scholarly journals ATRAID regulates the action of nitrogen-containing bisphosphonates on bone

2020 ◽  
Vol 12 (544) ◽  
pp. eaav9166 ◽  
Author(s):  
Lauren E. Surface ◽  
Damon T. Burrow ◽  
Jinmei Li ◽  
Jiwoong Park ◽  
Sandeep Kumar ◽  
...  
Keyword(s):  
Osteonecrosis Of The Jaw ◽  
Pharmacological Effects ◽  
Protein Prenylation ◽  
Genome Wide ◽  
Cellular Factors ◽  
Osteoclast Function ◽  
Differential Responsiveness ◽  
Coding Variants ◽  
Deficient Mice ◽  
Insight Into

Nitrogen-containing bisphosphonates (N-BPs), such as alendronate, are the most widely prescribed medications for diseases involving bone, with nearly 200 million prescriptions written annually. Recently, widespread use of N-BPs has been challenged due to the risk of rare but traumatic side effects such as atypical femoral fracture (AFF) and osteonecrosis of the jaw (ONJ). N-BPs bind to and inhibit farnesyl diphosphate synthase, resulting in defects in protein prenylation. Yet, it remains poorly understood what other cellular factors might allow N-BPs to exert their pharmacological effects. Here, we performed genome-wide studies in cells and patients to identify the poorly characterized gene, ATRAID. Loss of ATRAID function results in selective resistance to N-BP–mediated loss of cell viability and the prevention of alendronate-mediated inhibition of prenylation. ATRAID is required for alendronate inhibition of osteoclast function, and ATRAID-deficient mice have impaired therapeutic responses to alendronate in both postmenopausal and senile (old age) osteoporosis models. Last, we performed exome sequencing on patients taking N-BPs that suffered ONJ or an AFF. ATRAID is one of three genes that contain rare nonsynonymous coding variants in patients with ONJ or an AFF that is also differentially expressed in poor outcome groups of patients treated with N-BPs. We functionally validated this patient variation in ATRAID as conferring cellular hypersensitivity to N-BPs. Our work adds key insight into the mechanistic action of N-BPs and the processes that might underlie differential responsiveness to N-BPs in people.

scholarly journals ATRAID regulates the action of nitrogen-containing bisphosphonates on bone

2018 ◽  
Author(s):  
Lauren E. Surface ◽  
Damon T. Burrow ◽  
Jinmei Li ◽  
Jiwoong Park ◽  
Sandeep Kumar ◽  
...  
Keyword(s):  
Osteonecrosis Of The Jaw ◽  
Pharmacological Effects ◽  
Protein Prenylation ◽  
Genome Wide ◽  
Cellular Factors ◽  
Osteoclast Function ◽  
Differential Responsiveness ◽  
Coding Variants ◽  
Deficient Mice ◽  
Insight Into

AbstractNitrogen-containing bisphosphonates (N-BPs), such as alendronate, are the most widely prescribed medications for diseases involving bone, with nearly 200 million prescriptions written annually. Recently, widespread use of N-BPs has been challenged due to the risk of rare but traumatic side effects such as atypical femoral fracture (AFFs) and osteonecrosis of the jaw (ONJ). N-BPs bind to and inhibit farnesyl diphosphate synthase (FDPS), resulting in defects in protein prenylation. Yet it remains poorly understood what other cellular factors might allow N-BPs to exert their pharmacological effects. Here, we performed genome-wide studies in cells and patients to identify the poorly characterized gene, ATRAID. Loss of ATRAID function results in selective resistance to N-BP-mediated loss of cell viability and the prevention of alendronate-mediated inhibition of prenylation. ATRAID is required for alendronate inhibition of osteoclast function, and ATRAID-deficient mice have impaired therapeutic responses to alendronate in both postmenopausal and senile (old age) osteoporosis models. Lastly, we performed exome sequencing on patients taking N-BPs that suffered ONJ or an AFF. ATRAID is one of three genes that contain rare non-synonymous coding variants in patients with ONJ or AFF that is also differentially expressed in poor outcome groups of patients treated with N-BPs. We functionally validated this patient variation in ATRAID as conferring cellular hypersensitivity to N-BPs. Our work adds key insight into the mechanistic action of N-BPs and the processes that might underlie differential responsiveness to N-BPs in people.One Sentence SummaryATRAID is essential for responses to the commonly prescribed osteoporosis drugs nitrogen-containing bisphosphonates.OverlineBONE

Ultrastructure of neuromuscular relationships in the canine heartworm (dirofilaria immitis)

1986 ◽  
Vol 44 ◽  
pp. 278-279
Author(s):  
W. L. Steffens ◽  
Nancy B. Roberts ◽  
J. M. Bowen
Keyword(s):  
Dirofilaria Immitis ◽  
Domestic Dogs ◽  
Structural Description ◽  
Pharmacological Effects ◽  
Free Living ◽  
Canine Heartworm ◽  
The World ◽  
Synaptic Region ◽  
Muscle Innervation ◽  
Insight Into

The canine heartworm is a common and serious nematode parasite of domestic dogs in many parts of the world. Although nematode neuroanatomy is fairly well documented, the emphasis has been on sensory anatomy and primarily in free-living soil species and ascarids. Lee and Miller reported on the muscular anatomy in the heartworm, but provided little insight into the peripheral nervous system or myoneural relationships. The classical fine-structural description of nematode muscle innervation is Rosenbluth's earlier work in Ascaris. Since the pharmacological effects of some nematacides currently being developed are neuromuscular in nature, a better understanding of heartworm myoneural anatomy, particularly in reference to the synaptic region is warranted.

scholarly journals Genome-wide correlation analysis to identify amplitude regulators of circadian transcriptome output

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Evan S. Littleton ◽  
Madison L. Childress ◽  
Michaela L. Gosting ◽  
Ayana N. Jackson ◽  
Shihoko Kojima
Keyword(s):  
Clock Genes ◽  
Circadian System ◽  
Average Level ◽  
Relative Amplitude ◽  
Critical Component ◽  
Period 2 ◽  
Genome Wide ◽  
Mouse Tissues ◽  
Rhythmic Gene ◽  
Insight Into

AbstractCell-autonomous circadian system, consisting of core clock genes, generates near 24-h rhythms and regulates the downstream rhythmic gene expression. While it has become clear that the percentage of rhythmic genes varies among mouse tissues, it remains unclear how this variation can be generated, particularly when the clock machinery is nearly identical in all tissues. In this study, we sought to characterize circadian transcriptome datasets that are publicly available and identify the critical component(s) involved in creating this variation. We found that the relative amplitude of 13 genes and the average level of 197 genes correlated with the percentage of cycling genes. Of those, the correlation of Rorc in both relative amplitude and the average level was one of the strongest. In addition, the level of Per2AS, a novel non-coding transcript that is expressed at the Period 2 locus, was also linearly correlated, although with a much lesser degree compared to Rorc. Overall, our study provides insight into how the variation in the percentage of clock-controlled genes can be generated in mouse tissues and suggests that Rorc and potentially Per2AS are involved in regulating the amplitude of circadian transcriptome output.

scholarly journals Absence of Dap12 and the αvβ3 integrin causes severe osteopetrosis

2014 ◽  
Vol 208 (1) ◽  
pp. 125-136 ◽  
Author(s):  
Wei Zou ◽  
Steven L. Teitelbaum
Keyword(s):  
Bone Mass ◽  
Αvβ3 Integrin ◽  
Skeletal Phenotype ◽  
Osteoclast Function ◽  
Deficient Mice

In vitro, ligand occupancy of αvβ3 integrin induces phosphorylation of Dap12, which is essential for osteoclast function. Like mice deleted of only αvβ3, Dap12−/− mice exhibited a slight increase in bone mass, but Dap12−/− mice, lacking another ITAM protein, FcRγ, were severely osteopetrotic. The mechanism by which FcRγ compensates for Dap12 deficiency is unknown. We find that co-deletion of FcRγ did not exacerbate the skeletal phenotype of β3−/− mice. In contrast, β3/Dap12 double-deficient (DAP/β3−/−) mice (but not β1/Dap12 double-deficient mice) were profoundly osteopetrotic, reflecting severe osteoclast dysfunction relative to those lacking αvβ3 or Dap12 alone. Activation of OSCAR, the FcRγ co-receptor, rescued Dap12−/− but not DAP/β3−/−osteoclasts. Thus, the absence of αvβ3 precluded compensation for Dap12 deficiency by FcRγ. In keeping with this, Syk phosphorylation did not occur in OSCAR-activated DAP/β3−/− osteoclasts. Thus, FcRγ requires the osteoclast αvβ3 integrin to normalize the Dap12-deficient skeleton.

scholarly journals RECQL, a Member of the RecQ Family of DNA Helicases, Suppresses Chromosomal Instability

2006 ◽  
Vol 27 (5) ◽  
pp. 1784-1794 ◽  
Author(s):  
Sudha Sharma ◽  
Deborah J. Stumpo ◽  
Adayabalam S. Balajee ◽  
Cheryl B. Bock ◽  
Peter M. Lansdorp ◽  
...  
Keyword(s):  
Cellular Level ◽  
Sister Chromatid Exchanges ◽  
Cellular Phenotype ◽  
Chromosomal Breakage ◽  
Dna Helicases ◽  
Phenotypic Differences ◽  
Cytogenetic Analyses ◽  
Chromatid Exchanges ◽  
Deficient Mice ◽  
Insight Into

ABSTRACT The mouse gene Recql is a member of the RecQ subfamily of DEx-H-containing DNA helicases. Five members of this family have been identified in both humans and mice, and mutations in three of these, BLM, WRN, and RECQL4, are associated with human diseases and a cellular phenotype that includes genomic instability. To date, no human disease has been associated with mutations in RECQL and no cellular phenotype has been associated with its deficiency. To gain insight into the physiological function of RECQL, we disrupted Recql in mice. RECQL-deficient mice did not exhibit any apparent phenotypic differences compared to wild-type mice. Cytogenetic analyses of embryonic fibroblasts from the RECQL-deficient mice revealed aneuploidy, spontaneous chromosomal breakage, and frequent translocation events. In addition, the RECQL-deficient cells were hypersensitive to ionizing radiation, exhibited an increased load of DNA damage, and displayed elevated spontaneous sister chromatid exchanges. These results provide evidence that RECQL has a unique cellular role in the DNA repair processes required for genomic integrity. Genetic background, functional redundancy, and perhaps other factors may protect the unstressed mouse from the types of abnormalities that might be expected from the severe chromosomal aberrations detected at the cellular level.

scholarly journals Genome-wide identification of chitinase genes in Thalassiosira pseudonana and analysis of their expression under abiotic stresses

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Haomiao Cheng ◽  
Zhanru Shao ◽  
Chang Lu ◽  
Delin Duan
Keyword(s):  
Abiotic Stresses ◽  
Chitinase Activity ◽  
Thalassiosira Pseudonana ◽  
Centric Diatom ◽  
Carbon And Nitrogen ◽  
Genome Wide ◽  
Duplication Events ◽  
The Many ◽  
Chitinase Genes ◽  
Insight Into

Abstract Background The nitrogen-containing polysaccharide chitin is the second most abundant biopolymer on earth and is found in the cell walls of diatoms, where it serves as a scaffold for biosilica deposition. Diatom chitin is an important source of carbon and nitrogen in the marine environment, but surprisingly little is known about basic chitinase metabolism in diatoms. Results Here, we identify and fully characterize 24 chitinase genes from the model centric diatom Thalassiosira pseudonana. We demonstrate that their expression is broadly upregulated under abiotic stresses, despite the fact that chitinase activity itself remains unchanged, and we discuss several explanations for this result. We also examine the potential transcriptional complexity of the intron-rich T. pseudonana chitinase genes and provide evidence for two separate tandem duplication events during their evolution. Conclusions Given the many applications of chitin and chitin derivatives in suture production, wound healing, drug delivery, and other processes, new insight into diatom chitin metabolism has both theoretical and practical value.

26-OR: Meta-analyses of Genome-Wide Association Studies for Proinsulin Provide Insight into Glycemic Trait Dysregulation

Diabetes ◽  
2021 ◽  
Vol 70 (Supplement 1) ◽  
pp. 26-OR
Author(s):  
K. ALAINE BROADAWAY ◽  
XIANYONOG YIN ◽  
ALICE WILLIAMSON ◽  
EMMA WILSON ◽  
MAGIC INVESTIGATORS
Keyword(s):  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Meta Analyses ◽  
Insight Into
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