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View article: A 3′UTR Insertion Is a Candidate Causal Variant at the <i>TMEM106B</i> Locus Associated With Increased Risk for FTLD-TDP
A 3′UTR Insertion Is a Candidate Causal Variant at the <i>TMEM106B</i> Locus Associated With Increased Risk for FTLD-TDP Open
We identified a novel Alu element insertion in the 3'UTR of TMEM106B in tight linkage with the lead FTLD-TDP risk variant. The lead variant is associated with TMEM106B protein levels, but not expression. The 3'UTR insertion is a lead candi…
View article: <i>APOE</i> loss‐of‐function variants: Compatible with longevity and associated with resistance to Alzheimer’s Disease pathology
<i>APOE</i> loss‐of‐function variants: Compatible with longevity and associated with resistance to Alzheimer’s Disease pathology Open
Background The ε4 variant of APOE is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD). It remains unclear if the ε4 protein increases AD risk through a gain of abnormal function, or whether it functions less well t…
View article: Novel characterization of Alzheimer’s disease genetic loci using long‐read sequencing
Novel characterization of Alzheimer’s disease genetic loci using long‐read sequencing Open
Background Alzheimer’s disease (AD) is up to 60‐80% heritable, but less than ∼20% is explained by studies analyzing single nucleotide variants (SNVs). One limitation of short‐read whole‐genome sequencing (SRS) is the standard read length o…
View article: <i>APOE</i>loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer’s Disease pathology
<i>APOE</i>loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer’s Disease pathology Open
Summary The ε4 allele of apolipoprotein E ( APOE ) is the strongest genetic risk factor for sporadic Alzheimer’s Disease (AD). Knockdown of this allele may provide a therapeutic strategy for AD, but the effect of APOE loss-of-function (LoF…
View article: A 3’UTR Insertion Is a Candidate Causal Variant at the<i>TMEM106B</i>Locus Associated with Increased Risk for FTLD-TDP
A 3’UTR Insertion Is a Candidate Causal Variant at the<i>TMEM106B</i>Locus Associated with Increased Risk for FTLD-TDP Open
Background and Objectives Single nucleotide variants near TMEM106B associate with risk of frontotemporal lobar dementia with TDP-43 inclusions (FTLD-TDP) and Alzheimer’s disease (AD) in genome-wide association studies (GWAS), but the causa…
View article: Nested epistasis enhancer networks for robust genome regulation
Nested epistasis enhancer networks for robust genome regulation Open
Mammalian genomes have multiple enhancers spanning an ultralong distance (>megabases) to modulate important genes, but it is unclear how these enhancers coordinate to achieve this task. We combine multiplexed CRISPRi screening with machine…
View article: Multiplex CRISPR genome regulation in mouse retina with hyper-efficient Cas12a
Multiplex CRISPR genome regulation in mouse retina with hyper-efficient Cas12a Open
CRISPR-Cas nucleases and their nuclease-deactivated dCas variants have revolutionized the field of genome editing and gene regulation. Cas12a possesses intrinsic RNAse activity and can process multiple functional crRNAs from a single long …
View article: Leveraging nonstructural data to predict structures and affinities of protein–ligand complexes
Leveraging nonstructural data to predict structures and affinities of protein–ligand complexes Open
Significance Structure-based drug design depends on the ability to predict both the three-dimensional structures of candidate molecules bound to their targets and the associated binding affinities. We demonstrate that one can substantially…
View article: Development and Implementation of a Real-time Bundle-adherence Dashboard for Central Line-associated Bloodstream Infections
Development and Implementation of a Real-time Bundle-adherence Dashboard for Central Line-associated Bloodstream Infections Open
Introduction: Central line-associated bloodstream infections (CLABSIs) are the most common hospital-acquired infection in pediatric patients. High adherence to the CLABSI bundle mitigates CLABSIs. At our institution, there did not exist a …
View article: A comprehensive analysis and resource to use CRISPR-Cas13 for broad-spectrum targeting of RNA viruses
A comprehensive analysis and resource to use CRISPR-Cas13 for broad-spectrum targeting of RNA viruses Open
Summary: 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,…
View article: Computational Methods for Analysis of Large-Scale CRISPR Screens
Computational Methods for Analysis of Large-Scale CRISPR Screens Open
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 to technological advancement, there is a need to develop computational meth…
View article: Leveraging non-structural data to predict structures of protein–ligand complexes
Leveraging non-structural data to predict structures of protein–ligand complexes Open
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 to rational drug design. Such methods generally fall into two …
View article: Uncovering patterns of atomic interactions in static and dynamic structures of proteins
Uncovering patterns of atomic interactions in static and dynamic structures of proteins Open
The number of structures and molecular dynamics simulations of proteins is exploding owing to dramatic advances in cryo-electron microscopy, crystallography, and computing. One of the most powerful ways to analyze structural information in…