Disruption of mitochondrial folate transporter gene (Slc25a32) induces embryonic lethality and neural tube defects in mice

Neural tube defects (NTDs) represent the most common class of structural congenital malformations in humans. While periconceptional supplementation with folic acid (FA) may prevent up to 70% of NTDs, a well-developed intervention strategy is required to address the remaining 30±% of NTDs that are non-responsive to folate intervention. During pregnancy, FA provides essential one carbon (1C) units for nucleotide and methyl group biosynthesis through folate mediated 1C metabolism to proper neural tube closure (NTC). Mitochondrial folate transporter (MFT, encoded by the SLC25A32 gene) transports tetrahydrofolate (THF), the bioactive form of FA, into mitochondria. We characterized a novel folate mitochondrial transport mouse model by inactivating the Slc25a32 gene. Inactivation of the Slc25a32 gene resulted in embryo-fetal lethality, as the Slc25a32[subscript gt/gt] fetuses die in utero by E12.5. Perturbation of the Slc25a32 allele exhibited abnormalities of NTC, resulting in fully penetrant NTDs of exencephaly and craniorachischisis in the Slc25a32[subscript gt/gt] embryos, as well as an increased prevalence of craniofacial defects and a reduction in embryonic growth compared to the wild-type embryos. Maternal folic acid supplementation, 5-methyl-tetrahydrofolate (5-mTHF), was ineffective in reducing the prevalence of NTDs in Slc25a32[subscript gt/gt] embryos. These NTDs were partially rescued by maternal supplementation with calcium formate, which is a downstream output product of the mitochondrial folate 1C pathway. This study proposed to utilize the Slc25a32 mouse model as a novel tool for studying the function FA in the mitochondria with respect to NTC, the mechanisms that underlie the failure of NTC in the mouse model of folate-resistant NTDs.Nutritional Science

Business Groups and Corporate Social Responsibility

© 2018, Springer Science+Business Media B.V., part of Springer Nature. There is a growing literature on corporate social responsibility (CSR), but few have focused on the implications of business groups for CSR. We examine the antecedents and outcomes of CSR behaviors of group firms in Korea. We find that group affiliation is associated with higher CSR overall and for its major societal and environmental components. However, the ownership disparity between cash flow and control by controlling inside shareholders is associated with lower CSR, consistent with opportunistic rent expropriation theory. We further find that CSR initiatives can impact group firms positively in the event of bad events, consistent with insurance theory. This motive for CSR as a means of enhancing reputation capital to buffer the bad events is pronounced for group firms because of group-wide dissemination of negative reputational externality

Troubleshooting Arterial-Phase MR Images of Gadoxetate Disodium-Enhanced Liver.

Gadoxetate disodium is a widely used magnetic resonance (MR) contrast agent for liver MR imaging, and it provides both dynamic and hepatobiliary phase images. However, acquiring optimal arterial phase images at liver MR using gadoxetate disodium is more challenging than using conventional extracellular MR contrast agent because of the small volume administered, the gadolinium content of the agent, and the common occurrence of transient severe motion. In this article, we identify the challenges in obtaining high-quality arterial-phase images of gadoxetate disodium-enhanced liver MR imaging and present strategies for optimizing arterial-phase imaging based on the thorough review of recent research in this field

Concurrence of Stevens-Johnson Syndrome and Bilateral Parotitis after Minocycline Therapy

Minocycline is an antibiotic of tetracycline derivatives that is commonly used in the treatment of moderate to severe acne vulgaris. It has been reported to cause rare adverse events from mild cutaneous eruption to severe forms including drug-induced lupus, serum sickness-like reaction, and hypersensitivity reactions, etc. The risks of adverse events attributed to minocycline have not been ascertained reliably and there are concerns about the safety of minocycline which could possibly result in life-threatening events such as the Stevens-Johnson syndrome. Here we demonstrate an unusual case of Stevens-Johnson syndrome in conjunction with bilateral parotitis after the intake of minocycline in a Korean boy suggesting discreet use of the drug

Comparison of on-Statin Lipid and Lipoprotein Levels for the Prediction of First Cardiovascular Event in Type 2 Diabetes Mellitus

Background A substantial cardiovascular disease risk remains even after optimal statin therapy. Comparative predictiveness of major lipid and lipoprotein parameters for cardiovascular events in patients with type 2 diabetes mellitus (T2DM) who are treated with statins is not well documented. Methods From the Korean Nationwide Cohort, 11,900 patients with T2DM (≥40 years of age) without a history of cardiovascular disease and receiving moderate- or high-intensity statins were included. The primary outcome was the first occurrence of major adverse cardiovascular events (MACE) including ischemic heart disease, ischemic stroke, and cardiovascular death. The risk of MACE was estimated according to on-statin levels of low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and non-HDL-C. Results MACE occurred in 712 patients during a median follow-up period of 37.9 months (interquartile range, 21.7 to 54.9). Among patients achieving LDL-C levels less than 100 mg/dL, the hazard ratios for MACE per 1-standard deviation change in on-treatment values were 1.25 (95% confidence interval [CI], 1.07 to 1.47) for LDL-C, 1.31 (95% CI, 1.09 to 1.57) for non-HDL-C, 1.05 (95% CI, 0.91 to 1.21) for TG, and 1.16 (95% CI, 0.98 to 1.37) for HDL-C, after adjusting for potential confounders and lipid parameters mutually. The predictive ability of on-statin LDL-C and non-HDL-C for MACE was prominent in patients at high cardiovascular risk or those with LDL-C ≥70 mg/dL. Conclusion On-statin LDL-C and non-HDL-C levels are better predictors of the first cardiovascular event than TG or HDL-C in patients with T2DM

Stevens-Johnson Syndrome Induced by Vandetanib

Vandetanib is a once-daily oral anticancer drug that selectively inhibits key signaling pathways in cancer by targeting vascular endothelial growth factor receptors, epidermal growth factor receptors tyrosine kinase, and rearranged during transfection-dependent tumor cell proliferation and survival. The most frequently reported adverse events attributed to vandetanib include diarrhea, elevated aminotransferase, asymptomatic corrected QT interval prolongation, and hypertension. Though a number of randomized, doubleblind studies, including cutaneous adverse events attributed to vandetanib, have been reported along with these general symptoms, no case of Stevens-Johnson syndrome (SJS) has been reported. This paper demonstrates a case of SJS induced by vandetanib

BubR1 acetylation at prometaphase is required for modulating APC/C activity and timing of mitosis

Regulation of BubR1 is central to the control of APC/C activity. We have found that BubR1 forms a complex with PCAF and is acetylated at lysine 250. Using mass spectrometry and acetylated BubR1-specific antibodies, we have confirmed that BubR1 acetylation occurs at prometaphase. Importantly, BubR1 acetylation was required for checkpoint function, through the inhibition of ubiquitin-dependent BubR1 degradation. BubR1 degradation began before the onset of anaphase. It was noted that the pre-anaphase degradation was regulated by BubR1 acetylation. Degradation of an acetylation-mimetic form, BubR1–K250Q, was inhibited and chromosome segregation in cells expressing BubR1–K250Q was markedly delayed. By contrast, the acetylation-deficient mutant, BubR1–K250R, was unstable, and mitosis was accelerated in BubR1–K250R-expressing cells. Furthermore, we found that APC/C–Cdc20 was responsible for BubR1 degradation during mitosis. On the basis of our collective results, we propose that the acetylation status of BubR1 is a molecular switch that converts BubR1 from an inhibitor to a substrate of the APC/C complex, thus providing an efficient way to modulate APC/C activity and mitotic timing