Genetic and clinical characteristics of catecholaminergic polymorphic ventricular tachycardia in a Taiwanese nationwide cohort.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare and lethal arrhythmia. Ryanodine receptor 2 (RYR2) mutation accounts for ∼60% of CPVT patients which is inherited in an autosomal dominant pattern. OBJECTIVE: This study aimed to identify CPVT-related mutations and clinical characteristics among Taiwanese CPVT patients and compare to other cohorts worldwide. METHODS: Clinical and genetic data were obtained from the Sudden Arrhythmia Death Syndrome Registry in Taiwan (SADS-TW). Forty clinically diagnosed Taiwanese CPVT patients were included. RESULTS: This is the first nationwide CPVT cohort in Taiwan. Among the 29 Taiwanese patients with CPVT-related gene mutations, 55% had RYR2 mutations, a rate similar to other ethnicities. Three out of 12 RYR2 variants were unreported. Exercise-induced symptoms including syncope and cardiac arrest were more frequent in East Asian cohorts (Taiwanese 79%, Japanese 91%), compared to Caucasian cohorts (59%) (p = 0.002). CONCLUSION: The discovery of diverse RYR2 mutations in the Taiwanese CVPT population demonstrates the importance of genetic testing in different ethnicities.

A brain cell atlas integrating single-cell transcriptomes across human brain regions.

While single-cell technologies have greatly advanced our comprehension of human brain cell types and functions, studies including large numbers of donors and multiple brain regions are needed to extend our understanding of brain cell heterogeneity. Integrating atlas-level single-cell data presents a chance to reveal rare cell types and cellular heterogeneity across brain regions. Here we present the Brain Cell Atlas, a comprehensive reference atlas of brain cells, by assembling single-cell data from 70 human and 103 mouse studies of the brain throughout major developmental stages across brain regions, covering over 26.3 million cells or nuclei from both healthy and diseased tissues. Using machine-learning based algorithms, the Brain Cell Atlas provides a consensus cell type annotation, and it showcases the identification of putative neural progenitor cells and a cell subpopulation of PCDH9high microglia in the human brain. We demonstrate the gene regulatory difference of PCDH9high microglia between hippocampus and prefrontal cortex and elucidate the cell-cell communication network. The Brain Cell Atlas presents an atlas-level integrative resource for comparing brain cells in different environments and conditions within the Human Cell Atlas.

Multimodal imaging diagnosis and analysis of prognostic factors in patients with adult-onset Coats disease.

AIM: To describe the multimodal imaging features, treatment, and outcomes of patients diagnosed with adult-onset Coats disease. METHODS: This retrospective study included patients first diagnosed with Coats disease at ≥18 years of age between September 2017 and September 2021. Some patients received anti-vascular endothelial growth factor (VEGF) therapy (conbercept, 0.5 mg) as the initial treatment, which was combined with laser photocoagulation as needed. All the patients underwent best corrected visual acuity (BCVA) and intraocular pressure examinations, fundus color photography, spontaneous fluorescence tests, fundus fluorescein angiography, optical coherence tomography (OCT), OCT angiography, and other examinations. BCVA alterations and multimodal image findings in the affected eyes following treatment were compared and the prognostic factors were analyzed. RESULTS: The study included 15 patients who were aged 24-72 (57.33±12.61)y at presentation. Systemic hypertension was the most common associated systemic condition, occurring in 13 (86.7%) patients. Baseline BCVA ranged from 2.0 to 5.0 (4.0±1.1), which showed improvement following treatment (4.2±1.0). Multimodal imaging revealed retinal telangiectasis in 13 patients (86.7%), patchy hemorrhage in 5 patients (33.3%), and stage 2B disease (Shield's staging criteria) in 11 patients (73.3%). OCT revealed that the baseline central macular thickness (CMT) ranged from 129 to 964 µm (473.0±230.1 µm), with 13 patients (86.7%) exhibiting a baseline CMT exceeding 250 µm. Furthermore, 8 patients (53.3%) presented with an epiretinal membrane at baseline or during follow-up. Hyper-reflective scars were observed on OCT in five patients (33.3%) with poor visual prognosis. Vision deteriorated in one patient who did not receive treatment. Final vision was stable in three patients who received laser treatment, whereas improvement was observed in one of two patients who received anti-VEGF therapy alone. In addition, 8 of 9 patients (88.9%) who received laser treatment and conbercept exhibited stable or improved BCVA. CONCLUSION: Multimodal imaging can help diagnose adult-onset Coats disease. Anti-VEGF treatment combined with laser therapy can be an option for improving or maintaining BCVA and resolving macular edema. The final visual outcome depends on macular involvement and the disease stage.

Optimizing young tennis players' development: Exploring the impact of emerging technologies on training effectiveness and technical skills acquisition.

The research analyzed the effect of weekly training plans, physical training frequency, AI-powered coaching systems, virtual reality (VR) training environments, wearable sensors on developing technical tennis skills, with and personalized learning as a mediator. It adopted a quantitative survey method, using primary data from 374 young tennis players. The model fitness was evaluated using confirmatory factor analysis (CFA), while the hypotheses were evaluated using structural equation modeling (SEM). The model fitness was confirmed through CFA, demonstrating high fit indices: CFI = 0.924, TLI = 0.913, IFI = 0.924, RMSEA = 0.057, and SRMR = 0.041, indicating a robust model fit. Hypotheses testing revealed that physical training frequency (ß = 0.198, p = 0.000), AI-powered coaching systems (ß = 0.349, p = 0.000), virtual reality training environments (ß = 0.476, p = 0.000), and wearable sensors (ß = 0.171, p = 0.000) significantly influenced technical skills acquisition. In contrast, the weekly training plan (ß = 0.024, p = 0.834) and personalized learning (ß = -0.045, p = 0.81) did not have a significant effect. Mediation analysis revealed that personalized learning was not a significant mediator between training methods/technologies and acquiring technical abilities. The results revealed that physical training frequency, AI-powered coaching systems, virtual reality training environments, and wearable sensors significantly influenced technical skills acquisition. However, personalized learning did not have a significant mediation effect. The study recommended that young tennis players' organizations and stakeholders consider investing in emerging technologies and training methods. Effective training should be given to coaches on effectively integrating emerging technologies into coaching regimens and practices.

Screening, epidemic trends and drug sensitivity analysis of nontuberculous mycobacteria in a local area of China.

OBJECTIVE: To analyze the isolation rate, prevalence trends, species distribution, and drug sensitivity of non-tuberculous mycobacteria (NTM) in Anhui Province, providing a reference for diagnosis and treatment strategies. METHODS: Specimens from suspected mycobacterial infection patients at Anhui Chest Hospital (including outpatients and inpatients) from January 2021 to December 2023 were cultured. Identified NTM strains were analyzed for species distribution and drug sensitivity. RESULTS: Of 10,519 mycobacteria strains cultured, 1,589 were NTM (15.11%). The top four species were Mycobacterium intracellulare (75.36%), Mycobacterium abscessus (11.78%), Mycobacterium kansasii (7.09%), and Mycobacterium avium (2.85%). NTM strains showed high sensitivity to amikacin and clarithromycin (≥90%) and significant sensitivity to rifabutin, moxifloxacin, and rifampicin (89.03%-79.61%). They exhibited high resistance to imipenem/cilastatin, sulfamethoxazole, minocycline, and doxycycline (≥95%). CONCLUSION: NTM isolation rates in Anhui have remained stable, with the predominant species being M. intracellulare, M. kansasii, M. abscessus, and M. avium. NTM strains are highly sensitive to amikacin, clarithromycin, rifabutin, moxifloxacin, and rifampicin. These findings can guide diagnosis, treatment strategies, and drug selection for NTM disease in Anhui Province.

A structured biomimetic nanoparticle as inflammatory factor sponge and autophagy-regulatory agent against intervertebral disc degeneration and discogenic pain.

Lower back pain (LBP) is a common condition closely associated with intervertebral disc degeneration (IDD), causing a significant socioeconomic burden. Inflammatory activation in degenerated discs involves pro-inflammatory cytokines, dysregulated regulatory cytokines, and increased levels of nerve growth factor (NGF), leading to further intervertebral disc destruction and pain sensitization. Macrophage polarization is closely related to autophagy. Based on these pathological features, a structured biomimetic nanoparticle coated with TrkA-overexpressing macrophage membranes (TMNP@SR) with a rapamycin-loaded mesoporous silica core is developed. TMNP@SR acted like sponges to adsorbe inflammatory cytokines and NGF and delivers the autophagy regulator rapamycin (RAPA) into macrophages through homologous targeting effects of the outer engineered cell membrane. By regulating autophagy activation, TMNP@SR promoted the M1-to-M2 switch of macrophages to avoid continuous activation of inflammation within the degenerated disc, which prevented the apoptosis of nucleus pulposus cells. In addition, TMNP@SR relieved mechanical and thermal hyperalgesia, reduced calcitonin gene-related peptide (CGRP) and substance P (SP) expression in the dorsal root ganglion, and downregulated GFAP and c-FOS signaling in the spinal cord in the rat IDD model. In summary, TMNP@SR spontaneously inhibits the aggravation of disc inflammation to alleviate disc degeneration and reduce the ingress of sensory nerves, presenting a promising treatment strategy for LBP induced by disc degeneration.

Insight into esterified and granular esterified-pregelatinized starch formation during esterification modification: Key role of temperature.

The formation conditions and functional property differences of esterified starch (ES) and granular esterified-pregelatinized starch (EPS) synchronously prepared by octenyl succinic anhydride (OSA) modification remain unclear. In this study, we explored the formation conditions and physicochemical properties of ES and EPS after OSA modification. The modification temperature controlled the formation amount and time for both starch types during OSA modification. Compared to ES, EPS exhibited a higher degree of substitution, cold-water swelling power, water-absorption capacity and apparent viscosity in cold water. The structural characterization confirmed the molecular weight and short/long-range molecular order of ES and EPS decreased. Moreover, scanning electron microscopy indicated EPS retained its granular morphology. The X-ray diffraction patterns confirmed the presence of more starch-lipid complexes formed in EPS than in ES. This study provides a novel method for preparing esterified and granularly esterified-pregelatinized starches that could be used as promising additives in low-energy formula foods.

Microplastics are associated with elevated atherosclerotic risk and increased vascular complexity in acute coronary syndrome patients.

BACKGROUND: Microplastics, widely present in the environment, are implicated in disease pathogenesis through oxidative stress and immune modulation. Prevailing research, primarily based on animal and cell studies, falls short in elucidating microplastics' impact on human cardiovascular health. This cross-sectional study detected blood microplastic concentrations in patients presenting with chest pain using pyrolysis-gas chromatography/mass spectrometry and evaluating inflammatory and immune markers through flow cytometry, to explore the potential effects of microplastic on acute coronary syndrome. RESULTS: The study included 101 participants, comprising 19 controls and 82 acute coronary syndrome cases. Notably, acute coronary syndrome patients exhibited elevated microplastic concentrations, with those suffering from acute myocardial infarction presenting higher loads compared to those with unstable angina. Furthermore, patients at intermediate to high risk of coronary artery disease displayed significantly higher microplastic accumulations than their low-risk counterparts. A significant relationship was observed between increased microplastic levels and enhanced IL-6 and IL-12p70 contents, alongside elevated B lymphocyte and natural killer cell counts. CONCLUSION: These results suggest an association between microplastics and both vascular pathology complexity and immunoinflammatory response in acute coronary syndrome, underscoring the critical need for targeted research to delineate the mechanisms of this association. HIGHLIGHTS: 1 Blood microplastic levels escalate from angiographic patency, to angina patients, peaking in myocardial infarction patients. 2 Microplastics in acute coronary syndrome patients are predominantly PE, followed by PVC, PS, and PP. 3 Microplastics may induce immune cell-associated inflammatory responses in acute coronary syndrome patients.

Structural basis for difunctional mechanism of m-AMSA against African swine fever virus pP1192R.

The African swine fever virus (ASFV) type II topoisomerase (Topo II), pP1192R, is the only known Topo II expressed by mammalian viruses and is essential for ASFV replication in the host cytoplasm. Herein, we report the structures of pP1192R in various enzymatic stages using both X-ray crystallography and single-particle cryo-electron microscopy. Our data structurally define the pP1192R-modulated DNA topology changes. By presenting the A2+-like metal ion at the pre-cleavage site, the pP1192R-DNA-m-AMSA complex structure provides support for the classical two-metal mechanism in Topo II-mediated DNA cleavage and a better explanation for nucleophile formation. The unique inhibitor selectivity of pP1192R and the difunctional mechanism of pP1192R inhibition by m-AMSA highlight the specificity of viral Topo II in the poison binding site. Altogether, this study provides the information applicable to the development of a pP1192R-targeting anti-ASFV strategy.

A 45-Year-Old With Multiple Skin Lesions on Sun-Protected Areas of the Body.

A patient had multiple erythematous macules and patches on the trunk, hyperpigmented patches on the intergluteal cleft and subgluteal fold, and poikiloderma in the axillae; results of laboratory testing, including antinuclear antibody test, were unremarkable. What is the diagnosis and what would you do next?

Blood Pressure Fluctuation During 72 Hours After Endovascular Therapy and Prognosis in Acute Ischemic Stroke Patients.

PURPOSE: Our study aimed to investigate the relationship between fluctuations in different blood pressure (BP) components within 72 hours following endovascular therapy (EVT) and the prognosis of acute ischemic stroke (AIS) patients. METHODS: This prospective multicenter study included 283 AIS patients who underwent EVT and had available BP data. The primary outcome was the ordinal modified Rankin Scale (mRS) score evaluated at 90 days. The secondary outcome was a combination of death and major disability, defined as an mRS score of 3 to 6 within 3 months. RESULTS: After adjusting for imbalanced variables, the highest tertile of systolic blood pressure (SBP) fluctuation had an odds ratio (OR) of 1.747 (95% confidence interval [CI]=1.031-2.961; p for trend=0.035) for the primary outcome and 1.889 (95% CI=1.015-3.516; p for trend=0.039) for the secondary outcome, respectively. Fluctuations in diastolic blood pressure (DBP) (OR=1.914, 95% CI=1.134-3.230, p for trend=0.015) and mean arterial pressure (MAP) (OR=1.759, 95% CI=1.026-3.015, p for trend=0.039) were only associated with the primary outcome. The multivariate-adjusted restricted cubic spline analyses supported these findings. Furthermore, the fluctuations in both SBP and MAP exhibited the significant discriminatory capability in predicting the prognosis, comparable to their mean values. CONCLUSION: Our study revealed that larger fluctuations in SBP, DBP, and MAP within 72 hours after EVT were associated with a higher risk of poor clinical outcomes within 3 months in AIS patients. Controlling BP fluctuations may be valuable for improving the prognosis in patients undergoing EVT. CLINICAL IMPACT: How will this change clinical practice?It provides physicians a new approach to directly monitor BP fluctuations over an extended observation period in AIS patients after EVT in routine clinical practice.What does it mean for the clinicians?These results underscore the importance of giving equal attention to controlling long-term BP fluctuations, in addition to managing mean BP, as a means to improve the prognosis of AIS patients after EVT.What is the innovation behind the study?This study systematically evaluated the association between fluctuations in different blood pressure components and clinical outcomes in AIS patients over an extended period following EVT.

Association between IL-2 Receptor and Severe Coronary Artery Calcification in Patients with Coronary Artery Disease.

Background: Coronary artery calcification (CAC) is a crucial marker for coronary atherosclerosis, and the extent of CAC is closely linked to the incidence and progression of cardiovascular diseases. The interleukin-2 (IL-2) receptor (IL-2R), which plays a critical role in mediating the proliferation and differentiation of immune cells, may also be involved in the development of CAC. The study aimed to investigate the relationship between IL-2R and CAC, with the goal of providing new insights into cardiovascular diseases. Methods: In this study, we enrolled 606 patients diagnosed with coronary artery disease to assess CAC. Based on coronary artery calcification score (CACS), patients were divided into two groups: the non-severe CAC group (CACS ≤ 400 Agatston units, AU) and the severe CAC group (CACS > 400 AU). Results: The results showed that IL-2R levels were significantly higher in patients with severe CAC compared to those with non-severe CAC (383 vs. 352 pg/mL, p = 0.002). Moreover, the level of IL-2R was positively correlated with the severity of CAC, independent of other clinical risk factors. According to Receiver Operating Characteristic (ROC) curve, the IL-2R prediction model demonstrated a good capability in distinguishing severe CAC with the Area Under the Curve (AUC) value of 0.726. Conclusions: Our study suggests that IL-2R is independently associated with the occurrence of severe CAC in coronary artery disease (CAD) patients. Additionally, IL-2R may play a crucial role in the development of advanced atherosclerosis. Consequently, therapeutic strategies targeting the IL-2/IL-2R pathway may be effective in preventing or treating CAD.

Highly Efficient Laser Bidirectional Graphene Printing: Integration of Synthesis, Transfer and Patterning.

Graphene has tremendous potential in future electronics due to its superior force, electrical, and thermal properties. However, the development of graphene devices is limited by its complex, high-cost, and low-efficiency preparation process. This study proposes a novel laser bidirectional graphene printing (LBGP) process for the large-scale preparation of patterned graphene films. In LBGP, a sandwich sample composed of a thermoplastic elastomer (TPE) substrate, carbon precursor powder, and a glass cover is irradiated by a nanosecond pulsed laser. The laser photothermal effect converts the carbon precursor into graphene, with partial graphene sheets deposited directly on the TPE substrate and the remaining transferred to the glass cover via a laser-induced plasma plume. This method simultaneously prepares two face-to-face graphene films in a single laser irradiation, integrating synthesis, transfer, and patterning. The resulting graphene patterns demonstrate good performance in flexible pressure sensing and Joule heating, showcasing high sensitivity (7.7 kPa-1), fast response (37 ms), and good cycling stability (2000 cycles) for sensors, and high heating rate (1 °C s-1) and long-term stability (3000 s) for heaters. It is believed that the simple, low-cost, and efficient LBGP process can promote the development of graphene electronics and laser manufacturing processes.

Comparing Transbrachial and Transradial as Alternatives to Transfemoral Access for Large-Bore Neuro Stenting: Insights From a Propensity-Matched Study.

RATIONALE AND OBJECTIVES: This study aimed to evaluate the safety and effectiveness of transbrachial access (TBA) and transradial access (TRA) compared to transfemoral access (TFA) for large-bore neuro stenting (≥7 F). METHODS: From January 2019 to January 2024, 4752 patients received large-bore neuro stenting in our center. The primary outcomes were procedural metrics. Safety outcomes were significant access site complications, including substantial hematoma, pseudoaneurysm, artery occlusion, and complications requiring treatment (medicine, intervention, or surgery). After propensity score matching with a ratio of 1:1:2 (TBA: TRA: TFA), adjusting for age, gender, aortic arch type, and neuro stenting as covariates, outcomes were compared between groups. RESULTS: 46 TBA, 46 TRA and 92 TFA patients were enrolled. The mean age was 67.8 ± 11.2 years, comprising 127 (69.0%) carotid artery stenting and 57 (31.0%) vertebral artery stenting. The rates of technical success (TBA: 100%, TRA: 95.7%, TFA: 100%) and significant access site complications (TBA: 4.3%, TRA: 6.5%, TFA: 1.1%) were comparable between the groups (P > 0.05). Compared to TFA, the TRA cohort exhibited significant delays in angiosuite arrival to puncture time (14 vs. 8 min, P = 0.039), puncture to angiography completion time (19 vs. 11 min, P = 0.027), and procedural duration (42 vs. 29 min, P = 0.031). There were no substantial differences in procedural time metrics between TBA (10, 14, and 31 min, respectively) and TFA. CONCLUSION: TBA and TRA as the primary access for large-bore neuro stenting are safe and effective. Procedural delays in TRA may favor TBA as the first-line alternative access to TFA.

Plastic debris mediates bacterial community coalescence by breaking dispersal limitation in the sediments of a large river.

Plastic debris has recently been proposed as a novel habitat for bacterial colonization, which can raise perturbations in bacterial ecology after burial in riverine sediments. However, community coalescence, as a prevalent process involving the interrelationships of multiple communities and their surrounding environments, has been rarely discussed to reveal the impact of the plastisphere on sedimentary bacterial community. This study analyzed the bacterial community in plastic debris and sediment along the Nujiang River, elucidating the role of the plastisphere in mediating community coalescence in sediments. Our results demonstrated that the plastisphere and sedimentary bacterial communities exhibited distinct biogeography along the river (r = 0.694, p < 0.01). Based on overlapped taxa and SourceTracker, the extent of coalescence between adjacent communities was in following orders: plastic-plastic (0.589) > plastic-sediment (0.561) > sediment-sediment (0.496), indicating the plastisphere promoted bacterial community coalescence along the river. Flow velocity and geographic distance were the major factors driving the plastisphere changes, suggesting that the plastisphere were vulnerable to dispersal. The null model and the neutral model provided additional support for the higher immigration ability of the plastisphere to overcome dispersal limitation, highlighting the potential importance of the plastisphere in community coalescence. Network analysis indicated the critical role of keystone species (Proteobacteria, Bacteroidetes, and Gemmatimonadetes) in mediating the coalescence between sedimentary bacterial community and the plastisphere. In summary, the plastisphere could mediate the coalescence of bacterial communities by overcoming dispersal limitation, which provides new perspectives on the plastisphere altering bacterial ecology in riverine sediments.

Study on full-scale pores characterization and heterogeneity of coal based on low-temperature nitrogen adsorption and low-field nuclear magnetic resonance experiments.

The characteristics and heterogeneity of coal pores are crucial for understanding the production mechanism of coalbed methane (CBM). In this study, coal samples with varying degrees of metamorphism (0.58% ≤ RO, max ≤ 3.44%) were collected. The characteristics of pore development and the heterogeneous properties of pores were revealed through low-temperature nitrogen adsorption (LTNA) and low-field nuclear magnetic resonance (NMR) experiments. The results indicate that pores with varying diameters exhibit favorable development in low-rank coals, along with favorable pores connectivity. The micropores composition of middle-rank coals was found to be 73.56%, however, the connectivity among transitional, meso, and macropores was observed to be poor. In high-rank coals, the proportion of micropores was 92.74%, with numerous micropores being closed or semi-closed. This resulted in inferior connectivity between micropores and transitional pores. As coal metamorphism progressed, the DL1 (characterizing the roughness of adsorption pores (AP) surface, ranging from 2.13 to 2.45) and DL2 (characterizing the complexity of AP structure, ranging from 2.56 to 2.77) initially decreased and then increased, whereas the DN (characterizing the heterogeneity of seepage pores (SP), ranging from 2.92 to 2.95) consistently improved. Furthermore, the roughness of pore surface and the complexity of pore structure in AP increased as the specific surface area and volume of pores increased. On the contrary, as the SP content increased, the uniformity of the pore structure improved. When the volume of SP remained constant, the complexity of the pore structure decreased due to increased pore connectivity.

m6A-Mediated Induction of 7-Dehydrocholesterol Reductase Stimulates Cholesterol Synthesis and cAMP Signaling to Promote Bladder Cancer Metastasis.

Dysregulation of cholesterol homeostasis occurs in multiple types of tumors and promotes cancer progression. Investigating the specific processes that induce abnormal cholesterol metabolism could identify therapeutic targets to improve cancer treatment. In this investigation, we observed upregulation of 7-dehydrocholesterol reductase (DHCR7), a vital enzyme involved in the synthesis of cholesterol, within bladder cancer (BC) tissues in comparison to normal tissues, which was correlated with increased BC metastasis. Increased expression of DHCR7 in BC was attributed to decreased mRNA degradation mediated by YTHDF2. Loss or inhibition of DHCR7 reduced BC cell invasion in vitro and metastasis in vivo. Mechanistically, DHCR7 promoted BC metastasis by activating the cAMP/PKA/FAK pathway. Specifically, DHCR7 increased cAMP levels by elevating cholesterol content in lipid rafts, thereby facilitating the transduction of signaling pathways mediated by cAMP receptors. DHCR7 additionally enhanced the cAMP signaling pathway by reducing the concentration of 7-DHC and promoting the transcription of the G protein-coupled receptor GIPR. Overall, these findings demonstrate that DHCR7 plays an important role in BC invasion and metastasis by modulating cholesterol synthesis and cAMP signaling. Furthermore, inhibition of DHCR7 shows promise as a viable therapeutic strategy for suppressing BC invasion and metastasis.

Alkynyl nicotinamides show antileukemic activity in drug-resistant acute myeloid leukemia.

Activating mutations of FLT3 contribute to deregulated hematopoietic stem and progenitor cell (HSC/Ps) growth and survival in patients with acute myeloid leukemia (AML), leading to poor overall survival. AML patients treated with investigational drugs targeting mutant FLT3, including Quizartinib and Crenolanib, develop resistance to these drugs. Development of resistance is largely due to acquisition of cooccurring mutations and activation of additional survival pathways, as well as emergence of additional FLT3 mutations. Despite the high prevalence of FLT3 mutations and their clinical significance in AML, there are few targeted therapeutic options available. We have identified 2 novel nicotinamide-based FLT3 inhibitors (HSN608 and HSN748) that target FLT3 mutations at subnanomolar concentrations and are potently effective against drug-resistant secondary mutations of FLT3. These compounds show antileukemic activity against FLT3ITD in drug-resistant AML, relapsed/refractory AML, and in AML bearing a combination of epigenetic mutations of TET2 along with FLT3ITD. We demonstrate that HSN748 outperformed the FDA-approved FLT3 inhibitor Gilteritinib in terms of inhibitory activity against FLT3ITD in vivo.

Correction: Physical compatibility of Xuebijing injection with 53 intravenous drugs during simulated Y-site administration.

[This corrects the article DOI: 10.1371/journal.pone.0299694.].

Silencing of CircTRIM25/miR-138-5p/CREB1 axis promotes chondrogenesis in osteoarthritis.

BACKGROUND: Dysregulated circular RNAs (circRNAs) are involved in osteoarthritis (OA) progression. OBJECTIVE: We aimed to explore the effect of hsa_circ_0044719 (circTRIM25) on the ferroptosis of chondrocytes. METHODS: Chondrocytes were treated with interleukin (IL)-1ß to generate cell model. Cellular behaviours were measured using cell counting kit-8, enzyme-linked immunosorbent assay, relevant kits, propidium iodide staining, and immunofluorescence assay. Quantitative real-time polymerase chain reaction was performed to examine the expression of circTRIM25, miR-138-5p, and cAMP responsive element binding protein 1 (CREB1), and their interactions were assessed using luciferase reporter analysis and RNA pull-down assay. RESULTS: CircTRIM25 was upregulated in OA tissues and IL-1ß-stimulated chondrocytes. Knockdown of circTRIM25 facilitated the viability and suppressed ferroptosis and inflammation of IL-1ß-induced cells. CircTRIM25 served as a sponge of miR-138-5p, which directly targets CREB1. Downregulation of miR-138-5p abrogated the effect induced by knockdown of circTRIM25. Furthermore, enforced CREB1 reversed the miR-138-5p induced effect. Moreover, knockdown of circTRIM25 attenuated cartilage injury in vivo. CONCLUSION: Silencing of circTRIM25 inhibited ferroptosis of chondrocytes via the miR-138-5p/CREB axis and thus attenuated OA progression.