bluuebunny/crossref_metadata_2025_split huggingface dataset:
The association between metformin use and colorectal cancer survival among patients with diabetes mellitus: An updated meta‐analysis
Authors: Tian Shan , Lei Hong‐Bo , Liu Yu‐Lan , Chen Yan , Dong Wei‐Guo 
Published: July 2017

AbstractObjectiveRecent studies have reported conflicting results on the correlation between metformin use and outcomes in patients with colorectal cancer (CRC). A meta‐analysis was performed to evaluate the efficacy of metformin therapy on the prognosis of CRC patients with type 2 diabetes mellitus (T2DM).MethodsWe conducted a systematic search of PubMed, EMBASE, the Cochrane Library, and the Web of Science for related articles up to August 2016. Two investigators independently identified and extracted information. Pooled risk estimates [hazard ratios (HRs)] and 95% confidence intervals (CIs) were calculated using fixed‐effects models. The risk of publication bias was assessed by examining funnel plot asymmetry as well as Egger's test and Begg's test.ResultsOf 81 articles identified, 8 retrospective cohort studies, representing 6098 cases of CRC patients with T2DM who used metformin and 4954 cases of CRC patients with T2DM who did not use metformin, were included in this meta‐analysis. There was no significant heterogeneity and quality difference between studies. Metformin users had significantly improved overall survival (OS) (HR = 0.82, 95% CI: 0.77–0.87, P = 0.000). However, Metformin use cannot affect CRC‐specific survival (HR = 0.84, 95% CI: 0.69–1.02, P = 0.079) compared to non‐users.ConclusionThis meta‐analysis suggests that metformin use may improve survival among CRC patients with T2DM. However, prospective controlled studies are still needed to rigorously evaluate the efficacy of metformin as an anti‐tumor agent.
BMP‐2 combined with salvianolic acid B promotes cardiomyocyte differentiation of rat bone marrow mesenchymal stem cells
Authors: Lv Yang , Gao Chen‐Wei , Liu Bo , Wang Hao‐Yu , Wang Hai‐Ping 
Published: July 2017

AbstractThe present study tested the hypotheses that bone morphogenetic protein 2(BMP‐2) combined with salvianolic acid B(Sal‐B) enhance the differentiation of rat bone marrow mesenchymal stem cells (BMSCs) towards cardiomyocytes in vitro. BMSCs were treated with BMP‐2 and Sal‐B, alone or in combination, for 72 h, then added new media (excluding inductive substance) and cultured for 4 weeks. The morphologic characteristics, surface antigens and mRNA expression of several transcription factors were also assessed. We found that they could all be identified by the positive staining for cardiomyocyte‐specific proteins, desmin and cardiac troponin T, in these cells. Furthermore, the mRNA expression of GATA‐4 and Nkx2.5 genes was slightly increased on day 7, enhanced on day 14 and decreased on day 28 while α‐MHC gene was not expressed on day 7, but expressed slightly on day 14 and enhanced on day 28. The expression of these cardiac‐specific markers in treatment groups were all significantly higher than those in the control group, respectively (P < 0.05). Transmission electron microscopy showed that BMSCs in treatment groups all had myofilaments, z line‐like substances and mitochondria. Taken together, these results indicate that BMP‐2 combined with Sal‐B promotes myocardial differentiation of BMSCs, which may represent a potential therapeutic strategy for the treatment of ischemic heart disease.
Through the Looking Glass: Young People, Work and the Transition between Education and Employment in a post-Brexit UK
Authors: ELLISON MARION 
Published: July 2017

AbstractThe prospect of a profound transformation in the relationship between the UK and the European Union has raised a range of economic, social and political concerns (Dhingraet al., 2016; Boothet al., 2015; Irwin, 2015; Ebell and Warren, 2016). Whilst the ultimate shape of a negotiated post-Brexit settlement is uncertain, the potential loss or reduction in access to EU funding streams, educational mobility, EU labour market access, and changes to employment rights and regulations will impact significantly upon young people across the UK. Underlining this, the transition between education and employment has been evidenced as a period when young people experience increased risk of poverty and social exclusion (MacDonald, 2011; Furlong and Cartmel, 2004; Ellison, 2014; ILO, 2016). This article provides an analysis of the role of EU funding streams and operational programmes directed at young people's transitions between education and employment across the UK. The co-ordinated use of EU funding instruments aimed at rebalancing economic and social inequalities between wealthier and poorer regions and groups within the EU is evidenced as improving labour market outcomes for young people living in the most disadvantaged regions of the UK. In light of this, the article contends that future post-Brexit UK governments will need to develop redistributive investment strategies within coherent policy architectures and inclusive forms of governance to ensure the continued delivery of operational programmes for young people which are relevant, effective and sustainable at a local level.
Re-Doubling the Crises of the Welfare State: The impact of Brexit on UK welfare politics
Authors: TAYLOR-GOOBY PETER 
Published: July 2017

AbstractThe double crisis approach distinguishes two kinds of challenge confronting modern welfare states: long-term structural problems and short-term difficulties resulting from policy choices which affect the success with which the long-term issues can be addressed. Structural challenges include two main areas:•globalisation and technological changes demanding that governments direct attention to national competitiveness, and•population ageing, requiring more spending on pensions, and health and social care.Recent policy-related problems include the austerity programme since 2010 which has been particularly directed towards benefits and services for working-age people. Responses to both kinds of challenge have set the stage for Brexit.
Atrial septal defect and an unusual anatomical variant of double-chambered right ventricle presenting with cyanosis
Authors: Rothman Abraham , Singh Gagandeep , Evans William N. 
Published: July 2017

AbstractWe treated two patients with unexplained cyanosis, an atrial septal defect and an unusual form of non-obstructive double-chambered right ventricle, with device closure of the atrial septal defect.
Ligand-induced type II interleukin-4 receptor dimers are sustained by rapid re-association within plasma membrane microcompartments
Authors: Richter David , Moraga Ignacio , Winkelmann Hauke , Birkholz Oliver , Wilmes Stephan , Schulte Markos , Kraich Michael , Kenneweg Hella , Beutel Oliver , Selenschik Philipp , Paterok Dirk , Gavutis Martynas , Schmidt Thomas , Garcia K. Christopher , Müller Thomas D. , Piehler Jacob 
Published: July 2017

AbstractThe spatiotemporal organization of cytokine receptors in the plasma membrane is still debated with models ranging from ligand-independent receptor pre-dimerization to ligand-induced receptor dimerization occurring only after receptor uptake into endosomes. Here, we explore the molecular and cellular determinants governing the assembly of the type II interleukin-4 receptor, taking advantage of various agonists binding the receptor subunits with different affinities and rate constants. Quantitative kinetic studies using artificial membranes confirm that receptor dimerization is governed by the two-dimensional ligand–receptor interactions and identify a critical role of the transmembrane domain in receptor dimerization. Single molecule localization microscopy at physiological cell surface expression levels, however, reveals efficient ligand-induced receptor dimerization by all ligands, largely independent of receptor binding affinities, in line with the similar STAT6 activation potencies observed for all IL-4 variants. Detailed spatiotemporal analyses suggest that kinetic trapping of receptor dimers in actin-dependent microcompartments sustains robust receptor dimerization and signalling.
DNA binding drives the association of BRG1/hBRM bromodomains with nucleosomes
Authors: Morrison Emma A. , Sanchez Julio C. , Ronan Jehnna L. , Farrell Daniel P. , Varzavand Katayoun , Johnson Jenna K. , Gu Brian X. , Crabtree Gerald R. , Musselman Catherine A. 
Published: July 2017

AbstractBRG1 and BRM, central components of the BAF (mSWI/SNF) chromatin remodelling complex, are critical in chromatin structure regulation. Here, we show that the human BRM (hBRM) bromodomain (BRD) has moderate specificity for H3K14ac. Surprisingly, we also find that both BRG1 and hBRM BRDs have DNA-binding activity. We demonstrate that the BRDs associate with DNA through a surface basic patch and that the BRD and an adjacent AT-hook make multivalent contacts with DNA, leading to robust affinity and moderate specificity for AT-rich elements. Although we show that the BRDs can bind to both DNA and H3K14ac simultaneously, the histone-binding activity does not contribute substantially to nucleosome targeting in vitro. In addition, we find that neither BRD histone nor DNA binding contribute to the global chromatin affinity of BRG1 in mouse embryonic stem cells. Together, our results suggest that association of the BRG1/hBRM BRD with nucleosomes plays a regulatory rather than targeting role in BAF activity.
Reactogenicity to major tuberculosis antigens absent in BCG is linked to improved protection against Mycobacterium tuberculosis
Authors: Aguilo Nacho , Gonzalo-Asensio Jesus , Alvarez-Arguedas Samuel , Marinova Dessislava , Gomez Ana Belen , Uranga Santiago , Spallek Ralf , Singh Mahavir , Audran Regine , Spertini François , Martin Carlos 
Published: July 2017

AbstractMTBVAC is a live-attenuated Mycobacterium tuberculosis vaccine, currently under clinical development, that contains the major antigens ESAT6 and CFP10. These antigens are absent from the current tuberculosis vaccine, BCG. Here we compare the protection induced by BCG and MTBVAC in several mouse strains that naturally express different MHC haplotypes differentially recognizing ESAT6 and CFP10. MTBVAC induces improved protection in C3H mice, the only of the three tested strains reactive to both ESAT6 and CFP10. Deletion of both antigens in MTBVAC reduces its efficacy to BCG levels, supporting a link between greater efficacy and CFP10- and ESAT6-specific reactogenicity. In addition, MTBVAC (but not BCG) triggers a specific response in human vaccinees against ESAT6 and CFP10. Our results warrant further exploration of this response as potential biomarker of protection in MTBVAC clinical trials.
4-alkyl-L-(Dehydro)proline biosynthesis in actinobacteria involves N-terminal nucleophile-hydrolase activity of γ-glutamyltranspeptidase homolog for C-C bond cleavage
Authors: Zhong Guannan , Zhao Qunfei , Zhang Qinglin , Liu Wen 
Published: July 2017

Abstractγ-Glutamyltranspeptidases (γ-GTs), ubiquitous in glutathione metabolism for γ-glutamyl transfer/hydrolysis, are N-terminal nucleophile (Ntn)-hydrolase fold proteins that share an autoproteolytic process for self-activation. γ-GT homologues are widely present in Gram-positive actinobacteria where their Ntn-hydrolase activities, however, are not involved in glutathione metabolism. Herein, we demonstrate that the formation of 4-Alkyl-L-(dehydro)proline (ALDP) residues, the non-proteinogenic α-amino acids that serve as vital components of many bioactive metabolites found in actinobacteria, involves unprecedented Ntn-hydrolase activity of γ-GT homologue for C–C bond cleavage. The related enzymes share a key Thr residue, which acts as an internal nucleophile for protein hydrolysis and then as a newly released N-terminal nucleophile for carboxylate side-chain processing likely through the generation of an oxalyl-Thr enzyme intermediate. These findings provide mechanistic insights into the biosynthesis of various ALDP residues/associated natural products, highlight the versatile functions of Ntn-hydrolase fold proteins, and particularly generate interest in thus far less-appreciated γ-GT homologues in actinobacteria.
Structural and functional characterization of a DARPin which inhibits Ras nucleotide exchange
Authors: Guillard Sandrine , Kolasinska-Zwierz Paulina , Debreczeni Judit , Breed Jason , Zhang Jing , Bery Nicolas , Marwood Rose , Tart Jon , Overman Ross , Stocki Pawel , Mistry Bina , Phillips Christopher , Rabbitts Terence , Jackson Ronald , Minter Ralph 
Published: July 2017

AbstractRas mutations are the oncogenic drivers of many human cancers and yet there are still no approved Ras-targeted cancer therapies. Inhibition of Ras nucleotide exchange is a promising new approach but better understanding of this mechanism of action is needed. Here we describe an antibody mimetic, DARPin K27, which inhibits nucleotide exchange of Ras. K27 binds preferentially to the inactive Ras GDP form with aKdof 4 nM and structural studies support its selectivity for inactive Ras. Intracellular expression of K27 significantly reduces the amount of active Ras, inhibits downstream signalling, in particular the levels of phosphorylated ERK, and slows the growth in soft agar of HCT116 cells. K27 is a potent, non-covalent inhibitor of nucleotide exchange, showing consistent effects across different isoforms of Ras, including wild-type and oncogenic mutant forms.
Probing low-energy hyperbolic polaritons in van der Waals crystals with an electron microscope
Authors: Govyadinov Alexander A. , Konečná Andrea , Chuvilin Andrey , Vélez Saül , Dolado Irene , Nikitin Alexey Y. , Lopatin Sergei , Casanova Fèlix , Hueso Luis E. , Aizpurua Javier , Hillenbrand Rainer 
Published: July 2017

AbstractVan der Waals materials exhibit intriguing structural, electronic, and photonic properties. Electron energy loss spectroscopy within scanning transmission electron microscopy allows for nanoscale mapping of such properties. However, its detection is typically limited to energy losses in the eV range—too large for probing low-energy excitations such as phonons or mid-infrared plasmons. Here, we adapt a conventional instrument to probe energy loss down to 100 meV, and map phononic states in hexagonal boron nitride, a representative van der Waals material. The boron nitride spectra depend on the flake thickness and on the distance of the electron beam to the flake edges. To explain these observations, we developed a classical response theory that describes the interaction of fast electrons with (anisotropic) van der Waals slabs, revealing that the electron energy loss is dominated by excitation of hyperbolic phonon polaritons, and not of bulk phonons as often reported. Thus, our work is of fundamental importance for interpreting future low-energy loss spectra of van der Waals materials.
A haplotype in CFH family genes confers high risk of rare glomerular nephropathies
Authors: Ding Yin , Zhao Weiwei , Zhang Tao , Qiang Hao , Lu Jianping , Su Xin , Wen Shuzhen , Xu Feng , Zhang Mingchao , Zhang Haitao , Zeng Caihong , Liu Zhihong , Chen Huimei 
Published: July 2017

AbstractDespite distinct renal lesions, a series of rare glomerular nephropathies are reportedly mediated by complement overactivation. Genetic variations in complement genes contribute to disease risk, but the relationship of genotype to phenotype has not been straightforward. Here, we screened 11 complement genes from 91 patients with atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G) and membranoproliferative glomerulonephritis type I (MPGN I), and identified the concomitant presence of three missense variations located within the human complement Factor H (CFH) gene cluster. The three variations, rs55807605, rs61737525 and rs57960694, have strong linkage disequilibrium; subsequent haplotype analysis indicated that ATA increased the susceptibility of these renal diseases. In silico analysis, the CFHR3 rs61737525-T risk allele altered the physical and structural properties and generated a reduction in binding affinity of the CFHR3/C3b complex. Surface plasmon resonance (SPR) binding analysis further demonstrated the substitution induced a decrease of two orders of magnitude in C3b-binding properties, with a declined cofactor activity in fluid phase. These data suggest that the haplotype carrying the causative allele behaves as a partial C3 convertase deficiency, predisposing individuals to diverse pathologic lesions underlying complement overactivation. Such genotype-phenotype discrepancies allow better understanding about these nephropathies mediated by genetic complement disorders.
Direct Growth of MoS2 Nanowalls on Carbon Nanofibers for Use in Supercapacitor
Authors: Sari Fitri Nur Indah , Ting Jyh-Ming 
Published: July 2017

AbstractDirect growth of MoS2 nanowalls on vapor grown carbon nanofibers (VGCNFs) has been achieved using a microwave-assisted hydrothermal (MAH) method under an acidic condition. The acidic condition was obtained through the addition of an HCl aqueous solution. We demonstrate that the HCl not only modifies the pH value for limiting the growth rate but also leads to the formation of NaCl, which is the key for the direct and unique growth of MoS2 on the VGCNF surface. A growth mechanism is therefore proposed. The growth of MoS2 onto the high electrically conducting VGCNF creates a unique structure that not only reduces the aggregation of MoS2 but also improves the electrical conductivity of the resulting composite electrode. The MoS2 nanowall/VGCNF composite shows Csp as high as 248 F g−1 at 5 mV s−1 and excellent electrochemical stability with a retention of 96% after 1,000 cycles at a high charge rate of 200 mV s−1. The ease of composite fabrication and electrochemical stability suggest that the MoS2 nanowall/VGCNF composite is a promising candidate electrode material for supercapacitor.
Comparative transcriptome analysis of the floral transition in Rosa chinensis ‘Old Blush’ and R. odorata var. gigantea
Authors: Guo Xuelian , Yu Chao , Luo Le , Wan Huihua , Li Yushu , Wang Jia , Cheng Tangren , Pan Huitang , Zhang Qixiang 
Published: July 2017

AbstractThe floral transition is a crucial developmental event, but little is known about the underlying regulatory networks in seasonally and continuously flowering roses. In this study, we compared the genetic basis of flowering in two rose species, Rosa chinensis ‘Old Blush’, which flowers continuously, and R. odorata var. gigantea, which blooms in early spring. Gene ontology (GO) terms related to methylation, light reaction, and starch metabolism were enriched in R. odorata var. gigantea and terms associated with sugar metabolism were enriched in R. chinensis ‘Old Blush’ during the floral transition. A MapMan analysis revealed that genes involved in hormone signaling mediate the floral transition in both taxa. Furthermore, differentially expressed genes (DEGs) involved in vernalization, photoperiod, gibberellin (GA), and starch metabolism pathways converged on integrators, e.g., LFY, AGL24, SOC1, CAL, and COLs, to regulate the floral transition in R. odorata var. gigantea, while DEGs related to photoperiod, sugar metabolism, and GA pathways, including COL16, LFY, AGL11, 6PGDH, GASA4, and BAM, modulated the floral transition in R. chinensis ‘Old Blush.’ Our analysis of the genes underlying the floral transition in roses with different patterns of flowering provides a basis for further functional studies.
Endolysosomal targeting of a clinical chlorin photosensitiser for light-triggered delivery of nano-sized medicines
Authors: Yaghini Elnaz , Dondi Ruggero , Tewari Kunal M. , Loizidou Marilena , Eggleston Ian M. , MacRobert Alexander J. 
Published: July 2017

AbstractA major problem with many promising nano-sized biotherapeutics including macromolecules is that owing to their size they are subject to cellular uptake via endocytosis, and become entrapped and then degraded within endolysosomes, which can significantly impair their therapeutic efficacy. Photochemical internalisation (PCI) is a technique for inducing cytosolic release of the entrapped agents that harnesses sub-lethal photodynamic therapy (PDT) using a photosensitiser that localises in endolysosomal membranes. Using light to trigger reactive oxygen species-mediated rupture of the photosensitised endolysosomal membranes, the spatio-temporal selectivity of PCI then enables cytosolic release of the agents at the selected time after administration so that they can reach their intracellular targets. However, conventional photosensitisers used clinically for PDT are ineffective for photochemical internalisation owing to their sub-optimal intracellular localisation. In this work we demonstrate that such a photosensitiser, chlorin e6, can be repurposed for PCI by conjugating the chlorin to a cell penetrating peptide, using bioorthogonal ligation chemistry. The peptide conjugation enables targeting of endosomal membranes so that light-triggered cytosolic release of an entrapped nano-sized cytotoxin can be achieved with consequent improvement in cytotoxicity. The photoproperties of the chlorin moiety are also conserved, with comparable singlet oxygen quantum yields found to the free chlorin.
Therapeutic effects of long-circulating miR-135a-containing cationic immunoliposomes against gallbladder carcinoma
Authors: Yang Guanghua , Yin Baobing 
Published: July 2017

AbstractGallbladder carcinoma (GBC) is the most common malignant tumour in the biliary tract, but effective therapeutics are lacking. Based on our previous studies, miR-135a is a potential tool to inhibit GBC proliferation. In this study, we constructed miR-135a-loaded DSPE-PEG2000 liposomes modified with Anti-EGFR antibodies (Anti-EGFR-CIL-miR-135a). The results of an analysis of their physicochemical properties indicated the particle size of it was 222.0 ± 2.1 nm in diameter with an uptake efficiency of 86.5%. Next, the post-treatment biological behaviours of GBC, specifically, invasion, metastasis and apoptosis, were evaluated. miR-135a inhibited GBC invasion and metastasis and promoted apoptosis compared to controls. Additionally, miR-135a targeted and regulated the expression of ROCK1, HOXA10 and BCL-2. Due to the targeted effects of Anti-EGFR-CIL-miR-135a, the GBC tumour growth rate was 60% lower in an in vivo xenograft-bearing mouse model compared to controls. Thus, Anti-EGFR-CIL-miR-135a is a promising therapeutic strategy to combat GBC.
A Model-Based Estimate of Regional Wheat Yield Gaps and Water Use Efficiency in Main Winter Wheat Production Regions of China
Authors: Lv Zunfu , Liu Xiaojun , Cao Weixing , Zhu Yan 
Published: July 2017

AbstractWheat production is of great importance for national food security and is greatly influenced by the spatial variation of climatic variables, soils, cultivars, etc. This study used WheatGrow and CERES-Wheat models integrated with a GIS to estimate winter wheat productivity, yield gap and water use in the main wheat production regions of China. The results showed that the potential wheat yield gradually increased from south to north and from west to east, with a spatial distribution consistent with the accumulated hours of sunshine. The gap between potential and actual yield varied from 382 to 7515 kg ha−1, with the highest values in Shanxi, Gansu and Shaanxi provinces and the lowest values in Sichuan province. The rainfed yield decreased gradually from south to north, roughly following the pattern of the ratio of accumulated precipitation to accumulated potential evapotranspiration. Under the scenario of autoirrigation, relatively high irrigation water use efficiency was found in western Shandong and southern Sichuan, as well as in northern Henan, Shanxi and Shaanxi. Furthermore, the limiting factors were analysed, and effective measures were suggested for improving regional winter wheat productivity. These results can be helpful for national policy making and water redistribution for agricultural production in China.