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In this paper, we investigate the split common split feasibility with multiple output sets when the relevant nonlinear mapping is demicontractive. To solve this problem, we propose several new methods and state their convergence theorems under some mild conditions. The split feasibility problem with numerous output sets is solved using the outcomes as an example. [ABSTRACT FROM AUTHOR]

In this paper, we investigate the split common fixed point problem with multiple output sets and develop novel approaches for effectively approximating its solution. We establish two convergence theorems under appropriate conditions for strictly pseudo-contractive mappings and demicontractive mappings, respectively, which cover some existing results as a special case. Furthermore, the numerical experiments demonstrate that we have developed a competitive method for solving the split common fixed point problem with multiple output sets. [ABSTRACT FROM AUTHOR]

A novel NiH-catalyzed highly regioselective coupling of alkenes with vinyl chlorosilanes, constructing C–Si bonds, is developed. Under mild reaction conditions, a series of benzyl organosilanes with various functional groups could be accessed. Further synthetic studies illustrate that the products of this chemistry could be used as versatile precursors to prepare complicated organosilicon compounds. Moreover, the NiH-catalyzed mechanism of the present transformation was proposed based on control experiments. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy has become a major treatment for lung adenocarcinoma. Better understanding of the tumor microenvironment (TME) in lung adenocarcinoma is needed in order to better treat it with this type of therapy. In this study, we evaluate the associations of PGK1 with prognosis and immunological characteristics in lung adenocarcinoma using bioinformatic analysis methods. The results of this study provide clues for a potential immunometabolic combination therapy strategy that may improve the immunotherapeutic efficacy of LUAD. Background: Aerobic glycolysis plays a key role in tumor metabolic reprogramming to reshape the immune microenvironment. The phosphoglycerate kinase 1 (PGK1) gene codes a glycolytic enzyme that converts 1,3-diphosphoglycerate to 3-phosphoglycerate. However, in lung adenocarcinoma (LUAD), the role of PGK1 in altering the tumor microenvironment (TME) has not yet been determined. Methods: Raw data, including bulk DNA and mRNA-seq data, methylation modification data, single-cell RNA-seq data, proteomics data, clinical case characteristics survival, immunotherapy data, and so on, were obtained from multiple independent public data sets. These data were reanalyzed to uncover the prognosis and immunological characteristics of PGK1 in LUAD. Results: We found that PGK1 mRNA and protein were considerably over-expressed in LUAD compared to normal tissue and that high PGK1 expression is associated with poorer prognostic outcomes in LUAD. The enrichment analysis of PGK1 co-expressed genes in lung adenocarcinoma revealed that PGK1 may be involved in hypoxia, metabolism, DNA synthesis, cell cycle, PI3K/AKT, and various immune and inflammatory signaling pathways. Furthermore, PGK1 is also linked to the recruitment of numerous immune cells, including aDC (dendritic cells), macrophages, and neutrophils. More importantly, PGK1 was highly expressed in immunosuppressive cells, including M2 macrophages, Tregs, and exhausted T cells, among others. Finally, higher PGK1 expression indicated significant correlations to immune checkpoints, TMB (tumor mutation burden), and high response to immunotherapy. Conclusions: The presented findings imply that PGK1, as a glycolysis core gene, may be important for the modification of the immune microenvironment by interacting with the tumor metabolism. The results of this study provide clues for a potential immunometabolic combination therapy strategy in LUAD, for which more experimental and clinical translational research is needed. [ABSTRACT FROM AUTHOR]

In this paper, we consider the multiple-set split common fixed point problem in Hilbert spaces. We first study a couple of critical properties of strictly pseudocontractive mappings and particularly the property under mix activity. By utilizing these properties, we propose new iterative strategies for settling this problem as well as several connected issues. Under delicate conditions, we state weak convergence of the proposed strategies that expands the current works from the case of two subsets to the instance of multiple subsets. As an application, we give an exhibit of the theoretical results to the multiple-set split equality problem and the elastic net regularization. [ABSTRACT FROM AUTHOR]

A galactoglucan (HCPA) was extracted from C. mollissima Blume fruits using hot water, which was composed of glucose and galactose, with a molecular weight of 5.5 kDa. Methylation and 1 D, 2 D NMR spectroscopy analysis showed that HCPA contained [→4)-α-D-Glcp(1→], [→4,6)-α-D-Glcp(1→], [→4)-β-D-Galp(1→] and [α-D-Glcp(1→] motifs in a molar ratio of approximately 6.11:1.08:1.00:1.03. HCPA showed a spherical-like structure as detected by scanning electron microscope (SEM). HCPA biological activity was investigated in vitro. The results showed that HCPA inhibited the proliferation of HeLa, MCF-7 and MGC-803 cells, induced HeLa cells apoptosis and arrested cell cycle in G2/M phase of HeLa cells. HCPA also enhanced the viability and phagocytic ability of RAW 264.7 cells and stimulated the production of NO, TNF-α and IL-6. The results demonstrated that HCPA had a potent antitumor and immunomodulating effects in vitro, suggesting its potential use as functional food and drug products. [ABSTRACT FROM AUTHOR]

A new and facile visible-light-enabled method for the synthesis of α-azidoketones has been developed via oxyazidation of alkenes with TMSN3 in air at room temperature. A series of α-azidoketones could be easily and efficiently obtained in moderate to excellent yields via cascade C–N and C=O bond formation by simply using low-toxic and inexpensive Rose Bengal (1 mol%) and PhSeSePh (5 mol%) as co-catalysts. [ABSTRACT FROM AUTHOR]

We are concerned with the split common fixed point problem in Hilbert spaces. We propose a new method for solving this problem and establish a weak convergence theorem whenever the involved mappings are demicontractive and Lipschitz continuous. As an application, we also obtain a new method for solving the split equality problem in Hilbert spaces. [ABSTRACT FROM AUTHOR]

A mild and convenient visible-light-induced method has been developed for the construction of 3-sulfonyl and 3-sulfenyl azaspiro[4,5]trienones through metal-free difunctionalization of alkynes with sulfinic acids or thiols at room temperature. The present protocol simply utilizes visible light as the safe and eco-friendly energy source, and inexpensive and non-toxic organic dyes (Eosin Y and Na2-Eosin Y) as photocatalysts providing various sulfur-containing azaspiro[4,5]trienones in moderate to good yields. [ABSTRACT FROM AUTHOR]

A highly selective synthesis of sulfoxides from alkenes and thiols was established by visible-light photoredox catalysis at room temperature. This metal-free transformation protocol, which uses inexpensive Rose Bengal as the photocatalyst and air as the green oxidant, opens a new door toward the facile and practical construction of sulfoxides. [ABSTRACT FROM AUTHOR]

Post-translational modifications of histones play a key role in the regulation of gene expression during development and differentiation. Numerous studies have shown the dynamics of combinatorial regulation by transcription factors and histone modifications, in the sense that different combinations lead to distinct expression outcomes. Here, we investigated gene regulation by stable enrichment patterns of histone marks H3K4me2 and H3K4me3 in combination with the chromatin binding of the muscle tissue-specific transcription factor MyoD during myogenic differentiation of C2C12 cells. Using k-means clustering, we found that specific combinations of H3K4me2/3 profiles over and towards the gene body impact on gene expression and marks a subset of genes important for muscle development and differentiation. By further analysis, we found that the muscle key regulator MyoD was significantly enriched on this subset of genes and played a repressive role during myogenic differentiation. Among these genes, we identified the pluripotency gene Patz1, which is repressed during myogenic differentiation through direct binding of MyoD to promoter elements. These results point to the importance of integrating histone modifications and MyoD chromatin binding for coordinated gene activation and repression during myogenic differentiation. [ABSTRACT FROM AUTHOR]

The proximal point algorithm (PPA) is a classical method for finding zeros of maximal monotone operators. It is known that the algorithm only has weak convergence in a general Hilbert space. Recently, Wang, Wang and Xu proposed two modifications of the PPA and established strong convergence theorems on these two algorithms. However, these two convergence theorems exclude an important case, namely, the over-relaxed case. In this paper, we extend the above convergence theorems from under-relaxed case to the over-relaxed case, which in turn improve the performance of these two algorithms. Preliminary numerical experiments show that the algorithm with over-relaxed parameter performs better than that with under-relaxed parameter. [ABSTRACT FROM PUBLISHER]

A simple and convenient method has been developed for the construction of 3-thioindoles via molecular iodine-catalyzed direct thiolation of indoles with thiols. The present protocol, which employs thiols as the thiolating agents, inexpensive molecular iodine as the catalyst, and environmentally benign air as the oxidant, allows the regioselective generation of 3-thioindoles in good to excellent yields. Graphical Abstract: [ABSTRACT FROM AUTHOR]

Bigels were formed by using glycerol monolaurate, MCT and cinnamaldehyde as the oil phase and chitosan as the aqueous phase. Oil and aqueous phase was gelled by the self-assembly of glycerol monolaurate, and cross-linking of cinnamaldehyde droplets with chitosan, respectively. [Display omitted] • Bigels were produced using plant-based ingredients and dual gelling method. • Chitosan crosslinking by cinnamaldehyde contributed to gel formation. • Covalent crosslinks modulated the structure and properties of bigels. • Cream was simulated with good texture and speadability. In this study, chitosan-based bigels were fabricated, where glycerol monolaurate was added in MCT oil to produce a gelled lipid phase and cinnamaldehyde was included in the lipid phase in order to act as a crosslinking agent. The synergistic effect of pH on chemical crosslinking effects was investigated. The potential of using these bigels as an alternative to cream was also investigated. The pH of the aqueous phase played an important role in controlling the extent of the Schiff-base reaction promoted by cinnamaldehyde. At pH 3.8, the bigels formed were homogenous but at pH 5.0 and 5.5 they exhibited phase separation, which highlighted the importance of chemical crosslinking. To better mimic the properties of real cream, span 80 was added to create a more homogeneous and smoother structure of the bigels. These bigels might provide a healthy and more sustainable alterative to food products that contain plastic fats, like cream. [ABSTRACT FROM AUTHOR]

Given two real sequences ( r n ) and ( α n ) , we study the iterative scheme: x n + 1 = α n u + ( 1 - α n ) J r n x n , for finding a zero of an accretive operator A , where u is a fixed element and J r n denotes the resolvent of A . To ensure its convergence, the real sequence ( r n ) is always assumed to satisfy ∑ n = 0 ∞ | r n + 1 - r n | < ∞ . In this paper we show this condition can be completely removed, which enables us to improve a result recently obtained by Saejung. [ABSTRACT FROM AUTHOR]

We study the contraction-proximal point algorithm that has the following iterative form:whereis a fixed element,is the resolvent operator andare all real sequences. The algorithm is known to converge strongly under the assumption thatis bounded below away from zero and above away from 1. In this paper, we show that this condition can be further relaxed as [ABSTRACT FROM PUBLISHER]

Probing children's understanding of science concepts has been a focus of research in science education since the 1980s. In the process of learning, learners often produce many conceptions that differ from established scientific knowledge, which are commonly labelled as alternative conceptions (ACs). Knowing these ACs, their prevalence, nature, strength, causes and its dynamic change in the learning process is very important for the formation of scientific conceptions. In order to better identify middle school students' ACs at different times in mainland china and analyse the differences between these ACs, taking the concept of 'the human blood circulatory system' as an example, this study constructed and validated two sets of Four-Tier Multiple-Choice tests (4TMC), and applied them to explore 501 seventh graders after they had learned the concept. The results show that the 4TMC can effectively explore not only the individual ACs but also the group ACs. In the first test, 1 week after learning human blood circulatory system, six ACs have been identified in this group. There are five ACs in the second test 6 months after learning this knowledge. Meanwhile, there is a significant difference between these ACs at different times. This research can provide examples for exploring students' ACs. [ABSTRACT FROM AUTHOR]

In their recent paper (Math. Model. Anal., 17(4):457–466, 2012), Tang, Peng and Liu proposed a cyclic algorithm for solving the split common fixed point problem and established its weak convergence under some certain conditions. In this paper, we shall present a simple proof of such a result and moreover we shall remove one condition, continuity of the mapping involved, ensuring the convergence of the algorithm. [ABSTRACT FROM PUBLISHER]

Phthalates are common endocrine disruptors. The placental barrier can be crossed by phthalates and may have a negative impact on the health of the fetus. However, the association between prenatal exposure to phthalates and birth size is still debatable. Here, we performed this meta-analysis to assess the relationship between prenatal phthalates exposure and birth size. Eighteen studies were finally included by searching PubMed, Embase, Scopus, Ovid, and Web of Science databases and standardized regression coefficients and standard errors were used to pool effect size. Our results showed that prenatal exposure to MMP (=-0.04, 95%CI: −0.08, −0.01) and MEP (=-0.01, 95%CI: −0.01, −0.002) was significantly associated with birth weight. However, no significant associations were identified for phthalate exposure with birth length, head circumference and chest circumference. Because the limiting of studies, more high-quality case–control studies or cohort studies are urgently needed to draw the best conclusions. [ABSTRACT FROM AUTHOR]

Abstract: Recently, the Banaś modulus of smoothness for the Bynum space was obtained by Zuo and Cui (Z. Zuo, Y. Cui, Some modulus and normal structure in Banach space, J. Inequal. Appl. 2009 (2009) 15. doi:10.1155/2009/676373. Article ID 676373). It is however not true in general. In this note, we will present the exact value for this modulus in the space. [Copyright &y& Elsevier]

The development of urbanization has led to emerging mental health issues. Green space was becoming increasingly important for mental health. Previous studies have demonstrated the value of green space for a variety of outcomes connected to mental health. However, uncertainty remains regarding the association between green spaces and the risk of depression and anxiety outcomes. This study aimed to integrate present evidence from observational studies to define the association of exposure to green space with depression and anxiety. A thorough electronic search of PubMed, Web of Science and Embase database was performed. We transformed the odds ratio (OR) of different green increments into per 0.1 unit increase in normalized difference vegetation index (NDVI) and per 10% increase in percentage of green space. Cochrane's Q and I2 statistics were used to assess study heterogeneity, and random-effects models were employed to calculate combined effect estimation OR with 95% confidence intervals (CIs). Pooled analysis was completed using Stata 15.0. According to this meta-analysis, a 10% increase in the proportion of green space was linked to a lower risk of depression (merged OR (95% CI) = 0.963 (0.948, 0.979)) and anxiety (merged OR (95% CI) = 0.938 (0.858, 1.025)) and a 0.1 unit increase in NDVI was linked to a lower risk of depression (merged OR (95% CI) = 0.931 (0.887, 0.977)). Results of this meta-analysis supported improving green space exposure in preventing depression and anxiety. Higher green space exposure might be helpful for depression and anxiety disorders. Therefore, improving or preserving green space should be regarded as a promising intervention for public health. [ABSTRACT FROM AUTHOR]

A graphical abstract of the article "Metal-Free Direct Construction of Sulfenylated Pyrazoles via the NaOH Promoted Sulfenylation of Pyrazolones with Aryl Thiols" is presented.

A three-component reaction of olefins, thiols, and aliphatic nitriles with molecular iodine as catalyst is presented to give β-acylamidosulfides. [ABSTRACT FROM AUTHOR]

The title compounds are not obtained when the N-Me group is changed to N-H or N-Ph, which might be caused by electronic effects. [ABSTRACT FROM AUTHOR]

[Display omitted] • Heterogeneity represents a vital character of ovarian cancer. • Homologous recombination deficiency was correlated with HGSOC. • A dualistic classification of HGSOC was proposed based on spatial heterogeneity. • Star topology group showed higher heterogeneity than tree topology group. • Patient within tree topology model undertook more mutations than the star topology model. • More driver events were observed in tree topology group than in star topology group. Widespread intra-peritoneal metastases is a main feature of high grade serous ovarian carcinoma (HGSOC). Recently, the extent of tumour heterogeneity was used to evaluate the cancer genomes among multi-regions in HGSOC. However, there is no consensus on the effect of tumour heterogeneity on the evolution of the tumour metastasis process in HGSOC. We performed whole-exome sequencing in multiple regions of matched primary and metastatic HGSOC specimens to reveal the genetic mechanisms of ovarian tumourigenesis and malignant progression. 63 samples (including ovarian carcinoma, omentum metastasis, and normal tissues) were used. We analyzed the genomic heterogeneity, traced the subclone dissemination and establishment history and compared the different genetic characters of cancer evolutionary models in HGSOC. We found that HGSOC had substantial intra-tumour heterogeneity (median 54.2, range 0 ∼ 106.7), high inter-patient heterogeneity (P < 0.001), but relatively limited intra-patient heterogeneity (P = 0.949). Two COSMIC mutational signatures were identified in HGSOCs: signature 3 was related to homologous recombination, and signature 1 was associated with aging. Two scenarios were identified by phylogenetic reconstruction in our study: 3 cases (33.3 %) showed star topology, and the other 6 cases (66.7 %) displayed tree topology. Compared with star topology group, more driver events were identified in tree topology group (P < 0.001), and occurred more frequently in early stage than in late stage of clonal evolution (P < 0.001). Moreover, compared with the star topology group, the tree topology group showed higher rate of intra-tumour heterogeneity (P = 0.045). A dualistic classification model was proposed for the classification of HGSOC based on spatial heterogeneity, which may contribute to better managing patients and providing individual treatment for HGSOC patients. [ABSTRACT FROM AUTHOR]

Previous studies have found several biomarkers for acute respiratory distress syndrome (ARDS), but the accuracy of most biomarkers is still in doubt due to the occurrence of other comorbidities. In this systematic review and meta-analysis, we aimed to explore ideal ARDS biomarkers which can reflect pathophysiology features precisely and better identify at-risk patients and predict mortality. Web of Science, PubMed, Embase, OVID, and the Cochrane Library were systematically searched for studies assessing the reliability of pulmonary-originated epithelial proteins in ARDS. A total of 32 studies appeared eligible for meta-analysis, including 2654 ARDS/ALI patients in this study. In the at-risk patients' identification group, the highest pooled effect size was observed in Krebs von den Lungren-6 (KL-6) (SMD: 1.17 [95% CI: 0.55, 1.79]), followed by club cell proteins 16 (CC16) (SMD: 0.74 [95% CI: 0.01, 1.46]), and surfactant proteins-D (SP-D) (SMD: 0.71 [95% CI: 0.57, 0.84]). For the mortality prediction group, CC16 exhibited the largest effect size with SMD of 0.92 (95% CI: 0.42, 1.43). Meanwhile, the summary receiver operating characteristic (SROC) of CC16 for ARDS diagnosis reached an AUC of 0.80 (95% CI: 0.76, 0.83). In conclusion, this study provides a ranking system for pulmonary-originated epithelial biomarkers according to their association with distinguishing at-risk patients and predicting mortality. In addition, the study provides evidence for the advantage of biomarkers over traditional diagnostic criteria. The performance of biomarkers may help to clinically improve the ARDS diagnosis and mortality prediction. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: The palladium‐catalyzed borylative cyclization via C—H activation has been developed. By this chemistry, the indole‐fused dihydro‐pyrrole motif, which is a kind of important unit in natural products and bio‐active molecules, could be constructed and installed with a boric ester group. Furthermore, the utilities of products have been illustrated by the study of further transformations. Importantly, by using chiral ligand, the enantioselectivity of this borylative cyclization reaction could be controlled. Moreover, the borylative mechanism, which should proceed through a Pd(II)/Pd(IV) catalytic cycle, has been proposed based on the DFT calculations. [ABSTRACT FROM AUTHOR]

Abstract: Objective: HIV infection is associated with elevated risk of cardiovascular disease. The effect of antiretroviral drugs on metabolism of atherogenic very low and low density lipoproteins is well studied, but a possible effect of these drugs on reverse cholesterol transport is still unclear. The objective of this study was to assess the effect of various classes of anti-HIV drugs on cellular cholesterol efflux. Methods: The effect of pharmacological concentrations of seven commonly used antiretroviral compounds, Stavudine, Efavirenz, Nevirapine, Lopinavir, Amprenavir, Nelfinavir and Ritonavir, on cholesterol efflux from RAW 264.7 mouse macrophages and human monocyte-derived macrophages to apolipoprotein A-I and high density lipoprotein was tested. Results: At high pharmacological concentration Nelfinavir and Ritonavir inhibited cholesterol efflux, while other compounds had no effect. However, the same concentrations of Nelfinavir and Ritonovir induced apoptosis, suggesting that the effect of these compounds on cholesterol efflux most likely resulted from their cytotoxicity. When tested in non-cytotoxic concentrations, Nelfinavir and Ritonavir did not affect cholesterol efflux from RAW 264.7 cells, human monocyte-derived macrophages, or human macrophages infected with HIV-1. Conclusions: We conclude that tested antiretroviral compounds do not have a specific effect on cholesterol efflux. [Copyright &y& Elsevier]

Sample multiplexing facilitates single‐cell sequencing by reducing costs, revealing subtle difference between similar samples, and identifying artifacts such as cell doublets. However, universal and cost‐effective strategies are rather limited. Here, we reported a concanavalin A‐based sample barcoding strategy (CASB), which could be followed by both single‐cell mRNA and ATAC (assay for transposase‐accessible chromatin) sequencing techniques. The method involves minimal sample processing, thereby preserving intact transcriptomic or epigenomic patterns. We demonstrated its high labeling efficiency, high accuracy in assigning cells/nuclei to samples regardless of cell type and genetic background, and high sensitivity in detecting doublets by three applications: 1) CASB followed by scRNA‐seq to track the transcriptomic dynamics of a cancer cell line perturbed by multiple drugs, which revealed compound‐specific heterogeneous response; 2) CASB together with both snATAC‐seq and scRNA‐seq to illustrate the IFN‐γ‐mediated dynamic changes on epigenome and transcriptome profile, which identified the transcription factor underlying heterogeneous IFN‐γ response; and 3) combinatorial indexing by CASB, which demonstrated its high scalability. Synopsis: CASB is a new method for sample multiplexing compatible with both single‐cell RNA‐seq and ATAC‐seq. CASB is highly accurate, efficient and sensitive and allows more diverse types of information to be incorporated in single‐cell sequencing experiments. CASB is the first single‐cell/nucleus sample multiplexing strategy compatible with both scRNA‐seq & snATAC‐seq.CASB allows both simultaneous combinatorial barcoding and sequential split‐pool barcoding.While being highly efficient, accurate and sensitive, CASB is experiment‐friendly and cost‐effective. [ABSTRACT FROM AUTHOR]

Due to the significance of corresponding products, enantioselective borylative cyclization reactions have been studied intensively in recent years. Many groups have developed efficient methods to transform unsaturated system into asymmetric cyclic organoboron compounds with the ring‐size range from three‐membered to six‐membered in general. Notably, in some cases, fused rings which contain more than two contiguous chiral centers could be obtained by this kind of strategies. This review summarized and reviewed the recent advances in this field and classified these work according to the species of metal catalysts. [ABSTRACT FROM AUTHOR]

Cellular RNA is decorated with over 170 types of chemical modifications. Many modifications in mRNA, including m6A and m5C, have been associated with critical cellular functions under physiological and/or pathological conditions. To understand the biological functions of these modifications, it is vital to identify the regulators that modulate the modification rate. However, a high‐throughput method for unbiased screening of these regulators is so far lacking. Here, we report such a method combining pooled CRISPR screen and reporters with RNA modification readout, termed CRISPR integrated gRNA and reporter sequencing (CIGAR‐seq). Using CIGAR‐seq, we discovered NSUN6 as a novel mRNA m5C methyltransferase. Subsequent mRNA bisulfite sequencing in HAP1 cells without or with NSUN6 and/or NSUN2 knockout showed that NSUN6 and NSUN2 worked on non‐overlapping subsets of mRNA m5C sites and together contributed to almost all the m5C modification in mRNA. Finally, using m1A as an example, we demonstrated that CIGAR‐seq can be easily adapted for identifying regulators of other mRNA modification. SYNOPSIS: CIGAR‐seq is a new method combining pooled CRISPR screen with an epitranscriptomic reporter for identifying mRNA modification regulators. NSUN6 is discovered as a novel mRNA m5C methyltransferase, which together with NSUN2, contributes to almost all the m5C modification in mRNA. 'CRISPR integrated gRNA and reporter sequencing' (CIGAR‐seq) is a new high‐throughput method for unbiased screening of mRNA modification regulators.The study presents the first pooled CRISPR screen with epitranscriptomic readout.NSUN6 is discovered as a novel mRNA m5C methyltransferase.NSUN6 and NSUN2 contribute to almost all the m5C modification in mRNA. [ABSTRACT FROM AUTHOR]

Patient-specific induced pluripotent stem cells (ps-iPSCs) and their differentiated cell types are a powerful model system to gain insight into mechanisms driving early developmental and disease-associated regulatory networks. In this study, we use ps-iPSCs to gain insights into Tetralogy of Fallot (TOF), which represents the most common cyanotic heart defect in humans. iPSCs were generated and further differentiated to cardiomyocytes (CMs) using standard methods from two well-characterized TOF patients and their healthy relatives serving as controls. Patient-specific expression patterns and genetic variability were investigated using whole genome and transcriptome sequencing data. We first studied the clonal mutational burden of the derived iPSCs. In two out of three iPSC lines of patient TOF-01, we found a somatic mutation in the DNA-binding domain of tumor suppressor P53, which was not observed in the genomic DNA from blood. Further characterization of this mutation showed its functional impact. For patient TOF-02, potential disease-relevant differential gene expression between and across cardiac differentiation was shown. Here, clear differences at the later stages of differentiation could be observed between CMs of the patient and its controls. Overall, this study provides first insights into the complex molecular mechanisms underlying iPSC-derived cardiomyocyte differentiation and its transcriptional alterations in TOF. [ABSTRACT FROM AUTHOR]

Background: Recombinant proteins are often engineered with an N-terminal signal peptide, which facilitates their secretion to the oxidising environment of the periplasm (gram-negative bacteria) or the culture supernatant (gram-positive bacteria). A commonly encountered problem is that the signal peptide influences the synthesis and secretion of the recombinant protein in an unpredictable manner. A molecular understanding of this phenomenon is highly sought after, as it could lead to improved methods for producing recombinant proteins in bacterial cell factories. Results: Herein we demonstrate that signal peptides contribute to an unpredictable translation initiation region. A directed evolution approach that selects a new translation initiation region, whilst leaving the amino acid sequence of the signal peptide unchanged, can increase production levels of secreted recombinant proteins. The approach can increase production of single chain antibody fragments, hormones and other recombinant proteins in the periplasm of E. coli. Conclusions: The study demonstrates that signal peptide performance is coupled to the efficiency of the translation initiation region. [ABSTRACT FROM AUTHOR]

An arabinogalactan (ICPA) was isolated from the water extract of Ixeris chinensis (Thunb.) Nakai. ICPA was mainly composed of galactose and arabinose with minor amount of glucose. The molecular weight of ICPA was 58.1 kDa. Structural analysis by methylation and NMR spectroscopy indicated that ICPA contained α-D-Glc p (1→, →5)-α-L-Ara f (1→, β-D-Gal f (1→, →3)-β-D-Gal f (1→, β-D-Gal p (1→, →6)-β-D-Gal p (1→, and → 3,6)-β-D-Gal p (1→, and that the molar ratio of the sugar residues was about 0.1:1.0:0.1:0.2:1.1:1.0:1.3, respectively. The immunomodulatory activity on RAW264.7 cells was measured in vitro. ICPA stimulated RAW 264.7 cell proliferation at 25–400 μg/mL in a dose-dependent manner. ICPA also enhanced phagocytosis, and the secretion of NO, TNF-α, and IL-6 by the cells. The results suggested the potential utilization of ICPA as an immunomodulatory agent. [ABSTRACT FROM AUTHOR]

A neutral water soluble polysaccharide (HPA) was isolated from the marine fungus Hansfordia sinuosae . Monosaccharide composition analysis indicated that HPA was mainly composed of mannose with minor amounts of galactose and glucose. The molecular weight of HPA was approximately 22.5 kDa as analyzed by HPGPC. Structure analysis of HPA with methylation and 1D, 2D NMR indicated that HPA was composed of [α- d -Man p (1→], [→2)-α- d -Man p (1→], [→3)-α- d -Man p (1→] and [→2,6)-α- d -Man p (1→] with [α- d -Man p (1→] linked to C-6 position of [→2,6)-α- d -Man p (1→]. The antitumor effect of HPA was evaluated in vitro. HPA showed remarkable inhibitory effect on human cervical carcinoma HeLa cells and human breast carcinoma MCF-7 cells. When cells were incubated with HPA at 400 μg/mL for 48 h, the inhibition rate on HeLa and MCF-7 cells was 79.5% and 73.8%, respectively. Furthermore, for HeLa cells, HPA could increase intracellular ROS levels, induce cells apoptosis, decrease mitochondrial membrane potential, and elevate the expression of caspase-3. The results suggested that HPA could be explored as a potential antitumor agent. [ABSTRACT FROM AUTHOR]

Ficellomycin is an aziridine antibiotic produced by Streptomyces ficellus, which displays high in vitro activity against Gram-positive bacteria including multidrug resistant strains of Staphylococcus aureus. Compared to currently available antibiotics, ficellomycin exhibits a unique mechanism of action—it impairs the semiconservative DNA replication by inducing the formation of deficient 34S DNA fragments, which lack the ability to integrate into larger DNA pieces and eventually the complete bacterial chromosome. Until recently, some important progress has been made in research on ficellomycin synthesis and biosynthesis, opening the perspective to develop a new generation of antibiotics with better clinical performance than the currently used ones. In this review, we will cover the discovery and biological activity of ficellomycin, its biosynthesis, mode of action, and related synthetic analogs. The role of ficellomycin and its analogs as an important source of drug prototypes will be discussed together with future research prospects. [ABSTRACT FROM AUTHOR]

A facile and efficient one-pot method has been developed for the construction of alkynyl sulfones via direct cross-coupling reaction of aryl alkynyliodines and arylsulfinic acids. The present transformation could be accomplished under catalyst- and additive-free conditions, providing a series of alkynyl sulfones in moderate to good yields with favorable functional group tolerance. [ABSTRACT FROM AUTHOR]

A facile I2O5-mediated direct oxidative coupling of aromatic alkenes with thiols toward vinyl sulfones has been developed under metal-free conditions. This methodology provides a convenient and efficient approach to various (E)-vinyl sulfones from readily available starting materials with excellent regioselectivity. The present oxidative coupling reaction, not only expands the scope of functionalization of alkenes with thiols, but also makes it a practical and powerful complement to traditional methods for the synthesis of (E)-vinyl sulfones. [ABSTRACT FROM AUTHOR]

Context Graves' orbitopathy ( GO) is a potentially sight-threatening disease for which currently available medical therapy is not reliably successful. Mycophenolate mofetil ( MMF) is a selective immunosuppressant used widely in many autoimmune diseases. Preliminary studies have shown that MMF is effective in the treatment of active GO. Objective To evaluate the efficacy and safety of MMF in patients with active moderate-to-severe GO. Patients One hundred and 74 patients with active moderate-to-severe GO were randomized to receive either MMF or glucocorticoids ( GC). Main Outcome Measures The primary outcome was overall response at the 12th and 24th weeks; the outcome assessments included clinical activity score ( CAS), soft tissue involvement, pain, visual acuity, proptosis, diplopia and reduction in eye movements. The secondary outcome was changes in those individual parameters. Adverse effects were recorded at each visit. Results A greater overall response rate was found in the MMF group compared with the GC group at the 24th week (91·3% vs 67·9%, P = 0·000). MMF therapy showed a better CAS response than GC (92·5% vs 70·5% improved, P < 0·05). Patients treated with MMF showed a significantly improved rate of diplopia and proptosis than patients treated with GC at the 24th week (90·4% and 68·8% improved, respectively). Disease reactivation was not observed in the patients treated with MMF but was observed in five patients after GC therapy. Adverse events occurred in 4 of 80 patients treated with MMF (5%), all of which were mild to moderate. A severe adverse event was only observed in one patient treated with GC but not at all in patients treated with MMF. Conclusion Compared with GC treatment, MMF therapy is more effective and safer for patients with active moderate-to-severe GO. [ABSTRACT FROM AUTHOR]

Conventional enhanced permeation and retention (EPR) mediates the effects of many drugs, including the accumulation of nanocarriers at tumor sites, but its efficiency remains low. In this study, this limitation was overcome by developing a dual-targeting delivery system based on hyaluronan (HA, a major ligand of CD44) and tetraiodothyroacetic acid (tetrac, a specific ligand of α v β 3 ), which was exploited to carry docetaxel (DTX) for the synergistic active targeting to tumors. First, a tetrac-HA (TeHA) conjugate was synthesized and grafted onto the surfaces of solid lipid nanoparticles (SLNs) (TeHA-SLNs/DTX), with a high encapsulation efficiency of > 91.6%. The resulting SLNs exhibited an approximately toroid morphology revealed using TEM. The cellular uptake and cytotoxicity of various formulations on CD44/α v β 3 -enriched B16F10 cells were then assessed, and both results confirmed the selective uptake and high cytotoxicity of the TeHA-SLNs/DTX in a TeHA-dependent manner. In vivo imaging and vessel distribution tests revealed the efficiency of synergistic active targeting was higher than that of EPR-mediated passive targeting by the TeHA-SLNs to α v β 3 -expressing tumor blood vessels and CD44-expressing tumor cells via selective targeting. Finally, in both xenograft tumor mice and in situ lung metastasis tumor mice, tumor growth was significantly inhibited by TeHA-SLNs/DTX. Therefore, TeHA-SLNs are an efficient system for the dual-targeted delivery of drugs to treat cancer in vivo . [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) regulate a wide variety of biological processes and contribute to metabolic homeostasis. Here, we demonstrate that microRNA-223 (miR-223), an miRNA previously associated with inflammation, also controls multiple mechanisms associated with cholesterol metabolism. miR-223 promoter activity and mature levels were found to be linked to cellular cholesterol states in hepatoma cells. Moreover, hypercholesterolemia was associated with increased hepatic miR-223 levels in athero-prone mice. miR-223 was found to regulate high-density lipoprotein-cholesterol (HDL-C) uptake, through direct targeting and repression of scavenger receptor Bl, and to inhibit cholesterol biosynthesis through the direct repression of sterol enzymes 3-hydroxy-3-methylglutaryl-CoA synthase 1 and methylsterol monooxygenase 1 in humans. Additionally, miR-223 was found to indirectly promote ATP-binding cassette transporter A1 expression (mRNA and protein) through Sp3, thereby enhancing cellular cholesterol efflux. Finally, genetic ablation of miR-223 in mice resulted in increased HDL-C levels and particle size, as well as increased hepatic and plasma total cholesterol levels. In summary, we identified a critical role for miR-223 in systemic cholesterol regulation by coordinated posttranscriptional control of multiple genes in lipoprotein and cholesterol metabolism. [ABSTRACT FROM AUTHOR]

Metabolic reprogramming is a hallmark of cancer cells in response to targeted therapy. Decreased glycolytic activity with enhanced mitochondrial respiration secondary to imatinib has been shown in imatinib-sensitive gastrointestional stromal tumors (GIST). However, the role of energy metabolism in imatinib-resistant GIST remains poorly characterized. Here, we investigated the effect of imatinib treatment on glycolysis and oxidative phosphorylation (OXPHOS), as well as the effect of inhibition of these energy metabolisms on cell viability in imatinib-resistant and -sensitive GIST cell lines. We observed that imatinib treatment increased OXPHOS in imatinib-sensitive, but not imatinib-resistant, GIST cells. Imatinib also reduced the expression of mitochondrial biogenesis activators (peroxisome proliferator-activated receptor coactivator-1 alpha (PGC1α), nuclear respiratory factor 2 (NRF2), and mitochondrial transcription factor A (TFAM)) and mitochondrial mass in imatinib-sensitive GIST cells. Lower TFAM levels were also observed in imatinib-sensitive GISTs than in tumors from untreated patients. Using the Seahorse system, we observed bioenergetics diversity among the GIST cell lines. One of the acquired resistant cell lines (GIST 882R) displayed a highly metabolically active phenotype with higher glycolysis and OXPHOS levels compared with the parental GIST 882, while the other resistant cell line (GIST T1R) had a similar basal glycolytic activity but lower mitochondrial respiration than the parental GIST T1. Further functional assays demonstrated that GIST 882R was more vulnerable to glycolysis inhibition than GIST 882, while GIST T1R was more resistant to OXPHOS inhibition than GIST T1. These findings highlight the diverse energy metabolic adaptations in GIST cells that allow them to survive upon imatinib treatment and reveal the potential of targeting the metabolism for GIST therapy. [ABSTRACT FROM AUTHOR]

One of the potential biomarkers for ovarian cancer patients is high serum level of prolactin (PRL), which is a growth factor that may promote tumor cell growth. The prolactin receptor (PRLR) and human cytomegalovirus (HCMV) proteins are frequently detected in ovarian tumor tissue specimens, but the potential impact of HCMV infection on the PRL system have so far not been investigated. In this study, HCMV's effects on PRL and PRLR expression were assessed in infected ovarian cancer cells (SKOV3) by PCR and Western blot techniques. The levels of both PRL and PRLR transcripts as well as the corresponding proteins were highly increased in HCMV-infected SKOV3 cells. Tissue specimens obtained from 10 patients with ovarian cancer demonstrated high expression of PRLR, HCMV-IE, and pp65 proteins. Extensive expression of PRLR was detected in all examined ovarian tumor tissue specimens except for one from a patient who had focal expression of PRLR and this patient was HCMV-negative in her tumor. In conclusion, PRL and PRLR were induced to high levels in HCMV-infected ovarian cancer cells and PRLR expression was extensively detected in HCMV-infected ovarian tissue specimens. Highly induced PRL and PRLR by HCMV infection may be of relevance for the oncomodulatory role of this virus in ovarian cancer. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma (GBM) is the most common malignant brain tumor with median survival of 12-15 months. Owing to uncertainty in clinical outcome, additional prognostic marker(s) apart from existing markers are needed. Since overexpression of endothelin B receptor (ETBR) has been demonstrated in gliomas, we aimed to test whether ETBR is a useful prognostic marker in GBM and examine if the clinically available endothelin receptor antagonists (ERA) could be useful in the disease treatment.Methods: Data from The Cancer Genome Atlas and the Gene Expression Omnibus database were analyzed to assess ETBR expression. For survival analysis, glioblastoma samples from 25 Swedish patients were immunostained for ETBR, and the findings were correlated with clinical history. The druggability of ETBR was assessed by protein-protein interaction network analysis. ERAs were analyzed for toxicity in in vitro assays with GBM and breast cancer cells.Results: By bioinformatics analysis, ETBR was found to be upregulated in glioblastoma patients, and its expression levels were correlated with reduced survival. ETBR interacts with key proteins involved in cancer pathogenesis, suggesting it as a druggable target. In vitro viability assays showed that ERAs may hold promise to treat glioblastoma and breast cancer.Conclusions: ETBR is overexpressed in glioblastoma and other cancers and may be a prognostic marker in glioblastoma. ERAs may be useful for treating cancer patients. [ABSTRACT FROM AUTHOR]