Academia Sinica

About: Academia Sinica is a facility organization based out in Taipei, Taiwan. It is known for research contribution in the topics: Population & Galaxy. The organization has 52086 authors who have published 65998 publications receiving 1728114 citations. The organization is also known as: Central Research Academy.

Shared and restricted T-cell receptor use is crucial for carbamazepine-induced Stevens-Johnson syndrome.

Abstract: Background Stevens-Johnson syndrome (SJS) and its related disease, toxic epidermal necrolysis (TEN), are life-threatening drug hypersensitivities with robust immune responses to drugs. Despite the strong HLA predisposition to drug hypersensitivities, such as HLA-B∗1502 to carbamazepine (CBZ)–induced SJS/TEN, it remains unknown whether particular T-cell receptors (TCRs) participate in recognition of small drug/peptide–HLA complexes. Objective Using the strong HLA predisposition in patients with CBZ-induced SJS/TEN as a model, we aimed to study the use of TCR repertoire in patients with drug hypersensitivity. Method We enrolled patients with CBZ-SJS/TEN, tolerant control subjects, and healthy subjects who had no history of CBZ exposure. We isolated PBMCs from the subjects, cultured CBZ-specific T cells, and globally investigated the expression level and third complementarity-determining region length distribution of the TCR profile. We further assessed the pathogenic role of the disease-specific clonotype using real-time PCR–based tests and functional analysis. Results On drug stimulation, CBZ-specific CD8 + T cells were expanded in vitro and activated to release granulysin. Notably, VB-11-ISGSY was identified as the most predominant clonotype and shared among different subjects. This clonotype was present in 16 (84%) of 19 patients with SJS/TEN, absent in all 17 tolerant patients, and present at a low frequency in healthy subjects (4/29 [14%]). CBZ-specific cytotoxicity could be primed in vitro in the PBMCs of healthy subjects who are carriers of HLA-B∗1502 and VB-11-ISGSY; this cytotoxicity could be blocked by an anti–TCR-VB-11 antibody. Furthermore, a single T-cell clone expressing VA-22-FISGTY/VB-11-ISGSY showed significant cytotoxicity against HLA-B∗1502–positive antigen-presenting cells and CBZ. Conclusion This study establishes the key role of the TCR in the pathogenic mechanism of SJS/TEN, explains why some HLA-B∗1502 carriers are tolerant to CBZ, and provides a biomarker profile for drug hypersensitivity.

Hepatitis C Virus Triggers Mitochondrial Permeability Transition with Production of Reactive Oxygen Species, Leading to DNA Damage and STAT3 Activation

Abstract: Hepatitis C virus (HCV) infection is frequently associated with the development of hepatocellular carcinomas and non-Hodgkin's B-cell lymphomas. Previously, we reported that HCV infection causes cellular DNA damage and mutations, which are mediated by nitric oxide (NO). NO often damages mitochondria, leading to induction of double-stranded DNA breaks (DSBs) and accumulation of oxidative DNA damage. Here we report that HCV infection causes production of reactive oxygen species (ROS) and lowering of mitochondrial transmembrane potential (DeltaPsi(m)) in in vitro HCV-infected cell cultures. The changes in membrane potential could be inhibited by BCL-2. Furthermore, an inhibitor of ROS production, antioxidant N-acetyl-L-cysteine (NAC), or an inhibitor of NO, 1,400W, prevented the alterations of DeltaPsi(m). The HCV-induced DSB was also abolished by a combination of NO and ROS inhibitors. These results indicated that the mitochondrial damage and DSBs in HCV-infected cells were mediated by both NO and ROS. Among the HCV proteins, core, E1, and NS3 are potent ROS inducers: their expression led to DNA damage and activation of STAT3. Correspondingly, core-protein-transgenic mice showed elevated levels of lipid peroxidation and oxidatively damaged DNA. These HCV studies thus identified ROS, along with the previously identified NO, as the primary inducers of DSBs and mitochondrial damage in HCV-infected cells.

A review of nitrogen isotopic alteration in marine sediments

Abstract: Key Points: Use of sedimentary nitrogen isotopes is examined; On average, sediment 15N/14N increases approx. 2 per mil during early burial; Isotopic alteration scales with water depth Abstract: Nitrogen isotopes are an important tool for evaluating past biogeochemical cycling from the paleoceanographic record. However, bulk sedimentary nitrogen isotope ratios, which can be determined routinely and at minimal cost, may be altered during burial and early sedimentary diagenesis, particularly outside of continental margin settings. The causes and detailed mechanisms of isotopic alteration are still under investigation. Case studies of the Mediterranean and South China Seas underscore the complexities of investigating isotopic alteration. In an effort to evaluate the evidence for alteration of the sedimentary N isotopic signal and try to quantify the net effect, we have compiled and compared data demonstrating alteration from the published literature. A >100 point comparison of sediment trap and surface sedimentary nitrogen isotope values demonstrates that, at sites located off of the continental margins, an increase in sediment 15N/14N occurs during early burial, likely at the seafloor. The extent of isotopic alteration appears to be a function of water depth. Depth-related differences in oxygen exposure time at the seafloor are likely the dominant control on the extent of N isotopic alteration. Moreover, the compiled data suggest that the degree of alteration is likely to be uniform through time at most sites so that bulk sedimentary isotope records likely provide a good means for evaluating relative changes in the global N cycle.