bluuebunny/crossref_metadata_2025 huggingface dataset:
Presynaptic and postsynaptic regulation of muscle contractions in the ascarid nematodeAscaris suum: a target for drug action
Authors: Trailović S.M. , Zurovac Z. , Gruborović S. , Marjanović D.S. , Nedeljković-Trailović J.
Published: November 2015

The aim of this study was to determine the role in contractions of postsynaptic nicotinic acetylcholine (nACh) and γ-aminobutyric acid (GABA) receptors, in the bag region ofAscaris suummuscle cells, as well as the role of synaptic receptors between interneurons and motor neurons in the dorsal and ventral nerve cord. We have measured the isometric contractions of isolated segments ofA. suum, with or without the nerve cord (dorsal or ventral). Contractions were caused by increasing concentrations of ACh or by electrical field stimulation (EFS). Based on our results, the presence of the nerve cord is essential for the contractile effects of ACh. The EC50value of ACh for innervated muscle strips was 10.88 μm. Unlike intact (innervated) preparations, there was no contraction of the muscle flaps when the nerve cord was mechanically removed. Furthermore, continuous EFS produced stable contractions of innervated muscle strips, but they are not sensitive to mecamylamine (100 μm). However, GABA (30 μm) significantly inhibited the EFS-induced contractions. EFS with the same characteristics did not cause muscle contractions of denervated muscle strips, but EFS with a wider pulse induced the increasing of tone and irregular contractions. These contractions were completely insensitive to the effect of GABA. The EC50for ACh did not differ between the dorsal and ventral segments (9.83 μmand 9.45 μm), while GABA exhibited features of competitive and non-competitive antagonists, regardless of whether it acted on the dorsal or ventral segments ofA. suum. It is obvious that drugs will be more effective if they act on both the synaptic and extrasynaptic nACh and GABA receptors.
Increased risk of sudden sensorineural hearing loss in patients with depressive disorders: population-based cohort study
Authors: Lin C-S , Lin Y-S , Liu C-F , Weng S-F , Lin C , Lin B-S
Published: November 2015

Objectives:

To evaluate the incidence rates and risk of sudden sensorineural hearing loss among patients with depressive disorders.

Method:

Data for 27 547 patients with newly diagnosed depressive disorders and 27 547 subjects without depressive disorders between 2001 and 2008 were yielded from the Taiwan National Health Insurance Research Database. Sudden sensorineural hearing loss incidence at the end of 2011 was determined. Cumulative incidence and adjusted hazard ratio were computed.

Results:

Sudden sensorineural hearing loss incidence was 1.45 times higher in the depressive disorders group compared to the non-depressive disorders group (p = 0.0041), with an adjusted hazard ratio of 1.460. A significant increased risk of developing sudden sensorineural hearing loss was noted in patients with diabetes mellitus, chronic kidney disease and hyperlipidaemia (p < 0.05).

Conclusion:

The results suggest an increased risk of developing sudden sensorineural hearing loss in patients with depressive disorders. Co-morbidities such as diabetes mellitus, chronic kidney disease and hyperlipidaemia significantly aggravated the risk. Depressive disorders might be considered a risk factor for sudden sensorineural hearing loss. It remains to be seen whether control of depressive disorders can decrease the incidence of sudden sensorineural hearing loss in patients with depressive disorders.
Asynchronous Pseudolite Navigation Using C/N0Measurements
Authors: Borio Daniele , Gioia Ciro , Baldini Gianmarco
Published: November 2015

The problem of indoor navigation is investigated using a Commercial Off-the-Shelf (COTS) pseudolite system. The system is operated in synchronous and asynchronous mode. It is shown that, when the system is operated in synchronous mode, it is unsuitable for deep indoor operations: in complex propagation environments, the synchronisation required for metre level navigation is difficult to achieve and different solutions have to be adopted. Two asynchronous approaches are thus considered and indoor navigation with metre level accuracy is demonstrated using C/N0measurements. The approaches use a modified Receiver Signal Strength (RSS) navigation algorithm and a weighted centroid technique, respectively. In both cases, a pre-filtering stage has been adopted to enhance the quality of C/N0measurements. The two methods have been compared under different operating conditions and the advantages and drawbacks of the two techniques have been analysed. The experiments demonstrate that metre level accuracy can be achieved using asynchronous pseudolites. These results are particularly encouraging since they were obtained without exploiting map constraints and prior knowledge of the user position.
Children of the postwar years: A two-generational multilevel risk assessment of child psychopathology in northern Uganda
Authors: Saile Regina , Ertl Verena , Neuner Frank , Catani Claudia
Published: November 2015

In postconflict settings risk factors at multiple levels of the social ecology, including community, family, and relationship factors, potentially affect children's mental health. In addition, intergenerational risk factors such as guardians’ history of childhood family violence, war exposure, and psychopathology may contribute to children's psychopathological symptoms. In this study, we aimed to identify risk constellations that predict child internalizing and externalizing behavior problems, depression, and posttraumatic stress symptoms in the postconflict setting of northern Uganda. In a cross-sectional epidemiological study, 513 second-grade students and their female guardians were interviewed using standardized clinical questionnaires. A higher exposure to traumatic events, more witnessed or experienced violence within the family, and lower child-reported care from female guardians independently predicted psychopathological symptoms in children. While controlling for intergenerational risk factors in female guardians, serial mediation modeling revealed that the effect of trauma exposure on children's psychopathological symptoms was partially mediated by higher exposure to family violence and lower child-perceived care from female guardians. The mediation appeared to be stronger for children's depression symptoms and internalizing and externalizing behavior problems than for posttraumatic stress symptoms. The current findings support the need for targeted interventions at the individual and family system levels that are matched to children's psychopathological symptoms.
Trajectories of internalizing and externalizing symptoms among adults with autism spectrum disorders
Authors: Woodman Ashley C. , Mailick Marsha R. , Greenberg Jan S.
Published: November 2015

Individuals with autism spectrum disorder (ASD) experience higher rates of psychopathology than their typically developing peers or peers with other intellectual or developmental disabilities. Little is known about the developmental course of psychiatric symptoms such as internalizing and externalizing behaviors in this population. Individual characteristics and aspects of the family environment may explain variability in outcomes for adults with ASD. The present study extends our current understanding of psychopathology among individuals with ASD by examining group-based trajectories of internalizing and externalizing symptoms in adulthood. Overall, the results showed that symptoms became less severe over time. Distinct patterns of change in psychopathology were observed and associated with differential profiles of psychotropic medication use, comorbid mental health diagnoses, and residential placement. The likelihood of following each developmental trajectory was estimated based on characteristics of the adults with ASD (gender, adaptive behavior, and autistic symptoms) and maternal expressed emotion (criticism and warmth). Maternal criticism and warmth were identified as key risk and protective factors, respectively, with important implications for future research and intervention for individuals with ASD.
Familial influences on the full range of variability in attention and activity levels during adolescence: A longitudinal twin study
Authors: Peng Chun-Zi , Grant Julia D. , Heath Andrew C. , Reiersen Angela M. , Mulligan Richard C. , Anokhin Andrey P.
Published: November 2015

To investigate familial influences on the full range of variability in attention and activity across adolescence, we collected maternal ratings of 339 twin pairs at ages 12, 14, and 16, and estimated the transmitted and new familial influences on attention and activity as measured by the Strengths and Weaknesses of Attention-Deficit/Hyperactivity Disorder Symptoms and Normal Behavior Scale. Familial influences were substantial for both traits across adolescence: genetic influences accounted for 54%–73% (attention) and 31%–73% (activity) of the total variance, and shared environmental influences accounted for 0%–22% of the attention variance and 13%–57% of the activity variance. The longitudinal stability of individual differences in attention and activity was largely accounted for by familial influences transmitted from previous ages. Innovations over adolescence were also partially attributable to familial influences. Studying the full range of variability in attention and activity may facilitate our understanding of attention-deficit/hyperactivity disorder's etiology and intervention.
A semiotic perspective on webconferencing-supported language teaching
Authors: Guichon Nicolas , Wigham Ciara R.
Published: November 2015

In webconferencing-supported teaching, the webcam mediates and organizes the pedagogical interaction. Previous research has provided a mixed picture of the use of the webcam: while it is seen as a useful medium to contribute to the personalization of the interlocutors’ relationship, help regulate interaction and facilitate learner comprehension and involvement, the limited access to visual cues provided by the webcam is felt to be useless or even disruptive.

This study examines the meaning-making potential of the webcam in pedagogical interactions from a semiotic perspective by exploring how trainee teachers use the affordances of the webcam to produce non-verbal cues that may be useful for mutual comprehension. The research context is a telecollaborative project where trainee teachers of French as a foreign language (FFL) met for online sessions in French with undergraduate Business students at an Irish university. Using multimodal transcriptions of the interaction data from these sessions, screen shot data, and students’ post-course interviews, it was found, firstly, that while a head and shoulders framing shot was favoured by the trainee teachers, there does not appear to be an optimal framing choice for desktop videoconferencing among the three framing types identified. Secondly, there was a loss between the number of gestures performed by the trainee teachers and those that were visible for the students. Thirdly, when trainee teachers were able to coordinate the audio and kinesic modalities, communicative gestures that were framed, and held long enough to be perceived by the learners, were more likely to be valuable for mutual comprehension.

The study highlights the need for trainee teachers to develop critical semiotic awareness to gain a better perception of the image they project of themselves in order to actualise the potential of the webcam and add more relief to their online teacher presence.
How Regulatory Networks Shaped Institutional Reform under the EU Telecoms Framework
Authors: Boeger Nina , Corkin Joseph
Published: November 2015

This chapter considers the evolving institutional responses to the challenge of regulating telecoms in the EU, taking in the Commission’s push for creating an EU agency versus the resilience of the transnationally networked model, which is usually attributed to the Member States’ sovereignty reflex. Were recent negotiations over the reform of the Regulatory Framework for telecoms, concluded in 2009, simply a turf-war in which the Commission sought to extend the EU’s role against resistance from the Member States, or did the national telecoms regulators and their existing transnational network influence the eventual compromise to retain the soft law, networked model, albeit with some hardening? Characterised as a classic integration struggle, the Member States’ intergovernmental instincts were pitched against the Commission’s supranational instincts and its preference for instruments of control premised on the centralised exercise of hierarchical power. But this chapter paints a more fine-grained picture of the negotiation’s dynamics and especially the influence of the national regulatory authorities (NRAs) and their existing transnational network; a community of expertise that stood to have its role either strengthened or diminished in the revised institutional architecture. In doing so, the chapter moves beyond orthodox (intergovernmental and neofunctionalist) accounts of these dynamics to take an institutionalist approach that is better suited to analysing the EU as a mature system of governance.
Behavioural Economics and the Autonomous Consumer
Authors: Scholes Annette Nordhausen
Published: November 2015

This chapter takes as its starting point the ‘information approach’ which is the basis of current EU consumer protection legislation. It argues that the findings of behavioural economics suggest that the ‘information approach’ does not in practice achieve the protection of the consumer which it is trying to achieve. Insights and techniques gained from behavioural economics can be used as the basis for more effective consumer protection legislation, while at the same time respecting the principle of consumer autonomy which is the fundamental (though sometimes unstated) principle of EU internal market law.
Who’s Afraid of the Big, Bad European Public Prosecutor?
Authors: Spencer John R.
Published: November 2015

In 1997 the idea of a European Public Prosecutor was floated in the Corpus Juris Project as one of a series of measures designed to ensure that fraud on the Community budget would be detected and punished. This chapter describes how in the UK the proposal was misrepresented by the eurosceptic press, and how Parliament reacted to the distorted version by changing the law to render any future participation by the UK in a project to create a European Public Prosecutor practically impossible.
Social Legitimacy and the Court of Justice of the EU: Some Reflections on the Role of the Advocate General
Authors: Hinarejos Alicia
Published: November 2015

The Court of Justice of the European Union (CJEU, Court of Justice or Court, for short) operates in circumstances that are similar to those of a national constitutional court; at the same time, some significant features set it apart and make it more difficult for the Court of Justice to command the institutional loyalty or public support that national constitutional courts seem to enjoy in Europe. This chapter will, first, offer a brief overview of how and why the Court acquired a markedly political, and problematic, role within the judicial and legal system of the Union (Section II). Section III will then examine the different concepts of legitimacy that may be applied to courts and their decisions, focusing more specifically on the social dimension of legitimacy. This chapter will argue that the fact that the Court of Justice has to operate in a transnational context leads to a shortfall in its social legitimacy, at least when compared to national constitutional courts in Europe. Finally, Section IV will focus on the figure of the Advocate General as a mechanism that may lend some extra social legitimacy to the Court and its decisions—obviously without solving the problem completely—and that, more generally, may foster dialogue, debate and deliberative democracy in the Union.
A meta-analysis of neonatal health outcomes from oocyte donation
Authors: Adams D. H. , Clark R. A. , Davies M. J. , de Lacey S.
Published: November 2015

Donated oocytes are a treatment modality for female infertility which is also associated with increased risks of preeclampsia. Subsequently it is important to evaluate if there is concomitant increased risks for adverse neonatal events in donated oocyte neonates. A structured search of the literature using PubMed, EMBASE and Cochrane Reviews was performed to investigate the perinatal health outcomes of offspring conceived from donor oocytes compared with autologous oocytes. Meta-analysis was performed on comparable outcomes data. Twenty-eight studies were eligible and included in the review, and of these, 23 were included in a meta-analysis. Donor oocyte neonates are at increased risk of being born with low birth weight (<2500 g) [risk ratio (RR): 1.18, 95% confidence interval (CI): 1.14–1.22, P-value (P)<0.00001], very low birth weight (<1500 g) (RR: 1.24, CI: 1.15–1.35, P<0.00001), preterm (<37 weeks) (RR: 1.26, CI: 1.23–1.30, P<0.00001), of lower gestational age (mean difference −0.3 weeks, CI: −0.35 weeks to −0.25 weeks, P<0.00001), and preterm with low birth weight (RR: 1.24, CI: 1.19–1.29, P<0.00001), when compared with autologous oocyte neonates. Conversely, low birth weight outcomes were improved in term donor oocyte neonates (RR: 0.86, CI: 0.8–0.93, P=0.0003). These negative outcomes remained significant when controlling for multiple deliveries. The donor oocyte risk rates are higher than those found in general ART outcomes, are important considerations for the counselling of infertile patients and may also influence the long term health of the offspring.
Deciding to Cooperate in Northern Ghana: Trust as an Evolutionary Constraint Across Cultural Diversity
Authors: Acedo-Carmona Cristina , Gomila Antoni
Published: November 2015

The upper-east and northern regions of Ghana offers a unique opportunity to study the influence of evolutionary social dynamics in making cooperation possible, despite cultural differences. These regions are occupied by several distinct ethnic groups, in interaction, such as the Kussasi, Mamprusi, Bimoba, Konkomba, and Fulani. We will report our fieldwork related to how cooperation takes places there, both within each group and among people from the different groups. Methods included personal networks of cooperation (ego networks), interviews and analysis of group contexts. The most important result is that, while each ethnic group may differ in terms of family and clan structure, a similar pattern can be found in all of them, of cooperation structured around small groups of trust-based close relationships. The study suggests that habitual decisions about cooperation are not strategic or self-interested, but instead are based on unconscious processes sustained by the emotional bonds of trust. These kind of emotional bonds are claimed to be relevant from an evolutionary point of view.
Development of synthetic anti‐cyclic citrullinated peptide antibody and its arthritogenic role
Authors: Kim Youngkyun , Lee Jennifer , Jung Hyerin , Yi Hyoju , Rim Yeri Alice , Jung Seung Min , Ju Ji Hyeon
Published: November 2015

This study was undertaken to develop a novel anti‐citrullinated peptide antibody (ACPA) and to investigate its arthritogenicity in a collagen‐induced arthritis (CIA) model. The novel ACPA, 12G1, was developed by injecting cyclic citrullinated antigen in mice and subsequently hybridizing the B cells producing citrullinated peptide‐specific antibodies with a myeloma cell line. The arthritic joints of mice with CIA and collagen antibody‐induced arthritis (CAIA) as well as interleukin‐1 receptor antagonist (IL‐1Ra) knockout (KO) mice were stained immunohistochemically using the 12G1 antibody. Confocal immunostaining was used to identify colocalization of 12G1 with various citrullinated proteins. 12G1 in the presence or absence of chelating beads was administered to CIA mice on days 21 and 28 after type II collagen (CII) immunization to investigate 12G1 arthritogenecity. 12G1 detected citrullinated proteins in the arthritic joints of all the experimental arthritis models used. Confocal immunostaining showed that 12G1 was colocalized with well‐known citrullinated proteins, including vimentin, collagen, anti‐immunoglobulin binding protein and fibronectin. Staining of citrullinated proteins using 12G1 was more diffuse in CIA mice compared with CAIA and IL‐1Ra KO mice. 12G1 injection apparently acted as a booster of immunization in CIA mice in combination with a single CII immunization, with this effect being abolished when 12G1 was injected with chelating beads. The novel ACPA, 12G1, identified various citrullinated proteins in the arthritic joints of three experimental arthritis models. 12G1‐treated mice developed arthritis following a single CII immunization, suggesting an arthritogenic potential for ACPA in CIA mice.
Synbiotic approach restores intestinal homeostasis and prolongs survival in leukaemic mice with cachexia
Authors: Bindels Laure B , Neyrinck Audrey M , Claus Sandrine P , Le Roy Caroline I , Grangette Corinne , Pot Bruno , Martinez Inés , Walter Jens , Cani Patrice D , Delzenne Nathalie M
Published: November 2015

Cancer cachexia is a multifactorial syndrome that includes muscle wasting and inflammation. As gut microbes influence host immunity and metabolism, we investigated the role of the gut microbiota in the therapeutic management of cancer and associated cachexia. A community-wide analysis of the caecal microbiome in two mouse models of cancer cachexia (acute leukaemia or subcutaneous transplantation of colon cancer cells) identified common microbial signatures, including decreased Lactobacillus spp. and increased Enterobacteriaceae and Parabacteroides goldsteinii/ASF 519. Building on this information, we administered a synbiotic containing inulin-type fructans and live Lactobacillus reuteri 100-23 to leukaemic mice. This treatment restored the Lactobacillus population and reduced the Enterobacteriaceae levels. It also reduced hepatic cancer cell proliferation, muscle wasting and morbidity, and prolonged survival. Administration of the synbiotic was associated with restoration of the expression of antimicrobial proteins controlling intestinal barrier function and gut immunity markers, but did not impact the portal metabolomics imprinting of energy demand. In summary, this study provided evidence that the development of cancer outside the gut can impact intestinal homeostasis and the gut microbial ecosystem and that a synbiotic intervention, by targeting some alterations of the gut microbiota, confers benefits to the host, prolonging survival and reducing cancer proliferation and cachexia.
Aβ-dependent reduction of NCAM2-mediated synaptic adhesion contributes to synapse loss in Alzheimer’s disease
Authors: Leshchyns’ka Iryna , Liew Heng Tai , Shepherd Claire , Halliday Glenda M. , Stevens Claire H. , Ke Yazi D. , Ittner Lars M. , Sytnyk Vladimir
Published: November 2015

Alzheimer’s disease (AD) is characterized by synapse loss due to mechanisms that remain poorly understood. We show that the neural cell adhesion molecule 2 (NCAM2) is enriched in synapses in the human hippocampus. This enrichment is abolished in the hippocampus of AD patients and in brains of mice overexpressing the human amyloid-β (Aβ) precursor protein carrying the pathogenic Swedish mutation. Aβ binds to NCAM2 at the cell surface of cultured hippocampal neurons and induces removal of NCAM2 from synapses. In AD hippocampus, cleavage of the membrane proximal external region of NCAM2 is increased and soluble extracellular fragments of NCAM2 (NCAM2-ED) accumulate. Knockdown of NCAM2 expression or incubation with NCAM2-ED induces disassembly of GluR1-containing glutamatergic synapses in cultured hippocampal neurons. Aβ-dependent disassembly of GluR1-containing synapses is inhibited in neurons overexpressing a cleavage-resistant mutant of NCAM2. Our data indicate that Aβ-dependent disruption of NCAM2 functions in AD hippocampus contributes to synapse loss.
Petrologic Characteristics of the Lunar Surface
Authors: Wang Xianmin , Pedrycz Witold
Published: November 2015

Petrologic analysis of the lunar surface is critical for determining lunar formation and evolution. Here, we report the first global petrologic map that includes the five most important lunar lithological units: the Ferroan Anorthositic (FAN) Unit, the Magnesian Suite (MS) Unit, the Alkali Suite (AS) Unit, the KREEP Basalt (KB) Unit and the Mare Basalt (MB) Unit. Based on the petrologic map and focusing on four long-debated and important issues related to lunar formation and evolution, we draw the following conclusions from the new insights into the global distribution of the five petrologic units: (1) there may be no petrogenetic relationship between MS rocks and KB; (2) there may be no petrogenetic link between MS and AS rocks; (3) the exposure of the KREEP component on the lunar surface is likely not a result of MB volcanism but is instead mainly associated with the combined action of plutonic intrusion, KREEP volcanism and celestial collision; (4) the impact size of the South Pole-Aitken basin is constrained, i.e., the basin has been excavated through the whole crust to exhume a vast majority of lower-crustal material and a very limited mantle components to the lunar surface.
Hybrid QM/MM study of FMO complex with polarized protein-specific charge
Authors: Jia Xiangyu , Mei Ye , Zhang John Z.H. , Mo Yan
Published: November 2015

The Fenna-Matthews-Olson (FMO) light-harvesting complex is now one of the primary model systems for the study of excitation energy transfer (EET). However, the mechanism of the EET in this system is still controversial. In this work, molecular dynamics simulations and the electrostatic-embedding quantum-mechanics/molecular-mechanics single-point calculations have been employed to predict the energy transfer pathways utilizing the polarized protein-specific charge (PPC), which provides a more realistic description of Coulomb interaction potential in the protein than conventional mean-field charge scheme. The recently discovered eighth pigment has also been included in this study. Comparing with the conventional mean-field charges, more stable structures of FMO complex were found under PPC scheme during molecular dynamic simulation. Based on the electronic structure calculations, an exciton model was constructed to consider the couplings during excitation. The results show that pigments 3 and 4 dominate the lowest exciton levels whereas the highest exciton level are mainly constituted of pigments 1 and 6. This observation agrees well with the assumption based on the spatial distribution of the pigments. Moreover, the obtained spectral density in this study gives a reliable description of the diverse local environment embedding each pigment.
Increased risks between Interleukin-10 gene polymorphisms and haplotype and head and neck cancer: a meta-analysis
Authors: Niu Yu-Ming , Du Xin-Ya , Cai Heng-Xing , Zhang Chao , Yuan Rui-Xia , Zeng Xian-Tao , Luo Jie
Published: November 2015

Molecular epidemiological research suggests that interleukin-10 (IL-10) polymorphisms may be associated with an increased risk of head and neck cancer (HNC), but results remain controversial. To derive a more precise evaluation, we performed a meta-analysis focused on genetic polymorphisms of IL-10. PubMed, Embase, CNKI and Wanfang databases were searched for studies that examined the relationship between IL-10 polymorphisms or haplotypes and HNC risk. The odds ratio (OR) and 95% confidence interval (CI) were applied to assess the relationship strength. Publication bias, sensitivity and cumulative analyses were conducted to measure the robustness of our findings. Overall, nine related studies involving 2,258 patients and 2,887 control samples were analyzed. Significant associations between the IL-10-1082A > G polymorphism and HNC risk were observed (G vs. A: OR = 1.56, 95% CI = 1.27–1.92, P < 0.01, I2 = 69.4%; AG vs. AA: OR = 1.64, 95% CI = 1.32–2.05, P < 0.01, I2 = 55.6%; GG vs. AA: OR = 2.24, 95% CI = 1.69–2.97, P < 0.01, I2 = 38.5%; AG + GG vs. AA: OR = 1.70, 95% CI = 1.36−2.14, P = 0.02, I2 = 61.8%; GG vs. AA + AG: OR = 1.89, 95% CI = 1.23−2.90, P = 0.01, I2 = 46.3%) in the total population, as well as in subgroup analysis. Moreover, increased HNC risks were also associated with the IL-10 −819T > C polymorphism and the GCC haplotype. In conclusion, our meta-analyses suggest that IL-10 polymorphisms, specifically the −1082A > G polymorphism, may be associated with increased risk of HNC development.
Add-on Protective Effect of Pentoxifylline in Advanced Chronic Kidney Disease Treated with Renin-Angiotensin-Aldosterone System Blockade - A Nationwide Database Analysis
Authors: Kuo Ko-Lin , Hung Szu-Chun , Liu Jia-Sin , Chang Yu-Kang , Hsu Chih-Cheng , Tarng Der-Cherng
Published: November 2015

A combination therapy of pentoxifylline with an angiotensin converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) decreased proteinuria or glomerular filtration rate decline in early chronic kidney disease (CKD). Whether adding pentoxifylline to ACEI/ARB provides additional benefits on outcome is unclear in CKD stage 5 patients who have not yet received dialysis (CKD 5 ND). A prospective cohort study was conducted based on the Taiwan National Health Insurance Research Database. From January 1, 2000 to June 30, 2009, we enrolled 14,117 CKD 5 ND with serum creatinine levels >6 mg/dL and hematocrit levels <28% and who have been treated with ACEI/ARB. All patients were divided into pentoxifylline users and nonusers. Patient follow-up took place until dialysis, death before initiation of dialysis or December 31, 2009. Finally, 9,867 patients (69.9%) required long-term dialysis and 2,805 (19.9%) died before dialysis. After propensity score-matching, use of pentoxifylline was associated with a lower risk for long-term dialysis or death in ACEI/ARB users (HR, 0.94; 95% CI, 0.90–0.99) or ARB users (HR, 0.91; 95% CI, 0.85–0.97). In conclusion, pentoxifylline exhibited a protective effect in reducing the risk for the composite outcome of long-term dialysis or death in ACEI/ARB treated CKD 5 ND.
Development of Endothelial-Specific Single Inducible Lentiviral Vectors for Genetic Engineering of Endothelial Progenitor Cells
Authors: Yang Guanghua , Kramer M. Gabriela , Fernandez-Ruiz Veronica , Kawa Milosz P. , Huang Xin , Liu Zhongmin , Prieto Jesus , Qian Cheng
Published: November 2015

Endothelial progenitor cells (EPC) are able to migrate to tumor vasculature. These cells, if genetically modified, can be used as vehicles to deliver toxic material to, or express anticancer proteins in tumor. To test this hypothesis, we developed several single, endothelial-specific and doxycycline-inducible self-inactivating (SIN) lentiviral vectors. Two distinct expression cassettes were inserted into a SIN-vector: one controlled by an endothelial lineage-specific, murine vascular endothelial cadherin (mVEcad) promoter for the expression of a transactivator, rtTA2S-M2; and the other driven by an inducible promoter, TREalb, for a firefly luciferase reporter gene. We compared the expression levels of luciferase in different vector constructs, containing either the same or opposite orientation with respect to the vector sequence. The results showed that the vector with these two expression cassettes placed in opposite directions was optimal, characterized by a robust induction of the transgene expression (17.7- to 73-fold) in the presence of doxycycline in several endothelial cell lines, but without leakiness when uninduced. In conclusion, an endothelial lineage-specific single inducible SIN lentiviral vector has been developed. Such a lentiviral vector can be used to endow endothelial progenitor cells with anti-tumor properties.
VASP, zyxin and TES are tension-dependent members of Focal Adherens Junctions independent of the α-catenin-vinculin module
Authors: Oldenburg Joppe , van der Krogt Gerard , Twiss Floor , Bongaarts Annika , Habani Yasmin , Slotman Johan A. , Houtsmuller Adriaan , Huveneers Stephan , de Rooij Johan
Published: November 2015

Mechanical forces are integrated at cadherin-based adhesion complexes to regulate morphology and strength of cell-cell junctions and organization of associated F-actin. A central mechanosensor at the cadherin complex is α-catenin, whose stretching recruits vinculin to regulate adhesion strength. The identity of the F-actin regulating signals that are also activated by mechanical forces at cadherin-based junctions has remained elusive. Here we identify the actin-regulators VASP, zyxin and TES as members of punctate, tensile cadherin-based junctions called Focal Adherens Junctions (FAJ) and show that they display mechanosensitive recruitment similar to that of vinculin. However, this recruitment is not altered by destroying or over-activating the α-catenin/vinculin module. Structured Illumination Microscopy (SIM) indicates that these tension sensitive proteins concentrate at locations within FAJs that are distinct from the core cadherin complex proteins. Furthermore, localization studies using mutated versions of VASP and zyxin indicate that these two proteins require binding to each other in order to localize to the FAJs. We conclude that there are multiple force sensitive modules present at the FAJ that are activated at distinct locations along the cadherin-F-actin axis and regulate specific aspects of junction dynamics.
Bones hold the key to DNA virus history and epidemiology
Authors: Toppinen M. , Perdomo M. F. , Palo J. U. , Simmonds P. , Lycett S. J. , Söderlund-Venermo M. , Sajantila A. , Hedman K.
Published: November 2015

DNA in human skeletal remains represents an important historical source of host genomic information and potentially of infecting viruses. However, little is known about viral persistence in bone. We searched ca. 70-year-old long bones of putative Finnish casualties from World War II for parvovirus B19 (B19V) DNA and found a remarkable prevalence of 45%. The viral sequences were exclusively of genotypes 2 (n = 41), which disappeared from circulation in 1970´s, or genotype 3 (n = 2), which has never been reported in Northern Europe. Based on mitochondrial and Y-chromosome profiling, the two individuals carrying B19V genotype 3 were likely from the Soviet Red Army. The most recent common ancestor for all genotypes was estimated at early 1800s. This work demonstrates the forms of B19V that circulated in the first half of the 20th century and provides the first evidence of the suitability of bone for exploration of DNA viruses.
Tandem Spinach Array for mRNA Imaging in Living Bacterial Cells
Authors: Zhang Jichuan , Fei Jingyi , Leslie Benjamin J. , Han Kyu Young , Kuhlman Thomas E. , Ha Taekjip
Published: November 2015

Live cell RNA imaging using genetically encoded fluorescent labels is an important tool for monitoring RNA activities. A recently reported RNA aptamer-fluorogen system, the Spinach, in which an RNA aptamer binds and induces the fluorescence of a GFP-like 3,5-difluoro-4-hydroxybenzylidene imidazolinone (DFHBI) ligand, can be readily tagged to the RNA of interest. Although the aptamer–fluorogen system is sufficient for imaging highly abundant non-coding RNAs (tRNAs, rRNAs, etc.), it performs poorly for mRNA imaging due to low brightness. In addition, whether the aptamer-fluorogen system may perturb the native RNA characteristics has not been systematically characterized at the levels of RNA transcription, translation and degradation. To increase the brightness of these aptamer-fluorogen systems, we constructed and tested tandem arrays containing multiple Spinach aptamers (8–64 aptamer repeats). Such arrays enhanced the brightness of the tagged mRNA molecules by up to ~17 fold in living cells. Strong laser excitation with pulsed illumination further increased the imaging sensitivity of Spinach array-tagged RNAs. Moreover, transcriptional fusion to the Spinach array did not affect mRNA transcription, translation or degradation, indicating that aptamer arrays might be a generalizable labeling method for high-performance and low-perturbation live cell RNA imaging.
Structural delineation of stem-loop RNA binding by human TAF15 protein
Authors: Kashyap Maruthi , Ganguly Akshay Kumar , Bhavesh Neel Sarovar
Published: November 2015

Human TATA binding protein associated factor 2 N (TAF15) and Fused in sarcoma (FUS) are nucleic acid binding proteins belonging to the conserved FET family of proteins. They are involved in diverse processes such as pre-mRNA splicing, mRNA transport and DNA binding. The absence of information regarding the structural mechanism employed by the FET family in recognizing and discriminating their cognate and non-cognate RNA targets has hampered the attainment of consensus on modes of protein-RNA binding for this family. Our study provides a molecular basis of this RNA recognition using a combination of solution-state NMR spectroscopy, calorimetry, docking and molecular dynamics simulation. Analysis of TAF15-RRM solution structure and its binding with stem-loop RNA has yielded conclusive evidence of a non-canonical mode of RNA recognition. Rather than classical stacking interactions that occur across nitrogen bases and aromatic amino acids on ribonucleoprotein sites, moderate-affinity hydrogen bonding network between the nitrogen bases in the stem-loop RNA and a concave face on the RRM surface primarily mediate TAF15-RRM RNA interaction. We have compared the binding affinities across a set of single-stranded RNA oligonucleotides to conclusively establish that RNA binding is dependent upon structural elements in the RNA rather than sequence.
Severity of DSS-induced colitis is reduced in Ido1-deficient mice with down-regulation of TLR-MyD88-NF-kB transcriptional networks
Authors: Shon Woo-Jeong , Lee Young-Kwan , Shin Ji Hee , Choi Eun Young , Shin Dong-Mi
Published: November 2015

Indoleamine 2,3 -dioxygenase 1 (IDO1) catalyzes L-tryptophan to kynurenine in the first and rate-limiting step of tryptophan metabolism. IDO1 is expressed widely throughout the body, with especially high expression in colonic intestinal tissues. To examine the role of IDO1 in the colon, transcriptome analysis was performed in both Ido1−/− and Ido1+/+ mice. Gene set enrichment analysis identified the Inflammatory Response as the most significant category modulated by the absence of IDO1. This observation prompted us to further investigate the function of IDO1 in the development of tissue inflammation. By using DSS-induced experimental colitis mice models, we found that the disease in Ido1−/− mice was less severe than in Ido1+/+ mice. Pharmacological inhibition of IDO1 by L-1MT attenuated the severity of DSS-colitis as well. Transcriptome analyses revealed that pathways involving TLR and NF-kB signaling were significantly down-regulated by the absence of IDO1. Furthermore, dramatic changes in TLR and NF-kB signaling resulted in substantial changes in the expression of many inflammatory cytokines and chemokines. Numbers of inflammatory cells in colon and peripheral blood were reduced in IDO1 deficiency. These findings suggest that IDO1 plays important roles in producing inflammatory responses and modulating transcriptional networks during the development of colitis.
Enhanced Charge Separation and FRET at Heterojunctions between Semiconductor Nanoparticles and Conducting Polymer Nanofibers for Efficient Solar Light Harvesting
Authors: Sardar Samim , Kar Prasenjit , Remita Hynd , Liu Bo , Lemmens Peter , Kumar Pal Samir , Ghosh Srabanti
Published: November 2015

Energy harvesting from solar light employing nanostructured materials offer an economic way to resolve energy and environmental issues. We have developed an efficient light harvesting heterostructure based on poly(diphenylbutadiyne) (PDPB) nanofibers and ZnO nanoparticles (NPs)viaa solution phase synthetic route. ZnO NPs (~20 nm) were homogeneously loaded onto the PDPB nanofibers as evident from several analytical and spectroscopic techniques. The photoinduced electron transfer from PDPB nanofibers to ZnO NPs has been confirmed by steady state and picosecond-resolved photoluminescence studies. The co-sensitization for multiple photon harvesting (with different energies) at the heterojunction has been achievedviaa systematic extension of conjugation from monomeric to polymeric diphenyl butadiyne moiety in the proximity of the ZnO NPs. On the other hand, energy transfer from the surface defects of ZnO NPs (~5 nm) to PDPB nanofibers through Förster Resonance Energy Transfer (FRET) confirms the close proximity with molecular resolution. The manifestation of efficient charge separation has been realized with ~5 fold increase in photocatalytic degradation of organic pollutants in comparison to polymer nanofibers counterpart under visible light irradiation. Our results provide a novel approach for the development of nanoheterojunctions for efficient light harvesting which will be helpful in designing future solar devices.
pH-susceptibility of HLA-DO tunes DO/DM ratios to regulate HLA-DM catalytic activity
Authors: Jiang Wei , Strohman Michael J. , Somasundaram Sriram , Ayyangar Sashi , Hou Tieying , Wang Nan , Mellins Elizabeth D.
Published: November 2015

The peptide-exchange catalyst, HLA-DM and its inhibitor, HLA-DO control endosomal generation of peptide/class II major histocompatibility protein (MHC-II) complexes; these complexes traffic to the cell surface for inspection by CD4+ T cells. Some evidence suggests that pH influences DO regulation of DM function, but pH also affects the stability of polymorphic MHC-II proteins, spontaneous peptide loading, DM/MHC-II interactions and DM catalytic activity, imposing challenges on approaches to determine pH effects on DM-DO function and their mechanistic basis. Using optimized biochemical methods, we dissected pH-dependence of spontaneous and DM-DO-mediated class II peptide exchange and identified an MHC-II allele-independent relationship between pH, DO/DM ratio and efficient peptide exchange. We demonstrate that active, free DM is generated from DM-DO complexes at late endosomal/lysosomal pH due to irreversible, acid-promoted DO destruction rather than DO/DM molecular dissociation. Any soluble DM that remains in complex with DO stays inert. pH-exposure of DM-DO in cell lysates corroborates such a pH-regulated mechanism, suggesting acid-activated generation of functional DM in DO-expressing cells.
Functional analysis of the 11q23.3 glioma susceptibility locus implicates PHLDB1 and DDX6 in glioma susceptibility
Authors: Baskin Rebekah , Woods Nicholas T. , Mendoza-Fandiño Gustavo , Forsyth Peter , Egan Kathleen M. , Monteiro Alvaro N.A.
Published: November 2015

Glioma is the most common malignant primary brain tumor and is associated with poor prognosis. Genetic factors contributing to glioma risk have recently been investigated through genome-wide association studies (GWAS), implicating seven independent glioma risk loci in six chromosomal regions. Here, we performed an in-depth functional analysis of the risk locus proximal to the PHLDB1 gene on 11q23.3. We retrieved all SNPs in linkage disequilibrium (r2 ≥ 0.2) with the glioma-associated SNP (rs498872) and performed a comprehensive bioinformatics and experimental functional analysis for the region. After testing candidate SNPs for allele-specific activity in a luciferase-based enhancer scanning assay, we established a subset of 10 functional SNPs in the promoters of PHLDB1 and DDX6, and in a putative enhancer element. Chromatin conformation capture (3C) identified a physical interaction between the enhancer element containing a functional SNP (rs73001406) and the promoter of the DDX6 gene. Knockdown experiments in cell culture and 3D assays to evaluate the role of PHLDB1 and DDX6 suggest that both genes may contribute to the phenotype. These studies reveal the functional landscape of the 11q23.3 glioma susceptibility locus and identify a network of functional SNPs in regulatory elements and two target genes as a possible mechanism driving glioma risk association.
Aminopeptidase T of M29 Family Acts as A Novel Intracellular Virulence Factor for Listeria monocytogenes Infection
Authors: Cheng Changyong , Wang Xiaowen , Dong Zhimei , Shao Chunyan , Yang Yongchun , Fang Weihuan , Fang Chun , Wang Hang , Yang Menghua , Jiang Lingli , Zhou Xiangyang , Song Houhui
Published: November 2015

The foodborne pathogen Listeria monocytogenes employs a number of virulence determinants including metalloproteases to infect hosts. Here for the first time, we identified an M29 family aminopeptidase T (encoded by lmo1603) from L. monocytogenes that possesses a typical feature to catalyze the cleavage of amino acids from peptide substrates, with a preference for arginine. The purified recombinant Lmo1603 was activated by Fe3+, Zn2+ and Mn2+, but strongly stimulated by Co2+, indicating that Lmo1603 is a cobalt-dependent aminopeptidase. Single mutation at any of the Glu216, Glu281, His308, Tyr315, His327 and Asp329 completely abolished the enzymatic activity of Lmo1603. More importantly, we showed that Lmo1603 was mainly involved in Listeria infection, but not required for growth in rich laboratory medium and minimal defined medium. Disruption of Lmo1603 resulted in almost complete attenuation of Listeria virulence in a mouse infection model. In addition, we demonstrated that Lmo1603 was mainly localized in the bacterial cytosol and required for invasion and survival inside human epithelial cells and murine macrophages. We conclude that Lmo1603 encodes a functional aminopeptidase T of M29 family, which acts as a novel intracellular virulence factor essential in the successful establishment of L. monocytogenes infections in a mouse model.
Genetic-deletion of Cyclooxygenase-2 Downstream Prostacyclin Synthase Suppresses Inflammatory Reactions but Facilitates Carcinogenesis, unlike Deletion of Microsomal Prostaglandin E Synthase-1
Authors: Sasaki Yuka , Kamiyama Shuhei , Kamiyama Azusa , Matsumoto Konomi , Akatsu Moe , Nakatani Yoshihito , Kuwata Hiroshi , Ishikawa Yukio , Ishii Toshiharu , Yokoyama Chieko , Hara Shuntaro
Published: November 2015

Prostacyclin synthase (PGIS) and microsomal prostaglandin E synthase-1 (mPGES-1) are prostaglandin (PG) terminal synthases that function downstream of inducible cyclooxygenase (COX)-2 in the PGI2 and PGE2 biosynthetic pathways, respectively. mPGES-1 has been shown to be involved in various COX-2-related diseases such as inflammatory diseases and cancers, but it is not yet known how PGIS is involved in these COX-2-related diseases. Here, to clarify the pathophysiological role of PGIS, we investigated the phenotypes of PGIS and mPGES-1 individual knockout (KO) or double KO (DKO) mice. The results indicate that a thioglycollate-induced exudation of leukocytes into the peritoneal cavity was suppressed by the genetic-deletion of PGIS. In the PGIS KO mice, lipopolysaccharide-primed pain nociception (as assessed by the acetic acid-induced writhing reaction) was also reduced. Both of these reactions were suppressed more effectively in the PGIS/mPGES-1 DKO mice than in the PGIS KO mice. On the other hand, unlike mPGES-1 deficiency (which suppressed azoxymethane-induced colon carcinogenesis), PGIS deficiency up-regulated both aberrant crypt foci formation at the early stage of carcinogenesis and polyp formation at the late stage. These results indicate that PGIS and mPGES-1 cooperatively exacerbate inflammatory reactions but have opposing effects on carcinogenesis and that PGIS-derived PGI2 has anti-carcinogenic effects.
Three-dimensional hydrodynamic focusing microfluidic emitter: a strategy to inhibit sample ion expansion in nanoelectrospray ionization
Authors: Xiong Bo , Wang Lingling , Wang Yujiao , Bao Yajing , Jiang Shichang , Ye Mingyue
Published: November 2015

A proposed 3D HFNE was used to generate a wrapped electrospray to achieve the inhibition of sample ion expansion, thus restraining injection loss in electrospray ionization.
Unprecedented copper-mediated oxidative demethylation of propionamides via bidentate-chelation assistance
Authors: Liu Jing-Hui , Cui Mian , Lu Xiao-Yu , Zhang Zhen-Qi , Xiao Bin , Fu Yao
Published: November 2015

The copper-mediated bidentate-chelation directing group assisted oxidative demethylation of substituted propionamides was developed for the first time.