Systemic Brain Delivery of Oligonucleotide Therapeutics Enhanced by Protein Corona-Assisted DNA Cubes.

The systemic delivery of oligonucleotide therapeutics to the brain is challenging but highly desirable for the treatment of brain diseases undruggable with traditional small-molecule drugs. In this study, a set of DNA nanostructures is prepared and screened them to develop a protein corona-assisted platform for the brain delivery of oligonucleotide therapeutics. The biodistribution analysis of intravenously injected DNA nanostructures reveals that a cube-shaped DNA nanostructure (D-Cb) can penetrate the brain-blood barrier (BBB) and reach the brain tissue. The brain distribution level of D-Cb is comparable to that of other previous nanoparticles conjugated with brain-targeting ligands. Proteomic analysis of the protein corona formed on D-Cb suggests that its brain distribution is driven by endothelial receptor-targeting ligands in the protein corona, which mediate transcytosis for crossing the BBB. D-Cb is subsequently used to deliver an antisense oligonucleotide (ASO) to treat glioblastoma multiforme (GBM) in mice. While free ASO is unable to reach the brain, ASO loaded onto D-Cb is delivered efficiently to the brain tumor region, where it downregulates the target gene and exerts an anti-tumor effect on GBM. D-Cb is expected to serve as a viable platform based on protein corona formation for systemic brain delivery of oligonucleotide therapeutics.

High level of gamma-glutamyltransferase is a possible risk factor for psoriasis: A nationwide population-based cohort study.

Background Gamma-glutamyl transferase (GGT) has been associated with coronary heart disease, diabetes mellitus, and hypertension, but its association with psoriasis has not yet been elucidated. Aims We conducted this study to determine the association between the risk of psoriasis and the serum GGT. Methods We conducted a nationwide population-based study. A total of 9,939,350 people met the enrolment criteria. The study population was classified into four groups based on GGT levels and the risk of psoriasis was calculated for each group. Results The incidence rates of psoriasis per 1,000 person-years were 2.96105 and 3.68577 in the lowest and highest GGT groups, respectively. After adjusting for age, sex, income, diabetes mellitus, hypertension, dyslipidemia, smoking, alcohol intake, exercise, and body mass index, the highest GGT group showed a significantly increased risk of developing psoriasis (hazard ratio: 1.057, 95% confidence interval: 1.044-1.07). This risk of psoriasis was significantly higher among the old age group (hazard ratio: 1.162, 95% confidence interval: 1.128-1.197) and women (hazard ratio: 1.14, 95% confidence interval: 1.117-1.164). Limitations The limitations of this study included the retrospective design, International Classification of Diseases code-based diagnosis, small hazard ratio, and non-availability of data on covariates. Conclusion The GGT level was found to be an independent risk factor for developing psoriasis.

Efficacy and safety of dapagliflozin in children with kidney disease: real-world data.

BACKGROUND: Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, has shown results in slowing estimated glomerular filtration rate (eGFR) decline and reducing proteinuria in adult patients with chronic kidney disease. This retrospective study examines dapagliflozin's effects in 22 children with kidney disease and proteinuria. METHODS: Children with a median age of 15.6 years were treated with dapagliflozin for > 3 months between July 2022 and December 2023. All children had been treated with either an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker for at least 1 month before starting dapagliflozin. RESULTS: The most common kidney disease diagnoses in this study included Alport syndrome (n = 7) and medication-resistant nephrotic syndrome or focal segmental glomerulosclerosis (n = 7). After 6.1 months of treatment, dapagliflozin treatment did not result in significant changes in eGFR or proteinuria. However, at the latest follow-up, a statistically significant decrease in eGFR was noted (65.5 compared to the baseline 71.1 mL/min/1.73 m2, P = 0.003). Proteinuria remained stable between baseline and the last follow-up (final spot urine protein/creatinine ratio (uPCR) 0.7 vs. baseline uPCR 0.6 mg/mg, P = 0.489). In the subgroup analysis of children treated for > 8 months, the eGFR decline post-treatment changed from - 0.5 to - 0.2 ml/min/1.73 m2 per month (P = 0.634). Only two children discontinued dapagliflozin due to suspected adverse events. CONCLUSIONS: Dapagliflozin has not been associated with serious side effects. Further prospective clinical trials are needed to confirm the efficacy and safety of dapagliflozin in children with kidney disease.

Combination of rituximab and methotrexate followed by rituximab and cytarabine in elderly patients with primary central nervous system lymphoma.

The optimal treatment strategy for newly diagnosed primary central nervous system lymphoma (PCNSL) has yet to be established, especially in the elderly. In the current study, we conducted a phase II study to evaluate the efficacy and safety of rituximab plus high-dose MTX followed by rituximab plus cytarabine in patients aged ≥60 years newly diagnosed with PCNSL. Patients received an induction treatment of high-dose methotrexate plus rituximab followed by two cycles of a consolidation treatment of cytarabine plus rituximab. The primary end-point was a 2-year progression-free survival (PFS) rate. A total of 35 patients were recruited, and their median age was 73 (range: 60-81). After induction treatment, the complete and partial responses (PRs) were 56% and 20% respectively. Twenty-six patients proceeded to the consolidation treatment; the complete and PRs were 59% and 9% respectively. After a median follow-up duration of 36.0 months, the 2-year PFS rate was 58.7%. Treatment was generally well-tolerated as only three patients were withdrawn from the study due to toxicity, and no treatment-related mortality was reported. The 2-year overall survival rate was 77.9%. The current study may suggest the feasibility of administering high-dose MTX plus cytarabine in PCNSL patients aged ≥60 years and the potential role of additive rituximab.

Decreased Sirtuin 4 Levels Promote Cellular Proliferation and Invasion in Papillary Thyroid Carcinoma.

OBJECTIVE: This study examined the effect of Sirtuin 4 (Sirt4), a NAD+-dependent deacetylase, on the proliferation and progression of papillary thyroid carcinoma (PTC). METHODS: Data from The Cancer Genome Atlas (TCGA) were analyzed to identify Sirt4 expression in thyroid cancer. Subsequently, the correlation between Sirt4 expression and clinical characteristics was examined in 205 PTC tissue samples. In vitro assays using three human thyroid cancer cell lines (B-CPAP, TPC-1, and SNU-790) were conducted to assess the effects of regulated Sirt4 expression on cell growth, apoptosis, invasion, and migration. Furthermore, in vivo experiments were performed in a xenograft mouse model. RESULTS: GEO and TCGA data indicated that Sirt4 expression is lower in thyroid cancer and Sirt4 downregulation is associated with poor overall survival. In our PTC tissues, positive Sirt4 expression was associated with decreased extracapsular extension. In in vitro experiments using three human thyroid cancer cell lines, overexpression of Sirt4 decreased cell survival, clonogenic potential, and invasion and migratory capabilities, as well as inducing apoptosis and increasing reactive oxygen species levels. Sirt4 overexpression upregulated E-cadherin and downregulated N-cadherin, suggesting its potential involvement in the regulation of epithelial-mesenchymal transition. These findings were confirmed in vivo using a xenograft mouse model. CONCLUSION: This study provides novel insight into the potential contribution of Sirt4 to regulation of the pathological progression of PTC. The data suggest that Sirt4 plays a tumor-suppressive role in PTC by inhibiting growth, survival, and invasive potential. Future research should investigate the molecular mechanisms underlying these effects of Sirt4.

Effect of Cost-Exemption Policy on Treatment Interruption in Patients With Newly Diagnosed Pulmonary Tuberculosis in South Korea.

BACKGROUND: In 2021, South Korea had the highest incidence rate (49 per 100 000 population) and the third highest mortality rate (3.8 per 100 000 population) due to pulmonary tuberculosis (TB) among Organization for Economic Co-operation and Development countries. Notably, premature interruption of TB treatment interferes with TB control efforts. Therefore, we examined the effect of the co-payment waiver on treatment interruption and mortality among patients with pulmonary TB in South Korea. METHODS: Patients who had newly treated TB in South Korea from 2013 to 2019 were selected from the nationwide data of the entire Korean National Health Insurance Service (NHIS) population. The effects of policy implementation on treatment adherence and mortality rates depending on treatment interruption history were evaluated. RESULTS: In total, 73 116 and 1673 patients with drug-susceptible (DS) and multidrug-resistant (MDR) pulmonary TB, respectively, were included in the final study population. After implementing the cost-exemption policy, the treatment interruption rate tended to decrease in the continuation phase in the DS-TB group (slope change: -0.097, P=.011). However, it increased in the intensive phase in the MDR-TB group (slope change: 0.733, P=.001). MDR-TB patients were likely to experience an interruption of TB treatment (adjusted odds ratio [aOR], 6.04; 95% CI, 5.43-6.71), and treatment interruption history was a significant risk factor for 1-year and overall mortality rates (adjusted hazard ratios [aHRs]: 2.01, 95% CI, 1.86-2.18 and 1.77, 95% CI, 1.70-1.84, respectively) in the DS-TB group. CONCLUSION: Implementing the cost-exemption policy effectively reduced the treatment interruption rate among patients with DS pulmonary TB.

Diagnostic value of a deep learning-based hyoid bone tracking model for aspiration in patients with post-stroke dysphagia.

Objective: Hyoid bone movement is potentially related to aspiration risk in post-stroke dysphagia (PSD) patients but is difficult to assess quantitatively. This study aimed to measure the distance of hyoid bone movement more efficiently and accurately using a deep learning model and determine the clinical usefulness of the model in PSD patients. Methods: This study included 85 patients with PSD within 6 months from onset. Patients were grouped into an aspiration group (n = 35) and a non-aspiration group (n = 50) according to the results of a videofluoroscopic swallowing study. Hyoid bone movement was tracked using a deep learning model constructed with the BiFPN-U-Net(T) architecture. The maximum distance of hyoid bone movement was measured horizontally (H max), vertically (V max), and diagonally (D max). Results: Compared with the non-aspiration group, the aspiration group showed significant decreases in hyoid bone movement in all directions. The area under the curve of V max was highest at 0.715 with a sensitivity of 0.680 and specificity of 0.743. The V max cutoff value for predicting aspiration risk was 1.61 cm. The success of oral feeding at the time of discharge was significantly more frequent when hyoid movement was equal to or larger than the cutoff value although no significant relationship was found between hyoid movement and other clinical characteristics. Conclusion: Hyoid bone movement of PSD patients can be measured quantitatively and efficiently using a deep learning model. Deep learning model-based analysis of hyoid bone movement seems to be useful for predicting aspiration risk and the possibility of resuming oral feeding.

Platelet-rich plasma protects hippocampal neurons and memory functions in a rat model of vascular dementia.

Platelet-rich plasma (PRP) is a promising biomaterial rich in bioactive growth factors, offering potential as a therapeutic agent for various diseases. However, its effectiveness in central nervous system disorders like vascular dementia (VaD) remains underexplored. This study investigated the potential of PRP to mitigate VaD progression in vivo. A rat model of VaD was established via bilateral common carotid artery occlusion and hypovolemia operation. Rats were randomly assigned to receive either PRP or platelet-poor plasma (PPP)-the latter being a byproduct of PRP preparation and used as a reference standard-resulting in the groups designated as 'operated group (OP)+PRP' and 'OP+PPP', respectively. PRP or PPP (500 µl) was administered intraperitoneally on the day of the operation and postoperative days 2, 4, 6, and 8. Cognitive function was assessed using the Y-maze, Barnes maze, and passive avoidance tests. On postoperative day 8, hippocampal samples were subjected to histological and semi-quantitative analyses. OP exhibited significant memory decline compared to controls, while the 'OP+PRP' group showed notable improvement. Histological analysis revealed increased neuronal loss and neuroinflammation in OP hippocampi, mitigated in 'OP+PRP'. Semi-quantitative analysis showed decreased expression of brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase B (TrkB) in OP, restored in 'OP+PPP' and further in 'OP+PRP'. These results highlight PRP's protective effects against VaD-induced hippocampal damage and cognitive impairment, partially attributed to BDNF/TrkB pathway upregulation.

Oxygen reserve index versus conventional peripheral oxygen saturation for prevention of hypoxaemia: A randomised controlled trial.

BACKGROUND: Hypoxaemia occurs frequently during paediatric laryngeal microsurgery. OBJECTIVE: The oxygen reserve index is a noninvasive and continuous parameter to assess PaO2 levels in the range of 100 to 200 mmHg. It ranges from 0 to 1.0. We investigated whether monitoring the oxygen reserve index can reduce the incidence of SpO2 90% or less. DESIGN: Randomised controlled trial. SETTING: A tertiary care paediatric hospital. PARTICIPANTS: Paediatric patients aged 18 years or less scheduled to undergo laryngeal microsurgery. INTERVENTION: The patients were randomly allocated to the oxygen reserve index or control groups, and stratified based on the presence of a tracheostomy tube. Rescue intervention was performed when the oxygen reserve index was 0.2 or less and the SpO2 was 94% or less in the oxygen reserve index and control groups, respectively. MAIN OUTCOME MEASURE: The primary outcome was the incidence of SpO2 90% or less during the surgery. RESULTS: Data from 88 patients were analysed. The incidence of SpO2 ≤ 90% did not differ between the oxygen reserve index and control groups [P = 0.114; 11/44, 25% vs. 18/44, 40.9%; relative risk: 1.27; and 95% confidence interval (CI): 0.94 to 1.72]. Among the 128 rescue interventions, SpO2 ≤ 90% event developed in 18 out of 75 events (24%) and 42 out of 53 events (79.2%) in the oxygen reserve index and control groups, respectively (P < 0.001; difference: 55.2%; and 95% CI 38.5 to 67.2%). The number of SpO2 ≤ 90% events per patient in the oxygen reserve index group (median 0, maximum 3) was less than that in the control group (median 0, maximum 8, P = 0.031). CONCLUSION: Additional monitoring of the oxygen reserve index, with a target value of greater than 0.2 during paediatric airway surgery, alongside peripheral oxygen saturation, did not reduce the incidence of SpO2 ≤ 90%.

α-CsPbI3 Quantum Dots ReRAM with High Air Stability Working by Valance Change Filamentary Mechanism.

The current memory system is facing obstacles to improvement, and ReRAM is considered a powerful alternative. All-inorganic α-CsPbI3 perovskite-based ReRAM working by electrochemical mechanism is reported, but the electrochemically active electrode raised difficulty in long-term stable operation, and bulk α-CsPbI3 device can not show resistive switching behavior with an inert metal top electrode. Herein, by making the α-CsPbI3 into QDs and applying it to the device with inert Au as the top electrode, the devices working by valence change mechanism are successfully fabricated. The large surface-to-volume ratio made an abundant amount of iodine vacancies and facile migration of vacancies allowed the device to work by valence change mechanism. The devices show reliable electrical characteristics, 800 cycles endurance and retention for over 4 × 104 s, and air stability for 1 month. This work demonstrates that applying the QDs can improve the stability and enable a new type of working mechanism in ReRAM.

Genetic Deletion of Skeletal Muscle Inositol Polyphosphate Multikinase Disrupts Glucose Homeostasis and Impairs Exercise Tolerance.

Inositol phosphates are critical signaling messengers involved in a wide range of biological pathways in which inositol polyphosphate multikinase (IPMK) functions as a rate-limiting enzyme for inositol polyphosphate metabolism. IPMK has been implicated in cellular metabolism, but its function at the systemic level is still poorly understood. Since skeletal muscle is a major contributor to energy homeostasis, we have developed a mouse model in which skeletal muscle IPMK is specifically deleted and examined how a loss of IPMK affects whole-body metabolism. Here, we report that mice in which IPMK knockout is deleted, specifically in the skeletal muscle, displayed an increased body weight, disrupted glucose tolerance, and reduced exercise tolerance under the normal diet. Moreover, these changes were associated with an increased accumulation of triglyceride in skeletal muscle. Furthermore, we have confirmed that a loss of IPMK led to reduced beta-oxidation, increased triglyceride accumulation, and impaired insulin response in IPMK-deficient muscle cells. Thus, our results suggest that IPMK mediates the whole-body metabolism via regulating muscle metabolism and may be potentially targeted for the treatment of metabolic syndromes.

Protective effect of Phyllostachys edulis (Carrière) J. Houz against chronic ethanol-induced cognitive impairment in vivo.

BACKGROUND/OBJECTIVES: Chronic alcohol consumption causes oxidative stress in the body, which may accumulate excessively and cause a decline in memory; problem-solving, learning, and exercise abilities; and permanent damage to brain structure and function. Consequently, chronic alcohol consumption can cause alcohol-related diseases. MATERIALS/METHODS: In this study, the protective effects of Phyllostachys edulis (Carrière) J. Houz (PE) against alcohol-induced neuroinflammation and cognitive impairment were evaluated using a mouse model. Alcohol (16%, 5 g/kg/day for 6 weeks) and PE (100, 250, and 500 mg/kg/day for 21 days) were administered intragastrically to mice. RESULTS: PE showed a protective effect against memory deficits and cognitive dysfunction caused by alcohol consumption, confirmed through behavioral tests such as the T-maze, object recognition, and Morris water maze tests. Additionally, PE attenuated oxidative stress by reducing lipid oxidation, nitric oxide, and reactive oxygen species levels in the mice's brains, livers, and kidneys. Improvement of neurotrophic factors and downregulation of apoptosis-related proteins were confirmed in the brains of mice fed low and medium concentrations of PE. Additionally, expression of antioxidant enzyme-related proteins GPx-1 and SOD-1 was enhanced in the liver of PE-treated mice, related to their inhibitory effect on oxidative stress. CONCLUSION: This suggests that PE has both neuroregenerative and antioxidant effects. Collectively, these behavioral and histological results confirmed that PE could improve alcohol-induced cognitive deficits through brain neurotrophic and apoptosis protection and modulation of oxidative stress.

Decreased Serum Cocaine- and Amphetamine-Regulated Transcript Level in Internet Gaming Disorder.

OBJECTIVE: Vulnerability to internet gaming disorder (IGD) has increased as internet gaming continues to grow. Cocaine- and amphetamine-regulated transcript (CART) is a hormone that plays a role in reward, anxiety, and stress. The purpose of this study was to identify the role of CART in the pathophysiology of IGD. METHODS: The serum CART levels were measured by enzyme-linked immunosorbent assay, and the associations of the serum CART level with psychological variables were analyzed in patients with IGD (n=31) and healthy controls (HC) (n=42). RESULTS: The serum CART level was significantly lower in the IGD than HC group. The IGD group scored significantly higher than the HC group on the psychological domains of depression, anxiety, the reward response in the Behavioral Activation System and Behavioral Inhibition System. There were no significant correlations between serum CART level and other psychological variables in the IGD group. CONCLUSION: Our results indicate that a decrease in the expression of the serum CART level is associated with the vulnerability of developing IGD. This study supports the possibility that CART is a biomarker in the pathophysiology of IGD.

Thermal characteristics of fire extinguishing agents in compartment fire suppression.

Water and foam have different fire-extinguishing mechanisms. Traditional foam and compressed air foam (CAF) have different bubble structures. These differences result in different thermal characteristics, which affect the extinguishing abilities during a fire. In this study, the differences in the thermal characteristics of three different extinguishing agents (water, traditional foam, and CAF) were investigated by suppressing a compartment fire. With an ignition source in the compartment (6 m × 3 m × 3 m), the agent was preferentially applied to the outside wall of the compartment. The effects of internal cooling and burnback resistance generated from the outer wall were evaluated. The performance of each agent in shielding firefighters from radiant heat while suppressing the fire inside the compartment was evaluated. When the outside wall of the compartment was covered with each of the agents, all agents were found to reduce the room temperature. When CAF was applied, the delay time until temperature re-rise was approximately 1.76-4.5 times longer than that when water was used. In addition, foaming agents exhibited a higher heat-shielding effect than water during the initial suppression. Thus, considering the thermal characteristics of these agents, fire suppression can be more effective if foam agents are used.

Study Design and Protocol for a Randomized Controlled Trial to Assess Long-Term Efficacy and Safety of a Triple Combination of Ezetimibe, Fenofibrate, and Moderate- Intensity Statin in Patients with Type 2 Diabetes and Modifiable Cardiovascular Risk Factors (ENSEMBLE).

Background: Atherogenic dyslipidemia, which is frequently associated with type 2 diabetes (T2D) and insulin resistance, contributes to the development of vascular complications. Statin therapy is the primary approach to dyslipidemia management in T2D, however, the role of non-statin therapy remains unclear. Ezetimibe reduces cholesterol burden by inhibiting intestinal cholesterol absorption. Fibrates lower triglyceride levels and increase high-density lipoprotein cholesterol (HDL-C) levels via peroxisome proliferator- activated receptor alpha agonism. Therefore, when combined, these drugs effectively lower non-HDL-C levels. Despite this, few clinical trials have specifically targeted non-HDL-C, and the efficacy of triple combination therapies, including statins, ezetimibe, and fibrates, has yet to be determined. Methods: This is a multicenter, prospective, randomized, open-label, active-comparator controlled trial involving 3,958 eligible participants with T2D, cardiovascular risk factors, and elevated non-HDL-C (≥100 mg/dL). Participants, already on moderate-intensity statins, will be randomly assigned to either Ezefeno (ezetimibe/fenofibrate) addition or statin dose-escalation. The primary end point is the development of a composite of major adverse cardiovascular and diabetic microvascular events over 48 months. Conclusion: This trial aims to assess whether combining statins, ezetimibe, and fenofibrate is as effective as, or possibly superior to, statin monotherapy intensification in lowering cardiovascular and microvascular disease risk for patients with T2D. This could propose a novel therapeutic approach for managing dyslipidemia in T2D.

A novel deep learning model for obstructive sleep apnea diagnosis: hybrid CNN-Transformer approach for radar-based detection of apnea-hypopnea events.

STUDY OBJECTIVES: The demand for cost-effective and accessible alternatives to polysomnography (PSG), the conventional diagnostic method for obstructive sleep apnea (OSA), has surged. In this study, we have developed and validated a deep learning model for detecting apnea-hypopnea events using radar data. METHODS: We conducted a single-center prospective cohort study, dividing participants with suspected sleep-disordered breathing into development and temporally independent test sets. Utilizing a hybrid CNN-Transformer architecture, we performed 5-fold cross-validation on the development set to develop and subsequently validate the model. Evaluation metrics included sensitivity for event detection, mean absolute error (MAE), intraclass correlation coefficient (ICC), and Pearson correlation coefficient (r) for apnea-hypopnea index (AHI) estimation. Linearly weighted kappa statistics (κ) assessed OSA severity. RESULTS: The development set comprised 54 participants (July 2021-May 2022), while the test set included 35 participants (June 2022-June 2023). In the test set, our model achieved an event detection sensitivity of 67.2% (95% CI: 65.8%, 68.5%) and demonstrated a MAE of 7.54 (95% CI: 5.36, 9.72), indicating good agreement (ICC = 0.889 [95% CI: 0.792, 0.942]) and a strong correlation (r = 0.892 [95% CI: 0.795, 0.945]) with the ground truth for AHI estimation. Furthermore, OSA severity estimation showed substantial agreement (κ = 0.780 [95% CI: 0.658, 0.903]). CONCLUSIONS: Our study highlights radar sensors and advanced AI models' potential to improve OSA diagnosis, paving the path for future radar-based diagnostic models in sleep medicine research.

Advanced Mechanical Transfer of Micro-LEDs Enabled by Structurally Modified Wide Sapphire Nanomembranes through Thermal Reflow of Photoresist.

Micro light-emitting diodes (micro-LEDs) are pivotal in next-generation display technologies, driven by the need for high pixel density. This study introduces a novel methodology utilizing wide sapphire nanomembranes (W-SNM) as a dual-purpose template for high-quality epitaxial growth and the mechanical lift-off of individual micro-LEDs. Micro-LEDs grow individually on W-SNM, obviating the chip singulation process. By employing mechanical fracturing of the thin W-SNM, our method facilitates the transfer of micro-LEDs without the conventional laser lift-off (LLO) process. Previously introduced sapphire nanomembranes (SNM) have shown promise in enhancing epitaxial layer quality; however, they encountered challenges in managing micro-LED size variation and achieving efficient mechanical transfer. Here, we apply simple yet effective adjustments to the SNM structure, specifically, its elevation and widening. This strategic modification allows micro-LEDs to endure applied forces without incurring cracks or defects, ensuring that only the targeted W-SNM are selectively fractured. The mechanically transferred vertical 15 × 15 µm2 micro-LED device operates at an optimal turn-on voltage of 3.3 V. Finite element simulations validate the mechanical strain distribution between the W-SNM and GaN when pressure is applied, confirming the efficacy of our design approach. This pioneering methodology offers a streamlined, efficient pathway for the production and mechanical transfer of micro-LEDs, presenting new avenues for their integration into next-generation, high-performance displays.

A Single Center Experience of Pulmonary Arterial Hypertension Management in Korea: A 25-Year Comparative Analysis Following the Introduction of Targeted Therapy.

BACKGROUND AND OBJECTIVES: The transformation of pulmonary arterial hypertension (PAH) treatment in Korea, ushered by targeted therapy's advent, prompted our analysis of baseline attributes, treatment trends, and survival shifts within our single-center registry. METHODS: We examined 230 patients (72.6% female, mean age 40.6±17.4 years) diagnosed and/or treated between 1980 and 2021 in our PAH clinic. Given targeted therapy's introduction and active use since 2007, we compared diagnostic classification, demographics, and treatment patterns at that juncture. Survival analysis encompassed PAH types and the overall population. For historical survival comparison, 50 non-registry patients were retrospectively added, and age-sex matching enabled pooled analysis. RESULTS: Congenital heart disease-associated pulmonary arterial hypertension (CHD-PAH) constituted the largest subset (43.0%), trailed by connective tissue disease-associated PAH (CTD-PAH, 29.6%) and idiopathic PAH (IPAH, 19.1%). Post-2007, CTD-PAH proportions surged, notably with an elevated initiation rate of targeted therapy (95.4%). Overall survival rates at 1, 5, and 10 years stood at 91.3%, 77.4%, and 65.8%, respectively, with CHD-PAH exhibiting superior survival to idiopathic or CTD-PAH. Age-sex matching analysis indicated survival disparities between those starting immediate targeted therapy vs. conservative treatment upon diagnosis, especially driven by IPAH. CONCLUSIONS: In the post-introduction of the targeted therapy era, patients with PAH promptly started treatment right away, and higher survival rates of patients who started initial PAH-targeted therapy were demonstrated. The transition towards early treatment initiation might have likely contributed to the elevated survival rates observed in Korea's PAH patient cohort.

Ameliorative Effects of Fermented Red Ginseng Extract on Muscle Atrophy in Dexamethasone-Induced C2C12 Cell And Hind Limb-Immobilized C57BL/6J Mice.

Fermented red ginseng (FRG) enhances the bioactivity and bioavailability of ginsenosides, which possess various immunomodulatory, antiaging, anti-obesity, and antidiabetic properties. However, the effects of FRG extract on muscle atrophy and the underlying molecular mechanisms remain unclear. This study aimed to elucidate the effects of FRG extract on muscle atrophy using both in vitro and in vivo models. In vitro experiments used dexamethasone (DEX)-induced C2C12 myotubes to assess cell viability, myotube diameter, and fusion index. In vivo experiments were conducted on hind limb immobilization (HI)-induced mice to evaluate grip strength, muscle mass, and fiber cross-sectional area (CSA) of the gastrocnemius (GAS), quadriceps (QUA), and soleus (SOL) muscles. Molecular mechanisms were investigated through the analysis of key signaling pathways associated with muscle protein synthesis, energy metabolism, and protein degradation. FRG extract treatment enhanced viability of DEX-induced C2C12 myotubes and restored myotube diameter and fusion index. In HI-induced mice, FRG extract improved grip strength, increased muscle mass and CSA of GAS, QUA, and SOL muscles. Mechanistic studies revealed that FRG extract activated the insulin-like growth factor 1/protein kinase B (Akt)/mammalian target of rapamycin signaling pathway, promoted muscle energy metabolism via the sirtuin 1/peroxisome proliferator-activated receptor gamma-coactivator-1α pathway, and inhibited muscle protein degradation by suppressing the forkhead box O3a, muscle ring-finger 1, and F-box protein (Fbx32) signaling pathways. FRG extract shows promise for ameliorating muscle atrophy by modulating key molecular pathways associated with muscle protein synthesis, energy metabolism, and protein degradation, offering insights for future drug development.

Fam49b dampens TCR signal strength to regulate survival of positively selected thymocytes and peripheral T cells.

The fate of developing T cells is determined by the strength of T cell receptor (TCR) signal they receive in the thymus. This process is finely regulated through the tuning of positive and negative regulators in thymocytes. The Family with sequence similarity 49 member B (Fam49b) protein is a newly discovered negative regulator of TCR signaling that has been shown to suppress Rac-1 activity in vitro in cultured T cell lines. However, the contribution of Fam49b to the thymic development of T cells is unknown. To investigate this important issue, we generated a novel mouse line deficient in Fam49b (Fam49b-KO). We observed that Fam49b-KO double positive (DP) thymocytes underwent excessive negative selection, whereas the positive selection stage was unaffected. Fam49b deficiency impaired the survival of single positive thymocytes and peripheral T cells. This altered development process resulted in significant reductions in CD4 and CD8 single-positive thymocytes as well as peripheral T cells. Interestingly, a large proportion of the TCRγδ+ and CD8αα+TCRαß+ gut intraepithelial T lymphocytes were absent in Fam49b-KO mice. Our results demonstrate that Fam49b dampens thymocytes TCR signaling in order to escape negative selection during development, uncovering the function of Fam49b as a critical regulator of the selection process to ensure normal thymocyte development and peripheral T cells survival.