| 1. |
- Yoo, Taekyeong, et al.
(author)
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Disease-specific eQTL screening reveals an anti-fibrotic effect of AGXT2 in non-alcoholic fatty liver disease.
- 2021
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In: Journal of hepatology. - : Elsevier BV. - 1600-0641 .- 0168-8278. ; 75:3, s. 514-523
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Journal article (peer-reviewed)abstract
- Nonalcoholic fatty liver disease (NAFLD) poses an impending clinical burden. Genome-wide association studies have revealed a limited contribution of genomic variants to the disease, requiring alternative but robust approaches to identify disease-associated variants and genes. We carried out a disease-specific expression quantitative trait loci (eQTL) screen to identify novel genetic factors that specifically act on NAFLD progression on the basis of genotype.We recruited 125 Korean biopsy-proven NAFLD patients and healthy individuals and performed eQTL analyses using 21,272 transcripts and 3,234,941 genotyped and imputed SNPs. We then selected eQTLs that were detected only in the NAFLD group, but not in the control group (i.e., NAFLD-eQTLs). An additional cohort of 162 Korean NAFLD individuals was used for replication. The function of the selected eQTL toward NAFLD development was validated using HepG2, primary hepatocytes and NAFLD mouse models.The NAFLD-specific eQTL screening yielded 242 loci. Among them, AGXT2, encoding alanine-glyoxylate aminotransferase 2, displayed decreased expression in NAFLD patients homozygous for the non-reference allele of rs2291702, compared to no-NAFLD subjects with the same genotype (P = 4.79 × 10-6). This change was replicated in an additional 162 individuals, yielding a combined P-value of 8.05 × 10-8 from a total of 245 NAFLD patients and 48 controls. Knockdown of AGXT2 induced palmitate-overloaded hepatocyte death by increasing ER stress, and exacerbated NAFLD diet-induced liver fibrosis in mice. However, overexpression of AGXT2 reversely attenuated liver fibrosis and steatosis as well.We implicate a new molecular role of AGXT2 in NAFLD. Our overall approach will serve as an efficient tool for uncovering novel genetic factors that contribute to liver steatosis and fibrosis in patients with NAFLD.Elucidating causal genes for NAFLD has been challenging due to limited tissue availability and the polygenic nature of the disease. Using liver and blood samples from 125 biopsy-proven NAFLD and no-NAFLD Korean individuals and an additional 162 individuals for replication, we devised a new analytic method to identify causal genes. Among the candidates, we found that AGXT2-rs2291702 protects against liver fibrosis in a genotype-dependent manner with the potential for therapeutic interventions. Our approach enables the discovery of NAFLD causal genes that act on the basis of genotype.
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| 2. |
- Dudas, Marek, et al.
(author)
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Epithelial and ectomesenchymal role of the type I TGF-beta receptor ALK5 during facial morphogenesis and palatal fusion
- 2006
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In: Developmental Biology. - : Elsevier BV. - 1095-564X .- 0012-1606. ; 296:2, s. 298-314
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Journal article (peer-reviewed)abstract
- Transforming growth factor beta (TGF-beta) proteins play important roles in morphogenesis of many cramofacial tissues; however, detailed biological mechanisms of TGF-beta action, particularly in vivo, are still poorly understood. Here, we deleted the TGF-beta type I receptor gene Alk5 specifically in the embryonic ectodermal and neural crest cell lineages. Failure in signaling via this receptor, either in the epithelium or in the mesenchyme, caused severe craniofacial defects including cleft palate. Moreover, the facial phenotypes of neural crest-specific Alk5 mutants included devastating facial cleft and appeared significantly more severe than the defects seen in corresponding mutants lacking the TGF-beta type II receptor (TGF beta II), a prototypical binding partner of ALK5. Our data indicate that ALK5 plays unique, non-redundant cell-autonomous roles during facial development. Remarkable divergence between Tgfbr2 and A1k5 phenotypes, together with our biochemical in vitro data, imply that (1) ALK5 mediates signaling of a diverse set of ligands not limited to the three isoforms of TGF-beta, and (2) ALK5 acts also in conjunction with type II receptors other than TGF beta RII. (c) 2006 Elsevier Inc. All rights reserved.
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| 3. |
- Harris, Richard E, et al.
(author)
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Pregabalin rectifies aberrant brain chemistry, connectivity, and functional response in chronic pain patients.
- 2013
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In: Anesthesiology. - 1528-1175. ; 119:6, s. 1453-1464
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Journal article (peer-reviewed)abstract
- Chronic pain remains a significant challenge for modern health care as its pathologic mechanisms are largely unknown and preclinical animal models suffer from limitations in assessing this complex subjective experience. However, human brain neuroimaging techniques enable the assessment of functional and neurochemical alterations in patients experiencing chronic pain and how these factors may dynamically change with pharmacologic treatment.
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| 4. |
- Wang, Shih-Hao, et al.
(author)
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TAROGE-M : radio antenna array on antarctic high mountain for detecting near-horizontal ultra-high energy air showers
- 2022
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In: Journal of Cosmology and Astroparticle Physics. - : IOP Publishing. - 1475-7516. ; :11
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Journal article (peer-reviewed)abstract
- The TAROGE-M radio observatory is a self-triggered antenna array on top of the similar to 2700m high Mt. Melbourne in Antarctica, designed to detect impulsive geomagnetic emission from extensive air showers induced by ultra-high energy (UHE) particles beyond 1017 eV, including cosmic rays, Earth-skimming tau neutrinos, and particularly, the "ANITA anomalous events" (AAE) from near and below the horizon. The six AAE discovered by the ANITA experiment have signal features similar to tau neutrinos but that hypothesis is in tension either with the interaction length predicted by Standard Model or with the flux limits set by other experiments. Their origin remains uncertain, requiring more experimental inputs for clarification. The detection concept of TAROGE-M takes advantage of a high altitude with synoptic view toward the horizon as an efficient signal collector, and the radio quietness as well as strong and near vertical geomagnetic field in Antarctica, enhancing the relative radio signal strength. This approach has a low energy threshold, high duty cycle, and is easy to extend for quickly enlarging statistics. Here we report experimental results from the first TAROGEM station deployed in January 2020, corresponding to approximately one month of livetime. The station consists of six receiving antennas operating at 180-450 MHz, and can reconstruct source directions of impulsive events with an angular resolution of similar to 0.3 ffi, calibrated in situ with a drone-borne pulser system. To demonstrate TAROGE-M's ability to detect UHE air showers, a search for cosmic ray signals in 25.3-days of data together with the detection simulation were conducted, resulting in seven identified candidates. The detected events have a mean reconstructed energy of 0.95+0.46 -0.31 EeV and zenith angles ranging from 25 ffi to 82 ffi, with both distributions agreeing with the simulations, indicating an energy threshold at about 0.3 EeV. The estimated cosmic ray flux at that energy is 1.2+0.7 -0.9x10(-16) eV(-1) km(-2) yr(-1) sr(-1), also consistent with results of other experiments. The TAROGE-M sensitivity to AAEs is approximated by the tau neutrino exposure with simulations, which suggests comparable sensitivity as ANITA's at around 1 EeV energy with a few station-years of operation. These first results verified the station design and performance in a polar and high-altitude environment, and are promising for further discovery of tau neutrinos and AAEs after an extension in the near future.
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| 6. |
- Zieliński, Tomasz G., et al.
(author)
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Reproducibility of sound-absorbing periodic porous materials using additive manufacturing technologies : Round robin study
- 2020
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In: Additive Manufacturing. - : Elsevier B.V.. - 2214-8604 .- 2214-7810. ; 36
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Journal article (peer-reviewed)abstract
- The purpose of this work is to check if additive manufacturing technologies are suitable for reproducing porous samples designed for sound absorption. The work is an inter-laboratory test, in which the production of samples and their acoustic measurements are carried out independently by different laboratories, sharing only the same geometry codes describing agreed periodic cellular designs. Different additive manufacturing technologies and equipment are used to make samples. Although most of the results obtained from measurements performed on samples with the same cellular design are very close, it is shown that some discrepancies are due to shape and surface imperfections, or microporosity, induced by the manufacturing process. The proposed periodic cellular designs can be easily reproduced and are suitable for further benchmarking of additive manufacturing techniques for rapid prototyping of acoustic materials and metamaterials.
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