A5027876177- CRISPR and Genetic Engineering
- RNA and protein synthesis mechanisms
- Genomics and Rare Diseases
- SARS-CoV-2 and COVID-19 Research
- Viral Infections and Immunology Research
- Alzheimer's disease research and treatments
- Protein Structure and Dynamics
- Central Venous Catheters and Hemodialysis
- Mitochondrial Function and Pathology
- Pluripotent Stem Cells Research
- Genetic Associations and Epidemiology
- Computational Drug Discovery Methods
- SARS-CoV-2 detection and testing
- Single-cell and spatial transcriptomics
- RNA modifications and cancer
- Advanced biosensing and bioanalysis techniques
- Acute Ischemic Stroke Management
- Antibiotic Use and Resistance
- Receptor Mechanisms and Signaling
- Neuroscience and Neural Engineering
- Bioinformatics and Genomic Networks
- Plant biochemistry and biosynthesis
- 14-3-3 protein interactions
- Genomics and Chromatin Dynamics
- Genetic Neurodegenerative Diseases
Stanford University
2019-2024
Neurosciences Institute
2024
Quantitative BioSciences
2024
Washington University in St. Louis
2024
Lucile Packard Children's Hospital
2023
Compact and versatile CRISPR-Cas systems will enable genome engineering applications through high-efficiency delivery in a wide variety of contexts. Here, we create an efficient miniature Cas system (CasMINI) engineered from the type V-F Cas12f (Cas14) by guide RNA protein engineering, which is less than half size currently used CRISPR (Cas9 or Cas12a). We demonstrate that CasMINI can drive high levels gene activation (up to thousands-fold increases), while natural fails function mammalian...
Mammalian genomes have multiple enhancers spanning an ultralong distance (>megabases) to modulate important genes, but it is unclear how these coordinate achieve this task. We combine multiplexed CRISPRi screening with machine learning define quantitative enhancer-enhancer interactions. find that the enhancer network has a nested multilayer architecture confers functional robustness of gene expression. Experimental characterization reveals epistasis maintained by three-dimensional...
Abstract The number of structures and molecular dynamics simulations proteins is exploding owing to dramatic advances in cryo-electron microscopy, crystallography, computing. One the most powerful ways analyze structural information involves comparisons interatomic interactions across different or same protein related from family ( e.g. GPCRs). Such comparative analyses are interest a wide range researchers but currently prove challenging for all few. To facilitate analyses, we have...
Abstract A major challenge in coronavirus vaccination and treatment is to counteract rapid viral evolution mutations. Here we demonstrate that CRISPR-Cas13d offers a broad-spectrum antiviral (BSA) inhibit many SARS-CoV-2 variants diverse human strains with >99% reduction of the titer. We show Cas13d-mediated inhibition dependent on crRNA cellular spatial colocalization Cas13d target RNA. can significantly enhance therapeutic effects small molecule drugs against coronaviruses for...
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) and variants has led to significant mortality. We recently reported that an RNA-targeting CRISPR-Cas13 system, called prophylactic antiviral CRISPR in human cells (PAC-MAN), offered strategy against SARS-CoV-2 influenza A virus. Here, we expand silico analysis use PAC-MAN target a broad spectrum of human- or livestock-infectious RNA viruses with high specificity, coverage,...
Significance Structure-based drug design depends on the ability to predict both three-dimensional structures of candidate molecules bound their targets and associated binding affinities. We demonstrate that one can substantially improve accuracy these predictions using easily obtained data about completely different bind same target without requiring any target-bound molecules. The approach we developed integrate physical data-driven modeling may find a variety applications in rapidly...
ABSTRACT The outbreak of the coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome 2 (SARS-CoV-2), has infected more than 100,000 people worldwide with over 3,000 deaths since December 2019. There is no cure for COVID-19 and vaccine development estimated to require 12-18 months. Here we demonstrate a CRISPR-Cas13-based strategy, PAC-MAN ( P rophylactic A ntiviral C RISPR in huMAN cells), viral inhibition that can effectively degrade SARS-CoV-2 sequences live...
Single nucleotide variants near
Single-nucleotide variants near TMEM106B associate with the risk of frontotemporal lobar dementia TDP-43 inclusions (FTLD-TDP) and Alzheimer disease (AD) in genome-wide association studies (GWASs), but causal variant at this locus remains unclear. Here, we asked whether a novel structural on is variant.
Summary The ε4 allele of apolipoprotein E ( APOE ) is the strongest genetic risk factor for sporadic Alzheimer’s Disease (AD). Knockdown this may provide a therapeutic strategy AD, but effect loss-of-function (LoF) on AD pathogenesis unknown. We searched LoF variants in large cohort older controls and patients with identified six heterozygote carriers variants. Five were (ages 71-90) one was an case unremarkable age-at-onset between 75-79. Two ε3/ε4 (Subjects 1 2) carried stop-gain affecting...
OBJECTIVES: Identifying modifiable risk factors associated with central line-associated bloodstream infections (CLABSIs) may lead to modifications line (CL) management. We hypothesize that the number of CL accesses per day is an increased for CLABSI and a significant fraction access be substituted non-CL routes. DESIGN: conducted retrospective cohort study patients at least one device from January 1, 2015, December 31, 2019. A multivariate mixed-effects logistic regression model was used...
Large-scale CRISPR-Cas pooled screens have shown great promise to investigate functional links between genotype and phenotype at the genome-wide scale. In addition technological advancement, there is a need develop computational methods analyze large datasets obtained from high-throughput CRISPR screens. Many been developed identify reliable gene hits various this review, we provide an overview of technology development screening platforms, with focus on recent advances in model effects...
Central line-associated bloodstream infections (CLABSIs) are the most common hospital-acquired infection in pediatric patients. High adherence to CLABSI bundle mitigates CLABSIs. At our institution, there did not exist a hospital-wide system measure bundle-adherence. We developed an electronic dashboard monitor bundle-adherence across hospital and real time.Institutional stakeholders areas of opportunity were identified through interviews data analyses. created pipeline pull from twice-daily...
Abstract Over the past fifty years, tremendous effort has been devoted to computational methods for predicting properties of ligands that bind macromolecular targets, a problem critical rational drug design. Such generally fall into two categories: physics-based methods, which directly model ligand interactions with target given target’s three-dimensional (3D) structure, and ligand-based predict experimental measurements similar ligands. Here we present rigorous statistical framework combine...
Abstract CRISPR-Cas nucleases and their nuclease-deactivated dCas variants have revolutionized the field of genome editing gene regulation. Cas12a possesses intrinsic RNAse activity can process multiple functional crRNAs from a single long transcript, making it powerful tool for multiplex targeting. We engineered dCas12a variant termed hyperCas12a with superior efficacy in regulation, especially at restrictive crRNA concentrations. Here, we describe step-by-step protocol constructing...
Abstract Background The ε4 variant of APOE is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD). It remains unclear if protein increases AD through a gain abnormal function, or whether it functions less well than ε3 protein. Framed bluntly: Would knocking down in an carrier increase decrease risk? Method We searched whole‐exomes and whole‐genomes from ∼47,000 older controls cases Disease Sequencing Project (ADSP) looking early loss‐of‐function variants on . Five...
Abstract Background Alzheimer’s disease (AD) is up to 60‐80% heritable, but less than ∼20% explained by studies analyzing single nucleotide variants (SNVs). One limitation of short‐read whole‐genome sequencing (SRS) the standard read length 150 base pairs, which does not enable detection longer structural (SVs). Here we sequenced individuals using long‐read (LRS), can sequence reads with an average ∼20 kilobases, allowing us identify SVs previously uncaptured. Method All participants...