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Reconnection after mitral isthmus (MI) block with radiofrequency ablation is common.

Polyvinylpyrrolidone-iodine (PVP-I) complexes are widely used in the medical and health field due to its strong antimicrobial properties and good biocompatibility, but their water solubility negates the possibility to be used as a wound dressing. In this work, the problem of PVP dissolving in water was solved by the method of thermally crosslinking, and it was found that the thermally crosslinked PVP nanofiber heated at 170 °C for 6 h had good liquid absorption capacity, stability and good fiber morphology. In addition, the thermally crosslinked PVP nanofiber is complexed with I2to endow it with excellent antibacterial properties. It has been demonstrated to have good biocompatibility through cytotoxicity and hemolysis experiments, which provides the possibility for it to be a dressing for the treatment of infectious wounds.

Medicinal plants are a valuable source of essential medicines and herbal products for healthcare and disease therapy. Compared with chemical synthesis and extraction, the biosynthesis of natural products is a very promising alternative for the successful conservation of medicinal plants, and its rapid development will greatly facilitate the conservation and sustainable utilization of medicinal plants. Here, we summarize the advances in strategies and methods concerning the biosynthesis and production of natural products of medicinal plants. The strategies and methods mainly include genetic engineering, plant cell culture engineering, metabolic engineering, and synthetic biology based on multiple “OMICS” technologies, with paradigms for the biosynthesis of terpenoids and alkaloids. We also highlight the biosynthetic approaches and discuss progress in the production of some valuable natural products, exemplifying compounds such as vindoline (alkaloid), artemisinin and paclitaxel (terpenoids), to illustrate the power of biotechnology in medicinal plants.

To report the global, regional, and national estimates of knee osteoarthritis (OA) burden and associated risk factors (high body mass index [BMI]) by age, sex, and sociodemographic index (SDI) for 204 countries from 1990 to 2019. We analyzed the prevalence, incidence, years lived with disability (YLDs), and age‐standardized rates of knee OA using data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019. Estimates of the knee OA burden were derived from data modeled using a Bayesian meta‐regression analytical tool (DisMod‐MR 2.1). The global prevalence of knee OA in 2019 was ~364.6 million (95% uncertainty interval [95% UI] 315.3 to 417.4). The age‐standardized prevalence in 2019 was 4,376.0 per 100,000 (95% UI 3,793.0 to 5,004.9), an increase of 7.5% between 1990 and 2019. There were ~29.5 million incident cases of knee OA in 2019 (95% UI 25.6 to 33.7), with an age‐standardized incidence of 350.3 per 100,000 (95% UI 303.4 to 398.9). The global age‐standardized YLD resulting from knee OA was 138.2 (95% UI 68.5 to 281.3) per 100,000 population in 2019, an increase of 7.8% (95% UI 7.1 to 8.4) from 1990. Globally in 2019, 22.4% (95% UI 12.1 to 34.2) of YLD resulting from knee OA was attributable to high BMI, an increase of 40.5% since 1990. The prevalence, incidence, YLDs, and age‐standardized rates of knee OA increased substantially in most countries and regions from 1990 to 2019. Continuous monitoring of this burden is important for establishing appropriate public prevention policies and raising public awareness, especially in high‐ and high–middle SDI regions.

Although surgical resection provides a straightforward and effective treatment for most malignant solid tumors, tumor recurrence and acute postoperative pain continue to be two big problems associated with this treatment. To resolve these problems, a nanocrystal composite slow-releasing ropivacaine and doxorubicin was fabricated in this study. Briefly, a self-assembling peptide was used to form nanoparticle complexes with the two drugs, based on which homogeneous nanocrystals were obtained by adjusting the pH. In cultured human melanoma cells, the nanocrystals exhibited improved antitumor activity due to a synergistic effect and enhanced cellular uptake of the two drugs. On the other hand, the nanocrystals could slowly release ropivacaine in vitroand in vivo, generating long-acting analgesia on the rat sciatic nerve block model and incisional pain model. On a nude mouse tumor resection model, the nanocrystals simultaneously suppressed the recurrence of solid tumor and relieved postoperative pain, indicating a potential postoperative treatment for tumor resection patients. This nanocrystal system also suggested a promising and facile strategy for developing multifunctional formulations combining different drugs, which could achieve better therapeutic outcomes in a synergistic and sustained manner.

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Osimertinib is recommended as the first-line treatment of advanced non-small cell lung cancer (NSCLC) in adults. The most commonly reported adverse events for osimertinib are skin effects, diarrhea, nausea, decreased appetite, fatigue, paronychia, and stomatitis. Severe thrombocytopenia is rarely reported. We present a case of severe thrombocytopenia in a 70-year-old NSCLC patient caused by osimertinib combined with sitagliptin. After remission of thrombocytopenia, the patient was well tolerated with osimertinib re-administration in the absence of sitagliptin. We speculated that declined platelet count might be related to the interaction between osimertinib and sitagliptin by acting with a synergistic effect on platelets. Osimertinib rechallenge can be considered after discontinuing drugs that may contribute to platelet decline if possible, and making a careful assessment of complete blood count and risk of bleeding.

High-performance polymers (HPPs) have good thermal and mechanical properties even under harsh environments and are widely used in aerospace, microelectronics, automobile, and other fields. Traditional employed highly cross-linked HPPs tend to fail in their performance at high temperatures due to the structural defects, which remains a challenge in both scientific investigation and engineering applications for decades. Herein, we employed a cyclosiloxane hybrid polymer (CHP) to investigate a new design strategy to compensate for the structural defects in the highly cross-linked network, which avoids catastrophic failure at high temperatures. Hyperbranched o-carborane was synthesized and used to compensate for structural defects of CHP. The antioxidant ability and toughness of CHP were improved, and it had better mechanical properties over a wide temperature range. Moreover, the anchoring effect of hyperbranched o-carborane in the cyclosiloxane network was systematically investigated. The hyperbranched o-carborane cage could stabilize the CHP network under dynamic thermal stress through anchoring the dangling bonds, and the highly cross-linked network suppressed the disintegration of the o-carborane cage by anchoring boron atoms of the o-carborane cage. Furthermore, the structural evolution mechanism of the o-carborane cage with increasing temperature was proposed. This fundamental research provided new insights into the design of HPPs for harsh environments.

The RAS–mitogen-activated protein kinase (MAPK) pathway includes KSR, RAF, MEK and the phospho-regulatory sensor 14-3-3. Specific assemblies among these components drive various diseases and likely dictate efficacy for numerous targeted therapies, including allosteric MEK inhibitors (MEKi). However, directly measuring drug interactions on physiological RAS–MAPK complexes in live cells has been inherently challenging to query and therefore remains poorly understood. Here we present a series of NanoBRET-based assays to quantify direct target engagement of MEKi on MEK1 and higher-order MEK1-bound complexes with ARAF, BRAF, CRAF, KSR1 and KSR2 in the presence and absence of 14-3-3 in living cells. We find distinct MEKi preferences among these complexes that can be compiled to generate inhibitor binding profiles. Further, these assays can report on the influence of the pathogenic mutants such as BRAF-V600E mutant on MEKi binding. Taken together, these approaches can be used as a platform to screen for compounds intended to target specific complexes in the RAS–MAPK cascade.

The exposure dose of reclaimed water is an important indicator to evaluate the potential risk of water reuse. This study summarized a general calculation model for the exposure dose of reclaimed water, taking into account the three exposure routes of oral intake, skin absorption and inhalation. The differences of reused scenarios, geographical and meteorological conditions, and evaluated populations were considered in the model. The exposure of reclaimed water in practical application was also studied. The daily intakes of reclaimed water of different populations could vary from 0.01 to 49 ​mL. The average annual exposure dose of reclaimed water in the regular reused scenarios was 2444 ​mL. Professional activities (mean was 42.63 ​L and median was 9.81 ​L) had a higher annual exposure dose than non-professional activities (mean was 7.91 ​L and median was 0.90 ​L). Annual exposure doses to road dust reduction, garden greening, road rinse and manual car washing were higher than the average for the professionals. Future research can focus on the exposure risk of reclaimed water of the above activities.

Urban and environmental researchers seek to obtain building features (e.g., building shapes, counts, and areas) at large scales. However, blurriness, occlusions, and noise from prevailing satellite images severely hinder the performance of image segmentation, super-resolution, or deep-learning-based translation networks. In this article, we combine globally available satellite images and spatial geometric feature datasets to create a generative modeling framework that enables obtaining significantly improved accuracy in per-building feature estimation and the generation of visually plausible building footprints. Our approach is a novel design that compensates for the degradation present in satellite images by using a novel deep network setup that includes segmentation, generative modeling, and adversarial learning for instance-level building features. Our method has proven its robustness through large-scale prototypical experiments covering heterogeneous scenarios from dense urban to sparse rural. Results show better quality over advanced segmentation networks for urban and environmental planning, and show promise for future continental-scale urban applications.

Selenium (Se) is an essential trace element involved in nearly all human physiological processes but suffers from a narrow margin between benefit and toxicity. The nanoform of selenium has been proven shown to be more bioavailable and less toxic, yet significant challenges remain regarding the efficient and feasible synthesis of biologically active nanoselenium. In addition, although nanoselenium has shown a variety of biological activities, more interesting nanoselenium features are expected. In this work, hydrosoluble nanoselenium termed Nano-Se in the zero oxidation state was synthesized between gray Se and PEG. A zebrafish screen was carried out in zebrafish larvae cocultured with Nano-Se. Excitingly, Nano-Se promoted the action of the FGFR, Wnt, and VEGF signaling pathways, which play crucial roles in tissue regeneration. As expected, Nano-Se not only achieved the regeneration of zebrafish tail fins and mouse skin but also promoted the repair of skin in diabetic mice while maintaining a profitable safe profile. In brief, the Nano-Se reported here provided an efficient and feasible method for bioactive nanoselenium synthesis and not only expanded the application of nanoselenium to regenerative medicine but also likely reinvigorated efforts for discovering more peculiarunique biofunctions of nanoselenium in a great variety of human diseases.

ABSTRACTThe environmental traffic assignment problem in the bimodal network with electric vehicles (EVs) and gasoline vehicles (GVs) has become a hot topic recently. However, few previous works consider the psychological difference between EV users and GV users in terms of environmental awareness , in order to fill in this research gap, we formulate an environment-oriented mixed-behavior user equilibrium (EMUE) model to distinguish the route choice criterion between EV users and GV users by considering the Pro-environmental behavior (PEB) of EV users. . We formulate a bi-objective optimization model and propose a differentiable road pricing scheme for EV and GV users to manage the congestion and emissions simultaneously. We investigate whether the differentiable road pricing can decentralize the Pareto-efficient flow as a unique mixed-behavior equilibrium. Moreover, we conduct numerical experiments based on the Sioux Falls network and the existing urban network in Qianhai Zone to evaluate the effectiveness of the proposed pricing scheme, models and algorithms.

With increasing interest in the rapid development of customized ceramic electronics, hybrid additive manufacturing (HAM) technology has become a competent alternative to traditional solutions such as printed circuit boards and cofired ceramic technology. Herein, the novel HAM technology is proposed by combining a dispensing three-dimensional (3D) printing process and selectively laser-activated electroless plating for fabricating 3D fully functional ceramic electronic products. An appropriative 3D-printable and metalizable low-temperature cofired ceramic slurry is developed to build the green body of ceramic electronics. After the debinding and sintering process, the 3D ceramic structure can be selectively laser-activated and then electrolessly plated to achieve electronic functionality. The thickness of the plated copper layer approaches 10 μm after 4 h of plating, and the electrical conductivity is 5.5 × 107S m–1, which is close to pure copper (5.8 × 107S m–1). To reduce the surface roughness of the laser-activated ceramic surface and thereby enhance the conductivity of the copper layer, the laser parameters are optimized as a 1250 mm s–1scan speed, a 0.4 W laser power, and a 20 kHz laser-spot frequency. A high-power 3D light-emitting diode circuit board with an internal cooling channel is successfully developed to prove the feasibility of this HAM technology for customizing fully functional 3D conformal ceramic electronics.

Imine-linked covalent organic frameworks (COFs) have received widespread attention because of their structure features such as high crystallinity and tunable pores. However, the intrinsic reversibility of the imine bond leads to the poor stability of imine-linked COFs under strong acid conditions. Also, their thermal stability is significantly lower than that of many other COFs. Herein, we report for the first time that the reversible imine bonds in the skeleton of COFs can be locked through the asymmetric hydrophosphonylation reaction of phosphite. The functionalized COFs not only retain the crystallinity and porous structure but also exhibit evidently improved chemical and thermal stabilities. In addition, the phosphorous acid groups generated by acidic hydrolysis attached to the skeleton endow the COFs with good intrinsic proton conductivity. Due to the diversity of phosphite derivatives and imine-linked COFs, this work may provide an avenue for extending the COF structures and functions through the asymmetric hydrophosphonylation reaction.

In this study, machine learning prediction models (MLPMs), including artificial neural network (ANN), support vector regression (SVR), K-nearest neighbors (KNN), and random forest (RF) algorithms, were developed to predict the peak shear stress values and shear stress-displacement curves of rock joints. The database used contained 693 records of peak shear stress and 162 original shear stress-displacement curves derived from direct shear tests. The results demonstrated that the MLPMs provided reliable predictions for shear stress, with the mean squared errors (MSEs) between their predicted and measured shear stress varying from 0.003 to 0.069 and the coefficients of determination (R2values) varying from 0.964 to 0.998. The feature importance values indicate that the joint surface roughness coefficient (JRC) is the most important influential factor in determining the peak shear stress, followed by the joint wall compressive strength (JCS), basic friction angle (φb), and shear surface area (As). Similarly, for the shear stress-displacement curve, the JRC is the dominant factor, followed by As, φb, and JCS. Additional direct shear tests were conducted for model validation. The validation shows that the MLPM predictions demonstrate improved consistency with the experimental results in relation to both the peak shear stress and peak shear displacement.

Objective. Limb loss experience is a type of body illusion characterized by the sensation of a missing limb or body part. We aimed to investigate the brain areas involved in this unusual somatosensory experience evoked by electric cortical stimulation with stereo‐electroencephalography electrodes. Methods. We retrospectively reviewed the data of patients with medical intractable epilepsy, from October 2015 to December 2020, who underwent stereo‐electroencephalography implantation and electric cortical stimulation in order to locate the epileptogenic zone and obtain a functional map. We included patients who reported experiences of limb loss during the process of electric cortical stimulation for functional mapping. Results. Three patients reported experiences of limb loss in the process of electric cortical stimulation. Limb loss experience (including the right hand, right upper limb and right side of the body) occurred when the cortex of the left posterior insula, posterior dorsal cingulate and parietal operculum were stimulated. Significance. Limb loss experience can be evoked by electric cortical stimulation of the posterior insula, parietal operculum, and posterior cingulate cortex, and provides additional evidence that these cortices play a role in the integration of body sensory perception.

The Ni–25%X (X=Fe, Co, Cu, molar fraction) solid solutions were prepared and then doped into MgH2through high-energy ball milling. The initial dehydrogenation temperatures of MgH2/Ni–25%X composites are all decreased by about 90 °C relative to the as-milled pristine MgH2. The Ni–25%Co solid solution exhibits the most excellent catalytic effect, and the milled MgH2/Ni–25%Co composite can release 5.19 wt.% hydrogen within 10 min at 300 °C, while the as-milled pristine MgH2can only release 1.78 wt.% hydrogen. More importantly, the dehydrogenated MgH2/Ni–25%Co composite can absorb 5.39 wt.% hydrogen at 275 °C within 3 min. The superior hydrogen sorption kinetics of MgH2/Ni–25%Co can be ascribed to the actual catalytic effect of in-situ formed Mg2Ni(Co) compounds. First-principles calculations show that the hydrogen absorption/desorption energy barriers of Mg/MgH2systems decrease significantly after doping with transition metal atoms, which interprets well the improved hydrogen sorption properties of MgH2catalyzed by Ni-based solid solutions.

Structurally unique 2,2-disubstituted indolin-3-ones with a quaternary carbon center have been constructed through a novel C–C bond formation at the C3 position of Ugi N-acylamino amide adducts employing an organic base-mediated Dieckmann condensation. This facile, flexible protocol can be fine-tuned to construct drug-like pyrazino[1,2-a]indole fragments with the same quaternary carbon center only through the variation of the acid part in Ugi input. This novel and expeditious methodology has a broad scope and can rapidly generate the drug-like indolin-3-one core.

The genetic signature of natural CRISPR-Cas systems were first noted in a 1989 publication and were characterized in detail from 2002 to 2007, culminating in the first report of a prokaryotic adaptive immune system. Since then, CRISPR-Cas enzymes have been adapted into molecular biology tools that have transformed genetic engineering across domains of life. In this feature article, we describe origins, uses and futures of CRISPR-Cas enzymes in genetic engineering: we highlight advances made in the past 10 years. Central to these advances is appreciation of interplay between CRISPR engineering and DNA repair. We highlight how this relationship has been manipulated to create further advances in the development of gene editing.

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[Display omitted] • Dynamic damage behavior of nanocrystalline NiTi alloy is studied at the atomic scale. • NiTi alloy exhibits similar damage response as ductile metallic materials. • The void evolution under high strain rate is strongly dependent upon grain size effect. • The sensitivity of fracture performance to grain size is significant. This study focused on the effect of grain size (GS) on dynamic damage performance of nano-crystalline nickel titanium (NC NiTi) alloy. Molecular dynamics simulations were conducted to triaxially expand it at a high strain rate (4 × 109 s−1), while the temperature and initial pressure remained 300 K and 0 bar, respectively. It was discovered that the superelastic NiTi alloy exhibited the similar damage response as ductile metallic materials, which was vividly characterized by void nucleation, growth, and coalescence. The stress-strain curves demonstrated that the void nucleations always occurred near the start of the strain softening region at various grain sizes. Interestingly, it was discovered that the void evolution was characteristic of an almost double-linear behavior, and the piecewise linearity became more prominent for the void volume fraction increase at larger grain size. More importantly, the fracture behavior was found to be strongly dependent upon the grain size in the NC NiTi alloy. For small grain size, the existing voids propagated along the grain boundaries and in the grains, leading to intergranular and transgranular fracture. Contrarily, the intergranular-dominated fracture was responsible for the void propagation in the large grain. In addition, the starting time, ending time, and threshold of void nucleation were found to be weak sensitivity to GS, and a reverse effect was appropriate to the void growth. The results highlighted that as the GS increased, more complete stress relaxation and shorter duration time were produced, leading to larger void volume fraction and faster growth rate. [ABSTRACT FROM AUTHOR]