Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations.

Patient-specific induced pluripotent stem cells (iPSCs) derived from somatic cells provide a unique tool for the study of human disease, as well as a promising source for cell replacement therapies. One crucial limitation has been the inability to perform experiments under genetically defined conditions. This is particularly relevant for late age onset disorders in which in vitro phenotypes are predicted to be subtle and susceptible to significant effects of genetic background variations. By combining zinc finger nuclease (ZFN)-mediated genome editing and iPSC technology, we provide a generally applicable solution to this problem, generating sets of isogenic disease and control human pluripotent stem cells that differ exclusively at either of two susceptibility variants for Parkinson's disease by modifying the underlying point mutations in the α-synuclein gene. The robust capability to genetically correct disease-causing point mutations in patient-derived hiPSCs represents significant progress for basic biomedical research and an advance toward hiPSC-based cell replacement therapies.

An Aerial Image Detection Algorithm Based on Improved YOLOv5.

To enhance aerial image detection in complex environments characterized by multiple small targets and mutual occlusion, we propose an aerial target detection algorithm based on an improved version of YOLOv5 in this paper. Firstly, we employ an improved Mosaic algorithm to address redundant boundaries arising from varying image scales and to augment the training sample size, thereby enhancing detection accuracy. Secondly, we integrate the constructed hybrid attention module into the backbone network to enhance the model's capability in extracting pertinent feature information. Subsequently, we incorporate feature fusion layer 7 and P2 fusion into the neck network, leading to a notable enhancement in the model's capability to detect small targets. Finally, we replace the original PAN + FPN network structure with the optimized BiFPN (Bidirectional Feature Pyramid Network) to enable the model to preserve deeper semantic information, thereby enhancing detection capabilities for dense objects. Experimental results indicate a substantial improvement in both the detection accuracy and speed of the enhanced algorithm compared to its original version. It is noteworthy that the enhanced algorithm exhibits a markedly improved detection performance for aerial images, particularly under real-time conditions.

Practical security analysis of a continuous-variable source-independent quantum random number generator based on heterodyne detection.

Heterodyne-based continuous-variable source-independent quantum random number generator (CV-SI-QRNG) can produce true random numbers without any assumptions on source. However, practical implementations always contain imperfections, which will greatly influence the extractable randomness and even open loopholes for eavesdroppers to steal information about the final output. In this work, based on the theoretical model, we systematically analyzed the effects of imperfect implementations on the practical security of heterodyne-based CV-SI-QRNG. The influences of local oscillator (LO) fluctuation under imbalanced heterodyne detection are first analyzed. The simulation results show that the lower bound of extractable randomness will be overestimated without considering the influence of LO fluctuation, which will threaten the practical security of CV-SI-QRNG system. Moreover, we analyze the effects of the degree of imbalance and the magnitude of LO fluctuation on evaluating the extractable randomness. Finally, we investigate the impact of an imperfect phase modulator on the practical security of CV-SI-QRNG and find it will reduce the extractable randomness. Our analysis reveals that one should carefully consider the imperfections in the actual implementations of CV-SI-QRNGs.

Optical polarization properties of TPP2MnBr4 perovskite crystal adjusted by the self-trapping state.

Low-dimensional networked organic-inorganic hybrid metal halide crystal has become an emerging hotspot material due to its opportunities and advantages in the development of white-light-emitting diodes. Therefore, its photoluminescence (PL) mechanism is important. Herein, we study the PL behavior of columniform TPP2MnBr4 crystals using multi-spectroscopy. The temperature-dependent PL data show that the PL of the TPP2MnBr4 crystal originates from the recombination of a self-trapping exciton. A polarization-dependent PL test suggests that the self-trapping exciton is anisotropic, which indicates that the distribution of self-trapping states is sensitive to the orientation of the crystal axis. Space-resolved PL spectroscopy shows that the anisotropy of PL gradually weakens along the orientation of the columniform crystal, which has a longer relaxation distance than traditional light-wave-guiding behavior. Thus, anisotropy of PL can exist before it disappears in the crystal. Our results elucidate the PL mechanism of low-dimensional networked organic-inorganic hybrid metal halide crystals and provide a foundation for advanced optical polarization devices based on them.

Effects of Recombinant Human Brain Natriuretic Peptide in Patients with Acute Pulmonary Embolism Complicated with Right Ventricular Dysfunction Who Underwent Catheter-Directed Therapy.

Acute pulmonary embolism (PE) remains a significant cause of cardiovascular morbidity and mortality worldwide. Brain natriuretic peptide (BNP) combined with catheter-directed therapy (CDT) may improve right ventricular (RV) dysfunction and stabilize hemodynamics in acute PE.We retrospectively studied 159 patients with confirmed acute PE who were treated with CDT and admitted to the intensive care unit of our department between September 2016 and May 2020. The patients were divided into the control group and the rhBNP group based on whether to receive recombinant human BNP treatment (rhBNP) or not. The basic characteristics of the patients between the control group and the rhBNP group was systematically compared during admission and follow-up. Risk factors for all-cause mortality within 30 days were determined using multivariate logistic regression analysis.Respiratory rate was found to be significantly lower in the rhBNP group than in the control group. Patients in the rhBNP group had significantly lower levels of white blood cell, C-reactive protein (CRP), D-dimers, troponin I, creatinine, and N-terminal (NT) -proBNP compared with those in the control group. Levels of tricuspid annular plane systolic excursion were significantly higher in the rhBNP group than in the control group. The percentage of patients with rehospitalization readmission due to PE differed significantly between the control group and the rhBNP group. On the basis of the multivariate regression analysis, CRP, creatinine, troponin I, and NT-proBNP were independent factors of all-cause mortality in 30 days.rhBNP is effective in the treatment of patients with RV dysfunction caused by acute PE who underwent CDT, which may be an alternative treatment option for improving clinical prognosis.

Quantum Circuit Optimization for Solving Discrete Logarithm of Binary Elliptic Curves Obeying the Nearest-Neighbor Constrained.

In this paper, we consider the optimization of the quantum circuit for discrete logarithm of binary elliptic curves under a constrained connectivity, focusing on the resource expenditure and the optimal design for quantum operations such as the addition, binary shift, multiplication, squaring, inversion, and division included in the point addition on binary elliptic curves. Based on the space-efficient quantum Karatsuba multiplication, the number of CNOTs in the circuits of inversion and division has been reduced with the help of the Steiner tree problem reduction. The optimized size of the CNOTs is related to the minimum degree of the connected graph.

Using Variational Quantum Algorithm to Solve the LWE Problem.

The variational quantum algorithm (VQA) is a hybrid classical-quantum algorithm. It can actually run in an intermediate-scale quantum device where the number of available qubits is too limited to perform quantum error correction, so it is one of the most promising quantum algorithms in the noisy intermediate-scale quantum era. In this paper, two ideas for solving the learning with errors problem (LWE) using VQA are proposed. First, after reducing the LWE problem into the bounded distance decoding problem, the quantum approximation optimization algorithm (QAOA) is introduced to improve classical methods. Second, after the LWE problem is reduced into the unique shortest vector problem, the variational quantum eigensolver (VQE) is used to solve it, and the number of qubits required is calculated in detail. Small-scale experiments are carried out for the two LWE variational quantum algorithms, and the experiments show that VQA improves the quality of the classical solutions.

Luminescent Thermochromism and White-Light Emission of a 3D [Ag4Br6] Cluster-Based Coordination Framework with Both Adamantane-like Node and Linker.

Herein, we report a dia-type metal-organic hybrid network based on the [Ag4Br6] clusters and hexamethylenetetramine molecules wherein both the inorganic nodes and organic linkers feature adamantane-like geometry with a Td symmetry. The silver bromine complex presents a dual emission and exhibits an interesting luminescent thermochromism behavior. Remarkably, white-light emission can be readily realized through variation of the temperature. In addition, the title compound is expected to be competent as a luminescent thermometer for temperature identification.

Synthesis and biological evaluation of 2,5-diaryl-1,3,4-oxadiazole derivatives as novel Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) inhibitors.

The Src homology-2 domain containing-protein tyrosine phosphatase-2 (SHP2) is a convergent node for oncogenic cell-signaling cascades including the PD-L1/PD-1 pathway. As an oncoprotein as well as a potential immunomodulator, SHP2 has now emerged as an attractive target for novel anti-cancer agents. Although significant progress has been made in identifying chemotypes of SHP2 inhibitors, these specific compounds might not be clinically useful to inhibit frequently encountered mutated SHP2 variants. Consequently, it is highly desirable to develop chemically different SHP2 inhibitors sensitive to SHP2 mutants. This work developed a new type of SHP2 inhibitors with 2,5-diaryl-1,3,4-oxadiazole scaffold. The representative compound 6l exhibited SHP2 inhibitory activity with IC50 of 2.73 ± 0.20 µM, showed about 1.56-fold, 5.26-fold, and 7.36-fold selectivity for SHP2 over SHP1, PTP1B and TCPTP respectively. Further investigations confirmed that 6l behaved as mixed-type inhibitor sensitive to leukemia cell TF-1 and inhibited SHP2 mediated cell signaling and proliferation. Molecular dynamics simulation provided more detailed information on the binding modes of compounds and SHP2 protein. These preliminary results could provide a possible opportunity for the development of novel SHP2 inhibitors sensitive to SHP2 mutants with optimal potency and improved pharmacological properties.

MCU Up-regulation contributes to myocardial ischemia-reperfusion Injury through calpain/OPA-1-mediated mitochondrial fusion/mitophagy Inhibition.

Mitochondrial dynamic disorder is involved in myocardial ischemia/reperfusion (I/R) injury. To explore the effect of mitochondrial calcium uniporter (MCU) on mitochondrial dynamic imbalance under I/R and its related signal pathways, a mouse myocardial I/R model and hypoxia/reoxygenation model of mouse cardiomyocytes were established. The expression of MCU during I/R increased and related to myocardial injury, enhancement of mitochondrial fission, inhibition of mitochondrial fusion and mitophagy. Suppressing MCU functions by Ru360 during I/R could reduce myocardial infarction area and cardiomyocyte apoptosis, alleviate mitochondrial fission and restore mitochondrial fusion and mitophagy. However, spermine administration, which could enhance MCU function, deteriorated the above-mentioned myocardial cell injury and mitochondrial dynamic imbalanced. In addition, up-regulation of MCU promoted the expression and activation of calpain-1/2 and down-regulated the expression of Optic atrophy type 1 (OPA1). Meantime, in transgenic mice (overexpression calpastatin, the endogenous inhibitor of calpain) I/R model and OPA1 knock-down cultured cell. In I/R models of transgenic mice over-expressing calpastatin, which is the endogenous inhibitor of calpain, and in H/R models with siOPA1 transfection, inhibition of calpains could enhance mitochondrial fusion and mitophagy, and inhibit excessive mitochondrion fission and apoptosis through OPA1. Therefore, we conclude that during I/R, MCU up-regulation induces calpain activation, which down-regulates OPA1, consequently leading to mitochondrial dynamic imbalance.

Improved specificity of TALE-based genome editing using an expanded RVD repertoire.

Transcription activator-like effector (TALE) proteins have gained broad appeal as a platform for targeted DNA recognition, largely owing to their simple rules for design. These rules relate the base specified by a single TALE repeat to the identity of two key residues (the repeat variable diresidue, or RVD) and enable design for new sequence targets via modular shuffling of these units. A key limitation of these rules is that their simplicity precludes options for improving designs that are insufficiently active or specific. Here we address this limitation by developing an expanded set of RVDs and applying them to improve the performance of previously described TALEs. As an extreme example, total conversion of a TALE nuclease to new RVDs substantially reduced off-target cleavage in cellular studies. By providing new RVDs and design strategies, these studies establish options for developing improved TALEs for broader application across medicine and biotechnology.

Application of color-coded quantitative digital subtraction angiography in predicting the outcomes of immediate type I and type III endoleaks.

OBJECTIVE: Immediate type I and type III endoleaks after endovascular aneurysm repair (EVAR) could be persistent or temporary. Reintervention is necessary for persistent ones. Color-coded quantitative digital subtraction angiography (CQDSA) could provide a quantitative evaluation of the endoleak hemodynamics. We aimed to use CQDSA to quantify immediate type I and type III endoleaks after EVAR and to find a practical way to predict their outcomes. METHODS: Between January 2012 and December 2014, 485 consecutive patients with abdominal aortic aneurysms underwent EVAR at our institution. Thirty-five patients (31 men, four women) with slight immediate type I and type III endoleaks after EVAR were recruited in the prospective observational nested case-control study. After at least 6 months of follow-up, these patients were divided into two groups based on endoleak-related adverse events. Their final intraprocedure DSA images were collected and converted into a single polychromatic image for CQDSA measurements. The parameter time to peak (TTP) of the selected regions of interest in the endoleak area and a reference area at the same latitude within the stent graft were derived from the time-intensity curve. A receiver operating characteristic curve was generated to test the ability of TTP to predict endoleak-related adverse events and to identify the optimal cutoff value. RESULTS: Finally, two groups were identified: 12 patients with endoleak-related adverse events and 23 patients without endoleak-related adverse events. Median follow-up time for all patients was 24.0 months. Age, gender, and comorbidity were similar in these two groups. TTP was significantly lower in patients with endoleak-related adverse events (P = .002). The risk of endoleak-related adverse events was significantly higher in patients with mixed-type endoleak than in those with simple-type endoleak (P = .003). According to the receiver operating characteristic curves, TTP ≤5 seconds reached the maximal sum of sensitivity and specificity (sensitivity, 91.67%; specificity, 69.57%). Logistic regression analysis confirmed that TTP ≤5 seconds (P = .016) and mixed-type endoleak (P = .044) were associated with higher risk of endoleak-related adverse events. CONCLUSIONS: CQDSA could help predict the outcomes of immediate type I or type III endoleaks after EVAR. TTP ≤5 seconds and mixed-type endoleak were two potential predictors of endoleak-related adverse events. This approach may offer an objective assessment of such immediate endoleaks and reference for immediate reintervention or conservative therapy.

CTAB-Assisted Fabrication of Bi2WO6 Thin Nanoplates with High Adsorption and Enhanced Visible Light-Driven Photocatalytic Performance.

Two-dimensional thin Bi2WO6 nanoplates have been fabricated using a cetyltrimethylammonium bromide (CTAB)-assisted hydrothermal method. We investigated the proposed formation mechanism based on the crystalline structures of the thin Bi2WO6 nanoplates. The high adsorption ability and excellent visible-light driven photocatalytic activities of the Bi2WO6 nanoplates were illustrated, in view of exposed (001) facets of nanoplates possessing faster separation of photo-generated charge carriers and increased catalytically active sites. Such a cost-effective way to obtain Bi2WO6 nanoplates offers new possibilities for the design of adsorptive semiconductor photocatalysts with strengthened photocatalytic activities.

Green and Tunable Decoration of Graphene with Spherical Nanoparticles Based on Laser Ablation in Water: A Case of Ag Nanoparticle/Graphene Oxide Sheet Composites.

A simple and green strategy is presented to decorate graphene with nanoparticles, based on laser ablation of targets in graphene auqeous solution. Ag and graphene oxide (GO) are chosen as model materials. The surface of GO sheets is strongly anchored with spherical Ag nanoparticles. The density and size of the Ag nanoparticles can be easily tuned by laser ablation conditions. Further, the GO sheets can be decorated with other nanoparticles from simple metals or semiconductors to multicomponent hybrids. Additionally, the Ag nanoparticle/GO sheet colloids can be utilized as blocks to build three-dimensional structures, such as sandwich membranes by evaporation-induced self-assembly. These graphene-based composite materials could be very useful in catalysis, sensors, and nanodevices. Particularly, the Ag nanoparticle/GO sheet sandwich composite membranes exhibit excellent surface-enhanced Raman scattering performance and possess the huge potential in trace-detecting persistent organic pollutants in the environment.

Precise genome modification in the crop species Zea mays using zinc-finger nucleases.

Agricultural biotechnology is limited by the inefficiencies of conventional random mutagenesis and transgenesis. Because targeted genome modification in plants has been intractable, plant trait engineering remains a laborious, time-consuming and unpredictable undertaking. Here we report a broadly applicable, versatile solution to this problem: the use of designed zinc-finger nucleases (ZFNs) that induce a double-stranded break at their target locus. We describe the use of ZFNs to modify endogenous loci in plants of the crop species Zea mays. We show that simultaneous expression of ZFNs and delivery of a simple heterologous donor molecule leads to precise targeted addition of an herbicide-tolerance gene at the intended locus in a significant number of isolated events. ZFN-modified maize plants faithfully transmit these genetic changes to the next generation. Insertional disruption of one target locus, IPK1, results in both herbicide tolerance and the expected alteration of the inositol phosphate profile in developing seeds. ZFNs can be used in any plant species amenable to DNA delivery; our results therefore establish a new strategy for plant genetic manipulation in basic science and agricultural applications.

Evaluation and application of modularly assembled zinc-finger nucleases in zebrafish.

Zinc-finger nucleases (ZFNs) allow targeted gene inactivation in a wide range of model organisms. However, construction of target-specific ZFNs is technically challenging. Here, we evaluate a straightforward modular assembly-based approach for ZFN construction and gene inactivation in zebrafish. From an archive of 27 different zinc-finger modules, we assembled more than 70 different zinc-finger cassettes and evaluated their specificity using a bacterial one-hybrid assay. In parallel, we constructed ZFNs from these cassettes and tested their ability to induce lesions in zebrafish embryos. We found that the majority of zinc-finger proteins assembled from these modules have favorable specificities and nearly one-third of modular ZFNs generated lesions at their targets in the zebrafish genome. To facilitate the application of ZFNs within the zebrafish community we constructed a public database of sites in the zebrafish genome that can be targeted using this archive. Importantly, we generated new germline mutations in eight different genes, confirming that this is a viable platform for heritable gene inactivation in vertebrates. Characterization of one of these mutants, gata2a, revealed an unexpected role for this transcription factor in vascular development. This work provides a resource to allow targeted germline gene inactivation in zebrafish and highlights the benefit of a definitive reverse genetic strategy to reveal gene function.

Efficient white light emitting diodes based on Cu-doped ZnInS/ZnS core/shell quantum dots.

We report the fabrication of efficient white light-emitting diodes (WLEDs) based on Cu : ZnInS/ZnS core/shell quantum dots (QDs) with super large Stokes shifts. The composition-controllable Cu : ZnInS/ZnS QDs with a tunable emission from deep red to green were prepared by a one-pot noninjection synthetic approach. The high performance Cu : ZnInS QD-WLEDs with the colour rendering index up to 96, luminous efficacy of 70-78 lm W(-1), and colour temperature of 3800-5760 K were successfully fabricated by integration of red and green Cu-doped QDs. Negligible energy transfer between Cu-doped QDs was clearly found by measuring the photoluminescence lifetimes of the QDs, consistent with the small spectral overlap between QD emission and absorption. The experimental results indicated low toxic Cu : ZnInS/ZnS QDs could be suitable for solid state lighting.

Efficient generation of a biallelic knockout in pigs using zinc-finger nucleases.

Zinc-finger nucleases (ZFNs) are powerful tools for producing gene knockouts (KOs) with high efficiency. Whereas ZFN-mediated gene disruption has been demonstrated in laboratory animals such as mice, rats, and fruit flies, ZFNs have not been used to disrupt an endogenous gene in any large domestic species. Here we used ZFNs to induce a biallelic knockout of the porcine α1,3-galactosyltransferase (GGTA1) gene. Primary porcine fibroblasts were treated with ZFNs designed against the region coding for the catalytic core of GGTA1, resulting in biallelic knockout of ∼1% of ZFN-treated cells. A galactose (Gal) epitope counter-selected population of these cells was used in somatic cell nuclear transfer (SCNT). Of the resulting six fetuses, all completely lacked Gal epitopes and were phenotypically indistinguishable from the starting donor cell population, illustrating that ZFN-mediated genetic modification did not interfere with the cloning process. Neither off-target cleavage events nor integration of the ZFN-coding plasmid was detected. The GGTA1-KO phenotype was confirmed by a complement lysis assay that demonstrated protection of GGTA1-KO fibroblasts relative to wild-type cells. Cells from GGTA1-KO fetuses and pooled, transfected cells were used to produce live offspring via SCNT. This study reports the production of cloned pigs carrying a biallelic ZFN-induced knockout of an endogenous gene. These findings open a unique avenue toward the creation of gene KO pigs, which could benefit both agriculture and biomedicine.

MOF-derived xPd-NPs@ZnO porous nanocomposites for ultrasensitive ppb-level gas detection with photoexcitation: Design, diverse-scenario characterization, and mechanism.

Metal-organic frameworks (MOFs) have been regarded as a potential candidate with great application prospects in the field of gas sensing. Although plenty of previous efforts have been made to improve the sensitivity of MOF-based nanocomposites, it is still a great challenge to realize ultrafast and high selectivity to typical flammable gases in a wide range. Herein, porous xPd-NPs@ZnO were prepared by optimized heat treatment, which maintained the controllable morphology and high specific surface area of 471.08 m2g-1. The coupling effects of photoexcitation and thermal excitation on the gas-sensing properties of nanocomposites were systematically studied. An ultrafast high response of 88.37 % towards 200 ppm H2 was realized within 1.2 s by 5.0Pd-NPs@ZnO under UV photoexcitation. All xPd-NPs@ZnO exhibited favorable linearity over an extremely wide range (0.2-4000 ppm H2) of experimental tests, indicating the great potential in quantitative detection. The photoexcited carriers enabled the nanocomposites a considerable response at lower operating temperatures, which made diverse applications of the sensors. The mechanisms of high sensing performances and the photoexcitation enhancement were systematically explained by DFT calculations. This work provides a solid experimental foundation and theoretical basis for the design of controllable porous materials and novel photoexcited gas detection.

Prediction of intraoperative red blood cell transfusion in valve replacement surgery: machine learning algorithm development based on non-anemic cohort.

Background: Our study aimed to develop machine learning algorithms capable of predicting red blood cell (RBC) transfusion during valve replacement surgery based on a preoperative dataset of the non-anemic cohort. Methods: A total of 423 patients who underwent valvular replacement surgery from January 2015 to December 2020 were enrolled. A comprehensive database that incorporated demographic characteristics, clinical conditions, and results of preoperative biochemistry tests was used for establishing the models. A range of machine learning algorithms were employed, including decision tree, random forest, extreme gradient boosting (XGBoost), categorical boosting (CatBoost), support vector classifier and logistic regression (LR). Subsequently, the area under the receiver operating characteristic curve (AUC), accuracy, recall, precision, and F1 score were used to determine the predictive capability of the algorithms. Furthermore, we utilized SHapley Additive exPlanation (SHAP) values to explain the optimal prediction model. Results: The enrolled patients were randomly divided into training set and testing set according to the 8:2 ratio. There were 16 important features identified by Sequential Backward Selection for model establishment. The top 5 most influential features in the RF importance matrix plot were hematocrit, hemoglobin, ALT, fibrinogen, and ferritin. The optimal prediction model was CatBoost algorithm, exhibiting the highest AUC (0.752, 95% CI: 0.662-0.780), which also got relatively high F1 score (0.695). The CatBoost algorithm also showed superior performance over the LR model with the AUC (0.666, 95% CI: 0.534-0.697). The SHAP summary plot and the SHAP dependence plot were used to visually illustrate the positive or negative effects of the selected features attributed to the CatBoost model. Conclusions: This study established a series of prediction models to enhance risk assessment of intraoperative RBC transfusion during valve replacement in no-anemic patients. The identified important predictors may provide effective preoperative interventions.