A5066778848- Genomics, phytochemicals, and oxidative stress
- Glutathione Transferases and Polymorphisms
- MicroRNA in disease regulation
- RNA Interference and Gene Delivery
- Epigenetics and DNA Methylation
- CRISPR and Genetic Engineering
- RNA Research and Splicing
- RNA modifications and cancer
- Advanced biosensing and bioanalysis techniques
- Neurogenesis and neuroplasticity mechanisms
- interferon and immune responses
- RNA regulation and disease
- Estrogen and related hormone effects
- Virus-based gene therapy research
- Enzyme Production and Characterization
- Inflammasome and immune disorders
- Circular RNAs in diseases
- GDF15 and Related Biomarkers
- Cancer Mechanisms and Therapy
- RNA and protein synthesis mechanisms
- Chemical Synthesis and Analysis
- Machine Learning in Bioinformatics
- Cancer-related molecular mechanisms research
- Melanoma and MAPK Pathways
- Cytomegalovirus and herpesvirus research
Longevity Biotech (United States)
2022
Integrated DNA Technologies (United States)
2012
SomaGenics (United States)
2012
Stanford University
2012
University of California, San Francisco
2005-2010
Philadelphia University
2009
University of Pennsylvania
2009
Diabetes Australia
2008
Drexel University
2007
To investigate the role of Dicer and microRNAs in mammalian CNS, we used mice which second RNase III domain was conditionally floxed. Conditional were bred with expressing an α-calmodulin kinase II Cre to selectively inactivate excitatory forebrain neurons vivo . Inactivation results array phenotypes including microcephaly, reduced dendritic branch elaboration, large increases spine length no concomitant change density. Microcephaly is likely caused by a 5.5-fold increase early postnatal...
A propensity for rewiring genetic and epigenetic regulatory networks, thus enabling sustained cell proliferation, suppression of apoptosis, the ability to evade immune system, is vital cancer propagation. An increased understanding how this achieved critical identifying or improving therapeutic interventions. In study, using acute myeloid leukemia (AML) human lines a custom CRISPR/Cas9 screening platform, we identify H3K9 methyltransferase SETDB1 as novel, negative regulator innate immunity....
MicroRNAs (miRNAs) are small noncoding RNAs that can act to repress target mRNAs by suppressing translation and/or reducing mRNA stability. Although it is clear miRNAs and Dicer, an RNase III enzyme central the production of mature miRNAs, have a role in early development neurons, their roles postmitotic neuron vivo largely unknown. To determine Dicer we ablated dopaminoceptive neurons. Mice lost these cells display range phenotypes including ataxia, front hind limb clasping, reduced brain...
Delivery of siRNA is a key hurdle to realizing the therapeutic promise RNAi. By targeting internalizing cell surface antigens, antibody–siRNA complexes provide possible solution. However, initial reports relied on non-specific charged interactions and have not been broadly applicable. To assess improve this delivery method, we built an industrial platform antibodies called THIOMABs, engineered enable precise covalent coupling siRNAs. We report that such generates monomeric conjugates (ARCs)...
Abstract The NLRC4 inflammasome recognizes bacterial flagellin and components of the type III secretion apparatus. stimulation leads to caspase-1 activation followed by a rapid lytic cell death known as pyroptosis. is linked pathogen-free auto-inflammatory diseases, suggesting role for in sterile inflammation. Here, we show that activates an alternative program morphologically similar apoptosis caspase-1-deficient BMDMs. By performing unbiased genome-wide CRISPR/Cas9 screen with subsequent...
Abstract Epigenetic aging clocks are computational models that predict age using DNA methylation information. Initially, first-generation were developed to make predictions CpGs change with age. Over time, next-generation created relate both and health. Since existing constructed in blood, we sought develop a clock optimized for prediction cheek swabs, which non-invasive easy collect. To do this, collected MethylationEPIC data as well lifestyle health information from 8045 diverse adults....
Mammalian Argonaute 2 (Ago2) protein associates with microRNAs (miRNAs) or small interfering RNAs (siRNAs) forming RNA-induced silencing complexes (RISCs/miRNPs). In the present work, we characterize RNA-binding and nucleolytic activity of recombinant mouse Ago2. Our studies show that Ago2 binds efficiently to miRNAs active RISC. Surprisingly, find forms RISC using pre-miRNAs long unstructured single stranded as guides. Furthermore, demonstrate that, in vivo , endogenous human directly...
The necroptotic cell death pathway is a key component of human pathogen defense that can become aberrantly derepressed during tissue homeostasis to contribute multiple types damage and disease. While formation the necrosome kinase signaling complex containing RIPK1, RIPK3, MLKL has been extensively characterized, additional mechanisms its regulation effector functions likely remain be discovered. We screened 19,883 mouse protein-coding genes by CRISPR/Cas9-mediated gene knockout for...
Small hairpin RNAs (shRNAs) having duplex lengths of 25–29 bp are normally processed by Dicer into short interfering (siRNAs) before incorporation the RNA-induced silencing complex (RISC). However, shRNAs ≤19 [short (sshRNAs)] too for to excise their loops, raising questions about mechanism action. sshRNAs designated as L-type or R-type according whether loop is positioned 3′ 5′ guide sequence, respectively. Using nucleotide modifications that inhibit RNA cleavage, we show R- but not...
A central event in Alzheimer's disease (AD) is the regulated intramembraneous proteolysis of beta-amyloid precursor protein (APP), to generate (Abeta) peptide and APP intracellular domain (AICD). Abeta major component amyloid plaques AICD displays transcriptional activation properties. We have taken advantage transactivation properties develop a genetic screen identify regulators metabolism. This relies on an APP-Gal4 fusion protein, which upon normal proteolysis, produces AICD-Gal4....
Incorporating miRNA-like features into vector-based hairpin scaffolds has been shown to augment small RNA processing and RNAi efficiency. Therefore, defining an optimal, native context may obviate a need for hairpin-specific targeting design schemes, which confound the movement of functional siRNAs shRNA/artificial miRNA backbones, or large-scale screens identify efficacious sequences. Thus, we used quantitative cell-based assays compare separate third generation artificial systems, miR-E...
Cytosolic double-stranded RNA (dsRNA) initiates type I IFN responses. Endogenous retroelements, notably Alu elements, constitute a source of dsRNA. Adenosine-to-inosine (A-to-I) editing by ADAR induces mismatches in dsRNA and prevents recognition MDA5 autoinflammation. To identify additional endogenous checkpoints, we conducted candidate screen THP-1 monocytes found that hnRNPC deficiency resulted synergistic induction MDA5-dependent RNA-seq analysis demonstrated dysregulation Alu-containing...
Mutant KRAS represents one of the most frequently observed oncogenes in NSCLC, yet no therapies are approved for tumors that express activated variants. While there is strong rationale use MEK inhibitors to treat with RAS/MAPK signaling, these have proven ineffective clinically. We therefore implemented a CRISPR screening approach identify novel agents sensitize mutant NSCLC cells inhibitor treatment. This identified multiple components canonical pathway consistent previous studies. In...
Mutations in KEAP1 and NFE2L2 (encoding the protein Nrf2) are prevalent both adeno squamous subtypes of non-small cell lung cancer, as well additional tumor indications. The consequence these mutations is stabilized Nrf2 chronic induction a battery target genes. We show that knockdown caused modest growth inhibition cells growing two-dimension, which was more pronounced lines expressing mutant KEAP1. In contrast, almost complete regression established KEAP1-mutant tumors mice, with little...
While earlier first-generation epigenetic aging clocks were trained to estimate chronological age as accurately possible, more recent next-generation incorporate DNA methylation information pertinent health, lifestyle, and/or outcomes. Recently, we produced a non-invasive clock using Infinium MethylationEPIC data from than 8,000 diverse adult buccal samples. this correlated with various and disease factors, did not assess its ability capture mortality. To address gap, applied CheekAge the...
Epigenetic aging clocks are computational models that use DNA methylation sites to predict age. Since cheek swabs non-invasive and painless, collecting from buccal tissue is highly desirable. Here, we review 11 existing have been applied tissue. Two of these were exclusively trained on adults and, while moderately accurate, not used capture health-relevant differences in epigenetic Using 130 common CpGs utilized by two or more clocks, generate a proof-of-concept predictor an adult methylomic...
<div>Abstract<p>Mutations in <i>KEAP1</i> and <i>NFE2L2</i> (encoding the protein Nrf2) are prevalent both adeno squamous subtypes of non–small cell lung cancer, as well additional tumor indications. The consequence these mutations is stabilized Nrf2 chronic induction a battery target genes. We show that knockdown caused modest growth inhibition cells growing two-dimension, which was more pronounced lines expressing mutant KEAP1. In contrast, almost...