed at the nanopore. In the method, there is applied a pulse of force operative to deterministically advance the enzyme clamp along the target polymer molecule by no more than one polymer subunit. The pulse of force is then repeatedly applied to cause deterministic translocation of a sequential plurality of polymer subunits of the target polymer molecule through the nanopore.

Abstract: Some aspects of this disclosure provide strategies, systems, reagents, methods, and kits that are useful for the targeted editing of nucleic acids, including editing a single site within the genome of a cell or subject, e.g., within the human genome. The disclosure provides fusion proteins of nucleic acid programmable DNA binding proteins (napDNAbp), e.g., Cas9 or variants thereof, and nucleic acid editing proteins such as cytidine deaminase domains (e.g., novel cytidine deaminases generated by ancestral sequence reconstruction), and adenosine deaminases that deaminate adenine in DNA. Aspects of the disclosure relate to fusion proteins (e.g., base editors) that have improved expression and/or localize efficiently to the nucleus. In some embodiments, base editors are codon optimized for expression in mammalian cells. In some embodiments, base editors include multiple nuclear localization sequences (e.g., bipartite NLSs), e.g., at least two NLSs.

Abstract: Wearable devices protect against musculoskeletal injuries and enhance performance. Systems and methods provide wearable devices to assist with human motion during physical activities, such as performing movements (e.g., lifting) and holding static poses (e.g., crouching, or holding a tool while working overhead). Materials, constructions, and system architectures allow the wearable devices to be worn over, under, or integrated into clothing for extended periods of time to improve performance or reduce risk of injury. Sensors may be included in the wearable devices to detect various activities, motions, and postures of the wearer, and various active and semi-active controls approaches may leverage sensor information to provide tailored assistance to individual users. Various controls optimization techniques ensure the wearable devices operate at peak efficiency.

Abstract: The present disclosure provides, in some aspects, nucleic acid-based molecular tools that enable the recording of molecular structure and soluble signals as well as the programmed assembly of molecular structures.

Abstract: Techniques Nuc-seq, Div-Seq, and Dronc-Seq are allow for unbiased analysis of any complex tissue. Nuc-Seq, a scalable single nucleus RNA-Seq method, can sensitively identify closely related cell types, including within the adult hippocampus. Div-seq combines Nuc-Seq with EdU-mediated labeling of proliferating cells, allowing tracking of transcriptional dynamics of newborn neurons in an adult neurogenic region in the hippocampus. Dronc-Seq uses a microfluidic device to co-encapsulate individual nuclei in reverse emulsion aqueous droplets in an oil medium together with one uniquely barcoded mRNA-capture bead.

Abstract: A soft brace to prevent injury to one or more target joints or body segments is disclosed. The soft brace includes one or more tensile elements configured to limit motion of one or more target joints based on placement of the one or more tensile elements relative to the one or more target joints such that the placement and tension of each of the one or more tensile elements provides resistance against motion of the one or more target joints; one or more soft tissue anchors positioned on a body around the one or more target joints, the one or more anchors being configured to anchor one or more of the one or more tensile elements to the body to provide force distribution relative to the one or more target joints; and wherein at least one of the one or more tensile elements is routed in parallel with the approximate center of rotation of at least one of the one or more target joints.

Abstract: Scents are perceived by the olfactory sensory neurons (OSNs) that line the upper nasal cavity. Each OSN expresses one odorant receptor, and these odorant receptors contact the scent molecules. Methods for determining which odorant receptor(s) are activated by a scent are lacking, making it difficult to replicate or improve scents. The technology as disclosed herein refers to methods relating to activating odor response genes found in olfactory sensory neurons after the neurons are exposed to at least one volatilized chemical compound.

Abstract: The present invention features novel peripherally-restricted non-benzodiazipene analogs with reduced blood brain barrier permeability and methods of use thereof for reducing tactile dysfunction, social impairment, and anxiety in a subject diagnosed with Autism Spectrum Disorder, Rett syndrome, Phelan McDermid syndrome, or Fragile X syndrome, or for treating touch over-reactivity, pain, or mechanical allodynia.

Abstract: The invention provides for systems, methods, and compositions for targeting RNA. In particular, the invention provides a non-naturally occurring or engineered RNA-targeting system comprising an RNA-targeting Cas protein and at least one RNA-targeting guide RNA, wherein said RNA-targeting guide RNA is capable of hybridizing with a target RNA in a cell.

Abstract: An optical device useful for spatial light modulation.

Abstract: The present disclosure relates to spatially modulating the light source used in microscopy. In some cases, a light source projects a sequence of two-dimensional spatial patterns onto a sample using a spatial light modulator. In some cases, the spatial patterns are based on Hadamard matrices. In some cases, an imaging device captures frames of image data in response to light emitted by the sample and orthogonal components of the image data are analyzed by cross-correlating the image data with the spatial pattern associated with each frame. A microscope may be calibrated by illuminating a sample with the sequence of spatial patterns, capturing image data, and storing calibration that maps each pixel of the spatial light modulator to at least one pixel of the imaging device.