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MYC-Targeting Inhibitors Generated From A New Method To Synthesize Stereo-Diversified Bicyclic Libraries

Professor Min Xue and colleagues from the University of California, Riverside have developed a new method of construction of a bicyclic peptide library featuring a novel stereo-diversified structure and a simplified construction strategy.  MYC inhibitors were synthesized to demonstrate this method. The method works by using a tandem ring-opening metathesis (ROM) and ring-closing metathesis (RCM) reaction (ROM-RCM) to cyclize the linear peptide library in a single step. This technology is advantageous because the resulting bicyclic peptide may be easily linearized for MS/MS sequencing with a one-step chemistry procedure. 

Artificial Intelligence-Based Evaluation Of Drug Efficacy

Researchers at the University of California, Davis have developed a method of using artificial intelligence for assessing the effectiveness or efficacy of drugs that is cheaper, faster, and more accurate than commonly used assay analyses.

Methods To Dysfluent Speech Transcription And Detection

Dysfluent speech modeling requires time-accurate and silence-aware transcription at both the word-level and phonetic-level. However, current research in dysfluency modeling primarily focuses on either transcription or detection, and the performance of each aspect remains limited.To address this problem, UC Berkeley researchers have developed a new unconstrained dysfluency modeling (UDM) approach that addresses both transcription and detection in an automatic and hierarchical manner. Furthermore, a simulated dysfluent dataset called VCTK++ enhances the capabilities of UDM in phonetic transcription. The effectiveness and robustness of UDM in both transcription and detection tasks has been demonstrated experimentally.UDM eliminates the need for extensive manual annotation by providing a comprehensive solution.

COMPOUNDS FOR MODULATING EPITHELIAL 15-(S)-LIPOXYGENASE-2 AND METHODS OF USE FOR SAME

Lipoxygenases (LOX) are enzymes that catalyze the peroxidation of certain fatty acids. The cell membrane is mostly made of lipids (which include fatty acids), and peroxidation can cause damage to the cell membrane. The human genome contains six functional LOX genes that encode for six LOX enzyme variants, or isozymes. The role that each LOX isozyme plays in health and disease varies greatly, spanning issues such as asthma, diabetes, and stroke. LOX enzymes are extremely difficult to target due to high hydrophobicity. Potential leads are often ineffective because they are either not readily soluble or not selective for a particular LOX enzyme.  Studies have implicated human epithelial 15-lipoxygenase-2 (h15-LOX-2, ALOX15B) in various diseases. h15-LOX-2 is highly expressed in atherosclerotic plaques and is linked to the progression of macrophages to foam cells, which are present in atherosclerotic plaques. h15-LOX-2 mRNA levels are also highly elevated in human macrophages isolated from carotid atherosclerotic lesions in symptomatic patients. Children with cystic fibrosis had reduced levels of h15-LOX-2, which affects the lipoxin A4 to leukotriene B4 ratio. Furthermore, the interactions of h15-LOX-2 and PEBP1 changes the substrate specificity of h15-LOX-2 from free polyunsaturated fatty acids (PUFA) to PUFA-phosphatidylethanolamines (PE), leading to the generation of hydroperoxyeicosatetraenoic acid (HpETE) esterified into PE (HpETE-PE). Accumulation of these hydroperoxyl membrane phospholipids has been shown to cause ferroptotic cell death, which implicates h15-LOX-2 in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s diseases.  

(SD2018-040) High Yield Fabrication of Sharp Vertically Aligned Nanowire Arrays for Intracellular Recordings and Applications Thereof

Engineers from UC San Diego have disclosed a new patent-pending technology (SHARP, VERTICALLY ALIGNED NANOWIRE ELECTRODE ARRAYS, HIGH-YIELD FABRICATION ANDINTRACELLULAR RECORDING) that minimizes the electrode size to an intracellular probe, and is scalable to integrate multiple channels at one platform and overcomes the previous disadvantages such as invasiveness and insensitivity. This newly disclosed improved technology reduces the number of steps and the number of metal layers used to increase the biocompatibility and device yield, as compared to an earlier disclosure for NEAs that were fabricated using a different process.

MR-Based Electrical Property Reconstruction Using Physics-Informed Neural Networks

Electrical properties (EP), such as permittivity and conductivity, dictate the interactions between electromagnetic waves and biological tissue. EP are biomarkers for pathology characterization, such as cancer. Imaging of EP helps monitor the health of the tissue and can provide important information in therapeutic procedures. Magnetic resonance (MR)-based electrical properties tomography (MR-EPT) uses MR measurements, such as the magnetic transmit field B1+, to reconstruct EP. These reconstructions rely on the calculations of spatial derivatives of the measured B1+. However, the numerical approximation of derivatives leads to noise amplifications introducing errors and artifacts in the reconstructions. Recently, a supervised learning-based method (DL-EPT) has been introduced to reconstruct robust EP maps from noisy measurements. Still, the pattern-matching nature of this method does not allow it to generalize for new samples since the network’s training is done on a limited number of simulated data pairs, which makes it unrealistic in clinical applications. Thus, there is a need for a robust and realistic method for EP map construction.

FlexThrough: a recirculation mechanism for point of care, centrifugal disk-based microfluidic devices

One of the key limitations for devices used in point-of-care diagnostics (POCD) is their limit of detection; patient samples used for POCD devices often contain too low of the target analyte. FlexThrough is a newly developed, centrifugal disk (CD)-based method that utilizes the entirety of a liquid sample via recirculation of the sample for efficient mixing as it iteratively passes through the system.

Rapid optical detection system for SARS-CoV-2 and other pathogens

Researchers at UC Irvine have developed an optical detection system for SARS-CoV-2 and other pathogens that features improvements in screening time, cost, sensitivity, and practicality. As vaccine availability, economic pressure, and mental health considerations has gradually returned society to pre-pandemic activities that require frequent and close interactions, it is imperative that SARS-CoV-2 detection systems remain effective.

Piericidin A1 And The Piericidin Derivative Mer-A 2026B As Inhibitors Of The Bacterial Type III Secretion System

 As currently available antibiotics become ineffective due to the rise in antibiotic resistance among pathogenic bacteria, development of completely new classes of antibiotics is critical. Classic antibiotics target pathogens and commensal bacteria indiscriminately; therefore, their use puts selective pressure on both populations. Because of the abundance of commensals within a mammalian host, antibiotic resistance is thought to arise more frequently in commensal bacteria and is horizontally transferred to pathogens. In contrast to classic antibiotics, virulence blockers are compounds that selectively inhibit the expression or function of a virulence factor in a pathogen or group of pathogens. Advantages of virulence blockers are twofold. For one, selective pressure on a limited number of microbes, i.e., only pathogens expressing the molecular target of the virulence blocker, should limit the evolution of resistance. Second, the decreased commensal killing by virulence blockers has the potential to preserve a healthy microbiota, which is critical for maintaining gut homeostasis and defending against opportunistic pathogens. Type III secretion systems (T3SS) are bacterial appendages required by dozens of pathogens to cause disease, including Salmonella, enteropathogenic Escherichia coli (EPEC), Shigella, Pseudomonas, and Yersinia, but they are largely absent in nonpathogenic bacteria. Bacteria use T3SS to inject bacterial effector proteins into target host cells to manipulate host processes for the benefit of the pathogen. Seven T3SS injectisome families have been identified and share a number of homologous membrane-associated components with the flagellar basal body. Agents that target T3SS would be key virulance blockers for a set of pathogens that are very important to human and animal health as are methods of screening for such agents. 

Biological and Hybrid Neural Networks Communication

During initial stages of development, the human brain self assembles from a vast network of billions of neurons into a system capable of sophisticated cognitive behaviors. The human brain maintains these capabilities over a lifetime of homeostasis, and neuroscience helps us explore the brain’s capabilities. The pace of progress in neuroscience depends on experimental toolkits available to researchers. New tools are required to explore new forms of experiments and to achieve better statistical certainty.Significant challenges remain in modern neuroscience in terms of unifying processes at the macroscopic and microscopic scale. Recently, brain organoids, three-dimensional neural tissue structures generated from human stem cells, are being used to model neural development and connectivity. Organoids are more realistic than two-dimensional cultures, recapitulating the brain, which is inherently three-dimensional. While progress has been made studying large-scale brain patterns or behaviors, as well as understanding the brain at a cellular level, it’s still unclear how smaller neural interactions (e.g., on the order of 10,000 cells) create meaningful cognition. Furthermore, systems for interrogation, observation, and data acquisition for such in vitro cultures, in addition to streaming data online to link with these analysis infrastructures, remains a challenge.

An accessible lab on a chip platform for single cell differentiation of cancerous tumors

Researchers at UC Irvine have developed a novel, machine learning-assisted biochip for rapid, affordable, and practical analysis of single cell tumor heterogeneity. The technology’s low cost and ease of manufacture makes it an optimal point-of-care diagnostic in developing countries, where early cancer detection is severely lacking.

Redesigned vaginal speculum for enhanced patient comfort and physician use

Researchers at UC Irvine have redesigned the vaginal speculum, a medical device routinely used for pap smears, and other medical procedures that involve inspection of the vaginal canal (i.e. IUD insertions, STD testing, and hysterectomies). The novel design addresses several patient discomforts associated with currently used speculums and is more time- and cost-effective for health professionals.

DP-L4056 Prophage-Cured Strain Of Listeria Monocytogenes

DP-L4056 is a prophage-cured strain of Listeria monocytogenes based on wild-type strain 10403S. A prophage is a bacteriophage genome that is integrated into a bacterial genome. It remains latent until activation by an external factor, and activation leads to production of new bacteriophage particles that lyse the bacterial cell and spread. Curing the prophages in Listeria monocytogenes strain 10403S, which is ubiquitous in the microbiology community as a wild-type reference strain, allows for more predictable engineering and performance of Listeria monocytogenes.

Aerosol Ionization For Charge Detection Mass Spectrometry Ion Mobility Analysis

Existing screening tools for respiratory pathogens, including PCR-based methods and antibody-based methods, are generally time-consuming to perform and analyze, difficult to manufacture at scale, and reliant on a detailed understanding of the targeted pathogen. Additionally, these traditional methods give little insight into the extent to which an individual is capable of spreading the disease. All of these features hamstring early responses to emerging pathogens and early-stage epidemics, as can be seen from the ongoing SARS-COV-2 pandemic. To address these problems, researchers at UC Berkeley have developed a device which ionizes large biomolecules from aerosol droplets and routes them to the inlet of a mass spectrometer or ion mobility spectrometer for identification based on size and/or mass. This can serve as the basis for a screening tool which measures the concentration of pathogenic particles, including common respiratory viruses and bacteria, in the breath. Results from this test could be read out in a matter of seconds, and it does not depend on detailed knowledge of the pathogen in question. Researchers have demonstrated the efficacy of such a device in detecting both large human proteins and virus-sized styrofoam particles.

Portable Neural Network Enabled Biofluid Spectroscopy

Researchers at the University of California, Davis have developed a method of biofluid assessment capable of real-time monitoring as well as compatible with machine learning and neural network processing.

PMUT for Blood Pressure Monitoring

Cardiovascular disease is among the leading causes of death for citizens in affluent nations, and the most significant cause of morbidity in those with cardiovascular disease is hypertension. Often called the “silent killer” because it has few clinical signs in its early stages, elevated blood pressure is often in an advanced stage before it is treated, leading to a substantially worse prognosis than if it had been detected earlier.In order to address this problem, researchers at UC Berkeley have developed a wearable device which continuously monitors diastolic blood pressure, transmitting data to a portable device such as a cell phone, where it can be stored and analyzed. The device utilizes piezoelectric transducers to perform the measurement, which allows the wearable device to remain small while containing a large number of sensors in order to reduce noise.

(SD2021-089) Unbiased approach for identification of regulators of materials and molecular uptake into cells

A major bottleneck in nanocarrier and macromolecule development for therapeutic delivery is our limited understanding of the processes involved in their uptake into target cells. This includes their active interactions with membrane transporters that co-ordinate cellular uptake and processing. Current strategies to elucidate the mechanism of uptake, such as painstaking manipulation of individual effectors with pharmacological inhibitors or specific genetic knockdowns, are limited in scope and biased towards previously studied pathways or the intuition of the investigators. Furthermore, each of these approaches present significant off-target effects, clouding the outcomes. Methods for intracellular transport of nucleic acids are much sought after in the context of both in vitro delivery reagents and in vivo therapeutics. Recently, we found that micellar assemblies of hundreds of amphiphiles consisting of single-stranded DNA which has been covalently linked to a hydrophobic polymer, referred to as DNA-polymer amphiphile nanoparticles or DPANPs, can readily access the cytosol of cells where they modulate mRNA expression of target genomes without transfection or other helper reagents, making them potential therapeutic nucleic acid carriers. However, despite their effective uptake properties and efficacy in the cytosol, it was unknown how these polyanionic structures can enter cells. Indeed, generally, bottlenecks in understanding and achieving delivery and uptake remain a forefront issue in translatability of macromolecular and nanomaterials-based therapeutics generally, including with respect to nucleic acid therapies. The nature of pooled screening requires amplifying a single ~200nt region per cell, leading to screens that require amplification from tens-to hundreds of micrograms of genomic DNA. Inhibitory effects of high DNA concentration per PCR have led to a variety of solutions, ranging from simply pooling hundreds of PCR reactions to utilizing restriction enzyme sites present in the lentiviral backbone constant regions flanking the sgRNA to perform DNA gel electrophoresis and size selection to remove undesired gDNA. However, these approaches can be both expensive and have significant handling challenges when scaled to large screens.

(SD2022-010) Method for transmembrane protein semisynthesis and reconstitution in lipid membranes

Cellular lipid membranes are embedded with transmembrane proteins crucial to cell function. Elucidating membrane proteins’ diverse structures and biophysical mechanisms is increasingly necessary due to their growing prevalence as a therapeutic target and sheer ubiquity in cells. Most biophysical characterization strategies of transmembrane proteins rely on the tedious overexpression and isolation of recombinant proteins and their reconstitution in model phospholipid bilayers.Unfortunately, membrane protein reconstitution depends on the use of denaturing and unnatural detergents that can interfere with protein structure and function. We have developed a detergent‐free method to reconstitute transmembrane proteins in model phospholipid vesicles and GUVs. Additionally, transmembrane proteins are difficult to express in cells due to the extreme insolubility of their transmembrane domain. By incorporating a synthetic transmembrane peptide into liposomes and simply expressing soluble portions of transmembrane proteins in cells, we can use this semisynthetic ligation strategy to more easily construct functional transmembrane proteins and reconstitute them into liposomes for biophysical and biochemical studies.Inteins can be found contiguously or non contiguously within some proteins. Non‐contiguous inteins are called “split inteins”. Inteins can be thought of as a type of protein intron which splices itself out of proteins. When non‐contiguous inteins find and bind to each other, they are then able to excise themselves resulting in the ligation of their respective exteins. Split intein pairs (C‐intein and N‐intein) can be attached to proteins of interest in synthetic and cellular systems to ligate protein sequences together.

Screening method for identifying compounds that treat disorders in circadian rhythms

The CRY1:CLOCK:BMAL1 sits at the core of the integrated transcription-translation feedback loop that regulates the expression of proteins that are dependent upon circadian rhythms. Disruption of circadian rhythms has been linked to altered cell homeostasis and diseases. 

Single-Cell Analysis of Somatic Mutation Burden

Brief description not available

Nanopore Sequencing of RNA Using Reverse Transcription

This invention demonstrates that an engineered cellular reverse transcriptase is a potent motor protein that can processively thread single-stranded RNA (ssRNA) through the MspA biological nanopore in single nucleotide steps while it is synthesizing cDNA. Notably, this represents a first-ever achievement for threading of ssRNA through the engineered Mycobacterium smegmatis porin A (MspA) nanopore in discrete steps, and also for ssRNA sequencing with the MspA nanopore. The inventors constructed the “quadromer map” for ssRNA in the MspA nanopore, which is essentially a table that can convert measured nanopore ion current to RNA sequences, using ssRNAs of known sequences. In addition, the inventors discovered that the single-molecule kinetic rates of the reverse transcriptase are affected by the presence of stable RNA secondary structures. Monitoring this biophysical behavior can be used to determine RNA structures during nanopore sequencing.  Nanopore sequencing is a powerful third generation sequencing technology that offers advantages such as ultra-long read length and direct detection of chemically modified bases. One of the key components of developing a successful nanopore sequencer is identifying potent motor proteins (such as polymerases or helicases) that can thread single-stranded (ss) DNA or ssRNA through the nanopore in discrete steps with high processivity.   

Deep Learning-Based Approach to Accelerate T cell Receptor Design

Researchers at the University of California, Davis have developed a deep learning simulation model to predict mutated T-cell receptor affinity and avidity for immunotherapy applications.

Fetal Oximetry Measurement via Maternal Transabdominal Spectroscopy

Researchers at the University of California, Davis have developed a non-invasive, near-infrared, spectroscopy technique that measures fetal oxygen saturation via the maternal abdomen.

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