| 1. |
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| 2. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 3. |
- Jung, Se Yong, et al.
(författare)
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Cardiovascular events and safety outcomes associated with remdesivir using a World Health Organization international pharmacovigilance database
- 2022
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Ingår i: Clinical and Translational Science. - : Wiley. - 1752-8054 .- 1752-8062. ; 15:2, s. 501-513
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Tidskriftsartikel (refereegranskat)abstract
- On October 2020, the US Food and Drug Administration (FDA) approved remdesivir as the first drug for the treatment of coronavirus disease 2019 (COVID-19), increasing remdesivir prescriptions worldwide. However, potential cardiovascular (CV) toxicities associated with remdesivir remain unknown. We aimed to characterize the CV adverse drug reactions (ADRs) associated with remdesivir using VigiBase, an individual case safety report database of the World Health Organization (WHO). Disproportionality analyses of CV-ADRs associated with remdesivir were performed using reported odds ratios and information components. We conducted in vitro experiments using cardiomyocytes derived from human pluripotent stem cell cardiomyocytes (hPSC-CMs) to confirm cardiotoxicity of remdesivir. To distinguish drug-induced CV-ADRs from COVID-19 effects, we restricted analyses to patients with COVID-19 and found that, after adjusting for multiple confounders, cardiac arrest (adjusted odds ratio [aOR]: 1.88, 95% confidence interval [CI]: 1.08-3.29), bradycardia (aOR: 2.09, 95% CI: 1.24-3.53), and hypotension (aOR: 1.67, 95% CI: 1.03-2.73) were associated with remdesivir. In vitro data demonstrated that remdesivir reduced the cell viability of hPSC-CMs in time- and dose-dependent manners. Physicians should be aware of potential CV consequences following remdesivir use and implement adequate CV monitoring to maintain a tolerable safety margin.
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| 4. |
- Choi, Jae Won, et al.
(författare)
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Interface-driven seebeck effect in two-dimensional trilayer-stacked PtTe2/MoS2/MoS2 heterostructures via electron-electron interactions
- 2023
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Ingår i: Nano Energy. - : Elsevier. - 2211-2855 .- 2211-3282. ; 115
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Tidskriftsartikel (refereegranskat)abstract
- Two-dimensional (2D) platinum telluride (PtTe2), which is one of the promising metallic transition metal dichalcogenides, has been proven as an essential candidate for electronic devices, magnetic devices, type-II Dirac fermions, topological superconductors, and other optoelectronic applications. However, the formation and thermal transport as important thermoelectric (TE) device applications have not been realized in large-area 2D PtTe2 films due to their semi-metallic properties. Here, we report an innovative approach to enhance the in-plane TE power factors by piling the metallic PtTe2 films on high-resistance (> 10 MO) intrinsic MoS2 films to form bilayer-PtTe2/MoS2 (5 nm/7 nm)//sapphire and trilayer-PtTe2/MoS2/MoS2 (5 nm/7 nm/7 nm)//sapphire heterostructures via wet-transfer stacking method. Such approaches can be achieved by utilizing 2D/2D heterostructure to increase the electron effective mass due to the strong electron-electron interaction at interface under temperature gradient along the samples and ultimately increase Seebeck coefficients via interface-driven Seebeck effect along with a metallic high-conductivity top-PtTe2 films. The trilayer-stacked PtTe2/MoS2/MoS2 heterostructures exhibit an extremely high Seebeck coefficient of 21.6 mu V/K and power factor of similar to 0.2 mW/m.K-2, which are 231 % and similar to 727 %, higher than those of the metallic 5-nm-thick single PtTe2 film on the sapphire substrate, respectively. Our new physics and observation can pave the way toward an effective strategy for understating 2D/2D TMDC heterostructure materials for high Fig.-of-merit TE energy harvesting devices.
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| 5. |
- Choi, Jae Won, et al.
(författare)
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Observation of a Strong Decoupling Phenomenon in Pt/Si Hybrid Structures for In-Plane Thermoelectric Properties
- 2022
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Ingår i: The Journal of Physical Chemistry C. - : American Chemical Society (ACS). - 1932-7447 .- 1932-7455. ; 126:40, s. 17283-17290
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Tidskriftsartikel (refereegranskat)abstract
- The performance of thermoelectric (TE) materials is limited by the intrinsic coupling of the Seebeck coefficient and the electrical conductivity such that an increase in one leads to a decrease in the other with respect to the carrier concentration. This coupling makes it particularly difficult to enhance the TE power factor in TE materials. In this study, we added a Pt top layer over a silicon wafer, forming a hybridized Pt/Si structure to drive a strong decoupling of the Seebeck coefficient and electrical conductivity. The results show that the electrical resistance in the Pt/Si hybrid structure decreased by ∼94 times compared to that of a single-layer lightly doped Si substrate at 300 K, while the Seebeck coefficient in the hybrid structure decreased slightly compared to that of the single layer. The remarkably high TE performance of the Pt/Si hybrid structure is brought about by the hybridization of the intrinsic high-conductivity Pt layer and the high-Seebeck coefficient Si substrate. In addition, we demonstrate that this novel and effective decoupling method enables the assessment of the in-plane intrinsic Seebeck coefficient of a lightly doped Si wafer, which typically has an electrical resistance that is extremely high to measure the Seebeck coefficient even with a high-resolution voltmeter. These results represent a significant advancement in the understanding of electrical transport in TE materials, which will invigorate further research on Si-based devices for realizing large-area watt-scale TE generation at room temperature.
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| 6. |
- Kang, Min-Sung, et al.
(författare)
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Enhanced Transverse Seebeck Coefficients in 2D/2D PtSe2/MoS2 Heterostructures Using Wet-Transfer Stacking
- 2022
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Ingår i: ACS Applied Materials and Interfaces. - : American Chemical Society (ACS). - 1944-8244 .- 1944-8252. ; 14:46, s. 51881-51888
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Tidskriftsartikel (refereegranskat)abstract
- It is very challenging to estimate thermoelectric (TE) properties when applying millimeter-scale two-dimensional (2D) transition metal dichalcogenide (TMDC) materials to TE device applications, particularly their Seebeck coefficient due to their high intrinsic electrical resistance. This paper proposes an innovative approach to measure large transverse (i.e., in-plane) Seebeck coefficients for 2D TMDC materials by placing a low resistance (LR) semimetallic PtSe2 film on high-resistance (HR) semiconducting MoS2 (>10 M omega), whose internal resistance is too high to measure the Seebeck coefficient, forming a heterojunction structure using wet-transfer stacking. The vertically stacked LRPtSe2 (3 nm)/HR-MoS2 (12 nm) heterostructure film exhibits a high Seebeck coefficient > 190 mu V/K up to 5 K temperature difference. This unusual behavior can be explained by an additional Seebeck effect induced at the interface between the LR-2D/HR2D heterostructure. The proposed stacked LR-PtSe2/HR-MoS2 heterostructure film offers promising phenomena 2D/2D materials that enable innovative TE device applications.
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| 7. |
- Kim, Min-Jeong, et al.
(författare)
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Intrinsic Seebeck coefficients of 2D polycrystalline PtSe2 semiconducting films through two-step annealing
- 2023
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Ingår i: Journal of Materials Chemistry A. - : Royal Society of Chemistry. - 2050-7488 .- 2050-7496. ; 11:11, s. 5714-5724
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Tidskriftsartikel (refereegranskat)abstract
- Because of the high contact resistance between a metal and a film, evaluating the intrinsic Seebeck coefficient of large-area two-dimensional (2D) semiconducting films with high-resistance is challenging. Here, we report a simple scheme to measure the large-area Seebeck coefficients of 2D polycrystalline platinum diselenide (PtSe2) thin films, whose electrical resistance (>2 M omega) is too high to measure the thermoelectric (TE) properties, by thermal annealing. As-prepared PtSe2 thin films deposited on sapphire substrates and treated by a two-step thermal annealing process at 574 K exhibited an intrinsic Seebeck coefficient > similar to 160 mu V K-1, which is 400% higher than that of the single-crystalline PtSe2 bulk, under a temperature gradient of up to 5 K along the samples. In addition, we confirm that the in-plane Seebeck coefficient of the two-step annealed samples was independent of the metal electrode. In addition, the role of thermal annealing in intrinsically-high-resistance 2D PtSe2 semiconducting films based on the atomic-scale crystallographic characteristics of these films and the measured contact resistance between the metal and PtSe2 layer is further discussed. Our finding represents an important achievement in understanding and measuring the Seebeck effect of high-TE-performance 2D layered transition metal dichalcogenide materials.
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| 8. |
- Kim, Yun-Ho, et al.
(författare)
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Barrier-free semimetallic PtSe2 contact formation in two-dimensional PtSe2/PtSe2 homostructure for high-performance field-effect transistors
- 2023
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Ingår i: Applied Surface Science. - : ELSEVIER. - 0169-4332 .- 1873-5584. ; 638
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Tidskriftsartikel (refereegranskat)abstract
- The search for low-resistance metal contacts on two-dimensional (2D) layered transition metal dichalcogenide (TMDC) materials for high-performance electronic devices remains challenging owing to the lack of interfacial bonding on the surface and a strong Fermi-level pinning effect. In this study, we demonstrate a high-performance 2D large-area homostructured PtSe2/PtSe2 field-effect transistor (FET) by introducing a Schottky-barrier-free and semimetallic PtSe2 film (top layer) as an ohmic contact to semiconducting 2D PtSe2 films (bottom layer) via the wet-transfer method. We successfully improved the current on/off ratio of homostructured 2D/2D PtSe2/PtSe2 FET by more than approximately twofold increase compared to the PtSe2 FET with Pt contacts owing to the barrier-free homojunction PtSe2 layer. Our finding represents a significant achievement in obtaining highperformance electronic devices with barrier-free contacts on homostructured PtSe2 FETs and paves the way toward a promising strategy for wafer-scale 2D TMDC electronic devices.
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| 9. |
- Lee, Won-Yong, et al.
(författare)
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Abnormal Seebeck Effect in Vertically Stacked 2D/2D PtSe2/PtSe2 Homostructure
- 2022
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Ingår i: Advanced Science. - : Wiley-VCH Verlagsgesellschaft. - 2198-3844. ; 9:36
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Tidskriftsartikel (refereegranskat)abstract
- When a thermoelectric (TE) material is deposited with a secondary TE material, the total Seebeck coefficient of the stacked layer is generally represented by a parallel conductor model. Accordingly, when TE material layers of the same thickness are stacked vertically, the total Seebeck coefficient in the transverse direction may change in a single layer. Here, an abnormal Seebeck effect in a stacked two-dimensional (2D) PtSe2/PtSe2 homostructure film, i.e., an extra in-plane Seebeck voltage is produced by wet-transfer stacking at the interface between the PtSe2 layers under a transverse temperature gradient is reported. This abnormal Seebeck effect is referred to as the interfacial Seebeck effect in stacked PtSe2/PtSe2 homostructures. This effect is attributed to the carrier-interface interaction, and has independent characteristics in relation to carrier concentration. It is confirmed that the in-plane Seebeck coefficient increases as the number of stacked PtSe2 layers increase and observed a high Seebeck coefficient exceeding ≈188 µV K−1 at 300 K in a four-layer-stacked PtSe2/PtSe2 homostructure.
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| 10. |
- Lee, Won-Yong, et al.
(författare)
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Alternatingly Stacked Low- and High-Resistance PtSe2/PtSe2 Homostructures Boost Thermoelectric Power Factors
- 2023
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Ingår i: Advanced Electronic Materials. - : John Wiley & Sons. - 2199-160X. ; 9:8
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Tidskriftsartikel (refereegranskat)abstract
- 2D transition-metal dichalcogenide (TMDC) materials are promising candidates with excellent thermoelectric (TE) properties owing to their low dimensionality in electronic and phonon transport. However, the considerable coupling of the Seebeck coefficient and electrical conductivity in such TE materials eventually results in the limit of the TE power factor increase, which severely hinders potential TE device applications. Herein, an alternative approach is demonstrated for breaking the strong coupling between the Seebeck coefficient and electrical conductivity in single TE materials by adopting a novel stacked PtSe2/PtSe2 homostructure. By alternately piling low-resistance (LR) PtSe2 (3 nm) onto high-resistance (HR) PtSe2 (2 nm) as one unit, the Seebeck coefficient and electrical conductivity of such stacked homostructures can be greatly enhanced with slightly improved electrical conductivity, ultimately resulting in a TE power factor in three-unit-stacked homostructures that is approximate to 1,648% higher than that of a single PtSe2 (15 nm) layer with the same thickness. This enhancement is attributed to an independent increase in the Seebeck coefficient, which depends on the interface among the LR and HR PtSe2 layers. The findings pave the way for a method that, unlike power factor optimization in conventional thermoelectric materials, can only utilize the Seebeck coefficient and electrical conductivity of each layer in a stacked homostructure.
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| 11. |
- Saeed, Muhammad Ahsan, et al.
(författare)
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2D MXene Additive-Induced Treatment Enabling High-Efficiency Indoor Organic Photovoltaics
- 2023
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Ingår i: Advanced Optical Materials. - : Wiley-VCH Verlagsgesellschaft. - 2162-7568 .- 2195-1071. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- The surge of Internet-of-everything applications over the past decade demands the adoption of novel material design and device engineering strategies for the development of state-of-the-art organic photovoltaics (OPVs) in low-light indoor environments. Owing to their excellent optoelectronic properties, two-dimensional MXenes possess outstanding potential in this regard. Herein, an unprecedented indoor power conversion efficiency (PCE) of 33.8% under light-emitting-diode (LED) illumination (1000-lx) is secured by additive-induced treatment of MXene in polymer-donor:non-fullerene-acceptor-based organic photoactive layer. The remarkable indoor performance of MXene OPVs mainly originates from the enhanced absorption, compact molecular packing, and smooth surface morphology with a reduced number of grain boundaries in the photoactive layer, resulting in an improved fill factor and balanced charge transport and extraction characteristics with suppressed recombination, thereby producing an impressive indoor PCE. In addition, the presence of MXene in the photoactive layer facilitates polaron-pair dissociation owing to improved free-charge generation, leading to enhanced photoconductivity. This performance represents the highest PCE among the OPVs measured under indoor illumination. This work highlights the promising prospect of 2D MXene and its composites for indoor light energy harvesting applications.
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| 12. |
- Yang, Seung Won, et al.
(författare)
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Harnessing an RNA-mediated chaperone for the assembly of influenza hemagglutinin in an immunologically relevant conformation
- 2018
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Ingår i: The FASEB Journal. - 0892-6638 .- 1530-6860. ; 32:5, s. 2658-2675
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Tidskriftsartikel (refereegranskat)abstract
- A novel protein-folding function of RNA has been recognized, which can outperform previously known molecular chaperone proteins. The RNA as a molecular chaperone (chaperna) activity is intrinsic to some ribozymes and is operational during viral infections. Our purpose was to test whether influenza hemagglutinin (HA) can be assembled in a soluble, trimeric, and immunologically activating conformation by means of an RNA molecular chaperone (chaperna) activity. An RNA-interacting domain (RID) from the host being immunized was selected as a docking tag for RNA binding, which served as a transducer for the chaperna function for de novo folding and trimeric assembly of RID-HA1. Mutations that affect tRNA binding greatly increased the soluble aggregation defective in trimer assembly, suggesting that RNA interaction critically controls the kinetic network in the folding/assembly pathway. Immunization of mice resulted in strong hemagglutination inhibition and high titers of a neutralizing antibody, providing sterile protection against a lethal challenge and confirming the immunologically relevant HA conformation. The results may be translated into a rapid response to a new influenza pandemic. The harnessing of the novel chaperna described herein with immunologically tailored antigen-folding functions should serve as a robust prophylactic and diagnostic tool for viral infections.
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| 13. |
- Yoo, Taekyeong, et al.
(författare)
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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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Ingår i: Journal of hepatology. - : Elsevier BV. - 1600-0641 .- 0168-8278. ; 75:3, s. 514-523
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Tidskriftsartikel (refereegranskat)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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| 14. |
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| 15. |
- Choi, Sungchul, et al.
(författare)
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Global burden of primary liver cancer and its asso- ciation with underlying aetiologies, sociodemo- graphic status, and sex differences from 1990-2019: A DALY-based analysis of the Global Burden of Disease 2019 study
- 2023
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Ingår i: Clinical and Molecular Hepatology. - : KOREAN ASSOC STUDY LIVER. - 2287-2728 .- 2287-285X. ; 29:2, s. 433-452
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aims: Global distribution of dominant liver cancer aetiologies has significantly changed over the past decades. This study analyzed the updated temporal trends of liver cancer aetiologies and sociodemographic status in 204 countries and territories from 1990 to 2019.Methods: The Global Burden of Disease 2019 report was used for statistical analysis. In addition, we performed stratification analysis to five quintiles using sociodemographic index and 21 geographic regions.Results: The crude numbers of liver cancer disease-adjusted life years (DALYs) and deaths significantly increased during the study period (DALYs; 11,278,630 in 1990 and 12,528,422 in 2019, deaths; 365,215 in 1990 and 484,577 in 2019). However, the Age-standardized DALY and mortality rates decreased. Hepatitis B virus (HBV) remains the leading cause of liver cancer DALYs and mortality, followed by hepatitis C virus (HCV), alcohol consumption, and non-alcoholic steatohepatitis/non-alcoholic fatty liver disease (NASH/NAFLD). Although Age-standardized DALY and mortality rates of liver cancer due to HBV and HCV have decreased, the rates due to alcohol consumption and NASH/NAFLD have increased. In 2019, the population of the East Asia region had the highest Age-standardized DALY and mortality rates, followed by high-income Asia-Pacific and Central Asia populations. Although East Asia and high-income Asia-Pacific regions showed a decrease during the study period, Age-standardized DALY rates increased in Central Asia. High-income North American and Australasian populations also showed a significant increase in Age-standardized DALY.Conclusions: Liver cancer remains an ongoing global threat. The burden of liver cancer associated with alcohol consumption and NASH/NAFLD is markedly increasing and projected to continuously increase. (Clin Mol Hepatol 2023;29:433-452)
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| 16. |
- Kim, Jong Yeob, et al.
(författare)
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Association between autism spectrum disorder and inflammatory bowel disease: A systematic review and meta-analysis
- 2022
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Ingår i: Autism Research. - : WILEY. - 1939-3792 .- 1939-3806. ; 15:2, s. 340-352
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Forskningsöversikt (refereegranskat)abstract
- Children with autism spectrum disorder (ASD) are frequently diagnosed with co-occurring medical conditions including inflammatory bowel disease (IBD). To investigate the association, we conducted a systematic review registered in PROSPERO (ID:CRD42021236263) with a random-effects meta-analysis. We searched PubMed, Embase, and PsycInfo (last search on January 25, 2021), and manually searched relevant publications. We included observational studies measuring the association between ASD and IBD. The primary outcome was the association (odds ratio, OR) between ASD and later development of IBD. Sensitivity analyses were conducted by quality, confounding adjustment, and study design. We performed meta-regression analyses and assessed heterogeneity, publication bias, and quality of studies with the Newcastle-Ottawa Scale. Overall, we included six studies consisting of eight datasets, including over 11 million participants. We found that ASD was significantly associated with subsequent incident IBD (any IBD, OR = 1.66, 95% confidence interval[CI] = 1.25-2.21, p < 0.001; ulcerative colitis, OR = 1.91, 95%CI = 1.41-2.6, p < 0.001; Crohns disease, OR = 1.47, 95%CI = 1.15-1.88, p = 0.002). ASD and IBD were also associated regardless of temporal sequence of diagnosis (any IBD, OR = 1.57, 95%CI = 1.28-1.93, p < 0.001; ulcerative colitis, OR = 1.7, 95%CI = 1.36-2.12, p < 0.001; Crohns disease, OR = 1.37, 95%CI = 1.12-1.69, p = 0.003). Sensitivity analyses confirmed the findings of the main analysis. Meta-regression did not identify any significant moderators. Publication bias was not detected. Quality was high in four datasets and medium in four. In conclusion, our findings highlight the need to screen for IBD in individuals with ASD, and future research should identify who, among those with ASD, has the highest risk of IBD, and elucidate the shared biological mechanisms between ASD and IBD.
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| 17. |
- Kim, Kwangwoo, et al.
(författare)
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High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci
- 2015
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 74:3
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Tidskriftsartikel (refereegranskat)abstract
- Objective A highly polygenic aetiology and high degree of allele-sharing between ancestries have been well elucidated in genetic studies of rheumatoid arthritis. Recently, the high-density genotyping array Immunochip for immune disease loci identified 14 new rheumatoid arthritis risk loci among individuals of European ancestry. Here, we aimed to identify new rheumatoid arthritis risk loci using Korean-specific Immunochip data. Methods We analysed Korean rheumatoid arthritis case-control samples using the Immunochip and genome-wide association studies (GWAS) array to search for new risk alleles of rheumatoid arthritis with anticitrullinated peptide antibodies. To increase power, we performed a meta-analysis of Korean data with previously published European Immunochip and GWAS data for a total sample size of 9299 Korean and 45 790 European case-control samples. Results We identified eight new rheumatoid arthritis susceptibility loci (TNFSF4, LBH, EOMES, ETS1-FLI1, COG6, RAD51B, UBASH3A and SYNGR1) that passed a genome-wide significance threshold (p<5x10(-8)), with evidence for three independent risk alleles at 1q25/TNFSF4. The risk alleles from the seven new loci except for the TNFSF4 locus (monomorphic in Koreans), together with risk alleles from previously established RA risk loci, exhibited a high correlation of effect sizes between ancestries. Further, we refined the number of single nucleotide polymorphisms (SNPs) that represent potentially causal variants through a trans-ethnic comparison of densely genotyped SNPs. Conclusions This study demonstrates the advantage of dense-mapping and trans-ancestral analysis for identification of potentially causal SNPs. In addition, our findings support the importance of T cells in the pathogenesis and the fact of frequent overlap of risk loci among diverse autoimmune diseases.
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| 18. |
- Lee, Hyun-Seob, et al.
(författare)
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Foxa2 and Nurr1 Synergistically Yield A9 Nigral Dopamine Neurons Exhibiting Improved Differentiation, Function, and Cell Survival
- 2010
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Ingår i: Stem Cells. - : Oxford University Press (OUP). - 1549-4918 .- 1066-5099. ; 28:3, s. 501-512
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Tidskriftsartikel (refereegranskat)abstract
- Effective dopamine (DA) neuron differentiation from neural precursor cells (NPCs) is prerequisite for precursor/stem cell-based therapy of Parkinson's disease (PD). Nurr1, an orphan nuclear receptor, has been reported as a transcription factor that can drive DA neuron differentiation from non-dopaminergic NPCs in vitro. However, Nurr1 alone neither induces full neuronal maturation nor expression of proteins found specifically in midbrain DA neurons. In addition, Nurr1 expression is inefficient in inducing DA phenotype expression in NPCs derived from certain species such as mouse and human. We show here that Foxa2, a forkhead transcription factor whose role in midbrain DA neuron development was recently revealed, synergistically cooperates with Nurr1 to induce DA phenotype acquisition, midbrain-specific gene expression, and neuronal maturation. Thus, the combinatorial expression of Nurr1 and Foxa2 in NPCs efficiently yielded fully differentiated nigral (A9)-type midbrain neurons with clearly detectable DA neuronal activities. The effects of Foxa2 in DA neuron generation were observed regardless of the brain regions or species from which NPCs were derived. Furthermore, DA neurons generated by ectopic Foxa2 expression were more resistant to toxins. Importantly, Foxa2 expression resulted in a rapid cell cycle exit and reduced cell proliferation. Consistently, transplantation of NPCs transduced with Nurr1 and Foxa2 generated grafts enriched with midbrain-type DA neurons but reduced number of proliferating cells, and significantly reversed motor deficits in a rat PD model. Our findings can be applied to ongoing attempts to develop an efficient and safe precursor/stem cell-based therapy for PD. STEM CELLS 2010; 28: 501-512
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| 19. |
- Wang, Haidong, et al.
(författare)
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Estimates of global, regional, and national incidence, prevalence, and mortality of HIV, 1980-2015 : the Global Burden of Disease Study 2015.
- 2016
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Ingår i: The lancet. HIV. - : Elsevier. - 2352-3018. ; 3:8, s. e361-e387
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Timely assessment of the burden of HIV/AIDS is essential for policy setting and programme evaluation. In this report from the Global Burden of Disease Study 2015 (GBD 2015), we provide national estimates of levels and trends of HIV/AIDS incidence, prevalence, coverage of antiretroviral therapy (ART), and mortality for 195 countries and territories from 1980 to 2015.METHODS: For countries without high-quality vital registration data, we estimated prevalence and incidence with data from antenatal care clinics and population-based seroprevalence surveys, and with assumptions by age and sex on initial CD4 distribution at infection, CD4 progression rates (probability of progression from higher to lower CD4 cell-count category), on and off antiretroviral therapy (ART) mortality, and mortality from all other causes. Our estimation strategy links the GBD 2015 assessment of all-cause mortality and estimation of incidence and prevalence so that for each draw from the uncertainty distribution all assumptions used in each step are internally consistent. We estimated incidence, prevalence, and death with GBD versions of the Estimation and Projection Package (EPP) and Spectrum software originally developed by the Joint United Nations Programme on HIV/AIDS (UNAIDS). We used an open-source version of EPP and recoded Spectrum for speed, and used updated assumptions from systematic reviews of the literature and GBD demographic data. For countries with high-quality vital registration data, we developed the cohort incidence bias adjustment model to estimate HIV incidence and prevalence largely from the number of deaths caused by HIV recorded in cause-of-death statistics. We corrected these statistics for garbage coding and HIV misclassification.FINDINGS: Global HIV incidence reached its peak in 1997, at 3·3 million new infections (95% uncertainty interval [UI] 3·1-3·4 million). Annual incidence has stayed relatively constant at about 2·6 million per year (range 2·5-2·8 million) since 2005, after a period of fast decline between 1997 and 2005. The number of people living with HIV/AIDS has been steadily increasing and reached 38·8 million (95% UI 37·6-40·4 million) in 2015. At the same time, HIV/AIDS mortality has been declining at a steady pace, from a peak of 1·8 million deaths (95% UI 1·7-1·9 million) in 2005, to 1·2 million deaths (1·1-1·3 million) in 2015. We recorded substantial heterogeneity in the levels and trends of HIV/AIDS across countries. Although many countries have experienced decreases in HIV/AIDS mortality and in annual new infections, other countries have had slowdowns or increases in rates of change in annual new infections.INTERPRETATION: Scale-up of ART and prevention of mother-to-child transmission has been one of the great successes of global health in the past two decades. However, in the past decade, progress in reducing new infections has been slow, development assistance for health devoted to HIV has stagnated, and resources for health in low-income countries have grown slowly. Achievement of the new ambitious goals for HIV enshrined in Sustainable Development Goal 3 and the 90-90-90 UNAIDS targets will be challenging, and will need continued efforts from governments and international agencies in the next 15 years to end AIDS by 2030.
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- Wang, Haidong, et al.
(författare)
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Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015 : a systematic analysis for the Global Burden of Disease Study 2015
- 2016
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 388:10053, s. 1459-1544
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Improving survival and extending the longevity of life for all populations requires timely, robust evidence on local mortality levels and trends. The Global Burden of Disease 2015 Study (GBD 2015) provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015. These results informed an in-depth investigation of observed and expected mortality patterns based on sociodemographic measures.METHODS: We estimated all-cause mortality by age, sex, geography, and year using an improved analytical approach originally developed for GBD 2013 and GBD 2010. Improvements included refinements to the estimation of child and adult mortality and corresponding uncertainty, parameter selection for under-5 mortality synthesis by spatiotemporal Gaussian process regression, and sibling history data processing. We also expanded the database of vital registration, survey, and census data to 14 294 geography-year datapoints. For GBD 2015, eight causes, including Ebola virus disease, were added to the previous GBD cause list for mortality. We used six modelling approaches to assess cause-specific mortality, with the Cause of Death Ensemble Model (CODEm) generating estimates for most causes. We used a series of novel analyses to systematically quantify the drivers of trends in mortality across geographies. First, we assessed observed and expected levels and trends of cause-specific mortality as they relate to the Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility. Second, we examined factors affecting total mortality patterns through a series of counterfactual scenarios, testing the magnitude by which population growth, population age structures, and epidemiological changes contributed to shifts in mortality. Finally, we attributed changes in life expectancy to changes in cause of death. We documented each step of the GBD 2015 estimation processes, as well as data sources, in accordance with Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER).FINDINGS: Globally, life expectancy from birth increased from 61·7 years (95% uncertainty interval 61·4-61·9) in 1980 to 71·8 years (71·5-72·2) in 2015. Several countries in sub-Saharan Africa had very large gains in life expectancy from 2005 to 2015, rebounding from an era of exceedingly high loss of life due to HIV/AIDS. At the same time, many geographies saw life expectancy stagnate or decline, particularly for men and in countries with rising mortality from war or interpersonal violence. From 2005 to 2015, male life expectancy in Syria dropped by 11·3 years (3·7-17·4), to 62·6 years (56·5-70·2). Total deaths increased by 4·1% (2·6-5·6) from 2005 to 2015, rising to 55·8 million (54·9 million to 56·6 million) in 2015, but age-standardised death rates fell by 17·0% (15·8-18·1) during this time, underscoring changes in population growth and shifts in global age structures. The result was similar for non-communicable diseases (NCDs), with total deaths from these causes increasing by 14·1% (12·6-16·0) to 39·8 million (39·2 million to 40·5 million) in 2015, whereas age-standardised rates decreased by 13·1% (11·9-14·3). Globally, this mortality pattern emerged for several NCDs, including several types of cancer, ischaemic heart disease, cirrhosis, and Alzheimer's disease and other dementias. By contrast, both total deaths and age-standardised death rates due to communicable, maternal, neonatal, and nutritional conditions significantly declined from 2005 to 2015, gains largely attributable to decreases in mortality rates due to HIV/AIDS (42·1%, 39·1-44·6), malaria (43·1%, 34·7-51·8), neonatal preterm birth complications (29·8%, 24·8-34·9), and maternal disorders (29·1%, 19·3-37·1). Progress was slower for several causes, such as lower respiratory infections and nutritional deficiencies, whereas deaths increased for others, including dengue and drug use disorders. Age-standardised death rates due to injuries significantly declined from 2005 to 2015, yet interpersonal violence and war claimed increasingly more lives in some regions, particularly in the Middle East. In 2015, rotaviral enteritis (rotavirus) was the leading cause of under-5 deaths due to diarrhoea (146 000 deaths, 118 000-183 000) and pneumococcal pneumonia was the leading cause of under-5 deaths due to lower respiratory infections (393 000 deaths, 228 000-532 000), although pathogen-specific mortality varied by region. Globally, the effects of population growth, ageing, and changes in age-standardised death rates substantially differed by cause. Our analyses on the expected associations between cause-specific mortality and SDI show the regular shifts in cause of death composition and population age structure with rising SDI. Country patterns of premature mortality (measured as years of life lost [YLLs]) and how they differ from the level expected on the basis of SDI alone revealed distinct but highly heterogeneous patterns by region and country or territory. Ischaemic heart disease, stroke, and diabetes were among the leading causes of YLLs in most regions, but in many cases, intraregional results sharply diverged for ratios of observed and expected YLLs based on SDI. Communicable, maternal, neonatal, and nutritional diseases caused the most YLLs throughout sub-Saharan Africa, with observed YLLs far exceeding expected YLLs for countries in which malaria or HIV/AIDS remained the leading causes of early death.INTERPRETATION: At the global scale, age-specific mortality has steadily improved over the past 35 years; this pattern of general progress continued in the past decade. Progress has been faster in most countries than expected on the basis of development measured by the SDI. Against this background of progress, some countries have seen falls in life expectancy, and age-standardised death rates for some causes are increasing. Despite progress in reducing age-standardised death rates, population growth and ageing mean that the number of deaths from most non-communicable causes are increasing in most countries, putting increased demands on health systems.
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