Carbene-Catalyzed [4+2] Cycloaddition of Cyclobutenones and Isatins for Quick Access to Chiral Chlorine-Containing Spirocyclic δ-Lactones.

Here we report a carbene-catalyzed enantio- and diastereoselective [4+2] cycloaddition reaction of cyclobutenones with isatins for the quick and efficient synthesis of spirocyclic δ-lactones bearing a chiral chlorine. A broad range of substrates with various substitution patterns proceed smoothly in this reaction, with the spirooxindole δ-lactone products afforded in generally good to excellent yields and optical purities under mild reaction conditions.

The value of cardiopulmonary comorbidity in patients with acute large vessel occlusion stroke undergoing endovascular thrombectomy: a retrospective, observational cohort study.

BACKGROUND: Chronic lung and heart diseases are more likely to lead an intensive end point after stroke onset. We aimed to investigate characteristics and outcomes of endovascular thrombectomy (EVT) in patients with acute large vessel occlusion stroke (ALVOS) and identify the role of comorbid chronic cardiopulmonary diseases in ALVOS pathogenesis. METHODS: In this single-center retrospective study, 191 consecutive patients who underwent EVT due to large vessel occlusion stroke in neurological intensive care unit were included. The chronic cardiopulmonary comorbidities and several conventional stroke risk factors were assessed. The primary efficacy outcome was functional independence (defined as a mRS of 0 to 2) at day 90. The primary safety outcomes were death within 90 days and the occurrence of symptomatic intracranial hemorrhage(sICH). Univariate analysis was applied to evaluate the relationship between factors and clinical outcomes, and logistic regression model were developed to predict the prognosis of ALVOS. RESULTS: Endovascular therapy in ALVOS patients with chronic cardiopulmonary diseases, as compared with those without comorbidity, was associated with an unfavorable shift in the NHISS 24 h after EVT [8(4,15.25) versus 12(7.5,18.5), P = 0.005] and the lower percentage of patients who were functionally independent at 90 days, defined as a score on the modified Rankin scale of 0 to 2 (51.6% versus 25.4%, P = 0.000). There was no significant between-group difference in the frequency of mortality (12.1% versus 14.9%, P = 0.580) and symptomatic intracranial hemorrhage (13.7% versus 19.4%, P = 0.302) or of serious adverse events. Moreover, a prediction model showed that existence of cardiopulmonary comorbidities (OR = 0.456, 95%CI 0.209 to 0.992, P = 0.048) was independently associated with functional independence at day 90. CONCLUSIONS: EVT was safe in ALVOS patients with chronic cardiopulmonary diseases, whereas the unfavorable outcomes were achieved in such patients. Moreover, cardiopulmonary comorbidity had certain clinical predictive value for worse stroke prognosis.

Enhanced burn wound healing by controlled-release 3D ADMSC-derived exosome-loaded hyaluronan hydrogel.

Adipose mesenchymal stem cell (ADMSC)-derived exosomes (ADMSC-Exos) have shown great potential in regenerative medicine and been evidenced benefiting wound repair such as burns. However, the low yield, easy loss after direct coating, and no suitable loading system to improve their availability and efficacy hinder their clinical application for wound healing. And few studies focused on the comparison of biological functions between exosomes derived from different culture techniques, especially in exosome-releasing hydrogel system. Therefore, we designed a high-performance exosome controllable releasing hydrogel system for burn wound healing, namely loading 3D-printed microfiber culture-derived exosomes in a highly biocompatible hyaluronic acid (HA). In this project, we compared the biological functions in vitro and in a burn model among exosomes derived from the conventional two-dimensional (2D) plate culture (2D-Exos), microcarrier culture (2.5D-Exos), and 3D-printed microfiber culture (3D-Exos). Results showed that compared with 2D-Exos and 2.5D-Exos, 3D-Exos promoted HACATs and HUVECs cell proliferation and migration more significantly. Additionally, 3D-Exos had stronger angiogenesis-promoting effects in tube formation of (HUVECs) cells. Moreover, we found HA-loaded 3D-Exos showed better burn wound healing promotion compared to 2D-Exos and 2.5D-Exos, including accelerated burn wound healing rate and better collagen remodeling. The study findings reveal that the HA-loaded, controllable-release 3D-Exos repair system distinctly augments therapeutic efficacy in terms of wound healing, while concurrently introducing a facile application approach. This system markedly bolsters the exosomal loading efficiency, provides a robust protective milieu, and potentiates the inherent biological functionalities of the exosomes. Our findings provide a rationale for more efficient utilization of high-quality and high-yield 3D exosomes in the future, and a novel strategy for healing severe burns.

Durable Ru Nanocrystal with HfO2 Modification for Acidic Overall Water Splitting.

Durable and efficient bi-functional catalyst, that is capable of both oxygen evolution reaction and hydrogen evolution reaction under acidic condition, are highly desired for the commercialization of proton exchange membrane water electrolysis. Herein, we report a robust L-Ru/HfO2 heterostructure constructed via confining crystalline Ru nanodomains by HfO2 matrix. When assembled with a proton exchange membrane, the bi-functional L-Ru/HfO2 catalyst-based electrolyzer presents a voltage of 1.57 and 1.67 V to reach 100 and 300 mA cm-2 current density, prevailing most of previously reported Ru-based materials as well as commercial Pt/C||RuO2 electrolyzer. It is revealed that the synergistic effect of HfO2 modification and small crystalline domain formation significantly alleviates the over-oxidation of Ru. More importantly, this synergistic effect facilitates a dual-site oxide path during the oxygen evolution procedure via optimization of the binding configurations of oxygenated adsorbates. As a result, the Ru active sites maintain the metallic state along with reduced energy barrier for the rate-determining step (*O→*OOH). Both of water adsorption and dissociation (Volmer step) are strengthened, while a moderate hydrogen binding is achieved to accelerate the hydrogen desorption procedure (Tafel step). Consequently, the activity and stability of acidic overall water splitting are simultaneously enhanced.

In Situ Defect Engineering in Carbon by Atomic Self-Activation to Boost the Accessible Low-Voltage Insertion for Advanced Potassium-Ion Full-Cells.

Enhancing the low-potential capacity of anode materials is significant in boosting the operating voltage of full-cells and constructing high energy-density energy storage devices. Graphitic carbons exhibit outstanding low-potential potassium storage performance, but show a low K+ diffusion kinetics. Herein, in situ defect engineering in graphitic nanocarbon is achieved by an atomic self-activation strategy to boost the accessible low-voltage insertion. Graphitic carbon layers grow on nanoscale-nickel to form the graphitic nanosphere with short-range ordered microcrystalline due to nickel graphitization catalyst. Meanwhile, the widely distributed K+ in the precursor induces the activation of surrounding carbon atoms to in situ generate carbon vacancies as channels. The graphite microcrystals with defect channels realize reversible K+ intercalation at low-potential and accessible ion diffusion kinetics, contributing to high reversible capacity (209 mAh g-1 at 0.05 A g-1 under 0.8 V) and rate capacity (103.2 mAh g-1 at 1 A g-1). The full-cell with Prussian blue cathode and graphitic nanocarbon anode maintains an obvious working platform at ca. 3.0 V. This work provides a strategy for the in situ design of carbon anode materials and gives insights into the potassium storage mechanism at low-potential for high-performance full-cells.

Low-intensity ultrasound combined with arsenic trioxide induced apoptosis of glioma via EGFR/AKT/mTOR.

AIMS: This study aimed to explore whether low-intensity ultrasound (LIUS) combined with low-concentration arsenic trioxide (ATO) could inhibit the proliferation of glioma and, if so, to clarify the potential mechanism. MAIN METHODS: The effects of ATO and LIUS alone or in combination on glioma were examined by CCK8, EdU, and flow cytometry assays. Western blot analysis was used to detect changes in expression of apoptosis-related proteins and their effects on the EGFR/AKT/mTOR pathway. The effects of ATO and LIUS were verified in vivo in orthotopic xenograft models, and tumor size, arsenic content in brain tissue, survival, and immunohistochemical changes were observed. KEY FINDINGS: LIUS enhanced the inhibitory effect of ATO on the proliferation of glioma, and EGF reversed the proliferation inhibition and protein changes induced by ATO and LIUS. The anti-glioma effect of ATO combined with LIUS was related to downstream AKT/mTOR pathway changes caused by inhibition of EGFR activation, which enhanced apoptosis of U87MG and U373 cells. In vivo experiments showed significant increases in arsenic content in brain tissue, as well as decreased tumor sizes and longer survival times in the combined treatment group compared with other groups. The trends of immunohistochemical protein changes were consistent with the in vitro results. SIGNIFICANCE: This study showed that LIUS enables ATO to exert anti-glioma effects at a safe dose by inhibiting the activation of EGFR and the downstream AKT/mTOR pathway to regulate apoptosis. LIUS in combination with ATO is a promising novel method for treating glioma and could improve patient prognosis.

Clinical evaluation of malignancy diagnosis of rare thyroid carcinomas by an artificial intelligent automatic diagnosis system.

PURPOSE: To evaluate the application value of a generally trained artificial intelligence (AI) automatic diagnosis system in the malignancy diagnosis of rare thyroid carcinomas, such as follicular thyroid carcinoma, medullary thyroid carcinoma, primary thyroid lymphoma and anaplastic thyroid carcinoma and compare the diagnostic performance with radiologists of different experience levels. METHODS: We retrospectively studied 342 patients with 378 thyroid nodules that included 196 rare malignant nodules by using postoperative pathology as the gold standard, and compared the diagnostic performances of three radiologists (one junior, one mid-level, one senior) and that of AI automatic diagnosis system. RESULTS: The accuracy of the AI system in malignancy diagnosis was 0.825, which was significantly higher than that of all three radiologists and higher than the best radiologist in this study by a margin of 0.097 with P-value of 2.252 × 10-16. The mid-level radiologist and senior radiologist had higher sensitivity (0.857 and 0.959) than that of the AI system (0.847) at the cost of having much lower specificity (0.533, 0.478 versus 0.802). The junior radiologist showed relatively balanced sensitivity and specificity (0.816 and 0.549) but both were lower than that of the AI system. CONCLUSIONS: The generally trained AI automatic diagnosis system showed high accuracy in the differential diagnosis of begin nodules and rare malignancy nodules. It may assist radiologists for screening of rare malignancy nodules that even senior radiologists are not acquainted with.

The value of ultrasound grayscale ratio in the diagnosis of papillary thyroid microcarcinomas and benign micronodules in patients with Hashimoto's thyroiditis: A two-center controlled study.

Objective: The value of ultrasound grayscale ratio (UGSR) in the diagnosis of papillary thyroid microcarcinomas (PTMCs) and benign micronodules (BMNs) has been recognized by some authors, but studies have not examined these aspects in patients with Hashimoto's thyroiditis (HT). This retrospective study investigated the value of UGSR in the diagnosis of PTMCs and BMNs in patients with HT using data from two medical centers. Methods: Ultrasound images of 428 PTMCs in 368 patients with HT and 225 BMNs in 181 patients with HT in center A were retrospectively analyzed and compared to the ultrasound images of 412 PTMCs in 324 patients with HT and 315 BMNs in 229 patients with HT in medical center B. All of the cases were surgically confirmed. The UGSR was calculated as the ratio of the grayscale value of lesions to the surrounding normal thyroid tissues. The optimal UGSR thresholds for the PTMCs and BMNs in patients with HT from the two medical centers were determined using a receiver operating characteristic (ROC) curve. Furthermore, other statistics, including the area under the curve (AUC), the optimal UGSR threshold, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy of the two medical centers, were pair analyzed in this study. Results: The UGSR of PTMCs and BMNs in patients with HT from medical center A were 0.513 (0.442, 0.592) and 0.857 (0.677, 0.977) (Z = -15.564, p = 0), and those from medical center B were 0.514 (0.431, 0.625) and 0.917 (0.705, 1.131) (Z = -15.564, p = 0). For both medical centers A and B, the AUC, optimal UGSR threshold, sensitivity, specificity, PPV, NPV, and diagnostic accuracy of the UGSR in differentiating between PTMCs and BMNs in patients with HT were 0.870 and 0.889, 0.68 and 0.70, 0.921 and 0.898, 0.747 and 0.759, 0.874 and 0.829, 0.832 and 0.848, and 0.861 and 0.836, respectively. There were no significant differences in the UGSR for the PTMCs between patients from the two medical centers (Z = -0.815, p = 0.415), while there was a significant difference in the UGSR of the BMNs between patients from the two medical centers (Z = -3.637, p = 0). Conclusion: In the context of HT, UGSR still has high sensitivity, accuracy, and stability in differentiating between PTMCs and BMNs, making it a complementary differentiator of thyroid imaging reporting and data systems. However, due to its low specificity, a comprehensive analysis of other ultrasound signs is required.

Fe Engineering on Ru Nanosheets for Enhanced Hydrogen Evolution in pH-Universal Media.

Fe-modified Ru nanosheets are achieved via preintercalated Al species serving as the self-sacrificial template. Benefiting from the amphoteric feature of Al and strong corrosion of Fe3+ ions, Fe is effectively incorporated into pristine Ru nanosheets. Correspondingly, the surface oxophilicity is improved, promoting the Volmer step. The charge density redistribution weakens hydrogen combination on Ru and thus accelerates the desorption kinetics (Heyrovsky step). Meanwhile, more defective sites are exposed, leading to an enhanced hydrogen production in pH-universal electrolytes.

Amorphous/Crystalline Heterophase Ruthenium Nanosheets for pH-Universal Hydrogen Evolution.

To design and synthesize heterophase noble-metal materials is of crucial importance owing to their unique structure and apparent properties. Ruthenium (Ru) is one of the most active candidates for hydrogen evolution reaction because of its low price compared with other precious metals, which is favorable for industrial hydrogen cycle operation. In this study, free-standing amorphous/crystalline Ru nanosheets are facilely synthesized through a controlled annealing method. Charge redistribution occurs at the phase interface because of the work function difference between amorphous and crystalline domains. The resulting structure and property are conductive to the adsorption and dissociation of water molecules, associated with optimized hydrogen interaction and enhanced binding between Ru atoms. Accordingly, electrochemical measurements demonstrate that the amorphous/crystalline heterophase Ru exhibits improved hydrogen evolution efficiency as compared with pure amorphous Ru and pure crystalline Ru, at pH-universal conditions. Specifically, only 16.7 mV overpotential is required to reach 10 mA cm-2 in 1.0 m KOH. Meanwhile, the heterophase structure displays a higher stability during operation than pure amorphous and crystalline structures. This study demonstrates the importance of phase engineering, broadens the Ru-based material family, and provides more insights for developing efficient metal materials.

Lewis acid mediated cyclization: synthesis of 2 spirocyclohexylindolines.

Herein, we report the synthesis of 2-spirocyclohexylindolines based on a Lewis acid mediated cyclization. This diastereoselective procedure provides the target structures in a straightforward way via dual activation.

Identifying the Active Site on Graphene Oxide Nanosheets for Ambient Electrocatalytic Nitrogen Reduction.

Identifying the active sites on graphene oxide (GO) nanosheets is of great importance. In situ electroreduction at different potentials is applied to control the oxygenated groups on GO surfaces. Both experiments and theoretical calculations suggest the C═O group is critical for N2 adsorption and activation, guaranteeing the ambient electrocatalytic N2 reduction.

Treatment with Minocycline Suppresses Microglia Activation and Reverses Neural Stem Cells Loss after Simulated Microgravity.

The present study aimed to investigate the effect of microglia on simulated microgravity-induced hippocampal neurogenesis reduction and the possible mechanism underlying. Adult rats were treated with tail suspension for different times and the changes of neural stem cells (NSCs) were examined by immunohistochemistry. Then, minocycline was used to inhibit the activation of microglia, and the numbers of microglia and NSCs were detected after microgravity. Additionally, liquid protein chip analysis was applied to detect proinflammatory factors in hippocampus in order to find out the cytokines responsible for microglia activation after microgravity. The results revealed that microgravity increased the numbers of Iba1+ cells and decreased the numbers of BrdU+ and DCX+ cells in hippocampus but did not affect the ratio of NeuN+/BrdU+ cells to the total number of BrdU+ cells. After treated with minocycline, activated microglia were suppressed and the reduction of NSCs induced by microgravity recovered. Besides, compared with the control, higher concentrations of INF-γ and TNF-α were detected in the rats treated with microgravity. Our study provides the first evidence that microglia-mediated inflammation plays an important part in microgravity-induced neurogenesis reduction in hippocampus, and INF-γ and TNF-α secreted by microglia might be the key factors in this process.

Activating Graphyne Nanosheet via sp-Hybridized Boron Modulation for Electrochemical Nitrogen Fixation.

Exploring new metal-free catalysts with high activity for nitrogen reduction reaction (NRR) is highly desirable but remains a big challenge. Graphyne (GY) is a typical two-dimensional carbon material with many excellent properties. However, the NRR has rarely been envisaged on a GY-based metal-free catalyst up to now. Density functional theory calculations reveal that although pristine GY is inactive for N2 reduction, boron modulation can endow it with efficient activity toward NRR. Natural bond orbitals analysis, spin/charge density distributions, and free energy change diagrams are performed and discussed. Three boron doping formats including sp2-substituted, sp-substituted, and adsorbed configuration are considered. The obtained data show sp-substitution will induce local moderate spin and charge densities at the boron site on the GY surface, which is convenient for N2 adsorption and activation, and conductive to N-related intermediates formation and transformation. Moreover, the incorporated sp-hybridized boron can provide one empty p orbital and one occupied p orbital around itself, which plays a key role as an electron reservoir to accept electrons from and donate electrons to the adsorbed N-related species, and thus facilitate N2 reduction and ammonia synthesis. Henceforth, it provides more opportunities for preparing GY and other carbon materials as efficient catalysts toward renewable energy conversion and storage.

Holey Ruthenium Nanosheets with Moderate Aluminum Modulation toward Hydrogen Evolution.

Theoretical calculations reveal that aluminum (Al) doping can effectively modulate the electronic structures of 2D ruthenium (Ru) catalysts. Moderate Al incorporation can endow Ru nanosheets with more delocalized electrons and optimal hydrogen adsorption Gibbs free energy, providing opportunities to achieve improved hydrogen evolution performance. Thus, Al-doped Ru nanosheets have been synthesized by a solvothermal strategy, in which they exhibit holey nanosheet structures and have more active sites exposed on the basal plane. The characterizations unraveling the Ru structure can be well maintained, and electrochemical measurements confirm the appropriate amount of Al modulation that can extremely enhance its hydrogen evolution activity.

Facile Preparation of Amorphous Fe-Co-Ni Hydroxide Arrays: A Highly Efficient Integrated Electrode for Water Oxidation.

Facile and fast synthesis of functional materials with high catalytic activity is highly demanded to meet the industrial production and applications such as electrolysis. In this study, Ni foam is employed as the current collector and Ni source, which is dipped into the mixture of Fe and Co metal ions solution at room temperature for several minutes, to in situ grow Fe-Co-Ni hydroxide arrays and construct the three-dimensional integrated electrode. This short-time preparation at room temperature is beneficial to avoid the rapid growth of the generated primary nanocrystallites and cause intimate interactions between Fe, Co, and Ni atoms. The obtained self-supported and vertically aligned Fe-Co-Ni hydroxides present an amorphous phase, which exhibit high activity with low overpotentials of 212 mV at 10 mA cm-2 and 319 mV at 100 mA cm-2, associated with a small Tafel slope of 52 mV dec-1 toward the oxygen evolution reaction.

Enhanced Oxygen Evolution Reaction for Single Atomic Co Catalyst via Support Modification: A Density Functional Theory Design Predication.

Design and development of a single atomic catalyst with high activity is desirable but proved to be very challenging in the renewable energy conversion and storage technologies. As a classic carbon material, graphene has many excellent properties and thus may be a good support to stabilize the isolated metal atoms. However, the oxygen evolution activity of a single cobalt atom supported on graphene is still very low. To improve its performance, support modification has been carried out based on a density functional theory framework for the design predication. In our theoretical study, two nitrogen formats are incorporated to the graphene substrates, including graphitic nitrogen and pyridine-like nitrogen, which are usually observed in experiment. The oxygen evolution process has been envisaged on these single cobalt atom catalysts via gas phase adsorption calculation. The electronic structure on the single Co active site can be effectively regulated by the support modification, which will contribute to its enhanced performance. Henceforth, free energy change diagrams, partial density of states, Raman spectra, and charge density difference are discussed. It is suggested that incorporating pyridine-like nitrogen on graphene is an ideal approach for the supported Co atom to achieve high OER activity, opening up new opportunity for the preparation and application of highly active and stable single atomic catalysts.

Design and discovery of thioether and nicotinamide containing sorafenib analogues as multikinase inhibitors targeting B-Raf, B-RafV600E and VEGFR-2.

New sorafenib derivatives containing thioether and nicotinamide moiety were designed and synthesized as B-Raf, B-RafV600E and VEGFR-2 multikinase inhibitors. Their in vitro enzymatic inhibitory activities against B-Raf, B-RafV600E and VEGFR-2 and their antiproliferative activities against HCT-116 and B16BL6 cell lines were evaluated and described. Most of the compounds showed potent activities against both cell lines and specific kinases. Compounds a1, b1 and c4, which exhibited the most potent inhibitory activities against B-Raf with IC50 of 21 nM, 27 nM and 17 nM, B-RafV600E with IC50 of 29 nM, 28 nM and 16 nM, VEGFR-2 with IC50 of 84 nM, 46 nM and 63 nM, respectively, and good antiproliferative activities, also demonstrated competitive antiangiogenic activities to sorafenib in in vitro HUVEC tube formation assay.

Anion Engineering on Free-Standing Two-Dimensional MoS2 Nanosheets toward Hydrogen Evolution.

On the basis of theoretical predictions, nitrogen was designed and incorporated into free-standing two-dimensional MoS2 nanosheets. Both the amount of electrochemical active sites on the surface and its intrinsic conductivity could be significantly increased as a result of anion engineering, which can extremely improve the electrocatalytic kinetics toward hydrogen evolution.

Free-Standing Holey Ni(OH)2 Nanosheets with Enhanced Activity for Water Oxidation.

Electrochemical water oxidation is the key technology in water-splitting reactions and rechargeable metal-air batteries, which is very attractive for renewable energy conversion and storage. Replacement of precious catalysts with cost-effective and highly active alternatives is still a great challenge. Herein, based on theoretical predictions, holey structures are designed and fabricated on the free-standing conventional 2D OER catalyst. By well-controlled defects engineering, uniform tiny holes are created on the free-standing Ni(OH)2 nanosheets via a sol-gel method, with the embedded Zn components as the template for holes production. The whole preparation process is feasible and effective to make full use of the basal plane of 2D nanomaterials, which can provide higher surface area, richer defects, more grain boundaries, and edge sites, as well as greater distorted surfaces. Meanwhile, these holes developed inside the sheet structure can supply tremendous permeable channels for ions adsorption and transportation, enable a fast interfacial charge transfer and accelerate the reaction process. The as-prepared 2D holey Ni(OH)2 nanostructures exhibit excellent catalytic performance toward electrochemical water oxidation, with lower onset overpotentials and higher current densities compared with the pristine Ni(OH)2 catalyst, suggesting the holey defects engineering is a promising strategy for efficient water-splitting devices and rechargeable metal-air batteries.