bluuebunny/crossref_metadata_2025 huggingface dataset:
Silencing FLI or targeting CD13/ANPEP lead to dephosphorylation of EPHA2, a mediator of BRAF inhibitor resistance, and induce growth arrest or apoptosis in melanoma cells
Authors: Azimi Alireza , Tuominen Rainer , Costa Svedman Fernanda , Caramuta Stefano , Pernemalm Maria , Frostvik Stolt Marianne , Kanter Lena , Kharaziha Pedram , Lehtiö Janne , Hertzman Johansson Carolina , Höiom Veronica , Hansson Johan , Egyhazi Brage Suzanne
Published: August 2017

A majority of patients with BRAF-mutated metastatic melanoma respond to therapy with BRAF inhibitors (BRAFi), but relapses are common owing to acquired resistance. To unravel BRAFi resistance mechanisms we have performed gene expression and mass spectrometry based proteome profiling of the sensitive parental A375 BRAF V600E-mutated human melanoma cell line and of daughter cell lines with induced BRAFi resistance. Increased expression of two novel resistance candidates, aminopeptidase-N (CD13/ANPEP) and ETS transcription factor FLI1 was observed in the BRAFi-resistant daughter cell lines. In addition, increased levels of the previously reported resistance mediators, receptor tyrosine kinase ephrine receptor A2 (EPHA2) and the hepatocyte growth factor receptor MET were also identified. The expression of these proteins was assessed in matched tumor samples from melanoma patients obtained before BRAFi and after disease progression. MET was overexpressed in all progression samples while the expression of the other candidates varied between the individual patients. Targeting CD13/ANPEP by a blocking antibody induced apoptosis in both parental A375- and BRAFi-resistant daughter cells as well as in melanoma cells with intrinsic BRAFi resistance and led to dephosphorylation of EPHA2 on S897, previously demonstrated to cause inhibition of the migratory capacity. AKT and RSK, both reported to induce EPHA2 S897 phosphorylation, were also dephosphorylated after inhibition of CD13/ANPEP. FLI1 silencing also caused decreases in EPHA2 S897 phosphorylation and in total MET protein expression. In addition, silencing of FLI1 sensitized the resistant cells to BRAFi. Furthermore, we show that BRAFi in combination with the multi kinase inhibitor dasatinib can abrogate BRAFi resistance and decrease both EPHA2 S897 phosphorylation and total FLI1 protein expression. This is the first report presenting CD13/ANPEP and FLI1 as important mediators of resistance to BRAF inhibition with potential as drug targets in BRAFi refractory melanoma.
HSPB1 facilitates ERK-mediated phosphorylation and degradation of BIM to attenuate endoplasmic reticulum stress-induced apoptosis
Authors: Kennedy Donna , Mnich Katarzyna , Oommen Deepu , Chakravarthy Reka , Almeida-Souza Leonardo , Krols Michiel , Saveljeva Svetlana , Doyle Karen , Gupta Sanjeev , Timmerman Vincent , Janssens Sophie , Gorman Adrienne M , Samali Afshin
Published: August 2017

BIM, a pro-apoptotic BH3-only protein, is a key regulator of the intrinsic (or mitochondrial) apoptosis pathway. Here, we show that BIM induction by endoplasmic reticulum (ER) stress is suppressed in rat PC12 cells overexpressing heat shock protein B1 (HSPB1 or HSP27) and that this is due to enhanced proteasomal degradation of BIM. HSPB1 and BIM form a complex that immunoprecipitates with p-ERK1/2. We found that HSPB1-mediated proteasomal degradation of BIM is dependent on MEK-ERK signaling. Other studies have shown that several missense mutations in HSPB1 cause the peripheral neuropathy, Charcot-Marie-Tooth (CMT) disease, which is associated with nerve degeneration. Here we show that cells overexpressing CMT-related HSPB1 mutants exhibited increased susceptibility to ER stress-induced cell death and high levels of BIM. These findings identify a novel function for HSPB1 as a negative regulator of BIM protein stability leading to protection against ER stress-induced apoptosis, a function that is absent in CMT-associated HSPB1 mutants.
Dual role of DR5 in death and survival signaling leads to TRAIL resistance in cancer cells
Authors: Shlyakhtina Yelyzaveta , Pavet Valeria , Gronemeyer Hinrich
Published: August 2017

Besides its tumor-selective apoptotic activity, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) promotes pro-survival, proliferative or migratory signaling (NF-κB, PI3K/Akt, MAPK and JNK; referred to as 'non-apoptotic' cascades). Indeed, apoptosis and non-apoptotic signaling can be activated in clonal populations of cancer cells in response to treatment and, as a result, only a part of the initial cellular population dies while a fraction survives and develops resistance to TRAIL-induced apoptosis (referred to as 'fractional survival'). Notably, the molecular characterization of the protein platforms streaming into tumoricidalversustumor-promoting cascades that control fractional survival remained elusive. Here we demonstrate that, in the context of DR4–DR5–DcR2 hetero-oligomeric complexes, a single death receptor (DR5) suffices to assemble composite plasma membrane-proximal pro-apoptotic/pro-survival platforms that propagate TRAIL signaling to both death and survival pathways in clonal populations of cancer cells. Moreover, we show that while all members of TRAIL-induced complexes support survival, none of them acted exclusively pro-apoptotic. Indeed, key apoptotic proteins as FADD and procaspase-8 were also involved in transducing non-apoptotic signaling in response to this cytokine. Collectively, this study reveals the Janus faces of DR5, and the contributions of other death complex components in fractional survival that foster the generation of resistance. Our data highlight a new level of complexity in TRAIL signaling and point to an improved therapeutic rationale in view of hitherto disappointing results.
Tunneling anisotropic magnetoresistance driven by magnetic phase transition
Authors: Chen X. Z. , Feng J. F. , Wang Z. C. , Zhang J. , Zhong X. Y. , Song C. , Jin L. , Zhang B. , Li F. , Jiang M. , Tan Y. Z. , Zhou X. J. , Shi G. Y. , Zhou X. F. , Han X. D. , Mao S. C. , Chen Y. H. , Han X. F. , Pan F.
Published: August 2017

The independent control of two magnetic electrodes and spin-coherent transport in magnetic tunnel junctions are strictly required for tunneling magnetoresistance, while junctions with only one ferromagnetic electrode exhibit tunneling anisotropic magnetoresistance dependent on the anisotropic density of states with no room temperature performance so far. Here, we report an alternative approach to obtaining tunneling anisotropic magnetoresistance in α′-FeRh-based junctions driven by the magnetic phase transition of α′-FeRh and resultantly large variation of the density of states in the vicinity of MgO tunneling barrier, referred to as phase transition tunneling anisotropic magnetoresistance. The junctions with only one α′-FeRh magnetic electrode show a magnetoresistance ratio up to 20% at room temperature. Both the polarity and magnitude of the phase transition tunneling anisotropic magnetoresistance can be modulated by interfacial engineering at the α′-FeRh/MgO interface. Besides the fundamental significance, our finding might add a different dimension to magnetic random access memory and antiferromagnet spintronics.
Community-like genome in single cells of the sulfur bacterium Achromatium oxaliferum
Authors: Ionescu Danny , Bizic-Ionescu Mina , De Maio Nicola , Cypionka Heribert , Grossart Hans-Peter
Published: August 2017

Polyploid bacteria are common, but the genetic and functional diversity resulting from polyploidy is unknown. Here we use single-cell genomics, metagenomics, single-cell amplicon sequencing, and fluorescence in situ hybridization, to show that individual cells of Achromatium oxaliferum, the world’s biggest known freshwater bacterium, harbor genetic diversity typical of whole bacterial communities. The cells contain tens of transposable elements, which likely cause the unprecedented diversity that we observe in the sequence and synteny of genes. Given the high within-cell diversity of the usually conserved 16S ribosomal RNA gene, we suggest that gene conversion occurs in multiple, separated genomic hotspots. The ribosomal RNA distribution inside the cells hints to spatially differential gene expression. We also suggest that intracellular gene transfer may lead to extensive gene reshuffling and increased diversity.
Silicon quantum processor with robust long-distance qubit couplings
Authors: Tosi Guilherme , Mohiyaddin Fahd A. , Schmitt Vivien , Tenberg Stefanie , Rahman Rajib , Klimeck Gerhard , Morello Andrea
Published: August 2017

Practical quantum computers require a large network of highly coherent qubits, interconnected in a design robust against errors. Donor spins in silicon provide state-of-the-art coherence and quantum gate fidelities, in a platform adapted from industrial semiconductor processing. Here we present a scalable design for a silicon quantum processor that does not require precise donor placement and leaves ample space for the routing of interconnects and readout devices. We introduce the flip-flop qubit, a combination of the electron-nuclear spin states of a phosphorus donor that can be controlled by microwave electric fields. Two-qubit gates exploit a second-order electric dipole-dipole interaction, allowing selective coupling beyond the nearest-neighbor, at separations of hundreds of nanometers, while microwave resonators can extend the entanglement to macroscopic distances. We predict gate fidelities within fault-tolerance thresholds using realistic noise models. This design provides a realizable blueprint for scalable spin-based quantum computers in silicon.
HSP90 inhibition enhances cancer immunotherapy by upregulating interferon response genes
Authors: Mbofung Rina M. , McKenzie Jodi A. , Malu Shruti , Zhang Min , Peng Weiyi , Liu Chengwen , Kuiatse Isere , Tieu Trang , Williams Leila , Devi Seram , Ashkin Emily , Xu Chunyu , Huang Lu , Zhang Minying , Talukder Amjad H. , Tripathi Satyendra C. , Khong Hiep , Satani Nikunj , Muller Florian L. , Roszik Jason , Heffernan Timothy , Allison James P. , Lizee Gregory , Hanash Sam M. , Proia David , Amaria Rodabe , Davis R. Eric , Hwu Patrick
Published: August 2017

T-cell-based immunotherapies are promising treatments for cancer patients. Although durable responses can be achieved in some patients, many patients fail to respond to these therapies, underscoring the need for improvement with combination therapies. From a screen of 850 bioactive compounds, we identify HSP90 inhibitors as candidates for combination with immunotherapy. We show that inhibition of HSP90 with ganetespib enhances T-cell-mediated killing of patient-derived human melanoma cells by their autologous T cells in vitro and potentiates responses to anti-CTLA4 and anti-PD1 therapy in vivo. Mechanistic studies reveal that HSP90 inhibition results in upregulation of interferon response genes, which are essential for the enhanced killing of ganetespib treated melanoma cells by T cells. Taken together, these findings provide evidence that HSP90 inhibition can potentiate T-cell-mediated anti-tumor immune responses, and rationale to explore the combination of immunotherapy and HSP90 inhibitors.
Multivariate discovery and replication of five novel loci associated with Immunoglobulin G N-glycosylation
Authors: Shen Xia , Klarić Lucija , Sharapov Sodbo , Mangino Massimo , Ning Zheng , Wu Di , Trbojević-Akmačić Irena , Pučić-Baković Maja , Rudan Igor , Polašek Ozren , Hayward Caroline , Spector Timothy D. , Wilson James F. , Lauc Gordan , Aulchenko Yurii S.
Published: August 2017

Joint modeling of a number of phenotypes using multivariate methods has often been neglected in genome-wide association studies and if used, replication has not been sought. Modern omics technologies allow characterization of functional phenomena using a large number of related phenotype measures, which can benefit from such joint analysis. Here, we report a multivariate genome-wide association studies of 23 immunoglobulin G (IgG) N-glycosylation phenotypes. In the discovery cohort, our multi-phenotype method uncovers ten genome-wide significant loci, of which five are novel (IGH, ELL2, HLA-B-C, AZI1, FUT6-FUT3). We convincingly replicate all novel loci via multivariate tests. We show that IgG N-glycosylation loci are strongly enriched for genes expressed in the immune system, in particular antibody-producing cells and B lymphocytes. We empirically demonstrate the efficacy of multivariate methods to discover novel, reproducible pleiotropic effects.
Promoting Drp1-mediated mitochondrial fission in midlife prolongs healthy lifespan of Drosophila melanogaster
Authors: Rana Anil , Oliveira Matheus P. , Khamoui Andy V. , Aparicio Ricardo , Rera Michael , Rossiter Harry B. , Walker David W.
Published: August 2017

The accumulation of dysfunctional mitochondria has been implicated in aging, but a deeper understanding of mitochondrial dynamics and mitophagy during aging is missing. Here, we show that upregulating Drp1—a Dynamin-related protein that promotes mitochondrial fission—in midlife, prolongs Drosophila lifespan and healthspan. We find that short-term induction of Drp1, in midlife, is sufficient to improve organismal health and prolong lifespan, and observe a midlife shift toward a more elongated mitochondrial morphology, which is linked to the accumulation of dysfunctional mitochondria in aged flight muscle. Promoting Drp1-mediated mitochondrial fission, in midlife, facilitates mitophagy and improves both mitochondrial respiratory function and proteostasis in aged flies. Finally, we show that autophagy is required for the anti-aging effects of midlife Drp1-mediated mitochondrial fission. Our findings indicate that interventions that promote mitochondrial fission could delay the onset of pathology and mortality in mammals when applied in midlife.
Reactivation of dead sulfide species in lithium polysulfide flow battery for grid scale energy storage
Authors: Jin Yang , Zhou Guangmin , Shi Feifei , Zhuo Denys , Zhao Jie , Liu Kai , Liu Yayuan , Zu Chenxi , Chen Wei , Zhang Rufan , Huang Xuanyi , Cui Yi
Published: August 2017

Lithium polysulfide batteries possess several favorable attributes including low cost and high energy density for grid energy storage. However, the precipitation of insoluble and irreversible sulfide species on the surface of carbon and lithium (called “dead” sulfide species) leads to continuous capacity degradation in high mass loading cells, which represents a great challenge. To address this problem, herein we propose a strategy to reactivate dead sulfide species by reacting them with sulfur powder with stirring and heating (70 °C) to recover the cell capacity, and further demonstrate a flow battery system based on the reactivation approach. As a result, ultrahigh mass loading (0.125 g cm–3, 2 g sulfur in a single cell), high volumetric energy density (135 Wh L–1), good cycle life, and high single-cell capacity are achieved. The high volumetric energy density indicates its promising application for future grid energy storage.
An in-silico approach to predict and exploit synthetic lethality in cancer metabolism
Authors: Apaolaza Iñigo , San José-Eneriz Edurne , Tobalina Luis , Miranda Estíbaliz , Garate Leire , Agirre Xabier , Prósper Felipe , Planes Francisco J.
Published: August 2017

Synthetic lethality is a promising concept in cancer research, potentially opening new possibilities for the development of more effective and selective treatments. Here, we present a computational method to predict and exploit synthetic lethality in cancer metabolism. Our approach relies on the concept of genetic minimal cut sets and gene expression data, demonstrating a superior performance to previous approaches predicting metabolic vulnerabilities in cancer. Our genetic minimal cut set computational framework is applied to evaluate the lethality of ribonucleotide reductase catalytic subunit M1 (RRM1) inhibition in multiple myeloma. We present a computational and experimental study of the effect of RRM1 inhibition in four multiple myeloma cell lines. In addition, using publicly available genome-scale loss-of-function screens, a possible mechanism by which the inhibition of RRM1 is effective in cancer is established. Overall, our approach shows promising results and lays the foundation to build a novel family of algorithms to target metabolism in cancer.
Probing the internal micromechanical properties of Pseudomonas aeruginosa biofilms by Brillouin imaging
Authors: Karampatzakis A. , Song C. Z. , Allsopp L. P. , Filloux A. , Rice S. A. , Cohen Y. , Wohland T. , Török P.
Published: August 2017

Biofilms are organised aggregates of bacteria that adhere to each other or surfaces. The matrix of extracellular polymeric substances that holds the cells together provides the mechanical stability of the biofilm. In this study, we have applied Brillouin microscopy, a technique that is capable of measuring mechanical properties of specimens on a micrometre scale based on the shift in frequency of light incident upon a sample due to thermal fluctuations, to investigate the micromechanical properties of an active, live Pseudomonas aeruginosa biofilm. Using this non-contact and label-free technique, we have extracted information about the internal stiffness of biofilms under continuous flow. No correlation with colony size was found when comparing the averages of Brillouin shifts of two-dimensional cross-sections of randomly selected colonies. However, when focusing on single colonies, we observed two distinct spatial patterns: in smaller colonies, stiffness increased towards their interior, indicating a more compact structure of the centre of the colony, whereas, larger (over 45 μm) colonies were found to have less stiff interiors.
Characteristics of newly diagnosed COPD patients treated with triple inhaled therapy by general practitioners: a real world Italian study
Authors: Di Marco Fabiano , Santus Pierachille , Terraneo Silvia , Peruzzi Elena , Muscianisi Elisa , Ripellino Claudio , Pegoraro Valeria
Published: August 2017

Factors predicting prescriptions of triple therapy were investigated in a large group of general practitioners in Italy. In the population treated by identified general practitioners, a cohort of newly diagnosed chronic obstructive pulmonary disease patients was extracted from IMS Health Longitudinal Database during the period 2010–2013. From the diagnosis, 1-year follow-up was evaluated. Thirty-two thousand forty-six newly diagnosed chronic obstructive pulmonary disease patients were evaluated (57.7% male, mean age 67 years). During 2 years prior to diagnosis less than 13% of patients were requested with a pulmonology evaluation and less than 5% with a spirometry; 65.1% cases were prescribed with a respiratory drug, which in 9.6% of cases was inhaled corticosteroid/long-acting β2-agonist fixed-dose combination. Two thousand and twenty eight patients (6.3% of the newly diagnosed chronic obstructive pulmonary disease patients) were treated with triple therapy during the first year of follow-up, whose 858 (42.3%) starting immediately, and 762 (37.6%) following an initial treatment with inhaled corticosteroid/long-acting β2-agonist fixed-dose combination. Being older, being requested with pulmonologist evaluation or spirometry, being prescribed with a inhaled corticosteroid/long-acting β2-agonist fixed-dose combination at diagnosis resulted independent predictors of triple therapy use.
Directed Differentiation of Human Induced Pluripotent Stem Cells into Fallopian Tube Epithelium
Authors: Yucer Nur , Holzapfel Marie , Jenkins Vogel Tilley , Lenaeus Lindsay , Ornelas Loren , Laury Anna , Sareen Dhruv , Barrett Robert , Karlan Beth Y. , Svendsen Clive N.
Published: August 2017

The fallopian tube epithelium (FTE) has been recognized as a site of origin of high-grade serous ovarian cancer (HGSC). However, the absence of relevant in vitro human models that can recapitulate tissue-specific architecture has hindered our understanding of FTE transformation and initiation of HGSC. Here, induced pluripotent stem cells (iPSCs) were used to establish a novel 3-dimensional (3D) human FTE organoid in vitro model containing the relevant cell types of the human fallopian tube as well as a luminal architecture that closely reflects the organization of fallopian tissues in vivo. Modulation of Wnt and BMP signaling directed iPSC differentiation into Müllerian cells and subsequent use of pro-Müllerian growth factors promoted FTE precursors. The expression and localization of Müllerian markers verified correct cellular differentiation. An innovative 3D growth platform, which enabled the FTE organoid to self-organize into a convoluted luminal structure, permitted matured differentiation to a FTE lineage. This powerful human-derived FTE organoid model can be used to study the earliest stages of HGSC development and to identify novel and specific biomarkers of early fallopian tube epithelial cell transformation.
Bioaccumulation and biomagnification of short and medium chain polychlorinated paraffins in different species of fish from Liaodong Bay, North China
Authors: Huang Huiting , Gao Lirong , Xia Dan , Qiao Lin
Published: August 2017

Chlorinated paraffins (CPs) are highly complex technical mixtures, and the short chain chlorinated paraffins (SCCPs) are classed as persistent and have been included in the Stockholm Convention. However, there have been few studies of SCCPs and medium chain chlorinated paraffins (MCCPs) and their bioaccumulation and biomagnification in different species of fish. The present study investigated the levels, congener group profiles, bioaccumulation, and biomagnification of SCCPs and MCCPs in different species of fish from Liaodong Bay, North China. The ranges for the ΣSCCP and ΣMCCP concentrations were 376.3–8596 ng/g lipid weight (lw) and 22.37–5097 ng/g lw, respectively. The logarithms of bioaccumulation factors of ΣSCCPs ranged from 4.69 to 6.05, implying that SCCPs bioaccumulated in the fish. The trophic magnification factor of ΣSCCPs was 2.57, indicating that SCCPs could biomagnify in fish. Carbon chain length, the numbers of chlorine atoms, and octanol/water partition coefficients of the SCCPs and MCCPs might be important factors affecting the bioaccumulation of these chemicals in fish. The risk posed to human health by consumption of fish containing SCCPs was low. New SCCPs with nine carbons (C9) were detected in fish in this study.
Hypoxia-inducible factor 1 alpha promotes cancer stem cells-like properties in human ovarian cancer cells by upregulating SIRT1 expression
Authors: Qin Jie , Liu Yan , Lu Yongkui , Liu Meiling , Li Manli , Li Juan , Wu Lijuan
Published: August 2017

Ovarian cancer have a poor overall survival rate in patients, and late disease presentation and chemoresistance are the main factors that lead to the mortality of ovarian cancer. Cancer stem cells (CSCs), a small subpopulation of cancer cells, have been associated with resistance to chemo- and radio-therapy in cancer treatment. Hypoxia is a common characteristic of many malignant tumors, and increased HIF-1α expression predicts the poor prognosis of ovarian cancer. In this study, we reported the relationship between hypoxia and cancer stem cells-like properties in human ovarian cancer cell lines SKOV3 and HO8910, we found that hypoxia induced cancer stem cells-like properties in ovarian cancer cells. Moreover, SIRT1 was found to be the downstream target gene of HIF-1α, which was involved in the promotion of cancer stem cells-like features in ovarian cancer cells by hypoxia, and NF-κB signaling pathway was involved in hypoxia-induced SIRT1 up-regulation. Our results hinted that HIF1α and SIRT1 might serve as potential therapeutic targets for ovarian cancer.
Erratum: Noncanonical cell death program independent of caspase activation cascade and necroptotic modules is elicited by loss of TGFβ-activated kinase 1
Authors: Mihaly September R. , Sakamachi Yosuke , Ninomiya-Tsuji Jun , Morioka Sho
Published: August 2017

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.
Metabolomic Profiling of Serum Retinol in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study
Authors: Huang Jiaqi , Panagiotou Orestis A. , Anic Gabriella M. , Mondul Alison M. , Liao Linda M. , Derkach Andriy , Stolzenberg-Solomon Rachael , Weinstein Stephanie J. , Albanes Demetrius
Published: August 2017

The role of retinol in the prevention of multifactorial chronic diseases remains uncertain, and there is sparse evidence regarding biological actions and pathways implicated in its effects on various outcomes. The aim is to investigate whether serum retinol in an un-supplemented state is associated with low molecular weight circulating metabolites. We performed a metabolomic analysis of 1,282 male smoker participants based on pre-supplementation fasting serum in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. We examined the association between 947 metabolites measured by ultra-high performance LC-MS/GC-MS and retinol concentration (from HPLC) using linear regression that estimated the difference in metabolite concentrations per unit difference in retinol concentration as standardized β-coefficients and standard errors (SE). We identified 63 metabolites associated with serum retinol below the Bonferroni-corrected P-value (p < 5.3 × 10–5). The strongest signals were for N-acetyltryptophan (β = 0.27; SE = 0.032; p = 9.8 × 10−17), myo-inositol (β = 0.23; SE = 0.032; p = 9.8 × 10−13), and 1-palmitoylglycerophosphoethanolamine (β = 0.22; SE = 0.032; p = 3.2 × 10−12). Several chemical class pathways were strongly associated with retinol, including amino acids (p = 1.6 × 10−10), lipids (p = 3.3 × 10–7), and cofactor/vitamin metabolites (3.3 × 10−7). The strongest sub-pathway association was for inositol metabolism (p = 2.0 × 10–14). Serum retinol concentration is associated with circulating metabolites in various metabolic pathways, particularly lipids, amino acids, and cofactors/vitamins. These interrelationships may have relevance to the biological actions of retinol, including its role in carcinogenesis.
Increased PD-L1 expression and IL-6 secretion characterize human lung tumor-derived perivascular-like cells that promote vascular leakage in a perfusable microvasculature model
Authors: Bichsel Colette A. , Wang Limei , Froment Laurène , Berezowska Sabina , Müller Stefan , Dorn Patrick , Marti Thomas M. , Peng Ren-Wang , Geiser Thomas , Schmid Ralph A. , Guenat Olivier T. , Hall Sean R. R.
Published: August 2017

Pericytes represent important support cells surrounding microvessels found in solid organs. Emerging evidence points to their involvement in tumor progression and metastasis. Although reported to be present in the human lung, their specific presence and functional orientation within the tumor microenvironment in non-small cell lung cancer (NSCLC) has not yet been adequately studied. Using a multiparameter approach, we prospectively identified, sorted and expanded mesenchymal cells from human primary NSCLC samples based on co-expression of CD73 and CD90 while lacking hematopoietic and endothelial lineage markers (CD45, CD31, CD14 and Gly-A) and the epithelial marker EpCAM. Compared to their normal counterpart, tumor-derived Lineage-EpCAM-CD73+CD90+ cells showed enhanced expression of the immunosuppressive ligand PD-L1, a higher constitutive secretion of IL-6 and increased basal αSMA levels. In an in vitro model of 3D microvessels, both tumor-derived and matched normal Lineage-EpCAM-CD73+CD90+ cells supported the assembly of perfusable vessels. However, tumor-derived Lineage-EpCAM-CD73+CD90+ cells led to the formation of vessels with significantly increased permeability. Together, our data show that perivascular-like cells present in NSCLC retain functional abnormalities in vitro. Perivascular-like cells as an eventual target in NSCLC warrants further investigation.
Spatial inhomogeneity and temporal dynamics of a 2D electron gas in interaction with a 2D adatom gas
Authors: Cheynis F. , Curiotto S. , Leroy F. , Müller P.
Published: August 2017

Fundamental interest for 2D electron gas (2DEG) systems has been recently renewed with the advent of 2D materials and their potential high-impact applications in optoelectronics. Here, we investigate a 2DEG created by the electron transfer from a Ag adatom gas deposited on a Si(111) $$\sqrt{{\bf{3}}}{\boldsymbol{\times }}\sqrt{{\bf{3}}}$$

3

×

3

-Ag surface to an electronic surface state. Using low-energy electron microscopy (LEEM), we measure the Ag adatom gas concentration and the 2DEG-induced charge transfer. We demonstrate a linear dependence of the surface work function change on the Ag adatom gas concentration. A breakdown of the linear relationship is induced by the occurrence of the Ag adatom gas superstructure identified as Si(111) $$\sqrt{{\bf{21}}}{\boldsymbol{\times }}\sqrt{{\bf{21}}}$$

21

×

21

-Ag only observed below room temperature. We evidence below room temperature a confinement of the 2DEG on atomic terraces characterised by spatial inhomogeneities of the 2DEG-induced charge transfer along with temporal fluctuations. These variations mirror the Ag adatom gas concentration changes induced by the growth of 3D Ag islands and the occurrence of an Ehrlich-Schwoebel diffusion barrier of 155 ± 10 meV.
Targeting Bacterial Cardiolipin Enriched Microdomains: An Antimicrobial Strategy Used by Amphiphilic Aminoglycoside Antibiotics
Authors: El Khoury Micheline , Swain Jitendriya , Sautrey Guillaume , Zimmermann Louis , Van Der Smissen Patrick , Décout Jean-Luc , Mingeot-Leclercq Marie-Paule
Published: August 2017

Some bacterial proteins involved in cell division and oxidative phosphorylation are tightly bound to cardiolipin. Cardiolipin is a non-bilayer anionic phospholipid found in bacterial inner membrane. It forms lipid microdomains located at the cell poles and division plane. Mechanisms by which microdomains are affected by membrane-acting antibiotics and the impact of these alterations on membrane properties and protein functions remain unclear. In this study, we demonstrated cardiolipin relocation and clustering as a result of exposure to a cardiolipin-acting amphiphilic aminoglycoside antibiotic, the 3′,6-dinonyl neamine. Changes in the biophysical properties of the bacterial membrane of P. aeruginosa, including decreased fluidity and increased permeability, were observed. Cardiolipin-interacting proteins and functions regulated by cardiolipin were impacted by the amphiphilic aminoglycoside as we demonstrated an inhibition of respiratory chain and changes in bacterial shape. The latter effect was characterized by the loss of bacterial rod shape through a decrease in length and increase in curvature. It resulted from the effect on MreB, a cardiolipin dependent cytoskeleton protein as well as a direct effect of 3′,6-dinonyl neamine on cardiolipin. These results shed light on how targeting cardiolipin microdomains may be of great interest for developing new antibacterial therapies.
Japanese Food Data Challenge the Claimed Link between Fukushima’s Releases and Recently Observed Thyroid Cancer Increase in Japan
Authors: Steinhauser Georg , Chávez-Ortega Manuel , Vahlbruch Jan-Willem
Published: August 2017

Internal, high-dose exposure with radioiodine is known to increase the risk for thyroid cancer in children and adolescents. Ingestion of contaminated food is generally regarded a dominant route of internal exposure. We analyzed the huge data set of the post-Fukushima food monitoring campaign and deployed a conservative model for the estimation of the doses to the general public in a worst-case scenario. Our data suggest that the committed equivalent ingestion doses to the thyroids of the affected Japanese public, even in the utmost conservative approach, remained below the limit on ingestion of radioiodine in foodstuffs and beverages of 50 mSv (as thyroid equivalent dose). This level of 50 mSv is also the intervention level for the administration of stable iodine, mainly after inhalation. Our study hence suggests that, based on the food data, the internal exposure of Japanese residents was too low to cause a statistically discernible increase in thyroid cancer, even if the contribution from inhalation is taken into account. The data also indicate that the governmental efforts in the food monitoring campaign were successful and cut the thyroid doses to the public by a factor of approximately 3 compared to a scenario without any monitoring.
Promotion effect of extracts from plastrum testudinis on alendronate against glucocorticoid-induced osteoporosis in rat spine
Authors: Ren Hui , Shen Gengyang , Tang Jingjing , Qiu Ting , Zhang Zhida , Zhao Wenhua , Yu Xiang , Huang Jinjing , Liang De , Yao Zhensong , Yang Zhidong , Jiang Xiaobing
Published: August 2017

Alendronate (ALN) is a key therapeutic used to treat glucocorticoid-induced osteoporosis (GIOP), but may induce severe side effects. We showed earlier that plastrum testudinis extracts (PTE) prevented and treated GIOP in vivo. However, clinically, PTE is seldom used alone. Herein, we reveal the synergistic effect of ALN and PTE can treat GIOP of the rat spine and define the mechanism. Sprague-Dawley rats were randomly assigned to four groups: a vehicle group, a GIOP group, an ALN group, and an ALN+PTE group. Each group was further divided into two experimental phases, including dexamethasone (DXM) intervention and withdrawal. Bone mass, microarchitecture, biomechanics, bone-turnover markers, and histomorphology were evaluated. The mRNA and protein expression levels of CTSK and Runx2 were detemined. We found that ALN+PTE improved bone quantity and quality, bone strength, bone turnover; and mitigated histological damage during glucocorticoid intervention and withdrawal. The therapeutic effect was better than that afforded by ALN alone. ALN+PTE reduced CTSK protein expression, promoted Runx2 mRNA and protein expression to varying extents, and more strongly inhibited bone resorption than did ALN alone. Overall, the synergistic effect mediated by ALN+PTE reversed GIOP during DXM intervention and withdrawal via affecting CTSK and Runx2 expression at mRNA and protein levels.
Tunable and high-sensitivity sensing based on Fano resonance with coupled plasmonic cavities
Authors: Deng Yan , Cao Guangtao , Yang Hui , Li Guanhai , Chen Xiaoshuang , Lu Wei
Published: August 2017

Tunable and high-sensitivity sensing based on Fano resonance is analytically and numerically investigated in coupled plasmonic cavities structure. To analyze and manipulate the Fano line shape, the coupled cavities are taken as a composite cavity that supports at least two resonance modes. A theoretical model is newly-established, and its results agree well with the finite difference time domain (FDTD) simulations for the plasmonic stub-pair structure. The detection sensitivity factor in coupled cavities approaches 6.541 × 107 m−1, which is an order of magnitude larger than single stub case. In addition, the wavelengths of resonant modes in the plasmonic stub-pair structure can be adjusted independently, which paves a new way for improving detection sensitivity. These discoveries hold potential applications for realizing tunable and highly integrated photonic devices.
Improving understanding of the functional diversity of fisheries by exploring the influence of global catch reconstruction
Authors: Nash Kirsty L. , Watson Reg A. , Halpern Benjamin S. , Fulton Elizabeth A. , Blanchard Julia L.
Published: August 2017

Functional diversity is thought to enhance ecosystem resilience, driving research focused on trends in the functional composition of fisheries, most recently with new reconstructions of global catch data. However, there is currently little understanding of how accounting for unreported catches (e.g. small-scale and illegal fisheries, bycatch and discards) influences functional diversity trends in global fisheries. We explored how diversity estimates varied among reported and unreported components of catch in 2010, and found these components had distinct functional fingerprints. Incorporating unreported catches had little impact on global-scale functional diversity patterns. However, at smaller, management-relevant scales, the effects of incorporating unreported catches were large (changes in functional diversity of up to 46%). Our results suggest there is greater uncertainty about the risks to ecosystem integrity and resilience from current fishing patterns than previously recognized. We provide recommendations and suggest a research agenda to improve future assessments of functional diversity of global fisheries.
A chalcone derivative reactivates latent HIV-1 transcription through activating P-TEFb and promoting Tat-SEC interaction on viral promoter
Authors: Wu Jun , Ao Ming-tao , Shao Rui , Wang Hui-ru , Yu Diao , Fang Mei-juan , Gao Xiang , Wu Zhen , Zhou Qiang , Xue Yu-hua
Published: August 2017

The principal barrier to the eradication of HIV/AIDS is the existence of latent viral reservoirs. One strategy to overcome this barrier is to use latency-reversing agents (LRAs) to reactivate the latent proviruses, which can then be eliminated by effective anti-retroviral therapy. Although a number of LRAs have been found to reactivate latent HIV, they have not been used clinically due to high toxicity and poor efficacy. In this study, we report the identification of a chalcone analogue called Amt-87 that can significantly reactivate the transcription of latent HIV provirses and act synergistically with known LRAs such as prostratin and JQ1 to reverse latency. Amt-87 works by activating the human transcriptional elongation factor P-TEFb, a CDK9-cyclin T1 heterodimer that is part of the super elongation complex (SEC) used by the viral encoded Tat protein to activate HIV transcription. Amt-87 does so by promoting the phosphorylation of CDK9 at the T-loop, liberating P-TEFb from the inactive 7SK snRNP, and inducing the formation of the Tat-SEC complex at the viral promoter. Together, our data reveal chalcones as a promising category of compounds that should be further explored to identify effective LRAs for targeted reversal of HIV latency.
Impulsivity influences betting under stress in laboratory gambling
Authors: Canale Natale , Rubaltelli Enrico , Vieno Alessio , Pittarello Andrea , Billieux Joël
Published: August 2017

Although recent research suggests that acute stress influences subsequent decision-making under ambiguity, less is known about the role of personality variables in this relationship. This study tested whether impulsivity traits and acute stress differentially influence the way in which a prior feedback is incorporated into further decisions involving ambiguity. Sixty college students (50% male; aged 18–25 years) were randomly assigned to a stress versus a non-stress condition before completing a laboratory gambling task. The results revealed that independently of the stress condition, subjects behaved as if the odds of winning increase after a single loss. Additionally, stress effects varied as a function of impulsivity traits. Individuals who lacked perseverance (i.e., had difficulty focusing on a difficult or boring task) gambled more after experiencing a loss in the stress condition than did those in the control condition. The present study supports that impulsivity traits can explain the differential effect of stress on the relationship between prior feedback and choices made under ambiguity.
Changes in Resting-State Cerebral Activity in Patients with Hyperthyroidism: A Short-Term Follow-Up Functional MR Imaging Study
Authors: Liu Bo , Ran Qian , Liu Daihong , Zhang Si , Zhang Dong
Published: August 2017

To investigate the brain functional abnormality of hyperthyroid patients before and after treatment for one month using resting-state functional magnetic resonance imaging (rs-fMRI). Amplitude of low-frequency fluctuation (ALFF) and seed-based functional connectivity (FC) analysis were performed in 27 new-onset untreated hyperthyroid patients relative to 30 healthy controls. In addition, follow-up data were available for 19 patients treated with methimazole for one month. Compared with healthy controls, patients exhibited lower ALFF in the right posterior cingulate cortex (PCC); increased FC in the bilateral anterior insula (AI), bilateral posterior insula (PI) and left anterior lobe of the cerebellum (ALC); and decreased FC in the bilateral lateral prefrontal cortex (LPFC), the right medial temporal gyrus (MTG) and the bilateral PCC. Compared with the hyperthyroid status, patients with improved thyroid function showed increased FC in the right LPFC and right dorsolateral prefrontal cortex (DLPFC). Subsequently, Pearson’s correlation analyses were performed between abnormal ALFF, FC, neuropsychological assessment and serum free triiodothyronine (FT3) levels. The results indicated that the alterations in regional and network-level brain functions, which might underlie different psychiatric complications were dynamic and interactional processes in hyperthyroidism. Moreover, the improvement in regional brain FC was correlated with the efficacy of anti-thyroid medication.
Harnessing no-photon exciton generation chemistry to engineer semiconductor nanostructures
Authors: Beke David , Károlyházy Gyula , Czigány Zsolt , Bortel Gábor , Kamarás Katalin , Gali Adam
Published: August 2017

Production of semiconductor nanostructures with high yield and tight control of shape and size distribution is an immediate quest in diverse areas of science and technology. Electroless wet chemical etching or stain etching can produce semiconductor nanoparticles with high yield but is limited to a few materials because of the lack of understanding the physical-chemical processes behind. Here we report a no-photon exciton generation chemistry (NPEGEC) process, playing a key role in stain etching of semiconductors. We demonstrate NPEGEC on silicon carbide polymorphs as model materials. Specifically, size control of cubic silicon carbide nanoparticles of diameter below ten nanometers was achieved by engineering hexagonal inclusions in microcrystalline cubic silicon carbide. Our finding provides a recipe to engineer patterned semiconductor nanostructures for a broad class of materials.
Culture-independent metagenomics supports discovery of uncultivable bacteria within the genus Chlamydia
Authors: Taylor-Brown Alyce , Spang Labolina , Borel Nicole , Polkinghorne Adam
Published: August 2017

Advances in culture-independent methods have meant that we can more readily detect and diagnose emerging infectious disease threats in humans and animals. Metagenomics is fast becoming a popular tool for detection and characterisation of novel bacterial pathogens in their environment, and is particularly useful for obligate intracellular bacteria such as Chlamydiae that require labour-intensive culturing. We have used this tool to investigate the microbial metagenomes of Chlamydia-positive cloaca and choana samples from snakes. The microbial complexity within these anatomical sites meant that despite previous detection of chlamydial 16S rRNA sequences by single-gene broad-range PCR, only a chlamydial plasmid could be detected in all samples, and a chlamydial chromosome in one sample. Comparative genomic analysis of the latter revealed it represented a novel taxon, Ca. Chlamydia corallus, with genetic differences in regards to purine and pyrimidine metabolism. Utilising statistical methods to relate plasmid phylogeny to the phylogeny of chromosomal sequences showed that the samples also contain additional novel strains of Ca. C. corallus and two putative novel species in the genus Chlamydia. This study highlights the value of metagenomics methods for rapid novel bacterial discovery and the insights it can provide into the biology of uncultivable intracellular bacteria such as Chlamydiae.
Manipulation of acoustic wavefront by gradient metasurface based on Helmholtz Resonators
Authors: Lan Jun , Li Yifeng , Xu Yue , Liu Xiaozhou
Published: August 2017

We designed a gradient acoustic metasurface to manipulate acoustic wavefront freely. The broad bandwidth and high efficiency transmission are achieved by the acoustic metasurface which is constructed with a series of unit cells to provide desired discrete acoustic velocity distribution. Each unit cell is composed of a decorated metal plate with four periodically arrayed Helmholtz resonators (HRs) and a single slit. The design employs a gradient velocity to redirect refracted wave and the impedance matching between the metasurface and the background medium can be realized by adjusting the slit width of unit cell. The theoretical and numerical results show that some excellent wavefront manipulations are demonstrated by anomalous refraction, non-diffracting Bessel beam, sub-wavelength flat focusing, and effective tunable acoustic negative refraction. Our designed structure may offer potential applications for the imaging system, beam steering and acoustic lens.
Typewriter tinnitus revisited: The typical symptoms and the initial response to carbamazepine are the most reliable diagnostic clues
Authors: Sunwoo Woongsang , Jeon Yung Jin , Bae Yun Jung , Jang Jeong Hun , Koo Ja-Won , Song Jae-Jin
Published: August 2017

Although neurovascular compression of the cochlear nerve (NVC-C) presenting as typewriter tinnitus is a discrete disease category, verified diagnostic criteria are lacking. We sought to refine the diagnostic criteria for NVC-C by reference to a relatively large case series. The medical records of 22 NVC-C patients were retrospectively reviewed. Psychoacoustic characteristics, the results of diagnostic work-up (including audiovestibular neurophysiological tests and radiological evaluations), and the initial treatment response to carbamazepine were investigated. All subjects described their tinnitus as a typical “typewriter” or “staccato” sound. Of the 22 subjects, 11 (50%) had histories of vertiginous spells, but none had ipsilesional hearing loss. Vestibular function tests in 11 subjects tested revealed only 2 (18.2%) isolated cervical vestibular evoked myogenic potential abnormalities. Radiological comparisons of the symptomatic and asymptomatic sides, regarding the type of the vascular loop and neurovascular contact, revealed no significant differences. However, all 22 subjects exhibited immediate and marked responses to short-term carbamazepine treatment. Meticulous history-taking in terms of the psychoacoustic characteristics and the response to initial carbamazepine, are more reliable diagnostic clues than are radiological or neurophysiological data in NVC-C subjects. Therefore, the typical psychoacoustic characteristics and the response to initial carbamazepine should be included in the diagnostic criteria.
Synthesis, structure, and luminescent properties of a family of lanthanide-functionalized peroxoniobiophosphates
Authors: Wang Haiying , Li Jing , Sun Junjun , Wang Yaya , Liang Zhijie , Ma Pengtao , Zhang Dongdi , Wang Jingping , Niu Jingyang
Published: August 2017

Eight new lanthanide derivatives containing 6-peroxoniobio-4-phosphate building block, [LnIII(H2O)6]2[H4(NbO2)6P4O24]·nH2O [Ln = Eu (1), Gd (2), Tb (3), Dy (4), Ho (5), Er (6), Tm (7), Yb (8), 1–5, 7, 8 n = 12; 6 n = 9], have been successfully obtained using an in-situ strategy and fully characterized in the solid state by single-crystal X-ray diffraction, IR spectra, TG-MS, PXRD. Structural analyses indicate that these isostructural polyanions 1–8 consist of one [P4(NbO2)6O24]10− (P
4
(NbO
2
)
6
) clusters and two pendant Ln3+ cations. In these compounds, P
4
(NbO
2
)
6
clusters are connected by lanthanide cations to form extended two-dimensional architectures. The approach takes advantage of the ability of in-situ formed P
4
(NbO
2
)
6
cluster to build frameworks by using it as ligands to lanthanide ions. The photoluminescence (PL) and lifetime decay behaviors of 1, 3 and 4 in solid state have been performed at room temperature. The PL emission of 1, 3 and 4 is mainly derived from the characteristic 5D0→7FJ (J = 1, 2, 3, 4), 5D4→7FJ (J = 6, 5, 4, 3) and 4F9/2→6H J (J = 15/2, 13/2, 11/2) transitions of the EuIII, TbIII and DyIII cations, respectively.