bluuebunny/crossref_metadata_2025 huggingface dataset:
Parsing interindividual drug variability: an emerging role for systems pharmacology
Authors: Turner Richard M. , Park B. Kevin , Pirmohamed Munir
Published: May 2015

There is notable interindividual heterogeneity in drug response, affecting both drug efficacy and toxicity, resulting in patient harm and the inefficient utilization of limited healthcare resources. Pharmacogenomics is at the forefront of research to understand interindividual drug response variability, but although many genotype‐drug response associations have been identified, translation of pharmacogenomic associations into clinical practice has been hampered by inconsistent findings and inadequate predictive values. These limitations are in part due to the complex interplay between drug‐specific, human body and environmental factors influencing drug response and therefore pharmacogenomics, whilst intrinsically necessary, is by itself unlikely to adequately parse drug variability. The emergent, interdisciplinary and rapidly developing field of systems pharmacology, which incorporates but goes beyond pharmacogenomics, holds significant potential to further parse interindividual drug variability. Systems pharmacology broadly encompasses two distinct research efforts, pharmacologically‐orientated systems biology and pharmacometrics. Pharmacologically‐orientated systems biology utilizes high throughput omics technologies, including next‐generation sequencing, transcriptomics and proteomics, to identify factors associated with differential drug response within the different levels of biological organization in the hierarchical human body. Increasingly complex pharmacometric models are being developed that quantitatively integrate factors associated with drug response. Although distinct, these research areas complement one another and continual development can be facilitated by iterating between dynamic experimental and computational findings. Ultimately, quantitative data‐derived models of sufficient detail will be required to help realize the goal of precision medicine. WIREs Syst Biol Med 2015, 7:221–241. doi: 10.1002/wsbm.1302

This article is categorized under:

Translational, Genomic, and Systems Medicine > Translational Medicine
Three Distinct Silver(I) Coordination Polymers: Bridging‐­Ligand Directed Syntheses, Crystal Structures, Luminescence, and Nitrobenzene Sensing Properties
Authors: Zhang Jinfang , Wang Yinlin , Chen Weitao , Long Lingliang , Zhang Chi
Published: May 2015

Three distinct AgI‐DMAP [DMAP = 4‐(dimethylamino)pyridine] coordination polymers [Ag2I2(DMAP)2]n (1), [Ag2(CN)2(DMAP)2.5·DMAP]n (2), and [Ag(SCN)(DMAP)]n (3) were constructed by monatomic I–, diatomic CN–, and triatomic SCN– bridges, respectively. 1–3 were determined by FT‐IR spectroscopy, elemental analyses, TGA, powder and single‐crystal X‐ray diffraction. 1 exhibits a 1D wavelike chain structure, sustained by 3‐connected I– bridges, whereas 2 shows a unique 1D single‐ and double‐strand alternating chain, supported by 3‐connected CN– bridges. Compound 3 has a 2D 3‐connected network architecture, fabricated by 3‐connected SCN– bridges, and exhibits a (4·82) topology. The luminescence and nitrobenzene sensing properties of 1–3 were explored in 2‐propanol suspensions, which revealed that compounds 1–3 exhibit DMAP originated luminescence emissions and are highly sensitive for nitrobenzene detection.
Synthesis and Crystal Structures of the Calcium Silicon Phosphides Ca2Si2P4, Ca3Si8P14 and Ca3Si2P4
Authors: Zhang Xiang , Yu Tongtong , Li Chunlong , Wang Shanpeng , Tao Xutang
Published: May 2015

Three calcium silicon phosphides: Ca2Si2P4, Ca3Si8P14, and Ca3Si2P4 were synthesized by solid state reaction and identified by single‐crystal X‐ray diffraction. Ca2Si2P4 crystallizes in the noncentrosymmetric space group P41212 (no.92) with a = 7.173 Å, c = 26.295 Å. Both Ca3Si8P14 and Ca3Si2P4 crystallize in the space group P21/c (no.14) with a = 12.138 Å, b = 13.476 Å, c = 6.2176 Å, β = 90.934°, and a = 7.073 Å, b = 17.210 Å, c = 6.918 Å, β = 111.791°, respectively. The Si–P tetrahedra construct one‐dimensional (1D), two‐dimensional (2D), and three‐dimensional (3D) networks in Ca3Si2P4, Ca2Si2P4, and Ca3Si8P14, respectively, and their calculated bandgaps are 0.826, 0.984, and 0.829 eV, respectively.
The Reaction of Bunsen's Cacodyl Disulfide, Me2As(S)‐S‐AsMe2, with Iodine: Preparation and Properties of Dimethylarsinosulfenyl Iodide, Me2As‐S‐I
Authors: Ioannou Panayiotis V. , Vachliotis Dimitris G. , Chrissanthopoulos Athanassios
Published: May 2015

Bunsen's cacodyl disulfide, Me2As(S)‐S‐AsMe2 (1), reacted with iodine giving the novel dimethylarsinosulfenyl iodide, Me2As‐S‐I (3) although theoretical calculations indicated that the AsV compound Me2As(S)‐I (4) was more stable in the gas phase. The oily product was stable neat and as a solution in CDCl3 at +4 °C and –20 °C for at least 15 d. Light, H2O, H2O2, and Zn dust, but not NaI or Ag, decomposed it. Compound 3 did not interact with Ph3N, with Ph2NH and PhNH2 it interacted but not reacted. 3 was decomposed by piperidine, with pyridine and 4‐dimethylaminopyridine it interacted and produced Me2As‐SS‐AsMe2 (2) and I2 that formed charge transfer complexes Base·I2, whereas Et3N decomposed 3, and 3Et3N·2I2 was isolated. 3 was desulfurized by Ph3P and (Me2N)3P completely, and by (PhO)3P and (PhS)3P partially. The reactions of 3 with (Me2N)3P, (PhS)3P, and (EtO)3P were complicated. From the AsIII nucleophiles, only Ph3As was bound, while (PhS)3As reacted slowly in a complicated manner with 3. No interaction of 3 with MeOH or PhOH was observed but NaOH, Ag2O, and PhONa decomposed it. Thiophenol produced traces of Me2As‐SPh (10) and sodium thiophenolate attacked mainly at AsIII of 3. Thus, externally stabilized sulfenium ions of the type Me2As‐S‐Nu+I– were not obtained.
Synthesis of Supported Ga Nanodrops by a Bottom‐up Route
Authors: Armbrüster Marc , Cardoso‐Gil Raul
Published: May 2015

Nanoparticulate gallium can be obtained in an unconfined state by reduction of gallium‐acetylacetonate with LiAlH4. The products were analyzed by scanning electron microscopy, elemental analysis together with X‐ray diffraction, and thermal analysis. EXAFS investigations reveal, in accordance with the results from thermal analyses, that the particles are liquid at room temperature. The reason for the lower melting point could not be clarified within this study and might be caused either by the lower melting point of β‐gallium or by the small particle size of 10–20 nm. Upon cooling, several of the low‐temperature modifications of gallium are observed depending on cooling‐rate and temperature.
An Improved Correction for Range Restricted Correlations Under Extreme, Monotonic Quadratic Nonlinearity and Heteroscedasticity
Authors: Culpepper Steven Andrew
Published: May 2015

Standardized tests are frequently used for selection decisions, and the validation of test scores remains an important area of research. This paper builds upon prior literature about the effect of nonlinearity and heteroscedasticity on the accuracy of standard formulas for correcting correlations in restricted samples. Existing formulas for direct range restriction require three assumptions: (1) the criterion variable is missing at random; (2) a linear relationship between independent and dependent variables; and (3) constant error variance or homoscedasticity. The results in this paper demonstrate that the standard approach for correcting restricted correlations is severely biased in cases of extreme monotone quadratic nonlinearity and heteroscedasticity. This paper offers at least three significant contributions to the existing literature. First, a method from the econometrics literature is adapted to provide more accurate estimates of unrestricted correlations. Second, derivations establish bounds on the degree of bias attributed to quadratic functions under the assumption of a monotonic relationship between test scores and criterion measurements. New results are presented on the bias associated with using the standard range restriction correction formula, and the results show that the standard correction formula yields estimates of unrestricted correlations that deviate by as much as 0.2 for high to moderate selectivity. Third, Monte Carlo simulation results demonstrate that the new procedure for correcting restricted correlations provides more accurate estimates in the presence of quadratic and heteroscedastic test score and criterion relationships.
The Effects of Gendered Social Capital on U.S. Migration: A Comparison of Four Latin American Countries
Authors: Côté Rochelle R. , Jensen Jessica Eva , Roth Louise Marie , Way Sandra M.
Published: May 2015

This article contributes to understandings of gendered social capital by analyzing the effects of gendered ties on the migration of men and women from four Latin American countries (Mexico, Costa Rica, Nicaragua, and the Dominican Republic) to the United States. The research theorizes the importance of strong and weak ties to men and women in each sending country as a product of the gender equity gap in economic participation (low/high) and incidence of female-led families (low/high). The findings reveal that ties to men increase the odds of migration from countries where gender equity and incidence of female-led families are low, while ties to women are more important for migration from countries where gender equity and female-led families are high. Previous research on migration and social capital details the importance of network ties for providing resources and the role of gender in mediating social capital quality and access to network support. Results reveal that not only are different kinds of ties important to female and male migration, but migrants from different countries look to different sources of social capital for assistance.
Parameter asymmetry and time‐scale separation in core genetic commitment circuits
Authors: Xi Hongguang , Turcotte Marc
Published: May 2015

Theory allows studying why Evolution might select core genetic commitment circuit topologies over alternatives. The nonlinear dynamics of the underlying gene regulation together with the unescapable subtle interplay of intrinsic biochemical noise impact the range of possible evolutionary choices. The question of why certain genetic regulation circuits might present robustness to phenotype‐delivery breaking over others, is therefore of high interest. Here, the behavior of systematically more complex commitment circuits is studied, in the presence of intrinsic noise, with a focus on two aspects relevant to biology: parameter asymmetry and time‐scale separation. We show that phenotype delivery is broken in simple two‐ and three‐gene circuits. In the two‐gene circuit, we show how stochastic potential wells of different depths break commitment. In the three‐gene circuit, we show that the onset of oscillations breaks the commitment phenotype in a systematic way. Finally, we also show that higher dimensional circuits (four‐gene and five‐gene circuits) may be intrinsically more robust.
“First Things First”: Fetal Nasal Bone Imaging in the First Trimester 11–13+6 Weeks Scan
Authors: Ratha Chinmayee , Khurana Ashok
Published: May 2015

The first trimester scan is an important tool of risk assessment for fetal aneuploidies. The presence or absence of fetal nasal bone is an important secondary marker for risk allocation. This article describes the method of obtaining an ideal image for assessment of fetal nasal bone during the 11–13+6 weeks scan.
A toolbox for miRNA analysis
Authors: Svoboda Petr
Published: May 2015

MicroRNAs (miRNAs) are small regulatory RNAs, which mediate selective repression of gene expression. miRNAs play important roles in many natural and pathological processes. Numerous tools were developed for their detection and functional analysis. There are many excellent articles covering different areas of miRNA biology in detail. At the same time, I think there are many colleagues who face a miRNA‐related research problem and would appreciate having an introductory general overview of tools for miRNA analysis, which would help them in considering available options. Accordingly, this review provides an elementary roadmap to navigate among available tools for miRNA analysis. The most common problems and errors observed in miRNA research are also discussed.
Risk factors for stillbirths in Tete, Mozambique
Authors: Geelhoed Diederike , Stokx Jocelijn , Mariano Xavier , Mosse Lázaro Carla , Roelens Kristien
Published: May 2015

Objective

To evaluate known risk factors for stillbirth and identify local priorities for stillbirth prevention among institutional deliveries in Tete, Mozambique.

Methods

A case–control study was conducted among 150 women who experienced stillbirths and 300 women who experienced live deliveries at three health facilities between December 1, 2009, and April 30, 2011. Case and control individuals were matched for health facility, age, and parity. Sociodemographic, pregnancy, and delivery characteristics (including HIV and syphilis serology) were assessed. Bivariate associations and a conditional logistic regression model identified variables contributing to fetal outcome.

Results

No between‐group differences were recorded in the frequency of infection with HIV (25 [16.7%] cases vs 55 [18.3%] controls; P = 0.663) or syphilis (6 [4.0%] vs 16 [5.3%]; P = 0.536) at delivery. Multivariate analysis revealed that stillbirth was associated with direct obstetric complications (mutually adjusted odds ratio [OR] 6.7; 95% confidence interval [CI] 3.6–12.1), low socioeconomic status (mutually adjusted OR 1.8; 95% CI 1.1–3.1), and referral during childbirth (mutually adjusted OR 3.2; 95% CI 1.7–6.1).

Conclusion

Stillbirths in Tete, Mozambique, were predominantly caused by direct obstetric complications requiring referral among women of low socioeconomic status. Prenatal management of HIV and syphilis limited effects on fetal outcome. Emergency obstetric care and referral systems should be the focus of interventions aimed at stillbirth prevention.
Contraceptive need and use among individuals with HIV/AIDS living in the slums of Nairobi, Kenya
Authors: Wekesa Eliud , Coast Ernestina
Published: May 2015

Objective

To understand contraceptive need and use among individuals with HIV/AIDS living in slums.

Methods

A sequential mixed‐methods study was conducted in two slums in Nairobi, Kenya, from November 6th, 2009 to April 18th, 2010. Data were obtained by quantitative survey (n = 513), qualitative in‐depth interviews (n = 41), and key informant interviews (n = 14).

Results

In all, 250 (55.5%) participants used contraceptives. Condoms were the most frequently reported modern method (n = 142; 60.4%), followed by injectables (n = 55; 23.4%) and dual methods (n = 38; 15.3%). Unmet need was reported by 151 (33.6%) individuals. Factors associated with contraceptive use were education, marital status, number of living children, discussion of contraception with a provider, and social support. Personal, conceptual, and structural barriers to contraceptive use were identified.

Conclusions

Individuals with HIV/AIDS wished to limit their fertility but experienced high unmet need for contraception. Multi‐level interventions, including educational campaigns and integration of HIV and family planning services, are required to overcome barriers.
Yakammaoto inhibits enterovirus 71 infection by reducing viral attachment, internalization, replication, and translation
Authors: Yeh Chia‐Feng , Wang Kuo‐Chih , Lu Chi‐Yu , Chiang Lien‐Chai , Shieh Den‐En , Yen Ming‐Hong , Chang Jung‐San
Published: May 2015

Enterovirus 71 (EV71) can cause central nervous system infections with mortality and neurologic sequelae. At present, there is no effective therapeutic modality for EV71 infection. The infection is more common in families with poor socioeconomic status. Therefore, finding a readily available, cost‐effective therapeutic modality would be very helpful to these socioeconomically disadvantaged families. Yakammaoto is a cheap and readily available traditional prescription that is proven to have antiviral activity against coxsackievirus B4 (CVB4). CVB4 and EV71 are enteroviruses. In this study, we evaluated the antiviral activity of hot water extract of yakammaoto against EV71. The results of plaque reduction assay and flow cytometry demonstrated that yakammaoto dose dependently inhibited EV71 infection. In addition, reverse transcription‐polymerase chain reaction (RT‐PCR) and quantitative RT‐PCR results showed that yakammaoto reduced viral replication. Western blotting analysis showed that yakammaoto can inhibit viral protein production. Thus, our results suggest that yakammaoto should be considered to manage EV71 infection in the future.
BRCA1‐like signature in triple negative breast cancer: Molecular and clinical characterization reveals subgroups with therapeutic potential
Authors: Severson Tesa M. , Peeters Justine , Majewski Ian , Michaut Magali , Bosma Astrid , Schouten Philip C. , Chin Suet-Feung , Pereira Bernard , Goldgraben Mae A. , Bismeijer Tycho , Kluin Roelof J.C. , Muris Jettie J.F. , Jirström Karin , Kerkhoven Ron M. , Wessels Lodewyk , Caldas Carlos , Bernards René , Simon Iris M. , Linn Sabine
Published: May 2015

Triple negative (TN) breast cancers make up some 15% of all breast cancers. Approximately 10–15% are mutant for the tumor suppressor, BRCA1. BRCA1 is required for homologous recombination‐mediated DNA repair and deficiency results in genomic instability. BRCA1‐mutated tumors have a specific pattern of genomic copy number aberrations that can be used to classify tumors as BRCA1‐like or non‐BRCA1‐like. BRCA1 mutation, promoter methylation, BRCA1‐like status and genome‐wide expression data was determined for 112 TN breast cancer samples with long‐term follow‐up. Mutation status for 21 known DNA repair genes and PIK3CA was assessed. Gene expression and mutation frequency in BRCA1‐like and non‐BRCA1‐like tumors were compared. Multivariate survival analysis was performed using the Cox proportional hazards model. BRCA1 germline mutation was identified in 10% of patients and 15% of tumors were BRCA1 promoter methylated. Fifty‐five percent of tumors classified as BRCA1‐like. The functions of genes significantly up‐regulated in BRCA1‐like tumors included cell cycle and DNA recombination and repair. TP53 was found to be frequently mutated in BRCA1‐like (P < 0.05), while PIK3CA was frequently mutated in non‐BRCA1‐like tumors (P < 0.05). A significant association with worse prognosis was evident for patients with BRCA1‐like tumors (adjusted HR = 3.32, 95% CI = 1.30–8.48, P = 0.01). TN tumors can be further divided into two major subgroups, BRCA1‐like and non‐BRCA1‐like with different mutation and expression patterns and prognoses. Based on these molecular patterns, subgroups may be more sensitive to specific targeted agents such as PI3K or PARP inhibitors.
Diffraction and radiation loads on open cylinders of thin and arbitrary shapes
Authors: Hariri Nokob Mohamed , Yeung Ronald W.
Published: May 2015

We study the effects of having an opening in a vertical cylinder of an arbitrary cross-sectional shape when subjected to incident waves from the outside field. Both the diffraction and radiation problems of linear potential-flow theory are addressed. The cylinders considered are bottom-mounted with vanishing thickness and the problem is formulated as a hypersingular boundary-integral method. A simple higher-order procedure is presented to handle the strong singularity. Comparisons are made between the hydrodynamic properties of open and closed cylinders, and the effects of increasing the opening size are discussed and explained. Results for square, circular and elliptical open cylindrical shells, presented as examples, indicate that wave loads on the structures could be dramatically decreased to zero (effectively) at certain frequencies and opening sizes. This leads to the surprising conclusion that directing an open structure into the incident-wave field results in lower loads on the structure. A model of an open harbour with a frontal breakwater in a wave field, inspired by the idea of the Portunus Project, is also analysed.
Effect of a mesh on boundary layer transitions induced by free-stream turbulence and an isolated roughness element
Authors: Phani Kumar P. , Mandal A. C. , Dey J.
Published: May 2015

Streamwise streaks, their lift-up and streak instability are integral to the bypass transition process. An experimental study has been carried out to find the effect of a mesh placed normal to the flow and at different wall-normal locations in the late stages of two transitional flows induced by free-stream turbulence (FST) and an isolated roughness element. The mesh causes an approximately 30 % reduction in the free-stream velocity, and mild acceleration, irrespective of its wall-normal location. Interestingly, when located near the wall, the mesh suppresses several transitional events leading to transition delay over a large downstream distance. The transition delay is found to be mainly caused by suppression of the lift-up of the high-shear layer and its distortion, along with modification of the spanwise streaky structure to an orderly one. However, with the mesh well away from the wall, the lifted-up shear layer remains largely unaffected, and the downstream boundary layer velocity profile develops an overshoot which is found to follow a plane mixing layer type profile up to the free stream. Reynolds stresses, and the size and strength of vortices increase in this mixing layer region. This high-intensity disturbance can possibly enhance transition of the accelerated flow far downstream, although a reduction in streamwise turbulence intensity occurs over a short distance downstream of the mesh. However, the shape of the large-scale streamwise structure in the wall-normal plane is found to be more or less the same as that without the mesh.
The spreading and stability of a surfactant-laden drop on an inclined prewetted substrate
Authors: Goddard J. V. , Naire S.
Published: May 2015

We consider a viscous drop, loaded with an insoluble surfactant, spreading over an inclined plane that is covered initially with a thin surfactant-free liquid film. Lubrication theory is employed to model the flow using coupled nonlinear evolution equations for the film thickness and surfactant concentration. Exploiting high-resolution numerical simulations, we describe the late-time multi-region asymptotic structure of the spatially one-dimensional spreading flow. A simplified differential–algebraic equation model is derived for key variables characterising the spreading process, using which the late-time spreading and thinning rates are determined. Focusing on the neighbourhood of the drop’s leading-edge effective contact line, we then examine the stability of this region to small-amplitude disturbances with transverse variation. A dispersion relationship is described using long-wavelength asymptotics and numerical simulations, which reveals physical mechanisms and new scaling properties of the instability.
Ellen van Neerven, 'Heat and Light', Brisbane: University of Queensland Press, 2014, ISBN 9780 7022 5321 8, 226 pp, $22.95
Authors: Gildersleeve Jessica
Published: May 2015

Ellen van Neerven, Heat and Light, Brisbane: University of Queensland Press, 2014, ISBN 9780 7022 5321 8, 226 pp, $22.95
Michelle Maloney and Peter Burdon (eds), 'Wild Law: In Practice', Abingdon: Routledge, 2014, ISBN 9 7804 1566 3342 2, 272 pp., $140.00
Authors: McCabe Ingrid
Published: May 2015

Michelle Maloney and Peter Burdon (eds), Wild Law: In Practice, Abingdon: Routledge, 2014, ISBN 9 7804 1566 3342 2, 272 pp., $140.00
Henrik Ibsen, 'A Doll’s House'. Adapted by Lally Katz and directed by Steven Mitchell Wright. La Boite Theatre, September 2014
Authors: Lee Elspeth
Published: May 2015

Henrik Ibsen, A Doll’s House. Adapted by Lally Katz and directed by Steven Mitchell Wright. La Boite Theatre, September 2014
'Macbeth', Director Michael Attenborough, Queensland Theatre Company, 24 March to 13 April 2014
Authors: Adams Cordelia
Published: May 2015

Macbeth, Director Michael Attenborough, Queensland Theatre Company, 24 March to 13 April 2014
Policing the G20 protests
Authors: Legrand Tim , Bronitt Simon
Published: May 2015

In the months leading up to November’s G20 summit in 2014, Brisbane’s residents would have been forgiven for anticipating the outbreak of a local civil war. Media outlets were leading with headlines stating, among other sensational claims, that ‘G20 anarchists vow chaos and mayhem for Brisbane’s streets’, ‘Black Bloc tactics aim for Brisbane G20 shock and awe’2 and ‘Destructive protest plan for G20’. We argue that the safety and security of G20 participants and protesters owed little to the restrictive powers granted by the G20 Act, but resulted from a policing strategy that successfully married traditional and modern precepts of policing large events.
'Ropes of stories'
Authors: Gildersleeve Jessica
Published: May 2015

Cultural narratives function as lifelines in the work of Queensland Indigenous woman writer, Vivienne Cleven. Cleven's novel, Bitin’ Back (2001), begins when Mavis Dooley's son, Nevil, announces that he is no longer Nevil, but the writer Jean Rhys. Although Nevil eventually reveals that he has simply been acting as a woman in order to understand the protagonist of the novel he is writing, his choice of Rhys in particular is significant. Nevil selected Jean Rhys as a signifier of his female role because, he explains:

'She's my favourite author; she wrote Wide Sargasso Sea [1966]. She was ahead of her time; she wrote about society's underdogs; about rejection and the madness of isolation. I know it sounds all crazy to you, Ma, but this is about who I am . . . [A] lot of people would never understand me and they wouldn't want to' (2001: 184).
Collection: Years of agony and joy: The Sadie and Xavier Herbert Collection
Authors: Farley Simon
Published: May 2015

Years of agony and joy: The Sadie and Xavier Herbert Collection
SMOOTH BIMODULES AND COHOMOLOGY OF II1 FACTORS
Authors: Galatan Alin , Popa Sorin
Published: May 2015

We prove that, under rather general conditions, the 1-cohomology of a von Neumann algebra $M$ with values in a Banach $M$-bimodule satisfying a combination of smoothness and operatorial conditions vanishes. For instance, we show that, if $M$ acts normally on a Hilbert space ${\mathcal{H}}$ and ${\mathcal{B}}_{0}\subset {\mathcal{B}}({\mathcal{H}})$ is a norm closed $M$-bimodule such that any $T\in {\mathcal{B}}_{0}$ is smooth (i.e., the left and right multiplications of $T$ by $x\in M$ are continuous from the unit ball of $M$ with the $s^{\ast }$-topology to ${\mathcal{B}}_{0}$ with its norm), then any derivation of $M$ into ${\mathcal{B}}_{0}$ is inner. The compact operators are smooth over any $M\subset {\mathcal{B}}({\mathcal{H}})$, but there is a large variety of non-compact smooth elements as well.
Spreading the Word About Climate Change
Authors:   Alexandra
Published: May 2015

It has been 1 year since the release of the third U.S. National Climate Assessment. What has been learned over this year, and how can you help to inform the public about these important results?
Geniposide promotes beta-cell regeneration and survival through regulating β-catenin/TCF7L2 pathway
Authors: Yao D D , Yang L , Wang Y , Liu C , Wei Y J , Jia X B , Yin W , Shu L
Published: May 2015

T-cell factor 7-like 2 (TCF7L2) is an important transcription factor of Wnt/β-catenin signaling, which has critical roles in β-cell survival and regeneration. In preliminary screening assay, we found geniposide, a naturally occurring compound, was able to increase TCF7L2 mRNA level in Min6 cells. Here we aimed to investigate the role of geniposide in β-cell and underlying mechanism involved. Geniposide was found to promote β-cell survival by increasing β-cell proliferation and decreasing β-cell apoptosis in cultured mouse islets after challenge with diabetic stimuli. Geniposide protected β-cell through activating Wnt signaling, enhanced expressions of TCF7L2 and GLP-1R, activated AKT, inhibited GSK3β activity, and promoted β-catenin nuclear translocation. The protective effect of geniposide was remarkably suppressed by siRNAs against β-catenin, or by ICG001 (β-catenin/TCF-mediated transcription inhibitor). Moreover, geniposide promoted β-cell regeneration in vivo to normalize blood glucose in high-fat diet and db/db mice. Increased β-cell proliferation was observed in pancreatic sections of geniposide-treated diabetic mice. Most importantly, geniposide triggered small islet-like cell clusters formation as a result of β-cell neogenesis from ductal epithelium, which was well correlated with the increase in TCF7L2 expression. In exocrine cells isolated from mouse pancreas, geniposide could induce duct cell differentiation through upregulating TCF7L2 expression and activating JAK2/STAT3 pathway. Taken together, we identified a novel role of geniposide in promoting β-cell survival and regeneration by mechanisms involving the activation of β-catenin/TCF7L2 signaling. Our finding highlights the potential value of geniposide as a possible treatment for type 2 diabetes.
Ubiquinone-binding site mutagenesis reveals the role of mitochondrial complex II in cell death initiation
Authors: Kluckova K , Sticha M , Cerny J , Mracek T , Dong L , Drahota Z , Gottlieb E , Neuzil J , Rohlena J
Published: May 2015

Respiratory complex II (CII, succinate dehydrogenase, SDH) inhibition can induce cell death, but the mechanistic details need clarification. To elucidate the role of reactive oxygen species (ROS) formation upon the ubiquinone-binding (Qp) site blockade, we substituted CII subunit C (SDHC) residues lining the Qpsite by site-directed mutagenesis. Cell lines carrying these mutations were characterized on the bases of CII activity and exposed to Qpsite inhibitors MitoVES, thenoyltrifluoroacetone (TTFA) and Atpenin A5. We found that I56F and S68A SDHC variants, which support succinate-mediated respiration and maintain low intracellular succinate, were less efficiently inhibited by MitoVES than the wild-type (WT) variant. Importantly, associated ROS generation and cell death induction was also impaired, and cell death in the WT cells was malonate and catalase sensitive. In contrast, the S68A variant was much more susceptible to TTFA inhibition than the I56F variant or the WT CII, which was again reflected by enhanced ROS formation and increased malonate- and catalase-sensitive cell death induction. The R72C variant that accumulates intracellular succinate due to compromised CII activity was resistant to MitoVES and TTFA treatment and did not increase ROS, even though TTFA efficiently generated ROS at low succinate in mitochondria isolated from R72C cells. Similarly, the high-affinity Qpsite inhibitor Atpenin A5 rapidly increased intracellular succinate in WT cells but did not induce ROS or cell death, unlike MitoVES and TTFA that upregulated succinate only moderately. These results demonstrate that cell death initiation upon CII inhibition depends on ROS and that the extent of cell death correlates with the potency of inhibition at the Qpsite unless intracellular succinate is high. In addition, this validates the Qpsite of CII as a target for cell death induction with relevance to cancer therapy.
PD-1 and Tim-3 pathways are associated with regulatory CD8+ T-cell function in decidua and maintenance of normal pregnancy
Authors: Wang S-C , Li Y-H , Piao H-L , Hong X-W , Zhang D , Xu Y-Y , Tao Y , Wang Y , Yuan M-M , Li D-J , Du M-R
Published: May 2015

CD8+ T cells are critical in the balance between fetal tolerance and antiviral immunity. T-cell immunoglobulin mucin-3 (Tim-3) and programmed cell death-1 (PD-1) are important negative immune regulatory molecules involved in viral persistence and tumor metastasis. Here, we demonstrate that Tim-3+PD-1+CD8+ T cells from decidua greatly outnumbered those from peripheral blood during human early pregnancy. Co-culture of trophoblasts with CD8+ T cells upregulated PD-1+ and/or Tim-3+ immune cells. Furthermore, the population of CD8+ T cells co-expressing PD-1 and Tim-3 was enriched within the intermediate memory subset in decidua. This population exhibited high proliferative activity and Th2-type cytokine producing capacity. Blockade of Tim-3 and PD-1 resulted in decreased in vitro proliferation and Th2-type cytokine production while increased trophoblast killing and IFN-γ producing capacities of CD8+ T cells. Pregnant CBA/J females challenged with Tim-3 and/or PD-1 blocking antibodies were more susceptible to fetal loss, which was associated with CD8+ T-cell dysfunction. Importantly, the number and function of Tim-3+PD-1+CD8+ T cells in decidua were significantly impaired in miscarriage. These findings underline the important roles of Tim-3 and PD-1 pathways in regulating decidual CD8+ T-cell function and maintaining normal pregnancy.
Neuronal developmental gene and miRNA signatures induced by histone deacetylase inhibitors in human embryonic stem cells
Authors: Meganathan K , Jagtap S , Srinivasan S P , Wagh V , Hescheler J , Hengstler J , Leist M , Sachinidis A
Published: May 2015

Human embryonic stem cells (hESCs) may be applied to develop human-relevant sensitive in vitro test systems for monitoring developmental toxicants. The aim of this study was to identify potential developmental toxicity mechanisms of the histone deacetylase inhibitors (HDAC) valproic acid (VPA), suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA) relevant to the in vivo condition using a hESC model in combination with specific differentiation protocols and genome-wide gene expression and microRNA profiling. Analysis of the gene expression data showed that VPA repressed neural tube and dorsal forebrain (OTX2, ISL1, EMX2 and SOX10)-related transcripts. In addition, VPA upregulates axonogenesis and ventral forebrain-associated genes, such as SLIT1, SEMA3A, DLX2/4 and GAD2. HDACi-induced expression of miR-378 and knockdown of miR-378 increases the expression of OTX2 and EMX2, which supports our hypothesis that HDACi targets forebrain markers through miR-378. In conclusion, multilineage differentiation in vitro test system is very sensitive for monitoring molecular activities relevant to in vivo neuronal developmental toxicity. Moreover, miR-378 seems to repress the expression of the OTX2 and EMX2 and therefore could be a regulator of the development of neural tube and dorsal forebrain neurons.
Podocyte apoptosis is prevented by blocking the Toll-like receptor pathway
Authors: Saurus P , Kuusela S , Lehtonen E , Hyvönen M E , Ristola M , Fogarty C L , Tienari J , Lassenius M I , Forsblom C , Lehto M , Saleem M A , Groop P-H , Holthöfer H , Lehtonen S
Published: May 2015

High serum lipopolysaccharide (LPS) activity in normoalbuminuric patients with type 1 diabetes (T1D) predicts the progression of diabetic nephropathy (DN), but the mechanisms behind this remain unclear. We observed that treatment of cultured human podocytes with sera from normoalbuminuric T1D patients with high LPS activity downregulated 3-phosphoinositide-dependent kinase-1 (PDK1), an activator of the Akt cell survival pathway, and induced apoptosis. Knockdown of PDK1 in cultured human podocytes inhibited antiapoptotic Akt pathway, stimulated proapoptotic p38 MAPK pathway, and increased apoptosis demonstrating an antiapoptotic role for PDK1 in podocytes. Interestingly, PDK1 was downregulated in the glomeruli of diabetic rats and patients with type 2 diabetes before the onset of proteinuria, further suggesting that reduced expression of PDK1 associates with podocyte injury and development of DN. Treatment of podocytes in vitro and mice in vivo with LPS reduced PDK1 expression and induced apoptosis, which were prevented by inhibiting the Toll-like receptor (TLR) signaling pathway with the immunomodulatory agent GIT27. Our data show that LPS downregulates the cell survival factor PDK1 and induces podocyte apoptosis, and that blocking the TLR pathway with GIT27 may provide a non-nephrotoxic means to prevent the progression of DN.
Divergent effects of RIP1 or RIP3 blockade in murine models of acute liver injury
Authors: Deutsch M , Graffeo C S , Rokosh R , Pansari M , Ochi A , Levie E M , Van Heerden E , Tippens D M , Greco S , Barilla R , Tomkötter L , Zambirinis C P , Avanzi N , Gulati R , Pachter H L , Torres-Hernandez A , Eisenthal A , Daley D , Miller G
Published: May 2015

Necroptosis is a recently described Caspase 8-independent method of cell death that denotes organized cellular necrosis. The roles of RIP1 and RIP3 in mediating hepatocyte death from acute liver injury are incompletely defined. Effects of necroptosis blockade were studied by separately targeting RIP1 and RIP3 in diverse murine models of acute liver injury. Blockade of necroptosis had disparate effects on disease outcome depending on the precise etiology of liver injury and component of the necrosome targeted. In ConA-induced autoimmune hepatitis, RIP3 deletion was protective, whereas RIP1 inhibition exacerbated disease, accelerated animal death, and was associated with increased hepatocyte apoptosis. Conversely, in acetaminophen-mediated liver injury, blockade of either RIP1 or RIP3 was protective and was associated with lower NLRP3 inflammasome activation. Our work highlights the fact that diverse modes of acute liver injury have differing requirements for RIP1 and RIP3; moreover, within a single injury model, RIP1 and RIP3 blockade can have diametrically opposite effects on tissue damage, suggesting that interference with distinct components of the necrosome must be considered separately.
Stochasticity, periodicity and localized light structures in partially mode-locked fibre lasers
Authors: Churkin D. V. , Sugavanam S. , Tarasov N. , Khorev S. , Smirnov S. V. , Kobtsev S. M. , Turitsyn S. K.
Published: May 2015

Physical systems with co-existence and interplay of processes featuring distinct spatio-temporal scales are found in various research areas ranging from studies of brain activity to astrophysics. The complexity of such systems makes their theoretical and experimental analysis technically and conceptually challenging. Here, we discovered that while radiation of partially mode-locked fibre lasers is stochastic and intermittent on a short time scale, it exhibits non-trivial periodicity and long-scale correlations over slow evolution from one round-trip to another. A new technique for evolution mapping of intensity autocorrelation function has enabled us to reveal a variety of localized spatio-temporal structures and to experimentally study their symbiotic co-existence with stochastic radiation. Real-time characterization of dynamical spatio-temporal regimes of laser operation is set to bring new insights into rich underlying nonlinear physics of practical active- and passive-cavity photonic systems.
JMJD1A is a signal-sensing scaffold that regulates acute chromatin dynamics via SWI/SNF association for thermogenesis
Authors: Abe Yohei , Rozqie Royhan , Matsumura Yoshihiro , Kawamura Takeshi , Nakaki Ryo , Tsurutani Yuya , Tanimura-Inagaki Kyoko , Shiono Akira , Magoori Kenta , Nakamura Kanako , Ogi Shotaro , Kajimura Shingo , Kimura Hiroshi , Tanaka Toshiya , Fukami Kiyoko , Osborne Timothy F. , Kodama Tatsuhiko , Aburatani Hiroyuki , Inagaki Takeshi , Sakai Juro
Published: May 2015

Histone 3 lysine 9 (H3K9) demethylase JMJD1A regulates β-adrenergic-induced systemic metabolism and body weight control. Here we show that JMJD1A is phosphorylated at S265 by protein kinase A (PKA), and this is pivotal to activate the β1-adrenergic receptor gene (Adrb1) and downstream targets including Ucp1 in brown adipocytes (BATs). Phosphorylation of JMJD1A by PKA increases its interaction with the SWI/SNF nucleosome remodelling complex and DNA-bound PPARγ. This complex confers β-adrenergic-induced rapid JMJD1A recruitment to target sites and facilitates long-range chromatin interactions and target gene activation. This rapid gene induction is dependent on S265 phosphorylation but not on demethylation activity. Our results show that JMJD1A has two important roles in regulating hormone-stimulated chromatin dynamics that modulate thermogenesis in BATs. In one role, JMJD1A is recruited to target sites and functions as a cAMP-responsive scaffold that facilitates long-range chromatin interactions, and in the second role, JMJD1A demethylates H3K9 di-methylation.
Competition between recombination and extraction of free charges determines the fill factor of organic solar cells
Authors: Bartesaghi Davide , Pérez Irene del Carmen , Kniepert Juliane , Roland Steffen , Turbiez Mathieu , Neher Dieter , Koster L. Jan Anton
Published: May 2015

Among the parameters that characterize a solar cell and define its power-conversion efficiency, the fill factor is the least well understood, making targeted improvements difficult. Here we quantify the competition between charge extraction and recombination by using a single parameter θ, and we demonstrate that this parameter is directly related to the fill factor of many different bulk-heterojunction solar cells. Our finding is supported by experimental measurements on 15 different donor:acceptor combinations, as well as by drift-diffusion simulations of organic solar cells in which charge-carrier mobilities, recombination rate, light intensity, energy levels and active-layer thickness are all varied over wide ranges to reproduce typical experimental conditions. The results unify the fill factors of several very different donor:acceptor combinations and give insight into why fill factors change so much with thickness, light intensity and materials properties. To achieve fill factors larger than 0.8 requires further improvements in charge transport while reducing recombination.
Thermally induced collision of droplets in an immiscible outer fluid
Authors: Davanlou Ashkan , Kumar Ranganathan
Published: May 2015

Micro-total analysis systems (μTAS) have attracted wide attention and are identified as a promising solution for sample transport, filtration, chemical reactions, separation and detection. Despite their popularity, the selection of an appropriate mechanism for droplet transport and coalescence has always been a challenge. This paper investigates the use of Marangoni flow as a mechanism for levitating and transporting droplets on immiscible liquid films at higher speeds than is possible currently. For the first time, we show that it is possible to realize the natural coalescence of droplets through Marangoni effect without any external stimulation and deliver the coalesced droplet to a certain destination through the use of surface tension gradients. The effects of shape and size on collision outcome are studied. Regions of coalescence and stretching separation of colliding droplets are delineated based on Weber number and impact number. In addition, the effect of viscosity on post collision regimes is studied. The findings in this fundamental study can be beneficial to many applications such as welding, drug delivery and microfluidics devices in controlling small droplets and targeting them to various locations.
On granular elasticity
Authors: Sun Qicheng , Jin Feng , Wang Guangqian , Song Shixiong , Zhang Guohua
Published: May 2015

Mesoscopic structures form in dense granular materials due to the self-organisation of the constituent particles. These structures have internal structural degrees of freedom in addition to the translational degree of freedom. The resultant granular elasticity, which exhibits intrinsic variations and inevitable relaxation, is a key quantity that accounts for macroscopic solid- or fluid-like properties and the transitions between them. In this work, we propose a potential energy landscape (PEL) with local stable basins and low elastic energy barriers to analyse the nature of granular elasticity. A function for the elastic energy density is proposed for stable states and is further calibrated with ultrasonic measurements. Fluctuations in the elastic energy due to the evolution of internal structures are proposed to describe a so-called configuration temperature Tc as a counterpart of the classical kinetic granular temperature Tk that is attributed to the translational degrees of freedom. The two granular temperatures are chosen as the state variables and a fundamental equation is established to develop non-equilibrium thermodynamics for granular materials. Due to the relatively low elastic energy barrier in the PEL, granular elasticity relaxes more under common mechanical loadings and a simple model based on mean-field theory is developed to account for this behaviour.
Using “Tender” X-ray Ambient Pressure X-Ray Photoelectron Spectroscopy as A Direct Probe of Solid-Liquid Interface
Authors: Axnanda Stephanus , Crumlin Ethan J. , Mao Baohua , Rani Sana , Chang Rui , Karlsson Patrik G. , Edwards Mårten O. M. , Lundqvist Måns , Moberg Robert , Ross Phil , Hussain Zahid , Liu Zhi
Published: May 2015

We report a new method to probe the solid-liquid interface through the use of a thin liquid layer on a solid surface. An ambient pressure XPS (AP-XPS) endstation that is capable of detecting high kinetic energy photoelectrons (7 keV) at a pressure up to 110 Torr has been constructed and commissioned. Additionally, we have deployed a “dip & pull” method to create a stable nanometers-thick aqueous electrolyte on platinum working electrode surface. Combining the newly constructed AP-XPS system, “dip & pull” approach, with a “tender” X-ray synchrotron source (2 keV–7 keV), we are able to access the interface between liquid and solid dense phases with photoelectrons and directly probe important phenomena occurring at the narrow solid-liquid interface region in an electrochemical system. Using this approach, we have performed electrochemical oxidation of the Pt electrode at an oxygen evolution reaction (OER) potential. Under this potential, we observe the formation of both Pt2+ and Pt4+ interfacial species on the Pt working electrode in situ. We believe this thin-film approach and the use of “tender” AP-XPS highlighted in this study is an innovative new approach to probe this key solid-liquid interface region of electrochemistry.
A seed mixture increases dominance of resistance to Bt cotton in Helicoverpa zea
Authors: Brévault Thierry , Tabashnik Bruce E. , Carrière Yves
Published: May 2015

Widely grown transgenic crops producing insecticidal proteins from Bacillus thuringiensis (Bt) can benefit agriculture, but adaptation by pests threatens their continued success. Refuges of host plants that do not make Bt toxins can promote survival of susceptible insects and delay evolution of resistance, particularly if resistance is inherited as a recessive trait. However, data have been lacking to compare the dominance of resistance when Bt and non-Bt seeds are planted in random mixtures versus separate blocks. Here we report results from greenhouse experiments with transgenic cotton producing Bt toxin Cry1Ac and the bollworm, Helicoverpa zea, showing that the dominance of resistance was significantly higher in a seed mixture relative to a block of Bt cotton. The proportion of larvae on non-Bt cotton plants in the seed mixture was also significantly higher than expected under the null hypothesis of random distribution. In simulations based on observed survival, resistance evolved 2- to 4.5-fold faster in the seed mixture relative to separate blocks of Bt and non-Bt cotton. These findings support previous modelling results indicating that block refuges may be more effective than seed mixtures for delaying resistance in pests with mobile larvae and inherently low susceptibility to the toxins in Bt crops.