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  1. Article: Social Isolation Causes Cortical and Trabecular Bone Loss in Adult Male, but not Female, C57BL/6J Mice.

    Mountain, Rebecca V / Langlais, Audrie L / Hu, Dorothy / Baron, Roland / Lary, Christine W / Motyl, Katherine J

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Social isolation is a potent form of psychosocial stress and is a growing public health concern, particularly among older adults. Even prior to the onset of the COVID-19 pandemic, which has significantly increased the prevalence of isolation and ... ...

    Abstract Social isolation is a potent form of psychosocial stress and is a growing public health concern, particularly among older adults. Even prior to the onset of the COVID-19 pandemic, which has significantly increased the prevalence of isolation and loneliness, researchers have been concerned about a rising "epidemic" of loneliness. Isolation is associated with an increased risk for many physical and mental health disorders and increased overall mortality risk. In addition to social isolation, older adults are also at greater risk for osteoporosis and related fractures. While researchers have investigated the negative effects of other forms of psychosocial stress on bone, including depression and PTSD, the effects of social isolation on bone have not been thoroughly investigated. The aim of this study was to test the hypothesis that social isolation would lead to bone loss in male and female C57BL/6J mice. 16-week-old mice were randomized into social isolation (1 mouse/cage) or grouped housing (4 mice/cage) for four weeks (N=16/group). Social isolation significantly decreased trabecular (BV/TV, BMD, Tb. N., Tb. Th.) and cortical bone (Ct.Th., Ct.Ar., Ct.Ar./Tt.Ar., pMOI, Ct.Por.) parameters in male, but not female mice. Isolated male mice had signs of reduced bone remodeling represented by reduced osteoblast numbers, osteoblast-related gene expression and osteoclast-related gene expression. However, isolated females had increased bone resorption-related gene expression, without any change in bone mass. Overall, our data suggest that social isolation has negative effects on bone in males, but not females, although females showed suggestive effects on bone resorption. These results provide critical insight into the effects of isolation on bone and have key clinical implications as we grapple with the long-term health impacts of the rise in social isolation related to the COVID-19 pandemic.
    Language English
    Publishing date 2023-01-28
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.01.27.525939
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Social isolation through single housing negatively affects trabecular and cortical bone in adult male, but not female, C57BL/6J mice.

    Mountain, Rebecca V / Langlais, Audrie L / Hu, Dorothy / Baron, Roland / Lary, Christine W / Motyl, Katherine J

    Bone

    2023  Volume 172, Page(s) 116762

    Abstract: Social isolation is a potent form of psychosocial stress and is a growing public health concern, particularly among older adults. Even prior to the onset of the COVID-19 pandemic, which has significantly increased the prevalence of isolation and ... ...

    Abstract Social isolation is a potent form of psychosocial stress and is a growing public health concern, particularly among older adults. Even prior to the onset of the COVID-19 pandemic, which has significantly increased the prevalence of isolation and loneliness, researchers have been concerned about a rising "epidemic" of loneliness. Isolation is associated with an increased risk for many physical and mental health disorders and increased overall mortality risk. In addition to social isolation, older adults are also at greater risk for osteoporosis and related fractures. While researchers have investigated the negative effects of other forms of psychosocial stress on bone, including depression and PTSD, the effects of social isolation on bone have not been thoroughly investigated. The aim of this study was to test the hypothesis that social isolation would lead to bone loss in male and female C57BL/6J mice. 16-week-old mice were randomized into social isolation (1 mouse/cage) or grouped housing (4 mice/cage) for four weeks. Social isolation significantly decreased trabecular (BV/TV, BMD, Tb. N., Tb. Th.) and cortical bone (Ct.Th., Ct.Ar., Ct.Ar./Tt.Ar., pMOI) parameters in male, but not female mice. Isolated male mice had signs of reduced bone remodeling represented by reduced osteoblast numbers, osteoblast-related gene expression and osteoclast-related gene expression. However, isolated females had increased bone resorption-related gene expression, without any change in bone mass. Overall, our data suggest that social isolation has negative effects on bone in male, but not female mice, although females showed suggestive effects on bone resorption. These results provide critical insight into the effects of isolation on bone and have key clinical implications as we grapple with the long-term health impacts of the rise in social isolation related to the COVID-19 pandemic.
    MeSH term(s) Female ; Male ; Mice ; Humans ; Animals ; Mice, Inbred C57BL ; Housing ; Pandemics ; COVID-19 ; Bone Density ; Bone Resorption ; Cortical Bone ; Social Isolation
    Language English
    Publishing date 2023-04-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 632515-4
    ISSN 1873-2763 ; 8756-3282
    ISSN (online) 1873-2763
    ISSN 8756-3282
    DOI 10.1016/j.bone.2023.116762
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Comparative study in estrogen-depleted mice identifies skeletal and osteocyte transcriptomic responses to abaloparatide and teriparatide.

    Lv, Zhengtao / Zhang, Jiaming / Liang, Shuang / Zhou, Chenhe / Hu, Dorothy / Brooks, Daniel J / Bouxsein, Mary L / Lanske, Beate / Kostenuik, Paul / Gori, Francesca / Baron, Roland

    JCI insight

    2023  Volume 8, Issue 20

    Abstract: Osteocytes express parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptors and respond to the PTHrP analog abaloparatide (ABL) and to the PTH 1-34 fragment teriparatide (TPTD), which are used to treat osteoporosis. Several studies indicate ... ...

    Abstract Osteocytes express parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptors and respond to the PTHrP analog abaloparatide (ABL) and to the PTH 1-34 fragment teriparatide (TPTD), which are used to treat osteoporosis. Several studies indicate overlapping but distinct skeletal responses to ABL or TPTD, but their effects on cortical bone may differ. Little is known about their differential effects on osteocytes. We compared cortical osteocyte and skeletal responses to ABL and TPTD in sham-operated and ovariectomized mice. Administered 7 weeks after ovariectomy for 4 weeks at a dose of 40 μg/kg/d, TPTD and ABL had similar effects on trabecular bone, but ABL showed stronger effects in cortical bone. In cortical osteocytes, both treatments decreased lacunar area, reflecting altered peri-lacunar remodeling favoring matrix accumulation. Osteocyte RNA-Seq revealed that several genes and pathways were altered by ovariectomy and affected similarly by TPTD and ABL. Notwithstanding, several signaling pathways were uniquely regulated by ABL. Thus, in mice, TPTD and ABL induced a positive osteocyte peri-lacunar remodeling balance, but ABL induced stronger cortical responses and affected the osteocyte transcriptome differently. We concluded that ABL affected the cortical osteocyte transcriptome in a manner subtly different from TPTD, resulting in more beneficial remodeling/modeling changes and homeostasis of the cortex.
    MeSH term(s) Female ; Mice ; Animals ; Teriparatide/pharmacology ; Teriparatide/therapeutic use ; Parathyroid Hormone-Related Protein/pharmacology ; Parathyroid Hormone-Related Protein/metabolism ; Osteocytes/metabolism ; Transcriptome ; Estrogens/pharmacology
    Chemical Substances Teriparatide (10T9CSU89I) ; abaloparatide (AVK0I6HY2U) ; Parathyroid Hormone-Related Protein ; Estrogens
    Language English
    Publishing date 2023-10-23
    Publishing country United States
    Document type Journal Article
    ISSN 2379-3708
    ISSN (online) 2379-3708
    DOI 10.1172/jci.insight.161932
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Sfrp4 is required to maintain Ctsk-lineage periosteal stem cell niche function.

    Chen, Ruiying / Dong, Han / Raval, Dhairya / Maridas, David / Baroi, Sudipta / Chen, Kun / Hu, Dorothy / Berry, Shawn R / Baron, Roland / Greenblatt, Matthew B / Gori, Francesca

    Proceedings of the National Academy of Sciences of the United States of America

    2023  Volume 120, Issue 46, Page(s) e2312677120

    Abstract: We have previously reported that the cortical bone thinning seen in mice lacking the Wnt signaling ... ...

    Abstract We have previously reported that the cortical bone thinning seen in mice lacking the Wnt signaling antagonist
    MeSH term(s) Mice ; Animals ; Cathepsin K/metabolism ; Stem Cell Niche ; Osteogenesis ; Periosteum/metabolism ; Cell Differentiation/genetics ; Wnt Signaling Pathway ; Proto-Oncogene Proteins/metabolism
    Chemical Substances Cathepsin K (EC 3.4.22.38) ; Sfrp4 protein, mouse ; Proto-Oncogene Proteins ; Ctsk protein, mouse (EC 3.4.22.38)
    Language English
    Publishing date 2023-11-06
    Publishing country United States
    Document type Journal Article
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2312677120
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Bone adaptation compensates resorption when sciatic neurectomy is followed by low magnitude induced loading.

    Piet, Judith / Hu, Dorothy / Baron, Roland / Shefelbine, Sandra J

    Bone

    2018  Volume 120, Page(s) 487–494

    Abstract: The uniaxial tibial loading model is commonly used to promote bone formation through mechanoadaptation in mice. Sciatic neurectomy on the other hand recruits osteoclasts, which results in bone loss. Previous studies have shown that combining sciatic ... ...

    Abstract The uniaxial tibial loading model is commonly used to promote bone formation through mechanoadaptation in mice. Sciatic neurectomy on the other hand recruits osteoclasts, which results in bone loss. Previous studies have shown that combining sciatic neurectomy with high magnitude loading increases the amount of bone formed. Here we determine whether low-intensity loading (low magnitude and few cycles) is sufficient to maintain bone mass after sciatic neurectomy, either by promoting bone formation (balance between concurrent resorption and formation), or by preventing bone resorption altogether. We examined bone adaptation in 4 groups of female C57BL/6J mice, 19-22 weeks old: (1) sham surgery +10 N loading; (2) sham surgery +5 N loading; (3) sciatic neurectomy; (4) sciatic neurectomy +5 N loading. Left legs were kept intact as internal controls. We examined changes in bone cross sectional properties and marrow area with micro-CT images, and histomorphometric measures with histological sections at the midpoint between tibiofibular junctions. Loading at 10 N caused a significant increase in the amount of bone, but bone formation after 5 N of loading was not detectable in micro-CT images. There was significant bone loss in mice with sciatic neurectomy alone, but when combined with loading there was no significant bone loss. Histomorphometric analyses showed that loading at 5 N augmented bone formation periosteally on the lateral and posterior-medial surfaces, and reduced the number of endosteal osteoclasts on the posterior-medial surface compared to the contralateral leg. Combining sciatic neurectomy and loading at 5 N promoted faster mineral apposition on the periosteal lateral surface and augmented bone resorption on the endosteal posterior surface compared to the contralateral leg. These data demonstrate that low-intensity loading is sufficient to maintain bone mass after sciatic neurectomy, both by preventing recruitment of osteoclasts on the endosteal surface and by compensating endosteal resorption caused by disuse with periosteal formation promoted by loading. This has implications for the loading required to maintain bone mass after injury or prolonged bedrest.
    MeSH term(s) Adaptation, Physiological ; Animals ; Bone Resorption/pathology ; Bone Resorption/physiopathology ; Bone and Bones/pathology ; Bone and Bones/physiopathology ; Cortical Bone/physiopathology ; Denervation ; Female ; Fluorescent Dyes/metabolism ; Mice, Inbred C57BL ; Sciatic Nerve/physiopathology ; Sciatic Nerve/surgery ; Tibia/pathology ; Tibia/physiopathology ; Weight-Bearing
    Chemical Substances Fluorescent Dyes
    Language English
    Publishing date 2018-12-23
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 632515-4
    ISSN 1873-2763 ; 8756-3282
    ISSN (online) 1873-2763
    ISSN 8756-3282
    DOI 10.1016/j.bone.2018.12.017
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  6. Article ; Online: Marrow aspiration in aged mice: intramedullary osteogenesis, reduced mechano-adaptation, increased marrow fat.

    Piet, Judith / Adamo, Sarah / Hu, Dorothy / Baron, Roland / Shefelbine, Sandra J

    Connective tissue research

    2019  Volume 63, Issue 2, Page(s) 97–111

    Abstract: Introduction: ...

    Abstract Introduction:
    MeSH term(s) Adipose Tissue ; Animals ; Bone Marrow ; Mice ; Mice, Inbred C57BL ; Osteogenesis/physiology ; Tibia
    Language English
    Publishing date 2019-12-22
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 185551-7
    ISSN 1607-8438 ; 0091-1690 ; 0300-8207
    ISSN (online) 1607-8438
    ISSN 0091-1690 ; 0300-8207
    DOI 10.1080/03008207.2019.1698557
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  7. Article ; Online: Increased Cellular Presence After Sciatic Neurectomy Improves the Bone Mechano-adaptive Response in Aged Mice.

    Piet, Judith / Hu, Dorothy / Meslier, Quentin / Baron, Roland / Shefelbine, Sandra J

    Calcified tissue international

    2019  Volume 105, Issue 3, Page(s) 316–330

    Abstract: The mechano-adaptive response of bone to loading in the murine uniaxial tibial loading model is impaired in aged animals. Previous studies have shown that in aged mice, the amount of bone formed in response to loading is augmented when loads are applied ... ...

    Abstract The mechano-adaptive response of bone to loading in the murine uniaxial tibial loading model is impaired in aged animals. Previous studies have shown that in aged mice, the amount of bone formed in response to loading is augmented when loads are applied following sciatic neurectomy. The synergistic effect of neurectomy and loading remains to be elucidated. We hypothesize that sciatic neurectomy increases cellular presence, thereby augmenting the response to load in aged mice. We examined bone adaptation in four groups of female C57BL/6J mice, 20-22 months old: (1) sham surgery + 9N loading; (2) sciatic neurectomy, sacrificed after 5 days; (3) sciatic neurectomy, sacrificed after 19 days; (4) sciatic neurectomy + 9N loading. We examined changes in bone cross sectional properties with micro-CT images, and static and dynamic histomorphometry with histological sections taken at the midpoint between tibiofibular junctions. The response to loading at 9N was not detectable with quantitative micro-CT data, but surface-specific histomorphometry captured an increase in bone formation in specific regions. 5 days following sciatic neurectomy, the amount of bone in the neurectomized leg was the same as the contralateral leg, but 19 days following sciatic neurectomy, there was significant bone loss in the neurectomized leg, and both osteoclasts and osteoblasts were recruited to the endosteal surfaces. When sciatic neurectomy and loading at 9N were combined, 3 out of 4 bone quadrants had increased bone formation, on the endosteal and periosteal surfaces (increased osteoid surface and mineralizing surface respectively). These data demonstrate that sciatic neurectomy increases cellular presence on the endosteal surface. With long-term sciatic-neurectomy, both osteoclasts and osteoblasts were recruited to the endosteal surface, which resulted in increased bone formation when combined with a sufficient mechanical stimulus. Controlled and localized recruitment of both osteoblasts and osteoclasts combined with appropriate mechanical loading could inform therapies for mechanically-directed bone formation.
    MeSH term(s) Adaptation, Physiological/physiology ; Aging/physiology ; Animals ; Cell Proliferation/physiology ; Denervation ; Female ; Mechanical Phenomena ; Mice ; Mice, Inbred C57BL ; Osteogenesis/physiology ; Sciatic Nerve/injuries ; Sciatic Nerve/pathology ; Tibia ; Weight-Bearing/physiology ; X-Ray Microtomography
    Language English
    Publishing date 2019-06-26
    Publishing country United States
    Document type Journal Article
    ZDB-ID 304266-2
    ISSN 1432-0827 ; 0944-0747 ; 0008-0594 ; 0171-967X
    ISSN (online) 1432-0827
    ISSN 0944-0747 ; 0008-0594 ; 0171-967X
    DOI 10.1007/s00223-019-00572-7
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  8. Article: Effects of abaloparatide and teriparatide on bone resorption and bone formation in female mice.

    Arlt, Heike / Mullarkey, Tara / Hu, Dorothy / Baron, Roland / Ominsky, Michael S / Mitlak, Bruce / Lanske, Beate / Besschetnova, Tatiana

    Bone reports

    2020  Volume 13, Page(s) 100291

    Abstract: Intermittent administration of PTH type 1 receptor (PTH1R) agonists increases bone remodeling, with greater stimulation of bone formation relative to bone resorption causing net gains in bone mass. This pharmacodynamic feature underlies the bone-building ...

    Abstract Intermittent administration of PTH type 1 receptor (PTH1R) agonists increases bone remodeling, with greater stimulation of bone formation relative to bone resorption causing net gains in bone mass. This pharmacodynamic feature underlies the bone-building effects of teriparatide and abaloparatide, the only PTH1R agonists approved to reduce osteoporotic fracture risk in postmenopausal women. This study in 8-week-old female mice compared bone resorption and formation responses to these agents delivered at the same 10 μg/kg dose, and a 40 μg/kg abaloparatide dose was also included to reflect its 4-fold higher approved clinical dose. Peptides or vehicle were administered by daily supra-calvarial subcutaneous injection for 12 days, and local (calvarial) and systemic (L5 vertebral and tibial) responses were evaluated by histomorphometry. Terminal bone histomorphometry data indicated that calvarial resorption cavities were similar in both abaloparatide groups versus vehicle controls, whereas the teriparatide group had more calvarial resorption cavities compared with the vehicle or abaloparatide 40 μg/kg groups. The bone resorption marker serum CTX was significantly lower in the abaloparatide 40 μg/kg group and similar in the other two active treatment groups compared with vehicle controls. Both peptides increased trabecular bone formation rate (BFR) in L5 and proximal tibia versus vehicle, and L5 BFR was higher with abaloparatide 40 μg/kg versus teriparatide. At the tibial diaphysis, periosteal BFR was higher with abaloparatide 40 μg/kg versus vehicle or teriparatide, and endocortical BFR was higher with teriparatide but not with abaloparatide 10 or 40 μg/kg versus vehicle. Few differences in structural or microarchitectural bone parameters were observed with this brief duration of treatment. In summary, calvarial bone resorption cavity counts were higher in the teriparatide group versus the vehicle and abaloparatide 40 μg/kg groups, and the abaloparatide 40 μg/kg group had lower serum CTX versus vehicle. L5 and tibial trabecular bone formation indices were higher in all three active treatment groups versus vehicle. The abaloparatide 40 μg/kg group had higher L5 trabecular BFR and tibial periosteal BFR versus teriparatide, whereas tibial endocortical BFR was higher with teriparatide but not abaloparatide. Together, these findings in female mice indicate that an improved balance of bone formation versus bone resorption is established shortly after initiating treatment with abaloparatide.
    Language English
    Publishing date 2020-06-26
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2821774-3
    ISSN 2352-1872
    ISSN 2352-1872
    DOI 10.1016/j.bonr.2020.100291
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  9. Article ; Online: Induced

    Khan, Sanjoy Kumar / Yadav, Prem Swaroop / Elliott, Gene / Hu, Dorothy Zhang / Xu, Ruoshi / Yang, Yingzi

    Proceedings of the National Academy of Sciences of the United States of America

    2018  Volume 115, Issue 3, Page(s) E418–E427

    Abstract: Fibrous dysplasia (FD; Online Mendelian Inheritance in Man no. 174800) is a crippling skeletal disease caused by activating mutations of ... ...

    Abstract Fibrous dysplasia (FD; Online Mendelian Inheritance in Man no. 174800) is a crippling skeletal disease caused by activating mutations of the
    MeSH term(s) Cell Differentiation ; Chromogranins/genetics ; Chromogranins/metabolism ; Fibrous Dysplasia of Bone/genetics ; GTP-Binding Protein alpha Subunits, Gs/genetics ; GTP-Binding Protein alpha Subunits, Gs/metabolism ; Gene Expression Regulation ; Humans ; Mesenchymal Stromal Cells/physiology ; Mutation ; Osteoblasts/physiology ; Signal Transduction ; Up-Regulation ; Wnt Proteins/genetics ; Wnt Proteins/metabolism ; beta Catenin/genetics ; beta Catenin/metabolism
    Chemical Substances Chromogranins ; Wnt Proteins ; beta Catenin ; Gnas protein, mouse (EC 3.6.1.-) ; GTP-Binding Protein alpha Subunits, Gs (EC 3.6.5.1)
    Language English
    Publishing date 2018--16
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1714313114
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  10. Article ; Online: Sfrp4 repression of the Ror2/Jnk cascade in osteoclasts protects cortical bone from excessive endosteal resorption.

    Chen, Kun / Ng, Pei Ying / Chen, Ruiying / Hu, Dorothy / Berry, Shawn / Baron, Roland / Gori, Francesca

    Proceedings of the National Academy of Sciences of the United States of America

    2019  Volume 116, Issue 28, Page(s) 14138–14143

    Abstract: Loss-of-function mutations in the Wnt inhibitor secreted frizzled receptor protein 4 (SFRP4) cause Pyle's disease (OMIM 265900), a rare skeletal disorder characterized by wide metaphyses, significant thinning of cortical bone, and fragility fractures. In ...

    Abstract Loss-of-function mutations in the Wnt inhibitor secreted frizzled receptor protein 4 (SFRP4) cause Pyle's disease (OMIM 265900), a rare skeletal disorder characterized by wide metaphyses, significant thinning of cortical bone, and fragility fractures. In mice, we have shown that the cortical thinning seen in the absence of
    MeSH term(s) Animals ; Autocrine Communication/genetics ; Bone Resorption/genetics ; Bone Resorption/pathology ; Bone and Bones/metabolism ; Cell Differentiation/genetics ; Cortical Bone/growth & development ; Cortical Bone/pathology ; Gene Expression Regulation, Developmental ; Humans ; MAP Kinase Kinase 4/genetics ; Mice ; Mice, Knockout ; Osteoblasts/metabolism ; Osteoblasts/pathology ; Osteochondrodysplasias/genetics ; Osteoclasts/metabolism ; Osteoclasts/pathology ; Paracrine Communication/genetics ; Proto-Oncogene Proteins/genetics ; Receptor Tyrosine Kinase-like Orphan Receptors/genetics ; Sequence Deletion ; Wnt Signaling Pathway/genetics
    Chemical Substances Proto-Oncogene Proteins ; Sfrp4 protein, mouse ; Receptor Tyrosine Kinase-like Orphan Receptors (EC 2.7.10.1) ; Ror2 protein, mouse (EC 2.7.10.1) ; MAP Kinase Kinase 4 (EC 2.7.12.2)
    Language English
    Publishing date 2019-06-25
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1900881116
    Database MEDical Literature Analysis and Retrieval System OnLINE

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