Search

Cerebral ischemic stroke remains one of the most serious neurological disorders that pose threats to human health, causing a large amount of long-term disability or even death throughout the world. Based on its physiologic and pathological features, there are limited available therapeutic options for effective ischemic stroke management. Encouragingly, a rapid advancement of nanobiotechnology is bringing new insights into exploring more alternative strategies against cerebral ischemic stroke, which can cleverly overcome the limitations related to conventional treatment methods. Therefore, this review focuses on the recent achievements of nanobiotechnology for ischemic stroke management, which emphasizes diverse targeted delivery strategies using various nanoplatforms including liposomes, micelles, polymeric nanoparticles, nanogels, inorganic nanomaterials, and cell-derived nano-vectors based on the pathophysiological features of ischemic stroke. Moreover, different therapeutic approaches against ischemic stroke such as neuroprotection, anti-inflammation, thrombolysis, increased blood-brain barrier penetration and reactive oxygen species scavenging are highlighted. Meanwhile, this review discusses how these versatile nanoplatforms were designed to assist in the treatment of ischemic stroke. Based on this, challenges, opportunities, and future perspectives using nanobiotechnology through rational design for effective ischemic stroke management are revealed.

Sleep staging is the essential step in sleep quality assessment and sleep disorders diagnosis. However, most current automatic sleep staging approaches use recurrent neural networks (RNN), resulting in a relatively large training burden. Moreover, these methods only extract information of the whole epoch or adjacent epochs, ignoring the local signal variations within epoch. To address these issues, a novel deep learning architecture named segmented attention network (SAN) is proposed in this paper. The architecture can be divided into feature extraction (FE) and time sequence encoder (TSE). The FE module consists of multiple multiscale CNN (MMCNN) and residual squeeze and excitation block (SE block). The former extracts features from multiple equal-length EEG segments and the latter reinforced the features. The TSE module based on a multi-head attention mechanism could capture the temporal information in the features extracted by FE module. Noteworthy, in SAN, we replaced the RNN module with a TSE module for temporal learning and made the network faster. The evaluation of the model was performed on two widely used public datasets, Montreal Archive of Sleep Studies (MASS) and Sleep-EDFX, and one clinical dataset from Huashan Hospital of Fudan University, Shanghai, China (HSFU). The proposed model achieved the accuracy of 85.5%, 86.4%, 82.5% on Sleep-EDFX, MASS and HSFU, respectively. The experimental results exhibited favorable performance and consistent improvements of SAN on different datasets in comparison with the state-of-the-art studies. It also proved the necessity of sleep staging by integrating the local characteristics within epochs and adjacent informative features among epochs.

There is an urgent need for animal models of coronavirus disease 2019 to study immunopathogenesis and test therapeutic intervenes. In this study, we showed that NOD/SCID IL2rg

Myocardial infarction (MI) remains the leading fatal disease in the world, and with subsequent adverse ventricular remodeling often leading to the development of heart failure, finding new ways to improve the prognosis of MI is important. Exosomes are extracellular vesicles of 30-150 nm secreted by various cells in the body. It is now well recognized that exosomes play an important role in MI, and exosomes may become a new approach to post-MI treatment. It is valuable to study how exosomes are involved in post-MI progression and how exosomes can be modified to improve their effectiveness. In this review, we focus on summarizing the therapeutic potential of exosomes for MI and the current status of clinical applications to provide evidence for the formal use of exosomes in the clinic.

Ticagrelor is a widely used anti-platelet drug. However, the mechanisms by which ticagrelor protects against sepsis-induced acute kidney injury (AKI) have not been clearly demonstrated. We designed this study to explore the protective effect of ticagrelor on sepsis-induced AKI and to explore the underlying mechanisms.C57BL6J mice received oral ticagrelor (20 mg/kg and 50 mg/kg) for 7 days, and then caecal ligation and puncture (CLP) were performed. An adenosine receptor antagonist, CGS15943, was administered (10 mg/kg, intraperitoneal injection) to block the adenosine pathway 2 h before CLP. After 24 h, serum creatinine levels were measured. Periodic acid-Schiff (PAS) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining were employed to analyze pathological changes and cell apoptosis. Serum concentrations of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and mRNA expression of tissue TNF-α and IL-1β were detected. Western blotting analysis was used to determine AKT and mammalian target of rapamycin (mTOR) protein expression in the kidney.PAS staining showed less swelling of renal tubules, and TUNEL staining revealed less cell apoptosis in the ticagrelor group than in the CLP group. Serum creatinine levels were significantly lower in the ticagrelor group than in the CLP group. Moreover, significantly lower serum and kidney levels of TNF-α and IL-1β were observed in the ticagrelor group. CGS15943 blocked the effects of ticagrelor. Western blotting analysis showed increased phosphorylation of AKT and mTOR in the kidneys of the 50 mg/kg ticagrelor group. The adenosine receptor antagonist inhibited the activation of AKT and mTOR.This study demonstrates that the protective effect of ticagrelor on sepsis-induced AKI depends on adenosine receptor activation and the subsequent increase of AKT and mTOR phosphorylation.

BackgroundSince the end of 2019, Corona Virus Disease 2019, also known as COVID-19, has broken out in various countries. However, the change of China's COVID-19 prevention and control policy and the sharp increase in the number of infected people are making the teenagers have post-traumatic reactions. Negative post-traumatic reactions include: post-traumatic stress disorder (PTSD), depression, anxiety. Positive post-traumatic reaction mainly refers to post-traumatic growth (PTG). The purpose of this study is to explore the post-traumatic reaction, which refers to PTSD, depression, anxiety and the co-occurrence pattern of growth after trauma and to further explore the influence of family function on different categories of Post-traumatic Reactions.MethodsLatent profile analysis (LPA) was used to explore the co-occurrence of PTSD, depression, anxiety, and PTG. Multiple logistics regression was used to analyze the influence of family function on different categories of post-traumatic response.ResultsThere were three categories of post-traumatic reactions in adolescents infected with COVID-19 adolescents infected with COVID-19, namely: growth class, struggling class, and pain class. Multivariate Logistic regression showed that the growth class and struggling class were affected by problem solving and behavior control in family function, while the growth class and pain class were affected by problem solving, roles, behavior control, and general functioning. Multiple logistic regression showed that the growth class and struggling class were affected by problem solving and roles.ConclusionsThe findings of this study provide evidence for the identification of high-risk individuals and the provision of effective interventions in clinical practice, as well as the influence of family functioning on the different categories of PTSD among adolescents infected with COVID-19.

Background l‑Fucose is a rare sugar that has beneficial biological activities, and its industrial production is mainly achieved with brown algae through acidic/enzymatic fucoidan hydrolysis and a cumbersome purification process. Fucoidan is synthesized through the condensation of a key substance, guanosine 5′‑diphosphate (GDP)‑l‑fucose. Therefore, a more direct approach for biomanufacturing l‑fucose could be the enzymatic degradation of GDP‑l‑fucose. However, no native enzyme is known to efficiently catalyze this reaction. Therefore, it would be a feasible solution to engineering an enzyme with similar function to hydrolyze GDP‑l‑fucose. Results Herein, we constructed a de novo l‑fucose synthetic route in Bacillus subtilis by introducing heterologous GDP‑l‑fucose synthesis pathway and engineering GDP‑mannose mannosyl hydrolase (WcaH). WcaH displays a high binding affinity but low catalytic activity for GDP‑l‑fucose, therefore, a substrate simulation‑based structural analysis of the catalytic center was employed for the rational design and mutagenesis of selected positions on WcaH to enhance its GDP‑l‑fucose‑splitting efficiency. Enzyme mutants were evaluated in vivo by inserting them into an artificial metabolic pathway that enabled B. subtilis to yield l‑fucose. WcaHR36Y/N38R was found to produce 1.6 g/L l‑fucose during shake‑flask growth, which was 67.3% higher than that achieved by wild‑type WcaH. The accumulated l‑fucose concentration in a 5 L bioreactor reached 6.4 g/L. Conclusions In this study, we established a novel microbial engineering platform for the fermentation production of l‑fucose. Additionally, we found an efficient GDP‑mannose mannosyl hydrolase mutant for L‑fucose biosynthesis that directly hydrolyzes GDP‑l‑fucose. The engineered strain system established in this study is expected to provide new solutions for l‑fucose or its high value‑added derivatives production.

Knowledge Graph Embedding (KGE) is a powerful way to express Knowledge Graphs (KGs), which can help machines learn patterns hidden in the KGs. Relation patterns are useful hidden patterns, and they usually assist machines to predict unseen facts. Many existing KGE approaches can model some common relation patterns like symmetry/antisymmetry, inversion, and commutative composition patterns. However, most of them are weak in modeling noncommutative composition patterns. It means these approaches can not distinguish a lot of composite relations like “father’s mother” and “mother’s father”. In this work, we propose a new KGE method called QuatRotatScalE (QRSE) to overcome this weakness, since it utilizes rotation and scaling transformations of quaternions to design the relation embedding. Specifically, we embed the relations and entities into a quaternion vector space under the difference norm KGE framework. Since the multiplication of quaternions does not satisfy the commutative law, QRSE can model noncommutative composition patterns naturally. The experimental results on the synthetic dataset also support that QRSE has this ability. In addition, the experimental results on real-world datasets show that QRSE reaches state-of-the-art in link prediction problem.

At present, there is no noninvasive biomarker of renal fibrosis. The potential diagnostic value of urinary exosome-derived circRNAs from glomerular disease patients for renal fibrosis is still uncertain. Here, we first detected the expression of hsa_circ_0008925 in TGF-β1-cultured HK-2 cell-derived exosomes. Secondly, we collected urine samples from 95 biopsy-proven glomerular disease patients and 34 healthy controls. The expression of hsa_circ_0008925 was analyzed, and the correlation with renal function and pathological changes was calculated. The receiver operating characteristic (ROC) curve for the diagnosis of renal fibrosis was performed. The results showed that in exosomes derived from TGF-β1-cultured HK-2 cells, the expression of hsa_circ_0008925 was increased compared with normal cultured. Further, the expression level of hsa_circ_0008925 was increased in urinary exosomes from renal fibrosis patients and correlated with serum creatinine, blood urea nitrogen (BUN), estimated glomerular filtration rate, and cystatin C. The level of hsa_circ_0008925 was furthermore correlated with the score of tubulointerstitial fibrosis (TIF) and the score of glomerular sclerosis. The ROC curve showed that hsa_circ_0008925 can diagnose renal fibrosis at a cut-off value of 0.093 with a sensitivity of 52.2% and specificity of 96.4%. In summary, we indicated that urinary exosomal hsa_circ_0008925 could be acted as a noninvasive biomarker for renal fibrosis in glomerular diseases patients.

BACKGROUND: Previous studies have already revealed that triggering receptor expressed on myeloid cells-2 (TREM2) plays a significant protective role during the pathogenesis of ischemia injury in both brain and liver. This study aims to investigate the effect of TREM2 in myocardial ischemic injury. METHODS: The mice myocardial infarction (MI) model was established via left anterior descending coronary artery ligation. TREM2 expression was examined with RT-PCR and Western blot. Whereafter, mice were randomly divided into control, sham, MI, Ad.TREM2 transfection group and Ad.Null transfection group. Recombinant adenovirus containing the gene coding full-length mouse TREM2 and EGFP (Ad.TREM2) or control vector containing EGFP gene only (Ad.Null) were immediately intramyocardial injected after left anterior descending ligated. After 7 days of MI, HE, Masson and TUNEL staining were performed to find the myocardial injury, infarcted size and cell apoptosis. Besides, echocardiography was performed to determine cardiac function. In addition, Western blot was performed to check the activity of PI3K/AKT signaling pathway in myocardial tissue. Furthermore, the plasma concentrations of TREM2 in 19 coronary artery disease (CAD) patients and 8 healthy controls were measured. RESULTS: Compared with the sham group, TREM2 expression was significantly up-regulated in cardiac tissue in mice with MI. Cardiac tissue in mice transfected with Ad.TREM2 was demonstrated with alleviated injury, reduced infarct size, and decreased number of apoptotic cells. Echocardiography revealed that heart function was significantly improved in Ad.TREM2 transfection mice. Also, TREM2 transfection significantly activated the phosphorylation of AKT. At last, the plasma concentration of TREM2 was significantly elevated in patients with CAD and correlated with the severity of CAD. CONCLUSIONS: TREM2 may curb myocardial ischemia injury via activating PI3K/AKT signal pathway. Besides, plasma TREM2 may be treated as a potential biomarker in the diagnosis of CAD to reflect the severity of coronary stenosis.

There are urgent needs for humanized mouse models of viral respiratory diseases to study immunopathogenesis and therapeutic interventions. Although human immune system (HIS) mice permit analysis in real time of human immune responses in vivo, evolutionary divergences preclude their usefulness for the respiratory viruses that do not infect mouse lungs. In this study, we sought to use HIS mice with human lung (HL) tissue xenografts (HISL mice) to address this issue. The grafted HL tissue maintained histologically normal structure, and populated with human tissue-resident immune cells, including CD11c+ dendritic cells and CD4+ and CD8+ tissue-resident memory T cells. HISL mice showed a marked expansion of tissue-resident memory T cells and generation of viral Ag-specific T cells in the HL xenografts, and production of antiviral IgM and IgG Abs upon immunization of the HL xenograft by H1N1 influenza viruses. RNA-seq analysis on H1N1-infected and control HL xenografts identified a total of 5089 differentially expressed genes with enrichments for genes involved in respiratory diseases, viral infections, and associated immune responses. Furthermore, prophylactic viral exposures resulted in protection against subsequent lethal challenge by intranasal viral inoculation. This study supports the usefulness of this preclinical model in exploring the immunopathology and therapies of respiratory viral diseases.

A stereodivergent synthesis of azepino[3,4,5-cd]-indoles bearing three stereogenic centers was established via synergistic dual-metal catalysis followed by acid-promoted epimerization, and up to all eight stereoisomers could be predictably achieved.

We report the evolution of the X-ray pulsations of EXO 2030+375 during its 2021 outburst using the observations from Insight-HXMT. Based on the accretion torque model, we study the correlation between the spin frequency derivatives and the luminosity. Pulsations can be detected in the energy band of 1–160 keV. The pulse profile evolves significantly with luminosity during the outburst, leading to that the whole outburst can be divided into several parts with different characteristics. The evolution of the pulse profile reveals the transition between the supercritical (fan-beam dominated) and the subcritical accretion (pencil-beam dominated) mode. From the accretion torque model and the critical luminosity model, based on a distance of 7.1 kpc, the inferred magnetic fields are (0.41 − 0.74) × 1012 and (3.48 − 3.96) × 1012 G, respectively, or based on a distance of 3.6 kpc, the estimated magnetic fields are (2.4 − 4.3) × 1013 and (0.98 − 1.11) × 1012 G, respectively. Two different sets of magnetic fields both support the presence of multipole magnetic fields of the neutron star.

Background: Recent artificial intelligence has exhibited great potential in breast imaging, but its value in precise risk stratification of mammography still needs further investigation. This study is to develop an artificial intelligence system (AIS) for accurate malignancy diagnosis and supportive decision-making on mammographic risk stratification. Methods: In this retrospective study, 49732 mammograms of 24866 breasts from 12815 women from two Asian clinics between August 2012 and December 2018 were included. We developed an AIS using multi-view mammograms and multi-level convolutional neural network features to diagnosis malignancy and further assess the relative strengths of AIS versus current BI-RADS categorization. We further evaluate AIS by conducting a counterbalance-designed AI-assisted study, where ten radiologists read 1302 cases with/without AIS assistance. The area under the receiver operating characteristic curve (AUC), sensitivity, specificity, accuracy, F1 score were measured. Results: The AIS yielded AUC of 0.910 to 0.995 for malignancy diagnosis in the validation and testing sets. Within BI-RADS 3–4 subgroups with pathological results, AIS can downgrade 83.1% of false-positives into benign groups, and upgrade 54.1% of false-negatives into malignant groups. Compared with BI-RADS, AIS performed better sensitivity and specificity in dense and no-calcification subgroups. AIS also can successfully assist radiologists identify 7 out of 43 malignancies initially diagnosed with BI-RADS 0 with specificity of 96.7%. In the counterbalance-designed AI-assisted study, the average AUC across 10 readers was significantly improved with AIS assistance (P = 0.001). Conclusion: AIS can identify malignancy on mammography and further serve as a supportive tool for stratifying BI-RADS categorization.

On April 27, 2020, the soft gamma ray repeater SGR J1935+2154 entered its intense outburst episode again. Insight-HXMT carried out about one month observation of the source. A total number of 75 bursts were detected during this activity episode by Insight-HXMT, and persistent emission data were also accumulated. We report on the spin period search result and the phase distribution of burst start times and burst photon arrival times of the Insight-HXMT high energy detectors and Fermi Gamma-ray Burst Monitor (GBM). We find that the distribution of burst start times is uniform within its spin phase for both Insight-HXMT and Fermi-GBM observations, whereas the phase distribution of burst photons is related to the type of a burst's energy spectrum. The bursts with the same spectrum have different distribution characteristics in the initial and decay episodes for the activity of magnetar SGR J1935+2154., Comment: 12 pages, 9 figures

Background: Since the mid 80’ies, the western palliative care philosophy has influenced the development of palliative care in mainland China. However, it has caused several challenges. Objective: To explore the understanding of the ‘good death’ among authorities, professionals, patients, and their relatives in end-of-life care settings in mainland China. Design: Scoping review. The PRISMA-ScR checklist was used. The study is not registered. Settings: End-of-life care settings, Mainland China Participants: Authorities, healthcare professionals, adult patients, and general population in mainland China. Method: Literature searches were performed through Medline, CINAHL, PsycInfo, and Web of Sciences from 2001-2021, last search 21.4.2021. Inclusion criteria were: Empirical research studies investigating ‘good death’ or political documents about ‘good death’, perspectives from authorities, professionals, patients, and/or relatives, and studies following the Declaration of Helsinki. Exclusion criteria were: Literature reviews, languages other than English and Chinese, editorials, letters, comments, and children's death/dying.The analysis consisted of analysing the data including a descriptive numerical summary analysis and a qualitative thematic analysis. Results: Nineteen articles and two political documents were included. The 19 studies were carried out from 2003-2020, with data collected from 1999 to 2019. The political documents were written in 2012 and 2017, respectively. The thematic analysis resulted in three themes: ‘Medicalisation of death’, ‘Communication about death - a clash between two philosophies’, and ‘Dying and death were socially dependent’. The medicalisation of death meant the understanding of the ‘good death’ primarily focused on physical symptoms and treatments. The good death was understood as painless and symptom-free, where all symptoms could be measured and assessed. Dignity and shared decision-making were connected to the understanding of the ‘good death’. However, the contents of the ‘good death’ varied across the different actors. The understanding of the ‘good death’ in mainland China was a negotiation between Chinese traditional philosophy and contemporary western medicine practice. There was a tension between openness and silence about death, which reflected the importance of death education. The understanding of the ‘good death’ consisted partly of a timely and practical preparation for the death and afterlife, partly of a matter of social and financial issues. Conclusions: There seemed to be a clash between two different cultures in the understanding of a good death in Mainland China, where western philosophy seemed to rule the political medical actors while traditional Chinese philosophy seemed to rule parts of the population.

As deep CNNs get larger, it becomes more challenging to deploy them on resource-restricted mobile devices. Filter-level pruning is one of the most popular methods to compress deep models for mobile deployment. It prunes unimportant filters in the pre-trained CNN to reduce its storage and computational cost, yielding a smaller and more efficient model. Though having made some progress, most filter-level pruning methods still suffer from at least one of the following two problems: 1) High redundancy: some methods pick out unimportant filters without considering their correlations, and thus many highly correlated filters are not pruned, yielding a model still with high redundancy. 2) Sub-optimal: all existing pruning methods achieve sub-optimal pruning plan because they neglect that a high parameters reduction ratio (PRR) does not always mean a high FLOPs reduction ratio (FRR). In this paper, we propose our customized correlation-based pruning (COP) to solve these problems. In particular, we observe redundant filters through their correlations. Moreover, to achieve the optimal pruning plan, PRR and FRR are considered when evaluating filters’ importance. Besides, we also propose a new pruning pipeline, which improves the accuracy of the pruned model. Extensive experiments show that our proposed method has outperformed the state-of-the-art on several popular architectures and datasets.

Two new maytansinoids, N-methyltreflorine (1) and methyltrewiasine (2), were isolated from the dried fruits of Trewia nudiflora, together with three known congeners (3 – 5). Their structures were elucidated by spectroscopic methods, and the absolute configuration of 1 and 2 was determined by X-ray crystallographic analysis. Compounds 1 – 5 exhibited strong cytotoxicity against human tumor cell lines, including HeLa, MV-4 – 11, and MCF-7, with IC50 values ranging from 0.12 to 11 nM. Compounds 1 and 4 also showed inhibitory activity against the MCF-7/ADR cell line with IC50 values of 13 and 28 nM, respectively. Compounds 1 and 2 significantly inhibited tubulin polymerization in vitro with IC50 values of 3.6 and 3.2 µM, respectively.

Cosmic rays, γ-rays, and X-ray-driven reactions on interstellar grains have been the main focus in understanding the extraterrestrial synthesis of complex organic molecules. Herein, using temperature-programmed desorption and X-ray photoelectron spectroscopy, we report for the first time X-ray-induced CO2 production from a CO-covered rutile TiO2(110) surface at 110 K, in addition to X-ray-induced CO desorption. The X-ray-induced CO2 production was found to follow a Mars and van Krevelen (MvK) mechanism via the reaction between adsorbed CO and surface lattice oxygen of TiO2. Defects of TiO2 suppress the X-ray-induced CO2 production but promote the X-ray-induced CO desorption. These findings suggest a novel X-ray-induced CO-to-CO2 reaction on oxide surfaces at cryogenic temperature likely occurring in the interstellar medium and also warn us to keep in mind the possibility of X-rays inducing chemical reactions during structural characterizations of oxides with X-ray-involved techniques.

Objective We aimed to elucidate the effects of and the potential mechanism underlying long-term magnesium supplementation on blood–brain barrier integrity in mice with neuromyelitis optica spectrum disorder (NMOSD), a severe and disabling autoimmune disease of the central nervous system, and in cultured human cerebral microvascular endothelial cells/D3 (hCMEC/D3). Methods Purified serum IgG collected from NMOSD patients was consecutively injected intraperitoneally into experimental autoimmune encephalomyelitis mice to induce the NMOSD model. Magnesium L-threonate (MgT) was orally administered to NMOSD mice from the start of model induction to experiment completion. In cultured hCMEC/D3, siRNA technology was used to knockdown the expression of the magnesium transporter transient receptor potential melastatin 7 (TRPM7) to explore the mechanism of MgT. Results Magnesium concentration in the cerebrospinal fluid was significantly lower in NMOSD patients than in control patients. Pre-treatment with MgT to NMOSD mice relieved aquaporin 4 (AQP4)-IgG–induced AQP4 loss, glial fibrillary acidic protein activation, expanded perivascular space, demyelination, and decreased tight junction (TJ) protein expression. In vitro experiments demonstrated that treatment with MgT ameliorated the damaged TJ protein function, which was originally due to NMOSD; this amelioration was dependent on TRPM7. Conclusions MgT treatment has a potential protective effect against NMOSD. Magnesium supplementation may be a novel therapeutic approach for NMOSD.

H2O2 is widely used as an oxidant for photocatalytic methane conversion to value-added chemicals over oxide-based photocatalysts under mild conditions, but suffers from low utilization efficiencies. Herein, we report that O2 is an efficient molecular additive to enhance the utilization efficiency of H2O2 by suppressing H2O2 adsorption on oxides and consequent photogenerated holes-mediated H2O2 dissociation into O2. In photocatalytic methane conversion over an anatase TiO2 nanocrystals predominantly enclosed by the {001} facets (denoted as TiO2{001})-C3N4 composite photocatalyst at room temperature and ambient pressure, O2 additive significantly enhances the utilization efficiency of H2O2 up to 93.3%, giving formic acid and liquid-phase oxygenates selectivities respectively of 69.8% and 97% and a formic acid yield of 486 μmolHCOOH·gcatalyst−1·h−1. Efficient charge separation within TiO2{001}-C3N4 heterojunctions, photogenerated holes-mediated activation of CH4 into ·CH3 radicals on TiO2{001} and photogenerated electrons-mediated activation of H2O2 into ·OOH radicals on C3N4, and preferential dissociative adsorption of methanol on TiO2{001} are responsible for the active and selective photocatalytic conversion of methane to formic acid over TiO2{001}-C3N4 composite photocatalyst.

Background Experimental and observational research suggests that combined epidural–general anesthesia may improve long-term survival after cancer surgery by reducing anesthetic and opioid consumption and by blunting surgery-related inflammation. This study therefore tested the primary hypothesis that combined epidural–general anesthesia improves long-term survival in elderly patients. Methods This article presents a long-term follow-up of patients enrolled in a previous trial conducted at five hospitals. Patients aged 60 to 90 yr and scheduled for major noncardiac thoracic and abdominal surgeries were randomly assigned to either combined epidural–general anesthesia with postoperative epidural analgesia or general anesthesia alone with postoperative intravenous analgesia. The primary outcome was overall postoperative survival. Secondary outcomes included cancer-specific, recurrence-free, and event-free survival. Results Among 1,802 patients who were enrolled and randomized in the underlying trial, 1,712 were included in the long-term analysis; 92% had surgery for cancer. The median follow-up duration was 66 months (interquartile range, 61 to 80). Among patients assigned to combined epidural–general anesthesia, 355 of 853 (42%) died compared with 326 of 859 (38%) deaths in patients assigned to general anesthesia alone: adjusted hazard ratio, 1.07; 95% CI, 0.92 to 1.24; P = 0.408. Cancer-specific survival was similar with combined epidural–general anesthesia (327 of 853 [38%]) and general anesthesia alone (292 of 859 [34%]): adjusted hazard ratio, 1.09; 95% CI, 0.93 to 1.28; P = 0.290. Recurrence-free survival was 401 of 853 [47%] for patients who had combined epidural–general anesthesia versus 389 of 859 [45%] with general anesthesia alone: adjusted hazard ratio, 0.97; 95% CI, 0.84 to 1.12; P = 0.692. Event-free survival was 466 of 853 [55%] in patients who had combined epidural–general anesthesia versus 450 of 859 [52%] for general anesthesia alone: adjusted hazard ratio, 0.99; 95% CI, 0.86 to 1.12; P = 0.815. Conclusions In elderly patients having major thoracic and abdominal surgery, combined epidural–general anesthesia with epidural analgesia did not improve overall or cancer-specific long-term mortality. Nor did epidural analgesia improve recurrence-free survival. Either approach can therefore reasonably be selected based on patient and clinician preference. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) is a newly defined meningoencephalomyelitis. The pathogenesis of GFAP-A is not well understood. The present study measured the expression levels of 200 serological cytokines in GFAP-A patients, NMOSD patients and healthy controls (HCs). The correlations between serum cytokine levels and clinical information in GFAP-A patients were analyzed. A total of 147 serological proteins were differentially expressed in GFAP-A patients compared to HCs, and 33 of these proteins were not observed in NMOSD patients. Serum levels of EG-VEGF negatively correlated with GFAP antibody titers, MIP-3 alpha positively correlated with clinical severity in GFAP-A patients, and LIGHT positively correlated with WBC counts and protein levels in the CSF of GFAP-A patients. These results suggest that GFAP and AQP4 astrocytopathy share some common pathology related to TNF signaling. Serum MIP 3 alpha may be a biomarker to assess clinical severity and a potential target for therapy of autoimmune GFAP astrocytopathy.

An unprecedented hydroalkylation of racemic allylic alcohols and racemic ketimine esters enabled by Cu/Ru relay catalysis has been developed via merging the ruthenium-catalyzed asymmetric borrowing-hydrogen reaction with a copper-catalyzed asymmetric Michael addition in a one-pot procedure. The current method enables the efficient preparation of highly functionalized δ-hydroxyesters bearing 1,4-nonadjacent stereocenters in good yields with high levels of diastereoselectivity and excellent enantioselectivity under mild reaction conditions. The full complement of the four stereoisomers of hydroalkylation products could be readily accessed by orthogonal permutations of two chiral metal catalysts. The current work highlights the power of relay catalysis for the stereodivergent construction of 1,4-nonadjacent stereocenters that were otherwise inaccessible.

A one-pot Cu-mediated H-D exchange with inexpensive heavy water as the deuterium source, followed by Cu- and Ir-catalyzed stereodivergent allylic alkylation, has been developed, providing efficient access to enantioenriched α-deuterium-labeled α-amino acids from readily available glycine imine esters in a high yield with excellent stereoselectivity. High deuterium enrichment, exquisite regioselectivity, precise stereoselectivity control, and operationally convenient procedures make this protocol appealing for the preparation of highly synthetically useful α-deuterated α-amino acids.

For conventional hydrogels, the phenomenon of crack generation and propagation caused by high-stress concentration is ubiquitous. However, this phenomenon is unfavorable in many applications, such as wearable electronics, tissue engineering, and tunable adhesion. Fortunately, many hydrogels that can suppress crack growth during deformation and maintain the original mechanical properties during deformation, called crack-resistant hydrogels, have been published. Herein, the state-of-the-art of crack-resistant hydrogels is comprehensively reviewed. Starting from the principle of designing a crack-resistant hydrogel, we first survey the relevant crack-resistant strategies. The latest crack-resistant hydrogels are then categorized according to their crack-resistant mechanisms (including energy dissipation at the molecular level, multiscale structure, crack pinning, crack deflection, and sliding of chain), and their crack-resistant processes are described in detail. Furthermore, we summarize the current challenges and make an outlook for crack-resistant hydrogels, which might lead to substantial progress in the future design and development of these high-performance materials.

Purpose: Diabetic retinopathy (DR) is a serious complication of diabetes mellitus, which nearly happens to all the diabetic sufferers. This study aims to identify the preliminary molecular regulation involved in the therapeutic efficacy of astragaloside IV (AS- IV) for DR.Methods: Diabetic rat models were established and treated with AS-IV. Optical coherence tomography (OCT) and Hematoxylin-eosin (HE) staining was employed to demonstrate the histopathological changes. The main targets of AS-IV were identified by searching from public databases of traditional Chinese medicine (GeneCards, PharmMapper and Swiss Target Prediction). Besides, disease targets of DR were also obtained by integrated data from GEO datasets and predicted from public databases. Protein-protein interaction (PPI) network was constructed by Cytoscape with overlapping genes and 10 core targets were selected, on which Gene Ontology (GO) along with Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were conducted. The interaction between AS-IV and these crucial genes were analyzed using molecular docking. RT-qPCR and western blot were used to verify the expression variation of core targets.Results: OCT imaging and HE staining demonstrated that AS-IV administration significantly increased retinal thickness in diabetic rats, obviously alleviating DR induced histopathological changes as well as elevated blood glucose levels. 107 common targets of AS-IV and DR were determined after intersection. PPI network analysis filtered 10 hub genes potentially targeted by AS-IV, including VEGFA, CASP3, HIF1α, STAT3, CTNNB1, SRC, AKT1, EGFR, IL1β and IL6. Enrichment analysis indicated that these genes were mainly enriched in biological processes like T cell activation, epithelial cell proliferation and protein kinase B signaling, and involved in oxidative stress, apoptosis and inflammation-related pathways. The molecular docking prediction suggested that AS-IV exhibited stable binding to these core targets. In addition, mRNA levels of core targets in diabetic rats were differentially expressed before and after AS-IV treatment. Western blot further revealed that AS-IV treatment elevated DR-depressed protein levels of PI3K and AKT.Conclusion: Our study elucidated the effect of AS-IV in attenuating retinopathy induced by diabetes in rats and preliminarily unveiled the therapeutic efficacy of AS-IV in the treatment of DR might be attributed to activation of PI3K-AKT signaling pathway.

Myeloid-derived suppressor cell (MDSC) mobilisation is an important immune event in acute myocardial infarction (AMI). The AIn AMI patients, the circulating MDSC ratio and AIn AMI patients, the circulating MDSC ratio was increased and positively correlated with ABlocking A

HDAC11, the sole member of HDAC class IV family, plays vital roles in activating mitosis and apoptosis of tumor cells, but its functions in meiosis are rarely investigated. In the present study, the effect of HDAC11 on meiosis during porcine oocytes maturation was fully studied. The results showed that HDAC11 inhibition by its specific inhibitor JB-3-22 dramatically decreased the porcine oocyte maturation rate by disturbing spindle organization and chromosomes alignment without affecting the cytoplasmic maturation. Further study indicated that HDAC11 inhibition significantly elevated the acetylation levels of α-tubulin and H4K16, which are crucial for spindle organization and chromosomes alignment. Moreover, immunofluorescence staining results showed that HDAC11 inhibition also disturbed other meiosis-related histone modifications, such as increased H3S10pho, H4K5ac and H4K12ac levels and reduced H3T3pho level. Furthermore, RNA-seq analysis results indicated that HDAC11 inhibition disturbed porcine oocytes transcriptome (157 up-regulation, 106 down-regulation). In addition, HDAC11 inhibition compromised oocytes quality and subsequent development after parthenogenetic activation, which may be caused by the aberrant nuclear maturation and transcriptome expression profile during oocytes maturation. Therefore, our results elucidate the function of HDAC11 in porcine oocytes maturation and embryos development through regulating α-tubulin acetylation, meiosis-related histone modifications and transcriptome.