TREK-1 and Best1 channels mediate fast and slow glutamate release in astrocytes upon GPCR activation.

Astrocytes release glutamate upon activation of various GPCRs to exert important roles in synaptic functions. However, the molecular mechanism of release has been controversial. Here, we report two kinetically distinct modes of nonvesicular, channel-mediated glutamate release. The fast mode requires activation of G(αi), dissociation of G(ßγ), and subsequent opening of glutamate-permeable, two-pore domain potassium channel TREK-1 through direct interaction between G(ßγ) and N terminus of TREK-1. The slow mode is Ca(2+) dependent and requires G(αq) activation and opening of glutamate-permeable, Ca(2+)-activated anion channel Best1. Ultrastructural analyses demonstrate that TREK-1 is preferentially localized at cell body and processes, whereas Best1 is mostly found in microdomains of astrocytes near synapses. Diffusion modeling predicts that the fast mode can target neuronal mGluR with peak glutamate concentration of 100 µM, whereas slow mode targets neuronal NMDA receptors at around 1 µM. Our results reveal two distinct sources of astrocytic glutamate that can differentially influence neighboring neurons.

An amygdala circuit that suppresses social engagement.

Innate social behaviours, such as mating and fighting, are fundamental to animal reproduction and survival1. However, social engagements can also put an individual at risk2. Little is known about the neural mechanisms that enable appropriate risk assessment and the suppression of hazardous social interactions. Here we identify the posteromedial nucleus of the cortical amygdala (COApm) as a locus required for the suppression of male mating when a female mouse is unhealthy. Using anatomical tracing, functional imaging and circuit-level epistatic analyses, we show that suppression of mating with an unhealthy female is mediated by the COApm projections onto the glutamatergic population of the medial amygdalar nucleus (MEA). We further show that the role of the COApm-to-MEA connection in regulating male mating behaviour relies on the neuromodulator thyrotropin-releasing hormone (TRH). TRH is expressed in the COApm, whereas the TRH receptor (TRHR) is found in the postsynaptic MEA glutamatergic neurons. Manipulating neural activity of TRH-expressing neurons in the COApm modulated male mating behaviour. In the MEA, activation of the TRHR pathway by ligand infusion inhibited mating even towards healthy female mice, whereas genetic ablation of TRHR facilitated mating with unhealthy individuals. In summary, we reveal a neural pathway that relies on the neuromodulator TRH to modulate social interactions according to the health status of the reciprocating individual. Individuals must balance the cost of social interactions relative to the benefit, as deficits in the ability to select healthy mates may lead to the spread of disease.

MDGAs perform activity-dependent synapse type-specific suppression via distinct extracellular mechanisms.

MDGA (MAM domain containing glycosylphosphatidylinositol anchor) family proteins were previously identified as synaptic suppressive factors. However, various genetic manipulations have yielded often irreconcilable results, precluding precise evaluation of MDGA functions. Here, we found that, in cultured hippocampal neurons, conditional deletion of MDGA1 and MDGA2 causes specific alterations in synapse numbers, basal synaptic transmission, and synaptic strength at GABAergic and glutamatergic synapses, respectively. Moreover, MDGA2 deletion enhanced both N-methyl-D-aspartate (NMDA) receptor- and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-mediated postsynaptic responses. Strikingly, ablation of both MDGA1 and MDGA2 abolished the effect of deleting individual MDGAs that is abrogated by chronic blockade of synaptic activity. Molecular replacement experiments further showed that MDGA1 requires the meprin/A5 protein/PTPmu (MAM) domain, whereas MDGA2 acts via neuroligin-dependent and/or MAM domain-dependent pathways to regulate distinct postsynaptic properties. Together, our data demonstrate that MDGA paralogs act as unique negative regulators of activity-dependent postsynaptic organization at distinct synapse types, and cooperatively contribute to adjustment of excitation-inhibition balance.

Jasmonate activates secondary cell wall biosynthesis through MYC2-MYB46 module.

Formation of secondary cell wall (SCW) is tightly regulated spatiotemporally by various developmental and environmental signals. Successful fine-tuning of the trade-off between SCW biosynthesis and stress responses requires a better understanding of how plant growth is regulated under environmental stress conditions. However, the current understanding of the interplay between environmental signaling and SCW formation is limited. The lipid-derived plant hormone jasmonate (JA) and its derivatives are important signaling components involved in various physiological processes including plant growth, development, and abiotic/biotic stress responses. Recent studies suggest that JA is involved in SCW formation but the signaling pathway has not been studied for how JA regulates SCW formation. We tested this hypothesis using the transcription factor MYB46, a master switch for SCW biosynthesis, and JA treatments. Both the transcript and protein levels of MYB46, a master switch for SCW formation, were significantly increased by JA treatment, resulting in the upregulation of SCW biosynthesis. We then show that this JA-induced upregulation of MYB46 is mediated by MYC2, a central regulator of JA signaling, which binds to the promoter of MYB46. We conclude that this MYC2-MYB46 module is a key component of the plant response to JA in SCW formation.

Astrocytic PAR1 and mGluR2/3 control synaptic glutamate time course at hippocampal CA1 synapses.

Astrocytes play an essential role in regulating synaptic transmission. This study describes a novel form of modulation of excitatory synaptic transmission in the mouse hippocampus by astrocytic G-protein-coupled receptors (GPCRs). We have previously described astrocytic glutamate release via protease-activated receptor-1 (PAR1) activation, although the regulatory mechanisms for this are complex. Through electrophysiological analysis and modeling, we discovered that PAR1 activation consistently increases the concentration and duration of glutamate in the synaptic cleft. This effect was not due to changes in the presynaptic glutamate release or alteration in glutamate transporter expression. However, blocking group II metabotropic glutamate receptors (mGluR2/3) abolished PAR1-mediated regulation of synaptic glutamate concentration, suggesting a role for this GPCR in mediating the effects of PAR1 activation on glutamate release. Furthermore, activation of mGluR2/3 causes glutamate release through the TREK-1 channel in hippocampal astrocytes. These data show that astrocytic GPCRs engage in a novel regulatory mechanism to shape the time course of synaptically-released glutamate in excitatory synapses of the hippocampus.

Reduction of Upper Gastrointestinal Bleeding Risk With Proton Pump Inhibitor Therapy in Asian Patients With Atrial Fibrillation Receiving Direct Oral Anticoagulant: A Nationwide Population-based Cohort Study.

BACKGROUND & AIMS: In patients with atrial fibrillation (AF) receiving direct oral anticoagulant (DOAC), upper gastrointestinal bleeding (UGIB) is a serious complication. There are limited data on the benefit of preventive proton pump inhibitor (PPI) use to reduce the risk of UGIB in DOAC users. METHODS: We included patients with AF receiving DOAC from 2015 to 2020 based on the Korean Health Insurance Review and Assessment database. The propensity score (PS) weighting method was used to compare patients with PPI use and those without PPI use. The primary outcome was hospitalization for UGIB. Weighted hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were evaluated using the Cox proportional hazards regression model. RESULTS: A total of 165,624 patients were included (mean age: 72.2 ± 10.8 years; mean CHA2DS2-VASc score: 4.3 ± 1.8; mean HAS-BLED score: 3.3 ± 1.2). Among them, 99,868 and 65,756 were in the non-PPI group and PPI group, respectively. During a median follow-up of 1.5 years, the PPI group was associated with lower risks of hospitalization for UGIB and UGIB requiring red blood cell transfusion than non-PPI group (weighted HR, 0.825; 95% CI, 0.761-0.894 and 0.798; 95% CI, 0.717-0.887, respectively, both P < .001). The benefits of PPI on the risk of hospitalization for UGIB were greater in those with older age (≥75 years), higher HAS-BLED score (≥3), prior GIB history, and concomitant use of antiplatelet agent (all P-for-interaction < .1). Low-dose PPI was consistently associated with a lower risk of significant UGIB by 43.6-49.3% (P < .001). CONCLUSIONS: In this large Asian cohort of patients with AF on DOAC, PPI co-therapy is beneficial for reducing the risk of hospitalization for UGIB, particularly in high-risk patients.

Effect of physical activity on incident atrial fibrillation in individuals with varying duration of diabetes: a nationwide population study.

BACKGROUND: Diabetes mellitus (DM) duration affects incident atrial fibrillation (AF) risk; the effect of physical activity on mitigating AF risk related to varying DM duration remains unknown. We assessed the effect of physical activity on incident AF in patients with DM with respect to known DM duration. METHODS: Patients with type 2 DM who underwent the Korean National Health Insurance Service health examination in 2015-2016 were grouped by DM duration: new onset and < 5, 5-9, and ≥ 10 years. Physical activity was classified into four levels: 0, < 500, 500-999, 1,000-1,499, and ≥ 1,500 metabolic equivalent task (MET)-min/week, with the primary outcome being new-onset AF. RESULTS: The study enrolled 2,392,486 patients (aged 59.3 ± 12.0 years, 39.8% female) with an average follow-up of 3.9 ± 0.8 years and mean DM duration of 5.3 ± 5.1 years. Greater physical activity was associated with a lower AF risk. Lowering of incident AF risk varied with different amounts of physical activity in relation to known DM duration. Among patients with new-onset DM, DM duration < 5 years and 5-9 years and 1,000-1,499 MET-min/week exhibited the lowest AF risk. Physical activity ≥ 1,500 MET-min/week was associated with the lowest incident AF risk in patients with DM duration ≥ 10 years (by 15%), followed DM duration of 5-9 years (12%) and < 5 years (9%) (p-for-interaction = 0.002). CONCLUSIONS: Longer DM duration was associated with a high risk of incident AF, while increased physical activity generally reduced AF risk. Engaging in > 1,500 MET-min/week was associated with the greatest AF risk reduction in patients with longer DM duration, highlighting the potential benefits of higher activity levels for AF prevention.

Association of temporal change in body mass index with sudden cardiac arrest in diabetes mellitus.

BACKGROUND: Underweight imposes significant burden on cardiovascular outcomes in patients with diabetes mellitus. However, less is known about the impact of serial change in body weight status measured as body mass index (BMI) on the risk of sudden cardiac arrest (SCA). This study investigated the association between SCA and temporal change in BMI among patients with diabetes mellitus. METHODS: Based on Korean National Health Insurance Service database, participants with diabetes mellitus who underwent health examination between 2009 and 2012 and had prior health examination data (four years ago, 2005-2008) were retrospectively analyzed. BMI was measured at baseline (2005-2008) and 4-year follow-up health examination (2009-2012). Patients were classified in four groups according to the body weight status and its temporal change: sustained non-underweight, sustained underweight, previous underweight, and newly developed underweight. Primary outcome was defined as occurrence of SCA. RESULTS: A total of 1,355,746 patients with diabetes mellitus were included for analysis, and SCA occurred in 12,554 cases. SCA was most common in newly developed underweight (incidence rate = 4.45 per 1,000 person-years), followed by sustained underweight (incidence rate = 3.90), previous underweight (incidence rate = 3.03), and sustained non-underweight (incidence rate = 1.34). Adjustment of covariates resulted highest risk of SCA in sustained underweight (adjusted hazard ratio = 2.60, 95% confidence interval [2.25-3.00], sustained non-underweight as a reference), followed by newly developed underweight (2.42, [2.15-2.74]), and previous underweight (2.12, [1.77-2.53]). CONCLUSIONS: In diabetes mellitus, sustained underweight as well as decrease in body weight during 4-year follow-up imposes substantial risk on SCA. Recovery from underweight over time had relatively lower, but yet increased risk of SCA. Both underweight and dynamic decrease in BMI can be associated with increased risk of SCA.

Risk of depression and anxiety in multiple sclerosis and neuromyelitis optica spectrum disorder: A nationwide cohort study in South Korea.

BACKGROUND: We investigated the risks of depression/anxiety in patients with multiple sclerosis (pwMS) or patients with neuromyelitis optica spectrum disorder (pwNMOSD). OBJECTIVES: MS/NMOSD cohorts were collected from Korean National Health Insurance Service, using the International Classification of Diseases-10th and information on Rare Intractable Disease program. Patients who were younger than 20 years, had a previous depression/anxiety, or died in the index year were excluded. METHODS: Hazard ratios (HRs) of depression/anxiety in pwMS and pwNMOSD from controls matched 1:5 for age, sex, hypertension, diabetes, and dyslipidemia were calculated using Cox regressions with a 1-year lag period and estimated over time. RESULTS: During a mean follow-up of 4.1 years, adjusted hazard ratios (aHR) for depression were 3.25 (95% confidence interval (CI) = 2.59-4.07) in MS and 2.17 (1.70-2.76) in NMOSD, and aHRs for anxiety were 1.83 (1.49-2.23) in MS and 1.56 (1.26-1.91) in NMOSD. The risks of anxiety/depression did not differ between MS and NMOSD and were highest in the second year after diagnosis of MS/NMOSD. The relative risk of depression was higher in younger pwMS/pwNMOSD, and the relative risk of anxiety was higher in pwMS who was male, had low income, or lived in a non-urban area. CONCLUSION: The risk of depression and anxiety was increased in pwMS/pwNMOSD.

Migraine Risk in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder: A Nationwide Cohort Study in South Korea.

INTRODUCTION: Although the relationship between migraine and multiple sclerosis (MS) has been reported, the risk of migraine in MS and neuromyelitis optica spectrum disorder (NMOSD) is unclear. Therefore, this study investigated the risk of migraine in the Korean MS and NMOSD populations. METHODS: This study analyzed claims data from 1492 patients with MS and 1551 patients with NMOSD based on diagnostic codes in the Korean National Health Insurance Service. Migraine risk was compared with a control group (matched 1:5 for age, sex, and comorbidities) using Cox proportional hazards analysis. Patients aged <20 years and with previous migraine were excluded. RESULTS: Migraine risk was higher in patients with MS (adjusted hazard ratio [aHR] 1.37; 95% confidence interval [CI]: 1.15-1.62) but did not differ significantly in patients with NMOSD (aHR 1.05; 95%CI: 0.87-1.27) compared to controls. No significant sex-based differences in migraine risk were observed. Patients with NMOSD showed decreasing risk with age (p for interaction=0.040). Comorbidities like hypertension, diabetes, or dyslipidemia did not significantly alter migraine risk in either group. CONCLUSION: The study results revealed an increased risk of migraines in patients with MS but not in patients with NMSOD compared with matched controls.

Association between Smoking Habit Changes and the Risk of Myocardial Infarction in Ischemic Stroke Patients: a Nationwide cohort study.

INTRODUCTION: Smoking is a well-known risk factor for cardiovascular diseases, including myocardial infarction (MI) and ischemic stroke (IS). While the relationship between smoking and the risk of cardiovascular diseases is established, the impact of changing smoking habits post-IS on the risk of subsequent MI remains unclear. This study aims to elucidate the effects of alterations in smoking behavior following an IS diagnosis on the likelihood of experiencing an MI. METHODS: Utilizing data from the Korean National Health Insurance Services Database, this nationwide population-based cohort study included 199,051 participants diagnosed with IS between January 2010 and December 2016. Smoking status was categorized based on changes in smoking habits before and after IS diagnosis. The association between changes in smoking behavior and the risk of subsequent MI was analyzed using multivariable Cox proportional hazard regression models. RESULTS: During a median follow-up of 4.17 person-years, a total of 5,734 (2.88%) patients were diagnosed with MI after IS. Smoking quitters (2.93%) or former smokers (2.47%) have a similar or lower rate of MI than the average, even if they have smoked cigarettes, while sustained smokers (3.46%) or new smokers (3.81%) have much higher rates of MI. Among sustained and new smokers, the risk of incident MI were significantly higher than never smokers (new smoker adjusted HR [aHR]: 1.496, 95% CI 1.262-1.774; sustained smoker aHR 1.494, 95% CI 1.361-1.641). Also, among the study participants, approximately two-thirds continued smoking after their IS diagnosis. CONCLUSION: Changing smoking habits after an IS diagnosis significantly influences the risk of subsequent MI. Specifically, continuing or starting to smoke after an IS diagnosis is associated with a higher risk of MI. These results underscore the importance of targeted smoking cessation interventions for stroke patients to reduce the risk of subsequent myocardial infarction.

Efficacy of immune-checkpoint inhibitors combined with cytotoxic chemotherapy in advanced or recurrent endometrial cancer: A systematic review and meta-analysis.

BACKGROUND: The combination of immune checkpoint inhibitors (ICIs) and platinum-based chemotherapy has emerged as a highly promising primary option for advanced or recurrent endometrial cancer (EC). The study aimed to evaluate treatment efficacy of ICIs with cytotoxic chemotherapy in EC. METHODS: We conducted a comprehensive review of randomized controlled trials up to November 11, 2023, focusing on immunotherapy combined with chemotherapy versus chemotherapy alone for EC. The primary endpoint was the pooled hazard ratio (HR), which was further analyzed across subgroups based on mismatch repair (MMR) status, race, histology, and programmed death-ligand 1 (PD-L1) status. The protocol was registered in PROSPERO (CRD42023475669). FINDINGS: Four trials with 2335 patients were analyzed. ICIs with chemotherapy significantly prolonged progression-free survival (PFS) (HR, 0.70; 95% CI, 0.62-0.79) and overall survival (OS) (HR, 0.75; 95% CI, 0.63-0.89) compared to chemotherapy alone. Stratification by MMR status showed substantial benefits for dMMR (PFS; HR, 0.33; 95% CI, 0.26-0.43; OS; HR, 0.37; 95% CI, 0.22-0.91) over pMMR cohorts in both PFS and OS. In the subgroup analysis, there was significant PFS advantage in Caucasian (HR, 0.63; 95% CI, 0.54-0.72) over non-Caucasian, in endometrioid histology (HR, 0.66; 95% CI, 0.56-0.78) over non-endometrioid, and in PD-L1 positive (HR, 0.39; 95% CI, 0.19-0.81) over PD-L1 negative population. INTERPRETATION: ICIs combined with platinum-based chemotherapy significantly prolonged PFS and OS in patients with advanced or recurrent EC. Patients with dMMR status, Caucasians, endometrioid histology, and positive PD-L1 status showed significant PFS benefits, emphasizing the need for personalized treatment approaches to improve outcomes.

A 52-week efficacy and safety study of enavogliflozin versus dapagliflozin as an add-on to metformin in patients with type 2 diabetes mellitus: ENHANCE-M extension study.

AIM: To evaluate the long-term safety and efficacy of enavogliflozin 0.3 mg/day added to metformin in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: After 24 weeks of a randomized, double-blind treatment period with enavogliflozin 0.3 mg/day (n = 101) or dapagliflozin 10 mg/day (n = 99) added to metformin, all patients received enavogliflozin 0.3 mg/day plus metformin for an additional 28 weeks during the open-label extension period. RESULTS: Eighty-two patients continued enavogliflozin (maintenance group), and 77 were switched from dapagliflozin to enavogliflozin (switch group). All adverse drug reactions (ADR) were mild in severity. In the maintenance group, ADRs (cystitis and vaginal infection) were reported in two patients (2.44%) during 52 weeks. In the switch group, ADR (hypoglycaemia) was reported in one patient (1.30%) during a 28-week open-label extension period. At week 52, glycated haemoglobin and fasting plasma glucose were significantly lower than at the baseline, by 0.85% and 29.08 mg/dl, respectively, in the maintenance group (p < .0001 for both), and by 0.81% and 32.77 mg/dl, respectively, in the switch group (p < .0001 for both). At week 52, 68.92% of patients from the maintenance group and 64.29% from the switch group achieved glycated haemoglobin <7%. A significant increase in the urine glucose-creatinine ratio was observed at week 52, by 58.81 g/g and 63.77 g/g in the maintenance and switch groups, respectively (p < .0001). CONCLUSIONS: Enavogliflozin added to metformin was tolerated well for up to 52 weeks and provided continual glycaemic control in type 2 diabetes mellitus, along with a significant increase in the urine glucose-creatinine ratio.

Dual add-on therapy of gemigliptin and dapagliflozin in patients with type 2 diabetes inadequately controlled with metformin alone: The SOLUTION 2 study.

AIM: To evaluate the efficacy and safety of gemigliptin and dapagliflozin dual add-on therapy (GEMI + DAPA) to metformin in type 2 diabetes (T2D) patients who had inadequate glycaemic control on metformin alone, compared with a single add-on of either gemigliptin (GEMI) or dapagliflozin (DAPA) to metformin. MATERIALS AND METHODS: In this randomized, double-blind, double-dummy, active-controlled, parallel-group, phase 3 study, 469 T2D patients treated with a stable dose of metformin for 8 weeks or longer were randomized to receive GEMI + DAPA (n = 157) and either GEMI (n = 156) or DAPA (n = 156). The primary endpoint was change in HbA1c levels from baseline at week 24. RESULTS: Baseline characteristics including body mass index and T2D duration were similar among groups. At week 24, the least square mean changes in HbA1c from baseline were -1.34% with GEMI + DAPA, -0.90% with GEMI (difference between GEMI + DAPA vs. GEMI -0.44% [95% confidence interval {CI}: -0.58% to -0.31%], P < .01) and -0.78% with DAPA (difference between GEMI + DAPA vs. DAPA -0.56% [95% CI: -0.69% to -0.42%], P < .01). Both upper CIs were less than 0, demonstrating the superiority of GEMI + DAPA for lowering HbA1c. The rates of responders achieving HbA1c less than 7% and less than 6.5% were greater with GEMI + DAPA (84.9%, 56.6%) than with GEMI (55.3%, 32.2%) and DAPA (49.3%, 15.3%). The incidence rate of adverse events was similar across groups, with low incidence rates of hypoglycaemia, urinary tract infection and genital infection. CONCLUSIONS: These results suggest that the addition of GEMI + DAPA to metformin as triple combination therapy was effective, safe and well-tolerated, especially for T2D patients who experienced poor glycaemic control on metformin alone.

Atopic Dermatitis Severity and Risk for Psoriasis: A Nationwide Population-Based Study.

INTRODUCTION: As research on the role of the Th17/IL-23 pathway gains importance, the relationship between atopic dermatitis (AD) and psoriasis is becoming elucidated. OBJECTIVE: The objective of this study wasto evaluate whether AD and its severity affect the risk for psoriasis. METHODS: This retrospective population-based study used the database from the 2009 National Health Insurance Services-Health Screening Cohort in Korea. A total of 3,957,922 adult subjects were included and observed until 2018. The primary outcome was newly diagnosed psoriasis. RESULTS: After adjusting for possible confounding factors, the moderate-to-severe AD group had the highest hazard ratio (HR) for psoriasis (HR = 2.50; 95% confidence interval (CI), 2.40-2.61), followed by the mild AD group (HR = 2.31; 95% CI: 2.19-2.44) compared with the non-AD group during a median 8.11 ± 1.19 years of follow-up. LIMITATIONS: It is difficult to define AD, which is not standardized, using a claims database and exclude patients who were misdiagnosed with AD. CONCLUSION: Patients with severe AD showed an increased risk for psoriasis compared to controls, and the risk for psoriasis was increased according to AD severity. This suggests that psoriasis and AD could share inflammatory, immune, and genetic features.

Social setting interacts with hyper dopamine to boost the stimulant effect of ethanol.

Alcohol consumption occurring in a social or solitary setting often yields different behavioural responses in human subjects. For example, social drinking is associated with positive effects while solitary drinking is linked to negative effects. However, the neurobiological mechanism by which the social environment during alcohol intake impacts on behavioural responses remains poorly understood. We investigated whether distinct social environments affect behavioural responses to ethanol and the role of the dopamine system in this phenomenon in the fruit fly Drosophila melanogaster. The wild-type Canton-S (CS) flies showed higher locomotor response when exposed to ethanol in a group setting than a solitary setting, and there was no difference in females and males. Dopamine signalling is crucial for the locomotor stimulating effect of ethanol. When subjected to ethanol exposure alone, the dopamine transport mutant flies fumin (fmn) with hyper dopamine displayed the locomotor response similar to CS. When subjected to ethanol in a group setting, however, the fmn's response to the locomotor stimulating effect was substantially augmented compared with CS, indicating synergistic interaction of dopamine signalling and social setting. To identify the dopamine signalling pathway important for the social effect, we examined the flies defective in individual dopamine receptors and found that the D1 receptor dDA1/Dop1R1 is the major receptor mediating the social effect. Taken together, this study underscores the influence of social context on the neural and behavioural responses to ethanol.

High remnant-cholesterol levels increase the risk for end-stage renal disease: a nationwide, population-based, cohort study.

BACKGROUND: The effect of remnant-cholesterol (remnant-C) on incident end-stage renal disease (ESRD) has not been studied longitudinally. This retrospective cohort study evaluated the association between remnant-C and the development of ESRD in a nationwide Korean cohort. METHODS: Participants in a National Health Insurance Service health examination (n = 3,856,985) were followed up until the onset of ESRD. The median duration of follow-up was 10.3 years. The Martin-Hopkins equation was used to determine low-density lipoprotein cholesterol (LDL-C) levels from directly measured triglyceride, high-density lipoprotein cholesterol (HDL-C), and total cholesterol levels. Remnant-C levels were determined by subtracting HDL-C and LDL-C from total cholesterol. The risk for incident ESRD was calculated for each quartile of remnant-C, adjusting for conventional risk factors such as baseline renal function, comorbidities, and total cholesterol levels. RESULTS: ESRD developed in 11,073 (0.29%) participants. The risk for ESRD exhibited a gradual increase according to higher levels of remnant-C, with a 61% increased risk in the highest quartile than in the lowest (hazard ratio [HR] 1.61 [95% confidence interval (CI) 1.50-1.72]). The elevated risk for ESRD in the highest quartile versus the lowest quartile was more prominent in younger than in older subjects (20-29 years, HR 4.07 [95% CI 2.85-5.83]; 30-39 years, HR 2.39 [95% CI 1.83-3.13]; ≥ 70 years, HR 1.32 [95% CI 1.16-1.51]). In addition, the increased risk for ESRD related to higher remnant-C levels was greater in females than in males. CONCLUSIONS: Independent of conventional risk factors, remnant-C levels were positively associated with incident ESRD, particularly in younger populations and adult females. Reducing remnant-C levels may be a novel preventive strategy against ESRD.

Association between physical activity changes and incident myocardial infarction after ischemic stroke: a nationwide population-based study.

BACKGROUND: The impact of changes in physical activity after ischemic stroke (IS) on the subsequent myocardial infarction (MI) risk is not fully understood. We aimed to investigate the effects of changes in physical activity on the risk of MI after acute IS using data from the Korean National Health Insurance Services Database. METHODS: 224,764 patients newly diagnosed with IS between 2010 and 2016 who underwent two serial biannual health checkups were included. The participants were divided into four categories according to changes in their physical activity: persistent non-exercisers, new exercisers, exercise dropouts, and exercise maintainers. The primary outcome was a new diagnosis of incident MI. Multivariable Cox proportional models were used to assess the effects of changes in exercise habits on the risk of MI. RESULTS: After a median of 4.25 years of follow-up, 6,611 (2.94%) MI cases were observed. After adjusting for confounders, new exercisers and exercise maintainers were significantly associated with a lower risk of incident MI than persistent non-exercisers (aHR, 0.849; 95% CI, 0.792-0.911; P-value < 0.001; and aHR, 0.746; 95% CI, 0.696-0.801; P-value < 0.001, respectively). Effects were consistent across sexes, more pronounced in those > 65 years. Notably, any level of physical activity after stroke was associated with a reduced MI risk compared to no exercise. CONCLUSIONS: In this nationwide cohort study, commencing or sustaining physical activity after an IS corresponded to a diminished likelihood of subsequent MI development. Advocating physical activity in ambulatory stroke survivors could potentially attenuate the prospective risk of MI.

Mitogen-activated protein kinase 6 negatively regulates secondary wall biosynthesis by modulating MYB46 protein stability in Arabidopsis thaliana.

The R2R3-MYB transcription factor MYB46 functions as a master switch for secondary cell wall biosynthesis, ensuring the exquisite expression of the secondary wall biosynthetic genes in the tissues where secondary walls are critical for growth and development. At the same time, suppression of its function is needed when/where formation of secondary walls is not desirable. Little is known about how this opposing control of secondary cell wall formation is achieved. We used both transient and transgenic expression of MYB46 and mitogen-activated protein kinase 6 (MPK6) to investigate the molecular mechanism of the post-translational regulation of MYB46. We show that MYB46 is phosphorylated by MPK6, leading to site specific phosphorylation-dependent degradation of MYB46 by the ubiquitin-mediated proteasome pathway. In addition, the MPK6-mediated MYB46 phosphorylation was found to regulate in planta secondary wall forming function of MYB46. Furthermore, we provide experimental evidences that MYB83, a paralog of MYB46, is not regulated by MPK6. The coupling of MPK signaling to MYB46 function provides insights into the tissue- and/or condition-specific activity of MYB46 for secondary wall biosynthesis.

Higher body mass index increases the risk of shoulder adhesive capsulitis in young adults: A nationwide cohort study.

BACKGROUND: The impact of overweight on the incidence of shoulder adhesive capsulitis (AC) has not been clearly proven. This study aimed to investigate the association between overweight and AC by age using a large-scale nationwide population-based cohort in Korea. METHODS: We analyzed clinical data from 3,517,066 individuals older than 20 years who had undergone a National Health Insurance Service health checkup in 2009. Patients who visited a hospital or private clinic to treat shoulder pain at least three times in one year and were assigned a diagnostic code for AC (ICD-10 code M75.00) were identified using claims data during a median follow-up duration of 8.3 years. Hazard ratios (HRs) and 95% confidence intervals for AC were calculated using the Cox proportional hazards model. RESULTS: The adjusted HR for AC in the < 40 year group started to increase in overweight status and was associated with the severity of obesity (body mass index (BMI) < 18.5; 0.654 (0.613-0.697), < 23; 1, < 25; 1.272 (1.231-1.315), < 30; 1.322 (1.281-1.364), ≥ 30; 1.332 (1.253-1.416)). But in the 40-64 year group and the ≥65 year group, there was no significant increasing trend of HR for AC according to BMI level. We conducted a subgroup analysis based on the BMI 23 for defining overweight and presence of comorbidities including diabetes and hyperlipidemia. The adjusted HR for AC was highest with overweight and comorbidities of diabetes and hyperlipidemia (diabetes; 1.528 (1.508-1.549), hyperlipidemia; 1.212 (1.199-1.226)). CONCLUSIONS: In the young age group (20-40 years), a higher BMI level increased the HR for AC. Overweight along with diabetes or hyperlipidemia significantly increased the risk of AC.