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CRISPR-CAS EFFECTOR POLYPEPTIDES AND METHODS OF USE THEREOF (“Cas-VariPhi”)

CRISPR-Cas systems include Cas proteins, which are involved in acquisition, targeting and cleavage of foreign DNA or RNA, and a guide RNA(s), which includes a segment that binds Cas proteins and a segment that binds to a target nucleic acid. For example, Class 2 CRISPR-Cas systems comprise a single Cas protein bound to a guide RNA, where the Cas protein binds to and cleaves a targeted nucleic acid. The programmable nature of these systems has facilitated their use as a versatile technology for use in modification of target nucleic acid.   UC Berkeley researchers have discovered a novel family of proteins (CasVariPhi) that utilize a guide RNA to perform RNA-directed cleavage of nucleic acids. Viral and microbial (cellular) genomes were assembled from a variety of environmental and animal microbiome sources, and variants of a novel and previously unknown Cas protein family were uncovered from the sequences decoded. 

CRISPR-CAS EFFECTOR POLYPEPTIDES AND METHODS OF USE THEREOF (“Cas-Omega”)

CRISPR-Cas systems include Cas proteins, which are involved in acquisition, targeting and cleavage of foreign DNA or RNA, and a guide RNA(s), which includes a segment that binds Cas proteins and a segment that binds to a target nucleic acid. For example, Class 2 CRISPR-Cas systems comprise a single Cas protein bound to a guide RNA, where the Cas protein binds to and cleaves a targeted nucleic acid. The programmable nature of these systems has facilitated their use as a versatile technology for use in modification of target nucleic acid.   UC Berkeley researchers have discovered a novel family of proteins (CasOmega) that utilize a guide RNA to perform RNA-directed cleavage of nucleic acids. Viral and microbial (cellular) genomes were assembled from a variety of environmental and animal microbiome sources, and variants of a novel and previously unknown Cas protein family were uncovered from the sequences decoded. 

CRISPR-CAS EFFECTOR POLYPEPTIDES AND METHODS OF USE THEREOF (“Cas-Theta”)

CRISPR-Cas systems include Cas proteins, which are involved in acquisition, targeting and cleavage of foreign DNA or RNA, and a guide RNA(s), which includes a segment that binds Cas proteins and a segment that binds to a target nucleic acid. For example, Class 2 CRISPR-Cas systems comprise a single Cas protein bound to a guide RNA, where the Cas protein binds to and cleaves a targeted nucleic acid. The programmable nature of these systems has facilitated their use as a versatile technology for use in modification of target nucleic acid.   UC Berkeley researchers have discovered a novel family of proteins (CasTheta) that utilize a guide RNA to perform RNA-directed cleavage of nucleic acids. Viral and microbial (cellular) genomes were assembled from a variety of environmental and animal microbiome sources, and variants of a novel and previously unknown Cas protein family were uncovered from the sequences decoded. 

CRISPR-CAS EFFECTOR POLYPEPTIDES AND METHODS OF USE THEREOF (CasGamma)

CRISPR-Cas systems include Cas proteins, which are involved in acquisition, targeting and cleavage of foreign DNA or RNA, and a guide RNA(s), which includes a segment that binds Cas proteins and a segment that binds to a target nucleic acid. For example, Class 2 CRISPR-Cas systems comprise a single Cas protein bound to a guide RNA, where the Cas protein binds to and cleaves a targeted nucleic acid. The programmable nature of these systems has facilitated their use as a versatile technology for use in modification of target nucleic acid.   UC Berkeley researchers have discovered a novel family of compact proteins (CasGamma) with a RuvC-like domain in the C-terminal end of the protein. These proteins are able to cleave nucleic acids. Viral and microbial (cellular) genomes were assembled from a variety of environmental and animal microbiome sources, and variants of a novel and previously unknown Cas protein family were uncovered from the sequences decoded. These CasGamma proteins utilize a guide RNA to perform RNA-directed cleavage of nucleic acids.  

2'-fluoro RNA Activators for Enhanced Activation of Csm6 in RNA Detection Assays

Csm6 constitutes a family of enzymes that are activated by cyclic oligoadenylates (cA(n)) or linear oligoadenylates with a 2´,3´-cyclic phosphate termini (A(n)>P). Cleavage of a nucleic acid sequence by an RNase to generate a linear oligoadenylate with exactly 4 or 6 A’s and the 2´,3´-cyclic phosphate terminus (A4>P or A6>P) leads to activation of Csm6/Csx1 for cleavage of a fluorescent RNA reporter. The linear A4 or A6 can be incorporated into an RNA sequence (e.g. A4-U6 or A6-U5) such that activation of Csm6 only occurs upon removal of the U-containing sequence by Cas13a, a programmable RNA-guided RNase that preferentially cleaves the phosphodiester bond that is 5’ to U’s and generates products with 2´,3´-cyclic phosphates. Csm6 is normally inactivated through self-cleavage of its activator, leading to low sensitivity when coupled with a Cas13-based RNA detection system or a Cas13-Csm6 feed-forward detection system.In this invention, the 2’-hydroxyl of the ribose in the second A in the linear A4 or the third A in the linear A6 is replaced with a 2’-fluorine (fA). This single 2’-fluoro modified RNA oligonucleotide (A-fA-AA>P or AA-fA-AAA>P) would bind and activate Csm6/Csx1 with fast kinetics and prevent degradation of the linear oligoadenylate by Csm6/Csx1. This single 2´-fluoro-modified polyA activator could be followed by any sequence to couple activation of Csm6 to a second enzyme. The purpose of this invention is to generate sustained activation of Csm6, when coupled with a Cas13 RNA detection system. In one iteration of this invention, the modified activator is followed by a linear chain of U’s, and is thus cleavable by Cas13 upon Cas13’s activation by a complementary sequence of RNA. Other nucleotides (e.g. C, A) or 2´-deoxy modifications can also be included 3´ to the first U to restrict the cleavage of Cas13a to the precise site that is required to release the single 2’-fluoro modified An>P (e.g. A-fA-AAUCCCCCC...). This activator leads to increased sensitivity and kinetics in RNA detection when coupled with Cas13. In another iteration of this invention, the modified activator is followed by a linear chain of C’s (Cn). This substrate can be acted upon by a pre-activated Csm6 (e.g. by Cas13) to produce A-fA-AA>P or AA-fA-AAA>P, which initiates a sustained feed-forward loop and prevents self-degradation of the activator by Csm6. Restricting the cleavage site of this activator by addition of chemical modifications (such as 2’-deoxy) on positions other than the cleavage site leads to a precise cut by Csm6. This activator can be combined with the previous iteration to generate even higher sensitivity and kinetics in RNA detection than the previous iteration alone. Cleavage of a fluorescent and colorimetric RNA reporter by the highly activated Csm6 in either iteration would then generate a detectable signal. In addition, nucleotides with modified bases that are not recognized by Csm6 or Cas13 may also be used in the cleavable “tail” of the activators to avoid competition with the RNA reporter or other activators in the system. Overall, the purpose of this invention is to enable elevated activation and kinetics of Csm6 when coupled with a Cas13 RNA detection system or a feed-forward reaction with Csm6 and Cas13. This could be used in low-copy detection of any type of single-stranded RNA, including viral RNA genomes, viral RNA transcripts, and cellular RNA transcripts. In addition, these activators could also be used with the related family of enzymes known as Csx1.

SARS-CoV-2 Detection by Carbon Nanotube-Based Nanosensors

The inventors have developed a real-time optical nanosensor for detection of active SARS-CoV-2 infection, which includes a modular synthesis scheme that is amenable to detection of other viral infections. The nanosensor is constructed from near-infrared fluorescent single-walled carbon nanotube (SWCNT) substrates functionalized with biomolecules that have high binding affinity to viral proteins and viral genomic material. Virus binding to the nanosensor instantaneously changes the SWCNT fluorescence. This fluorescent readout serves as the optical signal that coronavirus is present in the clinical sample. The near-infrared fluorescence signal is detectable in biological samples, offering the prospect of detecting active SARS-CoV-2 in unprocessed, crude biofluid samples from individuals with readouts provided in tens of minutes. These SWCNT-based nanosensors are adaptable to point-of-care diagnostic devices to enable accessible, rapid testing of active SARS-CoV-2 infection. Furthermore, the reagents and detection devices would be sourced from different supply chains than existing tests and provide orthogonal advantages to such tests.

Method for Motion Sensing in MRI Using Preamplifier RF Intermodulation

The inventors have developed a new flexible motion sensing method that exploits nonlinear intermodulation of MRI receiver coil preamplifiers to sense the motion of a subject in an MRI scanner without on-subject hardware. The method transmits two tones at two different frequencies, f1 and f2, designed to be received at frequency f_BPT by the receiver via intermodulation, where f1 and f2 are much greater than the MRI center frequency. These signals are picked up by the receiver coils, mixed at the pre-amplification stage by intermodulation, then digitized by the receiver chain. The method is 20 times more sensitive to motion than the state-of-the-art Pilot Tone (PT) method of motion sensing. The inventors have demonstrated the method with second order intermodulation. Additionally, more transmitters can be used, each with a different set of frequencies. Higher frequency tones enable greater sensitivity to subject motion. This method enables the detection of motion at multiple temporal and spatial scales, for example, breathing and rigid motion of the head. The method is used simultaneously with conventional MR imaging and does not adversely impact the signal-to-noise ratio (SNR) of the acquired MR image. The method has been demonstrated using inexpensive consumer grade hardware for the 2.4GHz ISM band as a proof-of-concept. Since the MR signal is small (< -30dBm), little transmit power is necessary to induce an intermodulation signal similar in amplitude to the MR signal.

Automated Tip Conditioning ML-Based Software For Scanning Tunneling Spectroscopy

Scanning tunneling microscopy (STM) techniques and associated spectroscopic (STS) methods, such as dI/dV point spectroscopy, have been widely used to measure electronic structures and local density of states of molecules and materials with unprecedented spatial and energy resolutions. However, the quality of dI/dV spectra highly depends on the shape of the probe tips, and atomically sharp tips with well-defined apex structures are required for obtaining reliable spectra. In most cases, STS measurements are performed in ultra-high vacuum  and low temperature (4 K) to minimize disturbances. Advance tip preparation and constant in situ tip conditioning are required before and during the characterization of target molecules and materials. A common way to prepare STM tips is to repetitively poke them on known and bare substrates (i.e. coinage metals or silicon) to remove contaminations and to potentially coat the tip with substrate atoms. The standard dI/dV spectra of the substrate is then used as a reference to determine whether the tip is available for further experiments. However, tip geometry changes during the poking process are unpredictable, and consequently tip conditioning is typically slow and needs to be constantly monitored. Therefore, it restricts the speed of high-quality STM spectroscopic studies. In order to make efficient use of instrument idle time and minimize the research time wasted on tip conditioning, UC Berkeley researchers developed software based on Python and machine learning that can automate the time-consuming tip conditioning processes. The program is designed to do tip conditioning on Au(111) surfaces that are clean or with low molecular coverage with little human intervention. By just one click, the program is capable of continued poking until the tip can generate near-publication quality spectroscopic data on gold surfaces. It can control the operation of a Scienta Omicron STM and automatically analyze the collected topographic images to find bare Au areas that are large enough for tip conditioning. It will then collect dI/dV spectra at selected positions and use machine learning models to determine their quality compared to standard dI/dV spectra for Au20 and determine if the tip is good enough for further STS measurements. If the tip condition is not ideal, the program will control the STM to poke at the identified positions until the machine learning model predicts the tip to be in good condition.