Isoglutaminyl Cyclase Overexpression Enhances KYSE30 Cancer Cell Proliferation and Migration via the MAPK Signaling Pathway.

To understand how upregulated isoglutaminyl cyclase (isoQC) is involved in the initiation of diseases such as cancer, we developed a human KYSE30 carcinoma cell model in which isoQC was stably overexpressed. GO and KEGG analysis of the DEGs (228) and DEPs (254) respectively implicated isoQC on the proliferation invasion and metastasis of cells and suggested that isoQC might participate in the regulation of MAPK, RAS, circadian rhythm, and related pathways. At the functional level, isoQC-overexpressing KYSE30 cells showed enhanced proliferation, migration, and invasion capacity. Next, we decided to study the precise effect of isoQC overexpression on JNK, p-JNK, AKT, p-AKT, ERK, p-ERK, and PER2, as RNA levels of these proteins are significantly correlated with signal levels indicated in RNA-Seq analysis, and these candidates are the top correlated DEPs enriched in RT-qPCR analysis. We saw that only p-ERK expression was inhibited, while PER2 was increased. These phenotypes were inhibited upon exposure to PER2 inhibitor KL044, which allowed for the restoration of p-ERK levels. These data support upregulated isoQC being able to promote cancer cell proliferation and migration in vitro, likely by helping to regulate the MAPK and RAS signaling pathways, and the circadian protein PER2 might be a potential mediator.

γ-MnO2 as an Electron Reservoir for RuO2 Oxygen Evolution Catalyst in Acidic Media.

Developing highly active and durable catalysts in acid conditions remains an urgent issue due to the sluggish kinetics of oxygen evolution reaction (OER). Although RuO2 has been a state-of-the-art commercial catalyst for OER, it encounters poor stability and high cost. In this study, the electronic reservoir regulation strategy is proposed to promote the performance of acidic water oxidation via constructing a RuO2/MnO2 heterostructure supported on carbon cloth (CC) (abbreviated as RuO2/MnO2/CC). Theoretical and experimental results reveal that MnO2 acts as an electron reservoir for RuO2. It facilitates electron transfer from RuO2, enhancing its activity prior to OER, and donates electrons to RuO2, improving its stability after OER. Consequently, RuO2/MnO2/CC exhibits better performance compared to commercial RuO2, with an ultrasmall overpotential of 189 mV at 10 mA cm-2 and no signs of deactivation even after 800 h of electrolysis in 0.5 m H2SO4 at 10 mA cm-2. When applied as the anode in a proton exchange membrane water electrolyzer, the cost-efficient RuO2/MnO2/CC catalyst only requires a cell voltage of 1.661 V to achieve the water-splitting current of 1 A cm-2, and the noble metal cost is as low as US$ 0.00962 cm-2, indicating potential for practical applications.

Significantly Enhanced Energy-Saving H2 Production Coupled with Urea Oxidation by Low- and Non-Pt Anchored on NiS-Based Conductive Nanofibers.

Rational designing electrocatalysts is of great significance for realizing high-efficiency H2 production in the water splitting process. Generally, reducing the usage of precious metals and developing low-potential nucleophiles oxidation reaction to replace anodic oxygen evolution reaction (OER) are efficient strategies to promote H2 generation. Here, NiS-coated nickel-carbon nanofibers (NiS@Ni-CNFs) are prepared for low-content Pt deposition (Pt-NiS@Ni-CNFs) to attain the alkaline HER catalyst. Due to the reconfiguration of NiS phase and synergistic effect between Pt and nickel sulfides, the Pt-NiS@Ni-CNFs catalyst shows a high mass activity of 2.74-fold of benchmark Pt/C sample. In addition, the NiS@Ni-CNFs catalyst performs a superior urea oxidation reaction (UOR) activity with the potential of 1.366 V versus reversible hydrogen electrode (RHE) at 10 mA cm-2 , which demonstrates the great potential in the replacement of OER. Thus, a urea-assisted water splitting electrolyzer of Pt-NiS@Ni-CNFs (cathode)||NiS@Ni-CNFs (anode) is constructed to exhibit small voltages of 1.44 and 1.65 V to reach 10 and 100 mA cm-2 , which is much lower than its overall water splitting process, and presents a 6.5-fold hydrogen production rate enhancement. This work offers great opportunity to design new catalysts toward urea-assisted water splitting with significantly promoted hydrogen productivity and reduced energy consumption.

Rationally Construction of Mn-Doped RuO2 Nanofibers for High-Activity and Stable Alkaline Ampere-Level Current Density Overall Water Splitting.

Nowadays, highly active and stable alkaline bifunctional electrocatalysts toward water electrolysis that can work at high current density (≥1000 mA cm-2) are urgently needed. Herein, Mn-doped RuO2 (MnxRu1-xO2) nanofibers (NFs) are constructed to achieve this object, presenting wonderful hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) performances with the overpotentials of only 269 and 461 mV at 1 A cm-2 in 1 m KOH solution, and remarkably stability under industrial demand with 1 A cm-2, significantly better than the benchmark Pt/C and commercial RuO2 electrocatalysts, respectively. More importantly, the assembled Mn0.05Ru0.95O2 NFs||Mn0.05Ru0.95O2 NFs electrolyzer toward overall water splitting reaches the current density of 10 mA cm-2 with a cell voltage of 1.52 V and also delivers an outstanding stability over 150 h of continuous operation, far surpassing commercial Pt/C||commercial RuO2, RuO2 NFs||RuO2 NFs and most previously reported exceptional electrolyzers. Theoretical calculations indicate that Mn-doping into RuO2 can significantly optimize the electronic structure and weaken the strength of O─H bond to achieve the near-zero hydrogen adsorption free energy (ΔGH*) value for HER, and can also effectively weaken the adsorption strength of intermediate O* at the relevant sites, achieving the higher OER catalytic activity, since the overlapping center of p-d orbitals is closer to the Fermi level.

Multi-omics panoramic analysis of HBV integration, transcriptional regulation, and epigenetic modifications in PLC/PRF/5 cell line.

The clearance or transcriptional silencing of integrated HBV DNA is crucial for achieving a functional cure in patients with chronic hepatitis B and reducing the risk of hepatocellular carcinoma development. The PLC/PRF/5 cell line is commonly used as an in vitro model for studying HBV integration. In this study, we employed a range of multi-omics techniques to gain a panoramic understanding of the characteristics of HBV integration in PLC/PRF/5 cells and to reveal the transcriptional regulatory mechanisms of integrated HBV DNA. Transcriptome long-read sequencing (ONT) was conducted to analyze and characterize the transcriptional activity of different HBV DNA integration sites in PLC/PRF/5 cells. Additionally, we collected data related to epigenetic regulation, including whole-genome bisulfite sequencing (WGBS), histone chromatin immunoprecipitation sequencing (ChIP-seq), and assays for transposase-accessible chromatin using sequencing (ATAC-seq), to explore the potential mechanisms involved in the transcriptional regulation of integrated HBV DNA. Long-read RNA sequencing analysis revealed significant transcriptional differences at various integration sites in the PLC/PRF/5 cell line, with higher HBV DNA transcription levels at integration sites on chr11, chr13, and the chr13/chr5 fusion chromosome t (13:5). Combining long-read DNA and RNA sequencing results, we found that transcription of integrated HBV DNA generally starts downstream of the SP1, SP2, or XP promoters. ATAC-seq data confirmed that chromatin accessibility has limited influence on the transcription of integrated HBV DNA in the PLC/PRF/5 cell line. Analysis of WGBS data showed that the methylation intensity of integrated HBV DNA was highly negatively correlated with its transcription level (r = -0.8929, p = 0.0123). After AzaD treatment, the transcription level of integrated HBV DNA significantly increased, especially for the integration chr17, which had the highest level of methylation. Through ChIP-seq data, we observed the association between histone modification of H3K4me3 and H3K9me3 with the transcription of integrated HBV DNA. Our findings suggest that the SP1, SP2 and XP in integrated HBV DNA, methylation level of surrounding host chromosome, and histone modifications affect the transcription of integrated HBV DNA in PLC/PRF/5 cells. This provides important clues for future studies on the expression and regulatory mechanisms of integrated HBV.

Symbiosis between Dendrobium catenatum protocorms and Serendipita indica involves the plant hypoxia response pathway.

Mycorrhizae are ubiquitous symbioses established between fungi and plant roots. Orchids, in particular, require compatible mycorrhizal fungi for seed germination and protocorm development. Unlike arbuscular mycorrhizal fungi, which have wide host ranges, orchid mycorrhizal fungi are often highly specific to their host orchids. However, the molecular mechanism of orchid mycorrhizal symbiosis is largely unknown compared to that of arbuscular mycorrhizal and rhizobial symbiosis. Here, we report that an endophytic Sebacinales fungus, Serendipita indica, promotes seed germination and the development of protocorms into plantlets in several epiphytic Epidendroideae orchid species (6 species in 2 genera), including Dendrobium catenatum, a critically endangered orchid with high medicinal value. Although plant-pathogen interaction and high meristematic activity can induce the hypoxic response in plants, it has been unclear whether interactions with beneficial fungi, especially mycorrhizal ones, also involve the hypoxic response. By studying the symbiotic relationship between D. catenatum and S. indica, we determined that hypoxia-responsive genes, such as those encoding alcohol dehydrogenase (ADH), are highly induced in symbiotic D. catenatum protocorms. In situ hybridization assay indicated that the ADH gene is predominantly expressed in the basal mycorrhizal region of symbiotic protocorms. Additionally, the ADH inhibitors puerarin and 4-methylpyrazole both decreased S. indica colonization in D. catenatum protocorms. Thus, our study reveals that S. indica is widely compatible with orchids and that ADH and its related hypoxia-responsive pathway are involved in establishing successful symbiotic relationships in germinating orchids.

Non-insulin-based insulin resistance indexes in predicting atrial fibrillation recurrence following ablation: a retrospective study.

BACKGROUND: Insulin resistance (IR) is involved in the pathophysiological processes of arrhythmias. Increasing evidence suggests triglyceride and glucose (TyG) index, metabolic score for insulin resistance (METS-IR), triglyceride glucose-body mass index (TyG-BMI), and triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio are simple and reliable surrogates for IR. Although they have been associated with atrial fibrillation (AF), evidence supporting this is limited. Here, this is the first study to investigate the association between TyG-BMI index and AF recurrence following radiofrequency catheter ablation (RFCA). The performance of the four non-insulin-based IR indexes in predicting AF recurrence after ablation was explored. METHODS: A total of 2242 AF patients who underwent a de novo RFCA between June 2018 to January 2022 at two hospitals in China were included in this retrospective study. The predictive values of IR indexes for AF recurrence after ablation were assessed. RESULTS: During 1-year follow-up, 31.7% of patients experienced AF recurrence. The multivariable analysis revealed that TyG index, METS-IR, and TyG-BMI index were independent risk factors for AF recurrence. Restricted cubic spline analysis revealed a connection between METS-IR, TyG-BMI index, and AF recurrence (P < 0.001). Furthermore, incorporating the METS-IR or TyG-BMI index to the basic risk model with fully adjusted factors considerably enhanced the forecast of AF recurrence, as demonstrated by the C-statistic, continuous net reclassification improvement, and integrated discrimination improvement. CONCLUSIONS: TyG index, METS-IR, and TyG-BMI index were independently associated with AF recurrence following ablation. Among the four non-insulin-based IR indexes, TyG-BMI had the highest predictive value, followed by METS-IR.

Dual-targeted delivery of temozolomide by multi-responsive nanoplatform via tumor microenvironment modulation for overcoming drug resistance to treat glioblastoma.

Glioblastoma (GBM) is the most aggressive primary brain tumor with low survival rate. Currently, temozolomide (TMZ) is the first-line drug for GBM treatment of which efficacy is unfortunately hindered by short circulation time and drug resistance associated to hypoxia and redox tumor microenvironment. Herein, a dual-targeted and multi-responsive nanoplatform is developed by loading TMZ in hollow manganese dioxide nanoparticles functionalized by polydopamine and targeting ligands RAP12 for photothermal and receptor-mediated dual-targeted delivery, respectively. After accumulated in GBM tumor site, the nanoplatform could respond to tumor microenvironment and simultaneously release manganese ion (Mn2+), oxygen (O2) and TMZ. The hypoxia alleviation via O2 production, the redox balance disruption via glutathione consumption and the reactive oxygen species generation, together would down-regulate the expression of O6-methylguanine-DNA methyltransferase under TMZ medication, which is considered as the key to drug resistance. These strategies could synergistically alleviate hypoxia microenvironment and overcome TMZ resistance, further enhancing the anti-tumor effect of chemotherapy/chemodynamic therapy against GBM. Additionally, the released Mn2+ could also be utilized as a magnetic resonance imaging contrast agent for monitoring treatment efficiency. Our study demonstrated that this nanoplatform provides an alternative approach to the challenges including low delivery efficiency and drug resistance of chemotherapeutics, which eventually appears to be a potential avenue in GBM treatment.

Comparative study of two different access points, one tibial vein and the popliteal vein, for catheter-directed thrombolysis in the treatment of acute mixed lower extremity deep vein thrombosis 1.

BACKGROUND: Although the popliteal vein approach is commonly used for catheter-directed thrombolysis (CDT) treatment in patients with acute lower extremity deep vein thrombosis (DVT), CDT via a new access route, the posterior tibial vein, is also used and has demonstrated good results. However, this tibial approach has not been tested in large samples. OBJECTIVE: To compare the early efficacy of CDT using the tibial and popliteal vein approaches for the treatment of acute mixed lower extremity DVT. METHODS: In this retrospective cohort study, 87 patients with acute mixed lower extremity DVT treated at the Department of Interventional Medicine of Zhuhai People's Hospital were enrolled; those with tibial vein access and popliteal vein access were included in the observation (n = 55) and control (n = 32) groups, respectively. The safety and efficacy of CDT via tibial vein access were investigated by collecting and comparing indicators such as venous patency, thrombus removal effect, thigh and calf circumference difference, swelling reduction rate of the affected limb, surgical complications, and post-discharge complication rate of the patients in the two groups. RESULTS: The postoperative thrombus clearance effect of the observation group was significantly better than that of the control group (P < 0.05), and the postoperative venous patency rate of the observation group was 83.2 ± 15.7%, which was higher than that of the control group (62.2 ± 38.2%) (P = 0.005). The swelling reduction rate of the lower extremity was 74.0 ± 33.8% in the observation group and 51.4 ± 30.0% in the control group, with a statistically significant difference (P = 0.002). However, there was no statistically significant difference (P > 0.05) in the rates of thigh swelling reduction, bleeding-related complications, or postoperative complications between the two groups of patients. CONCLUSIONS: CDT via the tibial vein approach is safe, effective, and may be a better approach for CDT access, offering superior thrombus clearance, venous patency, and lower extremity swelling reduction postoperatively.

Grouped-seq for integrated phenotypic and transcriptomic screening of patient-derived tumor organoids.

Patient-derived tumor organoids (PDOs) have emerged as a reliable in vitro model for drug discovery. However, RNA sequencing-based analysis of PDOs treated with drugs has not been realized in a high-throughput format due to the limited quantity of organoids. Here, we translated a newly developed pooled RNA-seq methodology onto a superhydrophobic microwell array chip to realize an assay of genome-wide RNA output unified with phenotypic data (Grouped-seq). Over 10-fold reduction of sample and reagent consumption together with a new ligation-based barcode synthesis method lowers the cost to ∼$2 per RNA-seq sample. Patient-derived colorectal cancer (CRC) organoids with a number of 10 organoids per microwell were treated with four anti-CRC drugs across eight doses and analyzed by the Grouped-seq. Using a phenotype-assisted pathway enrichment analysis (PAPEA) method, the mechanism of actions of the drugs were correctly derived, illustrating the great potential of Grouped-seq for pharmacological screening with tumor organoids.

When selection pays: Structured public goods game with a generalized interaction mode.

The public goods game is a broadly used paradigm for studying the evolution of cooperation in structured populations. According to the basic assumption, the interaction graph determines the connections of a player where the focal actor forms a common venture with the nearest neighbors. In reality, however, not all of our partners are involved in every game. To elaborate this observation, we propose a model where individuals choose just some selected neighbors from the complete set to form a group for public goods. We explore the potential consequences by using a pair-approximation approach in a weak selection limit. We theoretically analyze how the number of total neighbors and the actual size of the restricted group influence the critical enhancement factor where cooperation becomes dominant over defection. Furthermore, we systematically compare our model with the traditional setup and show that the critical enhancement factor is lower than in the case when all players are present in the social dilemma. Hence, the suggested restricted interaction mode offers a better condition for the evolution of cooperation. Our theoretical findings are supported by numerical calculations.

Distributed Nash equilibrium seeking in noncooperative game with partial decision information of neighbors.

In the real world, individuals may conceal some of their real decision information to their neighbors due to competition. It is a challenge to explore the distributed Nash equilibrium when individuals play the noncooperative game with partial decision information in complex networks. In this paper, we investigate the distributed Nash equilibrium seeking problem with partial decision information of neighbors. Specifically, we construct a two-layer network model, where players in the first layer engage in game interactions and players in the second layer exchange estimations of real actions with each other. We also consider the case where the actions of some players remain unchanged due to the cost of updating or personal reluctance. By means of the Lyapunov function method and LaSalle's invariance principle, we obtain the sufficient conditions in which the consensus of individual actions and estimations can be achieved and the population actions can converge to the Nash equilibrium point. Furthermore, we investigate the case with switched topologies and derive the sufficient conditions for the convergence of individual actions to Nash equilibrium by the average dwell time method. Finally, we give numerical examples for cases of fixed and switched topologies to verify our theoretical results.

Synergetic Conformational Regulations in Ground and Excited States for Realizing Stimulus-Responsive and Wide-Tuning Room-Temperature Phosphorescence.

Understanding the changes of molecular conformations is crucial for realizing multiple emissive triplet states in room-temperature phosphorescence (RTP) materials. In this work, we report two molecules, 4,4'-dimethylbenzil (DMBZ) and 4,4'-di-tert-butylbenzil (DBBZ) with conformation-dependent luminescence, and demonstrate that stimulus-responsive and wide-tuning RTP emissions can be realized via synergetic conformational regulations in ground and excited states. Due to conformational changes, DMBZ and DBBZ show abundant RTP variations upon external stimuli, including light, force, heat, and fumigation. Notably, DBBZ exhibits multiple conformational changes in both ground and excited states, which endow DBBZ with multiple emissive states and unique stimulus-responsive behaviors. DBBZ presents multiple phase transitions between the supercooled liquid state and different solid states accompanied by different phosphorescence transitions, in which the excited-state conformations are effectively regulated. Moreover, wide-range RTP regulations (between cyan, green, and yellow) are realized in both single component and host-guest systems of DBBZ, showing potential applications in temperature sensing, multicolor dynamic displays, and information encryption. These results may provide new visions for understanding the complicated conformational changes in the aggregated state, as well as unique insights into the relationship between molecular conformations, RTP emissions, and stimulus responsiveness.

Comparative genomics of the medicinal plants Lonicera macranthoides and L. japonica provides insight into genus genome evolution and hederagenin-based saponin biosynthesis.

Lonicera macranthoides (LM) and L. japonica (LJ) are medicinal plants widely used in treating viral diseases, such as COVID-19. Although the two species are morphologically similar, their secondary metabolite profiles are significantly different. Here, metabolomics analysis showed that LM contained ~86.01 mg/g hederagenin-based saponins, 2000-fold higher than LJ. To gain molecular insights into its secondary metabolite production, a chromosome-level genome of LM was constructed, comprising 9 pseudo-chromosomes with 40 097 protein-encoding genes. Genome evolution analysis showed that LM and LJ were diverged 1.30-2.27 million years ago (MYA). The two plant species experienced a common whole-genome duplication event that occurred ∼53.9-55.2 MYA before speciation. Genes involved in hederagenin-based saponin biosynthesis were arranged in clusters on the chromosomes of LM and they were more highly expressed in LM than in LJ. Among them, oleanolic acid synthase (OAS) and UDP-glycosyltransferase 73 (UGT73) families were much more highly expressed in LM than in LJ. Specifically, LmOAS1 was identified to effectively catalyse the C-28 oxidation of ß-Amyrin to form oleanolic acid, the precursor of hederagenin-based saponin. LmUGT73P1 was identified to catalyse cauloside A to produce α-hederin. We further identified the key amino acid residues of LmOAS1 and LmUGT73P1 for their enzymatic activities. Additionally, comparing with collinear genes in LJ, LmOAS1 and LmUGT73P1 had an interesting phenomenon of 'neighbourhood replication' in LM genome. Collectively, the genomic resource and candidate genes reported here set the foundation to fully reveal the genome evolution of the Lonicera genus and hederagenin-based saponin biosynthetic pathway.

Predictive performance of triglyceride glucose index (TyG index) to identify glucose status conversion: a 5-year longitudinal cohort study in Chinese pre-diabetes people.

OBJECTIVE: Triglyceride glucose index (TyG index) has been recommended as an alternative indicator of insulin resistance. However, the association between TyG and regression from prediabetes to normoglycemia remains to be elucidated. METHODS: This retrospective cohort study involved 25,248 subjects with prediabetes at baseline conducted from 2010 to 2016. A Cox proportional hazard regression model was designed to evaluate the role of TyG in identifying people at converting from prediabetes to normoglycemia. Cox proportional hazards regression with cubic spline functions and smooth curve fitting was used to dig out the nonlinear relationship between them. Detailed evaluations for TyG were also performed using sensitivity and subgroup analyse. RESULTS: Among the included prediabetes subjects (n = 25,248), the mean age was 49.27 ± 13.84 years old, and 16,701 (66.15%) were male. The mean TyG was 8.83 ± 0.60. The median follow-up time was 2.96 ± 0.90 years. 11,499 (45.54%) individuals had a final diagnosis of normoglycemia. After adjusting for covariates, TyG was negatively affecting the results of glucose status conversion in prediabetes people (HR 0.895, 95% CI 0.863, 0.928). There was a nonlinear connection between TyG and normoglycemia in prediabetes people, and the inflection point was 8.88. The effect sizes (HR) on the left and right sides of the inflection point were 0.99 (0.93, 1.05) and 0.79 (0.74, 0.85), respectively. Sensitivity analysis confirmed the robustness of these results. Subgroup analysis showed that TyG was more strongly associated with incident glucose status conversion in male, BMI ≥ 25. In contrast, there was a weaker relationship in those with female, BMI < 25. CONCLUSION: Based on sample of subjects evaluated between 2010 and 2016, TyG index appears to be a promising marker for predicting normoglycemic conversion among prediabetes people in China. This study demonstrates a negative and non-linear association between TyG and glucose status conversion from prediabetes to normoglycemia. TyG is strongly related to glucose status conversion when TyG is above 8.88. From a therapeutic point of view, it is meaningful to maintain TyG levels within the inflection point to 8.88.

Dysregulated Rbfox2 produces aberrant splicing of CaV1.2 calcium channel in diabetes-induced cardiac hypertrophy.

BACKGROUND: L-type Ca2+ channel CaV1.2 is essential for cardiomyocyte excitation, contraction and gene transcription in the heart, and abnormal functions of cardiac CaV1.2 channels are presented in diabetic cardiomyopathy. However, the underlying mechanisms are largely unclear. The functions of CaV1.2 channels are subtly modulated by splicing factor-mediated alternative splicing (AS), but whether and how CaV1.2 channels are alternatively spliced in diabetic heart remains unknown. METHODS: Diabetic rat models were established by using high-fat diet in combination with low dose streptozotocin. Cardiac function and morphology were assessed by echocardiography and HE staining, respectively. Isolated neonatal rat ventricular myocytes (NRVMs) were used as a cell-based model. Cardiac CaV1.2 channel functions were measured by whole-cell patch clamp, and intracellular Ca2+ concentration was monitored by using Fluo-4 AM. RESULTS: We find that diabetic rats develop diastolic dysfunction and cardiac hypertrophy accompanied by an increased CaV1.2 channel with alternative exon 9* (CaV1.2E9*), but unchanged that with alternative exon 8/8a or exon 33. The splicing factor Rbfox2 expression is also increased in diabetic heart, presumably because of dominate-negative (DN) isoform. Unexpectedly, high glucose cannot induce the aberrant expressions of CaV1.2 exon 9* and Rbfox2. But glycated serum (GS), the mimic of advanced glycation end-products (AGEs), upregulates CaV1.2E9* channels proportion and downregulates Rbfox2 expression in NRVMs. By whole-cell patch clamp, we find GS application hyperpolarizes the current-voltage curve and window currents of cardiac CaV1.2 channels. Moreover, GS treatment raises K+-triggered intracellular Ca2+ concentration ([Ca2+]i), enlarges cell surface area of NRVMs and induces hypertrophic genes transcription. Consistently, siRNA-mediated knockdown of Rbfox2 in NRVMs upregulates CaV1.2E9* channel, shifts CaV1.2 window currents to hyperpolarization, increases [Ca2+]i and induces cardiomyocyte hypertrophy. CONCLUSIONS: AGEs, not glucose, dysregulates Rbfox2 which thereby increases CaV1.2E9* channels and hyperpolarizes channel window currents. These make the channels open at greater negative potentials and lead to increased [Ca2+]i in cardiomyocytes, and finally induce cardiomyocyte hypertrophy in diabetes. Our work elucidates the underlying mechanisms for CaV1.2 channel regulation in diabetic heart, and targeting Rbfox2 to reset the aberrantly spliced CaV1.2 channel might be a promising therapeutic approach in diabetes-induced cardiac hypertrophy.

Efficacy and safety of rivaroxaban for the treatment of PICC-related upper extremity deep vein thrombosis in cancer patients: a retrospective study.

BACKGROUND: The optimal duration and choice of anticoagulant for the treatment of Peripherally inserted central catheters (PICC)-related upper extremity deep vein thrombosis (UEDVT) in cancer patients are still undetermined. OBJECTIVES: The aim of this study was to assess the efficacy and safety of rivaroxaban for the treatment of PICC-related UEDVT in cancer patients. METHODS: We conducted a retrospective cohort study including consecutive cancer patients for the management of acute symptomatic PICC-related UEDVT. The efficacy outcome of the study was the 180-day recurrence of any venous thromboembolism (VTE), while the safety outcome was the 180-day incidence of all bleeding events. The Kaplan‒Meier method was used to estimate the overall incidence. Hazard ratios (HRs) were obtained with a Cox proportional hazards model to estimate the risk of the outcome events. RESULTS: A total of 217 patients were included in the final analysis with a median age of 56 years old, 41.5% of whom had metastases. After the initial 3-5 days of nadroparin, patients received sequential anticoagulation, either with nadroparin (118 patients) or with rivaroxaban (99 patients). Four patients with recurrent VTE were observed (nadroparin, n = 2; rivaroxaban, n = 2). The 180-day cumulative VTE recurrence rates were 1.7% and 2.0% (p = 0.777) in patients receiving nadroparin and rivaroxaban, respectively. The overall bleeding rate at 180 days was 8.8%. Although no major bleeding events were observed, nineteen patients with clinically relevant nonmajor bleeding (CRNMB) were observed. The 180-day cumulative rate of CRNMB was 5.1% for nadroparin and 13.1% for rivaroxaban (HR = 3.303, 95% CI 1.149-9.497, p = 0.027). CONCLUSION: Our study supported the efficacy of rivaroxaban for treating PICC-related UEDVT in cancer patients. However, data on anticoagulation therapy for PICC-related UEDVT presented with a low risk of VTE recurrence and a relatively high risk of CRNMB bleeding events. Considering the risk-benefit ratio, further well-designed trials are required to optimize the drug selection and duration for the treatment of PICC-related UEDVT in cancer patients.

Impact of carotid atherosclerosis on arrhythmia recurrence following atrial fibrillation catheter ablation.

BACKGROUND: It remains unclear whether carotid atherosclerosis (CAS) increases the atrial fibrillation (AF) recurrence rate after ablation. The aim was to assess the association between CAS, defined as carotid intima-media thickness (CIMT) ≥1 mm and or presence of carotid plaques, and AF recurrence rate after ablation. METHODS: We retrospectively collected patients who underwent carotid ultrasonography and AF ablation at the First Affiliated Hospital of Zhengzhou University. The AF recurrence was defined as documented atrial arrhythmias over 30 s on ECG or 24-h Holter monitoring after the first three months blanking period. Cox regression models were used to analyze the risk of AF recurrence. RESULTS: Overall, 385 patients were analyzed (mean age, 60.58±10.98 years old; female, 41.30%; persistent AF, 47.27%). After a follow-up of 1 year, 138 (35.84%) patients experienced recurrence, Kaplan-Meier analysis showed that patients with the presence of carotid plaques, CIMT ≥1 mm, and CAS had a higher risk of recurrence compared with the absence (all log-rank p < .05). In multivariate Cox regression analysis, CAS (HR 2.159, ±95% CI 1.320-3.532, p = .002), carotid plaque (HR 1.815, ±95%CI 1.160-2.841, p = .009), and CIMT ≥1 mm (HR 1.696, ±95%CI 1.192-2.413, p = .003) were independently associated with a higher risk of recurrence. In subgroup analysis, the association of CAS, carotid plaque, and AF recurrence rate was weaker in men than women. CONCLUSION: Carotid atherosclerosis, CIMT ≥1 mm, and carotid plaque were significantly associated with a higher AF recurrence rate after radiofrequency catheter ablation. They were all risk factors for the recurrence of AF.

A PK/PD model for the evaluation of clinical rifaximin dosage for the treatment of dairy cow mastitis induced by Escherichia coli.

Escherichia coli (E. coli) is an opportunistic pathogen that can cause clinical mastitis in dairy cows worldwide. Mastitis produces severe symptoms in dairy cows, such as udder inflammation, the production of harmful substances, reduced milk production, and altered milk quality. Intramammary injections of rifaximin have a beneficial effect on dairy cow mastitis, especially for mastitis caused by E. coli. However, we do not know whether the currently accepted clinical administration scheme is reasonable. Therefore, the purpose of this experiment was to evaluate the clinical dosing regimen for curing mastitis induced by E. coli. In this study, the pharmacokinetics of four single dose groups (50, 100, 200, and 400 µg/gland) were studied in CD-1 lactating mice, and the main pharmacokinetic parameters were obtained by non-compartment and two-compartment model of Phoenix 8.1 software. A total of 5,000 colony-forming units (CFU) of E. coli ATCC25922 were injected into the mammary glands of mice under anatomic microscope guidance. After 12 h of growth in vivo, the mouse mastitis model was successfully developed. In pharmacodynamics experiment, 12 different dosing regimens (doses ranged from 25 to 800 µg/gland and two dosing intervals of 12 and 24 h) were used to study the therapeutic potential of rifaximin for mastitis. The PK/PD model was established by integrating pharmacokinetics and pharmacodynamics using the inhibitory sigmoid Emax model. The optimal antibacterial effect was 2log10CFU/gland reduction of bacterial colony counts in vivo, when the magnitude of AUC24/MIC exceeded 57.80 h. A total of 57.80 h of AUC24/MIC was defined as a target value in the Monte Carlo simulation. The clinically recommended dosage regimen of 100 mg/gland every 12 h in a day achieved a 91.08% cure rate for the treatment of bovine mastitis caused by E. coli infection.

Advances in targeted therapy for pulmonary arterial hypertension in children.

Pulmonary arterial hypertension (PAH) is a rare and devastating disease of the pulmonary vasculature with a high morbidity and mortality rate in infants and children. Currently, treatment approaches are mostly based on adult guidelines and pediatrician clinical experience, focusing on specific pulmonary antihypertensive therapy and conventional supportive care. The advent of targeted drugs has led to significant advances in the treatment of PAH in children, including endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclins, which have been studied and proven to improve hemodynamics and functional class in children PAH. A new targeted drug, riociguat, is assessing its safety and efficacy in clinical trials. However, more randomized controlled studies are needed to evaluate the combination of drugs, treatment strategies, and clinical endpoints of targeted therapy in children PAH. In this review, we summarize the research advances of PAH-targeted therapy in children over the last decade in order to provide a theoretical basis for future studies. CONCLUSION: Pulmonary arterial hypertension (PAH) is a rare and devastating pulmonary vascular disease that is associated with a variety of diseases of any age in childhood onset. WHAT IS KNOWN: • Therapeutic strategies for targeted drugs for PAH in children are based almost exclusively on data from adult studies and clinical experience of pediatric specialists. • Due to the complex etiology of PAH in children and the relative lack of clinical trial data, the selection of appropriate targeted drug therapy remains difficult. WHAT IS NEW: • We redefine the definition of pulmonary arterial hypertension in children and summarize the progress of targeted therapy of pulmonary arterial hypertension in children in the past ten years. • The dosage and adverse reactions were summarized, and the mechanism of action was drawn according to the available targeted drugs. It can provide theoretical support for the development of guidelines and treatment strategies for the diagnosis and treatment of pulmonary arterial hypertension in children.