Explore the vast range of titles available.

Cell death of retinal pigment epithelium (RPE) is characterized as an essential late-stage phenomenon of dry age-related macular degeneration (AMD). The aim of this study was to elucidate the molecular mechanism underlying RPE cell death after exposure to oxidative stress, which occurs often because of the anatomical location of RPE cells. ARPE-19, an established RPE cell line, exhibited necrotic features involving poly (ADP-ribose) polymerase-1 (PARP-1) activation in response to hydrogen peroxide (H 2 O 2 ). ARPE-19 cells were resistant to H 2 O 2 when PARP-1 was depleted using siRNA or inhibited by a pharmacological inhibitor of PARP-1, olaparib. Our data suggest a causal relationship between PARP-1 activation and ARPE-19 cell death in response to H 2 O 2 . Next, we investigated downstream molecular events in PARP-1 activation. Increased mitochondrial depolarization, mitochondrial fission and alterations of the cellular energy dynamics with reduced NAD+ and ATP were observed in H 2 O 2 -treated ARPE-19 cells. H 2 O 2 -triggered mitochondrial dysfunction was inhibited by olaparib. Nevertheless, translocation of apoptosis-inducing factor (AIF), a biochemical signature for PARP-1-dependent cell death (parthanatos), was not observed in our study. Moreover, the depletion of AIF did not affect the amplitude of cell death, demonstrating the lack of a role for AIF in the death of ARPE-19 cells in response to H 2 O 2 . This feature distinguishes the type of death observed in this study from canonical parthanatos. Next, we examined the in vivo role of PARP-1 in a dry AMD animal model system. Histological analysis of the outer nuclear layer in the mouse retina revealed protection against sodium iodate (SI) following treatment with olaparib. Moreover, retina fundus and electroretinograms also confirmed such a protective effect in the SI-treated rabbit. Collectively, we report that AIF-independent PARP-1-dependent necrosis constitutes a major mechanism of RPE cell death leading to retinal degeneration in dry AMD.

Huntington’s disease (HD) is caused by a CAG repeat expansion in the HTT gene, leading to altered gene expression. However, the mechanisms leading to disrupted RNA processing in HD remain unclear. Here we identify TDP-43 and the N6-methyladenosine (m6A) writer protein METTL3 to be upstream regulators of exon skipping in multiple HD systems. Disrupted nuclear localization of TDP-43 and cytoplasmic accumulation of phosphorylated TDP-43 occurs in HD mouse and human brains, with TDP-43 also co-localizing with HTT nuclear aggregate-like bodies distinct from mutant HTT inclusions. The binding of TDP-43 onto RNAs encoding HD-associated differentially expressed and aberrantly spliced genes is decreased. Finally, m6A RNA modification is reduced on RNAs abnormally expressed in the striatum of HD R6/2 mouse brain, including at clustered sites adjacent to TDP-43 binding sites. Our evidence supports TDP-43 loss of function coupled with altered m6A modification as a mechanism underlying alternative splicing in HD. Nguyen et al. identify TDP-43 and METTL3 as key regulators of disrupted RNA splicing in Huntington’s disease, offering insight into how TDP-43 mislocalization and aberrant m6A RNA modification and localization relate to disease pathogenesis.

Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the first exon of the gene encoding huntingtin. Prior reports have established a correlation between CAG expanded and altered gene expression. However, the mechanisms leading to disruption of RNA processing in HD remain unclear. Here, our analysis of the reported HTT protein interactome identifies interactions with known RNA-binding proteins (RBPs). Total, long-read sequencing and targeted RASL-seq of RNAs from cortex and striatum of the HD mouse model R6/2 reveals increased exon skipping which is confirmed in Q150 and Q175 knock-in mice and in HD human brain. We identify the RBP TDP-43 and the N6-methyladenosine (m6A) writer protein methyltransferase 3 (METTL3) to be upstream regulators of exon skipping in HD. Along with this novel mechanistic insight, we observe decreased nuclear localization of TDP-43 and cytoplasmic accumulation of phosphorylated TDP-43 in HD mice and human brain. In addition, TDP-43 co-localizes with HTT in human HD brain forming novel nuclear aggregate-like bodies distinct from mutant HTT inclusions or previously observed TDP-43 pathologies. Binding of TDP-43 onto RNAs encoding HD-associated differentially expressed and aberrantly spliced genes is decreased. Finally, m6A RNA modification is reduced on RNAs abnormally expressed in striatum from HD R6/2 mouse brain, including at clustered sites adjacent to TDP-43 binding sites. Our evidence supports TDP-43 loss of function coupled with altered m6A modification as a novel mechanism underlying alternative splicing/unannotated exon usage in HD and highlights the critical nature of TDP-43 function across multiple neurodegenerative diseases.

N6-adenosine methylation (m6A) is the most abundant mRNA modification that controls gene expression through multiple diverse mechanisms. m6A-dependent regulation of oncogenes and tumor suppressors indeed contribute to tumor development. However, the role of m6A-mediated gene regulation after drug treatment or resistance is poorly understood. Here, we report that m6A modification of mitogen-activated protein kinase 13 (MAPK13) determines the sensitivity of cancer cells to the mechanistic target of rapamycin complex 1 (mTORC1) 1-targeting chemotherapeutic agent rapamycin. mTORC1 induces m6A modification of MAPK13 mRNA at its 3′ untranslated region (3′UTR) through methyltransferase-like 3 (METTL3)-METTL14-Wilms' tumor 1-associating protein (WTAP) methyltransferase complex, thereby stimulating its mRNA degradation via an m6A reader protein YTH domain family proteins 2 (YTHDF2). Rapamycin blunts this process and stabilizes MAPK13. Unexpectedly, MAPK13 silencing suppresses cell growth and enhances rapamycin′s anti-cancer effects, suggesting that MAPK13 is an oncogenic gene activated by rapamycin through negative feedback regulation. Together, our data indicate that rapamycin-mediated MAPK13 mRNA stabilization may confer drug resistance, and it can thus be a therapeutic target to sensitize cancer cells to rapamycin. Competing Interest Statement The authors have declared no competing interest. Footnotes * Nope.

High-fructose corn syrup (HFCS) consumption is a risk factor for obesity and metabolic syndrome, yet the underlying mechanisms are incompletely understood. Catabolism of dietary fructose primarily occurs in the small intestine and liver, with fructose breakdown in the liver being pathological, while small intestinal fructose clearance protects the liver. Here, we unexpectedly found that inhibition of fructose catabolism specifically in the small intestine mitigates fructose-induced obesity and insulin resistance. Mechanistically, blocking intestinal fructose catabolism reduces dietary fat absorption, which is associated with a decrease in the surface area of the ileal lacteals and alterations in gut microbiome. Fecal transplantation experiments revealed that such a microbiome stimulates the intestine-resident macrophages, promoting lacteal growth and boosting dietary fat absorption. Given the preclinical and clinical studies reporting the effect of fructose catabolism suppression on mitigating diet-induced obesity, our data suggest that such effects are partly mediated by intestinal lacteal remodeling.

In a randomized trial of imaging-guided or angiography-guided PCI for complex coronary lesion revascularization procedures, imaging-guided PCI led to a lower risk of target-vessel failure than angiography-guided PCI.

Current guidelines recommend dual antiplatelet therapy (DAPT) of aspirin plus a P2Y12 inhibitor for at least 12 months after implantation of drug-eluting stents (DES) in patients with acute coronary syndrome. However, available data about the optimal duration of DAPT in patients with acute coronary syndrome undergoing percutaneous coronary intervention are scant. We aimed to investigate whether a 6-month duration of DAPT would be non-inferior to the conventional 12-month or longer duration of DAPT in this population. We did a randomised, open-label, non-inferiority trial at 31 centres in South Korea. Patients were eligible if they had unstable angina, non-ST-segment elevation myocardial infarction, or ST-segment elevation myocardial infarction, and underwent percutaneous coronary intervention. Enrolled patients were randomly assigned, via a web-based system by computer-generated block randomisation, to either the 6-month DAPT group or to the 12-month or longer DAPT group, with stratification by site, clinical presentation, and diabetes. Assessors were masked to treatment allocation. The primary endpoint was a composite of all-cause death, myocardial infarction, or stroke at 18 months after the index procedure in the intention-to-treat population. Secondary endpoints were the individual components of the primary endpoint; definite or probable stent thrombosis as defined by the Academic Research Consortium; and Bleeding Academic Research Consortium (BARC) type 2–5 bleeding at 18 months after the index procedure. The primary endpoint was also analysed per protocol. This trial is registered with ClinicalTrials.gov, number NCT01701453. Between Sept 5, 2012, and Dec 31, 2015, we randomly assigned 2712 patients; 1357 to the 6-month DAPT group and 1355 to the 12-month or longer DAPT group. Clopidogrel was used as a P2Y12 inhibitor for DAPT in 1082 (79·7%) patients in the 6-month DAPT group and in 1109 (81·8%) patients in the 12-month or longer DAPT group. The primary endpoint occurred in 63 patients in the 6-month DAPT group and in 56 patients in the 12-month or longer DAPT group (cumulative event rate 4·7% vs 4·2%; absolute risk difference 0·5%; upper limit of one-sided 95% CI 1·8%; pnon-inferiority=0·03 with a predefined non-inferiority margin of 2·0%). Although all-cause mortality did not differ significantly between the 6-month DAPT group and the 12-month or longer DAPT group (35 [2·6%] patients vs 39 [2·9%]; hazard ratio [HR] 0·90 [95% CI 0·57–1·42]; p=0·90) and neither did stroke (11 [0·8%] patients vs 12 [0·9%]; 0·92 [0·41–2·08]; p=0·84), myocardial infarction occurred more frequently in the 6-month DAPT group than in the 12-month or longer DAPT group (24 [1·8%] patients vs ten [0·8%]; 2·41 [1·15–5·05]; p=0·02). 15 (1·1%) patients had stent thrombosis in the 6-month DAPT group compared with ten (0·7%) in the 12-month or longer DAPT group (HR 1·50 [95% CI 0·68–3·35]; p=0·32). The rate of BARC type 2–5 bleeding was 2·7% (35 patients) in the 6-month DAPT group and 3·9% (51 patients) in the 12-month or longer DAPT group (HR 0·69 [95% CI 0·45–1·05]; p=0·09). Results from the per-protocol analysis were similar to those from the intention-to-treat analysis. The increased risk of myocardial infarction with 6-month DAPT and the wide non-inferiority margin prevent us from concluding that short-term DAPT is safe in patients with acute coronary syndrome undergoing percutaneous coronary intervention with current-generation DES. Prolonged DAPT in patients with acute coronary syndrome without excessive risk of bleeding should remain the standard of care. Abbott Vascular Korea, Medtronic Vascular Korea, Biosensors Inc, and Dong-A ST.

Surface solar irradiance (SSI) is a crucial component in climatological and agricultural applications. Because the use of renewable energy is crucial, the importance of SSI has increased. In situ measurements are often used to investigate SSI; however, their availability is limited in spatial coverage. To precisely estimate the distribution of SSI with fine spatiotemporal resolutions, we used the GEOstationary Korea Multi-Purpose SATellite 2A (GEO-KOMPSAT 2A, GK2A) equipped with the Advanced Meteorological Imager (AMI). To obtain an optimal model for estimating hourly SSI around Korea using GK2A/AMI, the convolutional neural network (CNN) model as a machine learning (ML) technique was applied. Through statistical verification, CNN showed a high accuracy, with a root mean square error (RMSE) of 0.180 MJ m−2, a bias of −0.007 MJ m−2, and a Pearson’s R of 0.982. The SSI obtained through a ML approach showed an accuracy higher than the GK2A/AMI operational SSI product. The CNN SSI was evaluated by comparing it with the in situ SSI from the Ieodo Ocean Research Station and from flux towers over land; these in situ SSI values were not used for training the model. We investigated the error characteristics of the CNN SSI regarding environmental conditions including local time, solar zenith angle, in situ visibility, and in situ cloud amount. Furthermore, monthly and annual mean daily SSI were calculated for the period from 1 January 2020 to 31 January 2022, and regional characteristics of SSI around Korea were analyzed. This study addressed the availability of satellite-derived SSI to resolve the limitations of in situ measurements. This could play a principal role in climatological and renewable energy applications.

Proper storage of excessive dietary fat into subcutaneous adipose tissue (SAT) prevents ectopic lipid deposition-induced insulin resistance, yet the underlying mechanism remains unclear. Here, we identify angiopoietin-2 (Angpt2)–integrin α5β1 signaling as an inducer of fat uptake specifically in SAT. Adipocyte-specific deletion of Angpt2 markedly reduced fatty acid uptake and storage in SAT, leading to ectopic lipid accumulation in glucose-consuming organs including skeletal muscle and liver and to systemic insulin resistance. Mechanistically, Angpt2 activated integrin α5β1 signaling in the endothelium and triggered fatty acid transport via CD36 and FATP3 into SAT. Genetic or pharmacological inhibition of the endothelial integrin α5β1 recapitulated adipocyte-specific Angpt2 knockout phenotypes. Our findings demonstrate the critical roles of Angpt2–integrin α5β1 signaling in SAT endothelium in regulating whole-body fat distribution for metabolic health and highlight adipocyte–endothelial crosstalk as a potential target for prevention of ectopic lipid deposition-induced lipotoxicity and insulin resistance. Fat uptake and storage in subcutaneous adipose tissue (SAT) prevents ectopic fat accumulation and associated metabolic complications, however, the underlying mechanisms are incompletely understood. Here, the authors show that adipose angiopoietin-2 (Angpt2) enhances SAT size via increased endothelial fatty acid transport.

Background Therapeutic inertia is defined as the failure to provide guideline-directed therapy and is a barrier to achieving optimal clinical outcomes. We aimed to evaluate therapeutic inertia in statin therapy after percutaneous coronary intervention (PCI) and its association with patient characteristics and physician’s prescribing practice. Methods We analyzed the medical claims data on patients undergoing PCI using National Health Insurance Service in Republic of Korea. The primary outcome of interest was therapeutic inertia, defined as not providing high-intensity statin (HIS) therapy within 30 days after discharge for PCI. To identify statin use in identical clinical setting, we restricted study duration to between 2013 American College of Cardiology/American Heart Association cholesterol guideline and publications of RACING (Randomized Comparison of Efficacy and Safety of Lipid-lowering with Statin Monotherapy Versus Statin–ezetimibe Combination for High-risk Cardiovascular Disease) and LODESTAR (Low-Density Lipoprotein Cholesterol-Targeting Statin Therapy Versus Intensity-Based Statin Therapy in Patients With Coronary Artery Disease) trials that demonstrated non-inferiority of alternative statin strategies compared with HIS therapy in atherosclerotic cardiovascular disease. We also assessed patient characteristics affecting HIS prescription, statin switching before and after PCI among previous statin users, and impact of previous statin regimen on prescribing of HIS. Results Of 204,708 participants (mean age 66.5 ± 11.3 years, 30.8% female, 56.6% previous statin users, 43.4% previous statin nonusers), therapeutic inertia was identified in 64.1%, and HIS prescription rate was higher in previous statin nonusers (42.0%) than in previous statin users (31.1%). There were few differences in patient characteristics as positive (male and acute coronary syndrome as indication for PCI) and negative (increase of age, comorbidities, and cardiovascular medications) predictors of HIS prescription between previous statin users and nonusers. Because 79.1% of previous HIS users and 23.8% of previous non-HIS users received HIS following PCI, previous HIS users were more likely to be prescribed HIS as compared to previous statin nonusers (odds ratio, 5.42; 95% confidence intervals, 4.44–6.61) and previous non-HIS users (odds ratio, 12.30; 95% confidence intervals, 9.95–15.19). Conclusions Suboptimal HIS prescription following PCI was substantially affected by patient characteristics and the practice of repetitive prescribing of previous statin without guideline-directed titration. Clinical trial number Not applicable.