37 results on '"Collette, Nicole M."'
Search Results
2. Naphthalene-DNA Adducts Detected in Mouse Liver Following Acute Oral Exposure
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Domanico, Morgan C., primary, Collette, Nicole M., additional, Ubick, Esther, additional, Ding, Xinxin, additional, Buchholz, Bruce A., additional, and Winkle, Laura S. Van, additional
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- 2024
- Full Text
- View/download PDF
3. Naphthalene genotoxicity: DNA adducts in primate and mouse airway explants
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Carratt, Sarah A, Hartog, Matthew, Buchholz, Bruce A, Kuhn, Edward A, Collette, Nicole M, Ding, Xinxin, and Van Winkle, Laura S
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Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Lung ,Genetics ,Animals ,Carcinogenesis ,Cytochrome P-450 Enzyme System ,DNA Adducts ,Female ,Gene Expression Regulation ,Enzymologic ,Macaca mulatta ,Male ,Mice ,Naphthalenes ,Rats ,Sex Factors ,Species Specificity ,Toxicity Tests ,Naphthalene ,Naphthoquinone ,DNA adducts ,Respiratory toxicity ,Environmental Science and Management ,Toxicology ,Pharmacology and pharmaceutical sciences ,Pollution and contamination - Abstract
Naphthalene (NA) is a ubiquitous environmental pollutant and possible human carcinogen that forms tumors in rodents with tissue/regional and species selectivity. This study seeks to determine whether NA is able to directly adduct DNA in an ex vivo culture system. Metabolically active lung tissue was isolated and incubated in explant culture with carbon-14 labeled NA (0, 25, 250 μM) or 1,2-naphthoquinone (NQ), followed by AMS analyses of metabolite binding to DNA. Despite relatively low metabolic bioactivation in the primate airway, dose-dependent NA-DNA adduct formation was detected. More airway adducts were detected in female mice (4.7-fold) and primates (2.1-fold) than in males of the same species. Few adducts were detected in rat airway or nasal epithelium. NQ, which is a metabolic product of NA, proved to be even more potent, with levels of adduct formation 70-80-fold higher than seen when tissues were incubated with the parent compound NA. This is the first study to demonstrate NA-DNA adduct formation at a site of carcinogenesis, the mouse lung. Adducts were also detected in non-human primate lung and with a NQ metabolite of NA. Taken together, this suggests that NA may contribute to in vivo carcinogenesis through a genotoxic mechanism.
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- 2019
4. Naphthalene DNA adduct formation and tolerance in the lung
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Buchholz, Bruce A, Carratt, Sarah A, Kuhn, Edward A, Collette, Nicole M, Ding, Xinxin, and Van Winkle, Laura S
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Nuclear and Plasma Physics ,Physical Sciences ,Condensed Matter Physics ,Lung ,Naphthalene ,DNA adducts ,Carcinogen ,Tolerance test ,carcinogen ,naphthalene ,tolerance test ,Atomic ,Molecular ,Nuclear ,Particle and Plasma Physics ,Geochemistry ,Interdisciplinary Engineering ,Applied Physics ,Condensed matter physics ,Nuclear and plasma physics - Abstract
Naphthalene (NA) is a respiratory toxicant and possible human carcinogen. NA is a ubiquitous combustion product and significant component of jet fuel. The National Toxicology Program found that NA forms tumors in two species, in rats (nose) and mice (lung). However, it has been argued that NA does not pose a cancer risk to humans because NA is bioactivated by cytochrome P450 monooxygenase enzymes that have very high efficiency in the lung tissue of rodents but low efficiency in the lung tissue of humans. It is thought that NA carcinogenesis in rodents is related to repeated cycles of lung epithelial injury and repair, an indirect mechanism. Repeated in vivo exposure to NA leads to development of tolerance, with the emergence of cells more resistant to NA insult. We tested the hypothesis that tolerance involves reduced susceptibility to the formation of NA-DNA adducts. NA-DNA adduct formation in tolerant mice was examined in individual, metabolically-active mouse airways exposed ex vivo to 250 μΜ 14C-NA. Ex vivo dosing was used since it had been done previously and the act of creating a radioactive aerosol of a potential carcinogen posed too many safety and regulatory obstacles. Following extensive rinsing to remove unbound 14C-NA, DNA was extracted and 14C-NA-DNA adducts were quantified by AMS. The tolerant mice appeared to have slightly lower NA-DNA adduct levels than non-tolerant controls, but intra-group variations were large and the difference was statistically insignificant. It appears the tolerance may be more related to other mechanisms, such as NA-protein interactions in the airway, than DNA-adduct formation.
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- 2019
5. SOST/Sclerostin Improves Posttraumatic Osteoarthritis and Inhibits MMP2/3 Expression After Injury
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Chang, Jiun C, Christiansen, Blaine A, Murugesh, Deepa K, Sebastian, Aimy, Hum, Nicholas R, Collette, Nicole M, Hatsell, Sarah, Economides, Aris N, Blanchette, Craig D, and Loots, Gabriela G
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Biomedical and Clinical Sciences ,Clinical Sciences ,Aging ,Osteoarthritis ,Prevention ,Arthritis ,Physical Injury - Accidents and Adverse Effects ,Aetiology ,2.1 Biological and endogenous factors ,Musculoskeletal ,Adaptor Proteins ,Signal Transducing ,Animals ,Anterior Cruciate Ligament Injuries ,Binding Sites ,Bone Morphogenetic Proteins ,Extracellular Matrix ,Genetic Markers ,Glycoproteins ,Humans ,Intercellular Signaling Peptides and Proteins ,Matrix Metalloproteinase 2 ,Matrix Metalloproteinase 3 ,Mice ,Inbred C57BL ,Models ,Biological ,NF-kappa B ,Osteoarthritis ,Knee ,Osteophyte ,Phenotype ,Recombinant Proteins ,Tumor Necrosis Factor-alpha ,Up-Regulation ,OSTEOARTHRITIS ,SCLEROSTIN ,SOST ,MMP ,OSTEOPHYTE ,WNT SIGNALING ,Biological Sciences ,Engineering ,Medical and Health Sciences ,Anatomy & Morphology ,Biological sciences ,Biomedical and clinical sciences - Abstract
Patients with anterior cruciate ligament (ACL) rupture are two times as likely to develop posttraumatic osteoarthritis (PTOA). Annually, there are ∼900,000 knee injuries in the United States, which account for ∼12% of all osteoarthritis (OA) cases. PTOA leads to reduced physical activity, deconditioning of the musculoskeletal system, and in severe cases requires joint replacement to restore function. Therefore, treatments that would prevent cartilage degradation post-injury would provide attractive alternatives to surgery. Sclerostin (Sost), a Wnt antagonist and a potent negative regulator of bone formation, has recently been implicated in regulating chondrocyte function in OA. To determine whether elevated levels of Sost play a protective role in PTOA, we examined the progression of OA using a noninvasive tibial compression overload model in SOST transgenic (SOSTTG ) and knockout (Sost-/- ) mice. Here we report that SOSTTG mice develop moderate OA and display significantly less advanced PTOA phenotype at 16 weeks post-injury compared with wild-type (WT) controls and Sost-/- . In addition, SOSTTG built ∼50% and ∼65% less osteophyte volume than WT and Sost-/- , respectively. Quantification of metalloproteinase (MMP) activity showed that SOSTTG had ∼2-fold less MMP activation than WT or Sost-/- , and this was supported by a significant reduction in MMP2/3 protein levels, suggesting that elevated levels of SOST inhibit the activity of proteolytic enzymes known to degrade articular cartilage matrix. Furthermore, intra-articular administration of recombinant Sost protein, immediately post-injury, also significantly decreased MMP activity levels relative to PBS-treated controls, and Sost activation in response to injury was TNFα and NF-κB dependent. These results provide in vivo evidence that sclerostin functions as a protective molecule immediately after joint injury to prevent cartilage degradation. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.
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- 2018
6. Osteophytes and fracture calluses share developmental milestones and are diminished by unloading
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Hsia, Allison W, Emami, Armaun J, Tarke, Franklin D, Cunningham, Hailey C, Tjandra, Priscilla M, Wong, Alice, Christiansen, Blaine A, and Collette, Nicole M
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Engineering ,Health Sciences ,Sports Science and Exercise ,Biomedical Engineering ,Physical Injury - Accidents and Adverse Effects ,Musculoskeletal ,Animals ,Anterior Cruciate Ligament Injuries ,Biomechanical Phenomena ,Bone and Bones ,Bony Callus ,Female ,Femoral Fractures ,Fracture Healing ,Gene Expression ,Mice ,Inbred C57BL ,Osteogenesis ,Osteophyte ,Peptide Hydrolases ,X-Ray Microtomography ,post-traumatic osteoarthritis ,osteophytes ,fracture healing ,hindlimb unloading ,Clinical Sciences ,Human Movement and Sports Sciences ,Orthopedics ,Biomedical engineering ,Sports science and exercise - Abstract
Osteophytes are a typical radiographic finding during osteoarthritis (OA), but the mechanisms leading to their formation are not well known. Comparatively, fracture calluses have been studied extensively; therefore, drawing comparisons between osteophytes and fracture calluses may lead to a deeper understanding of osteophyte formation. In this study, we compared the time courses of osteophyte and fracture callus formation, and investigated mechanisms contributing to development of these structure. Additionally, we investigated the effect of mechanical unloading on the formation of both fracture calluses and osteophytes. Mice underwent either transverse femoral fracture or non-invasive anterior cruciate ligament rupture. Fracture callus and osteophyte size and ossification were evaluated after 3, 5, 7, 14, 21, or 28 days. Additional mice were subjected to hindlimb unloading after injury for 3, 7, or 14 days. Protease activity and gene expression profiles after injury were evaluated after 3 or 7 days of normal ambulation or hindlimb unloading using in vivo fluorescence reflectance imaging (FRI) and quantitative PCR. We found that fracture callus and osteophyte growth achieved similar developmental milestones, but fracture calluses formed and ossified at earlier time points. Hindlimb unloading ultimately led to a threefold decrease in chondro/osteophyte area, and a twofold decrease in fracture callus area. Unloading was also associated with decreased inflammation and protease activity in injured limbs detected with FRI, particularly following ACL rupture. qPCR analysis revealed disparate cellular responses in fractured femurs and injured joints, suggesting that fracture calluses and osteophytes may form via different inflammatory, anabolic, and catabolic pathways. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:699-710, 2018.
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- 2018
7. Niche exclusion of a lung pathogen in mice with designed probiotic communities
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Hern, Kelsey E, primary, Phillips, Ashlee M. E, additional, Mageeney, Catherine M, additional, Williams, Kelly P, additional, Sinha, Anupama, additional, Carlson, Hans K, additional, Collette, Nicole M, additional, Branda, Steven S, additional, and Arkin, Adam P., additional
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- 2024
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8. Sostdc1 deficiency accelerates fracture healing by promoting the expansion of periosteal mesenchymal stem cells.
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Collette, Nicole M, Yee, Cristal S, Hum, Nicholas R, Murugesh, Deepa K, Christiansen, Blaine A, Xie, LiQin, Economides, Aris N, Manilay, Jennifer O, Robling, Alexander G, and Loots, Gabriela G
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Femur ,Bony Callus ,Periosteum ,Osteoblasts ,Stem Cells ,Mesenchymal Stem Cells ,Animals ,Mice ,Inbred C57BL ,Actins ,Bone Morphogenetic Proteins ,Organ Size ,Fracture Healing ,Cell Differentiation ,Cell Proliferation ,Gene Deletion ,Calcification ,Physiologic ,Osteogenesis ,Phenotype ,X-Ray Microtomography ,Wnt Signaling Pathway ,Nestin ,Biomechanical Phenomena ,Cancellous Bone ,Cortical Bone ,Sp7 Transcription Factor ,Bone regeneration ,Ectodin ,Fracture repair ,Sost ,Sost-like ,Sostdc1 ,Usag-1 ,Wise ,Wnt signaling ,Adaptor Proteins ,Signal Transducing ,Stem Cell Research ,Osteoporosis ,Stem Cell Research - Nonembryonic - Non-Human ,Regenerative Medicine ,2.1 Biological and endogenous factors ,Aetiology ,Musculoskeletal ,Biological Sciences ,Engineering ,Medical and Health Sciences ,Endocrinology & Metabolism - Abstract
Loss of Sostdc1, a growth factor paralogous to Sost, causes the formation of ectopic incisors, fused molars, abnormal hair follicles, and resistance to kidney disease. Sostdc1 is expressed in the periosteum, a source of osteoblasts, fibroblasts and mesenchymal progenitor cells, which are critically important for fracture repair. Here, we investigated the role of Sostdc1 in bone metabolism and fracture repair. Mice lacking Sostdc1 (Sostdc1(-/-)) had a low bone mass phenotype associated with loss of trabecular bone in both lumbar vertebrae and in the appendicular skeleton. In contrast, Sostdc1(-/-) cortical bone measurements revealed larger bones with higher BMD, suggesting that Sostdc1 exerts differential effects on cortical and trabecular bone. Mid-diaphyseal femoral fractures induced in Sostdc1(-/-) mice showed that the periosteal population normally positive for Sostdc1 rapidly expands during periosteal thickening and these cells migrate into the fracture callus at 3days post fracture. Quantitative analysis of mesenchymal stem cell (MSC) and osteoblast populations determined that MSCs express Sostdc1, and that Sostdc1(-/-) 5day calluses harbor >2-fold more MSCs than fractured wildtype controls. Histologically a fraction of Sostdc1-positive cells also expressed nestin and α-smooth muscle actin, suggesting that Sostdc1 marks a population of osteochondral progenitor cells that actively participate in callus formation and bone repair. Elevated numbers of MSCs in D5 calluses resulted in a larger, more vascularized cartilage callus at day 7, and a more rapid turnover of cartilage with significantly more remodeled bone and a thicker cortical shell at 21days post fracture. These data support accelerated or enhanced bone formation/remodeling of the callus in Sostdc1(-/-) mice, suggesting that Sostdc1 may promote and maintain mesenchymal stem cell quiescence in the periosteum.
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- 2016
9. Sclerostin antibody treatment improves fracture outcomes in a Type I diabetic mouse model
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Yee, Cristal S, Xie, LiQin, Hatsell, Sarah, Hum, Nicholas, Murugesh, Deepa, Economides, Aris N, Loots, Gabriela G, and Collette, Nicole M
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Biomedical and Clinical Sciences ,Clinical Sciences ,Osteoporosis ,Pediatric ,Diabetes ,Autoimmune Disease ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Metabolic and endocrine ,Musculoskeletal ,Adaptor Proteins ,Signal Transducing ,Animals ,Antibodies ,Diabetes Mellitus ,Type 1 ,Fracture Healing ,Fractures ,Bone ,Glycoproteins ,Intercellular Signaling Peptides and Proteins ,Male ,Mice ,Mice ,Inbred C57BL ,Treatment Outcome ,Sclerostin ,Type I diabetes ,Fracture repair ,Streptozotocin ,STZ ,Osteoblast differentiation ,Sclerostin antibody ,Biological Sciences ,Engineering ,Medical and Health Sciences ,Endocrinology & Metabolism ,Clinical sciences - Abstract
Type 1 diabetes mellitus (T1DM) patients have osteopenia and impaired fracture healing due to decreased osteoblast activity. Further, no adequate treatments are currently available that can restore impaired healing in T1DM; hence a significant need exists to investigate new therapeutics for treatment of orthopedic complications. Sclerostin (SOST), a WNT antagonist, negatively regulates bone formation, and SostAb is a potent bone anabolic agent. To determine whether SOST antibody (SostAb) treatment improves fracture healing in streptozotocin (STZ) induced T1DM mice, we administered SostAb twice weekly for up to 21days post-fracture, and examined bone quality and callus outcomes at 21days and 42days post-fracture (11 and 14weeks of age, respectively). Here we show that SostAb treatment improves bone parameters; these improvements persist after cessation of antibody treatment. Markers of osteoblast differentiation such as Runx2, collagen I, osteocalcin, and DMP1 were reduced, while an abundant number of SP7/osterix-positive early osteoblasts were observed on the bone surface of STZ calluses. These results suggest that STZ calluses have poor osteogenesis resulting from failure of osteoblasts to fully differentiate and produce mineralized matrix, which produces a less mineralized callus. SostAb treatment enhanced fracture healing in both normal and STZ groups, and in STZ+SostAb mice, also reversed the lower mineralization seen in STZ calluses. Micro-CT analysis of calluses revealed improved bone parameters with SostAb treatment, and the mineralized bone was comparable to Controls. Additionally, we found sclerostin levels to be elevated in STZ mice and β-catenin activity to be reduced. Consistent with its function as a WNT antagonist, SostAb treatment enhanced β-catenin activity, but also increased the levels of SOST in the callus and in circulation. Our results indicate that SostAb treatment rescues the impaired osteogenesis seen in the STZ induced T1DM fracture model by facilitating osteoblast differentiation and mineralization of bone.
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- 2016
10. SOST Inhibits Prostate Cancer Invasion.
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Hudson, Bryan D, Hum, Nicholas R, Thomas, Cynthia B, Kohlgruber, Ayano, Sebastian, Aimy, Collette, Nicole M, Coleman, Matthew A, Christiansen, Blaine A, and Loots, Gabriela G
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Cell Line ,Tumor ,Osteoblasts ,Animals ,Mice ,Inbred C57BL ,Mice ,Knockout ,Humans ,Mice ,Bone Neoplasms ,Prostatic Neoplasms ,Neoplasm Invasiveness ,Osteolysis ,Intercellular Signaling Peptides and Proteins ,Bone Morphogenetic Proteins ,Membrane Proteins ,Genetic Markers ,Coculture Techniques ,Neoplasm Transplantation ,Male ,Wnt3A Protein ,Wnt Signaling Pathway ,Heterografts ,Cell Line ,Tumor ,Inbred C57BL ,Knockout ,General Science & Technology - Abstract
Inhibitors of Wnt signaling have been shown to be involved in prostate cancer (PC) metastasis; however the role of Sclerostin (Sost) has not yet been explored. Here we show that elevated Wnt signaling derived from Sost deficient osteoblasts promotes PC invasion, while rhSOST has an inhibitory effect. In contrast, rhDKK1 promotes PC elongation and filopodia formation, morphological changes characteristic of an invasive phenotype. Furthermore, rhDKK1 was found to activate canonical Wnt signaling in PC3 cells, suggesting that SOST and DKK1 have opposing roles on Wnt signaling in this context. Gene expression analysis of PC3 cells co-cultured with OBs exhibiting varying amounts of Wnt signaling identified CRIM1 as one of the transcripts upregulated under highly invasive conditions. We found CRIM1 overexpression to also promote cell-invasion. These findings suggest that bone-derived Wnt signaling may enhance PC tropism by promoting CRIM1 expression and facilitating cancer cell invasion and adhesion to bone. We concluded that SOST and DKK1 have opposing effects on PC3 cell invasion and that bone-derived Wnt signaling positively contributes to the invasive phenotypes of PC3 cells by activating CRIM1 expression and facilitating PC-OB physical interaction. As such, we investigated the effects of high concentrations of SOST in vivo. We found that PC3-cells overexpressing SOST injected via the tail vein in NSG mice did not readily metastasize, and those injected intrafemorally had significantly reduced osteolysis, suggesting that targeting the molecular bone environment may influence bone metastatic prognosis in clinical settings.
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- 2015
11. Naphthalene DNA adduct formation and tolerance in the lung
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Buchholz, Bruce A., Carratt, Sarah A., Kuhn, Edward A., Collette, Nicole M., Ding, Xinxin, and Van Winkle, Laura S.
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- 2019
- Full Text
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12. Nanocomposite Scaffold for Chondrocyte Growth and Cartilage Tissue Engineering: Effects of Carbon Nanotube Surface Functionalization
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Chahine, Nadeen O, Collette, Nicole M, Thomas, Cynthia B, Genetos, Damian C, and Loots, Gabriela G
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Engineering ,Nanotechnology ,Biomedical Engineering ,Bioengineering ,Biotechnology ,5.2 Cellular and gene therapies ,Development of treatments and therapeutic interventions ,Musculoskeletal ,Biocompatible Materials ,Cartilage ,Cell Proliferation ,Chondrocytes ,Chondrogenesis ,Compressive Strength ,Elastic Modulus ,Equipment Design ,Equipment Failure Analysis ,Hardness ,Humans ,Materials Testing ,Nanocomposites ,Nanotubes ,Carbon ,Particle Size ,Stress ,Mechanical ,Surface Properties ,Tensile Strength ,Tissue Engineering ,Tissue Scaffolds ,Biochemistry and Cell Biology ,Materials Engineering ,Biomedical engineering - Abstract
The goal of this study was to assess the long-term biocompatibility of single-wall carbon nanotubes (SWNTs) for tissue engineering of articular cartilage. We hypothesized that SWNT nanocomposite scaffolds in cartilage tissue engineering can provide an improved molecular-sized substrate for stimulation of chondrocyte growth, as well as structural reinforcement of the scaffold's mechanical properties. The effect of SWNT surface functionalization (-COOH or -PEG) on chondrocyte viability and biochemical matrix deposition was examined in two-dimensional cultures, in three-dimensional (3D) pellet cultures, and in a 3D nanocomposite scaffold consisting of hydrogels+SWNTs. Outcome measures included cell viability, histological and SEM evaluation, GAG biochemical content, compressive and tensile biomechanical properties, and gene expression quantification, including extracellular matrix (ECM) markers aggrecan (Agc), collagen-1 (Col1a1), collagen-2 (Col2a1), collagen-10 (Col10a1), surface adhesion proteins fibronectin (Fn), CD44 antigen (CD44), and tumor marker (Tp53). Our findings indicate that chondrocytes tolerate functionalized SWNTs well, with minimal toxicity of cells in 3D culture systems (pellet and nanocomposite constructs). Both SWNT-PEG and SWNT-COOH groups increased the GAG content in nanocomposites relative to control. The compressive biomechanical properties of cell-laden SWNT-COOH nanocomposites were significantly elevated relative to control. Increases in the tensile modulus and ultimate stress were observed, indicative of a tensile reinforcement of the nanocomposite scaffolds. Surface coating of SWNTs with -COOH also resulted in increased Col2a1 and Fn gene expression throughout the culture in nanocomposite constructs, indicative of increased chondrocyte metabolic activity. In contrast, surface coating of SWNTs with a neutral -PEG moiety had no significant effect on Col2a1 or Fn gene expression, suggesting that the charged nature of the -COOH surface functionalization may promote ECM expression in this culture system. The results of this study indicate that SWNTs exhibit a unique potential for cartilage tissue engineering, where functionalization with bioactive molecules may provide an improved substrate for stimulation of cellular growth and repair.
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- 2014
13. Sost and its paralog Sostdc1 coordinate digit number in a Gli3-dependent manner.
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Collette, Nicole M, Yee, Cristal S, Murugesh, Deepa, Sebastian, Aimy, Taher, Leila, Gale, Nicholas W, Economides, Aris N, Harland, Richard M, and Loots, Gabriela G
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Extremities ,Ectoderm ,Animals ,Mice ,Knockout ,Mice ,Glycoproteins ,Intercellular Signaling Peptides and Proteins ,Adaptor Proteins ,Signal Transducing ,Bone Morphogenetic Proteins ,Nerve Tissue Proteins ,Microarray Analysis ,In Situ Hybridization ,Computational Biology ,Evolution ,Molecular ,Gene Expression Regulation ,Developmental ,Kruppel-Like Transcription Factors ,Hedgehog Proteins ,SOX9 Transcription Factor ,Wnt Signaling Pathway ,Zinc Finger Protein Gli3 ,Limb formation ,Polydactyly ,Sclerostin ,Shh ,Sost ,Sostdc1 ,WNT signaling ,syndactyly ,Musculoskeletal ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
WNT signaling is critical in most aspects of skeletal development and homeostasis, and antagonists of WNT signaling are emerging as key regulatory proteins with great promise as therapeutic agents for bone disorders. Here we show that Sost and its paralog Sostdc1 emerged through ancestral genome duplication and their expression patterns have diverged to delineate non-overlapping domains in most organ systems including musculoskeletal, cardiovascular, nervous, digestive, reproductive and respiratory. In the developing limb, Sost and Sostdc1 display dynamic expression patterns with Sost being restricted to the distal ectoderm and Sostdc1 to the proximal ectoderm and the mesenchyme. While Sostdc1(-/-) mice lack any obvious limb or skeletal defects, Sost(-/-) mice recapitulate the hand defects described for Sclerosteosis patients. However, elevated WNT signaling in Sost(-/-); Sostdc1(-/-) mice causes misregulation of SHH signaling, ectopic activation of Sox9 in the digit 1 field and preaxial polydactyly in a Gli1- and Gli3-dependent manner. In addition, we show that the syndactyly documented in Sclerosteosis is present in both Sost(-/-) and Sost(-/-); Sostdc1(-/-) mice, and is driven by misregulation of Fgf8 in the AER, a region lacking Sost and Sostdc1 expression. This study highlights the complexity of WNT signaling in skeletal biology and disease and emphasizes how redundant mechanism and non-cell autonomous effects can synergize to unveil new intricate phenotypes caused by elevated WNT signaling.
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- 2013
14. Genomic deletion of a long-range bone enhancer misregulates sclerostin in Van Buchem disease
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Loots, Gabriela G., Kneissel, Michaela, Keller, Hansjoerg, Baptist, Myma, Chang, Jessie, Collette, Nicole M., Ovcharenko, Dmitriy, Plajzer-Frick, Ingrid, and Rubin, Edward M.
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Applied life sciences - Abstract
Mutations in distant regulatory elements can negatively impact human development and health, yet due to the difficulty of detecting these critical sequences we predominantly focus on coding sequences for diagnostic purposes. We have undertaken a comparative sequence-based approach to characterize a large noncoding region deleted in patients affected by Van Buchem disease (VB), a severe sclerosing bone dysplasia. Using BAC recombination and transgenesis we characterized the expression of human sclerostin (sost) from normal (hSOSTwt) or Van Buchem (hSOSTvb D) alleles. Only the hSOSTwt allele faithfully expressed high levels of human sost in the adult bone and impacted bone metabolism, consistent with the model that the VB noncoding deletion removes a sostspecific regulatory element. By exploiting cross-species sequence comparisons with in vitro and in vivo enhancer assays we were able to identify a candidate enhancer element that drives human sost expression in osteoblast-like cell lines in vitro and in the skeletal anlage of the E14.5 mouse embryo, and discovered a novel function for sclerostin during limb development. Our approach represents a framework for characterizing distant regulatory elements associated with abnormal human phenotypes.
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- 2005
15. Whole‐Cell MALDI‐ToF MS Coupled with Untargeted Metabolomics Facilitates Investigations of Microbial Chemical Interactions
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Aiosa, Nicole, primary, Sinha, Anupama, additional, Albataineh, Hanan, additional, Phillips, Ashlee M., additional, Mageeney, Catherine M., additional, Wilde, Delaney S., additional, Williams, Kelly P., additional, Collette, Nicole M., additional, Branda, Steven S., additional, and Garg, Neha, additional
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- 2023
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16. Sostdc1 deficiency accelerates fracture healing by promoting the expansion of periosteal mesenchymal stem cells
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Collette, Nicole M., Yee, Cristal S., Hum, Nicholas R., Murugesh, Deepa K., Christiansen, Blaine A., Xie, LiQin, Economides, Aris N., Manilay, Jennifer O., Robling, Alexander G., and Loots, Gabriela G.
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- 2016
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17. Sclerostin antibody treatment improves fracture outcomes in a Type I diabetic mouse model
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Yee, Cristal S., Xie, LiQin, Hatsell, Sarah, Hum, Nicholas, Murugesh, Deepa, Economides, Aris N., Loots, Gabriela G., and Collette, Nicole M.
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- 2016
- Full Text
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18. Virus concentration and purification by a microfluidic filtering system with an integrated PEGylated antifouling membrane
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Kim, Sangil, Dehlinger, Dietrich, Peña, José, Seol, Hyang, Shusteff, Maxim, Collette, Nicole M., Elsheikh, Maher, Davenport, Matthew, Naraghi-Arani, Pejman, and Wheeler, Elizabeth
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- 2019
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19. Targeted deletion of Sost distal enhancer increases bone formation and bone mass
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Collette, Nicole M., Genetos, Damian C., Economides, Aris N., Xie, LiQin, Shahnazari, Mohammad, Yao, Wei, Lane, Nancy E., Harland, Richard M., and Loots, Gabriela G.
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- 2012
20. TGF-β regulates sclerostin expression via the ECR5 enhancer
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Loots, Gabriela G., Keller, Hansjoerg, Leupin, Olivier, Murugesh, Deepa, Collette, Nicole M., and Genetos, Damian C.
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- 2012
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21. Shotgun Immunoproteomic Approach for the Discovery of Linear B-Cell Epitopes in Biothreat Agents Francisella tularensis and Burkholderia pseudomallei
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D’haeseleer, Patrik, primary, Collette, Nicole M., additional, Lao, Victoria, additional, Segelke, Brent W., additional, Branda, Steven S., additional, and Franco, Magdalena, additional
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- 2021
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22. Development of Potent and Effective Synthetic SARS-CoV-2 Neutralizing Nanobodies
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Stefan, Maxwell A., primary, Light, Yooli K., additional, Schwedler, Jennifer L., additional, McIlroy, Peter R., additional, Courtney, Colleen M., additional, Saada, Edwin A., additional, Thatcher, Christine E., additional, Phillips, Ashlee M., additional, Bourguet, Feliza A., additional, Mageeney, Catherine M., additional, McCloy, Summer A., additional, Collette, Nicole M., additional, Negrete, Oscar A., additional, Schoeniger, Joseph S., additional, Weilhammer, Dina R., additional, and Harmon, Brooke, additional
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- 2021
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23. Genetic evidence that SOST inhibits WNT signaling in the limb
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Collette, Nicole M., Genetos, Damian C., Murugesh, Deepa, Harland, Richard M., and Loots, Gabriela G.
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Biological sciences - Abstract
To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2010.03.021 Byline: Nicole M. Collette (a)(b), Damian C. Genetos (c), Deepa Murugesh (a)(b), Richard M. Harland (b), Gabriela G. Loots (a)(b) Keywords: WNT signaling; SOST; Sclerostin; Shh; Limb formation Abstract: SOST is a negative regulator of bone formation, and mutations in human SOST are responsible for sclerosteosis. In addition to high bone mass, sclerosteosis patients occasionally display hand defects, suggesting that SOST may function embryonically. Here we report that overexpression of SOST leads to loss of posterior structures of the zeugopod and autopod by perturbing anterior-posterior and proximal-distal signaling centers in the developing limb. Mutant mice that overexpress SOST in combination with Grem1 and Lrp6 mutations display more severe limb defects than single mutants alone, while Sost.sup.- .sup./ .sup.- significantly rescues the Lrp6.sup.- .sup./ .sup.- skeletal phenotype, signifying that SOST gain-of-function impairs limb patterning by inhibiting the WNT signaling through LRP5/6. Author Affiliation: (a) Biology and Biotechnology Division, Lawrence Livermore National Laboratory, 7000 East Avenue, L-452, Livermore, CA 94550, USA (b) Department of Molecular and Cell Biology, Division of Genetics, Genomics, and Development, and Center for Integrative Genomics, University of California, Berkeley, CA 94720-3204, USA (c) Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA Article History: Received 19 June 2009; Revised 18 March 2010; Accepted 22 March 2010
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- 2010
24. Single Amino Acid Mutations Affect Zika Virus Replication In Vitro and Virulence In Vivo
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Collette, Nicole M., primary, Lao, Victoria H. I., additional, Weilhammer, Dina R., additional, Zingg, Barbara, additional, Cohen, Shoshana D., additional, Hwang, Mona, additional, Coffey, Lark L., additional, Grady, Sarah L., additional, Zemla, Adam T., additional, and Borucki, Monica K., additional
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- 2020
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25. Single amino acid mutations effect Zika virus replicationin vitroand virulencein vivo
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Collette, Nicole M., primary, Lao, Victoria H.I., additional, Weilhammer, Dina R., additional, Zingg, Barbara, additional, Cohen, Shoshana D., additional, Hwang, Mona, additional, Coffey, Lark L., additional, Grady, Sarah L., additional, Zemla, Adam T., additional, and Borucki, Monica K., additional
- Published
- 2020
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26. Multiscale analysis for patterns of Zika virus genotype emergence, spread, and consequence
- Author
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Borucki, Monica K., primary, Collette, Nicole M., additional, Coffey, Lark L., additional, Van Rompay, Koen K. A., additional, Hwang, Mona H., additional, Thissen, James B., additional, Allen, Jonathan E., additional, and Zemla, Adam T., additional
- Published
- 2019
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27. Shotgun Immunoproteomic Approach for the Discovery of Linear B-Cell Epitopes in Biothreat Agents Francisella tularensis and Burkholderia pseudomallei.
- Author
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D'haeseleer, Patrik, Collette, Nicole M., Lao, Victoria, Segelke, Brent W., Branda, Steven S., and Franco, Magdalena
- Subjects
BURKHOLDERIA pseudomallei ,FRANCISELLA tularensis ,EPITOPES ,CONVALESCENT plasma ,MEMBRANE proteins - Abstract
Peptide-based subunit vaccines are coming to the forefront of current vaccine approaches, with safety and cost-effective production among their top advantages. Peptide vaccine formulations consist of multiple synthetic linear epitopes that together trigger desired immune responses that can result in robust immune memory. The advantages of linear compared to conformational epitopes are their simple structure, ease of synthesis, and ability to stimulate immune responses by means that do not require complex 3D conformation. Prediction of linear epitopes through use of computational tools is fast and cost-effective, but typically of low accuracy, necessitating extensive experimentation to verify results. On the other hand, identification of linear epitopes through experimental screening has been an inefficient process that requires thorough characterization of previously identified full-length protein antigens, or laborious techniques involving genetic manipulation of organisms. In this study, we apply a newly developed generalizable screening method that enables efficient identification of B-cell epitopes in the proteomes of pathogenic bacteria. As a test case, we used this method to identify epitopes in the proteome of Francisella tularensis (Ft), a Select Agent with a well-characterized immunoproteome. Our screen identified many peptides that map to known antigens, including verified and predicted outer membrane proteins and extracellular proteins, validating the utility of this approach. We then used the method to identify seroreactive peptides in the less characterized immunoproteome of Select Agent Burkholderia pseudomallei (Bp). This screen revealed known Bp antigens as well as proteins that have not been previously identified as antigens. Although B-cell epitope prediction tools Bepipred 2.0 and iBCE-EL classified many of our seroreactive peptides as epitopes, they did not score them significantly higher than the non-reactive tryptic peptides in our study, nor did they assign higher scores to seroreactive peptides from known Ft or Bp antigens, highlighting the need for experimental data instead of relying on computational epitope predictions alone. The present workflow is easily adaptable to detecting peptide targets relevant to the immune systems of other mammalian species, including humans (depending upon the availability of convalescent sera from patients), and could aid in accelerating the discovery of B-cell epitopes and development of vaccines to counter emerging biological threats. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
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28. Naphthalene genotoxicity: DNA adducts in primate and mouse airway explants
- Author
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Carratt, Sarah A., primary, Hartog, Matthew, additional, Buchholz, Bruce A., additional, Kuhn, Edward A., additional, Collette, Nicole M., additional, Ding, Xinxin, additional, and Van Winkle, Laura S., additional
- Published
- 2019
- Full Text
- View/download PDF
29. Development of potent and effective synthetic SARS-CoV-2 neutralizing nanobodies.
- Author
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Stefan, Maxwell A., Light, Yooli K., Schwedler, Jennifer L., McIlroy, Peter R., Courtney, Colleen M., Saada, Edwin A., Thatcher, Christine E., Phillips, Ashlee M., Bourguet, Feliza A., Mageeney, Catherine M., McCloy, Summer A., Collette, Nicole M., Negrete, Oscar A., Schoeniger, Joseph S., Weilhammer, Dina R., and Harmon, Brooke
- Published
- 2021
- Full Text
- View/download PDF
30. Osteophytes and fracture calluses share developmental milestones and are diminished by unloading
- Author
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Hsia, Allison W., primary, Emami, Armaun J., additional, Tarke, Franklin D., additional, Cunningham, Hailey C., additional, Tjandra, Priscilla M., additional, Wong, Alice, additional, Christiansen, Blaine A., additional, and Collette, Nicole M., additional
- Published
- 2017
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- View/download PDF
31. Absence of sclerostin adversely affects B-cell survival
- Author
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Cain, Corey J, primary, Rueda, Randell, additional, McLelland, Bryce, additional, Collette, Nicole M, additional, Loots, Gabriela G, additional, and Manilay, Jennifer O, additional
- Published
- 2012
- Full Text
- View/download PDF
32. Global Gene Expression Analysis of Murine Limb Development
- Author
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Taher, Leila, primary, Collette, Nicole M., additional, Murugesh, Deepa, additional, Maxwell, Evan, additional, Ovcharenko, Ivan, additional, and Loots, Gabriela G., additional
- Published
- 2011
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- View/download PDF
33. Preaxial polydactyly caused by hyperactive WNT signaling in Sclerostin/Sostdc1 double knockouts
- Author
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Collette, Nicole M., primary, Yee, Cristal, additional, Murugesh, Deepa, additional, Harland, Richard, additional, and Loots, Gabriela, additional
- Published
- 2011
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- View/download PDF
34. Application of Carbon Nanotubes in Cartilage Tissue Engineering
- Author
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Chahine, Nadeen O., primary, Collette, Nicole M., additional, Thompson, Heather, additional, and Loots, Gabriela G., additional
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- 2008
- Full Text
- View/download PDF
35. Control of the SOST Bone Enhancer by PTH Using MEF2 Transcription Factors
- Author
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Leupin, Olivier, primary, Kramer, Ina, additional, Collette, Nicole M, additional, Loots, Gabriela G, additional, Natt, François, additional, Kneissel, Michaela, additional, and Keller, Hansjoerg, additional
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- 2007
- Full Text
- View/download PDF
36. Genomic deletion of a long-range bone enhancer misregulates sclerostin in Van Buchem disease
- Author
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Loots, Gabriela G., primary, Kneissel, Michaela, additional, Keller, Hansjoerg, additional, Baptist, Myma, additional, Chang, Jessie, additional, Collette, Nicole M., additional, Ovcharenko, Dmitriy, additional, Plajzer-Frick, Ingrid, additional, and Rubin, Edward M., additional
- Published
- 2005
- Full Text
- View/download PDF
37. Increased efficiency of transgenic livestock production.
- Author
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Maga EA, Sargent RG, Zeng H, Pati S, Zarling DA, Oppenheim SM, Collette NM, Moyer AL, Conrad-Brink JS, Rowe JD, BonDurant RH, Anderson GB, and Murray JD
- Subjects
- Animals, Base Sequence, DNA administration & dosage, DNA Primers, Female, Goats, Microinjections, Mosaicism, Pregnancy, Pregnancy Rate, Swine, Transgenes, Animals, Domestic genetics, Animals, Genetically Modified genetics
- Abstract
Production of transgenic livestock by pronuclear microinjection of DNA into fertilized zygotes suffers from the compounded inefficiencies of low embryo survival and low integration frequencies of the injected DNA into the genome. These inefficiencies are one of the major obstacles to the large-scale use of pronuclear microinjection techniques in livestock. We investigated exploiting the properties of recombinase proteins that allow them to bind DNA to generate transgenic animals via pronuclear microinjection. In theory, the use of recombinase proteins has the potential to generate transgenic animals with targeted changes, but in practice we found that the use of RecA recombinase-coated DNA increases the efficiency of transgenic livestock production. The use of RecA protein resulted in a significant increase in both embryo survival rates and transgene integration frequencies. Embryo survival rates were doubled in goats, and transgene integration was 11-fold higher in goats and three-fold higher in pigs when RecA protein-coated DNA was used compared with conventional DNA constructs without RecA protein coating. However, a large number of the transgenic founders generated with RecA protein-coated DNA were mosaic. The RecA protein coating of DNA is straightforward and can be applied to any species and any existing microinjection apparatus. These findings represent significant improvements on standard pronuclear microinjection methods by enabling the more efficient production of transgenic livestock.
- Published
- 2003
- Full Text
- View/download PDF
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