Berberine promotes the degradation of phenylacetic acid to prevent thrombosis by modulating gut microbiota.

BACKGROUND: Berberine is the main bioactive constituent of Coptis chinensis, a quaternary ammonium alkaloid. While berberine's cardiovascular benefits are well-documented, its impact on thrombosis remains not fully understood. PURPOSE: This study investigates the potential of intestinal microbiota as a novel target for preventing thrombosis, with a focus on berberine, a natural compound known for its effectiveness in managing cardiovascular conditions. METHODS: Intraperitoneal injection of carrageenan induces the secretion of chemical mediators such as histamine and serotonin from mast cells to promote thrombosis. This model can directly and visually observe the progression of thrombosis in a time-dependent manner. Thrombosis was induced by intravenous injection of 1 % carrageenan solution (20 mg/kg) to all mice except the vehicle control group. Quantitative analysis of gut microbiota metabolites through LC/MS. Then, the gut microbiota of mice was analyzed using 16S rRNA sequencing to assess the changes. Finally, the effects of gut microbiota on thrombosis were explored by fecal microbiota transplantation. RESULTS: Our research shows that berberine inhibits thrombosis by altering intestinal microbiota composition and related metabolites. Notably, berberine curtails the biosynthesis of phenylacetylglycine, a thrombosis-promoting coproduct of the host-intestinal microbiota, by promoting phenylacetic acid degradation. This research underscores the significance of phenylacetylglycine as a thrombosis-promoting risk factor, as evidenced by the ability of intraperitoneal phenylacetylglycine injection to reverse berberine's efficacy. Fecal microbiota transplantation experiment confirms the crucial role of intestinal microbiota in thrombus formation. CONCLUSION: Initiating our investigation from the perspective of the gut microbiota, we have, for the first time, unveiled that berberine inhibits thrombus formation by promoting the degradation of phenylacetic acid, consequently suppressing the biosynthesis of PAG. This discovery further substantiates the intricate interplay between the gut microbiota and thrombosis. Our study advances the understanding that intestinal microbiota plays a crucial role in thrombosis development and highlights berberine-mediated intestinal microbiota modulation as a promising therapeutic approach for thrombosis prevention.

The PIWI-specific insertion module helps load longer piRNAs for translational activation essential for male fertility.

PIWI-clade proteins harness piRNAs of 24-33 nt in length. Of great puzzles are how PIWI-clade proteins incorporate piRNAs of different sizes and whether the size matters to PIWI/piRNA function. Here we report that a PIWI-Ins module unique in PIWI-clade proteins helps define the length of piRNAs. Deletion of PIWI-Ins in Miwi shifts MIWI to load with shorter piRNAs and causes spermiogenic failure in mice, demonstrating the functional importance of this regulatory module. Mechanistically, we show that longer piRNAs provide additional complementarity to target mRNAs, thereby enhancing the assembly of the MIWI/eIF3f/HuR super-complex for translational activation. Importantly, we identify a c.1108C>T (p.R370W) mutation of HIWI (human PIWIL1) in infertile men and demonstrate in Miwi knock-in mice that this genetic mutation impairs male fertility by altering the property of PIWI-Ins in selecting longer piRNAs. These findings reveal a critical role of PIWI-Ins-ensured longer piRNAs in fine-tuning MIWI/piRNA targeting capacity, proven essential for spermatid development and male fertility.

Real-time wavefront correction using diffractive optical networks.

Real-time wavefront correction is a challenging problem to present for conventional adaptive optics systems. Here, we present an all-optical system to realize real-time wavefront correction. Using deep learning, the system, which contains only multiple transmissive diffractive layers, is trained to realize high-quality imaging for unknown, random, distorted wavefronts. Once physically fabricated, this passive optical system is physically positioned between the imaging lens and the image plane to all-optically correct unknown, new wavefronts whose wavefront errors are within the training range. Simulated experiments showed that the system designed for the on-axis field of view increases the average imaging Strehl Ratio from 0.32 to 0.94, and the other system intended for multiple fields of view increases the resolvable probability of binary stars from 30.5% to 69.5%. Results suggested that DAOS performed well when performing wavefront correction at the speed of light. The solution of real-time wavefront correction can be applied to other wavelengths and has great application potential in astronomical observation, laser communication, and other fields.

A secreted MIF homologue from Trichinella spiralis binds to and interacts with host monocytes.

Trichinella spiralis is a very successful parasite capable of surviving in many mammal hosts and residing in muscle tissues for long periods, indicating that it must have some effective strategies to escape from or guard against the host immune attack. The functions of MIF have been studied in other parasites and demonstrated to function as a virulence factor aiding in their survival by modulating the host immune response. However, the functions of Trichinella spiralis MIF (TsMIF) have not been addressed. Here, we successfully obtained the purified recombinant TsMIF and anti-TsMIF serum. Our results showed that TsMIF was expressed in all the Trichinella spiralis developmental stages, especially highly expressed in the muscle larvae (ML) and mainly located in stichocytes, midgut, cuticle, muscle cells of ML and around intrauterine embryos of female adults. We also observed TsMIF could be secreted from ML and bind to host monocytes. Next, our data demonstrated that TsMIF not only stimulated the phosphorylation of ERK1/2 and cell proliferation by binding to the host cell surface receptor CD74, but also interacted with a host intracellular protein, Jab1, which is a coactivator of AP-1 transcription. We concluded the secreted TsMIF plays an important role in the interaction between Trichinella spiralis and its host and could be a potential drug or vaccine target molecule against Trichinella spiralis infection.

Numerical Simulation Study on the Mechanism of Formation of Apical Aneurysm in Hypertrophic Cardiomyopathy With Midventricular Obstruction.

Apical aneurysm was observed to be associated with midventricular obstruction (MVO) in hypertrophic cardiomyopathy (HCM). To investigate the genesis of the apical aneurysm, the idealized numerical left ventricular models (finite-element left ventricle models) of the healthy left ventricle, subaortic obstruction, and midventricular obstruction in HCM of left ventricle were created. The mechanical effects in the formation of apical aneurysm were determined by comparing the myofiber stress on the apical wall between these three models (healthy, subaortic obstruction, and midventricular obstruction models). In comparing the subaortic obstruction model and MVO model with HCM, it was found that, at the time of maximum pressure, the maximum value of myofiber stress in MVO model was 75.0% higher than that in the subaortic obstruction model (654.5 kPa vs. 373.9 kPa). The maximum stress on the apex of LV increased 79.9, 69.3, 117.8% than that on the myocardium around the apex in healthy model, subaortic obstruction model, and MVO model, respectively. Our results indicated that high myofiber stress on the apical wall might initiate the formation process of the apical aneurysm.

Comparisons of simulation results between passive and active fluid structure interaction models for left ventricle in hypertrophic obstructive cardiomyopathy.

BACKGROUND: Patient-specific active fluid-structure interactions (FSI) model is a useful approach to non-invasively investigate the hemodynamics in the heart. However, it takes a lot of effort to obtain the proper external force boundary conditions for active models, which heavily restrained the time-sensitive clinical applications of active computational models. METHODS: The simulation results of 12 passive FSI models based on 6 patients' pre-operative and post-operative CT images were compared with corresponding active models to investigate the differences in hemodynamics and cardiac mechanics between these models. RESULTS: In comparing the passive and active models, it was found that there was no significant difference in pressure difference and shear stress on mitral valve leaflet (MVL) at the pre-SAM time point, but a significant difference was found in wall stress on the inner boundary of left ventricle (endocardium). It was also found that pressure difference on the coapted MVL and the shear stress on MVL were significantly decreased after successful surgery in both active and passive models. CONCLUSION: Our results suggested that the passive models may provide good approximated hemodynamic results at 5% RR interval, which is crucial for analyzing the initiation of systolic anterior motion (SAM). Comparing to active models, the passive models decrease the complexity of the modeling construction and the difficulty of convergence significantly. These findings suggest that, with proper boundary conditions and sufficient clinical data, the passive computational model may be a good substitution model for the active model to perform hemodynamic analysis of the initiation of SAM.

Surgical Design Optimization of Proximal Junctional Kyphosis.

Purpose: The objective of this study was to construct a procedural planning tool to optimize the proximal junction angle (PJA) to prevent postoperative proximal junctional kyphosis (PJK) for each scoliosis patient. Methods: Twelve patients (9 patients without PJK and 3 patients with PJK) who have been followed up for at least 2 years after surgery were included. After calculating the loading force on the cephalad intervertebral disc of upper instrumented vertebra of each patient, the finite-element method (FEM) was performed to calculate the stress of each element. The stress information was summarized into the difference value before and after operation in different regions of interest. A two-layer fully connected neural network method was applied to model the relationship between the stress information and the risk of PJK. Leave-one-out cross-validation and sensitivity analysis were implemented to assess the accuracy and stability of the trained model. The optimal PJA was predicted based on the learned model by optimization algorithm. Results: The mean prediction accuracy was 83.3% for all these cases, and the area under the curve (AUC) of prediction was 0.889. And the output variance of this model was less than 5% when the important factor values were perturbed in a range of 5%. Conclusion: Our approach integrated biomechanics and machine learning to support the surgical decision. For a new individual, the risk of PJK and optimal PJA can be simultaneously predicted based on the learned model.

Patient-Specific CT-Based Fluid-Structure-Interaction Aorta Model to Quantify Mechanical Conditions for the Investigation of Ascending Aortic Dilation in TOF Patients.

BACKGROUND: Some adult patients with Tetralogy of Fallot (TOF) were found to simultaneously develop ascending aortic dilation. Severe aortic dilation would lead to several aortic diseases, including aortic aneurysm and dissection, which seriously affect patients' living quality and even cause patients' death. Current practice guidelines of aortic-dilation-related diseases mainly focus on aortic diameter, which has been found not always a good indicator. Therefore, it may be clinically useful to identify some other factors that can potentially better predict aortic response to dilation. METHODS: 20 TOF patients scheduled for TOF repair surgery were recruited in this study and were divided into dilated and nondilated groups according to the Z scores of ascending aorta diameters. Patient-specific aortic CT images, pressure, and flow rates were used in the construction of computational biomechanical models. RESULTS: Simulation results demonstrated a good coincidence between numerical mean flow rate at inlet and the one obtained from color Doppler ultrasonography, which implied that computational models were able to simulate the movement of the aorta and blood inside accurately. Our results indicated that aortic stress can effectively differentiate patients of the dilated group from the ones of the nondilated group. Mean ascending aortic stress-P1 (maximal principal stress) from the dilated group was 54% higher than that from the nondilated group (97.97 kPa vs. 63.47 kPa, p value = 0.044) under systolic pressure. Velocity magnitude in the aorta and aortic wall displacement of the dilated group were also greater than those of the nondilated group with p value < 0.1. CONCLUSION: Computational modeling and ascending aortic biomechanical factors may be used as a potential tool to identify and analyze aortic response to dilation. Large-scale clinical studies are needed to validate these preliminary findings.

Woofer-tweeter deformable mirror driven by combined actuators with a piezoelectric unimorph and stack for astronomical application.

A woofer-tweeter deformable mirror (DM) driven by combined actuators with a piezoelectric unimorph and stack for astronomical applications is proposed. The piezoelectric unimorph "tweeter" part, made of a 200-µm-thick lead zirconate titanate film and 200-µm-thick silicon, has 234 separate elements for high-order correction. It is magnetically jointed with a seven-element "woofer" piezo-stack array, which is for low-order correction. The combined DM was fabricated and experimentally evaluated, showing a high resonant frequency near 1 kHz. The piezo-stack array together with the unimorph actuators enable the DM to produce wavefronts with RMS residue errors less than 20 nm. Experimental results indicate that the woofer-tweeter DM has the capability to compensate for the first 35 terms of Zernike aberrations with normalized RMS wavefront errors less than 20%. The woofer-tweeter DM has higher bandwidth than a conventional unimorph DM as well as simple structure, low cost, and good scalability, offering a potential alternative for large-aperture astronomical applications.

Flexible Polyimide Nanocomposites with dc Bias Induced Excellent Dielectric Tunability and Unique Nonpercolative Negative- k toward Intrinsic Metamaterials.

Intrinsic metamaterials with negative- k that originated from random-structured materials have drawn increasing attention. Currently, intrinsic negative- k was mainly achieved in percolative composites by tailoring the compositions and microstructures. Herein, plasmalike negative- k was successfully achieved in multiwalled carbon nanotubes (MWCNT)/polyimide (PI) nanocomposites via applying external dc bias which exhibited excellent capability in conveniently and accurately adjusting negative- k. Mechanism analysis indicated that the localized charges at the interfaces between MWCNT and PI became delocalized after gaining energy from the dc bias, resulting in elevated concentration of delocalized charges, and hence the enhanced negative- k. Furthermore, it is surprising to observe that negative- k also appeared in multilayer nanocomposites consisting of alternating BaTiO3/PI and PI layers, in which there was no percolative conducting network. On the basis of systematic analysis, it is proposed that the unique nonpercolative negative- k resulted from the mutual competition between plasma oscillations of delocalized charges and polarizations of localized charges. Negative- k appeared once the polarizations were overwhelmed by plasma oscillations. This work demonstrated that applying dc bias is a promising way to achieve highly tailorable negative- k. Meanwhile, the observation of unique nonpercolative negative- k and the clarification of underlying mechanisms offer new insights into negative- k metamaterials, which will greatly facilitate the exploration of high-performance electromagnetic metamaterials.

Comparison of Right Ventricle Morphological and Mechanical Characteristics for Healthy and Patients with Tetralogy of Fallot: An In Vivo MRI-Based Modeling Study.

Patients with repaired tetralogy of Fallot (TOF) account for the majority of cases with late onset right ventricle failure. Comparing TOF patients with healthy people may provide information to address this challenge. Cardiac magnetic resonance (CMR) data were obtained from 16 TOF patients (patient group, PG) and 6 healthy volunteers (healthy group, HG). At begin-of-ejection, better patient group (n=5, BPG) stress was very close to HG stress (54.7±38.4 kPa vs. 51.2±55.7 kPa, p=0.6889) while worse patient group (n=11, WPG) stress was 84% higher than HG stress (p=0.0418). Stress may be used as an indicator to differentiate BPG patients from WPG patients, with further validations.

Patient-Specific MRI-Based Right Ventricle Models Using Different Zero-Load Diastole and Systole Geometries for Better Cardiac Stress and Strain Calculations and Pulmonary Valve Replacement Surgical Outcome Predictions.

BACKGROUND: Accurate calculation of ventricular stress and strain is critical for cardiovascular investigations. Sarcomere shortening in active contraction leads to change of ventricular zero-stress configurations during the cardiac cycle. A new model using different zero-load diastole and systole geometries was introduced to provide more accurate cardiac stress/strain calculations with potential to predict post pulmonary valve replacement (PVR) surgical outcome. METHODS: Cardiac magnetic resonance (CMR) data were obtained from 16 patients with repaired tetralogy of Fallot prior to and 6 months after pulmonary valve replacement (8 male, 8 female, mean age 34.5 years). Patients were divided into Group 1 (n = 8) with better post PVR outcome and Group 2 (n = 8) with worse post PVR outcome based on their change in RV ejection fraction (EF). CMR-based patient-specific computational RV/LV models using one zero-load geometry (1G model) and two zero-load geometries (diastole and systole, 2G model) were constructed and RV wall thickness, volume, circumferential and longitudinal curvatures, mechanical stress and strain were obtained for analysis. Pairwise T-test and Linear Mixed Effect (LME) model were used to determine if the differences from the 1G and 2G models were statistically significant, with the dependence of the pair-wise observations and the patient-slice clustering effects being taken into consideration. For group comparisons, continuous variables (RV volumes, WT, C- and L- curvatures, and stress and strain values) were summarized as mean ± SD and compared between the outcome groups by using an unpaired Student t-test. Logistic regression analysis was used to identify potential morphological and mechanical predictors for post PVR surgical outcome. RESULTS: Based on results from the 16 patients, mean begin-ejection stress and strain from the 2G model were 28% and 40% higher than that from the 1G model, respectively. Using the 2G model results, RV EF changes correlated negatively with stress (r = -0.609, P = 0.012) and with pre-PVR RV end-diastole volume (r = -0.60, P = 0.015), but did not correlate with WT, C-curvature, L-curvature, or strain. At begin-ejection, mean RV stress of Group 2 was 57.4% higher than that of Group 1 (130.1±60.7 vs. 82.7±38.8 kPa, P = 0.0042). Stress was the only parameter that showed significant differences between the two groups. The combination of circumferential curvature, RV volume and the difference between begin-ejection stress and end-ejection stress was the best predictor for post PVR outcome with an area under the ROC curve of 0.855. The begin-ejection stress was the best single predictor among the 8 individual parameters with an area under the ROC curve of 0.782. CONCLUSION: The new 2G model may be able to provide more accurate ventricular stress and strain calculations for potential clinical applications. Combining morphological and mechanical parameters may provide better predictions for post PVR outcome.

Mechanical stress is associated with right ventricular response to pulmonary valve replacement in patients with repaired tetralogy of Fallot.

OBJECTIVE: Patients with repaired tetralogy of Fallot account for a substantial proportion of cases with late-onset right ventricular failure. The current surgical approach, which includes pulmonary valve replacement/insertion, has yielded mixed results. Therefore, it may be clinically useful to identify parameters that can be used to predict right ventricular function response to pulmonary valve replacement. METHODS: Cardiac magnetic resonance data before and 6 months after pulmonary valve replacement were obtained from 16 patients with repaired tetralogy of Fallot (8 male, 8 female; median age, 42.75 years). Right ventricular ejection fraction change from pre- to postpulmonary valve replacement was used as the outcome. The patients were divided into group 1 (n = 8, better outcome) and group 2 (n = 8, worst outcome). Cardiac magnetic resonance-based patient-specific computational right ventricular/left ventricular models were constructed, and right ventricular mechanical stress and strain, wall thickness, curvature, and volumes were obtained for analysis. RESULTS: Our results indicated that right ventricular wall stress was the best single predictor for postpulmonary valve replacement outcome with an area under the receiver operating characteristic curve of 0.819. Mean values of stress, strain, wall thickness, and longitudinal curvature differed significantly between the 2 groups with right ventricular wall stress showing the largest difference. Mean right ventricular stress in group 2 was 103% higher than in group 1. CONCLUSIONS: Computational modeling and right ventricular stress may be used as tools to identify right ventricular function response to pulmonary valve replacement. Large-scale clinical studies are needed to validate these preliminary findings.

[Development of a software standardizing optical density with operation settings related to several limitations].

OBJECTIVE: To develop a software that can be used to standardize optical density to normalize the procedures and results of standardization in order to effectively solve several problems generated during standardization of in-direct ELISA results. METHODS: The software was designed based on the I-STOD method with operation settings to solve the problems that one might encounter during the standardization. Matlab GUI was used as a tool for the development. The software was tested with the results of the detection of sera of persons from schistosomiasis japonica endemic areas. RESULTS: I-STOD V1.0 (WINDOWS XP/WIN 7, 0.5 GB) was successfully developed to standardize optical density. A serial of serum samples from schistosomiasis japonica endemic areas were used to examine the operational effects of I-STOD V1.0 software. The results indicated that the software successfully overcame several problems including reliability of standard curve, applicable scope of samples and determination of dilution for samples outside the scope, so that I-STOD was performed more conveniently and the results of standardization were more consistent. CONCLUSION: I-STOD V1.0 is a professional software based on I-STOD. It can be easily operated and can effectively standardize the testing results of in-direct ELISA.