| 1. |
- Marouli, Eirini, et al.
(författare)
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Rare and low-frequency coding variants alter human adult height
- 2017
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
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Tidskriftsartikel (refereegranskat)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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| 2. |
- Turcot, Valerie, et al.
(författare)
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Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
- 2018
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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| 3. |
- Justice, Anne E., et al.
(författare)
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Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:3, s. 452-469
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Tidskriftsartikel (refereegranskat)abstract
- Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF >= 5%) and nine low-frequency or rare (MAF < 5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
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| 4. |
- Zhang, Yuan, et al.
(författare)
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Quantitative Proteomics of TRAMP Mice Combined with Bioinformatics Analysis Reveals That PDGF-B Regulatory Network Plays a Key Role in Prostate Cancer Progression
- 2018
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Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 17:7, s. 2401-2411
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Tidskriftsartikel (refereegranskat)abstract
- Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice is a widely used transgenic animal model of prostate cancer (PCa). We performed a label-free quantitative proteomics analysis combined with a bioinformatics analysis on the entire prostate protein extraction from TRAMP mice and compared it with WT littermates. From 2379 total identified proteins, we presented a modest mice prostate reference proteome containing 919 proteins. 61 proteins presented a significant expression difference between two groups. The integrative bioinformatics analysis predicted the overexpression of platelet-derived growth factor B (PDGF-B) in tumor tissues and supports the hypothesis of the PDGF-B signaling network as a key upstream regulator in PCa progression. Furthermore, we demonstrated that Crenolanib, a novel PDGF receptor inhibitor, inhibited PCa cell proliferation in a dose-dependent manner. Finally, we revealed the importance of PDGF-B regulatory network in PCa progression, which will assist us in understanding the role and mechanisms of PDGF-B in promoting cancer growth and provide valuable knowledge for future research on anti-PDGF therapy.
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| 5. |
- Fan, Zhouzhou, et al.
(författare)
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Changes in Plant Rhizosphere Microbial Communities under Different Vegetation Restoration Patterns in Karst and Non-karst Ecosystems
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Understanding how patterns of recovery and geological conditions affect microbial communities is important for determining the stability of karst ecosystems. Here, we investigated the diversity and composition of microorganisms in karst and non-karst environments under natural restoration and artificial rehabilitation conditions. The results showed no significant differences in soil microbial diversity, but the microbial communities associated with geological conditions and tree species differed significantly. Variation partitioning analysis (VPA) showed that a total of 77.3% of the variation in bacteria and a total of 69.3% of the variation in fungi could be explained by vegetation type and geological background. There were significant differences in six bacterial classes (Actinobacteria, Alphaproteobacteria, Ktedonobacteria, TK10, Gammaproteobacteria, and Anaerolineae) and nine fungal classes (Eurotiomycetes, Agaricomycetes, unclassified _p_Ascomycota, Sordariomycetes, Tremellomycetes, norank_k_Fungi, Pezizomycetes, Leotiomycetes and Archaeorhizomycetes) among the soils collected from six plots. A Spearman correlation heatmap showed that the microbial community was affected by the major soil properties. Principal coordinates analysis indicated that the microbial community of Pinus yunnanensis in the artificial forest, which was established for the protection of the environment was most similar to that in the natural secondary forest in the karst ecosystem. These findings further our understanding of microbial responses to vegetation restoration and geological conditions.
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| 6. |
- Feng, Zhenhua, et al.
(författare)
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Multicore-Fiber-Enabled WSDM Optical Access Network With Centralized Carrier Delivery and RSOA-Based Adaptive Modulation
- 2015
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Ingår i: IEEE PHOTONICS JOURNAL. - : Institute of Electrical and Electronics Engineers (IEEE). - 1943-0655. ; 7:4
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Tidskriftsartikel (refereegranskat)abstract
- We proposed and experimentally demonstrated a wavelength-space division multiplexing (WSDM) optical access network architecture with centralized optical carrier delivery utilizing multicore fibers (MCFs) and adaptive modulation based on reflective semiconductor amplifier (RSOA). In our experiment, five of the outer cores are used for undirectional downstream (DS) transmission only, whereas the remaining outer core is utilized as a dedicated channel to transmit upstream (US) signals. Optical carriers for US are delivered from the optical line terminal (OLT) to the optical network unit (ONU) via the inner core and then transmitted back to the OLT after amplification and modulation by the RSOA in the colorless ONU side. The mobile backhaul (MB) service is also supported by the inner core. Wavelengths used in US transmission should be different from that of the MB in order to avoid the Rayleigh backscattering effect in bidirectional transmission. With quadrature phase-shift keying-orthogonal frequency-division multiplexing (QPSK-OFDM) modulation format, the aggregation DS capacity reaches 250 Gb/s using five outer cores and ten wavelengths, and it can be further scaled to 1 Tb/s using 20 wavelengths modulated with 16 QAM-OFDM. For US transmission, 2.5 Gb/s QPSK-OFDM transmission can be achieved just using a low-bandwidth RSOA, and adaptive modulation is applied to the RSOA to further enhance the US data rate to 3.12 Gb/s. As an emulation of high-speed MB transmission, 48 Gb/s inphase and quadrature (IQ) modulated popularization division multiplexing (PDM)-QPSK signal is transmitted in the inner core of MCF and coherently detected in the OLT side. Both DS and US optical signals exhibit acceptable performance with sufficient power budget.
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| 7. |
- Tong, Yiheng, et al.
(författare)
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Effects of the position of a bluff-body on the diffusion flames : A combined experimental and numerical study
- 2018
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Ingår i: Applied Thermal Engineering. - : Elsevier BV. - 1359-4311. ; 131, s. 507-521
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Tidskriftsartikel (refereegranskat)abstract
- The effects of the position of a bluff-body on diffusion flame structures and flame instability characteristics were investigated both experimentally and numerically. The flame pattern diagram and the stability limits of the methane-air diffusion flame were investigated to evaluate the effects caused by the alternation of the position of a bluff-body. A disk-shape bluff-body was mounted 10 mm above or at the same height with the annular channel exit. The bulk velocity of the annular air flow varied between Ua = 0 to 8 m/s; while the fuel jet velocity being ranged from Uj = 0 to 30 m/s. Various flame patterns, including the recirculation zone flame, the stable diffusion flame, the split flame and the lifted flame till flame blowoff, were observed and recorded by the high-speed camera. High-speed Particle Image Velocimetry (PIV) was also adopted to give deeper insight into the characteristics of the flow fields and the flame patterns. The hybrid RANS/LES model was utilized to simulate the mixing characters of the reactants, the scalar dissipation rates, the flow fields and their interactions with the flame structures. The size and strength of the recirculation zones downstream of the bluff-body altered with the change in the position of the bluff-body. It is found that flames in burners with two different bluff-body positions behave similarly with each other, except those under conditions with high annular air velocities (Ua > 6.8 m/s). Mounting the bluff-body 10 mm above the annular channel exit could better stabilize the flame. A recirculation vortex was found adjacent to the outer wall of the bluff-body. It played an important role in the flame stabilization. Combustion affected the flow fields significantly by accelerating the central jet and enlarging the outer recirculation zone.
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| 8. |
- Wang, Kai, et al.
(författare)
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Calculations with spectroscopic accuracy : Energies and transition rates in the nitrogen isoelectronic sequence from Ar XII to Zn XXIV
- 2016
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Ingår i: Astrophysical Journal Supplement Series. - : American Astronomical Society. - 0067-0049 .- 1538-4365. ; 223:1
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Tidskriftsartikel (refereegranskat)abstract
- Combined relativistic configuration interaction and many-body perturbation calculations are performed for the 359 fine-structure levels of the 2s2 2p3, 2 s2p4, 2p5, 2s2 2p2 3l, 2 s2p3 3l, 2p4 3l, and 2s2 2p2 4l configurations in N-like ions from Ar XII to Zn XXIV. Complete and consistent data sets of energies, wavelengths, radiative rates, oscillator strengths, and line strengths for all possible electric dipole, magnetic dipole, electric quadrupole, and magnetic quadrupole transitions among the 359 levels are given for each ion. The present work significantly increases the amount of accurate data for ions in the nitrogen-like sequence, and the accuracy of the energy levels is high enough to enable the identification and interpretation of observed spectra involving the n=3, 4 levels, for which experimental values are largely scarce. Meanwhile, the results should be of great help for modeling and diagnosing astrophysical and fusion plasmas.
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| 9. |
- Wang, Min, et al.
(författare)
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Apolipoprotein M induces inhibition of inflammatory responses via the S1PR1 and DHCR24 pathways
- 2019
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Ingår i: Molecular Medicine Reports. - 1791-2997. ; 19:2, s. 1272-1283
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Tidskriftsartikel (refereegranskat)abstract
- © 2019 Spandidos Publications. All rights reserved. Apolipoprotein M (ApoM) is a type of apolipoprotein. It is well known that high-density lipoprotein (HDL) decreases inflammatory responses via the apoM-sphingosine-1-phosphate (S1P) pathway. The present study further investigated the importance of ApoM in the inhibitory effects of HDL on inflammation. Mice with an apoM gene deficiency (apoM-/-) were employed to investigate the effects of ApoM on the expression of interleukin-1β (IL-1β), monocyte chemotactic protein-1 (MCP-1), S1P receptor-1 (S1PR1) and 3β-hydroxysterol Δ-24-reductase (DHCR24), as compared with in wild-type mice (apoM+/+). Furthermore, cell culture experiments were performed using a permanent human hybrid endothelial cell line (EA.hy926). Cells were cultured in the presence of recombinant human apoM (rec-apoM) or were induced to overexpress apoM (apoMTg); subsequently, cells were treated with tumor necrosis factor-α (TNF-α), in order to investigate the effects of ApoM on IL-1β and MCP-1. The results demonstrated that the mRNA expression levels of IL-1β and MCP-1 were significantly higher in the liver following administration of lipopolysaccharide in apoM-/- mice compared with in apoM+/+ mice. In cell culture experiments, when cells were pre-cultured with rec-apoM or were engineered to overexpress apoM (apoMTg), they exhibited decreased expression levels of IL-1β and MCP-1 following TNF-α treatment compared with in normal apoM-expressing cells (apoMTgN). Furthermore, the mRNA expression levels of IL-1β and MCP-1 were significantly elevated following addition of the S1PR1 inhibitor W146, but not by the scavenger receptor class B type I inhibitor, block lipid transport-1 (BLT-1), in apoMTg cells prior to TNF-α treatment. Conversely, there were no differences in these inflammatory biomarkers under the same conditions in apoMTgN cells. The mRNA expression levels of DHCR24 were significantly reduced by the addition of BLT-1 prior to TNF-α treatment in apoMTg cells; however, there was no difference in the expression of this inflammatory biomarker in apoMTgN cells. In conclusion, ApoM displayed inhibitory effects against the inflammatory response in vivo and in vitro; these effects may be induced via the S1PR1 and DHCR24 pathways.
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