Development and validation of risk prediction model for recurrent cardiovascular events among Chinese: the Personalized CARdiovascular DIsease risk Assessment for Chinese model.

Aims: Cardiovascular disease (CVD) is a leading cause of mortality, especially in developing countries. This study aimed to develop and validate a CVD risk prediction model, Personalized CARdiovascular DIsease risk Assessment for Chinese (P-CARDIAC), for recurrent cardiovascular events using machine learning technique. Methods and results: Three cohorts of Chinese patients with established CVD were included if they had used any of the public healthcare services provided by the Hong Kong Hospital Authority (HA) since 2004 and categorized by their geographical locations. The 10-year CVD outcome was a composite of diagnostic or procedure codes with specific International Classification of Diseases, Ninth Revision, Clinical Modification. Multivariate imputation with chained equations and XGBoost were applied for the model development. The comparison with Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention (TRS-2°P) and Secondary Manifestations of ARTerial disease (SMART2) used the validation cohorts with 1000 bootstrap replicates. A total of 48 799, 119 672 and 140 533 patients were included in the derivation and validation cohorts, respectively. A list of 125 risk variables were used to make predictions on CVD risk, of which 8 classes of CVD-related drugs were considered interactive covariates. Model performance in the derivation cohort showed satisfying discrimination and calibration with a C statistic of 0.69. Internal validation showed good discrimination and calibration performance with C statistic over 0.6. The P-CARDIAC also showed better performance than TRS-2°P and SMART2. Conclusion: Compared with other risk scores, the P-CARDIAC enables to identify unique patterns of Chinese patients with established CVD. We anticipate that the P-CARDIAC can be applied in various settings to prevent recurrent CVD events, thus reducing the related healthcare burden.

Canalicular laceration repair using a novel bicanalicular silicone stent versus traditional bicanalicular stent with nasal fixation.

PURPOSE: To compare the clinical effects of two types of lacrimal stents in the repair of canalicular lacerations. METHODS: A retrospective analysis was conducted on patients with canalicular lacerations between January 2017 and December 2022. The canalicular reconstruction was performed using either the Runshi-RS bicanalicular silicone stent or the traditional bicanalicular silicone stent with nasal fixation, under a surgical microscope. The stent was placed for 3 months, and patients were followed up for more than 3 months after extubation. The anatomical and functional success rates were compared between the two groups. Anatomical success was assessed through diagnostic probing and irrigation of lacrimal passage, while functional success was determined by the patient's subjective symptoms of epiphora. RESULTS: The study included 315 patients (315 eyes) undergoing canalicular laceration repair. The Runshi-RS stent was utilized in 147 patients (46.7%), while the traditional stent with nasal fixation was employed in 168 patients (53.3%). The anatomical success rates (99.3% vs 98.8%, P = 0.642) and functional success rates (87.2% vs 88.1%, P = 0.926) were similar between the RS group and the traditional stent group. Postoperative complications were fewer (4.1% vs 10.1%, P = 0.04) and the operation time was shorter (67.1 ± 35.3 min vs 86.1 ± 43.4 min, P < 0.001) in the RS group. CONCLUSION: The Runshi-RS tube demonstrates favorable surgical outcomes for the repair of canalicular lacerations. Compared to the traditional stent with nasal fixation, the RS stent allows for shorter operation times and fewer postoperative complications in the repair of canalicular lacerations.

Extra-High Mechanical and Phononic Anisotropy in Black Phosphorus Blisters.

Strain is an effective strategy to modulate the electrical, optical, and optoelectronic properties of 2D materials. Conventional circular blisters could generate a biaxial stretching of 2D membranes with notable strain gradients along the hoop direction. However, such a deformation mode cannot be utilized to investigate mechanical responses of in-plane anisotropic 2D materials, for example, black phosphorus (BP), due to its crystallographic orientation dependence. Here, a novel rectangular-shaped bulge device is developed to uniaxially stretch the membrane, and further provide a promising platform to detect orientation-dependent mechanical and optical properties of anisotropic 2D materials. Impressively, the derived anisotropic ratio of Young's modulus of BP flakes is much higher than the values obtained via the nanoindentation method. The extra-high strain-dependent phononic anisotropy in Raman modes along different crystalline orientations is also observed. The designed rectangular budge device expands the uniaxial deformation methods available, allowing to explore the mechanical, and strain-dependent physical properties of other anisotropic 2D materials more broadly.

Network integration and protein structural binding analysis of neurodegeneration-related interactome.

Neurodegenerative diseases (NDs) usually connect with aggregation and molecular interactions of pathological proteins. The integration of accumulative data from clinical and biomedical research will allow for the excavation of pathological proteins and related interactors. It is also important to systematically study their interacting proteins in order to find more related proteins and potential therapeutic targets. Understanding binding regions in protein interactions will help functional proteomics and provide an alternative method for predicting novel interactions. This study integrated data from biomedical research to achieve systematic mining and analysis of pathogenic proteins and their interaction network. A workflow has been built as a solution for the collective information of proteins involved in NDs, related protein-protein interactions (PPIs) and interactive visualizations. It also included protein isoforms and mapped them in a disease-related PPI network to illuminate the impact of alternative splicing on protein binding. The interacting proteins enriched by diseases and biological processes (BPs) revealed possible regulatory modules. A high-resolution network with structural affinity information was generated. Finally, Neurodegenerative Disease Atlas (NDAtlas) was constructed with an interactive and intuitive view of protein docking with 3D molecular graphics beyond the traditional 2D network. NDAtlas is available at http://bis.zju.edu.cn/ndatlas.

Development of a high-power pulse-forming network Marx generator with a long pulse duration.

To meet the application needs for producing long-pulse electron beams and high-power microwaves, a pulse-forming network Marx generator with a pulse duration of 260 ns is presented in this paper. This generator is composed of 20 stages of pulse-forming network modules. Each module is formed with nine capacitors connected in parallel. The generator functions at 44 kV, which is lower than the rated voltage of the mica paper capacitor, to improve the lifetime. The impedance of the generator is designed to reach 45 Ω. To avoid the strong coupling between the adjacent stages, the physical layout of the generator adopts a zigzag design. The generator is housed in a gas pressurized vessel of 600 mm in diameter and 580 mm in length. Across a 50 Ω load, it can deliver quasi-rectangular pulses with a pulse duration of 260 ns and an amplitude of 500 kV for a single shot. The output pulse features a plateau duration of 160 ns and a leading edge of 45 ns. In burst mode, it can steadily output ten pulses of 450 kV at a repetition rate of 10 Hz on either a resistive load or a diode.

Duet: SNP-assisted structural variant calling and phasing using Oxford nanopore sequencing.

BACKGROUND: Whole genome sequencing using the long-read Oxford Nanopore Technologies (ONT) MinION sequencer provides a cost-effective option for structural variant (SV) detection in clinical applications. Despite the advantage of using long reads, however, accurate SV calling and phasing are still challenging. RESULTS: We introduce Duet, an SV detection tool optimized for SV calling and phasing using ONT data. The tool uses novel features integrated from both SV signatures and single-nucleotide polymorphism signatures, which can accurately distinguish SV haplotype from a false signal. Duet was benchmarked against state-of-the-art tools on multiple ONT sequencing datasets of sequencing coverage ranging from 8× to 40×. At low sequencing coverage of 8×, Duet performs better than all other tools in SV calling, SV genotyping and SV phasing. When the sequencing coverage is higher (20× to 40×), the F1-score for SV phasing is further improved in comparison to the performance of other tools, while its performance of SV genotyping and SV calling remains higher than other tools. CONCLUSION: Duet can perform accurate SV calling, SV genotyping and SV phasing using low-coverage ONT data, making it very useful for low-coverage genomes. It has great performance when scaled to high-coverage genomes, which is adaptable to various clinical applications. Duet is open source and is available at https://github.com/yekaizhou/duet .

Transcription factor FOXP1 mediates vascular endothelial dysfunction in diabetic retinopathy.

BACKGROUND: Diabetic retinopathy (DR) is still the fastest growing cause of blindness in working aged adults, and its typical characteristics are endothelial cell dysfunction and pericytes loss. Transcription factor fork head box P1 (FOXP1) is a member of FOX family involved in diabetes progression and is expressed in endothelial cells. The purpose of this study was to investigate the role and mechanism of FOXP1 in DR. METHODS: The vitreous of DR patients and non-DR patients were collected, and the expression of FOXP1 was detected by real-time polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA). Human umbilical vein endothelial cells (HUVECs) cultured in high glucose simulated DR environment, and the expressions of FOXP1, vascular endothelial growth factor (VEGF), and pigment epithelium derived factor (PEDF) were detected by RT-qPCR and western blot (WB) after transfection of small interfering RNA (siRNA) to knock out FOXP1. At the same time, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay (MTT), 5-ethynyl-2'-deoxyuridine assay (EDU), flow cytometry, Transwell assay, and tube-forming experiment were performed to determine cell proliferation, migration, and tube-forming ability. RESULTS: We found that FOXP1 was highly expressed in the vitreous of DR patients and HUVECs under high glucose condition. After FOXP1 was decreased, the activation of VEGF expression and inhibition of PEDF expression in HUVECs induced by high glucose were reversed; meanwhile, cell proliferation, migration, and tube formation decreased, and apoptosis was promoted. CONCLUSION: Generally, FOXP1 is highly expressed in the vitreous of DR patients, and its silence prevented VEGF/PEDF signaling pathway stimulated by high glucose and also reduced the proliferation, migration, and tube formation of endothelial cell, thus improving vascular endothelial dysfunction caused by DR. The results indicate that FOXP1 may be a therapeutic target of DR.

mPPI: a database extension to visualize structural interactome in a one-to-many manner.

Protein-protein interaction (PPI) databases with structural information are useful to investigate biological functions at both systematic and atomic levels. However, most existing PPI databases only curate binary interactome. From the perspective of the display and function of PPI, as well as the structural binding interface, the related database and resources are summarized. We developed a database extension, named mPPI, for PPI structural visualization. Comparing with the existing structural interactomes that curate resolved PPI conformation in pairs, mPPI can visualize target protein and its multiple interactors simultaneously, which facilitates multi-target drug discovery and structure prediction of protein macro-complexes. By employing a protein-protein docking algorithm, mPPI largely extends the coverage of structural interactome from experimentally resolved complexes. mPPI is designed to be a customizable and convenient plugin for PPI databases. It possesses wide potential applications for various PPI databases, and it has been used for a neurodegenerative disease-related PPI database as demonstration. Scripts and implementation guidelines of mPPI are documented at the database tool website. Database URL  http://bis.zju.edu.cn/mppi/.

MicroRNA­126 suppresses the proliferation and migration of endothelial cells in experimental diabetic retinopathy by targeting polo­like kinase 4.

As a specific microvascular complication of diabetes, diabetic retinopathy (DR) causes severe visual impairment in patients with diabetes. The expression of microRNA­126 (miRNA/miR­126) has previously been found to be significantly decreased in the serum of patients with DR. In the present study, the functions of miR­126 and its mechanisms of action in experimental diabetic retinopathy were examined in rats with streptozotocin (STZ)­induced diabetes and in high glucose (HG)­induced human retinal capillary endothelial cells (HRCECs). In vivo, diabetic rat models were established and the rats were intravitreally injected with lentivirus expressing rno­miR­126 (lenti­miR­126) or negative control (lenti­NC). RT­qPCR was used to determine the miR­126 level in the serum and retina. Paraffin sections and retinal vasculature were used to determine the extent of retinopathy. The protein content of vascular endothelial growth factor (VEGF) and pigment epithelium­derived factor (PEDF) in the retina was used as an auxiliary measurement of retinopathy. Western blot analysis and immunofluorescence staining were used to measure the expression of polo­like kinase 4 (PLK4) in rat retinal tissue. In vitro, the cells were transfected with miR­126 inhibitor or mimic and treated with the PLK4 inhibitor, CFI­400945 fumarate. RT­qPCR and western blot analysis were used to detect the miR­126 level and PLK4 expression. Cell proliferation and migration were measured by EdU and Transwell assays. The diabetic rats were found to exhibit downregulated serum and retinal miR­126 levels compared with the non­diabetic rats. The intravitreal delivery of miR­126 alleviated retinopathy and reduced the diabetes­induced upregulation of PLK4 in retinal tissues. Luciferase reporter assays confirmed that PLK4 mRNA was the target of miR­126. In HG­induced HRCECs, transfection with miR­126 mimic increased the miR­126 level, whereas it downregulated that of its downstream target, PLK4, which was opposite to the effects exerted by the miR­126 inhibitor. Furthermore, miR­126 mimic and CFI­400945 fumarate reduced the HG­induced upregulation of PLK4 expression, as well as cell proliferation and migration. On the whole, the findings of the present study demonstrate that miR­126 reduces experimental diabetic retinopathy and suppresses endothelial cell proliferation and migration by targeting PLK4. Thus, miR­126 and CFI­400945 fumarate may be therapeutic targets for DR.

The expression and significance of mTORC1 in diabetic retinopathy.

BACKGROUND: To investigate the expression and significance of mechanistic target of rapamycin complex 1(mTORC1) in diabetic retinopathy (DR), and to find new targets and new methods for the treatment of DR. METHODS: A DR rat model was prepared by general feeding combined with intraperitoneal injection of 10% streptozotocin (60 mg/kg). The rats were randomly divided into a control group (NDM group) and a diabetes group (DM group). Three months later, the degrees of retinopathy was determined using hematoxylin and eosin staining, and the levels of p-S6, VEGF, and PEDF proteins were detected by immunohistochemistry and western blotting. Human retinal capillary endothelial cells (HRCECs) were cultured in high glucose (HG) conditions, then treated with rapamycin or transfected with siTSC1.The protein levels of p-S6 were assessed by western blotting. The 5-ethynyl-2'-deoxyuridine assay was used to detect cell proliferation, and the Transwell assay was used to detect cell migration. RESULTS: A DM rat model was successfully developed. The expressions of p-S6 and VEGF proteins were significantly increased in the DM group (p < 0.05), and the expression of PEDF protein was significantly decreased compared with the NDM group (p < 0.05). In vitro, the p-S6 protein, as well as cell proliferation and migration, in HG induced HRCECs were increased (p < 0.05) compared with the control (normal glucose) group (p < 0.05). After transfection with siTSC1 to activate mTORC1, the expression of p-S6, as well as cell proliferation and migration, were increased. In contrast, rapamycin decreased p-S6 expression, as well as proliferation and migration, in HG induced HRCECs compared to the control group (p < 0.05). CONCLUSION: mTORC1 plays an important role in DR. After activation, mTORC1 induced expression of the p-S6 protein, regulated the expressions of VEGF and PEDF proteins, and changed the proliferation and migration of endothelial cells. The mTORC1 can therefore be used as a new target,as well as in the treatment of DR.