bluuebunny/crossref_metadata_2025 huggingface dataset:
Combined universal and selective prevention for adolescent alcohol use: a cluster randomized controlled trial
Authors: Teesson M. , Newton N. C. , Slade T. , Carragher N. , Barrett E. L. , Champion K. E. , Kelly E. V. , Nair N. K. , Stapinski L. A. , Conrod P. J.
Published: February 2017

Background

No existing models of alcohol prevention concurrently adopt universal and selective approaches. This study aims to evaluate the first combined universal and selective approach to alcohol prevention.

Method

A total of 26 Australian schools with 2190 students (mean age: 13.3 years) were randomized to receive: universal prevention (Climate Schools); selective prevention (Preventure); combined prevention (Climate SchoolsandPreventure;CAP); or health education as usual (control). Primary outcomes were alcohol use, binge drinking and alcohol-related harms at 6, 12 and 24 months.

Results

Climate,PreventureandCAPstudents demonstrated significantly lower growth in their likelihood to drink and binge drink, relative to controls over 24 months.Preventurestudents displayed significantly lower growth in their likelihood to experience alcohol harms, relative to controls. While adolescents in both theCAPandClimategroups demonstrated slower growth in drinking compared with adolescents in the control group over the 2-year study period,CAPadolescents demonstrated faster growth in drinking compared withClimateadolescents.

Conclusions

Findings support universal, selective and combined approaches to alcohol prevention. Particularly novel are the findings of no advantage of the combined approach over universal or selective prevention alone.
Comparing planning problem compilation approaches for quantum annealing
Authors: O’Gorman Bryan , Rieffel Eleanor Gilbert , Do Minh , Venturelli Davide , Frank Jeremy
Published: February 2017

One approach to solving planning problems is to compile them to other problems for which powerful off-the-shelf solvers are available; common targets include SAT, CSP, and MILP. Recently, a novel optimization technique has become available: quantum annealing (QA). QA takes as input problem instances of quadratic unconstrained binary optimization (QUBO) problem. Early quantum annealers are now available, though their constraints restrict the types of QUBOs they can take as input. Here, we introduce the planning community to the key steps in compiling planning problems to QA hardware: a hardware-independent step, mapping, and a hardware-dependent step, embedding. After describing two approaches to mapping general planning problems to QUBO, we describe preliminary results from running an early quantum annealer on a parametrized family of hard planning problems. The results show that different mappings can substantially affect performance, even when many features of the resulting instances are similar. We conclude with insights gained from this early study that suggest directions for future work.
Social Physique Anxiety, Mental Health, and Exercise: Analyzing the Role of Basic Psychological Needs and Psychological Inflexibility
Authors: Alcaraz-Ibáñez Manuel , Sicilia Álvaro , Burgueño Rafael
Published: February 2017

This study aimed to determine the usefulness of integrating basic psychological needs theory (BPNT) and relational frames theory (RFT) in order to explain the effects of social physique anxiety (SPA) – in the context of exercise – on exercisers’ mental health. A total of 296 recreational cyclists and triathletes (100% males) aged 18 to 60 years old (Mage= 35.65,SD= 9.49) completed a multi-section questionnaire assessing the target variables. Two models of structural equations with multiple mediators were tested using 5000 bootstrap samples. While the BPNT-based model explained 20% of variance in satisfaction with life (SWL) and 25% of variance in mental health (MH), the model that also incorporated RFT explained 43% of variance in both of those variables. Results showed that SPA negatively impacted exercisers’ mental health via two different mechanisms: a) through a decrease in perceived satisfaction of basic psychological needs (β = –.05,p= .045 for SWL; β = –.07,p= .002 for MH); b) through an increase in psychological inflexibility, generated directly by SPA (β = –.24,p< .001 for SWL; β = –.20,p< .001 for MH) and also mediated by basic psychological need thwarting (β = –.09,p< .001 for SWL; β = –.08,p= .002 for MH). Results supported integrating the two theories, elucidating the processes by which a controlling social factor like SPA can affect the potential benefits of exercise.
Child Depression: Prevalence and Comparison between Self-Reports and Teacher Reports
Authors: Jaureguizar Joana , Bernaras Elena , Garaigordobil Maite
Published: February 2017

Depression is one of the most worrying diseases nowadays. The study had three main purposes: 1) to identify the prevalence of depressive symptomatology in 7–10 year olds, exploring differences according to gender and age; 2) to analyze the consistency between self-reports and teacher reports; and 3) to explore the relationship between depression and academic performance. Regarding the methodology, the sample comprised 420 students aged between 7 and 10 years from the Basque Country (53.3% boys, 46.7% girls). With a descriptive, comparative and correlational design, 4 assessment instruments were used. Results from the self-reports showed a depression rate fluctuating between 4.6% and 4.8% (clinically significant), and between 4.3% and 5% (moderate depression). However, prevalence rates from teacher reports varied between 0.2% and 3.6% (clinically significant) and between 4.6% and 7.7% (moderate depression). The consistency rate between self-reports and teacher reports was small. Differences according to gender varied depending on the instruments used and depression was higher in boys (BASC,d= .23; SPECId= .36). Symptomatology did not increase with age. Depression correlated negatively with academic performance (self-reported depression: CDS-Tr= –.12, SPECIr= –.17; depression reported by teachers: CDS-Tr= –.24, SPECIr= –.50). The importance of training teachers to better identify child depression is discussed, as well as the relevance of developing prevention programs.
Massive production of abiotic methane during subduction evidenced in metamorphosed ophicarbonates from the Italian Alps
Authors: Vitale Brovarone Alberto , Martinez Isabelle , Elmaleh Agnès , Compagnoni Roberto , Chaduteau Carine , Ferraris Cristiano , Esteve Imène
Published: February 2017

Alteration of ultramafic rocks plays a major role in the production of hydrocarbons and organic compounds via abiotic processes on Earth and beyond and contributes to the redistribution of C between solid and fluid reservoirs over geological cycles. Abiotic methanogenesis in ultramafic rocks is well documented at shallow conditions, whereas natural evidence at greater depths is scarce. Here we provide evidence for intense high-pressure abiotic methanogenesis by reduction of subducted ophicarbonates. Protracted (≥0.5–1 Ma), probably episodic infiltration of reduced fluids in the ophicarbonates and methanogenesis occurred from at least ∼40 km depth to ∼15–20 km depth. Textural, petrological and isotopic data indicate that methane reached saturation triggering the precipitation of graphitic C accompanied by dissolution of the precursor antigorite. Continuous infiltration of external reducing fluids caused additional methane production by interaction with the newly formed graphite. Alteration of high-pressure carbonate-bearing ultramafic rocks may represent an important source of abiotic methane, with strong implications for the mobility of deep C reservoirs.
Plasmon-assisted high-harmonic generation in graphene
Authors: Cox Joel D. , Marini Andrea , de Abajo F. Javier García
Published: February 2017

High-harmonic generation in condensed-matter systems is both a source of fundamental insight into quantum electron motion and a promising candidate to realize compact ultraviolet and ultrafast light sources. While graphene is anticipated to efficiently generate high-order harmonics due to its anharmonic charge-carrier dispersion, experiments performed on extended samples using THz illumination have revealed only a weak effect. The situation is further complicated by the enormous electromagnetic field intensities required by this highly nonperturbative nonlinear optical phenomenon. Here we argue that the large light intensity required for high-harmonic generation to occur can be reached by exploiting localized plasmons in doped graphene nanostructures. We demonstrate through rigorous time-domain simulations that the synergistic combination of strong plasmonic near-field enhancement and a pronounced intrinsic nonlinearity result in efficient broadband high-harmonic generation within a single material. Our results support the strong potential of nanostructured graphene as a robust, electrically tunable platform for high-harmonic generation.
Enhanced oxidation resistance of active nanostructures via dynamic size effect
Authors: Liu Yun , Yang Fan , Zhang Yi , Xiao Jianping , Yu Liang , Liu Qingfei , Ning Yanxiao , Zhou Zhiwen , Chen Hao , Huang Wugen , Liu Ping , Bao Xinhe
Published: February 2017

A major challenge limiting the practical applications of nanomaterials is that the activities of nanostructures (NSs) increase with reduced size, often sacrificing their stability in the chemical environment. Under oxidative conditions, NSs with smaller sizes and higher defect densities are commonly expected to oxidize more easily, since high-concentration defects can facilitate oxidation by enhancing the reactivity with O2 and providing a fast channel for oxygen incorporation. Here, using FeO NSs as an example, we show to the contrary, that reducing the size of active NSs can drastically increase their oxidation resistance. A maximum oxidation resistance is found for FeO NSs with dimensions below 3.2 nm. Rather than being determined by the structure or electronic properties of active sites, the enhanced oxidation resistance originates from the size-dependent structural dynamics of FeO NSs in O2. We find this dynamic size effect to govern the chemical properties of active NSs.
Towards high-resolution laser ionization spectroscopy of the heaviest elements in supersonic gas jet expansion
Authors: Ferrer R. , Barzakh A. , Bastin B. , Beerwerth R. , Block M. , Creemers P. , Grawe H. , de Groote R. , Delahaye P. , Fléchard X. , Franchoo S. , Fritzsche S. , Gaffney L. P. , Ghys L. , Gins W. , Granados C. , Heinke R. , Hijazi L. , Huyse M. , Kron T. , Kudryavtsev Yu. , Laatiaoui M. , Lecesne N. , Loiselet M. , Lutton F. , Moore I. D. , Martínez Y. , Mogilevskiy E. , Naubereit P. , Piot J. , Raeder S. , Rothe S. , Savajols H. , Sels S. , Sonnenschein V. , Thomas J-C , Traykov E. , Van Beveren C. , Van den Bergh P. , Van Duppen P. , Wendt K. , Zadvornaya A.
Published: February 2017

Resonant laser ionization and spectroscopy are widely used techniques at radioactive ion beam facilities to produce pure beams of exotic nuclei and measure the shape, size, spin and electromagnetic multipole moments of these nuclei. However, in such measurements it is difficult to combine a high efficiency with a high spectral resolution. Here we demonstrate the on-line application of atomic laser ionization spectroscopy in a supersonic gas jet, a technique suited for high-precision studies of the ground- and isomeric-state properties of nuclei located at the extremes of stability. The technique is characterized in a measurement on actinium isotopes around theN=126 neutron shell closure. A significant improvement in the spectral resolution by more than one order of magnitude is achieved in these experiments without loss in efficiency.
Clonal reversal of ageing-associated stem cell lineage bias via a pluripotent intermediate
Authors: Wahlestedt Martin , Erlandsson Eva , Kristiansen Trine , Lu Rong , Brakebusch Cord , Weissman Irving L. , Yuan Joan , Martin-Gonzalez Javier , Bryder David
Published: February 2017

Ageing associates with significant alterations in somatic/adult stem cells and therapies to counteract these might have profound benefits for health. In the blood, haematopoietic stem cell (HSC) ageing is linked to several functional shortcomings. However, besides the recent realization that individual HSCs might be preset differentially already from young age, HSCs might also age asynchronously. Evaluating the prospects for HSC rejuvenation therefore ultimately requires approaching those HSCs that are functionally affected by age. Here we combine genetic barcoding of aged murine HSCs with the generation of induced pluripotent stem (iPS) cells. This allows us to specifically focus on aged HSCs presenting with a pronounced lineage skewing, a hallmark of HSC ageing. Functional and molecular evaluations reveal haematopoiesis from these iPS clones to be indistinguishable from that associating with young mice. Our data thereby provide direct support to the notion that several key functional attributes of HSC ageing can be reversed.
Abnormal strong burn-in degradation of highly efficient polymer solar cells caused by spinodal donor-acceptor demixing
Authors: Li Ning , Perea José Darío , Kassar Thaer , Richter Moses , Heumueller Thomas , Matt Gebhard J. , Hou Yi , Güldal Nusret S. , Chen Haiwei , Chen Shi , Langner Stefan , Berlinghof Marvin , Unruh Tobias , Brabec Christoph J.
Published: February 2017

The performance of organic solar cells is determined by the delicate, meticulously optimized bulk-heterojunction microstructure, which consists of finely mixed and relatively separated donor/acceptor regions. Here we demonstrate an abnormal strong burn-in degradation in highly efficient polymer solar cells caused by spinodal demixing of the donor and acceptor phases, which dramatically reduces charge generation and can be attributed to the inherently low miscibility of both materials. Even though the microstructure can be kinetically tuned for achieving high-performance, the inherently low miscibility of donor and acceptor leads to spontaneous phase separation in the solid state, even at room temperature and in the dark. A theoretical calculation of the molecular parameters and construction of the spinodal phase diagrams highlight molecular incompatibilities between the donor and acceptor as a dominant mechanism for burn-in degradation, which is to date the major short-time loss reducing the performance and stability of organic solar cells.
Sex differences in microglial CX3CR1 signalling determine obesity susceptibility in mice
Authors: Dorfman Mauricio D. , Krull Jordan E. , Douglass John D. , Fasnacht Rachael , Lara-Lince Fernando , Meek Thomas H. , Shi Xiaogang , Damian Vincent , Nguyen Hong T. , Matsen Miles E. , Morton Gregory J. , Thaler Joshua P.
Published: February 2017

Female mice are less susceptible to the negative metabolic consequences of high-fat diet feeding than male mice, for reasons that are incompletely understood. Here we identify sex-specific differences in hypothalamic microglial activation via the CX3CL1-CX3CR1 pathway that mediate the resistance of female mice to diet-induced obesity. Female mice fed a high-fat diet maintain CX3CL1-CX3CR1 levels while male mice show reductions in both ligand and receptor expression. Female Cx3cr1 knockout mice develop ‘male-like’ hypothalamic microglial accumulation and activation, accompanied by a marked increase in their susceptibility to diet-induced obesity. Conversely, increasing brain CX3CL1 levels in male mice through central pharmacological administration or virally mediated hypothalamic overexpression converts them to a ‘female-like’ metabolic phenotype with reduced microglial activation and body-weight gain. These data implicate sex differences in microglial activation in the modulation of energy homeostasis and identify CX3CR1 signalling as a potential therapeutic target for the treatment of obesity.
Improved antitumor activity of TRAIL fusion protein via formation of self-assembling nanoparticle
Authors: Huang Kaizong , Duan Ningjun , Zhang Chunmei , Mo Ran , Hua Zichun
Published: February 2017

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been known as a promising agent for cancer therapy due to its specific apoptosis-inducing effect on tumor cells rather than most normal cells. However, systemically delivered TRAIL suffers from a rapid clearance from the body with an extremely short half-life. Thermally responsive elastin-like polypeptides (ELPs) are a promising class of temperature sensitive biopolymers based on the structural motif found in mammalian tropoelastin and retain the advantages of polymeric drug delivery systems. We therefore expressed RGD-TRAIL fused with ELP (RGD-TRAIL-ELP) in E. coli. Purification of RGD-TRAIL-ELP was achieved by the conveniently inverse transition cycling (ITC). The purified RGD-TRAIL-ELP without any chemical conjugation was able to self-assemble into nanoparticle under physiological condition. Non-reducing SDS-PAGE results showed that trimer content of RGD-TRAIL-ELP increased 3.4-fold than RGD-TRAIL. Flow cytometry confirmed that RGD-TRAIL-ELP 3-fold enhanced apoptosis-inducing capacity than RGD-TRAIL. Single intraperitoneal injection of the RGD-TRAIL-ELP nanoparticle induced nearly complete tumor regression in the COLO-205 tumor xenograft model. Histological observation confirmed that RGD-TRAIL-ELP induced significant tumor cell apoptosis without apparent liver toxicity. These findings suggested that a great potential application of the RGD-TRAIL-ELP nanoparticle system as a safe and efficient delivery strategy for cancer therapy.
Chemometric-assisted QuEChERS extraction method for post-harvest pesticide determination in fruits and vegetables
Authors: Li Minmin , Dai Chao , Wang Fengzhong , Kong Zhiqiang , He Yan , Huang Ya Tao , Fan Bei
Published: February 2017

An effective analysis method was developed based on a chemometric tool for the simultaneous quantification of five different post-harvest pesticides (2,4-dichlorophenoxyacetic acid (2,4-D), carbendazim, thiabendazole, iprodione, and prochloraz) in fruits and vegetables. In the modified QuEChERS (quick, easy, cheap, effective, rugged and safe) method, the factors and responses for optimization of the extraction and cleanup analyses were compared using the Plackett–Burman (P–B) screening design. Furthermore, the significant factors (toluene percentage, hydrochloric acid (HCl) percentage, and graphitized carbon black (GCB) amount) were optimized using a central composite design (CCD) combined with Derringer’s desirability function (DF). The limits of quantification (LOQs) were estimated to be 1.0 μg/kg for 2,4-D, carbendazim, thiabendazole, and prochloraz, and 1.5 μg/kg for iprodione in food matrices. The mean recoveries were in the range of 70.4–113.9% with relative standard deviations (RSDs) of less than 16.9% at three spiking levels. The measurement uncertainty of the analytical method was determined using the bottom-up approach, which yielded an average value of 7.6%. Carbendazim was most frequently found in real samples analyzed using the developed method. Consequently, the analytical method can serve as an advantageous and rapid tool for determination of five preservative pesticides in fruits and vegetables.
Early Spontaneous Abdominal Bleeding is associated with Poor Outcome in Moderate to Severe Acute Pancreatitis Patients: A Propensity Matched Study
Authors: Chen Yizhe , Zhou Jing , Li Gang , Tong Zhihui , Dong Jie , Pan Yiyuan , Ke Lu , Li Weiqin , Li Jieshou
Published: February 2017

Abdominal bleeding is a lethal complication in acute pancreatitis (AP) and it is commonly described as a late event. However, spontaneous intra-abdominal bleeding could occur very early but no study focusing on this phenomenon was published yet. In this study, 1137 AP patients were retrospectively screened and 24 subjects suffering early spontaneous bleeding (ESB) were selected. Meanwhile, a 1:1 well-balanced cohort of non-bleeding patients was generated by propensity score match. The clinical characteristics of these patients were compared and a multiple regression analysis was performed to assess the risk factors for ESB. Besides, patients with massive post-intervention bleeding (PIB) were collected for additional comparison. ESB patients suffered significantly worse outcome than the matched cohort evidenced by dramatically higher mortality than the non-bleeding patients and even the PIB group (54.2% versus 20.8%, P = 0.017; 54.2% versus 31.0%, P = 0.049). The regression analysis demonstrated computer tomography severity index (CTSI; OR, 3.34; 95% CI, 1.995–5.59, P < 0.001) and creatinine (OR, 1.008; 95% CI, 1.004–1.012, P < 0.001) were associated with the occurrence of ESB. In conclusion, ESB is a rare but dangerous complication of moderate-to-severe AP and may result in high mortality. CTSI and creatinine are independent risk factors for the development of ESB.
Autophagy Protects against Palmitic Acid-Induced Apoptosis in Podocytes in vitro
Authors: Jiang Xu-shun , Chen Xue-mei , Wan Jiang-min , Gui Hai-bo , Ruan Xiong-zhong , Du Xiao-gang
Published: February 2017

Autophagy is a highly conserved degradation process that is involved in the clearance of proteins and damaged organelles to maintain intracellular homeostasis and cell integrity. Type 2 diabetes is often accompanied by dyslipidemia with elevated levels of free fatty acids (FFAs). Podocytes, as an important component of the filtration barrier, are susceptible to lipid disorders. The loss of podocytes causes proteinuria, which is involved in the pathogenesis of diabetic nephropathy. In the present study, we demonstrated that palmitic acid (PA) promoted autophagy in podocytes. We further found that PA increased the production of reactive oxygen species (ROS) in podocytes and that NAC (N-acetyl-cysteine), a potent antioxidant, significantly eliminated the excessive ROS and suppressed autophagy, indicating that the increased generation of ROS was associated with the palmitic acid-induced autophagy in podocytes. Moreover, we also found that PA stimulation decreased the mitochondrial membrane potential in podocytes and induced podocyte apoptosis, while the inhibition of autophagy by chloroquine (CQ) enhanced palmitic acid-induced apoptosis accompanied by increased ROS generation, and the stimulation of autophagy by rapamycin (Rap) remarkably suppressed palmitic acid-induced ROS generation and apoptosis. Taken together, these in vitro findings suggest that PA-induced autophagy in podocytes is mediated by ROS production and that autophagy plays a protective role against PA-induced podocyte apoptosis.
Multiple sodium channel isoforms mediate the pathological effects of Pacific ciguatoxin-1
Authors: Inserra Marco C. , Israel Mathilde R. , Caldwell Ashlee , Castro Joel , Deuis Jennifer R. , Harrington Andrea M. , Keramidas Angelo , Garcia-Caraballo Sonia , Maddern Jessica , Erickson Andelain , Grundy Luke , Rychkov Grigori Y. , Zimmermann Katharina , Lewis Richard J. , Brierley Stuart M. , Vetter Irina
Published: February 2017

Human intoxication with the seafood poison ciguatoxin, a dinoflagellate polyether that activates voltage-gated sodium channels (NaV), causes ciguatera, a disease characterised by gastrointestinal and neurological disturbances. We assessed the activity of the most potent congener, Pacific ciguatoxin-1 (P-CTX-1), on NaV1.1–1.9 using imaging and electrophysiological approaches. Although P-CTX-1 is essentially a non-selective NaV toxin and shifted the voltage-dependence of activation to more hyperpolarising potentials at all NaV subtypes, an increase in the inactivation time constant was observed only at NaV1.8, while the slope factor of the conductance-voltage curves was significantly increased for NaV1.7 and peak current was significantly increased for NaV1.6. Accordingly, P-CTX-1-induced visceral and cutaneous pain behaviours were significantly decreased after pharmacological inhibition of NaV1.8 and the tetrodotoxin-sensitive isoforms NaV1.7 and NaV1.6, respectively. The contribution of these isoforms to excitability of peripheral C- and A-fibre sensory neurons, confirmed using murine skin and visceral single-fibre recordings, reflects the expression pattern of NaV isoforms in peripheral sensory neurons and their contribution to membrane depolarisation, action potential initiation and propagation.
Anticancer osmium complex inhibitors of the HIF-1α and p300 protein-protein interaction
Authors: Yang Chao , Wang Wanhe , Li Guo-Dong , Zhong Hai-Jing , Dong Zhen-Zhen , Wong Chun-Yuen , Kwong Daniel W. J. , Ma Dik-Lung , Leung Chung-Hang
Published: February 2017

The hypoxia inducible factor (HIF) pathway has been considered to be an attractive anti-cancer target. One strategy to inhibit HIF activity is through the disruption of the HIF-1α–p300 protein-protein interaction. We report herein the identification of an osmium(II) complex as the first metal-based inhibitor of the HIF-1α–p300 interaction. We evaluated the effect of complex 1 on HIF-1α signaling pathway in vitro and in cellulo by using the dual luciferase reporter assay, co-immunoprecipitation assay, and immunoblot assay. Complex 1 exhibited a dose-dependent inhibition of HRE-driven luciferase activity, with an IC50 value of 1.22 μM. Complex 1 interfered with the HIF-1α–p300 interaction as revealed by a dose-dependent reduction of p300 co-precipitated with HIF-1α as the concentration of complex 1 was increased. Complex 1 repressed the phosphorylation of SRC, AKT and STAT3, and had no discernible effect on the activity of NF-κB. We anticipate that complex 1 could be utilized as a promising scaffold for the further development of more potent HIF-1α inhibitors for anti-cancer treatment.
Blood-based omic profiling supports female susceptibility to tobacco smoke-induced cardiovascular diseases
Authors: Chatziioannou Aristotelis , Georgiadis Panagiotis , Hebels Dennie G. , Liampa Irene , Valavanis Ioannis , Bergdahl Ingvar A. , Johansson Anders , Palli Domenico , Chadeau-Hyam Marc , Siskos Alexandros P. , Keun Hector , Botsivali Maria , de Kok Theo M. C. M. , Pérez Almudena Espín , Kleinjans Jos C. S. , Vineis Paolo , Kyrtopoulos Soterios A. ,   The EnviroGenomarkers project consortium, Gottschalk Ralph , van Leeuwen Danitsja , Timmermans Leen , Bendinelli Benedetta , Kelly Rachel , Vermeulen Roel , Portengen Lutzen , Saberi-Hosnijeh Fatemeh , Melin Beatrice , Hallmans Göran , Lenner Per , Athersuch Toby J. , Kogevinas Manolis , Stephanou Euripides G. , Myridakis Antonis , Fazzo Lucia , De Santis Marco , Comba Pietro , Kiviranta Hannu , Rantakokko Panu , Airaksinen Riikka , Ruokojärvi Päivi , Gilthorpe Mark , Fleming Sarah , Fleming Thomas , Tu Yu-Kang , Jonsson Bo , Lundh Thomas , Chen Wei J. , Lee Wen-Chung , Hsiao Chuhsing Kate , Chien Kuo-Liong , Kuo Po-Hsiu , Hung Hung , Liao Shu-Fen
Published: February 2017

We recently reported that differential gene expression and DNA methylation profiles in blood leukocytes of apparently healthy smokers predicts with remarkable efficiency diseases and conditions known to be causally associated with smoking, suggesting that blood-based omic profiling of human populations may be useful for linking environmental exposures to potential health effects. Here we report on the sex-specific effects of tobacco smoking on transcriptomic and epigenetic features derived from genome-wide profiling in white blood cells, identifying 26 expression probes and 92 CpG sites, almost all of which are affected only in female smokers. Strikingly, these features relate to numerous genes with a key role in the pathogenesis of cardiovascular disease, especially thrombin signaling, including the thrombin receptors on platelets F2R (coagulation factor II (thrombin) receptor; PAR1) and GP5 (glycoprotein 5), as well as HMOX1 (haem oxygenase 1) and BCL2L1 (BCL2-like 1) which are involved in protection against oxidative stress and apoptosis, respectively. These results are in concordance with epidemiological evidence of higher female susceptibility to tobacco-induced cardiovascular disease and underline the potential of blood-based omic profiling in hazard and risk assessment.
Altered enhancer transcription underlies Huntington’s disease striatal transcriptional signature
Authors: Le Gras Stéphanie , Keime Céline , Anthony Anne , Lotz Caroline , De Longprez Lucie , Brouillet Emmanuel , Cassel Jean-Christophe , Boutillier Anne-Laurence , Merienne Karine
Published: February 2017

Epigenetic and transcriptional alterations are both implicated in Huntington’s disease (HD), a progressive neurodegenerative disease resulting in degeneration of striatal neurons in the brain. However, how impaired epigenetic regulation leads to transcriptional dysregulation in HD is unclear. Here, we investigated enhancer RNAs (eRNAs), a class of long non-coding RNAs transcribed from active enhancers. We found that eRNAs are expressed from many enhancers of mouse striatum and showed that a subset of those eRNAs are deregulated in HDvscontrol mouse striatum. Enhancer regions producing eRNAs decreased in HD mouse striatum were associated with genes involved in striatal neuron identity. Consistently, they were enriched in striatal super-enhancers. Moreover, decreased eRNA expression in HD mouse striatum correlated with down-regulation of associated genes. Additionally, a significant number of RNA Polymerase II (RNAPII) binding sites were lost within enhancers associated with decreased eRNAs in HDvscontrol mouse striatum. Together, this indicates that loss of RNAPII at HD mouse enhancers contributes to reduced transcription of eRNAs, resulting in down-regulation of target genes. Thus, our data support the view that eRNA dysregulation in HD striatum is a key mechanism leading to altered transcription of striatal neuron identity genes, through reduced recruitment of RNAPII at super-enhancers.
Full 3D modelling of pulse propagation enables efficient nonlinear frequency conversion with low energy laser pulses in a single-element tripler
Authors: Kardaś Tomasz M. , Nejbauer Michał , Wnuk Paweł , Resan Bojan , Radzewicz Czesław , Wasylczyk Piotr
Published: February 2017

Although new optical materials continue to open up access to more and more wavelength bands where femtosecond laser pulses can be generated, light frequency conversion techniques are still indispensable in filling the gaps on the ultrafast spectral scale. With high repetition rate, low pulse energy laser sources (oscillators) tight focusing is necessary for a robust wave mixing and the efficiency of broadband nonlinear conversion is limited by diffraction as well as spatial and temporal walk-off. Here we demonstrate a miniature third harmonic generator (tripler) with conversion efficiency exceeding 30%, producing 246 fs UV pulses via cascaded second order processes within a single laser beam focus. Designing this highly efficient and ultra compact frequency converter was made possible by full 3-dimentional modelling of propagation of tightly focused, broadband light fields in nonlinear and birefringent media.
Rapid and Reliable Detection of Nonsyndromic Hearing Loss Mutations by Multicolor Melting Curve Analysis
Authors: Wang Xudong , Hong Yongjun , Cai Peihong , Tang Ning , Chen Ying , Yan Tizhen , Liu Yinghua , Huang Qiuying , Li Qingge
Published: February 2017

Hearing loss is a common birth defect worldwide. The GJB2, SLC26A4, MT-RNR1 and MT-TS1 genes have been reported as major pathogenic genes in nonsyndromic hearing loss. Early genetic screening is recommended to minimize the incidence of hearing loss. We hereby described a multicolor melting curve analysis (MMCA)-based assay for simultaneous detection of 12 prevalent nonsyndromic hearing loss-related mutations. The three-reaction assay could process 30 samples within 2.5 h in a single run on a 96-well thermocycler. Allelic types of each mutation could be reproducibly obtained from 10 pg ~100 ng genomic DNA per reaction. For the mitochondrial mutations, 10% ~ 20% heteroplasmic mutations could be detected. A comparison study using 501 clinical samples showed that the MMCA assay had 100% concordance with both SNaPshot minisequencing and Sanger sequencing. We concluded that the MMCA assay is a rapid, convenient and cost-effective method for detecting the common mutations, and can be expectedly a reliable tool in preliminary screening of nonsyndromic hearing loss in the Chinese Han population.
Vulnerability of the British swine industry to classical swine fever
Authors: Porphyre Thibaud , Correia-Gomes Carla , Chase-Topping Margo E. , Gamado Kokouvi , Auty Harriet K. , Hutchinson Ian , Reeves Aaron , Gunn George J. , Woolhouse Mark E. J.
Published: February 2017

Classical swine fever (CSF) is a notifiable, highly contagious viral disease of swine which results in severe welfare and economic consequences in affected countries. To improve preparedness, it is critical to have some understanding of how CSF would spread should it be introduced. Based on the data recorded during the 2000 epidemic of CSF in Great Britain (GB), a spatially explicit, premises-based model was developed to explore the risk of CSF spread in GB. We found that large outbreaks of CSF would be rare and generated from a limited number of areas in GB. Despite the consistently low vulnerability of the British swine industry to large CSF outbreaks, we identified concerns with respect to the role played by the non-commercial sector of the industry. The model further revealed how various epidemiological features may influence the spread of CSF in GB, highlighting the importance of between-farm biosecurity in preventing widespread dissemination of the virus. Knowledge of factors affecting the risk of spread are key components for surveillance planning and resource allocation, and this work provides a valuable stepping stone in guiding policy on CSF surveillance and control in GB.
Combination of ruthenium(II)-arene complex [Ru(η6-p-cymene)Cl2(pta)] (RAPTA-C) and the epidermal growth factor receptor inhibitor erlotinib results in efficient angiostatic and antitumor activity
Authors: Berndsen Robert H. , Weiss Andrea , Abdul U. Kulsoom , Wong Tse J. , Meraldi Patrick , Griffioen Arjan W. , Dyson Paul J. , Nowak-Sliwinska Patrycja
Published: February 2017

Ruthenium-based compounds show strong potential as anti-cancer drugs and are being investigated as alternatives to other well-established metal-based chemotherapeutics. The organometallic compound [Ru(η6-p-cymene)Cl2(pta)], where pta = 1,3,5-triaza-7-phosphaadamantane (RAPTA-C) exhibits broad acting anti-tumor efficacy with intrinsic angiostatic activity. In the search for an optimal anti-angiogenesis drug combination, we identified synergistic potential between RAPTA-C and the epidermal growth factor receptor (EGFR) inhibitor, erlotinib. This drug combination results in strong synergistic inhibition of cell viability in human endothelial (ECRF24 and HUVEC) and human ovarian carcinoma (A2780 and A2780cisR) cells. Additionally, erlotinib significantly enhances the cellular uptake of RAPTA-C relative to treatment with RAPTA-C alone in human ovarian carcinoma cells, but not endothelial cells. Drug combinations induce the formation of chromosome bridges that persist after mitotic exit and delay abscission in A2780 and A2780cisR, therefore suggesting initiation of cellular senescence. The therapeutic potential of these compounds and their combination is further validated in vivo on A2780 tumors grown on the chicken chorioallantoic membrane (CAM) model, and in a preclinical model in nude mice. Immunohistochemical analysis confirms effective anti-angiogenic and anti-proliferative activity in vivo, based on a significant reduction of microvascular density and a decrease in proliferating cells.
Human peripheral blood mononuclear cells (PBMCs) from smokers release higher levels of IL-1-like cytokines after exposure to combustion-generated ultrafine particles
Authors: De Falco Gianluigi , Terlizzi Michela , Sirignano Mariano , Commodo Mario , D’Anna Andrea , Aquino Rita P. , Pinto Aldo , Sorrentino Rosalinda
Published: February 2017

Ultrafine particles (UFP) generated by combustion processes are often associated with adverse health effects. However, little is known about the inflammatory processes generated by UFP that may underlie their toxicological activity. Murine macrophages (J774.1 cells) and human peripheral blood mononuclear cells (PBMCs) were used to evaluate the molecular mechanism underlying the pro-inflammatory activity of UFP. The addition of soot particles to J774.1 cells induced a concentration-dependent release of IL-1α, IL-1β and IL-33 This effect was not associated with cell death and, in contrast to literature, was pronounced at very low concentrations (5–100 pg/ml). Similarly, UFP induced the release of IL-1α, IL-18 and IL-33 by PBMCs. However, this effect was solely observed in PBMCs obtained from smokers, as the PBMCs from non-smokers instead released higher levels of IL-10. The release of these cytokines after UFP exposure was caspase-1- and NLRP3 inflammasome-dependent in PBMCs from healthy smokers, whereas IL-1α release was calpain-dependent. These results show that UFP at very low concentrations are able to give rise to an inflammatory process that is responsible for IL-1α, IL-18 and IL-33 release, which is pronounced in PBMCs from smokers, confirming that these individuals are especially susceptible to inflammatory-based airway diseases once exposed to air pollution.
Membrane targeting of TIRAP is negatively regulated by phosphorylation in its phosphoinositide-binding motif
Authors: Zhao Xiaolin , Xiong Wen , Xiao Shuyan , Tang Tuo-Xian , Ellena Jeffrey F. , Armstrong Geoffrey S. , Finkielstein Carla V. , Capelluto Daniel G. S.
Published: February 2017

Pathogen-activated Toll-like receptors (TLRs), such as TLR2 and TLR4, dimerize and move laterally across the plasma membrane to phosphatidylinositol (4,5)-bisphosphate-enriched domains. At these sites, TLRs interact with the TIR domain-containing adaptor protein (TIRAP), triggering a signaling cascade that leads to innate immune responses. Membrane recruitment of TIRAP is mediated by its phosphoinositide (PI)-binding motif (PBM). We show that TIRAP PBM transitions from a disordered to a helical conformation in the presence of either zwitterionic micelles or monodispersed PIs. TIRAP PBM bound PIs through basic and nonpolar residues with high affinity, favoring a more ordered structure. TIRAP is phosphorylated at Thr28 within its PBM, which leads to its ubiquitination and degradation. We demonstrate that phosphorylation distorts the helical structure of TIRAP PBM, reducing PI interactions and cell membrane targeting. Our study provides the basis for TIRAP membrane insertion and the mechanism by which it is removed from membranes to avoid sustained innate immune responses.
Intracellular drug bioavailability: a new predictor of system dependent drug disposition
Authors: Mateus André , Treyer Andrea , Wegler Christine , Karlgren Maria , Matsson Pär , Artursson Per
Published: February 2017

Intracellular drug exposure is influenced by cell- and tissue-dependent expression of drug-transporting proteins and metabolizing enzymes. Here, we introduce the concept of intracellular bioavailability (Fic) as the fraction of extracellular drug available to bind intracellular targets, and we assess how Fic is affected by cellular drug disposition processes. We first investigated the impact of two essential drug transporters separately, one influx transporter (OATP1B1; SLCO1B1) and one efflux transporter (P-gp; ABCB1), in cells overexpressing these proteins. We showed that OATP1B1 increased Fic of its substrates, while P-gp decreased Fic. We then investigated the impact of the concerted action of multiple transporters and metabolizing enzymes in freshly-isolated human hepatocytes in culture configurations with different levels of expression and activity of these proteins. We observed that Fic was up to 35-fold lower in the configuration with high expression of drug-eliminating transporters and enzymes. We conclude that Fic provides a measurement of the net impact of all cellular drug disposition processes on intracellular bioavailable drug levels. Importantly, no prior knowledge of the involved drug distribution pathways is required, allowing for high-throughput determination of drug access to intracellular targets in highly defined cell systems (e.g., single-transporter transfectants) or in complex ones (including primary human cells).
Direct binding of MEK1 and MEK2 to AKT induces Foxo1 phosphorylation, cellular migration and metastasis
Authors: Procaccia Shiri , Ordan Merav , Cohen Izel , Bendetz-Nezer Sarit , Seger Rony
Published: February 2017

Crosstalk between the ERK cascade and other signaling pathways is one of the means by which it acquires its signaling specificity. Here we identified a direct interaction of both MEK1 and MEK2 with AKT. The interaction is mediated by the proline rich domain of MEK1/2 and regulated by phosphorylation of Ser298 in MEK1, or Ser306 in MEK2, which we identified here as a novel regulatory site. We further developed a blocking peptide, which inhibits the interaction between MEK and AKT, and when applied to cells, affects migration and adhesion, but not proliferation. The specific mechanism of action of the MEK-AKT complex involves phosphorylation of the migration-related transcription factor FoxO1. Importantly, prevention of the interaction results in a decreased metastasis formation in a breast cancer mouse model. Thus, the identified interaction both sheds light on how signaling specificity is determined, and represents a possible new therapeutic target for metastatic cancer.
Simulating future value in intertemporal choice
Authors: Solway Alec , Lohrenz Terry , Montague P. Read
Published: February 2017

The laboratory study of how humans and other animals trade-off value and time has a long and storied history, and is the subject of a vast literature. However, despite a long history of study, there is no agreed upon mechanistic explanation of how intertemporal choice preferences arise. Several theorists have recently proposed model-based reinforcement learning as a candidate framework. This framework describes a suite of algorithms by which a model of the environment, in the form of a state transition function and reward function, can be converted on-line into a decision. The state transition function allows the model-based system to make decisions based on projected future states, while the reward function assigns value to each state, together capturing the necessary components for successful intertemporal choice. Empirical work has also pointed to a possible relationship between increased prospection and reduced discounting. In the current paper, we look for direct evidence of a relationship between temporal discounting and model-based control in a large new data set (n = 168). However, testing the relationship under several different modeling formulations revealed no indication that the two quantities are related.
4-isopropylcyclohexanol has potential analgesic effects through the inhibition of anoctamin 1, TRPV1 and TRPA1 channel activities
Authors: Takayama Yasunori , Furue Hidemasa , Tominaga Makoto
Published: February 2017

Interactions between calcium-activated chloride channel anoctamin 1 (ANO1) and transient receptor potential vanilloid 1 (TRPV1) enhance pain sensations in mice, suggesting that ANO1 inhibition could have analgesic effects. Here we show that menthol and the menthol analogue isopropylcyclohexane (iPr-CyH) inhibited ANO1 channels in mice. The iPr-CyH derivative 4-isopropylcyclohexanol (4-iPr-CyH-OH) inhibited mouse ANO1 currents more potently than iPr-CyH. Moreover, 4-iPr-CyH-OH inhibited the activities of TRPV1, TRP ankyrin 1 (TRPA1), TRP melastatin 8 (TRPM8) and TRPV4. Single-channel analysis revealed that 4-iPr-CyH-OH reduced TRPV1 and TRPA1 current open-times without affecting unitary amplitude or closed-time, suggesting that it affected gating rather than blocking the channel pore. The ability of 4-iPr-CyH-OH to inhibit action potential generation and reduce pain-related behaviors induced by capsaicin in mice suggests that 4-iPr-CyH-OH could have analgesic applications. Thus, 4-iPr-CyH-OH is a promising base chemical to develop novel analgesics that target ANO1 and TRP channels.
Ruthenium based metallopolymer grafted reduced graphene oxide as a new hybrid solar light harvester in polymer solar cells
Authors: Vinoth R. , Babu S. Ganesh , Bharti Vishal , Gupta V. , Navaneethan M. , Bhat S. Venkataprasad , Muthamizhchelvan C. , Ramamurthy Praveen C. , Sharma Chhavi , Aswal Dinesh K. , Hayakawa Yasuhiro , Neppolian B.
Published: February 2017

A new class of pyridyl benzimdazole based Ru complex decorated polyaniline assembly (PANI-Ru) was covalently grafted onto reduced graphene oxide sheets (rGO) via covalent functionalization approach. The covalent attachment of PANI-Ru with rGO was confirmed from XPS analysis and Raman spectroscopy. The chemical bonding between PANI-Ru and rGO induced the electron transfer from Ru complex to rGO via backbone of the conjugated PANI chain. The resultant hybrid metallopolymer assembly was successfully demonstrated as an electron donor in bulk heterojunction polymer solar cells (PSCs). A PSC device fabricated with rGO/PANI-Ru showed an utmost ~6 fold and 2 fold enhancement in open circuit potential (Voc) and short circuit current density (Jsc) with respect to the standard device made with PANI-Ru (i.e., without rGO) under the illumination of AM 1.5 G. The excellent electronic properties of rGO significantly improved the electron injection from PANI-Ru to PCBM and in turn the overall performance of the PSC device was enhanced. The ultrafast excited state charge separation and electron transfer role of rGO sheet in hybrid metallopolymer was confirmed from ultrafast spectroscopy measurements. This covalent modification of rGO with metallopolymer assembly may open a new strategy for the development of new hybrid nanomaterials for light harvesting applications.
Unusual Anti-allergic Diterpenoids from the Marine Sponge Hippospongia lachne
Authors: Hong Li-Li , Yu Hao-Bing , Wang Jie , Jiao Wei-Hua , Cheng Bao-Hui , Yang Fan , Zhou Yong-Jun , Gu Bin-Bin , Song Shao-Jiang , Lin Hou-Wen
Published: February 2017

Hipposponlachnins A (1) and B (2), possessing an unprecedented tetracyclo [9.3.0.02,8.03,7] tetradecane ring system, and the probable biogenetic precursor [3, (1R*,2E,4R*,7E,10S*,11S*,12R*)-10, 18-diacetoxydolabella-2,7-dien-6-one] of 1‒2 were isolated from the South China Sea marine sponge Hippospongia lachne. The structures of the novel compounds were determined using integrated spectroscopic methods in combination with single-crystal X-ray diffraction analysis. Compounds 1‒2 showed potent inhibitory activity on the release of β-hexosaminidase, a biomarker for degranulation, as well as the production of pro-inflammatory cytokine IL-4 and lipid mediator LTB4 in DNP-IgE-stimulated RBL-2H3 cells.
Intrinsic Peroxidase-like Activity of Ficin
Authors: Yang Yufang , Shen Dongjun , Long Yijuan , Xie Zhixiong , Zheng Huzhi
Published: February 2017

Ficin is classified as a sulfhydryl protease isolated from the latex of fig trees. In most cases, a particular enzyme fits a few types of substrate and catalyzes one type of reaction. In this investigation, we found sufficient proofs for the intrinsic peroxidase-like activity of ficin and designed experiments to examine its effectiveness in a variety of scenarios. Ficin can transform peroxidase substrates to colored products in the existence of H2O2. Our results also indicate that the active sites of peroxidase-like activity of ficin are different from that of protease, which reveals that one enzyme may catalyze more than one kind of substrate to perform different types of reactions. On the basis of these findings, H2O2 releasing from MCF-7 cells was detected successfully. Our findings support a wider application of ficin in biochemistry and open up the possibility of utilizing ficin as enzymatic mimics in biotechnology and environmental monitoring.