Publications by authors named "Cheryl L Ackert-Bicknell"

Over 1,100 independent signals have been identified with genome-wide association studies (GWAS) for bone mineral density (BMD), a key risk factor for mortality-increasing fragility fractures; however, the effector gene(s) for most remain unknown. Informed by a variant-to-gene mapping strategy implicating 89 non-coding elements predicted to regulate osteoblast gene expression at BMD GWAS loci, we executed a single-cell CRISPRi screen in human fetal osteoblast 1.19 cells (hFOBs).

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  • * Sarcopenia (muscle loss) and osteoporosis (bone loss) are closely linked, with each condition serving as a predictor for the other, indicating the need for integrated research approaches.
  • * A recent workshop emphasized the importance of muscle characterization in musculoskeletal studies, advocating for more recognition and research on muscle phenotyping in both human and animal models like zebrafish and mice.
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Western diets are becoming increasingly common around the world. Western diets have high omega 6 (ω-6) and omega 3 (ω-3) fatty acids and are linked to bone loss in humans and animals. Dietary fats are not created equal; therefore, it is vital to understand the effects of specific dietary fats on bone.

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Purpose Of Review: GWAS, as a largely correlational analysis, requires in vitro or in vivo validation. Zebrafish (Danio rerio) have many advantages for studying the genetics of human diseases. Since gene editing in zebrafish has been highly valuable for studying embryonic skeletal developmental processes that are prenatally or perinatally lethal in mammalian models, we are reviewing pros and cons of this model.

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Detecting allelic imbalance at the isoform level requires accounting for inferential uncertainty, caused by multi-mapping of RNA-seq reads. Our proposed method, SEESAW, uses Salmon and Swish to offer analysis at various levels of resolution, including gene, isoform, and aggregating isoforms to groups by transcription start site. The aggregation strategies strengthen the signal for transcripts with high uncertainty.

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Genome-wide association studies (GWASs) have demonstrated the complexity of human height. Baronas et al. used a high-throughput CRISPR screen to identify genes that participate in growth plate chondrocyte maturation as a functional follow-up and validation screen to refine loci and establish causality after GWASs.

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Purpose Of Review: Intervertebral disc degeneration is a contributor to chronic back pain. While a part of the natural aging process, early or rapid intervertebral disc degeneration is highly heritable. In this review, we summarize recent progress towards unraveling the genetics associated with this degenerative process.

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  • - The study investigates the link between femoroacetabular impingement (FAI) and hip osteoarthritis (OA), using whole-genome RNA sequencing to identify differentially expressed genes (DEGs) in cartilage samples from FAI and OA patients.
  • - A total of 3531 DEGs were discovered, with notable gene expression patterns: FGF18 and WNT16 were increased in FAI samples, while MMP13 and ADAMTS4 were elevated in OA samples, indicating different biological responses in the progression from FAI to OA.
  • - The findings suggest that early FAI may involve heightened anabolic signaling, which shifts towards catabolic and inflammatory gene expression as the condition worsens, ultimately contributing to
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Purpose Of Review: RNA-sequencing (RNA-seq) is a novel and highly sought-after tool in the field of musculoskeletal regenerative medicine. The technology is being used to better understand pathological processes, as well as elucidate mechanisms governing development and regeneration. It has allowed in-depth characterization of stem cell populations and discovery of molecular mechanisms that regulate stem cell development, maintenance, and differentiation in a way that was not possible with previous technology.

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This protocol describes the application of the "omnigenic" model of the genetic architecture of complex traits to identify novel "core" genes influencing a disease-associated phenotype. Core genes are hypothesized to directly regulate disease and may serve as therapeutic targets. This protocol leverages GWAS data, a co-expression network, and publicly available data, including the GTEx database and the International Mouse Phenotyping Consortium Database, to identify modules enriched for genes with "core-like" characteristics.

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  • * A genome-wide association study analyzed data from over 256,000 Europeans aged 60 and above, identifying 15 genetic loci linked to muscle weakness, 12 of which were previously unassociated with grip strength.
  • * The study suggests that muscle weakness may involve different biological mechanisms than continuous strength, implicating factors related to autoimmune diseases, arthritis, and aspects of the aging process.
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This chapter describes the isolation and culture of neonatal mouse calvarial osteoblasts. This primary cell population is obtained by sequential enzymatic digestion of the calvarial bone matrix and is capable of differentiating in vitro into mature osteoblasts that deposit a collagen extracellular matrix and form mineralized bone nodules. Maturation of the cultures can be monitored by gene expression analyses and staining for the presence of alkaline phosphatase or matrix mineralization.

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The "omnigenic" model of the genetic architecture of complex traits proposed two categories of causal genes: core and peripheral. Core genes are hypothesized to directly regulate disease and may serve as therapeutic targets. Using a cell-type- and time-point-specific gene co-expression network for mineralizing osteoblasts, we identify a co-expression module enriched for genes implicated by bone mineral density (BMD) genome-wide association studies (GWASs), correlated with in vitro osteoblast mineralization and associated with skeletal phenotypes in human monogenic disease and mouse knockouts.

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Noninvasive diagnostics for musculoskeletal infections (MSKI) remain challenging. Abs from newly activated, pathogen-specific plasmablasts in human blood, which emerge during an ongoing infection, can be used for diagnosing and tracking treatment response in diabetic foot infections. Using multianalyte immunoassays on medium enriched for newly synthesized Abs (MENSA) from Ab-secreting cells, we assessed anti- IgG responses in 101 MSKI patients (63 culture-confirmed , 38 -negative) and 52 healthy controls.

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Osteoporosis is a genetic disease characterized by progressive reductions in bone mineral density (BMD) leading to an increased risk of fracture. Over the last decade, genome-wide association studies (GWASs) have identified over 1000 associations for BMD. However, as a phenotype BMD is challenging as bone is a multicellular tissue affected by both local and systemic physiology.

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Osteoporosis is a complex genetic disease in which the number of loci associated with the bone mineral density, a clinical risk factor for fracture, has increased at an exponential rate in the last decade. The identification of the causative variants and candidate genes underlying these loci has not been able to keep pace with the rate of locus discovery. A large number of tools and data resources have been built around the use of the mouse as model of human genetic disease.

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Bone mineral density (BMD) is a strong predictor of osteoporotic fracture. It is also one of the most heritable disease-associated quantitative traits. As a result, there has been considerable effort focused on dissecting its genetic basis.

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  • The article had an initial error in Fig. 5a where the data for 'DAAM2 gRNA1' was misrepresented.
  • It incorrectly used circles to show 'untreated' data instead of the correct squares for 'treated' data.
  • The mistake has been fixed in both the HTML and PDF versions of the article.
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Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.

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Article Synopsis
  • - CPED1 is an uncharacterized gene located on Chromosome 7, associated with bone mineral density, but its specific functions and impact on bone biology remain unexplored.
  • - Research using mouse models reveals that CPED1 undergoes alternative splicing, producing various transcript forms that may lack important functional domains.
  • - This study lays the groundwork for future investigations into CPED1's role in bone biology by suggesting that multiple protein products may arise from this gene, influencing bone development.
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Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD.

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Osteoporosis is a common disease diagnosed primarily by measurement of bone mineral density (BMD). We undertook a genome-wide association study (GWAS) in 142,487 individuals from the UK Biobank to identify loci associated with BMD as estimated by quantitative ultrasound of the heel. We identified 307 conditionally independent single-nucleotide polymorphisms (SNPs) that attained genome-wide significance at 203 loci, explaining approximately 12% of the phenotypic variance.

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Purpose: Familial exudative vitreoretinopathy (FEVR) is caused by mutations in the genes encoding low-density lipoprotein receptor-related protein (LRP5) or its interacting partners, namely frizzled class receptor 4 (FZD4) and norrin cystine knot growth factor (NDP). Mouse models for , , and have proven to be important for understanding the retinal pathophysiology underlying FEVR and systemic abnormalities related to defective Wnt signaling. Here, we report a new mouse mutant, , which was identified by electroretinogram (ERG) screening of mice generated in the Jackson Laboratory Translational Vision Research Models (TVRM) mutagenesis program.

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Genome-wide association studies (GWASs) have revealed numerous loci for areal bone mineral density (aBMD). We completed the first GWAS meta-analysis (n = 15,275) of lumbar spine volumetric BMD (vBMD) measured by quantitative computed tomography (QCT), allowing for examination of the trabecular bone compartment. SNPs that were significantly associated with vBMD were also examined in two GWAS meta-analyses to determine associations with morphometric vertebral fracture (n = 21,701) and clinical vertebral fracture (n = 5893).

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