bluuebunny/crossref_metadata_2025 huggingface dataset:
A variant at 9p21.3 functionally implicates CDKN2B in paediatric B-cell precursor acute lymphoblastic leukaemia aetiology
Authors: Hungate Eric A. , Vora Sapana R. , Gamazon Eric R. , Moriyama Takaya , Best Timothy , Hulur Imge , Lee Younghee , Evans Tiffany-Jane , Ellinghaus Eva , Stanulla Martin , Rudant Jéremie , Orsi Laurent , Clavel Jacqueline , Milne Elizabeth , Scott Rodney J. , Pui Ching-Hon , Cox Nancy J. , Loh Mignon L. , Yang Jun J. , Skol Andrew D. , Onel Kenan
Published: February 2016

Paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) is the most common cancer of childhood, yet little is known about BCP-ALL predisposition. In this study, in 2,187 cases of European ancestry and 5,543 controls, we discover and replicate a locus indexed by rs77728904 at 9p21.3 associated with BCP-ALL susceptibility (Pcombined=3.32 × 10−15, OR=1.72) and independent from rs3731217, the previously reported ALL-associated variant in this region. Of correlated SNPs tagged by this locus, only rs662463 is significant in African Americans, suggesting it is a plausible causative variant. Functional analysis shows that rs662463 is a cis-eQTL for CDKN2B, with the risk allele associated with lower expression, and suggests that rs662463 influences BCP-ALL risk by regulating CDKN2B expression through CEBPB signalling. Functional analysis of rs3731217 suggests it is associated with BCP-ALL by acting within a splicing regulatory element determining CDKN2A exon 3 usage (P=0.01). These findings provide new insights into the critical role of the CDKN2 locus in BCP-ALL aetiology.
PTEN modulates EGFR late endocytic trafficking and degradation by dephosphorylating Rab7
Authors: Shinde Swapnil Rohidas , Maddika Subbareddy
Published: February 2016

Tumour suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a lipid phosphatase that negatively regulates growth factor-induced survival signalling. Here, we demonstrate that PTEN attenuates epidermal growth factor receptor (EGFR) signalling by promoting late endosome maturation by virtue of its protein phosphatase activity. Loss of PTEN impairs the transition of ligand-bound EGFR from early to late endosomes. We unveil Rab7, a critical GTPase for endosome maturation, as a functional PTEN interacting partner. PTEN dephosphorylates Rab7 on two conserved residues S72 and Y183, which are necessary for GDP dissociation inhibitor (GDI)-dependent recruitment of Rab7 on to late endosomes and subsequent maturation. Thus, our findings reveal PTEN-dependent endosome maturation through phosphoregulation of Rab7 as an important route of controlling EGFR signalling.
Land use imperils plant and animal community stability through changes in asynchrony rather than diversity
Authors: Blüthgen Nico , Simons Nadja K. , Jung Kirsten , Prati Daniel , Renner Swen C. , Boch Steffen , Fischer Markus , Hölzel Norbert , Klaus Valentin H. , Kleinebecker Till , Tschapka Marco , Weisser Wolfgang W. , Gossner Martin M.
Published: February 2016

Human land use may detrimentally affect biodiversity, yet long-term stability of species communities is vital for maintaining ecosystem functioning. Community stability can be achieved by higher species diversity (portfolio effect), higher asynchrony across species (insurance hypothesis) and higher abundance of populations. However, the relative importance of these stabilizing pathways and whether they interact with land use in real-world ecosystems is unknown. We monitored inter-annual fluctuations of 2,671 plant, arthropod, bird and bat species in 300 sites from three regions. Arthropods show 2.0-fold and birds 3.7-fold higher community fluctuations in grasslands than in forests, suggesting a negative impact of forest conversion. Land-use intensity in forests has a negative net impact on stability of bats and in grasslands on birds. Our findings demonstrate that asynchrony across species—much more than species diversity alone—is the main driver of variation in stability across sites and requires more attention in sustainable management.
Mucosal immunoglobulins at respiratory surfaces mark an ancient association that predates the emergence of tetrapods
Authors: Xu Zhen , Takizawa Fumio , Parra David , Gómez Daniela , von Gersdorff Jørgensen Louise , LaPatra Scott E. , Sunyer J. Oriol
Published: February 2016

Gas-exchange structures are critical for acquiring oxygen, but they also represent portals for pathogen entry. Local mucosal immunoglobulin responses against pathogens in specialized respiratory organs have only been described in tetrapods. Since fish gills are considered a mucosal surface, we hypothesized that a dedicated mucosal immunoglobulin response would be generated within its mucosa on microbial exposure. Supporting this hypothesis, here we demonstrate that following pathogen exposure, IgT+ B cells proliferate and generate pathogen-specific IgT within the gills of fish, thus providing the first example of locally induced immunoglobulin in the mucosa of a cold-blooded species. Moreover, we demonstrate that gill microbiota is predominantly coated with IgT, thus providing previously unappreciated evidence that the microbiota present at a respiratory surface of a vertebrate is recognized by a mucosal immunoglobulin. Our findings indicate that respiratory surfaces and mucosal immunoglobulins are part of an ancient association that predates the emergence of tetrapods.
Oral health promotion: the economic benefits to the NHS of increased use of sugarfree gum in the UK
Authors: Claxton L. , Taylor M. , Kay E.
Published: February 2016

Introduction The effect of sugarfree gum (SFG) on the prevention of dental caries has been established for some time. With increased constraints placed on healthcare budgets, the importance of economic considerations in decision-making about oral health interventions has increased. The aim of this study was to demonstrate the potential cost savings in dental care associated with increased levels of SFG usage.

Methods The analysis examined the amount of money which would hypothetically be saved if the UK 12-year-old population chewed more SFG. The number of sticks chewed per year and the caries risk reduction were modelled to create a dose response curve. The costs of tooth restoration, tooth extraction in primary care settings and under general anaesthetic were considered, and the effects of caries reduction on these costs calculated.

Results If all members of the UK 12-year-old population chewed SFG frequently (twice a day), the potential cost savings for the cohort over the course of one year were estimated to range from £1.2 to £3.3 million and if they chewed three times a day, £8.2 million could be saved each year. Sensitivity analyses of the key parameters demonstrated that cost savings would still be likely to be observed even in scenarios with less significant increases in SFG use.

Conclusion This study shows that if levels of SFG usage in the teenage population in the UK could be increased, substantial cost savings might be achieved.
Tightening slip knots in raw and degummed silk to increase toughness without losing strength
Authors: Pantano Maria F. , Berardo Alice , Pugno Nicola M.
Published: February 2016

Knots are fascinating topological elements, which can be found in both natural and artificial systems. While in most of the cases, knots cannot be loosened without breaking the strand where they are tightened, herein, attention is focused on slip or running knots, which on the contrary can be unfastened without compromising the structural integrity of their hosting material. Two different topologies are considered, involving opposite unfastening mechanisms and their influence on the mechanical properties of natural fibers, as silkworm silk raw and degummed single fibers, is investigated and quantified. Slip knots with optimized shape and size result in a significant enhancement of fibers energy dissipation capability, up to 300–400%, without affecting their load bearing capacity.
Dynamic mesolimbic dopamine signaling during action sequence learning and expectation violation
Authors: Collins Anne L. , Greenfield Venuz Y. , Bye Jeffrey K. , Linker Kay E. , Wang Alice S. , Wassum Kate M.
Published: February 2016

Prolonged mesolimbic dopamine concentration changes have been detected during spatial navigation, but little is known about the conditions that engender this signaling profile or how it develops with learning. To address this, we monitored dopamine concentration changes in the nucleus accumbens core of rats throughout acquisition and performance of an instrumental action sequence task. Prolonged dopamine concentration changes were detected that ramped up as rats executed each action sequence and declined after earned reward collection. With learning, dopamine concentration began to rise increasingly earlier in the execution of the sequence and ultimately backpropagated away from stereotyped sequence actions, becoming only transiently elevated by the most distal and unexpected reward predictor. Action sequence-related dopamine signaling was reactivated in well-trained rats if they became disengaged in the task and in response to an unexpected change in the value, but not identity of the earned reward. Throughout training and test, dopamine signaling correlated with sequence performance. These results suggest that action sequences can engender a prolonged mode of dopamine signaling in the nucleus accumbens core and that such signaling relates to elements of the motivation underlying sequence execution and is dynamic with learning, overtraining and violations in reward expectation.
Responses of soil nitrogen fixation to Spartina alterniflora invasion and nitrogen addition in a Chinese salt marsh
Authors: Huang Jingxin , Xu Xiao , Wang Min , Nie Ming , Qiu Shiyun , Wang Qing , Quan Zhexue , Xiao Ming , Li Bo
Published: February 2016

Biological nitrogen fixation (BNF) is the major natural process of nitrogen (N) input to ecosystems. To understand how plant invasion and N enrichment affect BNF, we compared soil N-fixation rates and N-fixing microbes (NFM) of an invasive Spartina alterniflora community and a native Phragmites australis community in the Yangtze River estuary, with and without N addition. Our results indicated that plant invasion relative to N enrichment had a greater influence on BNF. At each N level, the S. alterniflora community had a higher soil N-fixation rate but a lower diversity of the nifH gene in comparison with the native community. The S. alterniflora community with N addition had the highest soil N-fixation rate and the nifH gene abundance across all treatments. Our results suggest that S. alterniflora invasion can increase soil N fixation in the high N-loading estuarine ecosystem and thus may further mediate soil N availability.
Seasonality of water quality and diarrheal disease counts in urban and rural settings in south India
Authors: Kulinkina Alexandra V. , Mohan Venkat R. , Francis Mark R. , Kattula Deepthi , Sarkar Rajiv , Plummer Jeanine D. , Ward Honorine , Kang Gagandeep , Balraj Vinohar , Naumova Elena N.
Published: February 2016

The study examined relationships among meteorological parameters, water quality and diarrheal disease counts in two urban and three rural sites in Tamil Nadu, India. Disease surveillance was conducted between August 2010 and March 2012; concurrently water samples from street-level taps in piped distribution systems and from household storage containers were tested for pH, nitrate, total dissolved solids and total and fecal coliforms. Methodological advances in data collection (concurrent prospective disease surveillance and environmental monitoring) and analysis (preserving temporality within the data through time series analysis) were used to quantify independent effects of meteorological conditions and water quality on diarrheal risk. The utility of a local calendar in communicating seasonality is also presented. Piped distribution systems in the study area showed high seasonal fluctuations in water quality. Higher ambient temperature decreased and higher rainfall increased diarrheal risk with temperature being the predominant factor in urban and rainfall in rural sites. Associations with microbial contamination were inconsistent; however, disease risk in the urban sites increased with higher median household total coliform concentrations. Understanding seasonal patterns in health outcomes and their temporal links to environmental exposures may lead to improvements in prospective environmental and disease surveillance tailored to addressing public health problems.
WISP1 mediates IL-6-dependent proliferation in primary human lung fibroblasts
Authors: Klee S. , Lehmann M. , Wagner D. E. , Baarsma H. A. , Königshoff M.
Published: February 2016

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease. IPF is characterized by epithelial cell injury and reprogramming, increases in (myo)fibroblasts and altered deposition of extracellular matrix. The Wnt1-inducible signaling protein 1 (WISP1) is involved in impaired epithelial-mesenchymal crosstalk in pulmonary fibrosis. Here, we aimed to further investigate WISP1 regulation and function in primary human lung fibroblasts (phLFs). We demonstrate that WISP1 is directly upregulated by Transforming growth factor β1 (TGFβ1) and Tumor necrosis factor α (TNFα) in phLFs, using a luciferase-based reporter system. WISP1 mRNA and protein secretion increased in a time- and concentration-dependent manner by TGFβ1 and TNFα in phLFs, as analysed by qPCR and ELISA, respectively. Notably, WISP1 is required for TGFβ1- and TNFα-dependent induction of interleukin 6 (IL-6), a mechanism that is conserved in IPF phLFs. The siRNA-mediated WISP1 knockdown led to a significant IL-6 reduction after TGFβ1 or TNFα stimulation. Furthermore, siRNA-mediated downregulation or antibody-mediated neutralization of WISP1 reduced phLFs proliferation, a process that was in part rescued by IL-6. Taken together, these results strongly indicate that WISP1-induced IL-6 expression contributes to the pro-proliferative effect on fibroblasts, which is likely orchestrated by a variety of profibrotic mediators, including Wnts, TGFβ1 and TNFα.
Predicting malaria vector distribution under climate change scenarios in China: Challenges for malaria elimination
Authors: Ren Zhoupeng , Wang Duoquan , Ma Aimin , Hwang Jimee , Bennett Adam , Sturrock Hugh J. W. , Fan Junfu , Zhang Wenjie , Yang Dian , Feng Xinyu , Xia Zhigui , Zhou Xiao-Nong , Wang Jinfeng
Published: February 2016

Projecting the distribution of malaria vectors under climate change is essential for planning integrated vector control activities for sustaining elimination and preventing reintroduction of malaria. In China, however, little knowledge exists on the possible effects of climate change on malaria vectors. Here we assess the potential impact of climate change on four dominant malaria vectors (An. dirus, An. minimus, An. lesteri and An. sinensis) using species distribution models for two future decades: the 2030 s and the 2050 s. Simulation-based estimates suggest that the environmentally suitable area (ESA) for An. dirus and An. minimus would increase by an average of 49% and 16%, respectively, under all three scenarios for the 2030 s, but decrease by 11% and 16%, respectively in the 2050 s. By contrast, an increase of 36% and 11%, respectively, in ESA of An. lesteri and An. sinensis, was estimated under medium stabilizing (RCP4.5) and very heavy (RCP8.5) emission scenarios. in the 2050 s. In total, we predict a substantial net increase in the population exposed to the four dominant malaria vectors in the decades of the 2030 s and 2050 s, considering land use changes and urbanization simultaneously. Strategies to achieve and sustain malaria elimination in China will need to account for these potential changes in vector distributions and receptivity.
Three-dimensional full-field X-ray orientation microscopy
Authors: Viganò Nicola , Tanguy Alexandre , Hallais Simon , Dimanov Alexandre , Bornert Michel , Batenburg Kees Joost , Ludwig Wolfgang
Published: February 2016

A previously introduced mathematical framework for full-field X-ray orientation microscopy is for the first time applied to experimental near-field diffraction data acquired from a polycrystalline sample. Grain by grain tomographic reconstructions using convex optimization and prior knowledge are carried out in a six-dimensional representation of position-orientation space, used for modelling the inverse problem of X-ray orientation imaging. From the 6D reconstruction output we derive 3D orientation maps, which are then assembled into a common sample volume. The obtained 3D orientation map is compared to an EBSD surface map and local misorientations, as well as remaining discrepancies in grain boundary positions are quantified. The new approach replaces the single orientation reconstruction scheme behind X-ray diffraction contrast tomography and extends the applicability of this diffraction imaging technique to material micro-structures exhibiting sub-grains and/or intra-granular orientation spreads of up to a few degrees. As demonstrated on textured sub-regions of the sample, the new framework can be extended to operate on experimental raw data, thereby bypassing the concept of orientation indexation based on diffraction spot peak positions. This new method enables fast, three-dimensional characterization with isotropic spatial resolution, suitable for time-lapse observations of grain microstructures evolving as a function of applied strain or temperature.
Regulation of functional KCNQ1OT1 lncRNA by β-catenin
Authors: Sunamura Naohiro , Ohira Takahito , Kataoka Miki , Inaoka Daigo , Tanabe Hideyuki , Nakayama Yuji , Oshimura Mitsuo , Kugoh Hiroyuki
Published: February 2016

Long noncoding RNAs (lncRNAs) have been implicated in many biological processes through epigenetic mechanisms. We previously reported that KCNQ1OT1, an imprinted antisense lncRNA in the human KCNQ1 locus on chromosome 11p15.5, is involved in cis-limited silencing within an imprinted KCNQ1 cluster. Furthermore, aberration of KCNQ1OT1 transcription was observed with a high frequency in colorectal cancers. However, the molecular mechanism of the transcriptional regulation and the functional role of KCNQ1OT1 in colorectal cancer remain unclear. Here, we show that the KCNQ1OT1 transcriptional level was significantly increased in human colorectal cancer cells in which β-catenin was excessively accumulated in the nucleus. Additionally, overexpression of β-catenin resulted in an increase in KCNQ1OT1 lncRNA-coated territory. On the other hand, knockdown of β-catenin resulted in significant decrease of KCNQ1OT1 lncRNA-coated territory and an increase in the mRNA expression of the SLC22A18 and PHLDA2 genes that are regulated by KCNQ1OT1. We showed that β-catenin can promote KCNQ1OT1 transcription through direct binding to the KCNQ1OT1 promoter. Our evidence indicates that β-catenin signaling may contribute to development of colorectal cancer by functioning as a novel lncRNA regulatory factor via direct targeting of KCNQ1OT1.
Changes in membrane sphingolipid composition modulate dynamics and adhesion of integrin nanoclusters
Authors: Eich Christina , Manzo Carlo , Keijzer Sandra de , Bakker Gert-Jan , Reinieren-Beeren Inge , García-Parajo Maria F. , Cambi Alessandra
Published: February 2016

Sphingolipids are essential constituents of the plasma membrane (PM) and play an important role in signal transduction by modulating clustering and dynamics of membrane receptors. Changes in lipid composition are therefore likely to influence receptor organisation and function, but how this precisely occurs is difficult to address given the intricacy of the PM lipid-network. Here, we combined biochemical assays and single molecule dynamic approaches to demonstrate that the local lipid environment regulates adhesion of integrin receptors by impacting on their lateral mobility. Induction of sphingomyelinase (SMase) activity reduced sphingomyelin (SM) levels by conversion to ceramide (Cer), resulting in impaired integrin adhesion and reduced integrin mobility. Dual-colour imaging of cortical actin in combination with single molecule tracking of integrins showed that this reduced mobility results from increased coupling to the actin cytoskeleton brought about by Cer formation. As such, our data emphasizes a critical role for the PM local lipid composition in regulating the lateral mobility of integrins and their ability to dynamically increase receptor density for efficient ligand binding in the process of cell adhesion.
Elevated CO2 as a driver of global dryland greening
Authors: Lu Xuefei , Wang Lixin , McCabe Matthew F.
Published: February 2016

While recent findings based on satellite records indicate a positive trend in vegetation greenness over global drylands, the reasons remain elusive. We hypothesize that enhanced levels of atmospheric CO2 play an important role in the observed greening through the CO2 effect on plant water savings and consequent available soil water increases. Meta-analytic techniques were used to compare soil water content under ambient and elevated CO2 treatments across a range of climate regimes, vegetation types, soil textures and land management practices. Based on 1705 field measurements from 21 distinct sites, a consistent and statistically significant increase in the availability of soil water (11%) was observed under elevated CO2 treatments in both drylands and non-drylands, with a statistically stronger response over drylands (17% vs. 9%). Given the inherent water limitation in drylands, it is suggested that the additional soil water availability is a likely driver of observed increases in vegetation greenness.
Decisions in Motion: Decision Dynamics during Intertemporal Choice reflect Subjective Evaluation of Delayed Rewards
Authors: O’Hora Denis , Carey Rachel , Kervick Aoife , Crowley David , Dabrowski Maciej
Published: February 2016

People tend to discount rewards or losses that occur in the future. Such delay discounting has been linked to many behavioral and health problems, since people choose smaller short-term gains over greater long-term gains. We investigated whether the effect of delays on the subjective value of rewards is expressed in how people move when they make choices. Over 600 patrons of the RISK LAB exhibition hosted by the Science Gallery DublinTMplayed a short computer game in which they used a computer mouse to choose between amounts of money at various delays. Typical discounting effects were observed and decision dynamics indicated that choosing smaller short-term rewards became easier (i.e., shorter response times, tighter trajectories, less vacillation) as the delays until later rewards increased. Based on a sequence of choices, subjective values of delayed outcomes were estimated and decision dynamics during initial choices predicted these values. Decision dynamics are affected by subjective values of available options and thus provide a means to estimate such values.
Long-Lasting Sound-Evoked Afterdischarge in the Auditory Midbrain
Authors: Ono Munenori , Bishop Deborah C. , Oliver Douglas L.
Published: February 2016

Different forms of plasticity are known to play a critical role in the processing of information about sound. Here, we report a novel neural plastic response in the inferior colliculus, an auditory center in the midbrain of the auditory pathway. A vigorous, long-lasting sound-evoked afterdischarge (LSA) is seen in a subpopulation of both glutamatergic and GABAergic neurons in the central nucleus of the inferior colliculus of normal hearing mice. These neurons were identified with single unit recordings and optogeneticsin vivo. The LSA can continue for up to several minutes after the offset of the sound. LSA is induced by long-lasting, or repetitive short-duration, innocuous sounds. Neurons with LSA showed less adaptation than the neurons without LSA. The mechanisms that cause this neural behavior are unknown but may be a function of intrinsic mechanisms or the microcircuitry of the inferior colliculus. Since LSA produces long-lasting firing in the absence of sound, it may be relevant to temporary or chronic tinnitus or to some other aftereffect of long-duration sound.
Activation and inhibition of tph2 serotonergic neurons operate in tandem to influence larval zebrafish preference for light over darkness
Authors: Cheng Ruey-Kuang , Krishnan Seetha , Jesuthasan Suresh
Published: February 2016

Serotonergic neurons have been implicated in a broad range of processes, but the principles underlying their effects remain a puzzle. Here, we ask how these neurons influence the tendency of larval zebrafish to swim in the light and avoid regions of darkness. Pharmacological inhibition of serotonin synthesis reduces dark avoidance, indicating an involvement of this neuromodulator. Calcium imaging of tph2-expressing cells demonstrates that a rostral subset of dorsal raphe serotonergic neurons fire continuously while the animal is in darkness, but are inhibited in the light. Optogenetic manipulation of tph2 neurons by channelrhodopsin or halorhodopsin expression modifies preference, confirming a role for these neurons. In particular, these results suggest that fish prefer swimming in conditions that elicits lower activity in tph2 serotonergic neurons in the rostral raphe.
GMOL: An Interactive Tool for 3D Genome Structure Visualization
Authors: Nowotny Jackson , Wells Avery , Oluwadare Oluwatosin , Xu Lingfei , Cao Renzhi , Trieu Tuan , He Chenfeng , Cheng Jianlin
Published: February 2016

It has been shown that genome spatial structures largely affect both genome activity and DNA function. Knowing this, many researchers are currently attempting to accurately model genome structures. Despite these increased efforts there still exists a shortage of tools dedicated to visualizing the genome. Creating a tool that can accurately visualize the genome can aid researchers by highlighting structural relationships that may not be obvious when examining the sequence information alone. Here we present a desktop application, known as GMOL, designed to effectively visualize genome structures so that researchers may better analyze genomic data. GMOL was developed based upon our multi-scale approach that allows a user to scale between six separate levels within the genome. With GMOL, a user can choose any unit at any scale and scale it up or down to visualize its structure and retrieve corresponding genome sequences. Users can also interactively manipulate and measure the whole genome structure and extract static images and machine-readable data files in PDB format from the multi-scale structure. By using GMOL researchers will be able to better understand and analyze genome structure models and the impact their structural relations have on genome activity and DNA function.
Heme Oxygenase-1 and 2 Common Genetic Variants and Risk for Multiple Sclerosis
Authors: Agúndez José A. G. , García-Martín Elena , Martínez Carmen , Benito-León Julián , Millán-Pascual Jorge , Díaz-Sánchez María , Calleja Patricia , Pisa Diana , Turpín-Fenoll Laura , Alonso-Navarro Hortensia , Pastor Pau , Ortega-Cubero Sara , Ayuso-Peralta Lucía , Torrecillas Dolores , García-Albea Esteban , Plaza-Nieto José Francisco , Jiménez-Jiménez Félix Javier
Published: February 2016

Several neurochemical, neuropathological and experimental data suggest a possible role of oxidative stress in the ethiopathogenesis of multiple sclerosis(MS). Heme-oxygenases(HMOX) are an important defensive mechanism against oxidative stress and HMOX1 is overexpressed in the brain and spinal cord of MS patients and in experimental autoimmune encephalomyelitis(EAE). We analyzed whether common polymorphisms affecting theHMOX1andHMOX2genes are related with the risk to develop MS. We analyzed the distribution of genotypes and allelic frequencies of theHMOX1rs2071746,HMOX1rs2071747,HMOX2rs2270363 andHMOX2rs1051308 SNPs, as well as the presence of Copy number variations(CNVs) of these genes in 292 subjects MS and 533 healthy controls, using TaqMan assays. The frequencies ofHMOX2 rs1051308AA genotype andHMOX2 rs1051308AandHMOX1 rs2071746Aalleles were higher in MS patients than in controls, although only that of the SNPHMOX2rs1051308 in men remained as significant after correction for multiple comparisons. None of the studied polymorphisms was related to the age at disease onset or with the MS phenotype. The present study suggests a weak association betweenHMOX2rs1051308 polymorphism and the risk to develop MS in Spanish Caucasian men and a trend towards association between theHMOX1 rs2071746Aand MS risk.
An Investigation of the Behavior of Solvent based Polycaprolactone ink for Material Jetting
Authors: He Yinfeng , Wildman Ricky D. , Tuck Chris J. , Christie Steven D. R. , Edmondson Steven
Published: February 2016

An initial study of processing bioresorbable polycaprolactone (PCL) through material jetting was conducted using a Fujifilm Dimatix DMP-2830 material printer. The aim of this work was to investigate a potential solvent based method of jetting polycaprolactone. Several solvents were used to prepare a PCL solvent based ink and 1, 4-dioxane was chosen with the consideration of both solubility and safety. The morphology of PCL formed under different substrate temperatures, droplet spacings were investigated. Multi-layer PCL structures were printed and characterized. This work shows that biodegradable polycaprolactone can be processed through material jetting.
Prostaglandin I2 Attenuates Prostaglandin E2-Stimulated Expression of Interferon γ in a β-Amyloid Protein- and NF-κB-Dependent Mechanism
Authors: Wang Pu , Guan Pei-Pei , Yu Xin , Zhang Li-Chao , Su Ya-Nan , Wang Zhan-You
Published: February 2016

Cyclooxygenase-2 (COX-2) has been recently identified as being involved in the pathogenesis of Alzheimer’s disease (AD). However, the role of an important COX-2 metabolic product, prostaglandin (PG) I2, in AD development remains unknown. Using mouse-derived astrocytes as well as APP/PS1 transgenic mice as model systems, we firstly elucidated the mechanisms of interferon γ (IFNγ) regulation by PGE2 and PGI2. Specifically, PGE2 accumulation in astrocytes activated the ERK1/2 and NF-κB signaling pathways by phosphorylation, which resulted in IFNγ expression. In contrast, the administration of PGI2 attenuated the effects of PGE2 on stimulating the production of IFNγ via inhibiting the translocation of NF-κB from the cytosol to the nucleus. Due to these observations, we further studied these prostaglandins and found that both PGE2 and PGI2 increased Aβ1–42 levels. In detail, PGE2 induced IFNγ expression in an Aβ1–42-dependent manner, whereas PGI2-induced Aβ1–42 production did not alleviate cells from IFNγ inhibition by PGI2 treatment. More importantly, our data also revealed that not only Aβ1–42 oligomer but also fibrillar have the ability to induce the expression of IFNγ via stimulation of NF-κB nuclear translocation in astrocytes of APP/PS1 mice. The production of IFNγ finally accelerated the deposition of Aβ1–42 in β-amyloid plaques.
Overexpression of RNF2 Is an Independent Predictor of Outcome in Patients with Urothelial Carcinoma of the Bladder Undergoing Radical Cystectomy
Authors: Li Xiang-Dong , Chen Si-Liang , Dong Pei , Chen Jie-Wei , Wang Feng-Wei , Guo Sheng-Jie , Jiang Li-Juan , Zhou Fang-Jian , Xie Dan , Liu Zhuo-Wei
Published: February 2016

RNF2 (ring finger protein 2) is frequently overexpressed in several types of human cancer, but the status of RNF2 amplification and expression in urothelial carcinoma of the bladder (UCB) and its clinical/prognostic significance is unclear. In this study, immunohistochemical analysis and fluorescence in situ hybridization (FISH) were used to examine the expression and amplification of RNF2 in 184 UCB patients after radical cystectomy. Overexpression of RNF2 was observed in 44.0% of UCBs and was found to significantly associate with shortened overall and cancer-specific survival (P < 0.001). In different subsets of UCBs, RNF2 overexpression was also identified as a prognostic indicator in patients with pT1, pT2, pN(−), and/or negative surgical margins (P < 0.05). Importantly, RNF2 overexpression together with pT status and surgical margin status provided significant independent prognostic parameters in multivariate analysis (P < 0.01). FISH results showed amplification of RNF2 in 8/79 (10.1%) of informative UCB cases. Additionally, RNF2 overexpression was significantly associated with RNF2 gene amplification (P = 0.004) and cell proliferation (P = 0.003). These findings suggested that overexpression of RNF2, as examined by immunohistochemical analysis, might serve as a novel prognostic biomarker and potential therapeutic target for UCB patients who undergo radical cystectomy.
cJun N-terminal kinase (JNK) phosphorylation of serine 36 is critical for p66Shc activation
Authors: Khalid Sana , Drasche Astrid , Thurner Marco , Hermann Martin , Ashraf Muhammad Imtiaz , Fresser Friedrich , Baier Gottfried , Kremser Leopold , Lindner Herbert , Troppmair Jakob
Published: February 2016

p66Shc-dependent ROS production contributes to many pathologies including ischemia/reperfusion injury (IRI) during solid organ transplantation. Inhibiting p66Shc activation may provide a novel therapeutic approach to prevent damage, which is poorly managed by antioxidants in vivo. Previous work suggested that pro-oxidant and a pro-apoptotic function of p66Shc required mitochondrial import, which depended on serine 36 phosphorylation. PKCß has been proposed as S36 kinase but cJun N-terminal kinases (JNKs) may also phosphorylate this residue. To simulate the early stages of ischemia/reperfusion (IR) we either used H2O2 treatment or hypoxia/reoxygenation (HR). As during reperfusion in vivo, we observed increased JNK and p38 activity in mouse embryonic fibroblasts (MEFs) and HL-1 cardiomyocytes along with significantly increased p66ShcS36 phosphorylation, ROS production and cell damage. Application of specific inhibitors caused a pronounced decrease in p66ShcS36 phosphorylation only in the case of JNK1/2. Moreover, S36 phosphorylation of recombinant p66Shc by JNK1 but not PKCß was demonstrated. We further confirmed JNK1/2-dependent regulation of p66ShcS36 phosphorylation, ROS production and cell death using JNK1/2 deficient MEFs. Finally, the low ROS phenotype of JNK1/2 knockout MEFs was reversed by the phosphomimetic p66ShcS36E mutant. Inhibiting JNK1/2-regulated p66Shc activation may thus provide a therapeutic approach for the prevention of oxidative damage.
13C Pathway Analysis for the Role of Formate in Electricity Generation by Shewanella Oneidensis MR-1 Using Lactate in Microbial Fuel Cells
Authors: Luo Shuai , Guo Weihua , H. Nealson Kenneth , Feng Xueyang , He Zhen
Published: February 2016

Microbial fuel cell (MFC) is a promising technology for direct electricity generation from organics by microorganisms. The type of electron donors fed into MFCs affects the electrical performance and mechanistic understanding of such effects is important to optimize the MFC performance. In this study, we used a model organism in MFCs, Shewanella oneidensis MR-1 and 13C pathway analysis to investigate the role of formate in electricity generation and the related microbial metabolism. Our results indicated a synergistic effect of formate and lactate on electricity generation and extra formate addition on the original lactate resulted in more electrical output than using formate or lactate as a sole electron donor. Based on the 13C tracer analysis, we discovered decoupled cell growth and electricity generation in S. oneidensis MR-1 during co-utilization of lactate and formate (i.e., while the lactate was mainly metabolized to support the cell growth, the formate was oxidized to release electrons for higher electricity generation). To our best knowledge, this is the first time that 13C tracer analysis was applied to study microbial metabolism in MFCs and it was demonstrated to be a valuable tool to understand the metabolic pathways affected by electron donors in the selected electrochemically-active microorganisms.
Genetic diversity at the Dhn3 locus in Turkish Hordeum spontaneum populations with comparative structural analyses
Authors: Uçarlı Cüneyt , McGuffin Liam J. , Çaputlu Süleyman , Aravena Andres , Gürel Filiz
Published: February 2016

We analysed Hordeum spontaneum accessions from 21 different locations to understand the genetic diversity of HsDhn3 alleles and effects of single base mutations on the intrinsically disordered structure of the resulting polypeptide (HsDHN3). HsDHN3 was found to be YSK2-type with a low-frequency 6-aa deletion in the beginning of Exon 1. There is relatively high diversity in the intron region of HsDhn3 compared to the two exon regions. We have found subtle differences in K segments led to changes in amino acids chemical properties. Predictions for protein interaction profiles suggest the presence of a protein-binding site in HsDHN3 that coincides with the K1 segment. Comparison of DHN3 to closely related cereals showed that all of them contain a nuclear localization signal sequence flanking to the K1 segment and a novel conserved region located between the S and K1 segments [E(D/T)DGMGGR]. We found that H. vulgare, H. spontaneum, and Triticum urartu DHN3s have a greater number of phosphorylation sites for protein kinase C than other cereal species, which may be related to stress adaptation. Our results show that the nature and extent of mutations in the conserved segments of K1 and K2 are likely to be key factors in protection of cells.
Pilocarpine-induced seizures trigger differential regulation of microRNA-stability related genes in rat hippocampal neurons
Authors: Kinjo Erika R. , Higa Guilherme S. V. , Santos Bianca A. , de Sousa Erica , Damico Marcio V. , Walter Lais T. , Morya Edgard , Valle Angela C. , Britto Luiz R. G. , Kihara Alexandre H.
Published: February 2016

Epileptogenesis in the temporal lobe elicits regulation of gene expression and protein translation, leading to reorganization of neuronal networks. In this process, miRNAs were described as being regulated in a cell-specific manner, although mechanistics of miRNAs activity are poorly understood. The specificity of miRNAs on their target genes depends on their intracellular concentration, reflecting the balance of biosynthesis and degradation. Herein, we confirmed that pilocarpine application promptly (<30 min) induces status epilepticus (SE) as revealed by changes in rat electrocorticogram particularly in fast-beta range (21–30 Hz). SE simultaneously upregulated XRN2 and downregulated PAPD4 gene expression in the hippocampus, two genes related to miRNA degradation and stability, respectively. Moreover, SE decreased the number of XRN2-positive cells in the hilus, while reduced the number of PAPD4-positive cells in CA1. XRN2 and PAPD4 levels did not change in calretinin- and CamKII-positive cells, although it was possible to determine that PAPD4, but not XRN2, was upregulated in parvalbumin-positive cells, revealing that SE induction unbalances the accumulation of these functional-opposed proteins in inhibitory interneurons that directly innervate distinct domains of pyramidal cells. Therefore, we were able to disclose a possible mechanism underlying the differential regulation of miRNAs in specific neurons during epileptogenesis.
Activation and Connectivity within the Default Mode Network Contribute Independently to Future-Oriented Thought
Authors: Xu Xiaoxiao , Yuan Hong , Lei Xu
Published: February 2016

Future-oriented thought, a projection of the self into the future to pre-experience an event, has been linked to default mode network (DMN). Previous studies showed that the DMN was generally divided into two subsystems: anterior part (aDMN) and posterior part (pDMN). The former is mostly related to self-referential mental thought and latter engages in episodic memory retrieval and scene construction. However, functional contribution of these two subsystems and functional connectivity between them during future-oriented thought has rarely been reported. Here, we investigated these issues by using an experimental paradigm that allowed prospective, episodic decisions concerning one’s future (Future Self) to be compared with self-referential decisions about one’s immediate present state (Present Self). Additionally, two parallel control conditions that relied on non-personal semantic knowledge (Future Non-Self Control and Present Non-Self Control) were conducted. Our results revealed that the aDMN was preferentially activated when participants reflected on their present states, whereas the pDMN exhibited preferentially activation when participants reflected on their personal future. Intriguingly, significantly decreased aDMN-pDMN connectivity was observed when thinking about their future relative to other conditions. These results support the notion that activation within these subsystems and connectivity between them contribute differently to future-oriented thought.
β-elemene sensitizes hepatocellular carcinoma cells to oxaliplatin by preventing oxaliplatin-induced degradation of copper transporter 1
Authors: Li Xiaoqiang , Lin Zhenhai , Zhang Bo , Guo Lei , Liu Shuang , Li Hui , Zhang Jubo , Ye Qinghai
Published: February 2016

β-elemene, a Curcuma wenyujin plant extract, has been used widely as a tumor adjuvant therapeutic agent. However, how to obtain optimum therapeutic effects by combining this compound with other agents remain unclear. In this study, we found that β-elemene, which alone had little effect on hepatocellular carcinoma (HCC) cell proliferation, exerted a synergistic anti-proliferative effect in HCC cells when dosed in combination with oxaliplatin, which increased the amounts of platinum accumulation and platinum-DNA adduct significantly and augmented the oxaliplatin-induced apoptosis. Western blot and laser scanning confocal microscopy studies indicated that β-elemene enhanced the sensitivity of HCC cells to oxaliplatin by upregulating copper transporter 1 (CTR1), a major controller of intracellular platinum accumulation. In an orthotopic transplantation HCC model in nude mice, HCC tumor growth was inhibited significantly by oxaliplatin combined with β-elemene, as compared with oxaliplatin alone. Notably, CTR1 protein expression in xenograft HCC was upregulated in mice who received β-elemene treatment. Taken together, our findings show that β-elemene can block the reduction of CTR1 resulting from oxaliplatin treatment, and therefore has a synergistic anti-HCC effect with oxaliplatin by enhancing cellular uptake of oxaliplatin. The synergistic effects of β-elemene and oxaliplatin deserve further evaluation in clinical settings.
Peptide mini-scaffold facilitates JNK3 activation in cells
Authors: Zhan Xuanzhi , Stoy Henriette , Kaoud Tamer S. , Perry Nicole A. , Chen Qiuyan , Perez Alejandro , Els-Heindl Sylvia , Slagis Jack V. , Iverson Tina M. , Beck-Sickinger Annette G. , Gurevich Eugenia V. , Dalby Kevin N. , Gurevich Vsevolod V.
Published: February 2016

Three-kinase mitogen-activated protein kinase (MAPK) signaling cascades are present in virtually all eukaryotic cells. MAPK cascades are organized by scaffold proteins, which assemble cognate kinases into productive signaling complexes. Arrestin-3 facilitates JNK activation in cells, and a short 25-residue arrestin-3 peptide was identified as the critical JNK3-binding element. Here we demonstrate that this peptide also binds MKK4, MKK7, and ASK1, which are upstream JNK3-activating kinases. This peptide is sufficient to enhance JNK3 activity in cells. A homologous arrestin-2 peptide, which differs only in four positions, binds MKK4, but not MKK7 or JNK3, and is ineffective in cells at enhancing activation of JNK3. The arrestin-3 peptide is the smallest MAPK scaffold known. This peptide or its mimics can regulate MAPKs, affecting cellular decisions to live or die.
Prediction Methods in Solar Sunspots Cycles
Authors: Ng Kim Kwee
Published: February 2016

An understanding of the Ohl’s Precursor Method, which is used to predict the upcoming sunspots activity, is presented by employing a simplified movable divided-blocks diagram. Using a new approach, the total number of sunspots in a solar cycle and the maximum averaged monthly sunspots number Rz(max) are both shown to be statistically related to the geomagnetic activity index in the prior solar cycle. The correlation factors are significant and they are respectively found to be 0.91 ± 0.13 and 0.85 ± 0.17. The projected result is consistent with the current observation of solar cycle 24 which appears to have attained at least Rz(max) at 78.7 ± 11.7 in March 2014. Moreover, in a statistical study of the time-delayed solar events, the average time between the peak in the monthly geomagnetic index and the peak in the monthly sunspots numbers in the succeeding ascending phase of the sunspot activity is found to be 57.6 ± 3.1 months. The statistically determined time-delayed interval confirms earlier observational results by others that the Sun’s electromagnetic dipole is moving toward the Sun’s Equator during a solar cycle.
Empirical evidence for large X-effects in animals with undifferentiated sex chromosomes
Authors: Dufresnes Christophe , Majtyka Tomasz , Baird Stuart J. E. , Gerchen Jörn F. , Borzée Amaël , Savary Romain , Ogielska Maria , Perrin Nicolas , Stöck Matthias
Published: February 2016

Reproductive isolation is crucial for the process of speciation to progress. Sex chromosomes have been assigned a key role in driving reproductive isolation but empirical evidence from natural population processes has been restricted to organisms with degenerated sex chromosomes such as mammals and birds. Here we report restricted introgression at sex-linked compared to autosomal markers in a hybrid zone between two incipient species of European tree frog,Hyla arboreaandH. orientalis, whose homologous X and Y sex chromosomes are undifferentiated. This large X-effect cannot result from the dominance or faster-X aspects of Haldane’s rule, which are specific to degenerated sex chromosomes, but rather supports a role for faster-heterogametic-sex or faster-male evolutionary processes. Our data suggest a prominent contribution of undifferentiated sex chromosomes to speciation.
Dislocation-enhanced experimental-scale vacancy loop formation in hcp Zirconium in one single collision cascade
Authors: Zhou Wei , Tian Jiting , Zheng Jian , Xue Jianming , Peng Shuming
Published: February 2016

Large defects are the main factor leading to the degradation of material properties under irradiation environments. It is commonly assumed that the large defects are mainly formed through cluster growth under continuous irradiations. Besides this mechanism, recent experiments and simulations show that sometimes an individual ion can also directly create a large defect. Here we report a novel mechanism for the formation of the large defects, as discovered by our Molecular Dynamics (MD) simulations of the collision cascades in hcp Zirconium (Zr): a pre-existing edge dislocation (ED) can significantly promote the nucleation of the vacancy clusters and even facilitate the direct formation of an experimental-scale large vacancy loop (about 3 nm) in only one single displacement cascade. This dislocation-related mechanism may be the key for understanding the experimental results in the low-dose irradiated Zr where the high-density large dislocation loops are observed but difficult to be explained by the two mechanisms mentioned above. Considering that intrinsic dislocations exist in nearly all crystalline materials, our results provide a significant concept: pre-existing dislocations have a strong influence on the primary damage production and taking them into account is indispensable for assessing and improving the material’s irradiation-resistance.