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  • 1
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    Mapping the human genetic architecture of COVID-19
    Springer Science and Business Media LLC ; 2021
    In:  Nature Vol. 600, No. 7889 ( 2021-12-16), p. 472-477
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 600, No. 7889 ( 2021-12-16), p. 472-477
    Kurzfassung: The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.
    Materialart: Online-Ressource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-021-03767-x
    RVK:
    TA 1000
    RVK:
    UA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Springer Science and Business Media LLC
    Publikationsdatum: 2021
    ZDB Id: 120714-3
    ZDB Id: 1413423-8
    SSG: 11
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  • 2
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    A second update on mapping the human genetic architecture of COVID-19
    Springer Science and Business Media LLC ; 2023
    In:  Nature Vol. 621, No. 7977 ( 2023-09-07), p. E7-E26
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 621, No. 7977 ( 2023-09-07), p. E7-E26
    Materialart: Online-Ressource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-023-06355-3
    RVK:
    TA 1000
    RVK:
    UA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Springer Science and Business Media LLC
    Publikationsdatum: 2023
    ZDB Id: 120714-3
    ZDB Id: 1413423-8
    SSG: 11
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
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    The Bone Sialoprotein RGD Domain Modulates and Maintains Periodontal Development
    SAGE Publications ; 2022
    In:  Journal of Dental Research Vol. 101, No. 10 ( 2022-09), p. 1238-1247
    Details
    In: Journal of Dental Research, SAGE Publications, Vol. 101, No. 10 ( 2022-09), p. 1238-1247
    Kurzfassung: Bone sialoprotein (gene: Ibsp; protein: BSP) is a multifunctional extracellular matrix protein present in bone, cementum, and dentin. Accumulating evidence supports BSP as a key regulator of mineralized tissue formation via evolutionarily conserved functional domains, including a C-terminal integrin-binding Arg-Gly-Asp (RGD) domain implicated in extracellular matrix–cell signaling. Ablation of Ibsp in mice ( Ibsp −/− ) results in impaired bone growth and mineralization and defective osteoclastogenesis, with effects in the craniofacial region including reduced acellular cementum formation, detachment of the periodontal ligament (PDL), alveolar bone hypomineralization, and severe periodontal breakdown. We hypothesized that BSP-RGD plays an important role in cementum and alveolar bone formation and mineralization, as well as periodontal function. This hypothesis was tested by replacing the RGD motif with a nonfunctional Lys-Ala-Glu (KAE) sequence in ( Ibsp KAE/KAE ) mice and OCCM.30 murine ( Ibsp KAE ) cementoblasts. The RGD domain was not critical for acellular or cellular cementum formation in Ibsp KAE/KAE mice. However, PDL volume and thickness were increased, and significantly more tartrate-resistant acid phosphatase–positive osteoclasts were found on alveolar bone surfaces of Ibsp KAE/KAE mice versus wild type mice. PDL organization was disrupted as indicated by picrosirius red stain, second harmonic generation imaging, dynamic mechanical analysis, and decreased asporin proteoglycan localization. In vitro studies implicated RGD functions in cell migration, adhesion, and mineralization, and this was confirmed by an ossicle implant model where cells lacking BSP-RGD showed substantial defects as compared with controls. In total, the BSP-RGD domain is implicated in periodontal development, though the scale and scope of changes indicated by in vitro studies indicate that other factors may partially compensate for and reduce the phenotypic severity of mice lacking BSP-RGD in vivo.
    Materialart: Online-Ressource
    ISSN: 0022-0345 , 1544-0591
    URL: Article
    DOI: 10.1177/00220345221100794
    Sprache: Englisch
    Verlag: SAGE Publications
    Publikationsdatum: 2022
    ZDB Id: 2057074-0
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  • 4
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    Delivery of Alkaline Phosphatase Promotes Periodontal Regeneration in Mice
    SAGE Publications ; 2021
    In:  Journal of Dental Research Vol. 100, No. 9 ( 2021-08), p. 993-1001
    Details
    In: Journal of Dental Research, SAGE Publications, Vol. 100, No. 9 ( 2021-08), p. 993-1001
    Kurzfassung: Factors regulating the ratio of pyrophosphate (PP i ) to phosphate (P i ) modulate biomineralization. Tissue-nonspecific alkaline phosphatase (TNAP) is a key promineralization enzyme that hydrolyzes the potent mineralization inhibitor PP i . The goal of this study was to determine whether TNAP could promote periodontal regeneration in bone sialoprotein knockout mice ( Ibsp −/− mice), which are known to have a periodontal disease phenotype. Delivery of TNAP was accomplished either systemically (through a lentiviral construct expressing a mineral-targeted TNAP-D 10 protein) or locally (through addition of recombinant human TNAP to a fenestration defect model). Systemic TNAP-D 10 delivered by intramuscular injection at 5 d postnatal (dpn) increased circulating alkaline phosphatase (ALP) levels in Ibsp −/− mice by 5-fold at 30 dpn, with levels returning to normal by 60 dpn when tissues were evaluated by micro–computed tomography and histology. Local delivery of recombinant human TNAP to fenestration defects in 5-wk-old wild type (WT) and Ibsp −/− mice did not alter long-term circulating ALP levels, and tissues were evaluated by micro–computed tomography and histology at postoperative day 45. Systemic and local delivery of TNAP significantly increased alveolar bone volume (20% and 37%, respectively) and cementum thickness (3- and 42-fold) in Ibsp −/− mice, with evidence for periodontal ligament attachment and bone/cementum marker localization. Local delivery significantly increased regenerated cementum and bone in WT mice. Addition of 100-μg/mL bovine intestinal ALP to culture media to increase ALP in vitro increased media P i concentration, mineralization, and Spp1 and Dmp1 marker gene expression in WT and Ibsp −/− OCCM.30 cementoblasts. Use of phosphonoformic acid, a nonspecific inhibitor of sodium P i cotransport, indicated that effects of bovine intestinal ALP on mineralization and marker gene expression were in part through P i transport. These findings show for the first time through multiple in vivo and in vitro approaches that pharmacologic modulation of P i /PP i metabolism can overcome periodontal breakdown and accomplish regeneration.
    Materialart: Online-Ressource
    ISSN: 0022-0345 , 1544-0591
    URL: Article
    DOI: 10.1177/00220345211005677
    Sprache: Englisch
    Verlag: SAGE Publications
    Publikationsdatum: 2021
    ZDB Id: 2057074-0
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 5
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    Ablation of Pyrophosphate Regulators Promotes Periodontal Regeneration
    SAGE Publications ; 2021
    In:  Journal of Dental Research Vol. 100, No. 6 ( 2021-06), p. 639-647
    Details
    In: Journal of Dental Research, SAGE Publications, Vol. 100, No. 6 ( 2021-06), p. 639-647
    Kurzfassung: Biomineralization is regulated by inorganic pyrophosphate (PP i ), a potent physiological inhibitor of hydroxyapatite crystal growth. Progressive ankylosis protein (ANK) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) act to increase local extracellular levels of PP i , inhibiting mineralization. The periodontal complex includes 2 mineralized tissues, cementum and alveolar bone (AB), both essential for tooth attachment. Previous studies demonstrated that loss of function of ANK or ENPP1 (reducing PP i ) resulted in increased cementum formation, suggesting PP i metabolism may be a target for periodontal regenerative therapies. To compare the effects of genetic ablation of Ank, Enpp1, and both factors concurrently on cementum and AB regeneration, mandibular fenestration defects were created in Ank knockout ( Ank KO), Enpp1 mutant ( Enpp1 asj/asj ), and double KO (dKO) mice. Genetic ablation of Ank, Enpp1, or both factors increased cementum regeneration compared to controls at postoperative days (PODs) 15 and 30 ( Ank KO: 8-fold, 3-fold; Enpp1 asj/asj : 7-fold, 3-fold; dKO: 11-fold, 4-fold, respectively) associated with increased fluorochrome labeling and expression of mineralized tissue markers, dentin matrix protein 1 ( Dmp1/DMP1), osteopontin ( Spp1/OPN), and bone sialoprotein ( Ibsp/BSP). Furthermore, dKO mice featured increased cementum thickness compared to single KOs at POD15 and Ank KO at POD30. No differences were noted in AB volume between genotypes, but osteoblast/osteocyte markers were increased in all KOs, partially mineralized osteoid volume was increased in dKO versus controls at POD15 (3-fold), and mineral density was decreased in Enpp1 asj/asj and dKOs at POD30 (6% and 9%, respectively). Increased numbers of osteoclasts were present in regenerated AB of all KOs versus controls. These preclinical studies suggest PP i modulation as a potential and novel approach for cementum regeneration, particularly targeting ENPP1 and/or ANK. Differences in cementum and AB regeneration in response to reduced PP i conditions highlight the need to consider tissue-specific responses in strategies targeting regeneration of the entire periodontal complex.
    Materialart: Online-Ressource
    ISSN: 0022-0345 , 1544-0591
    URL: Article
    DOI: 10.1177/0022034520981854
    Sprache: Englisch
    Verlag: SAGE Publications
    Publikationsdatum: 2021
    ZDB Id: 2057074-0
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  • 6
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    Optical Characterization of OMT-Coupled TES Bolometers for LiteBIRD
    Springer Science and Business Media LLC ; 2022
    In:  Journal of Low Temperature Physics Vol. 209, No. 3-4 ( 2022-11), p. 396-408
    Details
    In: Journal of Low Temperature Physics, Springer Science and Business Media LLC, Vol. 209, No. 3-4 ( 2022-11), p. 396-408
    Materialart: Online-Ressource
    ISSN: 0022-2291 , 1573-7357
    URL: Article
    DOI: 10.1007/s10909-022-02808-7
    Sprache: Englisch
    Verlag: Springer Science and Business Media LLC
    Publikationsdatum: 2022
    ZDB Id: 2016984-X
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  • 7
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    Sensitivity Modeling for LiteBIRD
    Springer Science and Business Media LLC ; 2023
    In:  Journal of Low Temperature Physics Vol. 211, No. 5-6 ( 2023-06), p. 384-397
    Details
    In: Journal of Low Temperature Physics, Springer Science and Business Media LLC, Vol. 211, No. 5-6 ( 2023-06), p. 384-397
    Materialart: Online-Ressource
    ISSN: 0022-2291 , 1573-7357
    URL: Article
    DOI: 10.1007/s10909-022-02921-7
    Sprache: Englisch
    Verlag: Springer Science and Business Media LLC
    Publikationsdatum: 2023
    ZDB Id: 2016984-X
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  • 8
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    Probing cosmic inflation with the LiteBIRD cosmic microwave background polarization survey
    Oxford University Press (OUP) ; 2023
    In:  Progress of Theoretical and Experimental Physics Vol. 2023, No. 4 ( 2023-04-04)
    Details
    In: Progress of Theoretical and Experimental Physics, Oxford University Press (OUP), Vol. 2023, No. 4 ( 2023-04-04)
    Kurzfassung: LiteBIRD, the Lite (Light) satellite for the study of B-mode polarization and Inflation from cosmic background Radiation Detection, is a space mission for primordial cosmology and fundamental physics. The Japan Aerospace Exploration Agency (JAXA) selected LiteBIRD in May 2019 as a strategic large-class (L-class) mission, with an expected launch in the late 2020s using JAXA’s H3 rocket. LiteBIRD is planned to orbit the Sun–Earth Lagrangian point L2, where it will map the cosmic microwave background polarization over the entire sky for three years, with three telescopes in 15 frequency bands between 34 and 448 GHz, to achieve an unprecedented total sensitivity of $2.2\, \mu$K-arcmin, with a typical angular resolution of 0.5○ at 100 GHz. The primary scientific objective of LiteBIRD is to search for the signal from cosmic inflation, either making a discovery or ruling out well-motivated inflationary models. The measurements of LiteBIRD will also provide us with insight into the quantum nature of gravity and other new physics beyond the standard models of particle physics and cosmology. We provide an overview of the LiteBIRD project, including scientific objectives, mission and system requirements, operation concept, spacecraft and payload module design, expected scientific outcomes, potential design extensions, and synergies with other projects.
    Materialart: Online-Ressource
    ISSN: 2050-3911
    URL: Article
    DOI: 10.1093/ptep/ptac150
    Sprache: Englisch
    Verlag: Oxford University Press (OUP)
    Publikationsdatum: 2023
    ZDB Id: 2705045-2
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  • 9
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    Endoscopic Surgical Skill Qualification System: propensity-score matched cohort analysis of accredited supervisors in laparoscopic rectal cancer surgery
    Oxford University Press (OUP) ; 2023
    In:  British Journal of Surgery ( 2023-09-11)
    Details
    In: British Journal of Surgery, Oxford University Press (OUP), ( 2023-09-11)
    Kurzfassung: The Endoscopic Surgical Skill Qualification System (ESSQS) in Japan evaluates the surgical skills required for laparoscopic surgery as an operator as well as a supervisor. This study aimed to demonstrate the benefits of an ESSQS-certified surgeon's participation in laparoscopic rectal resections as a supervisor (assistant or advisor). Methods We retrospectively reviewed laparoscopic resection results for cStage II and III rectal cancer performed at 56 Japanese hospitals between 2014 and 2016. We used propensity score matching to generate paired cohorts with or without an ESSQS-certified supervisor at a one-to-one ratio. The impact of ESSQS-certified supervisors' participation on short-term outcomes was assessed. In the matched cohort, multivariable logistic regression analysis and multivariable regression analysis of postoperative complication rate and intraoperative blood loss were performed to further mitigate the impact of pathological factors. Results Two groups (n = 399 each) with or without an ESSQS-certified supervisor were well matched by clinical factors. The group with an ESSQS-certified supervisor had lower blood loss (68 mL vs. 98 mL, P = 0.036) and a lower incidence of severe morbidities of Clavien-Dindo grade ≥IIIa (8.0% vs. 13.3%, P = 0.016). Multivariable logistic regression analysis and multivariable regression analysis confirmed that the attendance of ESSQS-certified supervisors reduced postoperative complication occurrence (adjusted odds ratio: 2.28, 95% confidence interval: 1.38 – 3.80, P = 0.001) and intraoperative blood loss (estimated difference: -15.7 mL, P = 0.016). Conclusion This study demonstrated the educational benefits of ESSQS-certified supervisors, including assistants and advisors, evidenced by their superior short-term outcomes.
    Materialart: Online-Ressource
    ISSN: 0007-1323 , 1365-2168
    URL: Article
    DOI: 10.1093/bjs/znad282
    Sprache: Englisch
    Verlag: Oxford University Press (OUP)
    Publikationsdatum: 2023
    ZDB Id: 2006309-X
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  • 10
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    Effect of ECH/ECCD on energetic-particle-driven MHD modes in helical plasmas
    IOP Publishing ; 2020
    In:  Nuclear Fusion Vol. 60, No. 6 ( 2020-06-01), p. 066018-
    Details
    In: Nuclear Fusion, IOP Publishing, Vol. 60, No. 6 ( 2020-06-01), p. 066018-
    Kurzfassung: The effect of electron cyclotron heating (ECH) and electron cyclotron current drive (ECCD) on energetic-particle (EP)-driven magnetohydrodynamic (MHD) modes is studied in the helical devices LHD, TJ-II and Heliotron J. We demonstrate that EP-driven MHD modes, including Alfvén eigenmodes (AEs) and energetic particle modes (EPMs), can be controlled by ECH/ECCD. In the LHD device, which has a moderate rotational transform and a high magnetic shear, co-ECCD enhances toroidal AEs (TAEs) and global AEs (GAEs), while counter-ECCD stabilizes them, which improves the neutron rate compared with the co-ECCD case. Counter-ECCD decreases the core rotational transform and increases the magnetic shear, strengthening the continuum damping on the shear Alfvén continua (SAC). In the TJ-II device, which has a high rotational transform, moderate magnetic shear and low toroidal field period, helical AEs (HAEs) appear when the HAE frequency gap of the SAC is changed by counter-ECCD combined with a bootstrap current and neutral-beam-driven current. On the other hand, both co- and counter-ECCD are effective in stabilizing GAEs and EPMs in the Heliotron J device, which has a low rotational transform and low magnetic shear. The experimental results indicate that the magnetic shear has a stabilizing effect regardless of its sign. Modeling analysis using the FAR3d code shows that the growth rates are reduced by both co- and counter-ECCD in Heliotron J, reproducing the experimental results. ECH only affects EP-driven MHD modes, and the experimental results show that the effect depends on the magnetic configuration. In Heliotron J, some modes are stabilized with an increase in ECH power in the low-bumpiness magnetic configuration, while some modes are destabilized in the high- and medium-bumpiness magnetic configurations.
    Materialart: Online-Ressource
    ISSN: 0029-5515 , 1741-4326
    URL: Article
    DOI: 10.1088/1741-4326/ab7f13
    Sprache: Unbekannt
    Verlag: IOP Publishing
    Publikationsdatum: 2020
    ZDB Id: 2037980-8
    Standort Signatur Einschränkungen Verfügbarkeit
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