Wei Zhang

We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which in turn may inform strategies for future therapeutic development.

The spatiotemporal organization and dynamics of chromatin play critical roles in regulating genome function. However, visualizing specific, endogenous genomic loci remains challenging in living cells. Here, we demonstrate such an imaging technique by repurposing the bacterial CRISPR/Cas system. Using an EGFP-tagged endonuclease-deficient Cas9 protein and a structurally optimized small guide (sg) RNA, we show robust imaging of repetitive elements in telomeres and coding genes in living cells. Furthermore, an array of sgRNAs tiling along the target locus enables the visualization of nonrepetitive genomic sequences. Using this method, we have studied telomere dynamics during elongation or disruption, the subnuclear localization of the MUC4 loci, the cohesion of replicated MUC4 loci on sister chromatids, and their dynamic behaviors during mitosis. This CRISPR imaging tool has potential to significantly improve the capacity to study the conformation and dynamics of native chromosomes in living human cells.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTEnantioselective epoxidation of unfunctionalized olefins catalyzed by salen manganese complexesWei Zhang, Jennifer L. Loebach, Scott R. Wilson, and Eric N. JacobsenCite this: J. Am. Chem. Soc. 1990, 112, 7, 2801–2803Publication Date (Print):March 1, 1990Publication History Published online1 May 2002Published inissue 1 March 1990https://doi.org/10.1021/ja00163a052RIGHTS & PERMISSIONSArticle Views17249Altmetric-Citations1379LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (394 KB) Get e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts

Our goal is to construct a model for genetic regulatory networks such that the model class: (i) incorporates rule-based dependencies between genes; (ii) allows the systematic study of global network dynamics; (iii) is able to cope with uncertainty, both in the data and the model selection; and (iv) permits the quantification of the relative influence and sensitivity of genes in their interactions with other genes.We introduce Probabilistic Boolean Networks (PBN) that share the appealing rule-based properties of Boolean networks, but are robust in the face of uncertainty. We show how the dynamics of these networks can be studied in the probabilistic context of Markov chains, with standard Boolean networks being special cases. Then, we discuss the relationship between PBNs and Bayesian networks--a family of graphical models that explicitly represent probabilistic relationships between variables. We show how probabilistic dependencies between a gene and its parent genes, constituting the basic building blocks of Bayesian networks, can be obtained from PBNs. Finally, we present methods for quantifying the influence of genes on other genes, within the context of PBNs. Examples illustrating the above concepts are presented throughout the paper.

Recent years have witnessed a proliferation of large-scale knowledge bases, including Wikipedia, Freebase, YAGO, Microsoft's Satori, and Google's Knowledge Graph. To increase the scale even further, we need to explore automatic methods for constructing knowledge bases. Previous approaches have primarily focused on text-based extraction, which can be very noisy. Here we introduce Knowledge Vault, a Web-scale probabilistic knowledge base that combines extractions from Web content (obtained via analysis of text, tabular data, page structure, and human annotations) with prior knowledge derived from existing knowledge repositories. We employ supervised machine learning methods for fusing these distinct information sources. The Knowledge Vault is substantially bigger than any previously published structured knowledge repository, and features a probabilistic inference system that computes calibrated probabilities of fact correctness. We report the results of multiple studies that explore the relative utility of the different information sources and extraction methods.

Most patients with small-cell lung cancer (SCLC) have extensive-stage disease at presentation, and prognosis remains poor. Recently, immunotherapy has demonstrated clinical activity in extensive-stage SCLC (ES-SCLC). The CASPIAN trial assessed durvalumab, with or without tremelimumab, in combination with etoposide plus either cisplatin or carboplatin (platinum-etoposide) in treatment-naive patients with ES-SCLC.This randomised, open-label, phase 3 trial was done at 209 sites across 23 countries. Eligible patients were adults with untreated ES-SCLC, with WHO performance status 0 or 1 and measurable disease as per Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were randomly assigned (in a 1:1:1 ratio) to durvalumab plus platinum-etoposide; durvalumab plus tremelimumab plus platinum-etoposide; or platinum-etoposide alone. All drugs were administered intravenously. Platinum-etoposide consisted of etoposide 80-100 mg/m2 on days 1-3 of each cycle with investigator's choice of either carboplatin area under the curve 5-6 mg/mL per min or cisplatin 75-80 mg/m2 (administered on day 1 of each cycle). Patients received up to four cycles of platinum-etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks in the immunotherapy groups and up to six cycles of platinum-etoposide every 3 weeks plus prophylactic cranial irradiation (investigator's discretion) in the platinum-etoposide group. The primary endpoint was overall survival in the intention-to-treat population. We report results for the durvalumab plus platinum-etoposide group versus the platinum-etoposide group from a planned interim analysis. Safety was assessed in all patients who received at least one dose of their assigned study treatment. This study is registered at ClinicalTrials.gov, NCT03043872, and is ongoing.Patients were enrolled between March 27, 2017, and May 29, 2018. 268 patients were allocated to the durvalumab plus platinum-etoposide group and 269 to the platinum-etoposide group. Durvalumab plus platinum-etoposide was associated with a significant improvement in overall survival, with a hazard ratio of 0·73 (95% CI 0·59-0·91; p=0·0047]); median overall survival was 13·0 months (95% CI 11·5-14·8) in the durvalumab plus platinum-etoposide group versus 10·3 months (9·3-11·2) in the platinum-etoposide group, with 34% (26·9-41·0) versus 25% (18·4-31·6) of patients alive at 18 months. Any-cause adverse events of grade 3 or 4 occurred in 163 (62%) of 265 treated patients in the durvalumab plus platinum-etoposide group and 166 (62%) of 266 in the platinum-etoposide group; adverse events leading to death occurred in 13 (5%) and 15 (6%) patients.First-line durvalumab plus platinum-etoposide significantly improved overall survival in patients with ES-SCLC versus a clinically relevant control group. Safety findings were consistent with the known safety profiles of all drugs received.AstraZeneca.

Although genome-wide association studies (GWAS) of complex traits have yielded more reproducible associations than had been discovered using any other approach, the loci characterized to date do not account for much of the heritability to such traits and, in general, have not led to improved understanding of the biology underlying complex phenotypes. Using a web site we developed to serve results of expression quantitative trait locus (eQTL) studies in lymphoblastoid cell lines from HapMap samples (http://www.scandb.org), we show that single nucleotide polymorphisms (SNPs) associated with complex traits (from http://www.genome.gov/gwastudies/) are significantly more likely to be eQTLs than minor-allele-frequency-matched SNPs chosen from high-throughput GWAS platforms. These findings are robust across a range of thresholds for establishing eQTLs (p-values from 10(-4)-10(-8)), and a broad spectrum of human complex traits. Analyses of GWAS data from the Wellcome Trust studies confirm that annotating SNPs with a score reflecting the strength of the evidence that the SNP is an eQTL can improve the ability to discover true associations and clarify the nature of the mechanism driving the associations. Our results showing that trait-associated SNPs are more likely to be eQTLs and that application of this information can enhance discovery of trait-associated SNPs for complex phenotypes raise the possibility that we can utilize this information both to increase the heritability explained by identifiable genetic factors and to gain a better understanding of the biology underlying complex traits.

Ferroptosis is an iron-dependent form of regulated necrosis. It is implicated in various human diseases, including ischemic organ damage and cancer. Here, we report the crucial role of autophagy, particularly autophagic degradation of cellular iron storage proteins (a process known as ferritinophagy), in ferroptosis. Using RNAi screening coupled with subsequent genetic analysis, we identified multiple autophagy-related genes as positive regulators of ferroptosis. Ferroptosis induction led to autophagy activation and consequent degradation of ferritin and ferritinophagy cargo receptor NCOA4. Consistently, inhibition of ferritinophagy by blockage of autophagy or knockdown of NCOA4 abrogated the accumulation of ferroptosis-associated cellular labile iron and reactive oxygen species, as well as eventual ferroptotic cell death. Therefore, ferroptosis is an autophagic cell death process, and NCOA4-mediated ferritinophagy supports ferroptosis by controlling cellular iron homeostasis.

A growing body of evidence indicates that an inflammatory process in the substantia nigra, characterized by activation of resident microglia, likely either initiates or aggravates nigral neurodegeneration in Parkinson's disease (PD). To study the mechanisms by which nigral microglia are activated in PD, the potential role of alpha-synuclein (a major component of Lewy bodies that can cause neurodegeneration when aggregated) in microglial activation was investigated. The results demonstrated that in a primary mesencephalic neuron-glia culture system, extracellular aggregated human alpha-synuclein indeed activated microglia; microglial activation enhanced dopaminergic neurodegeneration induced by aggregated alpha-synuclein. Furthermore, microglial enhancement of alpha-synuclein-mediated neurotoxicity depended on phagocytosis of alpha-synuclein and activation of NADPH oxidase with production of reactive oxygen species. These results suggest that nigral neuronal damage, regardless of etiology, may release aggregated alpha-synuclein into substantia nigra, which activates microglia with production of proinflammatory mediators, thereby leading to persistent and progressive nigral neurodegeneration in PD. Finally, NADPH oxidase could be an ideal target for potential pharmaceutical intervention, given that it plays a critical role in alpha-synuclein-mediated microglial activation and associated neurotoxicity.

Globally increasing energy demands and environmental concerns related to the use of fossil fuels have stimulated extensive research to identify new energy systems and economies that are sustainable, clean, low cost, and environmentally benign. Hydrogen generation from solar-driven water splitting is a promising strategy to store solar energy in chemical bonds. The subsequent combustion of hydrogen in fuel cells produces electric energy, and the only exhaust is water. These two reactions compose an ideal process to provide clean and sustainable energy. In such a process, a hydrogen evolution reaction (HER), an oxygen evolution reaction (OER) during water splitting, and an oxygen reduction reaction (ORR) as a fuel cell cathodic reaction are key steps that affect the efficiency of the overall energy conversion. Catalysts play key roles in this process by improving the kinetics of these reactions. Porphyrin-based and corrole-based systems are versatile and can efficiently catalyze the ORR, OER, and HER. Because of the significance of energy-related small molecule activation, this review covers recent progress in hydrogen evolution, oxygen evolution, and oxygen reduction reactions catalyzed by porphyrins and corroles.

Intelligent fault diagnosis techniques have replaced time-consuming and unreliable human analysis, increasing the efficiency of fault diagnosis. Deep learning models can improve the accuracy of intelligent fault diagnosis with the help of their multilayer nonlinear mapping ability. This paper proposes a novel method named Deep Convolutional Neural Networks with Wide First-layer Kernels (WDCNN). The proposed method uses raw vibration signals as input (data augmentation is used to generate more inputs), and uses the wide kernels in the first convolutional layer for extracting features and suppressing high frequency noise. Small convolutional kernels in the preceding layers are used for multilayer nonlinear mapping. AdaBN is implemented to improve the domain adaptation ability of the model. The proposed model addresses the problem that currently, the accuracy of CNN applied to fault diagnosis is not very high. WDCNN can not only achieve 100% classification accuracy on normal signals, but also outperform the state-of-the-art DNN model which is based on frequency features under different working load and noisy environment conditions.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTHighly enantioselective epoxidation catalysts derived from 1,2-diaminocyclohexaneEric N. Jacobsen, Wei Zhang, Alexander R. Muci, James R. Ecker, and Li DengCite this: J. Am. Chem. Soc. 1991, 113, 18, 7063–7064Publication Date (Print):August 1, 1991Publication History Published online1 May 2002Published inissue 1 August 1991https://doi.org/10.1021/ja00018a068Request reuse permissionsArticle Views17051Altmetric-Citations869LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (294 KB) Get e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts

<h2>Summary</h2><h3>Background</h3> The ongoing COVID-19 pandemic warrants accelerated efforts to test vaccine candidates. We aimed to assess the safety and immunogenicity of an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine candidate, BBIBP-CorV, in humans. <h3>Methods</h3> We did a randomised, double-blind, placebo-controlled, phase 1/2 trial at Shangqiu City Liangyuan District Center for Disease Control and Prevention in Henan Province, China. In phase 1, healthy people aged 18–80 years, who were negative for serum-specific IgM/IgG antibodies against SARS-CoV-2 at the time of screening, were separated into two age groups (18–59 years and ≥60 years) and randomly assigned to receive vaccine or placebo in a two-dose schedule of 2 μg, 4 μg, or 8 μg on days 0 and 28. In phase 2, healthy adults (aged 18–59 years) were randomly assigned (1:1:1:1) to receive vaccine or placebo on a single-dose schedule of 8 μg on day 0 or on a two-dose schedule of 4 μg on days 0 and 14, 0 and 21, or 0 and 28. Participants within each cohort were randomly assigned by stratified block randomisation (block size eight) and allocated (3:1) to receive vaccine or placebo. Group allocation was concealed from participants, investigators, and outcome assessors. The primary outcomes were safety and tolerability. The secondary outcome was immunogenicity, assessed as the neutralising antibody responses against infectious SARS-CoV-2. This study is registered with www.chictr.org.cn, ChiCTR2000032459. <h3>Findings</h3> In phase 1, 192 participants were enrolled (mean age 53·7 years [SD 15·6]) and were randomly assigned to receive vaccine (2 μg [n=24], 4 μg [n=24], or 8 μg [n=24] for both age groups [18–59 years and ≥60 years]) or placebo (n=24). At least one adverse reaction was reported within the first 7 days of inoculation in 42 (29%) of 144 vaccine recipients. The most common systematic adverse reaction was fever (18–59 years, one [4%] in the 2 μg group, one [4%] in the 4 μg group, and two [8%] in the 8 μg group; ≥60 years, one [4%] in the 8 μg group). All adverse reactions were mild or moderate in severity. No serious adverse event was reported within 28 days post vaccination. Neutralising antibody geometric mean titres were higher at day 42 in the group aged 18–59 years (87·7 [95% CI 64·9–118·6], 2 μg group; 211·2 [158·9–280·6], 4 μg group; and 228·7 [186·1–281·1], 8 μg group) and the group aged 60 years and older (80·7 [65·4–99·6], 2 μg group; 131·5 [108·2–159·7], 4 μg group; and 170·87 [133·0–219·5], 8 μg group) compared with the placebo group (2·0 [2·0–2·0]). In phase 2, 448 participants were enrolled (mean age 41·7 years [SD 9·9]) and were randomly assigned to receive the vaccine (8 μg on day 0 [n=84] or 4 μg on days 0 and 14 [n=84], days 0 and 21 [n=84], or days 0 and 28 [n=84]) or placebo on the same schedules (n=112). At least one adverse reaction within the first 7 days was reported in 76 (23%) of 336 vaccine recipients (33 [39%], 8 μg day 0; 18 [21%], 4 μg days 0 and 14; 15 [18%], 4 μg days 0 and 21; and ten [12%], 4 μg days 0 and 28). One placebo recipient in the 4 μg days 0 and 21 group reported grade 3 fever, but was self-limited and recovered. All other adverse reactions were mild or moderate in severity. The most common systematic adverse reaction was fever (one [1%], 8 μg day 0; one [1%], 4 μg days 0 and 14; three [4%], 4 μg days 0 and 21; two [2%], 4 μg days 0 and 28). The vaccine-elicited neutralising antibody titres on day 28 were significantly greater in the 4 μg days 0 and 14 (169·5, 95% CI 132·2–217·1), days 0 and 21 (282·7, 221·2–361·4), and days 0 and 28 (218·0, 181·8–261·3) schedules than the 8 μg day 0 schedule (14·7, 11·6–18·8; all p<0·001). <h3>Interpretation</h3> The inactivated SARS-CoV-2 vaccine, BBIBP-CorV, is safe and well tolerated at all tested doses in two age groups. Humoral responses against SARS-CoV-2 were induced in all vaccine recipients on day 42. Two-dose immunisation with 4 μg vaccine on days 0 and 21 or days 0 and 28 achieved higher neutralising antibody titres than the single 8 μg dose or 4 μg dose on days 0 and 14. <h3>Funding</h3> National Program on Key Research Project of China, National Mega projects of China for Major Infectious Diseases, National Mega Projects of China for New Drug Creation, and Beijing Science and Technology Plan.

The well-known Hall effect describes the transverse deflection of charged particles (electrons or holes) in an electric-current carrying conductor under the influence of perpendicular magnetic fields, as a result of the Lorentz force. Similarly, it is intriguing to examine if quasi-particles without an electric charge, but with a topological charge, show related transverse motion. Chiral magnetic skyrmions with a well-defined spin topology resulting in a unit topological charge serve as good candidates to test this hypothesis. In spite of the recent progress made on investigating magnetic skyrmions, direct observation of the skyrmion Hall effect in real space has, remained elusive. Here, by using a current-induced spin Hall spin torque, we experimentally observe the skyrmion Hall effect by driving skyrmions from creep motion into the steady flow motion regime. We observe a Hall angle for the magnetic skyrmion motion as large as 15 degree for current densities smaller than 10 MA/cm^(2) at room temperature. The experimental observation of transverse transport of skyrmions due to topological charge may potentially create many exciting opportunities for the emerging field of skyrmionics, including novel applications such as topological selection.

Single-cell RNA sequencing (scRNA-seq) is a powerful tool for defining cellular diversity in tumors, but its application toward dissecting mechanisms underlying immune-modulating therapies is scarce. We performed scRNA-seq analyses on immune and stromal populations from colorectal cancer patients, identifying specific macrophage and conventional dendritic cell (cDC) subsets as key mediators of cellular cross-talk in the tumor microenvironment. Defining comparable myeloid populations in mouse tumors enabled characterization of their response to myeloid-targeted immunotherapy. Treatment with anti-CSF1R preferentially depleted macrophages with an inflammatory signature but spared macrophage populations that in mouse and human expresses pro-angiogenic/tumorigenic genes. Treatment with a CD40 agonist antibody preferentially activated a cDC population and increased Bhlhe40+ Th1-like cells and CD8+ memory T cells. Our comprehensive analysis of key myeloid subsets in human and mouse identifies critical cellular interactions regulating tumor immunity and defines mechanisms underlying myeloid-targeted immunotherapies currently undergoing clinical testing.

Major depressive disorder (MDD), one of the most frequently encountered forms of mental illness and a leading cause of disability worldwide, poses a major challenge to genetic analysis. To date, no robustly replicated genetic loci have been identified, despite analysis of more than 9,000 cases. Here, using low-coverage whole-genome sequencing of 5,303 Chinese women with recurrent MDD selected to reduce phenotypic heterogeneity, and 5,337 controls screened to exclude MDD, we identified, and subsequently replicated in an independent sample, two loci contributing to risk of MDD on chromosome 10: one near the SIRT1 gene (P = 2.53 × 10(-10)), the other in an intron of the LHPP gene (P = 6.45 × 10(-12)). Analysis of 4,509 cases with a severe subtype of MDD, melancholia, yielded an increased genetic signal at the SIRT1 locus. We attribute our success to the recruitment of relatively homogeneous cases with severe illness.

Aneuploidy, whole chromosome or chromosome arm imbalance, is a near-universal characteristic of human cancers. In 10,522 cancer genomes from The Cancer Genome Atlas, aneuploidy was correlated with TP53 mutation, somatic mutation rate, and expression of proliferation genes. Aneuploidy was anti-correlated with expression of immune signaling genes, due to decreased leukocyte infiltrates in high-aneuploidy samples. Chromosome arm-level alterations show cancer-specific patterns, including loss of chromosome arm 3p in squamous cancers. We applied genome engineering to delete 3p in lung cells, causing decreased proliferation rescued in part by chromosome 3 duplication. This study defines genomic and phenotypic correlates of cancer aneuploidy and provides an experimental approach to study chromosome arm aneuploidy.

This work examines the molecular mechanism of action of a class of bactericidal gold nanoparticles (NPs) which show potent antibacterial activities against multidrug-resistant Gram-negative bacteria by transcriptomic and proteomic approaches. Gold NPs exert their antibacterial activities mainly by two ways: one is to collapse membrane potential, inhibiting ATPase activities to decrease the ATP level; the other is to inhibit the subunit of ribosome from binding tRNA. Gold NPs enhance chemotaxis in the early-phase reaction. The action of gold NPs did not include reactive oxygen species (ROS)-related mechanism, the cause for cellular death induced by most bactericidal antibiotics and nanomaterials. Our investigation would allow the development of antibacterial agents that target the energy-metabolism and transcription of bacteria without triggering the ROS reaction, which may be at the same time harmful for the host when killing bacteria.

In this article, we experimentally demonstrate that the transport gap of phosphorene can be tuned monotonically from ∼0.3 to ∼1.0 eV when the flake thickness is scaled down from bulk to a single layer. As a consequence, the ON current, the OFF current, and the current ON/OFF ratios of phosphorene field effect transistors (FETs) were found to be significantly impacted by the layer thickness. The transport gap was determined from the transfer characteristics of phosphorene FETs using a robust technique that has not been reported before. The detailed mathematical model is also provided. By scaling the thickness of the gate oxide, we were also able to demonstrate enhanced ambipolar conduction in monolayer and few layer phosphorene FETs. The asymmetry of the electron and the hole current was found to be dependent on the layer thickness that can be explained by dynamic changes of the metal Fermi level with the energy band of phosphorene depending on the layer number. We also extracted the Schottky barrier heights for both the electron and the hole injection as a function of the layer thickness. Finally, we discuss the dependence of field effect hole mobility of phosphorene on temperature and carrier concentration.

Chronic mucosal inflammation and tissue damage predisposes patients to the development of colorectal cancer. This association could be explained by the hypothesis that the same factors and pathways important for wound healing also promote tumorigenesis. A sensor of tissue damage should induce these factors to promote tissue repair and regulate their action to prevent development of cancer. Interleukin 22 (IL-22), a cytokine of the IL-10 superfamily, has an important role in colonic epithelial cell repair, and its levels are increased in the blood and intestine of inflammatory bowel disease patients. This cytokine can be neutralized by the soluble IL-22 receptor, known as the IL-22 binding protein (IL-22BP, also known as IL22RA2); however, the significance of endogenous IL-22BP in vivo and the pathways that regulate this receptor are unknown. Here we describe that IL-22BP has a crucial role in controlling tumorigenesis and epithelial cell proliferation in the colon. IL-22BP is highly expressed by dendritic cells in the colon in steady-state conditions. Sensing of intestinal tissue damage via the NLRP3 or NLRP6 inflammasomes led to an IL-18-dependent downregulation of IL-22BP, thereby increasing the ratio of IL-22/IL-22BP. IL-22, which is induced during intestinal tissue damage, exerted protective properties during the peak of damage, but promoted tumour development if uncontrolled during the recovery phase. Thus, the IL-22-IL-22BP axis critically regulates intestinal tissue repair and tumorigenesis in the colon.

We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer.

The selective introduction of fluorine atom(s) and fluorinated moieties into organic molecules has become an important and fast-growing research field, since fluorine atoms play crucial roles in life science and materials science-related applications. Similar to the trifluoromethyl group, both difluoromethyl and monofluoromethyl groups can often bring about many beneficial effects to the target molecules, and a variety of CF(2)H- and CH(2)F-containing pharmaceuticals and agrochemicals have been developed. Among the synthetic methods for CF(2)H- and CH(2)F-containing compounds, selective di- and monofluoromethylation (i.e., introduction of CF(2)H and CH(2)F groups into organic molecules) represent one of the most straightforward synthetic methods and thus can be conveniently used in the synthetic design. This feature article summarizes the presently known selective difluoromethylation and monofluoromethylation methods, including nucleophilic, electrophilic, and free radical di- and monofluoromethylation reagents and reactions.

Apelin is an endogenous ligand of the human orphan receptor APJ. We detected apelin-like immunoreactivity in the adipocytes, gastric mucosa, and Kupffer cells in the liver. We also detected apelin-like immunoreactivity localized within the endothelia of small arteries in various organs. Further, it was found that mean arterial pressure after the administration of apelin-12, apelin-13, and apelin-36 at a dose of 10 nmol/kg in anaesthetized rats was reduced by 26±5, 11±4, and 5±4 mm Hg, respectively. In the presence of a nitric oxide (NO) synthase inhibitor, the effect of apelin-12 on blood pressure was abolished. Furthermore, the administration of apelin-12 (10 nmol/kg) in rats produced a transitory elevation of the plasma nitrite/nitrate concentration from a basal level of 21.4±1.6 to 27.0±1.5 μM. Thus, apelin may lower blood pressure via a nitric oxide-dependent mechanism.

Recently, less invasive methods have emerged as potential alternatives for staging with tissue confirmation of suspected metastatic mediastinal lymph nodes in lung cancer. The objective of this review was to assess the overall diagnostic accuracy of EBUS-TBNA in detecting metastatic mediastinal lymph node in lung cancer with a meta-analysis.The MEDLINE, EMBASE, Cancerlit and Cochrane Library database, from January 1995 to September 2008, were searched for studies evaluating EBUS-TBNA accuracy. Meta-analysis methods were used to pool sensitivity and specificity and to construct summary receiver-operating characteristic.A total of 11 studies with 1299 patients, who fulfilled all of the inclusion criteria, were considered for the analysis. No publication bias was found. EBUS-TBNA had a pooled sensitivity of 0.93 (95% CI, 0.91-0.94) and a pooled specificity of 1.00 (95% CI, 0.99-1.00). The subgroup of patients who were selected on the basis of CT or PET positive results had higher pooled sensitivity (0.94, 95% CI 0.93-0.96) than the subgroup of patients without any selection of CT or PET (0.76, 95% CI 0.65-0.85) (p<0.05). Study sensitivity was not correlated with the prevalence of lymph node metastasis. Only two complications occurred (0.15%).EBUS-TBNA was an accurate, safe and cost-effective tool in lung cancer staging. The selection of patients who had positive results of suspected lymph node metastasis in CT or PET may improve the sensitivity of EBUS-TBNA. High-quality prospective studies regarding EBUS-TBNA in lung cancer staging are still needed to be conducted.

Mathematical and computational modeling of genetic regulatory networks promises to uncover the fundamental principles governing biological systems in an integrative and holistic manner. It also paves the way toward the development of systematic approaches for effective therapeutic intervention in disease. The central theme in this paper is the Boolean formalism as a building block for modeling complex, large-scale, and dynamical networks of genetic interactions. We discuss the goals of modeling genetic networks as well as the data requirements. The Boolean formalism is justified from several points of view. We then introduce Boolean networks and discuss their relationships to nonlinear digital filters. The role of Boolean networks in understanding cell differentiation and cellular functional states is discussed. The inference of Boolean networks from real gene expression data is considered from the viewpoints of computational learning theory and nonlinear signal processing, touching on computational complexity of learning and robustness. Then, a discussion of the need to handle uncertainty in a probabilistic framework is presented, leading to an introduction of probabilistic Boolean networks and their relationships to Markov chains. Methods for quantifying the influence of genes on other genes are presented. The general question of the potential effect of individual genes on the global dynamical network behavior is considered using stochastic perturbation analysis. This discussion then leads into the problem of target identification for therapeutic intervention via the development of several computational tools based on first-passage times in Markov chains. Examples from biology are presented throughout the paper.

The functional roles of SNPs within the 8q24 gene desert in the cancer phenotype are not yet well understood. Here, we report that CCAT2 , a novel long noncoding RNA transcript (lncRNA) encompassing the rs6983267 SNP, is highly overexpressed in microsatellite-stable colorectal cancer and promotes tumor growth, metastasis, and chromosomal instability. We demonstrate that MYC , miR–17–5p, and miR–20a are up-regulated by CCAT2 through TCF7L2-mediated transcriptional regulation. We further identify the physical interaction between CCAT2 and TCF7L2 resulting in an enhancement of WNT signaling activity. We show that CCAT2 is itself a WNT downstream target, which suggests the existence of a feedback loop. Finally, we demonstrate that the SNP status affects CCAT2 expression and the risk allele G produces more CCAT2 transcript. Our results support a new mechanism of MYC and WNT regulation by the novel lncRNA CCAT2 in colorectal cancer pathogenesis, and provide an alternative explanation of the SNP-conferred cancer risk.

Hydrogels are a unique class of polymeric materials that possess an interconnected porous network across various length scales from nano- to macroscopic dimensions and exhibit remarkable structure-derived properties, including high surface area, an accommodating matrix, inherent flexibility, controllable mechanical strength, and excellent biocompatibility. Strong and robust adhesion between hydrogels and substrates is highly desirable for their integration into and subsequent performance in biomedical devices and systems. However, the adhesive behavior of hydrogels is severely weakened by the large amount of water that interacts with the adhesive groups reducing the interfacial interactions. The challenges of developing tough hydrogel-solid interfaces and robust bonding in wet conditions are analogous to the adhesion problems solved by marine organisms. Inspired by mussel adhesion, a variety of catechol-functionalized adhesive hydrogels have been developed, opening a door for the design of multi-functional platforms. This review is structured to give a comprehensive overview of adhesive hydrogels starting with the fundamental challenges of underwater adhesion, followed by synthetic approaches and fabrication techniques, as well as characterization methods, and finally their practical applications in tissue repair and regeneration, antifouling and antimicrobial applications, drug delivery, and cell encapsulation and delivery. Insights on these topics will provide rational guidelines for using nature's blueprints to develop hydrogel materials with advanced functionalities and uncompromised adhesive properties.

We wished to develop a highly selective positron emission tomography (PET) imaging agent targeting PHF-tau in human Alzheimer's disease (AD) brains.To screen potential tau binders, human AD brain sections were used as a source of native paired helical filament (PHF)-tau and Aβ rather than synthetic tau aggregates or Aβ fibrils generated in vitro to measure the affinity and selectivity of [(18)F]T807 to tau and Aβ. Brain uptake and biodistribution of [(18)F]T807 in mice were also tested.In vitro autoradiography results show that [(18)F]T807 exhibits strong binding to PHF-tau-positive human brain sections. A dissociation constant (Kd) of [(18)F]T807 (14.6 nM) was measured using brain sections from the frontal lobe of AD patients. A comparison of autoradiography and double immunohistochemical staining of PHF-tau and Aβ on adjacent sections demonstrated that [(18)F]T807 binding colocalized with immunoreactive PHF-tau pathology, but did not highlight Aβ plaques. In vivo studies in mice demonstrated that [(18)F]T807 was able to cross the blood-brain barrier and washed out quickly.[(18)F]T807 demonstrates high affinity and selectivity to PHF-tau as well as favorable in vivo properties, making this a promising candidate as an imaging agent for AD.

Abstract Shape‐persistent arylene ethynylene macrocycles have attracted much attention in supramolecular chemistry and materials science because of their unique structures and novel properties. In this Review we describe recent examples of macrocycle synthesis by cross‐coupling (Sonogashira: aryl acetylene macrocycle or Glaser: aryl diacetylene macrocycle) and dynamic covalent chemistry. The primary disadvantage of the coupling methods is the kinetically determined product distribution, since a significant portion of oligomers grow beyond the length of the cyclic targets (“overshooting”). Better results have been obtained recently by a dynamic covalent approach involving reversible metathesis reactions that afford macrocycles in one step. Mechanistic studies demonstrate that macrocycle formation is thermodynamically controlled by this route. Remaining synthetic challenges include the efficient preparation of site‐specifically functionalized structures and larger, more complex two‐ and three‐dimensional molecules.

<h2>Summary</h2> COVID-19 has spread worldwide since 2019 and is now a severe threat to public health. We previously identified the causative agent as a novel SARS-related coronavirus (SARS-CoV-2) that uses human angiotensin-converting enzyme 2 (hACE2) as the entry receptor. Here, we successfully developed a SARS-CoV-2 hACE2 transgenic mouse (HFH4-hACE2 in C3B6 mice) infection model. The infected mice generated typical interstitial pneumonia and pathology that were similar to those of COVID-19 patients. Viral quantification revealed the lungs as the major site of infection, although viral RNA could also be found in the eye, heart, and brain in some mice. Virus identical to SARS-CoV-2 in full-genome sequences was isolated from the infected lung and brain tissues. Last, we showed that pre-exposure to SARS-CoV-2 could protect mice from severe pneumonia. Our results show that the hACE2 mouse would be a valuable tool for testing potential vaccines and therapeutics.

Modern nanotechnology opens the possibility of combining nanocrystals of various materials with very different characteristics in one superstructure. Here we study theoretically the optical properties of hybrid molecules composed of semiconductor and metal nanoparticles. Excitons and plasmons in such a hybrid molecule become strongly coupled and demonstrate novel properties. At low incident light intensity, the exciton peak in the absorption spectrum is broadened and shifted due to incoherent and coherent interactions between metal and semiconductor nanoparticles. At high light intensity, the absorption spectrum demonstrates a surprising, strongly asymmetric shape. This shape originates from the coherent internanoparticle Coulomb interaction and can be viewed as a nonlinear Fano effect which is quite different from the usual linear Fano resonance.

Intracellular cleavage of immature flaviviruses is a critical step in assembly that generates the membrane fusion potential of the E glycoprotein. With cryo–electron microscopy we show that the immature dengue particles undergo a reversible conformational change at low pH that renders them accessible to furin cleavage. At a pH of 6.0, the E proteins are arranged in a herringbone pattern with the pr peptides docked onto the fusion loops, a configuration similar to that of the mature virion. After cleavage, the dissociation of pr is pH-dependent, suggesting that in the acidic environment of the trans-Golgi network pr is retained on the virion to prevent membrane fusion. These results suggest a mechanism by which flaviviruses are processed and stabilized in the host cell secretory pathway.

Gliomas are the most common and malignant intracranial tumors in adults. Recent studies have revealed the significance of functional genomics for glioma pathophysiological studies and treatments. However, access to comprehensive genomic data and analytical platforms is often limited. Here, we developed the Chinese Glioma Genome Atlas (CGGA), a user-friendly data portal for the storage and interactive exploration of cross-omics data, including nearly 2000 primary and recurrent glioma samples from Chinese cohort. Currently, open access is provided to whole-exome sequencing data (286 samples), mRNA sequencing (1018 samples) and microarray data (301 samples), DNA methylation microarray data (159 samples), and microRNA microarray data (198 samples), and to detailed clinical information (age, gender, chemoradiotherapy status, WHO grade, histological type, critical molecular pathological information, and survival data). In addition, we have developed several tools for users to analyze the mutation profiles, mRNA/microRNA expression, and DNA methylation profiles, and to perform survival and gene correlation analyses of specific glioma subtypes. This database removes the barriers for researchers, providing rapid and convenient access to high-quality functional genomic data resources for biological studies and clinical applications. CGGA is available at http://www.cgga.org.cn.

Traditional Chinese medicine (TCM) is not only an effective solution for primary health care, but also a great resource for drug innovation and discovery. To meet the increasing needs for TCM-related data resources, we developed ETCM, an Encyclopedia of Traditional Chinese Medicine. ETCM includes comprehensive and standardized information for the commonly used herbs and formulas of TCM, as well as their ingredients. The herb basic property and quality control standard, formula composition, ingredient drug-likeness, as well as many other information provided by ETCM can serve as a convenient resource for users to obtain thorough information about a herb or a formula. To facilitate functional and mechanistic studies of TCM, ETCM provides predicted target genes of TCM ingredients, herbs, and formulas, according to the chemical fingerprint similarity between TCM ingredients and known drugs. A systematic analysis function is also developed in ETCM, which allows users to explore the relationships or build networks among TCM herbs, formulas,ingredients, gene targets, and related pathways or diseases. ETCM is freely accessible at http://www.nrc.ac.cn:9090/ETCM/. We expect ETCM to develop into a major data warehouse for TCM and to promote TCM related researches and drug development in the future.

Renal cell carcinoma (RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival.

Global optimization of single-molecule localizations using compressed sensing allows stochastic optical reconstruction microscopy (STORM) at high molecular densities and live cell super-resolution imaging with a temporal resolution of 3 seconds. In super-resolution microscopy methods based on single-molecule switching, the rate of accumulating single-molecule activation events often limits the time resolution. Here we developed a sparse-signal recovery technique using compressed sensing to analyze images with highly overlapping fluorescent spots. This method allows an activated fluorophore density an order of magnitude higher than what conventional single-molecule fitting methods can handle. Using this method, we demonstrated imaging microtubule dynamics in living cells with a time resolution of 3 s.

We describe the physical properties of excitons in hybrid complexes composed of semiconductor and metal nanoparticles. The interaction between individual nanoparticles is revealed as an enhancement or suppression of emission. Enhanced emission comes from electric field amplified by the plasmon resonance, whereas emission suppression is a result of energy transfer from semiconductor to metal nanoparticles. The emission intensity and energy transfer rate depend strongly on the geometrical parameters of the superstructure and the physical and material properties of the nanoparticles. In particular, the emission enhancement effect appears for nanoparticles with relatively small quantum yield, and silver nanoparticles have stronger enhancement compared to gold ones. Using realistic models, we review and analyze available experimental data on energy transfer between nanoparticles. In hybrid superstructures conjugated with polymer linkers, optical emission is sensitive to environmental parameters such as, for example, temperature. This sensitivity comes from expansion or contraction of a linker. With increasing temperature, emission of polymer-conjugated complexes can decrease or increase depending on the organization of a superstructure. The structures described here have potential as sensors and actuators.

OBJECTIVE: Treatment-resistant depression is a significant public health concern; drug switching or augmentation often produce limited results. The authors hypothesized that fluoxetine could be augmented with olanzapine to successfully treat resistant depression. METHOD: An 8-week double-blind study was conducted with 28 patients who were diagnosed with recurrent, nonbipolar, treatment-resistant depression without psychotic features. Subjects were randomly assigned to one of three groups: olanzapine plus placebo, fluoxetine plus placebo, or olanzapine plus fluoxetine. RESULTS: Fluoxetine monotherapy produced minimal improvement on various scales that rate severity of depression. The benefits of olanzapine monotherapy were modest. Olanzapine plus fluoxetine produced significantly greater improvement than either monotherapy on one measure and significantly greater improvement than olanzapine monotherapy on the other measures after 1 week. There were no significant differences between treatment groups on extrapyramidal measures nor significant adverse drug interactions. CONCLUSIONS: Olanzapine plus fluoxetine demonstrated superior efficacy for treating resistant depression compared to either agent alone.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAsymmetric olefin epoxidation with sodium hypochlorite catalyzed by easily prepared chiral manganese(III) salen complexesWei Zhang and Eric N. JacobsenCite this: J. Org. Chem. 1991, 56, 7, 2296–2298Publication Date (Print):March 1, 1991Publication History Published online1 May 2002Published inissue 1 March 1991https://doi.org/10.1021/jo00007a012Request reuse permissions Article Views6808Altmetric-Citations410LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (325 KB) Get e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts

Abstract Artificial photosynthesis provides a blueprint to harvest solar energy to sustain the future energy demands. Solar‐driven water splitting, converting solar energy into hydrogen energy, is the prototype of photosynthesis. Various systems have been designed and evaluated to understand the reaction pathways and/or to meet the requirements of potential applications. In solar‐to‐hydrogen conversion, electrocatalytic hydrogen and oxygen evolution reactions are key research areas that are meaningful both theoretically and practically. To utilize hydrogen energy, fuel cell technology has been extensively investigated because of its high efficiency in releasing chemical energy. In this review, general concepts of the photosynthesis in green plants are discussed, different strategies for the light‐driven water splitting proposed in laboratories are introduced, the progress of electrocatalytic hydrogen and oxygen evolution reactions are reviewed, and finally, the reactions in hydrogen fuel cells are briefly discussed. Overall, the mass and energy circulation in the solar‐hydrogen‐electricity circle are delineated. The authors conclude that attention from scientists and engineers of relevant research areas is still highly needed to eliminate the wide disparity between the aspirations and realities of artificial photosynthesis.

The purpose of this study was to explore factors affecting users’ acceptance of automated vehicles (AVs, Level 3). A theoretical acceptance model was proposed by extending the Technology Acceptance Model (TAM) with new constructs: initial trust and two types of perceived risk (i.e., perceived safety risk [PSR] and perceived privacy risk [PPR]). It was hypothesized that initial trust was built upon perception factors (i.e., perceived usefulness [PU], perceived ease of use [PEOU], PSR, and PPR) and was a key determinant of AV acceptance. The validity of the model was confirmed with a structure equation modeling analysis based on data collected from 216 survey samples. Results revealed that initial trust was the most critical factor in promoting a positive attitude towards AVs, which, together with PU, determined users’ intention to use AVs. Initial trust could be enhanced by improving PU and reducing PSR associated with AVs. Theoretically, these findings suggest that initial trust offers another and probably more important pathway for other factors to impact consumers’ adoption of systems with uncertainty. Practically, the findings provide guidance for designing interventions aimed at improving public’s acceptance towards AVs.

We report the synthesis of highly active NiS/CdS photocatalysts via a simple hydrothermal loading method for H(2) evolution from lactic acid sacrificial solution under visible light. In the absence of noble metals, a high quantum efficiency of 51.3% was measured at 420 nm.

Demand response is playing an increasingly important role in the efficient and reliable operation of the electric grid. Modeling the dynamic behavior of a large population of responsive loads is especially important to evaluate the effectiveness of various demand response strategies. In this paper, a highly accurate aggregated model is developed for a population of air conditioning loads. The model effectively includes statistical information of the load population, systematically deals with load heterogeneity, and accounts for second-order dynamics necessary to accurately capture the transient dynamics in the collective response. Based on the model, a novel aggregated control strategy is designed for the load population under realistic conditions. The proposed controller is fully responsive and achieves the control objective without sacrificing end-use performance. The proposed aggregated modeling and control strategy is validated through realistic simulations using GridLAB-D. Extensive simulation results indicate that the proposed approach can effectively manage a large number of air conditioning systems to provide various demand response services, such as frequency regulation and peak load reduction.

Improved technology for reconstructing cryo-electron microscopy (cryo-EM) images has now made it possible to determine secondary structural features of membrane proteins in enveloped viruses. The structure of mature dengue virus particles was determined to a resolution of 9.5 A by cryo-EM and image reconstruction techniques, establishing the secondary structural disposition of the 180 envelope (E) and 180 membrane (M) proteins in the lipid envelope. The alpha-helical 'stem' regions of the E molecules, as well as part of the N-terminal section of the M proteins, are buried in the outer leaflet of the viral membrane. The 'anchor' regions of E and the M proteins each form antiparallel E-E and M-M transmembrane alpha-helices, leaving their C termini on the exterior of the viral membrane, consistent with the predicted topology of the unprocessed polyprotein. This is one of only a few determinations of the disposition of transmembrane proteins in situ and shows that the nucleocapsid core and envelope proteins do not have a direct interaction in the mature virus.

Dengue virus, a member of the Flaviviridae family, has a surface composed of 180 copies each of the envelope (E) glycoprotein and the membrane (M) protein. The crystal structure of an N-terminal fragment of E has been determined and compared with a previously described structure. The primary difference between these structures is a 10 degrees rotation about a hinge relating the fusion domain DII to domains DI and DIII. These two rigid body components were used for independent fitting of E into the cryo-electron microscopy maps of both immature and mature dengue viruses. The fitted E structures in these two particles showed a difference of 27 degrees between the two components. Comparison of the E structure in its postfusion state with that in the immature and mature virions shows a rotation approximately around the same hinge. Flexibility of E is apparently a functional requirement for assembly and infection of flaviviruses.

Inductive power transfer (IPT) is an emerging technology that may create new possibilities for wireless power charging and transfer applications. However, the rather complex control method and low efficiency remain the key obstructing factors for general deployment. In a regularly compensated IPT circuit, high efficiency and controllability of the voltage transfer function are always conflicting requirements under varying load conditions. In this paper, the relationships among compensation parameters, circuit efficiency, voltage transfer function, and conduction angle of the input current relative to the input voltage are studied. A design and optimization method is proposed to achieve a better overall efficiency as well as good output voltage controllability. An IPT system design procedure is illustrated with design curves to achieve a desirable voltage transfer ratio, optimizing between efficiency enhancement and current rating of the switches. The analysis is supported with experimental results.

<h2>Summary</h2> Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as <i>TMPRSS2</i>, <i>RET</i>, <i>FGFR3</i>, <i>ALK</i>, and <i>ESR1</i> in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy.

One-dimensionally connected organic nanostructures with dissimilar semiconducting properties are expected to provide a reliable platform in understanding the behaviors of photocarriers, which are important for the development of efficient photon-to-electrical energy conversion systems. Although bottom-up supramolecular approaches are considered promising for the realization of such nanoscale heterojunctions, the dynamic nature of molecular assembly is problematic. We report a semiconducting nanoscale organic heterojunction, demonstrated by stepwise nanotubular coassembly of two strategically designed molecular graphenes. The dissimilar nanotubular segments, thus connected noncovalently, were electronically communicable with one another over the heterojunction interface and displayed characteristic excitation energy transfer and charge transport properties not present in a mixture of the corresponding homotropically assembled nanotubes.

Background Colorectal cancer (CRC) remains one of the major cancer types and cancer related death worldwide. Sensitive, non-invasive biomarkers that can facilitate disease detection, staging and prediction of therapeutic outcome are highly desirable to improve survival rate and help to determine optimized treatment for CRC. The small non-coding RNAs, microRNAs (miRNAs), have recently been identified as critical regulators for various diseases including cancer and may represent a novel class of cancer biomarkers. The purpose of this study was to identify and validate circulating microRNAs in human plasma for use as such biomarkers in colon cancer. Methodology/Principal Findings By using quantitative reverse transcription-polymerase chain reaction, we found that circulating miR-141 was significantly associated with stage IV colon cancer in a cohort of 102 plasma samples. Receiver operating characteristic (ROC) analysis was used to evaluate the sensitivity and specificity of candidate plasma microRNA markers. We observed that combination of miR-141 and carcinoembryonic antigen (CEA), a widely used marker for CRC, further improved the accuracy of detection. These findings were validated in an independent cohort of 156 plasma samples collected at Tianjin, China. Furthermore, our analysis showed that high levels of plasma miR-141 predicted poor survival in both cohorts and that miR-141 was an independent prognostic factor for advanced colon cancer. Conclusions/Significance We propose that plasma miR-141 may represent a novel biomarker that complements CEA in detecting colon cancer with distant metastasis and that high levels of miR-141 in plasma were associated with poor prognosis.

In this study, a novel fibrous nano-silica (KCC-1) based nanocatalyst ([email protected]/KCC-1) was synthesized by modifying KCC-1 using [email protected] core–shell nanoparticles (NPs). The [email protected]/KCC-1 was used in the catalytic reduction of 4-nitrophenol (4-NP) and hydrodechlorination (HDC) of 4-chlorophenol (4-CP). KCC-1, prepared by hydrothermal method, exhibited a dandelion-like shape, high surface area, and easy accessibility of active sites. The [email protected] NPs possessed a magnetic nickel (Ni) core with palladium (Pd) shell structural composite. Thus, use of Ni led to the reduced consumption of Pd without sacrificing the overall catalytic performance, simultaneously making it reusable as it could be conveniently recovered from the reaction mixture by using an external magnetic field. Immobilization of the [email protected] NPs on KCC-1 nanospheres not only prevented their aggregation, but also significantly enhanced the accessibility of the catalytic active sites. The [email protected]/KCC-1 nanocatalyst displayed excellent catalytic activities for both the reduction of 4-NP and the HDC of 4-CP under green conditions. The above-mentioned approach based on fibrous KCC-1 and [email protected] NPs provided a useful platform for the fabrication of noble metal-based cost-effective nanocatalyst with easy accessibility, and acted as a promising candidate for numerous catalytic applications.

We characterized the epigenetic landscape of genes encoding long noncoding RNAs (lncRNAs) across 6,475 tumors and 455 cancer cell lines. In stark contrast to the CpG island hypermethylation phenotype in cancer, we observed a recurrent hypomethylation of 1,006 lncRNA genes in cancer, including EPIC1 (epigenetically-induced lncRNA1). Overexpression of EPIC1 is associated with poor prognosis in luminal B breast cancer patients and enhances tumor growth in vitro and in vivo. Mechanistically, EPIC1 promotes cell-cycle progression by interacting with MYC through EPIC1's 129–283 nt region. EPIC1 knockdown reduces the occupancy of MYC to its target genes (e.g., CDKN1A, CCNA2, CDC20, and CDC45). MYC depletion abolishes EPIC1's regulation of MYC target and luminal breast cancer tumorigenesis in vitro and in vivo.

Quantum efficiencies of organic-inorganic hybrid lead halide perovskite light-emitting devices (LEDs) have increased significantly, but poor device operational stability still impedes their further development and application. All-inorganic perovskites show better stability than the hybrid counterparts, but the performance of their respective films used in LEDs is limited by the large perovskite grain sizes, which lowers the radiative recombination probability and results in grain boundary related trap states. We realize smooth and pinhole-free, small-grained inorganic perovskite films with improved photoluminescence quantum yield by introducing trifluoroacetate anions to effectively passivate surface defects and control the crystal growth. As a result, efficient green LEDs based on inorganic perovskite films achieve a high current efficiency of 32.0 cd A-1 corresponding to an external quantum efficiency of 10.5%. More importantly, our all-inorganic perovskite LEDs demonstrate a record operational lifetime, with a half-lifetime of over 250 h at an initial luminance of 100 cd m-2.

Using high resolution MRI scans and automated tissue segmentation, gray and white matter (GM, WM) volumes of the frontal, temporal, parietal, and occipital lobes, cingulate gyrus, and insula were calculated. Subjects included 23 male and 23 female healthy, right-handed subjects. For all structures, male volumes were greater than female, but the gray/white (G/W) ratio was consistently higher across structures in women than men. Sexual dimorphism was greater for WM than GM: most of the G/W ratio sex differences can be attributed to variation in WM volume. The corpus callosum, although larger in men, is less sexually dimorphic than the WM as a whole. Several regions demonstrate pair-wise asymmetries in G/W ratio and WM volume. Both the cingulate gyrus and insula exhibit strong asymmetries. The left cingulate gyrus is significantly larger than the right, and the G/W ratio of the left insula is significantly greater than that of the right. Although statistically significant sex differences and asymmetries are present at this level of analysis, we argue that researchers should be wary of ascribing cognitive functional significance to these patterns at this time. This is not to say, however, that these patterns are not important for understanding the natural history of the human brain, and its evolution and development.

Abstract ARID1A, SWI/SNF chromatin remodeling complex subunit, is a recently identified tumor suppressor that is mutated in a broad spectrum of human cancers. Thus, it is of fundamental clinical importance to understand its molecular functions and determine whether ARID1A deficiency can be exploited therapeutically. In this article, we report a key function of ARID1A in regulating the DNA damage checkpoint. ARID1A is recruited to DNA double-strand breaks (DSB) via its interaction with the upstream DNA damage checkpoint kinase ATR. At the molecular level, ARID1A facilitates efficient processing of DSB to single-strand ends and sustains DNA damage signaling. Importantly, ARID1A deficiency sensitizes cancer cells to PARP inhibitors in vitro and in vivo, providing a potential therapeutic strategy for patients with ARID1A-mutant tumors. Significance: ARID1A has been identified as one of the most frequently mutated genes across human cancers. Our data suggest that clinical utility of PARP inhibitors might be extended beyond patients with BRCA mutations to a larger group of patients with ARID1A-mutant tumors, which may exhibit therapeutic vulnerability to PARP inhibitors. Cancer Discov; 5(7); 752–67. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 681

The miR-200 family is well known to inhibit the epithelial-mesenchymal transition, suggesting it may therapeutically inhibit metastatic biology. However, conflicting reports regarding the role of miR-200 in suppressing or promoting metastasis in different cancer types have left unanswered questions. Here we demonstrate a difference in clinical outcome based on miR-200's role in blocking tumour angiogenesis. We demonstrate that miR-200 inhibits angiogenesis through direct and indirect mechanisms by targeting interleukin-8 and CXCL1 secreted by the tumour endothelial and cancer cells. Using several experimental models, we demonstrate the therapeutic potential of miR-200 delivery in ovarian, lung, renal and basal-like breast cancers by inhibiting angiogenesis. Delivery of miR-200 members into the tumour endothelium resulted in marked reductions in metastasis and angiogenesis, and induced vascular normalization. The role of miR-200 in blocking cancer angiogenesis in a cancer-dependent context defines its utility as a potential therapeutic agent.

(Cell 173, 371–385.e1–e9; April 5, 2018) It has come to our attention that we made two errors in preparation of this manuscript. First, in the STAR Methods, under the subheading of “Hypermutators and Immune Infiltrates” within the “Quantification and Statistical Analysis” section, we inadvertently referred to Figures S7A–S7C for data corresponding to sample stratification by hypermutator status alone in the last sentence. It should have referred to Figure S6A–S6C. Second, the lists of highly frequent missense mutations for COAD (colon adenocarcinoma) and READ (rectum adenocarcinoma) displayed in Figure S7 were incorrect because when we ordered the mutations in the initial analysis, we mistakenly combined the two cancer types COAD and READ for analysis, despite the fact that they were listed as two separate cancer types in the x-axis of the figure. After re-ordering the mutations by frequency for COAD and READ independently, information on highly frequent missense mutations for each of these cancer types is different and updated now in the revised Figure S7. These errors don’t change the major conclusions of the paper and have been corrected online. We apologize for any confusion they may have caused.Figure S7On-Label/Off-Label Calculations for Druggable Mutations in Cancer (original)View Large Image Figure ViewerDownload Hi-res image Download (PPT) Comprehensive Characterization of Cancer Driver Genes and MutationsBailey et al.CellApril 05, 2018In BriefA comprehensive analysis of oncogenic driver genes and mutations in >9,000 tumors across 33 cancer types highlights the prevalence of clinically actionable cancer driver events in TCGA tumor samples. Full-Text PDF Open Access

Abstract Dieser Aufsatz fasst die bisherigen Entwicklungen auf dem Gebiet der katalytischen asymmetrischen Desaromatisierungen (CADAs) zusammen. Die hier diskutierten katalytischen asymmetrischen Desaromatisierungen umfassen oxidative Desaromatisierungen, Desaromatisierungen durch Diels‐Alder‐ und verwandte Reaktionen, alkylierende Desaromatisierungen elektronenreicher Arene, Übergangsmetall‐katalysierte Desaromatisierungen, Kaskadensequenzen mit asymmetrischer Desaromatisierung sowie nucleophile Desaromatisierungen von Pyridinium‐Derivaten. Zudem werden kurz asymmetrische Desaromatisierungen mithilfe chiraler Auxiliare sowie katalytische asymmetrische Reaktionen mit desaromatisierten Substraten eingeführt. Ziel dieses Aufsatzes ist es, ein Konzept für die asymmetrische Desaromatisierung zu liefern.

Cancer cells exhibit increased glycolysis for ATP production due, in part, to respiration injury (the Warburg effect). Because ATP generation through glycolysis is less efficient than through mitochondrial respiration, how cancer cells with this metabolic disadvantage can survive the competition with other cells and eventually develop drug resistance is a long-standing paradox. We report that mitochondrial respiration defects lead to activation of the Akt survival pathway through a novel mechanism mediated by NADH. Respiration-deficient cells (ρ-) harboring mitochondrial DNA deletion exhibit dependency on glycolysis, increased NADH, and activation of Akt, leading to drug resistance and survival advantage in hypoxia. Similarly, chemical inhibition of mitochondrial respiration and hypoxia also activates Akt. The increase in NADH caused by respiratory deficiency inactivates PTEN through a redox modification mechanism, leading to Akt activation. These findings provide a novel mechanistic insight into the Warburg effect and explain how metabolic alteration in cancer cells may gain a survival advantage and withstand therapeutic agents.

Integrated genomic analyses revealed a miRNA-regulatory network that further defined a robust integrated mesenchymal subtype associated with poor overall survival in 459 cases of serous ovarian cancer (OvCa) from The Cancer Genome Atlas and 560 cases from independent cohorts. Eight key miRNAs, including miR-506, miR-141, and miR-200a, were predicted to regulate 89% of the targets in this network. Follow-up functional experiments illustrate that miR-506 augmented E-cadherin expression, inhibited cell migration and invasion, and prevented TGFβ-induced epithelial-mesenchymal transition by targeting SNAI2, a transcriptional repressor of E-cadherin. In human OvCa, miR-506 expression was correlated with decreased SNAI2 and VIM, elevated E-cadherin, and beneficial prognosis. Nanoparticle delivery of miR-506 in orthotopic OvCa mouse models led to E-cadherin induction and reduced tumor growth.

Secondary series- and parallel-compensations are widely used in inductive power transfer (IPT) systems for various applications. These compensations are often studied under some isolated constraints of maximum power transfer, optimal efficiency at a particular loading condition, etc. These constraints constitute an insufficient set of requirements for engineers to select appropriate compensation techniques to be used as a voltage converter with optimal efficiency and loading conditions. This paper studies the characteristics of the IPT system at various frequencies of operation utilizing the two compensation techniques to work as a voltage converter. The frequencies that can provide maximum efficiency of operation and load-independent voltage-transfer ratio are analyzed. The optimal frequencies corresponding to the two compensation techniques are found and compared to facilitate the design of voltage converters with efficient power conversion and load-independent frequency of operation. The analysis is supported by experimental measurements.

A series of novel porous polymer frameworks (PPFs) with [3 + 4] structure motif have been synthesized from readily accessible building blocks via imine condensation, and the dependence of gas adsorption properties on the building block dimensions and functionalities was studied. The resulting imine-linked frameworks exhibit high surface area: the Brunauer–Emmett–Teller (BET) specific surface area up to 1740 m2 g–1, and a Langmuir surface area up to 2157 m2 g–1. More importantly, the porous frameworks exhibit outstanding H2 (up to 2.75 wt %, 77 K, 1 bar), CO2 (up to 26.7 wt %, 273 K, 1 bar), CH4 (up to 2.43 wt %, 273 K, 1 bar), and C2H2 (up to 17.9 wt %, 273 K, 1 bar) uptake, which are among the highest reported for organic porous materials. PPFs exhibit good ideal selectivities for CO2/N2 (14.5/1–20.4/1), and CO2/CH4 adsorption (8.6/1–11.0/1), and high thermal stabilities (up to 500 °C), thus showing a great potential in gas storage and separation applications.

Coronavirus disease 2019 (Covid-19) has resulted in a global outbreak. Few existing targeted medications are available. Lianhuaqingwen (LH) capsule, a repurposed marketed Chinese herb product, has been proven effective for influenza.To determine the safety and efficacy of LH capsule in patients with Covid-19.We did a prospective multicenter open-label randomized controlled trial on LH capsule in confirmed cases with Covid-19. Patients were randomized to receive usual treatment alone or in combination with LH capsules (4 capsules, thrice daily) for 14 days. The primary endpoint was the rate of symptom (fever, fatigue, coughing) recovery.We included 284 patients (142 each in treatment and control group) in the full-analysis set. The recovery rate was significantly higher in treatment group as compared with control group (91.5% vs. 82.4%, p = 0.022). The median time to symptom recovery was markedly shorter in treatment group (median: 7 vs. 10 days, p < 0.001). Time to recovery of fever (2 vs. 3 days), fatigue (3 vs. 6 days) and coughing (7 vs. 10 days) was also significantly shorter in treatment group (all p < 0.001). The rate of improvement in chest computed tomographic manifestations (83.8% vs. 64.1%, p < 0.001) and clinical cure (78.9% vs. 66.2%, p = 0.017) was also higher in treatment group. However, both groups did not differ in the rate of conversion to severe cases or viral assay findings (both p > 0.05). No serious adverse events were reported.In light of the safety and effectiveness profiles, LH capsules could be considered to ameliorate clinical symptoms of Covid-19.

Abstract We synthesized six polyurethane networks from 4,4′‐diphenylmethane diisocyanate and polyols based on midoleic sunflower, canola, soybean, sunflower, corn, and linseed oils. The differences in network structures reflected differences in the composition of fatty acids and number of functional groups in vegetable oils and resulting polyols. The number average molecular weights of polyols were between 1120 and 1300 and the functionality varied from 3.0 for the midoleic sunflower polyol to 5.2 for the linseed polyol. The functionality of the other four polyols was around 3.5. Canola, corn, soybean, and sunflower oils gave polyurethane resins of similar crosslinking density and similar glass transitions and mechanical properties despite somewhat different distribution of fatty acids. Linseed oil–based polyurethane had higher crosslinking density and higher mechanical properties, whereas midoleic sunflower oil gave softer polyurethanes characterized by lower T g and lower strength but higher elongation at break. It appears that the differences in properties of polyurethane networks resulted primarily from different crosslinking densities and less from the position of reactive sites in the fatty acids. © 2004 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 42: 809–819, 2004

Water splitting is a green strategy for hydrogen generation but greatly hindered by the sluggish anodic oxygen evolution reaction (OER). Herein, ultrathin rhodium-doped nickel iron layered double hydroxide nanosheets are successfully synthesized, which exhibit outstanding hydrogen evolution reaction (HER) and OER performance, and advanced overall water splitting. More impressively, the remarkable mass activity of 960 mA mg1 at 1.55 V (1.7 times larger than NiFe-LDH) for urea electro-oxidation reaction (UOR) shows the great potential to surmount the sluggish OER for overall water splitting. A urine-mediated electrolysis cell is subsequently configured, delivering a current density of 10 mA cm-2 with a potential of 1.35 V, which is 105 mV lower than that of urea-free counterpart. The enhanced catalytic activity and cell performance are attributed to the introduction of Rh into NiFe-LDH matrix by changing the electronic structure, allowing optimization of the adsorbed species, as confirmed by experimental measurements and computational analyses.

Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in The Cancer Genome Atlas (TCGA), and we identified 119 splicing factor genes with significant non-silent mutation patterns, including mutation over-representation, recurrent loss of function (tumor suppressor-like), or hotspot mutation profile (oncogene-like). Furthermore, RNA sequencing analysis revealed altered splicing events associated with selected splicing factor mutations. In addition, we were able to identify common gene pathway profiles associated with the presence of these mutations. Our analysis suggests that somatic alteration of genes involved in the RNA-splicing process is common in cancer and may represent an underappreciated hallmark of tumorigenesis.

Angewandte ChemieVolume 120, Issue 48 p. 9470-9473 Zuschrift Efficient Aerobic Oxidative Synthesis of 2-Substituted Benzoxazoles, Benzothiazoles, and Benzimidazoles Catalyzed by 4-Methoxy-TEMPO† Yong-Xing Chen, Yong-Xing Chen State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou 730000 (P. R. China), Fax: (+86) 931-891-2582Search for more papers by this authorLing-Feng Qian, Ling-Feng Qian State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou 730000 (P. R. China), Fax: (+86) 931-891-2582Search for more papers by this authorWei Zhang Dr., Wei Zhang Dr. State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou 730000 (P. R. China), Fax: (+86) 931-891-2582Search for more papers by this authorBing Han Dr., Bing Han Dr. hanb@lzu.edu.cn State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou 730000 (P. R. China), Fax: (+86) 931-891-2582Search for more papers by this author Yong-Xing Chen, Yong-Xing Chen State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou 730000 (P. R. China), Fax: (+86) 931-891-2582Search for more papers by this authorLing-Feng Qian, Ling-Feng Qian State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou 730000 (P. R. China), Fax: (+86) 931-891-2582Search for more papers by this authorWei Zhang Dr., Wei Zhang Dr. State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou 730000 (P. R. China), Fax: (+86) 931-891-2582Search for more papers by this authorBing Han Dr., Bing Han Dr. hanb@lzu.edu.cn State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou 730000 (P. R. China), Fax: (+86) 931-891-2582Search for more papers by this author First published: 12 November 2008 https://doi.org/10.1002/ange.200803381Citations: 72 † We are grateful to the National Natural Science Foundation of China (Grant No. 20472027) for financial support. We also thank Dr. Wei Yu for helpful discussions. TEMPO=2,2,6,6-tetramethyl-1-piperidinyloxy free radical. Read the full textAboutPDF ToolsRequest permissionAdd to favorites ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Graphical Abstract Mit TEMPO oxidiert: Bei der im Schema gezeigten Synthese von 2-substituierten Benzoxazolen, Benzothiazolen und Benzimidazolen wirkt das Radikal 4-Methoxy-2,2,6,6-tetramethyl-1-piperidinyloxy (4-Methoxy-TEMPO) als Katalysator. Citing Literature Supporting Information Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Filename Description miscellaneous information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume120, Issue48November 17, 2008Pages 9470-9473 This is the German version of Angewandte Chemie. Note for articles published since 1962: Do not cite this version alone. Take me to the International Edition version with citable page numbers, DOI, and citation export. We apologize for the inconvenience. RelatedInformation

While bulk-sized metal–organic frameworks (MOFs) face limits to their utilization in various research fields such as energy storage applications, nanoarchitectonics is believed to be a possible solution.

Immunoconjugates are being explored as novel cancer therapies with the promise of target-specific drug delivery. The immunoconjugate, huN901-DM1, composed of the humanized monoclonal IgG1 antibody, huN901, and the maytansinoid drug, DM1, is being tested in clinical trials to treat small cell lung carcinoma (SCLC). huN901-DM1 contains an average of three to four DM1 drug molecules per huN901 antibody molecule. The drug molecules are linked to huN901 through random modification of huN901 at epsilon-amino groups of lysine residues, thus yielding a heterogeneous population of conjugate species. We studied the drug distribution profile of huN901-DM1 by electrospray time-of-flight mass spectrometry(ESI-TOFMS), which showed that one to six DM1 drug molecules were attached to an antibody molecule. Both light and heavy chains contained linked drugs. The conjugation sites in both chains were determined by peptide mapping using trypsin and Asp-N protease digestion. Trypsin digestion identified modified lysine residues, since these residues were no longer susceptible to enzymatic cleavage after conjugation with the drug. With respect to Asp-N digestion, modified peptides were identified by observing a mass increase corresponding to the modification. The two digestion methods provided consistent results, leading to the identification of 20 modified lysine residues in both light and heavy chains. Each lysine residue was only partially modified. No conjugation sites were found in complementarity determining regions (CDRs). Using structural models of human IgG1, it was found that modified lysine residues were on the surface in areas of structural flexibility and had large solvent accessibility.

A catalytic enantioselective syn-1,4-bromolactonization of conjugated (Z)-enynes was reported. Diastereomeric ratios >20:1 and up to 99% enantiomeric excesses were observed. Di-, tri-, and tetra-substituted bromoallenes were prepared together with lactone heterocycles efficiently and stereoselectively. Preliminary investigations suggest that the chiral catalyst may serve as a bifunctional reagent by interacting with both a carboxylic acid nucleophile and NBS electrophile.

Studies of gene rearrangements and the consequent oncogenic fusion proteins have laid the foundation for targeted cancer therapy. To identify oncogenic fusions associated with glioma progression, we catalogued fusion transcripts by RNA-seq of 272 gliomas. Fusion transcripts were more frequently found in high-grade gliomas, in the classical subtype of gliomas, and in gliomas treated with radiation/temozolomide. Sixty-seven in-frame fusion transcripts were identified, including three recurrent fusion transcripts: FGFR3-TACC3, RNF213-SLC26A11, and PTPRZ1-MET (ZM). Interestingly, the ZM fusion was found only in grade III astrocytomas (1/13; 7.7%) or secondary GBMs (sGBMs, 3/20; 15.0%). In an independent cohort of sGBMs, the ZM fusion was found in three of 20 (15%) specimens. Genomic analysis revealed that the fusion arose from translocation events involving introns 3 or 8 of PTPRZ and intron 1 of MET. ZM fusion transcripts were found in GBMs irrespective of isocitrate dehydrogenase 1 (IDH1) mutation status. sGBMs harboring ZM fusion showed higher expression of genes required for PIK3CA signaling and lowered expression of genes that suppressed RB1 or TP53 function. Expression of the ZM fusion was mutually exclusive with EGFR overexpression in sGBMs. Exogenous expression of the ZM fusion in the U87MG glioblastoma line enhanced cell migration and invasion. Clinically, patients afflicted with ZM fusion harboring glioblastomas survived poorly relative to those afflicted with non-ZM-harboring sGBMs (P < 0.001). Our study profiles the shifting RNA landscape of gliomas during progression and reveled ZM as a novel, recurrent fusion transcript in sGBMs.

Corticosteroids are routinely utilized to alleviate edema in patients with intracranial lesions and are first-line agents to combat immune-related adverse events (irAEs) that arise with immune checkpoint blockade treatment. However, it is not known if or when corticosteroids can be administered without abrogating the efforts of immunotherapy. The purpose of this study was to evaluate the impact of dexamethasone on lymphocyte activation and proliferation during checkpoint blockade to provide guidance for corticosteroid use while immunotherapy is being implemented as a cancer treatment.Lymphocyte proliferation, differentiation, and cytokine production were evaluated during dexamethasone exposure. Human T cells were stimulated through CD3 ligation and co-stimulated either directly by CD28 ligation or by providing CD80, a shared ligand for CD28 and CTLA-4. CTLA-4 signaling was inhibited by antibody blockade using ipilimumab which has been approved for the treatment of several solid tumors. The in vivo effects of dexamethasone during checkpoint blockade were evaluated using the GL261 syngeneic mouse intracranial model, and immune populations were profiled by flow cytometry.Dexamethasone upregulated CTLA-4 mRNA and protein in CD4 and CD8 T cells and blocked CD28-mediated cell cycle entry and differentiation. Naïve T cells were most sensitive, leading to a decrease of the development of more differentiated subsets. Resistance to dexamethasone was conferred by blocking CTLA-4 or providing strong CD28 co-stimulation prior to dexamethasone exposure. CTLA-4 blockade increased IFNγ expression, but not IL-2, in stimulated human peripheral blood T cells exposed to dexamethasone. Finally, we found that CTLA-4 blockade partially rescued T cell numbers in mice bearing intracranial gliomas. CTLA-4 blockade was associated with increased IFNγ-producing tumor-infiltrating T cells and extended survival of dexamethasone-treated mice.Dexamethasone-mediated T cell suppression diminishes naïve T cell proliferation and differentiation by attenuating the CD28 co-stimulatory pathway. However, CTLA-4, but not PD-1 blockade can partially prevent some of the inhibitory effects of dexamethasone on the immune response.

Touch sensation is essential for behaviours ranging from environmental exploration to social interaction; however, the underlying mechanisms are largely unknown. In Drosophila larvae, two types of sensory neurons, class III and class IV dendritic arborization neurons, tile the body wall. The mechanotransduction channel PIEZO in class IV neurons is essential for sensing noxious mechanical stimuli but is not involved in gentle touch. On the basis of electrophysiological-recording, calcium-imaging and behavioural studies, here we report that class III dendritic arborization neurons are touch sensitive and contribute to gentle-touch sensation. We further identify NOMPC (No mechanoreceptor potential C), a member of the transient receptor potential (TRP) family of ion channels, as a mechanotransduction channel for gentle touch. NOMPC is highly expressed in class III neurons and is required for their mechanotransduction. Moreover, ectopic NOMPC expression confers touch sensitivity to the normally touch-insensitive class IV neurons. In addition to the critical role of NOMPC in eliciting gentle-touch-mediated behavioural responses, expression of this protein in the Drosophila S2 cell line also gives rise to mechanosensitive channels in which ion selectivity can be altered by NOMPC mutation, indicating that NOMPC is a pore-forming subunit of a mechanotransduction channel. Our study establishes NOMPC as a bona fide mechanotransduction channel that satisfies all four criteria proposed for a channel to qualify as a transducer of mechanical stimuli and mediates gentle-touch sensation. Our study also suggests that different mechanosensitive channels may be used to sense gentle touch versus noxious mechanical stimuli.

Fluorescent dyes have enabled much progress in the broad range of biomedical fields. However, many commercially available dyes suffer from small Stokes shifts, resulting in poor signal-to-noise ratio and self-quenching on current microscope configurations. In this work, we have developed a general method to significantly increase the Stokes shifts of common fluorophores. By simply appending a 1,4-diethyl-decahydro-quinoxaline (DQ) moiety onto the conjugated structure, we introduced a vibronic backbone that could facilely expand the Stokes shifts, emission wavelength, and photostability of 11 different fluorophores by more than 3-fold. This generalizable method could significantly improve the imaging efficiency of commercial fluorophores. As a demonstration, we showed that the DQ derivative of hemicyanine generated 5-fold signal in mouse models over indocyanine green. Furthermore, the DQ-modified fluorophores could pair with their parent molecules to conduct one-excitation, multiple emission imaging, allowing us to study the cell behavior more robustly. This approach shows promise in generating dyes suitable for super-resolution microscopy and second window near-infrared imaging.

Ozonolysis was used to obtain polyols with terminal primary hydroxyl groups and different functionalities from trilinolein (or triolein), low-saturation canola oil, and soybean oil. The functionality of the model polyol from triolein (trilinolein) was 3.0 and that of soy polyol was 2.5, due to the presence of unreactive saturated fatty acids, while canola gave a polyol with a functionality of 2.8. All polyols exhibited a high tendency to crystallize at room temperature. The resulting waxes had melting points comparable to that of paraffin and very low viscosities in the liquid state. The polyols were cross-linked using 4,4'-methylenebis(phenyl isocyanate) to give polyurethanes. Glass transitions (T(g)) for the model-, canola-, and soy-based polyurethanes were 53, 36, and 22 degrees C, respectively. The about 30 degrees C lower T(g) of the soy-based polyurethane than that of the model polyurethane was the result not only of lower functionality but also of the presence of saturated fatty acids in the former. Polyurethane from the canola polyol had intermediate cross-linking density and properties. These polyurethanes displayed excellent mechanical properties and higher glass transition temperatures compared to polyurethanes from epoxidized and hydroformylated polyols of the same functionality, presumably due to the absence or lower content of dangling chains in the former.

This paper discusses the effect and mechanisms of digital economy (diec) on carbon emission performance (cop). Specifically, based on the panel data of 277 cities in China from 2011 to 2019, carbon emission performance and digital economy at the city level were evaluated through global super efficiency Epsilon-Based Measure (EBM) with unexpected output, and the vertical and horizontal scatter degree method, respectively. The OLS, mediation effect model, threshold model and spatial Durbin model (SDM) were adopted to investigate the nexus of diec and cop. The results show that: First, digital economy improves carbon emission performance, and this conclusion holds even after a series of robustness tests and endogenous treatment. The main impact mechanisms are energy intensity (ei), energy consumption scale (ec) and urban afforestation. And the effect and its impact mechanisms show regional heterogeneity. Second, under different levels of energy consumption structure, ei, ec, government intervention and urban afforestation, the impact of diec on cop is non-linear. Third, there's a spatial effect between diec and cop. The impact of diec on cop is significantly positive in local cities, while insignificant in the neighboring cities. Based on the above conclusions, specific recommendations are proposed for diec to improve cop.

Operation time of implantable electronic devices is largely constrained by the lifetime of batteries, which have to be replaced periodically by surgical procedures once exhausted, causing physical and mental suffering to patients and increasing healthcare costs. Besides the efficient scavenging of the mechanical energy of internal organs, this study proposes a self-powered, flexible, and one-stop implantable triboelectric active sensor (iTEAS) that can provide continuous monitoring of multiple physiological and pathological signs. As demonstrated in human-scale animals, the device can monitor heart rates, reaching an accuracy of ∼99%. Cardiac arrhythmias such as atrial fibrillation and ventricular premature contraction can be detected in real-time. Furthermore, a novel method of monitoring respiratory rates and phases is established by analyzing variations of the output peaks of the iTEAS. Blood pressure can be independently estimated and the velocity of blood flow calculated with the aid of a separate arterial pressure catheter. With the core-shell packaging strategy, monitoring functionality remains excellent during 72 h after closure of the chest. The in vivo biocompatibility of the device is examined after 2 weeks of implantation, proving suitability for practical use. As a multifunctional biomedical monitor that is exempt from needing an external power supply, the proposed iTEAS holds great potential in the future of the healthcare industry.

Several functional MRI (fMRI) activation studies have highlighted specific differences in brain response in social anxiety disorder (SAD) patients. Little is known, so far, about the changes in the functional architecture of resting state networks (RSNs) in SAD during resting state. We investigated statistical differences in RSNs on 20 SAD and 20 controls using independent component analysis. A diffuse impact on widely distributed RSNs and selective changes of RSN intrinsic functional connectivity were observed in SAD. Functional connectivity was decreased in the somato-motor (primary and motor cortices) and visual (primary visual cortex) networks, increased in a network including medial prefrontal cortex which is thought to be involved in self-referential processes, and increased or decreased in the default mode network (posterior cingulate cortex/precuneus, bilateral inferior parietal gyrus, angular gyrus, middle temporal gyrus, and superior and medial frontal gyrus) which has been suggested to be involved in episodic memory, and self-projection, the dorsal attention network (middle and superior occipital gyrus, inferior and superior parietal gyrus, and middle and superior frontal gyrus) which is thought to mediate goal-directed top-down processing, the core network (insula-cingulate cortices) which is associated with task control function, and the central-executive network (fronto-parietal cortices). A relationship between functional connectivity and disease severity was found in specific regions of RSNs, including medial and lateral prefrontal cortex, as well as parietal and occipital regions. Our results might supply a novel way to look into neuro-pathophysiological mechanisms in SAD patients.

Behaviors of functional interfaces are crucial factors in the performance and safety of energy storage and conversion devices. Indeed, solid electrode-solid electrolyte interfacial impedance is now considered the main limiting factor in all-solid-state batteries rather than low ionic conductivity of the solid electrolyte. Here, we present a new approach to conducting in situ scanning transmission electron microscopy (STEM) coupled with electron energy loss spectroscopy (EELS) in order to uncover the unique interfacial phenomena related to lithium ion transport and its corresponding charge transfer. Our approach allowed quantitative spectroscopic characterization of a galvanostatically biased electrochemical system under in situ conditions. Using a LiCoO2/LiPON/Si thin film battery, an unexpected structurally disordered interfacial layer between LiCoO2 cathode and LiPON electrolyte was discovered to be inherent to this interface without cycling. During in situ charging, spectroscopic characterization revealed that this interfacial layer evolved to form highly oxidized Co ions species along with lithium oxide and lithium peroxide species. These findings suggest that the mechanism of interfacial impedance at the LiCoO2/LiPON interface is caused by chemical changes rather than space charge effects. Insights gained from this technique will shed light on important challenges of interfaces in all-solid-state energy storage and conversion systems and facilitate improved engineering of devices operated far from equilibrium.

A weak polyelectrolyte, poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA), was grafted onto the surface of cellulose nanocrystals via free radical polymerization. The resultant suspension of PDMAEMA-grafted-cellulose nanocrystals (PDMAEMA-g-CNC) possessed pH-responsive properties. The grafting was confirmed by FTIR, potentiometric titration, elementary analysis, and thermogravimetric analysis (TGA); the surface and interfacial properties of the modified particles were characterized by surface tensiometer. Compared to pristine cellulose nanocrystals, modified CNC significantly reduced the surface and interfacial tensions. Stable heptane-in-water and toluene-in-water emulsions were prepared with PDMAEMA-g-CNC. Various factors, such as polarity of solvents, concentration of particles, electrolytes, and pH, on the properties of the emulsions were investigated. Using Nile Red as a florescence probe, the stability of the emulsions as a function of pH and temperature was elucidated. It was deduced that PDMAEMA chains promoted the stability of emulsion droplets and their chain conformation varied with pH and temperature to trigger the emulsification and demulsification of oil droplets. Interestingly, for heptane system, the macroscopic colors varied depending on the pH condition, while the color of the toluene system remained the same. Reversible emulsion systems that responded to pH were observed and a thermoresponsive Pickering emulsion system was demonstrated.

China has implemented its carbon emission trading system (ETS) in seven pilots since 2013. Many methods have been used to evaluate the effect and efficiency of the ETS in reducing carbon emissions. Evaluating the carbon ETS to determine whether it has co-benefited the economy and environment in the seven pilots is crucial for the development of China. Moreover, different methods of measurement reveal different results on how efficient the seven carbon emission trading markets (ETMs) are. We use the difference-in-differences (DID) method to evaluate the impact of carbon emissions and economic growth following ETS implementation. Based on the data of industrial carbon emissions in 30 provinces of China from 2008 to 2016, the impact of ETS on the carbon emission reduction and economic growth of enterprises is empirically tested. Data envelopment analysis (DEA) evaluates the operating efficiency of the carbon ETMs. Based on the seven carbon emission trading pilots conducted in China in 2014–2016, the carbon ETMs differentiation system in the pilot area is taken as the input index and the ETS implementation effect is used as the output index to construct the full DEA evaluation model for gauging the operation efficiency of the carbon ETMs. The results show that the implementation of the carbon trading policy increases the economic dividend (13.6%) generated by the gross industrial output value, but significantly reduces the emission (24.2%) of industrial CO2 in all seven carbon emission trading pilots. The average DEA efficiency of the seven carbon ETMs operations in China have increased annually.

CD4+CD25+ regulatory T cells (Treg) play a central role in the prevention of autoimmunity and in the control of immune responses by down-regulating the function of effector CD4+ or CD8+ T cells. The role of Treg in Mycobacterium tuberculosis infection and persistence is inadequately documented. Therefore, the current study was designed to determine whether CD4+CD25+FoxP3+ regulatory T cells may modulate immunity against human tuberculosis (TB). Our results indicate that the number of CD4+CD25+FoxP3+ Treg increases in the blood or at the site of infection in active TB patients. The frequency of CD4+CD25+FoxP3+ Treg in pleural fluid inversely correlates with local MTB-specific immunity (p < 0.002). These CD4+CD25+FoxP3+ T lymphocytes isolated from the blood and pleural fluid are capable of suppressing MTB-specific IFN-γ and IL-10 production in TB patients. Therefore, CD4+CD25+FoxP3+ Treg expanded in TB patients suppress M. tuberculosis immunity and may therefore contribute to the pathogenesis of human TB.

The recent progress made on porphyrin-based frameworks and their applications in energy-related conversion technologies (<italic>e.g.</italic>, ORR, OER and CO₂RR) and storage technologies (<italic>e.g.</italic>, Zn–air batteries).

Oxygen-bearing copper (OBC) has been widely studied for enabling the C–C coupling of the electrocatalytic CO2 reduction reaction (CO2RR) since this is a distinctive hallmark of strongly correlated OBC systems and may benefit many other Cu-based catalytic processes. Unresolved problems, however, include the instability of and limited knowledge regarding OBC under realistic operating conditions, raising doubts about its role in CO2RR. Here, an atypical and stable OBC catalyst with a hierarchical pore and nanograin-boundary structure was constructed and was found to exhibit efficient CO2RR for the production of ethylene with a Faradaic efficiency of 45% at a partial current density of 44.7 mA cm–2 in neutral media, and the ethylene partial current density is nearly 26 and 116 times that of oxygen-free copper (OFC) and commercial Cu foam, respectively. More importantly, the structure–activity relationship in CO2RR was explored through a comprehensive analysis of experimental data and computational techniques, thus increasing the fundamental understanding of CO2RR. A systematic characterization analysis suggests that atypical OBC (Cu4O) was formed and that it is stable even at −1.00 V [(vs the reversible hydrogen electrode (RHE)]. Density functional theory calculations show that the atypical OBC enables control over CO adsorption and dimerization, making it possible to implement a preference for the electrosynthesis of ethylene (C2) products. These results provide insight into the synthesis and structural characteristics of OBC as well as its interplay with ethylene selectivity.

We have previously identified reductions in mean pyramidal cell somal volume in deep layer 3 of BA 41 and 42 and reduced axon terminal density in deep layer 3 of BA 41. In other brain regions demonstrating similar deficits, reduced dendritic spine density has also been identified, leading us to hypothesize that dendritic spine density would also be reduced in BA 41 and 42. Because dendritic spines and their excitatory inputs are regulated in tandem, we further hypothesized that spine density would be correlated with axon terminal density. We used stereologic methods to quantify a marker of dendritic spines, spinophilin-immunoreactive (SP-IR) puncta, in deep layer 3 of BA 41 and 42 of 15 subjects with schizophrenia, each matched to a normal comparison subject. The effect of long-term haloperidol exposure on SP-IR puncta density was evaluated in nonhuman primates. SP-IR puncta density was significantly lower by 27.2% in deep layer 3 of BA 41 in the schizophrenia subjects, and by 22.2% in deep layer 3 of BA 42. In both BA 41 and 42, SP-IR puncta density was correlated with a marker of axon terminal density, but not with pyramidal cell somal volume. SP-IR puncta density did not differ between haloperidol-exposed and control monkeys. Lower SP-IR puncta density in deep layer 3 of BA 41 and 42 of subjects with schizophrenia may reflect concurrent reductions in excitatory afferent input. This may contribute to impairments in auditory sensory processing that are present in subjects with schizophrenia.

Carbon nanomaterials (CNMs) are novel nanomaterials with excellent physicochemical properties, which are widely used in biomedicine, energy and sensing. Besides, CNMs also play an important role in environmental pollution control, which can absorb heavy metals, antibiotics and harmful gases. However, CNMs are inevitably entering the environment while they are rapidly developing. They are harmful to living organisms in the environment and are difficult to degrade under natural conditions. Here, we systematically describe the toxicity of carbon nanotubes (CNTs), graphene (GRA) and C60 to cells, animals, humans, and microorganisms. According to the current research results, the toxicity mechanism is summarized, including oxidative stress response, mechanical damage and effects on biological enzymes. In addition, according to the latest research progress, we focus on the two major degradation methods of chemical degradation and biodegradation of CNTs, GRA and C60. Meanwhile, the reaction conditions and degradation mechanisms of degradation are respectively stated. Moreover, we have prospects for the limitations of CNM degradation under non-experimental conditions and their potential application.

Yttrium iron garnet (YIG) films that are in the nanometer thickness range and show extremely low damping are reported. The films were deposited via sputtering at room temperature and were then annealed in O <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><tex-math>$_{2}$</tex-math></inline-formula> at high temperature. A 22-nm-thick YIG film showed a Gilbert damping constant <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><tex-math>$\alpha = (8.58\pm 0.21)\times 10^{-5}$</tex-math></inline-formula> , which represents the lowest damping ever reported for nanometer-thick magnetic films. The film had a gyromagnetic ratio of <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><tex-math>$\vert\gamma \vert = 2.83$</tex-math></inline-formula> MHz/Oe and a saturation induction of <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><tex-math>$4\pi M_{\rm s} = 1766$</tex-math></inline-formula> G, which are both very close to those of single-crystal YIG bulk materials. The film had a very smooth surface, with an rms surface roughness of about 0.13 nm.

Dynamic covalent chemistry (DCC) provides an intriguing and highly efficient approach for building molecules that are usually thermodynamically favored. However, the DCC methods that are efficient enough to construct large, complex molecules, particularly those with three-dimensional (3-D) architectures, are still very limited. Here, for the first time, we have successfully utilized alkyne metathesis, a highly efficient DCC approach, to construct the novel 3-D rectangular prismatic molecular cage COP-5 in one step from a readily accessible porphyrin-based precursor. COP-5 consists of rigid, aromatic porphyrin and carbazole moieties as well as linear ethynylene linkers, rendering its shape-persistent nature. Interestingly, COP-5 serves as an excellent receptor for fullerenes. It forms 1:1 complexes with C60 and C70 with association constants of 1.4 × 105 M–1 (C60) and 1.5 × 108 M–1 (C70) in toluene. This represents one of the highest binding affinities reported so far for purely organic fullerene receptors. COP-5 shows an unprecedented high selectivity in binding C70 over C60 (KC70/KC60 > 1000). Moreover, the binding between the cage and fullerene is fully reversible under the acid–base stimuli, thus allowing successful separation of C70 from a C60-enriched fullerene mixture (C60/C70, 10/1 mol/mol) through the “selective complexation–decomplexation” strategy.

Chronic inflammation is a major contributing factor in the pathogenesis of many age-associated diseases. One central protein that regulates inflammation is NF-κB, the activity of which is modulated by post-translational modifications as well as by association with co-activator and co-repressor proteins. SIRT1, an NAD(+)-dependent protein deacetylase, has been shown to suppress NF-κB signaling through deacetylation of the p65 subunit of NF-κB resulting in the reduction of the inflammatory responses mediated by this transcription factor. The role of SIRT1 in the regulation of NF-κB provides the necessary validation for the development of pharmacological strategies for activating SIRT1 as an approach for the development of a new class of anti-inflammatory therapeutics. We report herein the development of a quantitative assay to assess compound effects on acetylated p65 protein in the cell. We demonstrate that small molecule activators of SIRT1 (STACs) enhance deacetylation of cellular p65 protein, which results in the suppression of TNFα-induced NF-κB transcriptional activation and reduction of LPS-stimulated TNFα secretion in a SIRT1-dependent manner. In an acute mouse model of LPS-induced inflammation, the STAC SRTCX1003 decreased the production of the proinflammatory cytokines TNFα and IL-12. Our studies indicate that increasing SIRT1-mediated NF-κB deacetylation using small molecule activating compounds is a novel approach to the development of a new class of therapeutic anti-inflammatory agents.

Lower limb rehabilitation exoskeleton robots integrate sensing, control, and other technologies and exhibit the characteristics of bionics, robotics, information and control science, medicine, and other interdisciplinary areas. In this review, the typical products and prototypes of lower limb exoskeleton rehabilitation robots are introduced and state-of-the-art techniques are analyzed and summarized. Because the goal of rehabilitation training is to recover patients’ sporting ability to the normal level, studying the human gait is the foundation of lower limb exoskeleton rehabilitation robot research. Therefore, this review critically evaluates research progress in human gait analysis and systematically summarizes developments in the mechanical design and control of lower limb rehabilitation exoskeleton robots. From the performance of typical prototypes, it can be deduced that these robots can be connected to human limbs as wearable forms; further, it is possible to control robot movement at each joint to simulate normal gait and drive the patient’s limb to realize robot-assisted rehabilitation training. Therefore human–robot integration is one of the most important research directions, and in this context, rigid-flexible-soft hybrid structure design, customized personalized gait generation, and multimodal information fusion are three key technologies.

A porous Ni–Fe oxide with improved crystallinity has been prepared as a highly efficient electrocatalytic water oxidation catalyst. It has a small overpotential, a low Tafel slope, and an outstanding stability. The remarkably improved electrocatalytic performance is due to the porous structure, high extent homogeneous iron incorporation, ameliorative crystallinity, and the low mass transfer resistance. Water splitting for the generation of clean and sustainable energy resource represents one of the most promising processes toward environmental remediation.1 Oxygen evolution reaction (OER) is the bottleneck in water splitting as it is kinetically slow and requires high overpotential (η) to reach a substantial current density in water electrolysis.2 Broad attention has been therefore attracted to seek efficient OER electrocatalysts working at low overpotentials to reduce the energy input for water splitting.3 Regarding this, IrO2 and RuO2 were reported to have good electrocatalytic OER activity.[3] However, the use of scarce noble metals limited their widespread applications. Toward identifying cheap and efficient electrocatalysts for OER, transition metal oxides,4 hydroxides,5 and oxyhydroxides6 based on earth abundant elements have been extensively examined. Among them, mixed-metal materials containing iron group elements (Fe, Co, Ni) have been generally acknowledged as one of the most competent candidates for OER in aqueous media.[3],[4],[6],7 For the fabrication of iron group metal based materials as OER catalysts, one of the widely employed techniques is in situ electrodeposition method for the generation of amorphous films on the surface of electrodes. The structure and electrochemical activity of electrodeposited Ni, Co, Ni–Fe, Co–Fe, and Ni–Co films have been extensively studied.[4],6, 8 Our recent work reported the first Fe-based film prepared by a fast and simple cyclic voltammetry (CV) electrodeposition method as an OER electrocatalyst in neutral media with a high turnover frequency (TOF).[5] Besides the electrodeposition route, photochemical deposition method for a soft loading of mixed Ni–Fe–Co film on electrode with controlled metal stoichiometry has also been developed.[4] Alongside the deposition methods, mixed-metal materials containing iron group elements have also been synthesized via a variety of techniques such as spin-coating,9 pulsed-laser ablation,10 aerosol spray,11 template synthesis,[5],[7] solid-state reaction,12 as well as exfoliation of bulk materials13 toward improved electrochemical activity. Moreover, Ni–Fe layered double hydroxides (LDH) with the incorporation of carbon materials have been reported for significant enhancement of the OER activity.14 Typically, mixed Ni–Fe materials have shown excellent electrocatalytic activities in basic media.[6],[14] Ni is the active oxygen evolution center, and Fe incorporation will improve the conductivity of the material.[4],[6] It is universally acknowledged that high surface area will contribute to the activity improvement, whereas the poor crystallinity arisen from high surface area is adverse to the electrocatalytic stability. Thermal treatment of the materials for improved crystallinity can ameliorate their electrochemical stability.[7],12 However, thermal treatment has been rarely applied to Ni–Fe electrocatalysts as it can largely reduce the surface area and thus the activity of the materials.[4] Although considerable efforts have been devoted to fabricating electrode materials with optimized surface active sites via porous structure or 3D architecture,[5],7,[14],15 limited work has been documented on porous electrocatalysts with improved crystallinity for enhanced stability without the damage of their efficient OER performance. Thus, it is highly desirable to develop novel protocols for the synthesis of porous Ni–Fe materials with abundant surface active sites, and meanwhile, with improved crystallinity for ameliorative electrochemical stability. Herein, we report a facile synthesis of porous Ni–Fe mixed oxides in the presence of organic surfactant Tween 85. By using Tween, which has a perfect boiling point for the synthesis of the catalyst in this work, the porous structure can be created at low temperature from evaporation of the mixed surfactant. While in traditional method, those carbon-based surfactant templates are burnt out under high temperatures to get the porous structure. Heating treatment at elevated temperature not only requires large energy cost but also limits the application in thermal instable or unfavorable systems. Ni–Fe OER catalyst is a thermal unfavorable system. The creation of porous structure under mild temperature is not only suitable for the formation of active phase, but also preferable for the reservation of high surface area. The sample after thermal treatment under 200 °C has a porous structure and improved crystallinity compared to traditional Ni–Fe hydroxides synthesized under room temperature. This porous Ni–Fe catalyst outperformed its bulk material counterpart (Tween free sample) for OER. In CV studies, it can highly efficiently catalyze water oxidation in a 0.1 m KOH aqueous solution. Small overpotentials of 328 and 420 mV are required to reach OER current densities of 10 and 50 mA cm−2, respectively. In controlled potential electrolysis (CPE) at η = 387 mV, an extremely stable current density of ≈10.2 mA cm−2 maintained, giving an extraordinary TOF value of 432 h−1. Besides the outstanding performance of the material, our synthesis method is suitable for large-scale production, and thus delivers a valuable contribution to electrocatalytic water splitting research. The Ni–Fe composites were obtained through coprecipitation strategy in the presence of Tween 85, a polysorbate surfactant with a boiling point above 100 °C. The solids were collected and subjected to mild heat treatment under elevated temperatures for the removal of Tween to construct pores in the material. X-ray diffraction (XRD) patterns for composites with different starting Ni–Fe ratios after calcination under 200 °C for 3 h (all the thermal treatment time is 3 h in this work), which is the thermal treatment condition toward the highest OER activity (see below), are shown in Figure 1A. Samples are denoted as Ni-X-Y, in which X stands for the starting Ni percentage and Y stands for the treatment temperature in degrees Celsius. The two samples with high nickel concentration tended to form β-Ni(OH)2 (JCPDS 742075) phase showing selected better crystallinity from (100) and (110) reflections at 2θ degree of 33° and 59°, respectively. Increased Fe incorporation in Ni-90-200 and Ni-85-200 samples resulted in a dominant NiO (JCPDS 780643) phase with mixed weak signals from NiFe2O4 (JCPDS 742081) observed in the latter sample. The peaks around 62° and 75° in these two samples were assigned to NiO, as the characteristic XRD peak of NiFe2O4 at 30° was not observed. The iron incorporation in the composites can promote the transfer of hydroxides to oxides under thermal treatment, which is consistent to the X-ray photoelectron spectroscopy (XPS) studies of Ni–Fe material by Smith et al.[4] Samples with further increased iron content existed as NiFe2O4 with mixed NiO, and it was a mixture of NiFe2O4 and γ-Fe2O3 (JCPDS 871166) for sample with even higher Fe content. For Ni-50-200 sample, which contains actually over 94% of iron as suggested by XPS, the crystallinity is quite poor with a dominant γ-Fe2O3 phase. With a starting Ni–Fe ratio of 85:15, which is the tested Ni–Fe ratio toward the highest OER activity (see below), the synergic effects of heat treatment on crystal structure can be referred from the XRD patterns shown in Figure 1B. The freshly synthesized composite showed a structure that can be indexed to α-Ni(OH)2 (JCPDS 380715). After heat treatment under 100 °C for 3 h, the α-Ni(OH)2 phase maintained with an emerging peak around 11° from the (003) reflection perpendicular to the α-Ni(OH)2 layers. This phenomenon resembles the structure conversion of electrodeposited Ni–Fe LDH with new XRD peak from (003) direction after aging in a hot solution for a period of time.[6] Due to the high content of Tween in our samples as determined by element analysis (≈40 wt%), the Ni–Fe layers in the freshly prepared samples are probably wrapped by Tween molecules leading to the formation of Ni–Fe hydroxide nanosheets with limited layers. Upon heat treatment, Tween molecules were released. As a consequence, the Ni–Fe layers assembled together causing the XRD peak at 11° due to the diffraction from Ni–Fe hydroxide interlayers. The XRD result of the sample Ni-85-200 without the addition of Tween shown in Figure S1 (Supporting Information) suggested a distinguishable crystalline phase of α-Ni(OH)2, which is consistent with the above discussions on the formation of assembled layers in Tween wrapped samples. With elevated temperature treatment, the hydroxides start to form a dominant NiO (JCPDS 780643) structure under 200 °C and an NiO/NiFe2O4 (JCPDS 742081) composites starting from 300 °C. As demonstrated in Figure 2A, the release of Tween upon heat treatment can be verified from infrared spectra of the samples studied in Figure 1B. The red line sample was synthesized from the same conditions without Tween. The freshly prepared sample with Tween before heat treatment displays distinct peaks from C–H stretching vibrations of methylene and methyl groups (2860, 2940 cm−1), CO/C–O stretching vibrations of ester/ether groups (1750, 1130 cm−1). Tween molecules were gradually removed from the sample after heat treatment, and only trace was left in the sample after 200 °C treatment. The O–H stretching vibration peaks (≈3480 cm−1) and scissoring vibration peaks (1700–1500 cm−1 from water, 1400–1300 cm−1 from structure hydroxyl groups) are obvious in all the samples, especially in samples under low-temperature treatment. Thermal gravimetric analysis (TGA) and derivative thermogravimetric (DTG) analysis studies of the above mentioned sample are shown in Figure 2B. Upon elevated heat treatment, the mixture starts to lose weight from a sequence of absorbed water, structure water, Tween, and eventually undergoes a phase transfer from hydroxide to oxide. Upon the removal of Tween in the samples, porous structure was obtained and demonstrated by transmission electron microscopy (TEM) images (Figure 3A–D), Brunauer–Emmett–Teller (BET) surface area, and pore size distribution measurements (Table S1, Supporting Information, and Figure 3E,F). After heat treatment, the bulk hydroxides (Figure 3A) turned into aggregates comprised of Ni–Fe domains (darker areas) and pores (lighter areas) as illustrated in Figure 3B,C. Higher temperature treatment converts the aggregates into more separated nanoparticles as shown in Figure 3D. Scanning electron microscope (SEM) and high-resolution TEM (HRTEM) images of the Ni-85-200 sample are provided in Figures S2 and S3 (Supporting Information). Well-dispersed electrocatalysts on indium tin oxide (ITO) electrode was observed from the SEM image. In HRTEM, the lattice can be fairly indexed to the dominant reflection peaks of NiO. Elemental mapping of the material was demonstrated via energy dispersive X-ray (EDX) spectroscopy, suggesting a homogeneous nickel/iron dispersion in the material as shown in Figures S4 and S5 (Supporting Information). BET surface areas and pore size distributions of the materials studied in TEM have been examined through N2 physical adsorption measurements. Figure 3E shows the pore size distribution of the aforementioned sample with a pore diameter around 3 nm. The pore size expanded with increasing temperature treatment. After calcination under 200 °C for 3 h, the pore volume of the sample with the addition of Tween during synthesis (red line, Figure 3E) is significantly higher than that from the sample without Tween (blue line, Figure 3E). The adsorption–desorption isotherm plot for the sample treated under 200 °C displays a type-IV isotherm with a closure at P/P0 around 0.4, suggesting the presence of small mesopores in the material. Integrally, we are capable to illustrate the evolution procedure of the Ni–Fe material under heat treatment in Figure 4. The freshly synthesized Tween wrapped Fe doped α-Ni(OH)2 sheets assembled into layered Fe doped α-Ni(OH)2 after heat treatment as the hydroxide sheets were less wrapped by Tween. Subsequently, it evolved into porous Fe-doped NiO with the complete removal of Tween under higher temperature. With further elevated temperature treatment, the pore expanded and separated nanoparticles were formed eventually. The actual Ni–Fe composition information of the samples determined by XPS analysis is summarized in Table S1 (Supporting Information) with the foregoing discussed physical properties. The Ni/Fe 2p spectra for the Ni-X-200 and Ni-85-Y samples are presented in Figure S6 (Supporting Information). The XPS results from the Ni-50-Y samples as displayed in gray line in Figure S6A,B (Supporting Information) indicate the very low nickel content, which is due to the much smaller solubility product from Fe(OH)3 (Ksp = 2.8 × 10−39) than Ni(OH)2 (Ksp = 5.5 × 10−16).16 FeIII will be precipitated from basic solutions much easier than NiII, leading to a low nickel content sample when base is not sufficient during synthesis. The Ni 2p and Fe 2p peaks for the Ni-85-200 sample can be fairly resolved to support the XRD results of the composite (Figure 5). A dominant Fe-incorporated NiO phase and trace amount of NiFe2O4 was suggested from the XRD results. The Ni 2p3/2 peak centered at 855.5 eV is higher than that from pure NiO around 854 eV. The high extent doping of FeIII with high electronegativity causes a higher valence state of NiII.[4],[6] The small orange line peak with binding energy of 857.0 eV is assigned to the trace amount of isolated NiFe2O4, whose weak signals in XRD analysis can also be observed.17 The NiFe2O4 content is around 3.1 mol%. The Fe 2p3/2 peak is well fitted into the FeIII signals at 710.2 and 715.6 eV based on the method developed for the spectrum of ferric with a nickel environment.18 The electrocatalytic performance of the porous Ni–Fe materials for water oxidation was tested. CVs of the Ni-X-200 samples are shown in Figure 6A. Pure nickel material has poor OER activity and displays distinct self-redox peaks due to the oxidation of NiII to NiIII at 1.45 V versus reversible hydrogen electrode (RHE, all potentials reported in this work are vs RHE).[5],[6] The addition of two percent of Fe during synthesis will significantly suppress the oxidation of NiII. There is hardly notable NiII self-redox peaks from samples with higher percentage of Fe incorporation. It is rationalized that FeIII with high electronegativity can increase the valence state of surrounding nickel atoms, which become harder to be further oxidized. With the electron-withdrawing effect on nickel, iron incorporation facilitates the partial charge transfer in the material for possible higher OER kinetics.[6] The OER activity is remarkably improved as the starting Fe content increased to 15%. Further increase of the Fe content to 20% dramatically deteriorates the OER performance, and there is hardly notable water oxidation peak from the sample with 30% or higher starting Fe content. Thermal treatment effects on the electrocatalytic activity have also been studied for the Ni-85-Y samples (Figure 6B). Thermal treatment of the freshly prepared sample at 100 °C for 3 h can improve its OER performance notably. For the Ni-85-200 sample, the current can reach as high as 62 mA cm−2 at 1.72 V (η = 487 mV). Thermal treatment under further increased temperature will remarkably decrease the OER activity, probably due to the reduced surface area as well as structure change of the material. As proved by XRD analysis, the mixture was in the form of Fe-doped NiO after 200 °C calcination. After higher temperature treatment, it turned into a mixture of NiO and NiFe2O4, which neither is reported to have excellent OER performance.[3],[4],12 As for Ni-85-200 sample, the trace amount of NiFe2O4 in the sample is not believed to deteriorate the OER performance too much. Meanwhile, the Fe content is a significant determinant for the activity of Ni–Fe materials. Thus, the higher activity from the Ni-85-200 is due to the saturated and optimally doped Fe content in the NiO phase. For comparison, Figure 6C shows the CV of the best porous Ni-85-200 sample, the CV from the corresponding bulk sample synthesized without Tween, and the CV from blank glassy carbon (GC) electrode. The porous sample dominantly outperformed the bulk Ni–Fe hydroxide that is reported extensively as an efficient OER electrocatalyst. In addition, the benchmarked Ir/C (20 wt% of Ir) electrocatalyst was drop-casted onto the GC electrode for comparison. Its CV study from the same condition showed a less active performance compared to the porous Ni–Fe oxides, although an earlier onset potential for OER was observed. The obtained porous Ni–Fe oxides can efficiently catalyze water oxidation with small overpotentials of 328 and 420 mV to reach current densities of 10 and 50 mA cm−2, respectively. To better evaluate our electrocatalysts, a comparison of the current densities from the samples with/without the addition of Tween during synthesis is shown in Figure 6D. For the freshly prepared samples, the addition of Tween can suppress the OER activity, which is due to the blocking of surface active sites by large Tween molecules. With elevated heat treatment, the Tween molecules were removed steadily leaving a porous structure. As a consequence, it is reasonable to notice that the samples with Tween during synthesis greatly outperform the corresponding bulk material samples after heat treatment. It is also notable that high-temperature calcination up to 400 °C made the structure difference less significant between plain and Tween added samples, and thus resulted in closer OER performances. The Ni-85-100 sample with Tween has the same α-Ni(OH)2 structure to the Ni-85-200 sample without Tween. The higher performance from the former is probably due to the less assembled α-Ni(OH)2 nanosheets as demonstrated from the XRD reflection from (003) facets around 11° as shown in Figure 1B and Figure S1 (Supporting Information). Tween wrapped sample can be converted from Ni(OH)2 to NiO under a relatively lower temperature, probably due to its poorer crystallinity. This feature helps to reserve the high surface area of the resultant active Ni-85-200 sample. The detailed comparisons of the CV studies for samples with or without Tween are shown in Figure S7 (Supporting Information). The self-redox peaks due to the oxidation of NiII to NiIII were increasingly suppressed along with the increase of thermal treatment temperature. This is consistent with the increased valence state of Ni in the nickel ferrite after annealing under high temperature as studied by Solís et al.19 To this extent, thermal treatment causes a closer Ni–Fe interaction in the samples after calcination, which contributes to the improvement of electrocatalytic activity. Considering the reduced surface area after calcination, it is reasonable to observe the highest activity from the sample after thermal treatment under 200 °C. As shown in Figure 7A, CPE at 1.62 V was conducted in 0.1 m KOH aqueous solution using ITO electrodes casted with the porous Ni-85-200 catalyst (red line) or without thermal treatment (purple line), and the corresponding catalyst without Tween (blue line). In CPE, a stable current density at ≈10.2 mA cm−2 maintained from the porous sample, indicating its outstanding electrocatalytic durability. Moreover, no activation process, which is widely reported for Ni–Fe based materials in water oxidation, is required to reach the high current density for this porous catalyst. These stability features are attributed to the improved crystallinity of our sample as a consequence of thermal treatment.[7],12 The CPE results from the same sample without thermal treatment showed a much smaller current density and a rapid degradation of activity after 10 min of electrolysis. Before and after electrolysis, CVs were recorded and provided in Figure S8 (Supporting Information) for the samples with or without thermal treatment. The stable performance of the Ni-85-200 is further expounded from the SEM and HRTEM images of the sample after electrolysis (Figure S9, Supporting Information), which suggested almost unchanged morphology and phase. Compared to the sample dried under room temperature, the porous sample showed much better stability due to its improved crystallinity after thermal treatment. With the Tween assisted synthesis, the mild heat treatment preserves the high surface area porous structure for efficient activity, and on the other hand, increases the crystallinity of the material for stability. For comparison, the sample without Tween during synthesis showed a much smaller current density of ≈2 mA cm−2 with a gradually increased current after the initial 1 h sluggish period. A movie of the vigorous evolution of oxygen bubbles during electrolysis under 1.62 V is provided (Movie S1, Supporting Information). The amount of evolved oxygen was measured using a calibrated Ocean Optics FOXY probe. During 6 h electrolysis, 55 C of charges passed with 141 μmol of O2 evolved, which gave a Faradaic yield of >98%. A high TOF value of 432 h−1 based on the nickel amount loaded was achieved, which is among those highest values reported for OER.[4],[5],[6] It should be noted that the OER performance of metal oxides/hydroxides can be substantially improved in concentrated alkaline solution11,[14],[15] or from Au coated substrate electrodes.[6],20 Thus, any comparison of the OER performance should be made based on the same experimental details. Figure 7B shows the Tafel plot of the porous sample and the bulk sample. A small Tafel slope of 42 mV decade−1 for the porous catalyst is achieved. Correspondingly, a higher value of 72 mV decade−1 is obtained for the bulk catalyst (Ni-85-250 without Tween), which has the same NiO phase as Ni-85-200 with Tween. The electrochemical impedance spectroscopy (EIS) was referred for more information of the electrocatalysts as shown in the Nyquist plots in Figure 8. As confirmed from Figure 8A for the EIS of the porous sample under different potentials, the first semicircle in the high-frequency region represents the charge transfer resistance from the bulk electrolyte to the catalyst surface, which is independent of the potential applied. The following second semicircle in the low-frequency region represents the resistance from the mass transfer during electrocatalytic reactions, which is the reference of the redox reaction efficiency. The porous electrocatalyst has a much lower mass transfer resistance in OER as shown in Figure 8B, which is attributed to the porous structure. The ESI plots of the Ni-85-Y samples are provided in Figure S10 (Supporting Information) for reference. The lowest mass transfer resistance is from the Ni-85-200 sample, which is the most active catalyst studied in this work. In summary, a porous Ni–Fe oxide has been prepared with the assistance of Tween molecules. Upon mild thermal treatment, the polysorbate was removed gradually from the composite leaving the porous structure material with large surface area. Likewise, the crystallinity was improved and a homogeneous high extent Fe doping in NiO was achieved by heat treatment. The material is highly efficient for electrocatalytic water oxidation. From the porous sample, small overpotentials of 328 and 420 mV are required for OER to reach current densities of 10 and 50 mA cm−2, respectively. The current density of ≈10.2 mA cm−2 stays almost constant under 1.62 V electrolysis. The remarkably improved electrocatalytic performance compared to the bulk material is due to the porous structure, homogeneous Fe incorporation, ameliorative crystallinity, and the low mass transfer resistance. Synthesis of Electrocatalysts: The materials were obtained through coprecipitation strategy with the presence of Tween 85, a polysorbate surfactant with a boiling point above 100 °C. The oily polysorbate of 10 mL was first dissolved in 50 mL of 1 m NaOH solution at 60 °C under vigorous stirring, and then a mixed aqueous solution containing Ni(NO3)2 and Fe(NO3)3 at different ratios (the total metal concentration is 2.5 m, volume is 20 mL) was added into the hot basic solution dropwise. The suspension was stirred under the given temperature for 4 h. The solids were collected and washed by centrifugation in a sequence of water (two times), acetone (one time), and water (two times) thoroughly. The obtained solids were dried in an oven at 60 °C and were subjected to further thermal treatment under different temperatures as required. The bulk samples for comparison were synthesized from the same procedure except the addition of Tween. Electrochemical Studies: All electrochemical experiments were carried out using a CH Instruments (CHI 660E Electrochemical Analyzer) at 20 °C. CVs were obtained in 15 mL of 0.1 m KOH aqueous solution using a conventional three-electrode configuration with a 0.07 cm2 GC electrode as the working electrode, saturated Ag/AgCl as the reference electrode, and Pt wire as the auxiliary electrode. The working electrode was prepared through a drop-casting method. Typically, 2 mg of sample and 30 μL of Nafion solution (5 wt%, DuPont) were dispersed in 1 mL of water–ethanol solution at volume ratio of 2:1 by ultrasonicating for 1 h to form a homogeneous suspension. Then 5 μL of the mixture was loaded onto the glassy carbon electrode. Compensation for iR drop was used for all CVs. All potentials were reported versus the RHE based on the equation: ERHE = EAg/AgCl + (0.197 + 0.0591 × pH). Current–potential data for Tafel plots were acquired by implementing controlled potential electrolysis in 15 mL of 0.1 m KOH solution at a variety of applied potentials in two-compartment cells. The stable currents were measured at applied potentials ranging from 1.42 to 1.62 V in every 20 mV step for 600 s CPE experiments with the solution being gently stirred. CPE was recorded at 1.62 V in a fritted cell with ITO working electrode (5 × 5 mm2) with the catalyst (18.0 μL of the aforesaid suspension). The EIS was recorded on an ITO electrode over a frequency range from 0.1 Hz to 1 mHz at the amplitude of the sinusoidal voltage of 5 mV under different potentials ranging from 1.52 to 1.67 V. The TOF value was calculated by assuming that every nickel atom was involved in the catalysis (lower limit): TOF = i/(4F × n). Here, i (A) is the measured current, the number 4 means four electrons are required for the generation of one oxygen molecule, F is Faraday's constant (96 485.3 C mol−1), and n is the moles of the nickel atom on the electrode based on the amount of coated catalyst. Analysis of O2 produced in CPE experiments was conducted by using a calibrated Ocean Optics FOXY probe (Model NeoFox). The authors are grateful for support from the Fundamental Research Funds for the Central Universities, the Research Funds of Shaanxi Normal University, the “Thousand Talents Program” of China, and the National Natural Science Foundation of China under Grant No. 21101170. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Through undefined mechanisms, dominant mutations in (Cu/Zn) superoxide dismutase-1 (mSOD1) cause the non-cell-autonomous death of motoneurons in inherited amyotrophic lateral sclerosis (ALS). Microgliosis at sites of motoneuron injury is a neuropathological hallmark of ALS. Extracellular mutant SOD1 (mSOD1) causes motoneuron injury and triggers microgliosis in spinal cord cultures, but it is unclear whether the injury results from extracellular mSOD1 directly interacting with motoneurons or is mediated through mSOD1-activated microglia. To dissociate these potential mSOD1-mediated neurotoxic mechanisms, the effects of extracellular human mSOD1(G93A) or mSOD1(G85R) were assayed using primary cultures of motoneurons and microglia. The data demonstrate that exogenous mSOD1(G93A) did not cause detectable direct killing of motoneurons. In contrast, mSOD1(G93A) or mSOD1(G85R) did induce the morphological and functional activation of microglia, increasing their release of pro-inflammatory cytokines and free radicals. Furthermore, only when microglia was co-cultured with motoneurons did extracellular mSOD1(G93A) injure motoneurons. The microglial activation mediated by mSOD1(G93A) was attenuated using toll-like receptors (TLR) 2, TLR4 and CD14 blocking antibodies, or when microglia lacked CD14 expression. These data suggest that extracellular mSOD1(G93A) is not directly toxic to motoneurons but requires microglial activation for toxicity, utilizing CD14 and TLR pathways. This link between mSOD1 and innate immunity may offer novel therapeutic targets in ALS.

The bromodomain and extraterminal (BET) family of proteins comprises four members-BRD2, BRD3, BRD4 and the testis-specific isoform BRDT-that largely function as transcriptional coactivators and play critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion. BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia, or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer. Pathologically, BET proteins are frequently overexpressed and are clinically linked to various types of human cancer; they are therefore being pursued as attractive therapeutic targets for selective inhibition in patients with cancer. To this end, a number of bromodomain inhibitors, including JQ1 and I-BET, have been developed and have shown promising outcomes in early clinical trials. Although resistance to BET inhibitors has been documented in preclinical models, the molecular mechanisms underlying acquired resistance are largely unknown. Here we report that cullin-3SPOP earmarks BET proteins, including BRD2, BRD3 and BRD4, for ubiquitination-mediated degradation. Pathologically, prostate cancer-associated SPOP mutants fail to interact with and promote the degradation of BET proteins, leading to their elevated abundance in SPOP-mutant prostate cancer. As a result, prostate cancer cell lines and organoids derived from individuals harboring SPOP mutations are more resistant to BET-inhibitor-induced cell growth arrest and apoptosis. Therefore, our results elucidate the tumor-suppressor role of SPOP in prostate cancer in which it acts as a negative regulator of BET protein stability and also provide a molecular mechanism for resistance to BET inhibitors in individuals with prostate cancer bearing SPOP mutations.

Abstract The increasing demand for higher‐energy‐density batteries driven by advancements in electric vehicles, hybrid electric vehicles, and portable electronic devices necessitates the development of alternative anode materials with a specific capacity beyond that of traditional graphite anodes. Here, the state‐of‐the‐art developments made in the rational design of Si‐based electrodes and their progression toward practical application are presented. First, a comprehensive overview of fundamental electrochemistry and selected critical challenges is given, including their large volume expansion, unstable solid electrolyte interface (SEI) growth, low initial Coulombic efficiency, low areal capacity, and safety issues. Second, the principles of potential solutions including nanoarchitectured construction, surface/interface engineering, novel binder and electrolyte design, and designing the whole electrode for stability are discussed in detail. Third, applications for Si‐based anodes beyond LIBs are highlighted, specifically noting their promise in configurations of Li–S batteries and all‐solid‐state batteries. Fourth, the electrochemical reaction process, structural evolution, and degradation mechanisms are systematically investigated by advanced in situ and operando characterizations. Finally, the future trends and perspectives with an emphasis on commercialization of Si‐based electrodes are provided. Si‐based anode materials will be key in helping keep up with the demands for higher energy density in the coming decades.

A series of novel organic cage compounds 1-4 were successfully synthesized from readily available starting materials in one-pot in decent to excellent yields (46-90%) through a dynamic covalent chemistry approach (imine condensation reaction). Covalently cross-linked cage framework 14 was obtained through the cage-to-framework strategy via the Sonogashira coupling of cage 4 with the 1,4-diethynylbenzene linker molecule. Cage compounds 1-4 and framework 14 exhibited exceptional high ideal selectivity (36/1-138/1) in adsorption of CO(2) over N(2) under the standard temperature and pressure (STP, 20 °C, 1 bar). Gas adsorption studies indicate that the high selectivity is provided not only by the amino group density (mol/g), but also by the intrinsic pore size of the cage structure (distance between the top and bottom panels), which can be tuned by judiciously choosing building blocks of different size. The systematic studies on the structure-property relationship of this novel class of organic cages are reported herein for the first time; they provide critical knowledge on the rational design principle of these cage-based porous materials that have shown great potential in gas separation and carbon capture applications.

Centrioles are essential for the formation of microtubule-derived structures, including cilia and centrosomes. Abnormalities in centrosome number and structure occur in many cancers and are associated with genomic instability. In most dividing animal cells, centriole formation is coordinated with DNA replication and is highly regulated such that only one daughter centriole forms close to each mother centriole. Centriole formation is triggered and dependent on a conserved kinase, SAK/PLK4. Downregulation and overexpression of SAK/PLK4 is associated with cancer in humans, mice, and flies. Here we show that centrosome amplification is normally inhibited by degradation of SAK/PK4 degradation, mediated by the SCF/Slimb ubiquitin ligase. This complex physically interacts with SAK/PLK4, and in its absence, SAK/PLK4 accumulates, leading to the striking formation of multiple daughter centrioles surrounding each mother. This interaction is mediated via a conserved Slimb binding motif in SAK/PLK4, mutations of which leads to centrosome amplification. This regulation is likely to be conserved, because knockout of the ortholog of Slimb, beta-Trcp1 in mice, also leads to centrosome amplification. Because the SCF/beta-Trcp complex plays an important role in cell-cycle progression, our results lead to new understanding of the control of centrosome number and how it may go awry in human disease.