bluuebunny/crossref_metadata_2025 huggingface dataset:
Extracellular vesicles derived from T regulatory cells suppress T cell proliferation and prolong allograft survival
Authors: Aiello Sistiana , Rocchetta Federica , Longaretti Lorena , Faravelli Silvia , Todeschini Marta , Cassis Linda , Pezzuto Francesca , Tomasoni Susanna , Azzollini Nadia , Mister Marilena , Mele Caterina , Conti Sara , Breno Matteo , Remuzzi Giuseppe , Noris Marina , Benigni Ariela
Published: September 2017

We have previously shown that rat allogeneic DC, made immature by adenoviral gene transfer of the dominant negative form of IKK2, gave risein-vitroto a unique population of CD4+CD25−regulatory T cells (dnIKK2-Treg). These cells inhibited Tcell responsein-vitro, without needing cell-to-cell contact, and induced kidney allograft survival prolongationin-vivo. Deep insight into the mechanisms behind dnIKK2-Treg-induced suppression of Tcell proliferation remained elusive. Here we document that dnIKK2-Treg release extracellular vesicles (EV) riched in exosomes, fully accounting for the cell-contact independent immunosuppressive activity of parent cells. DnIKK2-Treg-EV contain a unique molecular cargo of specific miRNAs and iNOS, which, once delivered into target cells, blocked cell cycle progression and induced apoptosis. DnIKK2-Treg-EV-exposed T cells were in turn converted into regulatory cells. Notably, when administeredin-vivo, dnIKK2-Treg-EV prolonged kidney allograft survival. DnIKK2-Treg-derived EV could be a tool for manipulating the immune system and for discovering novel potential immunosuppressive molecules in the context of allotransplantation.
Determining Ribavirin’s mechanism of action against Lassa virus infection
Authors: Carrillo-Bustamante Paola , Nguyen Thi Huyen Tram , Oestereich Lisa , Günther Stephan , Guedj Jeremie , Graw Frederik
Published: September 2017

Ribavirin is a broad spectrum antiviral which inhibits Lassa virus (LASV) replicationin vitrobut exhibits a minor effect on viremiain vivo. However, ribavirin significantly improves the disease outcome when administered in combination with sub-optimal doses of favipiravir, a strong antiviral drug. The mechanisms explaining these conflicting findings have not been determined, so far. Here, we used an interdisciplinary approach combining mathematical models and experimental data in LASV-infected mice that were treated with ribavirin alone or in combination with the drug favipiravir to explore different putative mechanisms of action for ribavirin. We test four different hypotheses that have been previously suggested for ribavirin’s mode of action: (i) acting as a mutagen, thereby limiting the infectivity of new virions; (ii) reducing viremia by impairing viral production; (iii) modulating cell damage, i.e., by reducing inflammation, and (iv) enhancing antiviral immunity. Our analysis indicates that enhancement of antiviral immunity, as well as effects on viral production or transmission are unlikely to be ribavirin’s main mechanism mediating its antiviral effectiveness against LASV infection. Instead, the modeled viral kinetics suggest that the main mode of action of ribavirin is to protect infected cells from dying, possibly reducing the inflammatory response.
Lipopolysaccharide-initiated persistent rhinitis causes gliosis and synaptic loss in the olfactory bulb
Authors: Hasegawa-Ishii Sanae , Shimada Atsuyoshi , Imamura Fumiaki
Published: September 2017

The olfactory mucosa (OM) is exposed to environmental agents and therefore vulnerable to inflammation. To examine the effects of environmental toxin-initiated OM inflammation on the olfactory bulb (OB), we induced persistent rhinitis in mice and analyzed the spatial and temporal patterns of histopathological changes in the OM and OB. Mice received unilateral intranasal administration of lipopolysaccharide (LPS) or saline three times per week, and were immunohistologically analyzed at 1, 3, 7, 14 and 21 days after the first administration. LPS administration induced an inflammatory response in the OM, including the infiltration of Ly-6G-, CD11b-, Iba-1- and CD3-positive cells, the production of interleukin-1β by CD11b- and Iba-1-positive cells, and loss of olfactory sensory neurons (OSNs). In the OB, we observed activation of microglia and astrocytes and decreased expression of tyrosine hydroxylase in periglomerular cells, vesicular glutamate transporter 1, a presynaptic protein, in mitral and tufted projection neurons, and 5T4 in granule cells. Thus, the OM inflammation exerted a detrimental effect, not only on OSNs, but also on OB neurons, which might lead to neurodegeneration.
Epicutaneous allergen application preferentially boosts specific T cell responses in sensitized patients
Authors: Campana Raffaela , Moritz Katharina , Neubauer Angela , Huber Hans , Henning Rainer , Brodie Tess M. , Kaider Alexandra , Sallusto Federica , Wöhrl Stefan , Valenta Rudolf
Published: September 2017

The effects of epicutaneous allergen administration on systemic immune responses in allergic and non-allergic individuals has not been investigated with defined allergen molecules. We studied the effects of epicutaneous administration of rBet v 1 and rBet v 1 fragments on systemic immune responses in allergic and non-allergic subjects. We conducted a clinical trial in which rBet v 1 and two hypoallergenic rBet v 1 fragments were applied epicutaneously by atopy patch testing (APT) to 15 birch pollen (bp) allergic patients suffering from atopic dermatitis, 5 bp-allergic patients suffering from rhinoconjunctivitis only, 5 patients with respiratory allergy without bp allergy and 5 non-allergic individuals. Epicutaneous administration of rBet v 1 and rBet v 1 fragments led to strong and significant increases of allergen-specific T cell proliferation (CLA+ and CCR4+T cell responses) only in bp-allergic patients with a positive APT reaction. There were no relevant changes of Bet v 1-specific IgE and IgG responses. No changes were noted in allergic subjects without bp allergy and in non-allergic subjects. Epicutaneous allergen application boosts specific T cell but not antibody responses mainly in allergic, APT-positive patients suggesting IgE-facilitated allergen presentation as mechanism for its effects on systemic allergen-specific immune responses.
The molecular epidemiology of HIV-1 in the Comunidad Valenciana (Spain): analysis of transmission clusters
Authors: Patiño-Galindo Juan Ángel , Torres-Puente Manoli , Bracho María Alma , Alastrué Ignacio , Juan Amparo , Navarro David , Galindo María José , Ocete Dolores , Ortega Enrique , Gimeno Concepción , Belda Josefina , Domínguez Victoria , Moreno Rosario , González-Candelas Fernando
Published: September 2017

HIV infections are still a very serious concern for public heath worldwide. We have applied molecular evolution methods to study the HIV-1 epidemics in the Comunidad Valenciana (CV, Spain) from a public health surveillance perspective. For this, we analysed 1804 HIV-1 sequences comprising protease and reverse transcriptase (PR/RT) coding regions, sampled between 2004 and 2014. These sequences were subtyped and subjected to phylogenetic analyses in order to detect transmission clusters. In addition, univariate and multinomial comparisons were performed to detect epidemiological differences between HIV-1 subtypes, and risk groups. The HIV epidemic in the CV is dominated by subtype B infections among local men who have sex with men (MSM). 270 transmission clusters were identified (>57% of the dataset), 12 of which included ≥10 patients; 11 of subtype B (9 affecting MSMs) and one (n = 21) of CRF14, affecting predominately intravenous drug users (IDUs). Dated phylogenies revealed these large clusters to have originated from the mid-80s to the early 00 s. Subtype B is more likely to form transmission clusters than non-B variants and MSMs to cluster than other risk groups. Multinomial analyses revealed an association between non-B variants, which are not established in the local population yet, and different foreign groups.
The Impact of Young Age for Prognosis by Subtype in Women with Early Breast Cancer
Authors: Lian Weibin , Fu Fangmeng , Lin Yuxiang , Lu Minjun , Chen Boyang , Yang Peidong , Zeng Bangwei , Huang Meng , Wang Chuan
Published: September 2017

Young age (≤40 years) use to be considered an independent risk factor for the prognosis of women with early-stage breast cancer. We conducted a retrospective analysis to investigate this claim in a population of young patients who were stratified by molecular subtype. We identified 2,125 women with stage I to III breast cancer from the Fujian Medical University Union Hospital. Multivariable Cox proportional hazards models were used to analyze the relationship between age groups stratified by molecular subtype and 5-year disease-free survival (DFS), 5-year distant metastasis-free survival (DMFS), and 5-year breast cancer-specific survival (BCSS). Median follow-up time was 77 months. Patients ≤40 years of age presented with a significantly worse 5-year DFS and 5-year DMFS. In stratified analyses, young women with luminal A subtype disease were associated with a worse 5-year DFS, 5-year DMFS, and 5-year BCSS. Women with luminal B (Her2−) tumors showed a decrease in 5-year DFS and 5-year DMFS. Our findings support the hypothesis that young age seems to be an independent risk factor for the prognosis for breast cancer patients with the luminal A and luminal B (Her2−) subtypes but not in those with luminal B (Her2+), Her2 over-expression, and triple-negative disease.
Chronic interfacing with the autonomic nervous system using carbon nanotube (CNT) yarn electrodes
Authors: McCallum Grant A. , Sui Xiaohong , Qiu Chen , Marmerstein Joseph , Zheng Yang , Eggers Thomas E. , Hu Chuangang , Dai Liming , Durand Dominique M.
Published: September 2017

The ability to reliably and safely communicate chronically with small diameter (100–300 µm) autonomic nerves could have a significant impact in fundamental biomedical research and clinical applications. However, this ability has remained elusive with existing neural interface technologies. Here we show a new chronic nerve interface using highly flexible materials with axon-like dimensions. The interface was implemented with carbon nanotube (CNT) yarn electrodes to chronically record neural activity from two separate autonomic nerves: the glossopharyngeal and vagus nerves. The recorded neural signals maintain a high signal-to-noise ratio (>10 dB) in chronic implant models. We further demonstrate the ability to process the neural activity to detect hypoxic and gastric extension events from the glossopharyngeal and vagus nerves, respectively. These results establish a novel, chronic platform neural interfacing technique with the autonomic nervous system and demonstrate the possibility of regulating internal organ function, leading to new bioelectronic therapies and patient health monitoring.
The relation between cesarean birth and child cognitive development
Authors: Polidano Cain , Zhu Anna , Bornstein Joel C.
Published: September 2017

This is the first detailed study of the relation between cesarean birth and child cognitive development. We measure differences in child cognitive performance at 4 to 9 years of age between cesarean-born and vaginally-born children (n = 3,666) participating in the Longitudinal Study of Australian Children (LSAC). LSAC is a nationally representative birth cohort surveyed biennially. Using multivariate regression, we control for a large range of confounders related to perinatal risk factors and the socio-economic advantage associated with cesarean-born children. Across several measures, we find that cesarean-born children perform significantly below vaginally-born children, by up to a tenth of a standard deviation in national numeracy test scores at age 8–9. Estimates from a low-risk sub-sample and lower-bound analysis suggest that the relation is not spuriously related to unobserved confounding. Lower rates of breastfeeding and adverse child and maternal health outcomes that are associated with cesarean birth are found to explain less than a third of the cognitive gap, which points to the importance of other mechanisms such as disturbed gut microbiota. The findings underline the need for a precautionary approach in responding to requests for a planned cesarean when there are no apparent elevated risks from vaginal birth.
The SRGAP2 SNPs, their haplotypes and G × E interactions on serum lipid traits
Authors: Miao Liu , Yin Rui-Xing , Wu Jin-Zhen , Yang Shuo , Lin Wei-Xiong , Pan Shang-Ling
Published: September 2017

Maonan nationality is a relatively conservative and isolated minority in China. Little is known about the association of the Slit-Robo Rho GTPase activating protein 2 gene (SRGAP2) single nucleotide polymorphisms (SNPs) and serum lipid levels in the Chinese populations. This study was performed to clarify the association of the SRGAP2 rs2483058 and rs2580520 SNPs and their haplotypes with serum lipid traits in the Maonan and Han populations. Genotyping of the 2 SNPs was performed in 2444 unrelated subjects (Han, 1210 and Maonan, 1234) by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. The allelic (rs2483058) and genotypic (rs2483058 and rs2580520) frequencies were different between the two ethnic groups. Four haplotypes were identified in our populations, and the rs2483058G-rs2580520C haplotype was the commonest one. The rs2483058C-rs2580520G haplotype was associated with an increased risk of dyslipidemia, and showed consistent association with serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), apolipoprotein (Apo) A1 levels, and the ApoA1/ApoB ratio. These results indicated that the SRGAP2 SNPs and their haplotypes were associated with serum lipid levels. Their haplotypes can explain much more serum lipid variation than any single SNP alone, especially for serum TC, HDL-C and ApoA1 levels.
ROS induced distribution of mitochondria to filopodia by Myo19 depends on a class specific tryptophan in the motor domain
Authors: Shneyer Boris I. , Ušaj Marko , Wiesel-Motiuk Naama , Regev Ronit , Henn Arnon
Published: September 2017

The role of the actin cytoskeleton in relation to mitochondria function and dynamics is only recently beginning to be recognized. Myo19 is an actin-based motor that is bound to the outer mitochondrial membrane and promotes the localization of mitochondria to filopodia in response to glucose starvation. However, how glucose starvation induces mitochondria localization to filopodia, what are the dynamics of this process and which enzymatic adaptation allows the translocation of mitochondria to filopodia are not known. Here we show that reactive oxygen species (ROS) mimic and mediate the glucose starvation induced phenotype. In addition, time-lapse fluorescent microscopy reveals that ROS-induced Myo19 motility is a highly dynamic process which is coupled to filopodia elongation and retraction. Interestingly, Myo19 motility is inhibited by back-to-consensus-mutation of a unique residue of class XIX myosins in the motor domain. Kinetic analysis of the purified mutant Myo19 motor domain reveals that the duty ratio (time spent strongly bound to actin) is highly compromised in comparison to that of the WT motor domain, indicating that Myo19 unique motor properties are necessary to propel mitochondria to filopodia tips. In summary, our study demonstrates the contribution of actin-based motility to the mitochondrial localization to filopodia by specific cellular cues.
Local Juvenile Hormone activity regulates gut homeostasis and tumor growth in adult Drosophila
Authors: Rahman M. M. , Franch-Marro X. , Maestro J. L. , Martin D. , Casali A.
Published: September 2017

Hormones play essential roles during development and maintaining homeostasis in adult organisms, regulating a plethora of biological processes. Generally, hormones are secreted by glands and perform a systemic action. Here we show that Juvenile Hormones (JHs), insect sesquiterpenoids synthesized by the corpora allata, are also synthesized by the adult Drosophila gut. This local, gut specific JH activity, is synthesized by and acts on the intestinal stem cell and enteroblast populations, regulating their survival and cellular growth through the JH receptors Gce/Met and the coactivator Tai. Furthermore, we show that this local JH activity is important for damage response and is necessary for intestinal tumor growth driven by activating mutations in Wnt and EGFR/Ras pathways. Together, our results identify JHs as key hormonal regulators of gut homeostasis and open the possibility that analogous hormones may play a similar role in maintaining vertebrate adult intestinal stem cell population and sustaining tumor growth.
Fast-track development of an in vitro 3D lung/immune cell model to study Aspergillus infections
Authors: Chandorkar P. , Posch W. , Zaderer V. , Blatzer M. , Steger M. , Ammann C. G. , Binder U. , Hermann M. , Hörtnagl P. , Lass-Flörl C. , Wilflingseder D.
Published: September 2017

To study interactions of airborne pathogens, e.g. Aspergillus (A.) fumigatus with upper and lower respiratory tract epithelial and immune cells, we set up a perfused 3D human bronchial and small airway epithelial cell system. Culturing of normal human bronchial or small airway epithelial (NHBE, SAE) cells under air liquid interphase (ALI) and perfusion resulted in a significantly accelerated development of the lung epithelia associated with higher ciliogenesis, cilia movement, mucus-production and improved barrier function compared to growth under static conditions. Following the accelerated differentiation under perfusion, epithelial cells were transferred into static conditions and antigen-presenting cells (APCs) added to study their functionality upon infection with A. fumigatus. Fungi were efficiently sensed by apically applied macrophages or basolaterally adhered dendritic cells (DCs), as illustrated by phagocytosis, maturation and migration characteristics. We illustrate here that perfusion greatly improves differentiation of primary epithelial cells in vitro, which enables fast-track addition of primary immune cells and significant shortening of experimental procedures. Additionally, co-cultured primary DCs and macrophages were fully functional and fulfilled their tasks of sensing and sampling fungal pathogens present at the apical surface of epithelial cells, thereby promoting novel possibilities to study airborne infections under conditions mimicking the in vivo situation.
Dynamic Changes in the Splenic Transcriptome of Chickens during the Early Infection and Progress of Marek’s Disease
Authors: Dang Lu , Teng Man , Li Hua-Wei , Li Hui-Zhen , Ma Sheng-Ming , Zhao Pu , Li Xiu-Jie , Deng Rui-Guang , Zhang Gai-Ping , Luo Jun
Published: September 2017

Gallid alphaherpesvirus 2 (GaHV2) is an oncogenic avian herpesvirus inducing Marek’s disease (MD) and rapid-onset T-cell lymphomas. To reveal molecular events in MD pathogenesis and tumorigenesis, the dynamic splenic transcriptome of GaHV2-infected chickens during early infection and pathogenic phases has been determined utilizing RNA-seq. Based on the significant differentially expressed genes (DEGs), analysis of gene ontology, KEGG pathway and protein-protein interaction network has demonstrated that the molecular events happening during GaHV2 infection are highly relevant to the disease course. In the ‘Cornell Model’ description of MD, innate immune responses and inflammatory responses were established at early cytolytic phase but persisted until lymphoma formation. Humoral immunity in contrast began to play a role firstly in the intestinal system and started at late cytolytic phase. Neurological damage caused by GaHV2 is first seen in early cytolytic phase and is then sustained throughout the following phases over a long time period. During the proliferative phase many pathways associated with transcription and/or translation were significantly enriched, reflecting the cell transformation and lymphoma formation. Our work provides an overall view of host responses to GaHV2 infection and offers a meaningful basis for further studies of MD biology.
RNA-seq analysis of the kidneys of broiler chickens fed diets containing different concentrations of calcium
Authors: Park Woncheoul , Rengaraj Deivendran , Kil Dong-Yong , Kim Heebal , Lee Hak-Kyo , Song Ki-Duk
Published: September 2017

Calcium (Ca) is required for normal growth and is involved in cellular physiology, signal transduction, and bone mineralization. In humans, inadequate Ca intake causes hypocalcaemia, and excessive Ca intake causes hypercalcemia. In chicken, Ca is also required for body weight gain and eggshell formation. However, transcriptomic responses to low/high Ca intake, and mechanisms affecting body weight have not been explored. In this study, we performed comparative RNA sequencing (RNA-seq) using the kidney of broiler chickens fed diets containing 0.8, 1.0, and 1.2% Ca. Annotation of RNA-seq data revealed a significant number of differentially expressed genes (DEGs) in the kidney via pairwise comparison using Cufflinks and edgeR. Using edgeR, we identified 12 DEGs; seven overlapped with those found by cufflinks. Seven DEGs were validated by real-time quantitative-PCR (qRT-PCR) in Ca-supplemented kidneys, and the results correlated with the RNA-seq data. DEGs identified by cufflinks/edgeR were subjected to pathway enrichment, protein/protein interaction, and co-occurrence analyses to determine their involvement in disease. The National Research Council (NRC) recommended Ca intake for 21-day post-hatch broilers is about 1.0%. Our findings suggest that higher-than-recommended Ca intake (1.2%) could reduce body weight gain in broilers, and that affected DEGs are related to stress-induced diseases, such as hypertension.
Role of the venus kinase receptor in the female reproductive physiology of the desert locust, Schistocerca gregaria
Authors: Lenaerts Cynthia , Palmans Jolien , Marchal Elisabeth , Verdonck Rik , Vanden Broeck Jozef
Published: September 2017

Venus kinase receptors (VKR) are a subfamily of invertebrate receptor tyrosine kinases, which have only recently been discovered. They contain an intracellular tyrosine kinase domain and an extracellular Venus FlyTrap domain. VKRs have been functionally and pharmacologically characterized in only two invertebrate species, namely the human parasiteSchistosoma mansoniand the mosquitoAedes aegypti, where they play a crucial role in oogenesis. Here, we report the characterization of a VKR in the desert locust,Schistocerca gregaria. We performed an in-depth profiling study of theSgVKRtranscript levels in different tissues throughout the female adult stage. Using the RNA interference technique, the possible role ofSgVKRwas investigated.SgVKRknockdown had significant effects on ovarian ecdysteroid levels and on the size of oocytes during the vitellogenic stage.SgVKR is probably involved in the complex cross-talk between several important pathways regulating female reproductive physiology. Contrary toA. aegyptiandS. mansoni, we cannot conclude that this receptor is essential for reproduction, since silencingSgVKRdid not affect fecundity or fertility. Considering the evolutionary distance betweenA. aegyptiandS. gregaria, as well as the differences in regulation of their female reproductive physiology, this article constitutes a valuable asset in better understanding VKRs.
Use of anthropogenic linear features by two medium-sized carnivores in reserved and agricultural landscapes
Authors: Andersen Georgina E. , Johnson Christopher N. , Barmuta Leon A. , Jones Menna E.
Published: September 2017

Many carnivores are threatened by habitat loss and fragmentation. These changes create linear features and habitat edges that can facilitate foraging and/or travel. To understand the significance of anthropogenic linear features in the ecology of carnivores, fine-scaled studies are needed. We studied two medium-sized carnivores: the endangered Tasmanian devil (Sarcophilus harrisii) and the near threatened spotted-tailed quoll (Dasyurus maculatus), in a mixed landscape of conservation and agricultural land. Using GPS tracking, we investigated their use of intact habitat versus linear features such as roads, fences and the pasture/cover interface. Both species showed a positive selection for anthropogenic linear features, using the pasture/cover interface for foraging and roads for movement and foraging. Devils travelled along fence lines, while quolls showed little preference for them. Otherwise, both species foraged in forest and travelled through pasture. While devils and quolls can utilise anthropogenic linear features, we suggest that their continued survival in these habitats may depend on the intensity of other threats, e.g. persecution, and providing that sufficient intact habitat remains to sustain their ecological needs. We suggest that the management of both species and probably many other species of carnivores should focus on controlling mortality factors associated with human use of landscapes.
Elemental and Molecular Segregation in Oil Paintings due to Lead Soap Degradation
Authors: Chen-Wiegart Yu-chen Karen , Catalano Jaclyn , Williams Garth J. , Murphy Anna , Yao Yao , Zumbulyadis Nicholas , Centeno Silvia A. , Dybowski Cecil , Thieme Juergen
Published: September 2017

The formation of Pb, Zn, and Cu carboxylates (soaps) has caused visible deterioration in hundreds of oil paintings dating from the 15th century to the present. Through transport phenomena not yet understood, free fatty acids in the oil binding medium migrate through the paint and react with pigments containing heavy metals to form soaps. To investigate the complex correlation among the elemental segregation, types of chemical compounds formed, and possible mechanisms of the reactions, a paint sample cross-section from a 15th century oil painting was examined by synchrotron X-ray techniques. X-ray fluorescence (XRF) microscopy, quantified with elemental correlation density distribution, showed Pb and Sn segregation in the soap-affected areas. X-ray absorption near edge structure (XANES) around the Pb-L3 absorption edge showed that Pb pigments and Pb soaps can be distinguished while micro-XANES gave further information on the chemical heterogeneity in the paint film. The advantages and limitations of these synchrotron-based techniques are discussed and compared to those of methods routinely used to analyze paint samples. The results presented set the stage for improving the information extracted from samples removed from works of art and for correlating observations in model paint samples to those in the naturally aged samples, to shed light onto the mechanism of soap formation.
Nestlings reduce their predation risk by attending to predator-information encoded within conspecific alarm calls
Authors: Barati Ahmad , McDonald Paul G.
Published: September 2017

Predation is one of the main threats to altricial nestlings, with predators often locating nests via eavesdropping on begging signals. Nestlings may be able to adjust their begging based on the current level of risk by monitoring both intra- and interspecific alarm calls near the nest. We show that noisy miner (Manorina melanocephala) nestlings can differentiate between terrestrial and aerial alarm calls of their own species, as they suppressed begging behaviour for longer in response to terrestrial rather than aerial alarm calls. This differential response is potentially due to greater danger that terrestrial calls encode. In contrast, nestlings ignored alarm calls of the sympatric grey butcherbird (Cracticus torquatus) and continued to beg but reduced begging intensity in response to the non-alarm calls of a sympatric eastern rosella (Platycercus eximius), suggesting nestlings were likely responding based upon similarity to a known signal as opposed to expressing a learnt behaviour. Results show that nestlings respond adaptively to two different intraspecific alarm signals but have not learnt to respond to the alarm calls of sympatric species. These suggest that nestlings are able to take advantage of the complex vocal repertoire that adults produce, although discernment is an issue when filtering out irrelevant stimuli.
Synthesis and in-vitro anticancer evaluation of polyarsenicals related to the marine sponge derived Arsenicin A
Authors: Mancini Ines , Planchestainer Matteo , Defant Andrea
Published: September 2017

In the light of the promising bioactivity of the tetraarsenic marine metabolite arsenicin A, the dimethyl analogue 2 and four isomeric methylene homologues (including the natural product itself) were obtained using a one-pot microwave-assisted synthesis, starting from arsenic (III) oxide. Due to the poor diagnostic value of the NMR technique in the structural elucidation of these molecules, they were fully characterized by mass spectrometry and infrared (IR)-spectroscopy, comparing density functional theory (DFT) simulated and experimental spectra. This synthetic procedure provided a fast and efficient access to the cytotoxicity evaluation of organoarsenical leads of the natural hit molecule. From in vitro screening, each tested compound resulted in being more active than the FDA-approved arsenic trioxide, with the most lipophilic molecule in the series showing the best growth inhibition of both leukemia and solid tumor cell lines. These results may open promising perspectives in the development of new more potent and selective arsenical drugs against solid tumors.
Brain barriers and functional interfaces with sequential appearance of ABC efflux transporters during human development
Authors: Møllgård Kjeld , Dziegielewska Katarzyna M. , Holst Camilla B. , Habgood Mark D. , Saunders Norman R.
Published: September 2017

Adult brain is protected from entry of drugs and toxins by specific mechanisms such as ABC (ATP-binding Cassette) efflux transporters. Little is known when these appear in human brain during development. Cellular distribution of three main ABC transporters (ABCC1, ABCG2, ABCB1) was determined at blood-brain barriers and interfaces in human embryos and fetuses in first half of gestation. Antibodies against claudin-5 and -11 and antibodies to α-fetoprotein were used to describe morphological and functional aspects of brain barriers. First exchange interfaces to be established, probably at 4–5 weeks post conception, are between brain and embryonic cerebrospinal fluid (eCSF) and between outer surface of brain anlage and primary meninx. They already exclude α-fetoprotein and are immunopositive for both claudins, ABCC1 and ABCG2. ABCB1 is detectable within a week of blood vessels first penetrating into brain parenchyma (6–7 weeks post conception). ABCC1, ABCB1 and ABCG2 are present at blood-CSF barrier in all choroid plexuses from first appearance (7 weeks post conception). Outer CSF-brain interfaces are established between 9–11 weeks post conception exhibiting immunoreactivity for all three transporters. Results provide evidence for sequential establishment of brain exchange interfaces and spatial and temporal timetable for three main ABC transporters in early human brain.
6-bromo-indirubin-3′-oxime (6BIO), a Glycogen synthase kinase-3β inhibitor, activates cytoprotective cellular modules and suppresses cellular senescence-mediated biomolecular damage in human fibroblasts
Authors: Sklirou Aimilia D. , Gaboriaud-Kolar Nicolas , Papassideri Issidora , Skaltsounis Alexios-Leandros , Trougakos Ioannis P.
Published: September 2017

As genetic interventions or extended caloric restriction cannot be applied in humans, many studies have been devoted to the identification of natural products that can prolong healthspan. 6-bromoindirubin-3′-oxime (6BIO), a hemi-synthetic derivative of indirubins found in edible mollusks and plants, is a potent inhibitor of Glycogen synthase kinase 3β (Gsk-3β). This pleiotropic kinase has been implicated in various age-related diseases including tumorigenesis, neurodegeneration and diabetes. Accordingly, 6BIO has shown anti-tumor and anti-neurodegenerative activities; nevertheless, the potential role of 6BIO in normal human cells senescence remains largely unknown. We report herein that treatment of human diploid skin fibroblasts with 6BIO reduced the oxidative load, conferred protection against oxidative stress-mediated DNA damage, and it also promoted the activation of antioxidant and proteostatic modules; these effects were largely phenocopied by genetic inhibition of Gsk-3. Furthermore, prolonged treatment of cells with 6BIO, although it decreased the rate of cell cycling, it significantly suppressed cellular senescence-related accumulation of biomolecular damage. Taken together, our presented findings suggest that 6BIO is a novel activator of antioxidant responses and of the proteostasis network in normal human cells; moreover, and given the low levels of biomolecules damage in 6BIO treated senescing cells, this compound likely exerts anti-tumor properties.
Quantification of Aquaporin-Z reconstituted into vesicles for biomimetic membrane fabrication
Authors: Gan Hui Xian , Zhou Hu , Lin Qingsong , Tong Yen Wah
Published: September 2017

Aquaporin incorporated biomimetic membranes are anticipated to offer unprecedented desalination capabilities. However, the lack of accurate methods to quantify the reconstituted aquaporin presents a huge hurdle in investigating aquaporin performance and optimizing membrane fabrication. Herein, we present three quantification methods to determine the Aquaporin-Z reconstituted into E. coli lipid vesicles: 1) nanogold labeling with transmission electron microscopy (TEM) visualization, 2) nickel labeling with inductively coupled plasma-mass spectrometry (ICP-MS) and 3) gel electrophoresis. The TEM method serves as a quick way to determine if aquaporin has been reconstituted, but is not quantitative. The numerical results from quantitative methods, ICP-MS and gel electrophoresis, correlate closely, showing that 60 ± 20% vs 66 ± 4% of Aquaporin-Z added is successfully reconstituted into vesicles respectively. These methods allow more accurate determination of Aquaporin-Z reconstituted and loss during reconstitution, with relatively commonly available equipment and without complex sample handling, or lengthy data analysis. These would allow them to be widely applicable to scientific studies of protein function in the biomimetic environment and engineering studies on biomimetic membrane fabrication.
Physical activity is prospectively associated with spinal pain in children (CHAMPS Study-DK)
Authors: Franz Claudia , Møller Niels Christian , Korsholm Lars , Jespersen Eva , Hebert Jeffrey J. , Wedderkopp Niels
Published: September 2017

Abstarct

Spinal pain and physical inactivity are critical public health issues. We investigated the prospective associations of physical activity intensity with spinal pain in children. Physical activity was quantified with accelerometry in a cohort of primary school students. Over 19 months, parents of primary school students reported children’s spinal pain status each week via text-messaging (self-reported spinal pain). Spinal pain reports were followed-up by trained clinicians who diagnosed each child’s complaint and classified the pain as non-traumatic or traumatic. Associations were examined with logistic regression modeling using robust standard errors and reported with odds ratios (OR). Children (n = 1205, 53.0% female) with mean ± SD age of 9.4 ± 1.4 years, participated in 75,180 weeks of the study. Nearly one-third (31%) of children reported spinal pain, and 14% were diagnosed with a spinal problem. Moderate intensity physical activity was protectively associated with self-reported [OR(95%CI) = 0.84(0.74, 0.95)], diagnosed [OR(95%CI) = 0.79(0.67, 0.94)] and traumatic [OR(95%CI) = 0.77(0.61, 0.96)] spinal pain. Vigorous intensity physical activity was associated with increased self-reported [OR(95%CI) = 1.13(1.00, 1.27)], diagnosed [OR(95%CI) = 1.25(1.07, 1.45)] and traumatic [OR(95%CI) = 1.28(1.05, 1.57)] spinal pain. The inclusion of age and sex covariates weakened these associations. Physical activity intensity may be a key consideration in the relationship between physical activity behavior and spinal pain in children.
Advanced glycation end-product (AGE)-albumin from activated macrophage is critical in human mesenchymal stem cells survival and post-ischemic reperfusion injury
Authors: Son Myeongjoo , Kang Woong Chol , Oh Seyeon , Bayarsaikhan Delger , Ahn Hyosang , Lee Jaesuk , Park Hyunjin , Lee Sojung , Choi Junwon , Lee Hye Sun , Yang Phillip C. , Byun Kyunghee , Lee Bonghee
Published: September 2017

Post-ischemic reperfusion injury (PIRI) triggers an intense inflammatory response which is essential for repair but is also implicated in pathogenesis of post-ischemic remodeling in several organs in human. Stem cell therapy has recently emerged as a promising method for treatment of PIRI in human. However, satisfactory results have not been reported due to severe loss of injected stem cells in PIRI including critical limb ischemia (CLI). For investigating the advanced glycation end-product-albumin (AGE-albumin) from activated macrophages is critical in both muscle cell and stem cell death, we evaluated the recovery of PIRI-CLI by injection of human bone marrow derived mesenchymal stem cells (hBD-MSCs) with or without soluble receptor for AGEs (sRAGE). Our results showed that activated M1 macrophages synthesize and secrete AGE-albumin, which induced the skeletal muscle cell death and injected hBD-MSCs in PIRI-CLI through RAGE increase. Combined injection of sRAGE and hBD-MSCs resulted in enhanced survival of hBD-MSCs and angiogenesis in PIRI-CLI mice. Taken together, AGE-albumin from activated macrophages is critical for both skeletal muscle cell and hBD-MSCs death in PIRI-CLI. Therefore, the inhibition of AGE-albumin from activated macrophages could be a successful therapeutic strategy for treatment of PIRI including CLI with or without stem cell therapy.
Intrinsic neural network dysfunction in quiescent Crohn’s Disease
Authors: Thomann Anne K. , Griebe Martin , Thomann Philipp A. , Hirjak Dusan , Ebert Matthias P. , Szabo Kristina , Reindl Wolfgang , Wolf Robert C.
Published: September 2017

Psychological factors and comorbidities play an important role in inflammatory bowel diseases. Such comorbidity could be associated with a specific neural phenotype. Brain regions associated with emotion regulation and self-referential processing, including areas assigned to the “default mode network” (DMN), could be promising candidates in this regard. We investigated the functional integrity of multiple intrinsic neural networks in remitted patients with Crohn’s disease (CD) and sought to establish relationships between neural network connectivity and psychiatric symptoms. Fifteen CD patients in remission and 14 controls were investigated. We employed resting-state functional magnetic resonance imaging (fMRI) at 3 Tesla followed by a spatial Independent Component Analysis for fMRI data. Abnormal connectivity in CD patients was observed in DMN subsystems only (p < 0.05, cluster-corrected). Increased connectivity was found in the anterior cingulate and left superior medial frontal gyrus (aDMN) and the middle cingulate cortex (pDMN). Middle cingulate activity showed a significant association with anxiety scores in patients (p = 0.029). This study provides first evidence of selectively disrupted intrinsic neural network connectivity in CD and suggests abnormalities of self-referential neural networks. An increased sensitivity to self-related affective and somatic states in CD patients could account for these findings and explain a higher risk for anxiety symptoms.
Calcium-Mediated Adhesion of Nanomaterials in Reservoir Fluids
Authors: Eichmann Shannon L. , Burnham Nancy A.
Published: September 2017

Globally, a small percentage of oil is recovered from reservoirs using primary and secondary recovery mechanisms, and thus a major focus of the oil industry is toward developing new technologies to increase recovery. Many new technologies utilize surfactants, macromolecules, and even nanoparticles, which are difficult to deploy in harsh reservoir conditions and where failures cause material aggregation and sticking to rock surfaces. To combat these issues, typically material properties are adjusted, but recent studies show that adjusting the dispersing fluid chemistry could have significant impact on material survivability. Herein, the effect of injection fluid salinity and composition on nanomaterial fate is explored using atomic force microscopy (AFM). The results show that the calcium content in reservoir fluids affects the interactions of an AFM tip with a calcite surface, as surrogates for nanomaterials interacting with carbonate reservoir rock. The extreme force sensitivity of AFM provides the ability to elucidate small differences in adhesion at the pico-Newton (pN) level and provides direct information about material survivability. Increasing the calcium content mitigates adhesion at the pN-scale, a possible means to increase nanomaterial survivability in oil reservoirs or to control nanomaterial fate in other aqueous environments.
Measuring critical transitions in financial markets
Authors: Jurczyk Jan , Rehberg Thorsten , Eckrot Alexander , Morgenstern Ingo
Published: September 2017

Tipping points in complex systems are structural transitions from one state to another. In financial markets these critical points are connected to systemic risks, which have led to financial crisis in the past. Due to this, researchers are studying tipping points with different methods. This paper introduces a new method which bridges the gap between real-world portfolio management and statistical facts in financial markets in order to give more insight into the mechanics of financial markets.
Identification of 4-phenylquinolin-2(1H)-one as a specific allosteric inhibitor of Akt
Authors: Huang Bill X. , Newcomer Kenny , Kevala Karl , Barnaeva Elena , Zheng Wei , Hu Xin , Patnaik Samarjit , Southall Noel , Marugan Juan , Ferrer Marc , Kim Hee-Yong
Published: September 2017

Akt plays a major role in tumorigenesis and the development of specific Akt inhibitors as effective cancer therapeutics has been challenging. Here, we report the identification of a highly specific allosteric inhibitor of Akt through a FRET-based high-throughput screening, and characterization of its inhibitory mechanism. Out of 373,868 compounds screened, 4-phenylquinolin-2(1H)-one specifically decreased Akt phosphorylation at both T308 and S473, and inhibited Akt kinase activity (IC50 = 6 µM) and downstream signaling. 4-Phenylquinolin-2(1H)-one did not alter the activity of upstream kinases including PI3K, PDK1, and mTORC2 as well as closely related kinases that affect cell proliferation and survival such as SGK1, PKA, PKC, or ERK1/2. This compound inhibited the proliferation of cancer cells but displayed less toxicity compared to inhibitors of PI3K or mTOR. Kinase profiling efforts revealed that 4-phenylquinolin-2(1H)-one does not bind to the kinase active site of over 380 human kinases including Akt. However, 4-phenylquinolin-2(1H)-one interacted with the PH domain of Akt, apparently inducing a conformation that hinders S473 and T308 phosphorylation by mTORC2 and PDK1. In conclusion, we demonstrate that 4-phenylquinolin-2(1H)-one is an exquisitely selective Akt inhibitor with a distinctive molecular mechanism, and a promising lead compound for further optimization toward the development of novel cancer therapeutics.
Cold atmospheric helium plasma causes synergistic enhancement in cell death with hyperthermia and an additive enhancement with radiation
Authors: Moniruzzaman Rohan , Rehman Mati Ur , Zhao Qing-Li , Jawaid Paras , Takeda Keigo , Ishikawa Kenji , Hori Masaru , Tomihara Kei , Noguchi Kyo , Kondo Takashi , Noguchi Makoto
Published: September 2017

Cold atmospheric plasmas (CAPs) have been proposed as a novel therapeutic method for its anti-cancer potential. However, its biological effects in combination with other physical modalities remain elusive. Therefore, this study examined the effects of cold atmospheric helium plasma (He-CAP) in combination with hyperthermia (HT) 42 °C or radiation 5 Gy. Synergistic enhancement in the cell death with HT and an additive enhancement with radiation were observed following He-CAP treatment. The synergistic effects were accompanied by increased intracellular reactive oxygen species (ROS) production. Hydrogen peroxide (H2O2) and superoxide (O2•–) generation was increased immediately after He-CAP treatment, but fails to initiate cell death process. Interestingly, at late hour’s He-CAP-induced O2•–generation subsides, however the combined treatment showed sustained increased intracellular O2•–level, and enhanced cell death than either treatment alone. He-CAP caused marked induction of ROS in the aqueous medium, but He-CAP-induced ROS seems insufficient or not completely incorporated intra-cellularly to activate cell death machinery. The observed synergistic effects were due to the HT effects on membrane fluidity which facilitate the incorporation of He-CAP-induced ROS into the cells, thus results in the enhanced cancer cell death following combined treatment. These findings would be helpful when establishing a therapeutic strategy for CAP in combination with HT or radiation.
Semaphorin 3 C drives epithelial-to-mesenchymal transition, invasiveness, and stem-like characteristics in prostate cells
Authors: Tam Kevin J. , Hui Daniel H. F. , Lee Wilson W. , Dong Mingshu , Tombe Tabitha , Jiao Ivy Z. F. , Khosravi Shahram , Takeuchi Ario , Peacock James W. , Ivanova Larissa , Moskalev Igor , Gleave Martin E. , Buttyan Ralph , Cox Michael E. , Ong Christopher J.
Published: September 2017

Prostate cancer (PCa) is among the most commonly-occurring cancers worldwide and a leader in cancer-related deaths. Local non-invasive PCa is highly treatable but limited treatment options exist for those with locally-advanced and metastatic forms of the disease underscoring the need to identify mechanisms mediating PCa progression. The semaphorins are a large grouping of membrane-associated or secreted signalling proteins whose normal roles reside in embryogenesis and neuronal development. In this context, semaphorins help establish chemotactic gradients and direct cell movement. Various semaphorin family members have been found to be up- and down-regulated in a number of cancers. One family member, Semaphorin 3 C (SEMA3C), has been implicated in prostate, breast, ovarian, gastric, lung, and pancreatic cancer as well as glioblastoma. Given SEMA3C’s roles in development and its augmented expression in PCa, we hypothesized that SEMA3C promotes epithelial-to-mesenchymal transition (EMT) and stem-like phenotypes in prostate cells. In the present study we show that ectopic expression of SEMA3C in RWPE-1 promotes the upregulation of EMT and stem markers, heightened sphere-formation, and cell plasticity. In addition, we show that SEMA3C promotes migration and invasion in vitro and cell dissemination in vivo.