DNA Framework-Enabled 3D Organization of Antiarrhythmic Drugs for Radiofrequency Catheter Ablation.

Preorganizing molecular drugs within a microenvironment is crucial for the development of efficient and controllable therapeutic systems. Here, the use of tetrahedral DNA framework (TDF) is reported to preorganize antiarrhythmic drugs (herein doxorubicin, Dox) in 3D for catheter ablation, a minimally invasive treatment for fast heartbeats, aiming to address potential complications linked to collateral tissue damage and the post-ablation atrial fibrillation (AF) recurrence resulting from incomplete ablation. Dox preorganization within TDF transforms its random distribution into a confined, regular spatial arrangement governed by DNA. This, combined with the high affinity between Dox and DNA, significantly increases local Dox concentration. The exceptional capacity of TDF for cellular internalization leads to a 5.5-fold increase in intracellular Dox amount within cardiomyocytes, effectively promoting cellular apoptosis. In vivo investigations demonstrate that administering TDF-Dox reduces the recurrence rate of electrical conduction after radiofrequency catheter ablation (RFCA) to 37.5%, compared with the 77.8% recurrence rate in the free Dox-treated group. Notably, the employed Dox dosage exhibits negligible adverse effects in vivo. This study presents a promising treatment paradigm that strengthens the efficacy of catheter ablation and opens a new avenue for reconciling the paradox of ablation efficacy and collateral damage.

Numerical Investigation on Precipitation Hardening of Mg-Gd Alloys.

The second-phase particles in magnesium alloys could affect the mechanical properties of the material significantly. In this work, 3D finite element models with explicit incorporation of second-phase particles are established. The simulations are calibrated with the experimental results of the Mg-1Gd alloy. The influences of factors, such as the particle distribution, size, and orientation of cylindrical particles, on precipitation hardening are investigated in detail. Three interface conditions between particles and the matrix-perfect bonding and high- and low-strength bonding-are studied at the same time. The interface conditions are shown to exert a stronger influence on precipitation hardening compared to the factors of particle distribution and size. In contrast, the influence of the orientation of cylindrical particles at grain boundaries outweighs the effect of interface property. When second-phase particles are relatively large and all located at grain boundaries, the hardening effect can be improved, and the magnesium alloy shows relatively high flow stress. However, the high hardening effect from the second-phase particles could result in high local stress concentration and possible early failure or low ductility of Mg alloys.

The serum soluble scavenger with 5 domains levels: A novel biomarker for individuals with heart failure.

Background: We aimed to explore the relationship between the serum Soluble Scavenger with 5 Domains (SSC5D) levels and heart failure (HF). Methods and Results: We retrospectively enrolled 276 patients diagnosed with HF or normal during hospitalization in Shanghai General Hospital between September 2020 and December 2021. Previously published RNA sequencing data were re-analyzed to confirm the expression profile of SSC5D in failing and non-failing human and mouse heart tissues. Quantitative real-time polymerase chain reaction assay was used to quantify Ssc5d mRNA levels in murine heart tissue after myocardial infarction and transverse aortic constriction surgery. To understand the HF-induced secreted proteins profile, 1,755 secreted proteins were investigated using human dilated cardiomyopathy RNA-seq data, and the results indicated that SSC5D levels were significantly elevated in failing hearts compared to the non-failing. Using single-cell RNA sequencing data, we demonstrated that Ssc5d is predominantly expressed in cardiac fibroblasts. In a murine model of myocardial infarction or transverse aortic constriction, Ssc5d mRNA levels were markedly increased compared with those in the sham group. Similarly, serum SSC5D levels were considerably elevated in the HF group compared with the control group [15,789.35 (10,745.32-23,110.65) pg/mL, 95% CI (16,263.01-19,655.43) vs. 8,938.72 (6,154.97-12,778.81) pg/mL, 95% CI (9,337.50-11,142.93); p < 0.0001]. Moreover, serum SSC5D levels were positively correlated with N-terminal pro-B-type natriuretic peptide (R = 0.4, p = 7.9e-12) and inversely correlated with left ventricular ejection fraction (R = -0.46, p = 9.8e-16). Conclusion: We concluded that SSC5D was a specific response to HF. Serum SSC5D may function as a novel biomarker and therapeutic target for patients with HF.

Canine model of electrical conduction recurrence after radiofrequency catheter ablation constructed by CARTO3 and preliminary application evaluation of DOX-L.

BACKGROUND: Radiofrequency catheter ablation (RFCA) is widely used to treat arrhythmias. However, for atrial fibrillation, the recurrence rate after RFCA is still high. The development of an animal model that mimics the recurrence of electrical conduction after ablation is essential before we can explore the mechanisms involved or develop new therapeutic strategies. METHODS: Eighteen beagles aged 12 to 24 months were randomly assigned to this study. RFCA ablation of the right atrial free wall was performed. Then, electrical block and conduction recovery in the ablation area were evaluated using voltage mapping and pacing tests assisted by CARTO3 system. Finally, liposome doxorubicin (DOX-L) was intravenously injected after ablation to investigate the effect of DOX-L on this animal model. RESULTS: The conduction block (CB) rates at 5 min after ablation were 16.7%, 83.3%, and 100%, corresponding to 30w, 35w, and 40w power, respectively. However, after 20 min, the rate of CB was 0%, 33.3%, and 75%; thus, the combined success rate of CB and conduction recurrence was 16.7%, 50%, and 25%, respectively. The optimal ablation parameter is 35 W for 20 s, based on the CB rate, REC rate. After 10 days of ablation, the residual conduction recurrence rate was as high as 83.3% in the RFCA alone group, whereas there was no recurrence with RFCA combined with DOX-L treatment. CONCLUSIONS: The novel model accurately simulated the electrical conduction recurrence after cardiac radiofrequency ablation. RFCA combined with DOX-L treatment dramatically reduces the recurrence rate of electrical conduction after ablation.

Hypoxic Cell-Derived Extracellular Vesicles Aggravate Rectal Injury Following Radiotherapy via MiR-122-5p.

Radiation-induced rectal injury is a common side effect of radiotherapy. Hypoxia often occurs after radiotherapy. This study aimed to explore the bystander effect of hypoxia on radiation-induced rectal injury. In vivo, apoptosis increased nearby the highly hypoxic area in the rectal tissues in the mouse models of radiation-induced rectal injury, indicating the potential involvement of hypoxia. In vitro, flow cytometry and Western blotting showed that both hypoxia and hypoxic human intestinal epithelial crypt (HIEC) cell supernatant promoted apoptosis in normoxic HIEC cells. The pro-apoptotic effect of extracellular vesicles (EVs) derived from hypoxic HIEC cell to normoxic HIEC cells was then determined. MiR-122-5p was chosen for further studies through a microRNA (miRNA) microarray assay and apoptosis was alleviated in cells receiving miR-122-5p inhibiting hypoxic EVs. Together, our study demonstrated that the miR-122-5p containing-EVs derived from hypoxic HIEC cells promoted apoptosis in normoxic HIEC cells. Hypoxic EV-derived miR-122-5p plays a critical pathologic role in radiation-induced rectal injury and may be a potential therapeutic target.

High Proteoglycan Decorin Levels Are Associated With Acute Coronary Syndrome and Provoke an Imbalanced Inflammatory Response.

Background and Aims: Acute coronary syndrome (ACS) has become one of the most common causes of disability. It is thus important to identify ACS early in the disease course of patients using novel biomarkers for prompt management. Decorin (DCN) was well-acknowledged for its effect on collagen fibrillogenesis and maintaining tissue integrity. Additionally, DCN could release as secreted proteoglycan under pathological conditions. Hence, we aimed to determine the relationship between serum DCN concentration and ACS. Methods: A total of 388 patients who underwent coronary angiography (CAG) in the cardiovascular center of Ruijin Hospital between June 2016 and December 2017 were enrolled in this study. Blood samples were drawn during CAG surgery to determine the serum DCN level of patients with ACS (n = 210) and control subjects (n = 178) using enzyme-linked immunosorbent assay. Results: We found that the serum DCN levels of ACS patients were elevated compared with those of the control subjects (13.59 ± 0.50 vs. 13.17 ± 0.38, respectively, p < 0.001). Furthermore, the serum DCN level, after being adjusted with other cardiovascular factors, was independently associated with ACS. Moreover, an increased serum DCN level was positively correlated with the number of white blood cells and the level of high-sensitivity C-reactive protein (R = 0.3 and 0.11, respectively). Mechanistically, DCN might have elicited an imbalanced inflammatory response during cardiac ischemia by suppressing the expression of anti-inflammatory genes. Conclusion: Serum DCN is a novel biomarker of ACS and contributes to the increased inflammatory response in ischemic heart disease.

An Investigation of Precise Orbit and Clock Products for BDS-3 from Different Analysis Centers.

A quality evaluation of precise products for BDS-3 constellations is presented for the first time in this contribution. Then, the tropospheric delay retrieval and positioning performance of BDS-3 precise point positioning (PPP) solutions using the precise products (gbm, wum, iac, sha, cnt) with observations from 24 stations from DOY 280 to 317 in 2020 was comprehensively investigated. The orbit comparisons present consistencies of 0.09-0.22 m for the C19-C37 satellites and of 0.5-1.2 m for the C38-C46 satellites among the final products. The standard deviation (STD) values of the clock differences of iac showed the best agreement with those of gbm, followed by wum, sha. The clock differences performance of cnt was the worst. For BDS-3 PPP solutions with five Analysis centers (ACs) products, the median convergence times of static PPP mode incorporating the gbm, wum, iac, sha, and cnt products were 31.0, 33.5, 34.5, 37.8, and 72.0 min, respectively; the median convergence times of kinematic PPP model incorporating the same products were 40.5, 41.0, 50.5, 55.0, and 94.0 min, respectively. The positioning accuracies in the static and kinematic modes were approximately 1-4 cm, 2-6 cm in the horizontal and vertical components, respectively. With the final products in kinematic mode, the performance of PPP with real-time products (cnt) is poorer than all PPP with final products. The median of ZTD accuracies of the five products gbm, wum, iac, sha, and cnt were 7.84, 7.58, 7.04, 7.19, and 10.1 mm, respectively, and the accuracy differences were very small among five AC products (gbm, wum, iac, sha).

Nrf2 alleviates radiation-induced rectal injury by inhibiting of necroptosis.

Radiation-induced rectal injury is one of the common side effects of pelvic radiation therapy. This study aimed to explore the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in this process. In vivo, knockout (KO) of Nrf2 led to aggravated radiation-induced histological changes in the rectums. In vitro, interference or overexpression of Nrf2 resulted in enhanced or reduced radiosensitivity in human intestinal epithelial crypts (HIEC) cells, respectively. A potential relationship between Nrf2 and necroptosis was identified using RNA sequencing (RNA-seq) and western blotting (WB), which showed that necroptosis-related proteins were negatively correlated with Nrf2. Upon treatment with necrostatin-1 (Nec-1), the increased radiosensitivity, decreased cell viability, increased γH2AX foci formation, and decreased mitochondrial membrane potential (MMP) in Nrf2-interfered HIEC cells were alleviated. A significant recovery in morphological alterations was also observed in Nrf2 KO mice administered with Nec-1. Taken together, our results highlight the important protective effect of Nrf2 in radiation-induced rectal injury through the inhibition of necroptosis, and the physiological significance of necroptosis in radiation-induced rectal injury.

Dual-mode endogenous and exogenous sensitization of tumor radiotherapy through antifouling dendrimer-entrapped gold nanoparticles.

Development of a powerful sensitization system to alleviate radioresistance for enhanced tumor radiotherapy (RT) remains to be explored. Herein, we present a unique dual-mode endogenous and exogenous nanosensitizer based on dendrimer-entrapped gold nanoparticles (Au DENPs) to realize enhanced tumor RT. Methods: Generation 5 poly(amidoamine) dendrimers partially modified with 1,3-propanesultone were used for templated synthesis of Au NPs, and the created zwitterionic Au DENPs were adopted for serum-enhanced delivery of siRNA to lead to the knockdown of hypoxia-inducible factor-1α (HIF-1α) protein and downstream genes to relieve tumor invasion. The Au DENPs/siRNA polyplexes were also used for dual-mode endogenous and exogenous sensitization of tumor RT in vivo. Results: Due to the dual-mode endogenous sensitization through HIF-1α gene silencing and the exogenous sensitization through the existing Au component, enhanced RT of cancer cells in vitro and a tumor model in vivo can be realized, which was confirmed by enhanced cytotoxic reactive oxygen species (ROS) generation in vitro and double-strand DNA damage verified from the γ-H2AX protein expression in tumor cells in vivo. By integrating the advantages of HIF-1α gene silencing-induced downregulation of downstream genes and the dual-mode sensitization-enhanced RT, simultaneous inhibition of primary tumors and metastasis can be readily realized. Conclusions: The developed zwitterionic Au DENPs may be used as a promising platform for dual-mode endogenously and exogenously sensitized RT of other tumor types.

MiR-122-5p increases radiosensitivity and aggravates radiation-induced rectal injury through CCAR1.

Radiation-induced rectal injury is a major side-effect observed in patients with pelvic malignancies who receive radiotherapy. MicroRNA (miRNA), involved in many cellular biological processes, can be disturbed by ionizing radiation (IR). In this study, we have investigated the function of microRNA-122-5p (miR-122-5p) in radiation-induced rectal injury. MiR-122-5p levels in the serum of rectal cancer patients or in the rectal tissues of C57BL/6 mice before and after IR were detected by quantitative real-time PCR (qRT-PCR). We found that the miR-122-5p levels were significantly up-regulated in patients' serum or in mice rectal tissues after IR. Elevation of miR-122-5p levels sensitized human intestinal epithelial crypt (HIEC) cells to IR both in vitro and in vivo. MiR-122-5p mimic was transfected to HIEC cells and the downstream targets were predicted by bioinformatic analysis. Two putative target sites of miR-122-5p in the 3'UTR of the cell cycle and apoptosis regulator 1 (CCAR1) mRNA were found and verified by luciferase reporter assay. Overexpression of miR-122-5p or silencing CCAR1 combined with IR significantly inhibited cell survival, enhanced radiosensitivity, and increased cell apoptosis compared to that in the negative control group in vitro. In vivo injection of miR-122-5p antagomir after IR significantly alleviated radiation-induced rectal injury in mice. These results suggest that miR-122-5p aggravates radiation-induced rectal injury through targeting CCAR1.

Assessment of BeiDou-3 and Multi-GNSS Precise Point Positioning Performance.

With the launch of BDS-3 and Galileo new satellites, the BeiDou navigation satellite system (BDS) has developed from the regional to global system, and the Galileo constellation will consist of 26 satellites in space. Thus, BDS, GPS, GLONASS, and Galileo all have the capability of global positioning services. It is meaningful to evaluate the ability of global precise point positioning (PPP) of the GPS, BDS, GLONASS, and Galileo. This paper mainly contributes to the assessment of BDS-2, BDS-2/BDS-3, GPS, GLONASS, and Galileo PPP with the observations that were provided by the international Global Navigation Satellite System (GNSS) Monitoring and Assessment System (iGMAS). The Position Dilution of Precision (PDOP) value was utilized to research the global coverage of GPS, BDS-2, BDS-2/BDS-3, GLONASS, and Galileo. In particular, GPS-only, BDS-2-only, BDS-2/BDS-3, GLONASS-only, Galileo-only, and multi-GNSS combined PPP solutions were analyzed to verify the capacity of the PPP performances in terms of positioning accuracy, convergence time, and zenith troposphere delay (ZTD) accuracy. In view of PDOP, the current BDS and Galileo are capable of global coverage. The BDS-2/BDS-3 and Galileo PDOP values are fairly evenly distributed around the world similar to GPS and GLONASS. The root mean square (RMS) of positioning errors for static BDS-2/BDS-3 PPP and Galileo-only PPP are 10.7, 19.5, 20.4 mm, and 6.9, 18.6, 19.6 mm, respectively, in the geographic area of the selected station, which is the same level as GPS and GLONASS. It is worth mentioning that, by adding BDS-3 observations, the positioning accuracy of static BDS PPP is improved by 17.05%, 24.42%, and 35.65%, and the convergence time is reduced by 27.15%, 27.87%, and 35.76% in three coordinate components, respectively. Similar to the static positioning, GPS, BDS-2/BDS-3, GLONASS, and Galileo have the basically same kinematic positioning accuracy. Multi-GNSS PPP significantly improves the positioning performances in both static and kinematic positioning. In terms of ZTD accuracy, the difference between GPS, BDS-2/BDS-3, GLONASS, and Galileo is less than 1 mm, and the BDS-2/BDS-3 improves ZTD accuracy by 20.48% over the BDS-2. The assessment of GPS, BDS-2, BDS-2/BDS-3, GLONASS, Galileo, and multi-GNSS global PPP performance are shown to make comments for the development of multi-GNSS integration, global precise positioning, and the construction of iGMAS.

FAK alleviates radiation-induced rectal injury by decreasing apoptosis.

Radiation-induced rectal injury is closely related with radiotherapy efficiency. Here, we investigated the effect of focal adhesion kinase (FAK) in radiation-induced rectal injury. Peripheral blood samples of patients with rectal cancer were collected prior to radiotherapy. Differentially expressed genes and copy number variations (CNVs) were analyzed by microarray analysis. The CTCAE v3.0 toxicity grades were used to assess acute rectal injury. The radiosensitivity of human intestinal epithelial crypt (HIEC) cells were assayed by colony formation, mitochondrial membrane potential, flow cytometry and western blotting. The rectums of C57BL/6 mice were X-irradiated locally with a single dose of 15 Gy. The effect of FAK on radiation-induced injury was investigated by hematoxylin-eosin (H&E) staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), immunohistochemistry (IHC) and quantitative real-time PCR (qRT-PCR). FAK mRNA level was inversely correlated with rectal injury severity in patient samples. A CNV amplification located on chromosome 8 was closely related with FAK. Further functional assays revealed increased levels of γH2AX expression and apoptosis-related proteins in FAK-silenced HIEC cells. The ratio of TUNEL, cl-caspase-3, cyto-c and bax/bcl-2 expression in the rectum mucosa treated with a FAK inhibitor increased significantly. These results demonstrated that FAK reduced radiation-induced rectal injury by decreasing apoptosis.

The Impact of Satellite Time Group Delay and Inter-Frequency Differential Code Bias Corrections on Multi-GNSS Combined Positioning.

We present quad-constellation (namely, GPS, GLONASS, BeiDou and Galileo) time group delay (TGD) and differential code bias (DCB) correction models to fully exploit the code observations of all the four global navigation satellite systems (GNSSs) for navigation and positioning. The relationship between TGDs and DCBs for multi-GNSS is clearly figured out, and the equivalence of TGD and DCB correction models combining theory with practice is demonstrated. Meanwhile, the TGD/DCB correction models have been extended to various standard point positioning (SPP) and precise point positioning (PPP) scenarios in a multi-GNSS and multi-frequency context. To evaluate the effectiveness and practicability of broadcast TGDs in the navigation message and DCBs provided by the Multi-GNSS Experiment (MGEX), both single-frequency GNSS ionosphere-corrected SPP and dual-frequency GNSS ionosphere-free SPP/PPP tests are carried out with quad-constellation signals. Furthermore, the author investigates the influence of differential code biases on GNSS positioning estimates. The experiments show that multi-constellation combination SPP performs better after DCB/TGD correction, for example, for GPS-only b1-based SPP, the positioning accuracies can be improved by 25.0%, 30.6% and 26.7%, respectively, in the N, E, and U components, after the differential code biases correction, while GPS/GLONASS/BDS b1-based SPP can be improved by 16.1%, 26.1% and 9.9%. For GPS/BDS/Galileo the 3rd frequency based SPP, the positioning accuracies are improved by 2.0%, 2.0% and 0.4%, respectively, in the N, E, and U components, after Galileo satellites DCB correction. The accuracy of Galileo-only b1-based SPP are improved about 48.6%, 34.7% and 40.6% with DCB correction, respectively, in the N, E, and U components. The estimates of multi-constellation PPP are subject to different degrees of influence. For multi-constellation combination SPP, the accuracy of single-frequency is slightly better than that of dual-frequency combinations. Dual-frequency combinations are more sensitive to the differential code biases, especially for the 2nd and 3rd frequency combination, such as for GPS/BDS SPP, accuracy improvements of 60.9%, 26.5% and 58.8% in the three coordinate components is achieved after DCB parameters correction. For multi-constellation PPP, the convergence time can be reduced significantly with differential code biases correction. And the accuracy of positioning is slightly better with TGD/DCB correction.

In vitro dissolution enhancement of micronized l-nimodipine by antisolvent re-crystallization from its crystal form H.

In order to enhance solubility and dissolution rate in water, micronized l-nimodipine (NMD) has been successfully prepared by antisolvent re-crystallization process using acetone as solvent and deionized water as antisolvent. The effects of five experimental parameters on the mean particle size (MPS) of NMD nanosuspension were investigated. It was found that the MPS of NMD nanosuspension decreased significantly when the concentration of NMD-acetone solution increased from 50 to 150 mg/mL along with the increase of volume ratio of antisolvent to solvent from 1 to 3, and then increased slightly with the following increase of them. By contrast, the MPS decreased with the increased feed rate of NMD-acetone solution and the amount of surfactant, from 1 to 3 mL/min and 0.025% to 0.2%, respectively. Thereafter, the MPS did not show any obvious change. The precipitation temperature had no significant effects on MPS. The optimum micronization conditions were determined as follows: NMD-acetone solution concentration of 150 mg/mL, the volume ratio of antisolvent to solvent of 3, the flow rate of NMD-acetone solution of 9 mL/min, the preparation temperature of 15°C and the amount of the surfactant of 0.2%. Under optimum conditions, micronized NMD with a MPS of 708.3 nm was obtained. The micronized product was characterized using scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), high performance liquid chromatography-mass spectrometry (LC-MS), X-ray diffraction (XRD), differential scanning calorimetry (DSC), and thermo gravimetric (TG), to verify the influences of micronization process on the final product. The results showed that the chemical structure of micronized NMD was not changed, but the crystalline structure had undergone transition during precipitation, which changed from form H into L. The dissolution test showed that micronized NMD exhibited enhanced dissolution rate and solubility of 5.22 folds compared to raw H-NMD. These results suggested that micronized NMD may have potential value to become a new oral NMD formulation with high bioavailability.