bluuebunny/crossref_metadata_2025 huggingface dataset:
Prospective longitudinal study on quality of life in relapsed/refractory multiple myeloma patients receiving second- or third-line lenalidomide or bortezomib treatment
Authors: Leleu X , Kyriakou C , Vande Broek I , Murphy P , Bacon P , Lewis P , Gilet H , Arnould B , Petrucci M T
Published: March 2017

Treatment advances for multiple myeloma (MM) that have prolonged survival emphasise the importance of measuring patients’ health-related quality of life (HRQoL) in clinical studies. HRQoL/functioning and symptoms of patients with relapsed/refractory MM (RRMM) receiving second- or third-line lenalidomide or bortezomib treatment were measured in a prospective European multicentre, observational study at different time points. At baseline, patients in the lenalidomide cohort were frailer than in the bortezomib cohort with more rapid disease progression at study entry (more patients with Eastern Cooperative Oncology Group performance status >2, shorter time from diagnosis, more chronic heart failure, higher serum creatinine levels, more patients with dialysis required). About 40% of the patients receiving lenalidomide discontinued the study in <6 months while 55% in the bortezomib cohort discontinued. No substantial HRQoL deterioration was observed for the first 6 months in patients with RRMM receiving one or the other treatment. For patients still on treatment at study completion (month 6), only the European Organization for Research and Treatment of Cancer Quality-of-Life Core domains of Diarrhoea and Global Health Status/QoL had worsened in the lenalidomide and bortezomib cohorts, respectively. A clinically meaningful deterioration in HRQoL was more often observed for patients who discontinued the study prior to 6 months in the bortezomib cohort than in the lenalidomide cohort.
Understanding CD8+ T‐cell responses toward the native and alternate HLA‐A∗02:01‐restricted WT1 epitope
Authors: Nguyen Thi HO , Tan Amabel CL , Xiang Sue D , Goubier Anne , Harland Kim L , Clemens E Bridie , Plebanski Magdalena , Kedzierska Katherine
Published: March 2017

The Wilms’ tumor 1 (WT1) antigen is expressed in solid and hematological malignancies, but not healthy tissues, making it a promising target for cancer immunotherapies. Immunodominant WT1 epitopes, the native HLA‐A2/WT1126‐134 (RMFPNAPYL) (HLA‐A2/RMFPNAPYL epitope (WT1A)) and its modified variant YMFPNAPYL (HLA‐A2/YMFPNAPYL epitope (WT1B)), can induce WT1‐specific CD8+ T cells, although WT1B is more stably bound to HLA‐A∗02:01. Here, to further determine the benefits of those two targets, we assessed the naive precursor frequencies; immunogenicity and cross‐reactivity of CD8+ T cells directed toward these two WT1 epitopes. Ex vivo naive WT1A‐ and WT1B‐specific CD8+ T cells were detected in healthy HLA‐A∗02:01+ individuals with comparable precursor frequencies (1 in 105–106) to other naive CD8+ T‐cell pools (for example, A2/HIV‐Gag77‐85), but as expected, ~100 × lower than those found in memory populations (influenza, A2/M158‐66; EBV, A2/BMLF1280‐288). Importantly, only WT1A‐specific naive precursors were detected in HLA‐A2.1 mice. To further assess the immunogenicity and recruitment of CD8+ T cells responding to WT1A and WT1B, we immunized HLA‐A2.1 mice with either peptide. WT1A immunization elicited numerically higher CD8+ T‐cell responses to the native tumor epitope following re‐stimulation, although both regimens produced functionally similar responses toward WT1A via cytokine analysis and CD107a expression. Interestingly, however, WT1B immunization generated cross‐reactive CD8+ T‐cell responses to WT1A and could be further expanded by WT1A peptide revealing two distinct populations of single‐ and cross‐reactive WT1A+CD8+ T cells with unique T‐cell receptor‐αβ gene signatures. Therefore, although both epitopes are immunogenic, the clinical benefits of WT1B vaccination remains debatable and perhaps both peptides may have separate clinical benefits as treatment targets.
DNA methylation signatures in peripheral blood strongly predict all-cause mortality
Authors: Zhang Yan , Wilson Rory , Heiss Jonathan , Breitling Lutz P. , Saum Kai-Uwe , Schöttker Ben , Holleczek Bernd , Waldenberger Melanie , Peters Annette , Brenner Hermann
Published: March 2017

DNA methylation (DNAm) has been revealed to play a role in various diseases. Here we performed epigenome-wide screening and validation to identify mortality-related DNAm signatures in a general population-based cohort with up to 14 years follow-up. In the discovery panel in a case-cohort approach, 11,063 CpGs reach genome-wide significance (FDR<0.05). 58 CpGs, mapping to 38 well-known disease-related genes and 14 intergenic regions, are confirmed in a validation panel. A mortality risk score based on ten selected CpGs exhibits strong association with all-cause mortality, showing hazard ratios (95% CI) of 2.16 (1.10–4.24), 3.42 (1.81–6.46) and 7.36 (3.69–14.68), respectively, for participants with scores of 1, 2–5 and 5+ compared with a score of 0. These associations are confirmed in an independent cohort and are independent from the ‘epigenetic clock’. In conclusion, DNAm of multiple disease-related genes are strongly linked to mortality outcomes. The DNAm-based risk score might be informative for risk assessment and stratification.
IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2
Authors: Jandl Christoph , Liu Sue M. , Cañete Pablo F. , Warren Joanna , Hughes William E. , Vogelzang Alexis , Webster Kylie , Craig Maria E. , Uzel Gulbu , Dent Alexander , Stepensky Polina , Keller Bärbel , Warnatz Klaus , Sprent Jonathan , King Cecile
Published: March 2017

T follicular regulatory (Tfr) cells control the magnitude and specificity of the germinal centre reaction, but how regulation is contained to ensure generation of high-affinity antibody is unknown. Here we show that this balance is maintained by the reciprocal influence of interleukin (IL)-2 and IL-21. The number of IL-2-dependent FoxP3+ regulatory T cells is increased in the peripheral blood of human patients with loss-of-function mutations in the IL-21 receptor (IL-21R). In mice, IL-21:IL-21R interactions influence the phenotype of T follicular cells, reducing the expression of CXCR4 and inhibiting the expansion of Tfr cells after T-cell-dependent immunization. The negative effect of IL-21 on Tfr cells in mice is cell intrinsic and associated with decreased expression of the high affinity IL-2 receptor (CD25). Bcl-6, expressed in abundance in Tfr cells, inhibits CD25 expression and IL-21-mediated inhibition of CD25 is Bcl-6 dependent. These findings identify a mechanism by which IL-21 reinforces humoral immunity by restricting Tfr cell proliferation.
Circulating tumour DNA reflects treatment response and clonal evolution in chronic lymphocytic leukaemia
Authors: Yeh Paul , Hunter Tane , Sinha Devbarna , Ftouni Sarah , Wallach Elise , Jiang Damian , Chan Yih-Chih , Wong Stephen Q. , Silva Maria Joao , Vedururu Ravikiran , Doig Kenneth , Lam Enid , Arnau Gisela Mir , Semple Timothy , Wall Meaghan , Zivanovic Andjelija , Agarwal Rishu , Petrone Pasquale , Jones Kate , Westerman David , Blombery Piers , Seymour John F. , Papenfuss Anthony T. , Dawson Mark A. , Tam Constantine S. , Dawson Sarah-Jane
Published: March 2017

Several novel therapeutics are poised to change the natural history of chronic lymphocytic leukaemia (CLL) and the increasing use of these therapies has highlighted limitations of traditional disease monitoring methods. Here we demonstrate that circulating tumour DNA (ctDNA) is readily detectable in patients with CLL. Importantly, ctDNA does not simply mirror the genomic information contained within circulating malignant lymphocytes but instead parallels changes across different disease compartments following treatment with novel therapies. Serial ctDNA analysis allows clonal dynamics to be monitored over time and identifies the emergence of genomic changes associated with Richter’s syndrome (RS). In addition to conventional disease monitoring, ctDNA provides a unique opportunity for non-invasive serial analysis of CLL for molecular disease monitoring.
Major advance of South Georgia glaciers during the Antarctic Cold Reversal following extensive sub-Antarctic glaciation
Authors: Graham Alastair G. C. , Kuhn Gerhard , Meisel Ove , Hillenbrand Claus-Dieter , Hodgson Dominic A. , Ehrmann Werner , Wacker Lukas , Wintersteller Paul , dos Santos Ferreira Christian , Römer Miriam , White Duanne , Bohrmann Gerhard
Published: March 2017

The history of glaciations on Southern Hemisphere sub-polar islands is unclear. Debate surrounds the extent and timing of the last glacial advance and termination on sub-Antarctic South Georgia in particular. Here, using sea-floor geophysical data and marine sediment cores, we resolve the record of glaciation offshore of South Georgia through the transition from the Last Glacial Maximum to Holocene. We show a sea-bed landform imprint of a shelf-wide last glacial advance and progressive deglaciation. Renewed glacier resurgence in the fjords between c. 15,170 and 13,340 yr ago coincided with a period of cooler, wetter climate known as the Antarctic Cold Reversal, revealing a cryospheric response to an Antarctic climate pattern extending into the Atlantic sector of the Southern Ocean. We conclude that the last glaciation of South Georgia was extensive, and the sensitivity of its glaciers to climate variability during the last termination more significant than implied by previous studies.
The best features of diamond nanothread for nanofibre applications
Authors: Zhan Haifei , Zhang Gang , Tan Vincent B. C. , Gu Yuantong
Published: March 2017

Carbon fibres have attracted interest from both the scientific and engineering communities due to their outstanding physical properties. Here we report that recently synthesized ultrathin diamond nanothread not only possesses excellent torsional deformation capability, but also excellent interfacial load-transfer efficiency. Compared with (10,10) carbon nanotube bundles, the flattening of nanotubes is not observed in diamond nanothread bundles, which leads to a high-torsional elastic limit that is almost three times higher. Pull-out tests reveal that the diamond nanothread bundle has an interface transfer load of more than twice that of the carbon nanotube bundle, corresponding to an order of magnitude higher in terms of the interfacial shear strength. Such high load-transfer efficiency is attributed to the strong mechanical interlocking effect at the interface. These intriguing features suggest that diamond nanothread could be an excellent candidate for constructing next-generation carbon fibres.
Observation of biexcitonic emission at extremely low power density in tungsten disulfide atomic layers grown on hexagonal boron nitride
Authors: Okada Mitsuhiro , Miyauchi Yuhei , Matsuda Kazunari , Taniguchi Takashi , Watanabe Kenji , Shinohara Hisanori , Kitaura Ryo
Published: March 2017

Monolayer transition metal dichalcogenides (TMDCs) including WS2, MoS2, WSe2 and WS2, are two-dimensional semiconductors with direct bandgap, providing an excellent field for exploration of many-body effects in 2-dimensions (2D) through optical measurements. To fully explore the physics of TMDCs, the prerequisite is preparation of high-quality samples to observe their intrinsic properties. For this purpose, we have focused on high-quality samples, WS2 grown by chemical vapor deposition method with hexagonal boron nitride as substrates. We observed sharp exciton emissions, whose linewidth is typically 22~23 meV, in photoluminescence spectra at room temperature, which result clearly demonstrates the high-quality of the current samples. We found that biexcitons formed with extremely low-excitation power (240 W/cm2) at 80 K, and this should originate from the minimal amount of localization centers in the present high-quality samples. The results clearly demonstrate that the present samples can provide an excellent field, where one can observe various excitonic states, offering possibility of exploring optical physics in 2D and finding new condensates.
Acclimation of a low iron adapted Ostreococcus strain to iron limitation through cell biomass lowering
Authors: Botebol Hugo , Lelandais Gaelle , Six Christophe , Lesuisse Emmanuel , Meng Arnaud , Bittner Lucie , Lecrom Stéphane , Sutak Robert , Lozano Jean-Claude , Schatt Philippe , Vergé Valérie , Blain Stéphane , Bouget François-Yves
Published: March 2017

Iron is an essential micronutrient involved in many biological processes and is often limiting for primary production in large regions of the World Ocean. Metagenomic and physiological studies have identified clades or ecotypes of marine phytoplankton that are specialized in iron depleted ecological niches. Although less studied, eukaryotic picophytoplankton does contribute significantly to primary production and carbon transfer to higher trophic levels. In particular, metagenomic studies of the green picoalga Ostreococcus have revealed the occurrence of two main clades distributed along coast-offshore gradients, suggesting niche partitioning in different nutrient regimes. Here, we present a study of the response to iron limitation of four Ostreococcus strains isolated from contrasted environments. Whereas the strains isolated in nutrient-rich waters showed high iron requirements, the oceanic strains could cope with lower iron concentrations. The RCC802 strain, in particular, was able to maintain high growth rate at low iron levels. Together physiological and transcriptomic data indicate that the competitiveness of RCC802 under iron limitation is related to a lowering of iron needs though a reduction of the photosynthetic machinery and of protein content, rather than to cell size reduction. Our results overall suggest that iron is one of the factors driving the differentiation of physiologically specialized Ostreococcus strains in the ocean.
Prosocial Orientation Alters Network Dynamics and Fosters Cooperation
Authors: Melamed David , Simpson Brent , Harrell Ashley
Published: March 2017

Dynamic networks have been shown to increase cooperation, but prior findings are compatible with two different mechanisms for the evolution of cooperation. It may be that dynamic networks promote cooperation even in networks composed entirely of egoists, who strategically cooperate to attract and maintain profitable interaction partners. Alternatively, drawing on recent insights into heterogeneous social preferences, we expect that dynamic networks will increase cooperation only when nodes are occupied by persons with more prosocial preferences, who tend to attract and keep more cooperative partners relative to egoists. Our experiment used a standard procedure to classify participants a priori as egoistic or prosocial and then embedded them in homogeneous networks of all prosocials or all egoists, or in heterogeneous networks (50/50). Participants then interacted in repeated prisoner's dilemma games with alters in both static and dynamic networks. In both heterogeneous and homogeneous networks, we find dynamic networks only promote cooperation among prosocials. Resulting from their greater cooperation, prosocials’ relations are more stable, yielding substantially higher fitness compared to egoists in both heterogeneous and homogeneous dynamic networks. Our results suggest that a key to the evolution and stability of cooperation is the ability of those with prosocial preferences to alter their networks.
Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model
Authors: Tokunaga Yuko , Osawa Yosuke , Ohtsuki Takahiro , Hayashi Yukiko , Yamaji Kenzaburo , Yamane Daisuke , Hara Mitsuko , Munekata Keisuke , Tsukiyama-Kohara Kyoko , Hishima Tsunekazu , Kojima Soichi , Kimura Kiminori , Kohara Michinori
Published: March 2017

Chronic hepatitis C virus (HCV) infection is one of the major causes of serious liver diseases, including liver cirrhosis. There are no anti-fibrotic drugs with efficacy against liver cirrhosis. Wnt/β-catenin signaling has been implicated in the pathogenesis of a variety of tissue fibrosis. In the present study, we investigated the effects of a β-catenin/CBP (cyclic AMP response element binding protein) inhibitor on liver fibrosis. The anti-fibrotic activity of PRI-724, a selective inhibitor of β-catenin/CBP, was assessed in HCV GT1b transgenic mice at 18 months after HCV genome expression. PRI-724 was injected intraperitoneally or subcutaneously in these mice for 6 weeks. PRI-724 reduced liver fibrosis, which was indicated by silver stain, Sirius Red staining, and hepatic hydroxyproline levels, in HCV mice while attenuating αSMA induction. PRI-724 led to increased levels of matrix metalloproteinase (MMP)-8 mRNA in the liver, along with elevated levels of intrahepatic neutrophils and macrophages/monocytes. The induced intrahepatic neutrophils and macrophages/monocytes were identified as the source of MMP-8. In conclusion, PRI-724 ameliorated HCV-induced liver fibrosis in mice. We hypothesize that inhibition of hepatic stellate cells activation and induction of fibrolytic cells expressing MMP-8 contribute to the anti-fibrotic effects of PRI-724. PRI-724 is a drug candidate which possesses anti-fibrotic effect.
Rtn1a-Mediated Endoplasmic Reticulum Stress in Podocyte Injury and Diabetic Nephropathy
Authors: Fan Ying , Zhang Jing , Xiao Wenzhen , Lee Kyung , Li Zhengzhe , Wen Jiejun , He Li , Gui Dingkun , Xue Rui , Jian Guihua , Sheng Xiaohua , He John Cijiang , Wang Niansong
Published: March 2017

We previously reported a critical role of reticulon (RTN) 1A in mediating endoplasmic reticulum (ER) stress in kidney tubular cells and the expression of RTN1A correlates with the renal function and the severity of kidney injury in patients with diabetic nephropathy (DN). Here, we determined the roles of RTN1A and ER stress in podocyte injury and DN. We used db/db mice with early unilateral nephrectomy (Unx) as a murine model of progressive DN and treated mice with tauroursodeoxycholic acid (TUDCA), a specific inhibitor of ER stress. We found increased expression of RTN1A and ER stress markers in the kidney of db/db-Unx mice. Treatment of TUDCA not only attenuated proteinuria and kidney histological changes, but also ameliorated podocyte and glomeruli injury in diabetic mice, which were associated with reduction of RTN1A and ER stress marker expression in the podocytes of TUDCA-treated mice. In vitro, we showed RTN1A mediates albumin-induced ER stress and apoptosis in human podocytes. A positive feedback loop between RTN1A and CHOP was found leading to an enhanced ER stress in podocytes. Our data suggest that ER stress plays a major role in podocyte injury in DN and RTN1A might be a key regulator of ER stress in podocytes.
Cortical cells reveal APP as a new player in the regulation of GABAergic neurotransmission
Authors: Doshina Anna , Gourgue Florian , Onizuka Michiho , Opsomer Remi , Wang Peng , Ando Kunie , Tasiaux Bernadette , Dewachter Ilse , Kienlen-Campard Pascal , Brion Jean-Pierre , Gailly Philippe , Octave Jean-Noël , Pierrot Nathalie
Published: March 2017

The amyloid precursor protein (APP) modulates synaptic activity, resulting from the fine tuning of excitatory and inhibitory neurotransmission. GABAergic inhibitory neurotransmission is affected by modifications in intracellular chloride concentrations regulated by Na+-K+-2Cl− cotransporter 1 (NKCC1) and neuronal K+-Cl− cotransporter 2 (KCC2), allowing entrance and efflux of chloride, respectively. Modifications in NKCC1 and KCC2 expression during maturation of cortical cells induce a shift in GABAergic signaling. Here, we demonstrated that APP affects this GABA shift. Expression of APP in cortical cells decreased the expression of KCC2, without modifying NKCC1, eliciting a less inhibitory GABA response. Downregulation of KCC2 expression by APP was independent of the APP intracellular domain, but correlated with decreased expression of upstream stimulating factor 1 (USF1), a potent regulator of Slc12a5 gene expression (encoding KCC2). KCC2 was also downregulated in vivo following APP expression in neonatal mouse brain. These results argue for a key role of APP in the regulation of GABAergic neurotransmission.
Regulation of membrane ruffling by polarized STIM1 and ORAI1 in cortactin-rich domains
Authors: Lopez-Guerrero Aida M. , Tomas-Martin Patricia , Pascual-Caro Carlos , Macartney Thomas , Rojas-Fernandez Alejandro , Ball Graeme , Alessi Dario R. , Pozo-Guisado Eulalia , Martin-Romero Francisco Javier
Published: March 2017

Cell motility and migration requires the reorganization of the cortical cytoskeleton at the leading edge of cells and extracellular Ca2+ entry is essential for this reorganization. However the molecular nature of the regulators of this pathway is unknown. This work contributes to understanding the role of STIM1 and ORAI1 in the promotion of membrane ruffling by showing that phospho-STIM1 localizes at the leading edge of cells, and that both phospho-STIM1 and ORAI1 co-localize with cortactin (CTTN), a regulator of the cytoskeleton at membrane ruffling areas. STIM1-KO and ORAI1-KO cell lines were generated by CRISPR/Cas9 genome editing in U2OS cells. In both cases, KO cells presented a notable reduction of store-operated Ca2+ entry (SOCE) that was rescued by expression of STIM1-mCherry and ORAI1-mCherry. These results demonstrated that SOCE regulates membrane ruffling at the leading edge of cells. Moreover, endogenous ORAI1 and overexpressed ORAI1-GFP co-immunoprecipitated with endogenous CTTN. This latter result, in addition to the KO cells’ phenotype, the preservation of ORAI1-CTTN co-localization during ruffling, and the inhibition of membrane ruffling by the Ca2+-channel inhibitor SKF96365, further supports a functional link between SOCE and membrane ruffling.
Populus trichocarpa encodes small, effector-like secreted proteins that are highly induced during mutualistic symbiosis
Authors: Plett Jonathan M. , Yin Hengfu , Mewalal Ritesh , Hu Rongbin , Li Ting , Ranjan Priya , Jawdy Sara , De Paoli Henrique C. , Butler George , Burch-Smith Tessa Maureen , Guo Hao-Bo , Ju Chen Chun , Kohler Annegret , Anderson Ian C. , Labbé Jessy L. , Martin Francis , Tuskan Gerald A. , Yang Xiaohan
Published: March 2017

During symbiosis, organisms use a range of metabolic and protein-based signals to communicate. Of these protein signals, one class is defined as ‘effectors’, i.e., small secreted proteins (SSPs) that cause phenotypical and physiological changes in another organism. To date, protein-based effectors have been described in aphids, nematodes, fungi and bacteria. Using RNA sequencing of Populus trichocarpa roots in mutualistic symbiosis with the ectomycorrhizal fungus Laccaria bicolor, we sought to determine if host plants also contain genes encoding effector-like proteins. We identified 417 plant-encoded putative SSPs that were significantly regulated during this interaction, including 161 SSPs specific to P. trichocarpa and 15 SSPs exhibiting expansion in Populus and closely related lineages. We demonstrate that a subset of these SSPs can enter L. bicolor hyphae, localize to the nucleus and affect hyphal growth and morphology. We conclude that plants encode proteins that appear to function as effector proteins that may regulate symbiotic associations.
Fission-fusion dynamics over large distances in raven non-breeders
Authors: Loretto Matthias-Claudio , Schuster Richard , Itty Christian , Marchand Pascal , Genero Fulvio , Bugnyar Thomas
Published: March 2017

The influence of fission-fusion dynamics, i.e., temporal variation in group size and composition, on social complexity has been studied in large-brained mammals that rely on social bonds. Little is known about birds, even though some species like ravens have recently received attention for their socio-cognitive skills and use of social bonds. While raven breeders defend territories year-round, non-breeders roam through large areas and form groups at food sources or night roosts. We here examined the fission-fusion patterns of non-breeding ravens over years, investigating whether birds meet repeatedly either at the same or at different locations. We combined four large datasets: presence-absence observations from two study sites (Austria, Italy) and GPS-tracking of ravens across two study areas (Austria, France). As expected, we found a highly dynamic system in which individuals with long phases of temporary settlement had a high probability of meeting others. Although GPS-tagged ravens spread out over thousands of square kilometres, we found repeated associations between almost half of the possible combinations at different locations. Such a system makes repeated interactions between individuals at different sites possible and likely. High fission-fusion dynamics may thus not hinder but shape the social complexity of ravens and, possibly, other long-term bonded birds.
Tmeff2 is expressed in differentiating oligodendrocytes but dispensable for their differentiation in vivo
Authors: Huang Hao , Teng Peng , Mei Ruyi , Yang Aifen , Zhang Zunyi , Zhao Xiaofeng , Qiu Mengsheng
Published: March 2017

Myelin elaborated by oligodendrocytes (OLs) in the central nervous system (CNS) is required for saltatory conduction of action potentials along neuronal axons. We found that TMEFF2, a transmembrane protein with EGF-like and two follistatin-like domains, is selectively expressed in differentiating/myelinating OLs. Previous studies showed that TMEFF2 is capable of binding to PDGFA, which plays important roles in the proliferation, migration and differentiation of oligodendrocyte progenitor cells (OPCs). However, molecular and genetic analysis revealed that Tmeff2 is a weak binder of PDGFA, and not required for OL differentiation and myelin gene expression in vivo. Together, our data suggested that Tmeff2 is specifically upregulated in OLs, but dispensable for OL differentiation and maturation.
A DFT Study on the Electronic Structures and Conducting Properties of Rubrene and its Derivatives in Organic Field-Effect Transistors
Authors: Ma Huipeng , Liu Na , Huang Jin-Dou
Published: March 2017

We systematically studied the electronic structures and conducting properties of rubrene and its derivatives reported recently, and disscussed the influences of electron-withdrawing groups and chemical oxidation on the reorganization energies, crystal packing, electronic couplings, and charge injection barrier of rubrene. Hirshfeld surface analysis and quantum-chemical calculations revealed that the introduction of CF3 groups into rubrene decreases the H···H repulsive interaction and increases intermolecular F···H/H···F attractive interactions, which resulted in the tight packing arrangement and the increase of the electronic couplings, and finally cause the higer intrinsic hole-mobility in bis(trifluoromethyl)-dimethyl-rubrene crystal (μh = 19.2 cm2 V−1 s−1) than in rubrene crystal (μh = 15.8 cm2 V−1 s−1). In comparison, chemical oxidation reduces charge-carrier mobility of rubrene crystal by 2~4 orders of magnitude and increased the hole and electron injection barrier, which partly explains the rubrene-based field-effect transistor performance degrades upon exposure to air. Furthermore, we also discussed the influence of structural parameters of carbon nanotube (CNT) electrode on charge injection process, which suggests that the regulation of CNT diameters and increasing in thickness is an effective strategy to optimize CNT work functions and improve n-type OFET performances based on these organic materials.
Complete genome sequence and comparative genomics of the probiotic yeast Saccharomyces boulardii
Authors: Khatri Indu , Tomar Rajul , Ganesan K. , Prasad G. S. , Subramanian Srikrishna
Published: March 2017

The probiotic yeast, Saccharomyces boulardii (Sb) is known to be effective against many gastrointestinal disorders and antibiotic-associated diarrhea. To understand molecular basis of probiotic-properties ascribed to Sb we determined the complete genomes of two strains of Sb i.e. Biocodex and unique28 and the draft genomes for three other Sb strains that are marketed as probiotics in India. We compared these genomes with 145 strains of S. cerevisiae (Sc) to understand genome-level similarities and differences between these yeasts. A distinctive feature of Sb from other Sc is absence of Ty elements Ty1, Ty3, Ty4 and associated LTR. However, we could identify complete Ty2 and Ty5 elements in Sb. The genes for hexose transporters HXT11 and HXT9, and asparagine-utilization are absent in all Sb strains. We find differences in repeat periods and copy numbers of repeats in flocculin genes that are likely related to the differential adhesion of Sb as compared to Sc. Core-proteome based taxonomy places Sb strains along with wine strains of Sc. We find the introgression of five genes from Z. bailii into the chromosome IV of Sb and wine strains of Sc. Intriguingly, genes involved in conferring known probiotic properties to Sb are conserved in most Sc strains.
A PSO-based multi-objective multi-label feature selection method in classification
Authors: Zhang Yong , Gong Dun-wei , Sun Xiao-yan , Guo Yi-nan
Published: March 2017

Feature selection is an important data preprocessing technique in multi-label classification. Although a large number of studies have been proposed to tackle feature selection problem, there are a few cases for multi-label data. This paper studies a multi-label feature selection algorithm using an improved multi-objective particle swarm optimization (PSO), with the purpose of searching for a Pareto set of non-dominated solutions (feature subsets). Two new operators are employed to improve the performance of the proposed PSO-based algorithm. One operator is adaptive uniform mutation with action range varying over time, which is used to extend the exploration capability of the swarm; another is a local learning strategy, which is designed to exploit the areas with sparse solutions in the search space. Moreover, the idea of the archive, and the crowding distance are applied to PSO for finding the Pareto set. Finally, experiments verify that the proposed algorithm is a useful approach of feature selection for multi-label classification problem.
Drosophila dyskerin is required for somatic stem cell homeostasis
Authors: Vicidomini Rosario , Petrizzo Arianna , di Giovanni Annamaria , Cassese Laura , Lombardi Antonella Anna , Pragliola Caterina , Furia Maria
Published: March 2017

Drosophila represents an excellent model to dissect the roles played by the evolutionary conserved family of eukaryotic dyskerins. These multifunctional proteins are involved in the formation of H/ACA snoRNP and telomerase complexes, both involved in essential cellular tasks. Since fly telomere integrity is guaranteed by a different mechanism, we used this organism to investigate the specific role played by dyskerin in somatic stem cell maintenance. To this aim, we focussed on Drosophila midgut, a hierarchically organized and well characterized model for stemness analysis. Surprisingly, the ubiquitous loss of the protein uniquely affects the formation of the larval stem cell niches, without altering other midgut cell types. The number of adult midgut precursor stem cells is dramatically reduced, and this effect is not caused by premature differentiation and is cell-autonomous. Moreover, a few dispersed precursors found in the depleted midguts can maintain stem identity and the ability to divide asymmetrically, nor show cell-growth defects or undergo apoptosis. Instead, their loss is mainly specifically dependent on defective amplification. These studies establish a strict link between dyskerin and somatic stem cell maintenance in a telomerase-lacking organism, indicating that loss of stemness can be regarded as a conserved, telomerase-independent effect of dyskerin dysfunction.
Microsatellite analysis for differentiating the origin of renal angiomyolipoma and involved regional lymph node
Authors: Tan Ping , Xu Huan , Jiang Yong , Yang Lu , Zou Yan , Liu Liangren , Liu Nian , Cao Dehong , Fan Yu , Li Qiyuan , Wei Qiang
Published: March 2017

Renal angiomyolipoma (AML) with the regional lymph node (LN) involved leads to a question of metastasis versus multicentric origin when their histology are similar. As the genomic instability is a common feature of cancer, we hypothesized that independently arising neoplasms in an individual patient would exhibit measurable genomic variation, facilitating the discrimination of tumor lineage and relatedness. Our study enrolled 12 patients who were diagnosed with nodal-involved renal AML at West China Hospital. Genomic DNA from kidney and lymph node lesion from individuals was analyzed through PCR-based analysis which using six microsatellite markers to identify discordant allelic variation. The results showed all 12 patients underwent surgical treatment and none suffered local recurrence or distant metastasis during the follow-up. Ten patients of the included cases showed a consistent trend that all corresponding to six microsatellite markers were detected in DNA from renal AMLs but were reduced or not observed in DNA from the paired LN. With this technique, a possible lineage relationship cannot be excluded between renal AMLs and LN. Thus when enlarged LN were found in images, active surveillance should be taken into consider; if enlarged LN were found intraoperatively, LN resection might be necessary to demonstrate their pathological nature.
Dual regulation of water retention and cell growth by a stress-associated protein (SAP) gene in Prunus
Authors: Lloret Alba , Conejero Ana , Leida Carmen , Petri César , Gil-Muñoz Francisco , Burgos Lorenzo , Badenes María Luisa , Ríos Gabino
Published: March 2017

We have identified a gene (PpSAP1) of Prunus persica coding for a stress-associated protein (SAP) containing Zn-finger domains A20 and AN1. SAPs have been described as regulators of the abiotic stress response in plant species, emerging as potential candidates for improvement of stress tolerance in plants. PpSAP1 was highly expressed in leaves and dormant buds, being down-regulated before bud dormancy release. PpSAP1 expression was moderately induced by water stresses and heat in buds. In addition, it was found that PpSAP1 strongly interacts with polyubiquitin proteins in the yeast two-hybrid system. The overexpression of PpSAP1 in transgenic plum plants led to alterations in leaf shape and an increase of water retention under drought stress. Moreover, we established that leaf morphological alterations were concomitant with a reduced cell size and down-regulation of genes involved in cell growth, such as GROWTH-REGULATING FACTOR (GRF)1-like, TONOPLAST INTRINSIC PROTEIN (TIP)-like, and TARGET OF RAPAMYCIN (TOR)-like. Especially, the inverse expression pattern of PpSAP1 and TOR-like in transgenic plum and peach buds suggests a role of PpSAP1 in cell expansion through the regulation of TOR pathway.
Microbial community composition is related to soil biological and chemical properties and bacterial wilt outbreak
Authors: Wang Rui , Zhang Hongchun , Sun Liguang , Qi Gaofu , Chen Shu , Zhao Xiuyun
Published: March 2017

Soil microbes play important roles in plant growth and health. Little is known about the differences of soil microbes between healthy and bacterial wilt infected soils with Ralstonia solanacearum. By Illumina-MiSeq sequencing of 16S rRNA and 18S rRNA gene amplicons, we found the soil microbial composition and diversity were distinct between healthy and bacterial wilt infected soils. Soil microbial community varied at different plant growth stages due to changes of root exudates composition and soil pH. Healthy soils exhibited higher microbial diversity than the bacterial wilt infected soils. More abundant beneficial microbes including Bacillus, Agromyces, Micromonospora, Pseudonocardia, Acremonium, Lysobacter, Mesorhizobium, Microvirga, Bradyrhizobium, Acremonium and Chaetomium were found in the healthy soils rather than the bacterial wilt infected soils. Compared to bacterial wilt infected soils, the activities of catalase, invertase and urease, as well as soil pH, available phosphorous and potassium content, were all significantly increased in the healthy soils. In a conclusion, the higher abundance of beneficial microbes are positively related the higher soil quality, including better plant growth, lower disease incidence, and higher nutrient contents, soil enzyme activities and soil pH.
Integrative analysis of multi-omics data reveals distinct impacts of DDB1-CUL4 associated factors in human lung adenocarcinomas
Authors: Yan Hong , Bi Lei , Wang Yunshan , Zhang Xia , Hou Zhibo , Wang Qian , Snijders Antoine M. , Mao Jian-Hua
Published: March 2017

Many DDB1-CUL4 associated factors (DCAFs) have been identified and serve as substrate receptors. Although the oncogenic role of CUL4A has been well established, specific DCAFs involved in cancer development remain largely unknown. Here we infer the potential impact of 19 well-defined DCAFs in human lung adenocarcinomas (LuADCs) using integrative omics analyses, and discover that mRNA levels of DTL, DCAF4, 12 and 13 are consistently elevated whereas VBRBP is reduced in LuADCs compared to normal lung tissues. The transcriptional levels of DCAFs are significantly correlated with their gene copy number variations. SKIP2, DTL, DCAF6, 7, 8, 13 and 17 are frequently gained whereas VPRBP, PHIP, DCAF10, 12 and 15 are frequently lost. We find that only transcriptional level of DTL is robustly, significantly and negatively correlated with overall survival across independent datasets. Moreover, DTL-correlated genes are enriched in cell cycle and DNA repair pathways. We also identified that the levels of 25 proteins were significantly associated with DTL overexpression in LuADCs, which include significant decreases in protein level of the tumor supressor genes such as PDCD4, NKX2-1 and PRKAA1. Our results suggest that different CUL4-DCAF axis plays the distinct roles in LuADC development with possible relevance for therapeutic target development.
Sprint Interval Training Induces A Sexual Dimorphism but does not Improve Peak Bone Mass in Young and Healthy Mice
Authors: Koenen Kathrin , Knepper Isabell , Klodt Madlen , Osterberg Anja , Stratos Ioannis , Mittlmeier Thomas , Histing Tina , Menger Michael D. , Vollmar Brigitte , Bruhn Sven , Müller-Hilke Brigitte
Published: March 2017

Elevated peak bone mass in early adulthood reduces the risk for osteoporotic fractures at old age. As sports participation has been correlated with elevated peak bone masses, we aimed to establish a training program that would efficiently stimulate bone accrual in healthy young mice. We combined voluntary treadmill running with sprint interval training modalities that were tailored to the individual performance limits and were of either high or intermediate intensity. Adolescent male and female STR/ort mice underwent 8 weeks of training before the hind legs were analyzed for cortical and trabecular bone parameters and biomechanical strength. Sprint interval training led to increased running speeds, confirming an efficient training. However, males and females responded differently. The males improved their running speeds in response to intermediate intensities only and accrued cortical bone at the expense of mechanical strength. High training intensities induced a significant loss of trabecular bone. The female bones showed neither adverse nor beneficial effects in response to either training intensities. Speculations about the failure to improve geometric alongside mechanical bone properties include the possibility that our training lacked sufficient axial loading, that high cardio-vascular strains adversely affect bone growth and that there are physiological limits to bone accrual.
Automated Protein Biomarker Analysis: on-line extraction of clinical samples by Molecularly Imprinted Polymers
Authors: Rossetti Cecilia , Świtnicka-Plak Magdalena A. , Grønhaug Halvorsen Trine , Cormack Peter A.G. , Sellergren Börje , Reubsaet Léon
Published: March 2017

Robust biomarker quantification is essential for the accurate diagnosis of diseases and is of great value in cancer management. In this paper, an innovative diagnostic platform is presented which provides automated molecularly imprinted solid-phase extraction (MISPE) followed by liquid chromatography-mass spectrometry (LC-MS) for biomarker determination using ProGastrin Releasing Peptide (ProGRP), a highly sensitive biomarker for Small Cell Lung Cancer, as a model. Molecularly imprinted polymer microspheres were synthesized by precipitation polymerization and analytical optimization of the most promising material led to the development of an automated quantification method for ProGRP. The method enabled analysis of patient serum samples with elevated ProGRP levels. Particularly low sample volumes were permitted using the automated extraction within a method which was time-efficient, thereby demonstrating the potential of such a strategy in a clinical setting.
Increased chemical weathering during the deglacial to mid-Holocene summer monsoon intensification
Authors: Miriyala Pavan , Sukumaran N. P. , Nath B. Nagender , Ramamurty P. B. , Sijinkumar A. V. , Vijayagopal B. , Ramaswamy V. , Sebastian Tyson
Published: March 2017

Chemical weathering and the ensuing atmospheric carbon dioxide consumption has long been considered to work on geological time periods until recently when some modelling and natural records have shown that the weathering-related CO2 consumption can change at century to glacial-interglacial time scale. Last glacial to interglacial transition period is a best test case to understand the interplay between Pco2-temperature-chemical weathering when a pulse of rapid chemical weathering was initiated. Here we show, from a high resolution 54 ka record from the Andaman Sea in the northern Indian Ocean, that the chemical weathering responds to deglacial to mid-Holocene summer monsoon intensification in the Myanmar watersheds. The multi-proxy data (Al/K, CIA, Rb/Sr, 87Sr/86Sr for degree of weathering and 143Nd/144Nd for provenance) reveal an increase in silicate weathering with initiation of interglacial warm climate at ~17.7 ka followed by a major change at 15.5 ka. Inferred changes in chemical weathering have varied in tandem with the regional monsoonal proxies (δ18Osw-salinity changes of Northern Indian Ocean, effective Asian moisture content and δ18O records of Chinese caves) and are synchronous with changes in summer insolation at 30°N and δ18O of GISP2 implying that chemical weathering was not a later amplifier but worked in tandem with global climate change.
Collection and characterization of grapevine genetic resources (Vitis vinifera) in the Holy Land, towards the renewal of ancient winemaking practices
Authors: Drori Elyashiv , Rahimi Oshrit , Marrano Annarita , Henig Yakov , Brauner Hodaya , Salmon-Divon Mali , Netzer Yishay , Prazzoli Maria Lucia , Stanevsky Maria , Failla Osvaldo , Weiss Ehud , Grando Maria Stella
Published: March 2017

The importance and extent of wine consumption in all life aspects at the Holy Land is well documented. The Muslim influence in this region led to the abandonment of winemaking practices, and possible loss of indigenous wine varieties. Here we present a country wide collection of the local grapevine population including wild and cultivated forms, and its characterization by genetic, ampelographic and enological methods. The ampelographic analysis shows clear differences between Sativa and Sylvestris groups in flower, leaf and cluster parameters, and that most Sativa belong to proles orientalis. Genetic population analysis was conducted by analyzing 22 common SSR markers, determining first the unique genotypes, and internally assessing the population’s structure, showing the existence of two distinct Sativa and Sylvestris populations, and a third mixed one. Likewise, the relationship between the Israeli grapevine population and grapevine populations in Europe and parts of Asia was investigated, showing that the Israeli Sativa and Sylvestris populations cluster closely together, suggesting a common genetic source. Lastly, the enological characteristics of selected Sativa and Sylvestris genotypes are presented, demonstrating their potential for quality wine production. This research significantly contributes toward the re-establishment of indigenous and traditional local grapevine varieties into the modern international wine industry.
Structural Analysis of Human Cofilin 2/Filamentous Actin Assemblies: Atomic-Resolution Insights from Magic Angle Spinning NMR Spectroscopy
Authors: Yehl Jenna , Kudryashova Elena , Reisler Emil , Kudryashov Dmitri , Polenova Tatyana
Published: March 2017

Cellular actin dynamics is an essential element of numerous cellular processes, such as cell motility, cell division and endocytosis. Actin’s involvement in these processes is mediated by many actin-binding proteins, among which the cofilin family plays unique and essential role in accelerating actin treadmilling in filamentous actin (F-actin) in a nucleotide-state dependent manner. Cofilin preferentially interacts with older filaments by recognizing time-dependent changes in F-actin structure associated with the hydrolysis of ATP and release of inorganic phosphate (Pi) from the nucleotide cleft of actin. The structure of cofilin on F-actin and the details of the intermolecular interface remain poorly understood at atomic resolution. Here we report atomic-level characterization by magic angle spinning (MAS) NMR of the muscle isoform of human cofilin 2 (CFL2) bound to F-actin. We demonstrate that resonance assignments for the majority of atoms are readily accomplished and we derive the intermolecular interface between CFL2 and F-actin. The MAS NMR approach reported here establishes the foundation for atomic-resolution characterization of a broad range of actin-associated proteins bound to F-actin.
Identification of the metabolic alterations associated with the multidrug resistant phenotype in cancer and their intercellular transfer mediated by extracellular vesicles
Authors: Lopes-Rodrigues Vanessa , Di Luca Alessio , Mleczko Justyna , Meleady Paula , Henry Michael , Pesic Milica , Cabrera Diana , van Liempd Sebastiaan , Lima Raquel T. , O’Connor Robert , Falcon-Perez Juan M. , Vasconcelos M. Helena
Published: March 2017

Multidrug resistance (MDR) is a serious obstacle to efficient cancer treatment. Overexpression of P-glycoprotein (P-gp) plays a significant role in MDR. Recent studies proved that targeting cellular metabolism could sensitize MDR cells. In addition, metabolic alterations could affect the extracellular vesicles (EVs) cargo and release. This study aimed to: i) identify metabolic alterations in P-gp overexpressing cells that could be involved in the development of MDR and, ii) identify a potential role for the EVs in the acquisition of the MDR. Two different pairs of MDR and their drug-sensitive counterpart cancer cell lines were used. Our results showed that MDR (P-gp overexpressing) cells have a different metabolic profile from their drug-sensitive counterparts, demonstrating decreases in the pentose phosphate pathway and oxidative phosphorylation rate; increases in glutathione metabolism and glycolysis; and alterations in the methionine/S-adenosylmethionine pathway. Remarkably, EVs from MDR cells were capable of stimulating a metabolic switch in the drug-sensitive cancer cells, towards a MDR phenotype. In conclusion, obtained results contribute to the growing knowledge about metabolic alterations in MDR cells and the role of EVs in the intercellular transfer of MDR. The specific metabolic alterations identified in this study may be further developed as targets for overcoming MDR.