bluuebunny/crossref_metadata_2025 huggingface dataset:
Finite-Time Synchronization of Chaotic Complex Networks with Stochastic Disturbance
Authors: Li Liangliang , Jian Jigui
Published: December 2014

This paper is concerned with the problem of finite-time synchronization in complex networks with stochastic noise perturbations. By using a novel finite-time ℒ -operator differential inequality and other inequality techniques, some novel sufficient conditions are obtained to ensure finite-time stochastic synchronization for the complex networks concerned, where the coupling matrix need not be symmetric. The effects of control parameters on synchronization speed and time are also analyzed, and the synchronization time in this paper is shorter than that in the existing literature. The results here are also applicable to both directed and undirected weighted networks without any information of the coupling matrix. Finally, an example with numerical simulations is given to demonstrate the effectiveness of the proposed method.
Synergistic Effect of Bolus Exposure to Zinc Oxide Nanoparticles on Bleomycin-Induced Secretion of Pro-Fibrotic Cytokines without Lasting Fibrotic Changes in Murine Lungs
Authors: Wu Wenting , Ichihara Gaku , Hashimoto Naozumi , Hasegawa Yoshinori , Hayashi Yasuhiko , Tada-Oikawa Saeko , Suzuki Yuka , Chang Jie , Kato Masashi , D'Alessandro-Gabazza Corina , Gabazza Esteban , Ichihara Sahoko
Published: December 2014

Zinc oxide (ZnO) nanoparticles are widely used in various products, and the safety evaluation of this manufactured material is important. The present study investigated the inflammatory and fibrotic effects of pulmonary exposure to ZnO nanoparticles in a mouse model of pulmonary fibrosis. Pulmonary fibrosis was induced by constant subcutaneous infusion of bleomycin (BLM). Female C57BL/6Jcl mice were divided into BLM-treated and non-treated groups. In each treatment group, 0, 10, 20 or 30 µg of ZnO nanoparticles were delivered into the lungs through pharyngeal aspiration. Bronchoalveolar lavage fluid (BALF) and the lungs were sampled at Day 10 or 14 after administration. Pulmonary exposure by a single bolus of ZnO nanoparticles resulted in severe, but transient inflammatory infiltration and thickening of the alveolar septa in the lungs, along with the increase of total and differential cell counts in BLAF. The BALF level of interleukin (IL)-1β and transforming growth factor (TGF)-β was increased at Day 10 and 14, respectively. At Day 10, the synergistic effect of BLM and ZnO exposure was detected on IL-1β and monocyte chemotactic protein (MCP)-1 in BALF. The present study demonstrated the synergistic effect of pulmonary exposure to ZnO nanoparticles and subcutaneous infusion of BLM on the secretion of pro-fibrotic cytokines in the lungs.
Reduced 5-Methylcytosine Level as a Potential Progression Predictor in Patients with T1 or Non-Invasive Urothelial Carcinoma
Authors: Chung Chi-Jung , Chang Chao-Hsiang , Chuu Chih-Pin , Yang Chi-Rei , Chang Yi-Huei , Huang Chi-Ping , Chen Wen-Chi , Chung Mu-Chi , Chang Han
Published: December 2014

This study aims to elucidate the level of DNA methylation in urothelial carcinomas (UCs) using 5-methylcytosine (5-MeC) immunohistochemistry (IHC). We examined the relationship among 5-MeC levels, DNA (cytosine-5)-methyltransferase 1 (DNMT1) immunostaining levels, and clinicopathologic features. Tissue samples included 23 normal urothelia and 150 urothelial neoplasia, which comprised 40 non-invasive and 110 invasive UCs. The levels of 5-MeC and DNMT1 were assessed based on their immunoreactivities and then divided into low and high levels. In addition, we collected information on clinical variables, pathologic features, and recurrent status from patient questionnaires and medical records. Chi-square test and multivariate logistic regression model were used for analyses. Results showed that 5-MeC levels were positively associated with DNMT1 levels in UC (p = 0.0288). Both 5-MeC and DNMT1 were low in approximately 50% (76/150) of UC. The percentage of low 5-MeC levels was higher in invasive UC (65/110; 59%) than in normal urothelia (2/23; 13%) and non-invasive UC (18/40; 45%). Clinical factors were independently associated with low 5-MeC levels after adjusting for age and sex, including cancer stages II–IV, presence of UC in situ, and marked inflammation. Low 5-MeC levels in stage I invasive UC were not significantly different from those of non-invasive tumors (p = 0.8478). Low DNMT1 levels were only associated with UC with squamous differentiation (p = 0.0365). Neither 5-MeC nor DNMT1 levels were associated with UC recurrence. In conclusion, a low 5-MeC level could predict the progression of UC invasion into muscle.
Chlamydia pneumoniae and Oxidative Stress in Cardiovascular Disease: State of the Art and Prevention Strategies
Authors: Di Pietro Marisa , Filardo Simone , De Santis Fiorenzo , Mastromarino Paola , Sessa Rosa
Published: December 2014

Chlamydia pneumoniae, a pathogenic bacteria responsible for respiratory tract infections, is known as the most implicated infectious agent in atherosclerotic cardiovascular diseases (CVDs). Accumulating evidence suggests that C. pneumoniae-induced oxidative stress may play a critical role in the pathogenesis of CVDs. Indeed, the overproduction of reactive oxygen species (ROS) within macrophages, endothelial cells, platelets and vascular smooth muscle cells (VSMCs) after C. pneumoniae exposure, has been shown to cause low density lipoprotein oxidation, foam cell formation, endothelial dysfunction, platelet adhesion and aggregation, and VSMC proliferation and migration, all responsible for the typical pathological changes of atherosclerotic plaque. The aim of this review is to improve our insight into C. pneumoniae-induced oxidative stress in order to suggest potential strategies for CVD prevention. Several antioxidants, acting on multi-enzymatic targets related to ROS production induced by C. pneumoniae, have been discussed. A future strategy for the prevention of C. pneumoniae-associated CVDs will be to target chlamydial HSP60, involved in oxidative stress.
Malignant Cardiac Tamponade from Non-Small Cell Lung Cancer: Case Series from the Era of Molecular Targeted Therapy
Authors: Li Bob , Pearson Antonia , Pavlakis Nick , Bell David , Lee Adrian , Chan David , Harden Michael , Mathur Manu , Marshman David , Brady Peter , Clarke Stephen
Published: December 2014

Cardiac tamponade complicating malignant pericardial effusion from non-small cell lung cancer (NSCLC) is generally associated with extremely poor prognosis. With improved systemic chemotherapy and molecular targeted therapy for NSCLC in recent years, the prognosis of such patients and the value of invasive cardiothoracic surgery in this setting have not been adequately examined. We report outcomes from a contemporary case series of eight patients who presented with malignant cardiac tamponade due to NSCLC to an Australian academic medical institution over an 18 months period. Two cases of cardiac tamponade were de novo presentations of NSCLC and six cases were presentations following previous therapy for NSCLC. The median survival was 4.5 months with a range between 9 days to alive beyond 17 months. The two longest survivors are still receiving active therapy at 17 and 15 months after invasive surgical pericardial window respectively. One survivor had a histological subtype of large cell neuroendocrine carcinoma and the other received targeted therapy for epidermal growth factor receptor mutation. These results support the consideration of active surgical palliation to treating this oncological emergency complicating NSCLC, including the use of urgent drainage, surgical creation of pericardial window followed by appropriate systemic therapy in suitably fit patients.
The Bi-Directional Prediction of Carbon Fiber Production Using a Combination of Improved Particle Swarm Optimization and Support Vector Machine
Authors: Xiao Chuncai , Hao Kuangrong , Ding Yongsheng
Published: December 2014

This paper creates a bi-directional prediction model to predict the performance of carbon fiber and the productive parameters based on a support vector machine (SVM) and improved particle swarm optimization (IPSO) algorithm (SVM-IPSO). In the SVM, it is crucial to select the parameters that have an important impact on the performance of prediction. The IPSO is proposed to optimize them, and then the SVM-IPSO model is applied to the bi-directional prediction of carbon fiber production. The predictive accuracy of SVM is mainly dependent on its parameters, and IPSO is thus exploited to seek the optimal parameters for SVM in order to improve its prediction capability. Inspired by a cell communication mechanism, we propose IPSO by incorporating information of the global best solution into the search strategy to improve exploitation, and we employ IPSO to establish the bi-directional prediction model: in the direction of the forward prediction, we consider productive parameters as input and property indexes as output; in the direction of the backward prediction, we consider property indexes as input and productive parameters as output, and in this case, the model becomes a scheme design for novel style carbon fibers. The results from a set of the experimental data show that the proposed model can outperform the radial basis function neural network (RNN), the basic particle swarm optimization (PSO) method and the hybrid approach of genetic algorithm and improved particle swarm optimization (GA-IPSO) method in most of the experiments. In other words, simulation results demonstrate the effectiveness and advantages of the SVM-IPSO model in dealing with the problem of forecasting.
The Potential of Double Blinding with Two Placebo Acupuncture Needles: A Randomized Controlled Pilot-Trial
Authors: Takayama Miho , Yajima Hiroyoshi , Kawase Akiko , Homma Ikuo , Izumizaki Masahiko , Takakura Nobuari
Published: December 2014

Background: Whether acupuncture treatment employing multiple penetrating, skin-touch placebo, or no-touch placebo needles designed for double blinding actually do blind practitioners and patients has not been investigated. We aimed to investigate this question. Subjects: 120 patients with functional neck/shoulder stiffness but in otherwise healthy condition were randomly assigned to a treatment using four penetrating, four skin-touch placebo, or four no-touch placebo needles. Each of six acupuncturists applied four needles to four acupoints in the neck/shoulder of 20 patients. Acupuncturists and patients were asked to guess the treatment mode and their confidence in their guesses on 100 mm visual analog scales. Results: The kappa coefficients between practitioner guesses and treatment type and between patient guesses and treatment type were 0.15 and 0.44, respectively. The median score of practitioner confidence was 46.8, and no significant difference in confidence between correct and incorrect guesses was revealed for any treatment. The median score of patient confidence for correct guesses was 77.6. The kappa coefficient between practitioner and patient guesses was 0.06. Conclusions: The practitioners were blinded to the nature of treatment using the same multiple needles, but patient blinding was insufficient. Further improvement is necessary to achieve satisfactory patient blinding with these acupuncture needles.
Coplanar Electrode Layout Optimized for Increased Sensitivity for Electrical Impedance Spectroscopy
Authors: Clausen Casper , Skands Gustav , Bertelsen Christian , Svendsen Winnie
Published: December 2014

This work describes an improvement in the layout of coplanar electrodes for electrical impedance spectroscopy. We have developed, fabricated, and tested an improved electrode layout, which improves the sensitivity of an impedance flow cytometry chip. The improved chip was experimentally tested and compared to a chip with a conventional electrode layout. The improved chip was able to discriminate 0.5 μm beads from 1 μm as opposed to the conventional chip. Furthermore, finite element modeling was used to simulate the improvements in electrical field density and uniformity between the electrodes of the new electrode layout. Good agreement was observed between the model and the obtained experimental results.
A Rapid and Low-Cost Nonlithographic Method to Fabricate Biomedical Microdevices for Blood Flow Analysis
Authors: Pinto Elmano , Faustino Vera , Rodrigues Raquel , Pinho Diana , Garcia Valdemar , Miranda João , Lima Rui
Published: December 2014

Microfluidic devices are electrical/mechanical systems that offer the ability to work with minimal sample volumes, short reactions times, and have the possibility to perform massive parallel operations. An important application of microfluidics is blood rheology in microdevices, which has played a key role in recent developments of lab-on-chip devices for blood sampling and analysis. The most popular and traditional method to fabricate these types of devices is the polydimethylsiloxane (PDMS) soft lithography technique, which requires molds, usually produced by photolithography. Although the research results are extremely encouraging, the high costs and time involved in the production of molds by photolithography is currently slowing down the development cycle of these types of devices. Here we present a simple, rapid, and low-cost nonlithographic technique to create microfluidic systems for biomedical applications. The results demonstrate the ability of the proposed method to perform cell free layer (CFL) measurements and the formation of microbubbles in continuous blood flow.
Cellular Uptake of Tile-Assembled DNA Nanotubes
Authors: Kocabey Samet , Meinl Hanna , MacPherson Iain , Cassinelli Valentina , Manetto Antonio , Rothenfusser Simon , Liedl Tim , Lichtenegger Felix
Published: December 2014

DNA-based nanostructures have received great attention as molecular vehicles for cellular delivery of biomolecules and cancer drugs. Here, we report on the cellular uptake of tubule-like DNA tile-assembled nanostructures 27 nm in length and 8 nm in diameter that carry siRNA molecules, folic acid and fluorescent dyes. In our observations, the DNA structures are delivered to the endosome and do not reach the cytosol of the GFP-expressing HeLa cells that were used in the experiments. Consistent with this observation, no elevated silencing of the GFP gene could be detected. Furthermore, the presence of up to six molecules of folic acid on the carrier surface did not alter the uptake behavior and gene silencing. We further observed several challenges that have to be considered when performing in vitro and in vivo experiments with DNA structures: (i) DNA tile tubes consisting of 42 nt-long oligonucleotides and carrying single- or double-stranded extensions degrade within one hour in cell medium at 37 °C, while the same tubes without extensions are stable for up to eight hours. The degradation is caused mainly by the low concentration of divalent ions in the media. The lifetime in cell medium can be increased drastically by employing DNA tiles that are 84 nt long. (ii) Dyes may get cleaved from the oligonucleotides and then accumulate inside the cell close to the mitochondria, which can lead to misinterpretation of data generated by flow cytometry and fluorescence microscopy. (iii) Single-stranded DNA carrying fluorescent dyes are internalized at similar levels as the DNA tile-assembled tubes used here.
Piper and Vismia Species from Colombian Amazonia Differentially Affect Cell Proliferation of Hepatocarcinoma Cells
Authors: Lizcano Leandro , Siles Maite , Trepiana Jenifer , Hernández M. , Navarro Rosaura , Ruiz-Larrea M. , Ruiz-Sanz José
Published: December 2014

There is an increasing interest to identify plant-derived natural products with antitumor activities. In this work, we have studied the effects of aqueous leaf extracts from Amazonian Vismia and Piper species on human hepatocarcinoma cell toxicity. Results showed that, depending on the cell type, the plants displayed differential effects; thus, Vismia baccifera induced the selective killing of HepG2, while increasing cell growth of PLC-PRF and SK-HEP-1. In contrast, these two last cell lines were sensitive to the toxicity by Piper krukoffii and Piper putumayoense, while the Piperaceae did not affect HepG2 growth. All the extracts induced cytotoxicity to rat hepatoma McA-RH7777, but were innocuous (V. baccifera at concentrations < 75 µg/mL) or even protected cells from basal death (P. putumayoense) in primary cultures of rat hepatocytes. In every case, cytotoxicity was accompanied by an intracellular accumulation of reactive oxygen species (ROS). These results provide evidence for the anticancer activities of the studied plants on specific cell lines and suggest that cell killing could be mediated by ROS, thus involving mechanisms independent of the plants free radical scavenging activities. Results also support the use of these extracts of the Vismia and Piper genera with opposite effects as a model system to study the mechanisms of the antitumoral activity against different types of hepatocarcinoma.
Optofluidic Approaches for Enhanced Microsensor Performances
Authors: Testa Genni , Persichetti Gianluca , Bernini Romeo
Published: December 2014

Optofluidics is a relatively young research field able to create a tight synergy between optics and micro/nano-fluidics. The high level of integration between fluidic and optical elements achievable by means of optofluidic approaches makes it possible to realize an innovative class of sensors, which have been demonstrated to have an improved sensitivity, adaptability and compactness. Many developments in this field have been made in the last years thanks to the availability of a new class of low cost materials and new technologies. This review describes the Italian state of art on optofluidic devices for sensing applications and offers a perspective for further future advances. We introduce the optofluidic concept and describe the advantages of merging photonic and fluidic elements, focusing on sensor developments for both environmental and biomedical monitoring.
Nanomaterials-Based Optical Techniques for the Detection of Acetylcholinesterase and Pesticides
Authors: Xia Ning , Wang Qinglong , Liu Lin
Published: December 2014

The large amount of pesticide residues in the environment is a threat to global health by inhibition of acetylcholinesterase (AChE). Biosensors for inhibition of AChE have been thus developed for the detection of pesticides. In line with the rapid development of nanotechnology, nanomaterials have attracted great attention and have been intensively studied in biological analysis due to their unique chemical, physical and size properties. The aim of this review is to provide insight into nanomaterial-based optical techniques for the determination of AChE and pesticides, including colorimetric and fluorescent assays and surface plasmon resonance.
Development and Characterization of a Diamond-Insulated Graphitic Multi Electrode Array Realized with Ion Beam Lithography
Authors: Picollo Federico , Battiato Alfio , Carbone Emilio , Croin Luca , Enrico Emanuele , Forneris Jacopo , Gosso Sara , Olivero Paolo , Pasquarelli Alberto , Carabelli Valentina
Published: December 2014

The detection of quantal exocytic events from neurons and neuroendocrine cells is a challenging task in neuroscience. One of the most promising platforms for the development of a new generation of biosensors is diamond, due to its biocompatibility, transparency and chemical inertness. Moreover, the electrical properties of diamond can be turned from a perfect insulator into a conductive material (resistivity ~mΩ·cm) by exploiting the metastable nature of this allotropic form of carbon. A 16‑channels MEA (Multi Electrode Array) suitable for cell culture growing has been fabricated by means of ion implantation. A focused 1.2 MeV He+ beam was scanned on a IIa single-crystal diamond sample (4.5 × 4.5 × 0.5 mm3) to cause highly damaged sub-superficial structures that were defined with micrometric spatial resolution. After implantation, the sample was annealed. This process provides the conversion of the sub-superficial highly damaged regions to a graphitic phase embedded in a highly insulating diamond matrix. Thanks to a three-dimensional masking technique, the endpoints of the sub-superficial channels emerge in contact with the sample surface, therefore being available as sensing electrodes. Cyclic voltammetry and amperometry measurements of solutions with increasing concentrations of adrenaline were performed to characterize the biosensor sensitivity. The reported results demonstrate that this new type of biosensor is suitable for in vitro detection of catecholamine release.
New synonym of Tipula (Vestiplex) wahlgrenana Alexander, 1968 (Diptera: Tipulidae)
Authors: Starkevich Pavel , Podenas Sigitas
Published: December 2014

Based on examination of type specimens a crane fly species Tipula (Vestiplex) hugueniniana Alexander, 1971 is proposed as junior synonym of Tipula (V.) wahlgrenana Alexander, 1968. The new synonymy is based on similarity of male genitalia.
Effector T Cells Boost Regulatory T Cell Expansion by IL-2, TNF, OX40, and Plasmacytoid Dendritic Cells Depending on the Immune Context
Authors: Baeyens Audrey , Saadoun David , Billiard Fabienne , Rouers Angéline , Grégoire Sylvie , Zaragoza Bruno , Grinberg-Bleyer Yenkel , Marodon Gilles , Piaggio Eliane , Salomon Benoît L.
Published: December 2014

CD4+CD25+Foxp3+ regulatory T (Treg) cells play a major role in peripheral tolerance. Multiple environmental factors and cell types affect their biology. Among them, activated effector CD4+ T cells can boost Treg cell expansion through TNF or IL-2. In this study, we further characterized this effector T (Teff) cell–dependent Treg cell boost in vivo in mice. This phenomenon was observed when both Treg and Teff cells were activated by their cognate Ag, with the latter being the same or different. Also, when Treg cells highly proliferated on their own, there was no additional Treg cell boost by Teff cells. In a condition of low inflammation, the Teff cell–mediated Treg cell boost involved TNF, OX40L, and plasmacytoid dendritic cells, whereas in a condition of high inflammation, it involved TNF and IL-2. Thus, this feedback mechanism in which Treg cells are highly activated by their Teff cell counterparts depends on the immune context for its effectiveness and mechanism. This Teff cell–dependent Treg cell boost may be crucial to limit inflammatory and autoimmune responses.
IFN-γ Production by Memory Helper T Cells Is Required for CD40-Independent Alloantibody Responses
Authors: Gorbacheva Victoria , Fan Ran , Wang Xi , Baldwin William M. , Fairchild Robert L. , Valujskikh Anna
Published: December 2014

Cognate T–B cell interactions and CD40–CD154 costimulation are essential for productive humoral immunity against T-dependent Ags. We reported that memory CD4 T cells can deliver help to B cells and induce pathogenic IgG alloantibodies in the absence of CD40–CD154 interactions. To determine cytokine requirements for CD40-independent help, we used CD40−/− mice containing differentiated subsets of donor-reactive memory Th cells as heart allograft recipients. Th1 and Th17, but not Th2, memory CD4 T cells elicited high titers of anti-donor Ab. Abs induced by Th17 memory CD4 T cells had decreased reactivity against donor MHC class I molecules and inferior ability to cause complement deposition in heart allografts compared with Abs induced by Th1 cells, suggesting a requirement for IFN-γ during CD40-independent help. IFN-γ neutralization inhibited helper functions of memory CD4 T cells in both CD40−/− recipients and wild type recipients treated with anti-CD154 mAb. Our results suggest that IFN-γ secreted by pre-existing memory helper cells determines both isotype and specificity of donor-reactive alloantibodies and can thus affect allograft pathology. This information may be valuable for identifying transplant patients at risk for de novo development of pathogenic alloantibodies and for preventing alloantibody production in T cell–sensitized recipients.
Antibody-Mediated Trapping of Helminth Larvae Requires CD11b and Fcγ Receptor I
Authors: Esser-von Bieren Julia , Volpe Beatrice , Kulagin Manuel , Sutherland Duncan B. , Guiet Romain , Seitz Arne , Marsland Benjamin J. , Verbeek J. Sjef , Harris Nicola L.
Published: December 2014

Infections with intestinal helminths severely impact on human and veterinary health, particularly through the damage that these large parasites inflict when migrating through host tissues. Host immunity often targets the motility of tissue-migrating helminth larvae, which ideally should be mimicked by anti-helminth vaccines. However, the mechanisms of larval trapping are still poorly defined. We have recently reported an important role for Abs in the rapid trapping of tissue-migrating larvae of the murine parasite Heligmosomoides polygyrus bakeri. Trapping was mediated by macrophages (MΦ) and involved complement, activating FcRs, and Arginase-1 (Arg1) activity. However, the receptors and Ab isotypes responsible for MΦ adherence and Arg1 induction remained unclear. Using an in vitro coculture assay of H. polygyrus bakeri larvae and bone marrow–derived MΦ, we now identify CD11b as the major complement receptor mediating MΦ adherence to the larval surface. However, larval immobilization was largely independent of CD11b and instead required the activating IgG receptor FcγRI (CD64) both in vitro and during challenge H. polygyrus bakeri infection in vivo. FcγRI signaling also contributed to the upregulation of MΦ Arg1 expression in vitro and in vivo. Finally, IgG2a/c was the major IgG subtype from early immune serum bound by FcγRI on the MΦ surface, and purified IgG2c could trigger larval immobilization and Arg1 expression in MΦ in vitro. Our findings reveal a novel role for IgG2a/c-FcγRI–driven MΦ activation in the efficient trapping of tissue-migrating helminth larvae and thus provide important mechanistic insights vital for anti-helminth vaccine development.
CD40L Induces Functional Tunneling Nanotube Networks Exclusively in Dendritic Cells Programmed by Mediators of Type 1 Immunity
Authors: Zaccard Colleen R. , Watkins Simon C. , Kalinski Pawel , Fecek Ronald J. , Yates Aarika L. , Salter Russell D. , Ayyavoo Velpandi , Rinaldo Charles R. , Mailliard Robbie B.
Published: December 2014

The ability of dendritic cells (DC) to mediate CD4+ T cell help for cellular immunity is guided by instructive signals received during DC maturation, as well as the resulting pattern of DC responsiveness to the Th signal, CD40L. Furthermore, the professional transfer of antigenic information from migratory DC to lymph node–residing DC is critical for the effective induction of cellular immune responses. In this study we report that, in addition to their enhanced IL-12p70 producing capacity, human DC matured in the presence of inflammatory mediators of type 1 immunity are uniquely programmed to form networks of tunneling nanotube-like structures in response to CD40L-expressing Th cells or rCD40L. This immunologic process of DC reticulation facilitates intercellular trafficking of endosome-associated vesicles and Ag, but also pathogens such HIV-1, and is regulated by the opposing roles of IFN-γ and IL-4. The initiation of DC reticulation represents a novel helper function of CD40L and a superior mechanism of intercellular communication possessed by type 1 polarized DC, as well as a target for exploitation by pathogens to enhance direct cell-to-cell spread.
IRAK4 as a Molecular Target in the Amelioration of Innate Immunity–Related Endotoxic Shock and Acute Liver Injury by Chlorogenic Acid
Authors: Park Sun Hong , Baek Seung-Il , Yun Jieun , Lee Seungmin , Yoon Da Young , Jung Jae-Kyung , Jung Sang-Hun , Hwang Bang Yeon , Hong Jin Tae , Han Sang-Bae , Kim Youngsoo
Published: December 2014

Mice lacking the IL-1R–associated kinase 4 (IRAK4) are completely resistant to LPS-induced endotoxic disorder or the TLR9 agonist CpG DNA plus d-galactosamine–induced acute liver injury (ALI), whereas wild-type strains succumb. However, translational drugs against sepsis or ALI remain elusive. Lonicerae flos extract is undergoing the clinical trial phase I in LPS-injected healthy human volunteers for sepsis treatment. In the current study, chlorogenic acid (CGA), a major anti-inflammatory constituent of lonicerae flos extract, rescued endotoxic mortality of LPS-intoxicated C57BL/6 mice, as well as ameliorated ALI of LPS/d-galactosamine–challenged C57BL/6 mice. As a mechanism, CGA inhibited various TLR agonist–, IL-1α–, or high-mobility group box-1–stimulated autophosphorylation (activation) of IRAK4 in peritoneal macrophages from C57BL/6 or C3H/HeJ mice via directly affecting the kinase activity of IRAK4, a proximal signal transducer in the MyD88-mediated innate immunity that enhances transcriptional activity of NF-κB or AP-1. CGA consequently attenuated protein or mRNA levels of NF-κB/AP-1 target genes encoding TNF-α, IL-1α, IL-6, and high-mobility group box-1 in vivo under endotoxemia or ALI. Finally, this study suggests IRAK4 as a molecular target of CGA in the treatment of innate immunity–related shock and organ dysfunction following insult of various TLR pathogens from bacteria and viruses.
CD26-Mediated Induction of EGR2 and IL-10 as Potential Regulatory Mechanism for CD26 Costimulatory Pathway
Authors: Hatano Ryo , Ohnuma Kei , Otsuka Haruna , Komiya Eriko , Taki Izumi , Iwata Satoshi , Dang Nam H. , Okumura Ko , Morimoto Chikao
Published: December 2014

CD26 is associated with T cell signal transduction processes as a costimulatory molecule, and CD26+ T cells have been suggested to be involved in the pathophysiology of diverse autoimmune diseases. Although the cellular and molecular mechanisms involved in CD26-mediated T cell activation have been extensively evaluated by our group and others, potential negative feedback mechanisms to regulate CD26-mediated activation still remain to be elucidated. In the present study, we examine the expression of inhibitory molecules induced via CD26-mediated costimulation. We show that coengagement of CD3 and CD26 induces preferential production of IL-10 in human CD4+ T cells, mediated through NFAT and Raf-MEK-ERK pathways. A high level of early growth response 2 (EGR2) is also induced following CD26 costimulation, possibly via NFAT and AP-1–mediated signaling, and knockdown of EGR2 leads to decreased IL-10 production. Furthermore, CD3/CD26-stimulated CD4+ T cells clearly suppress proliferative activity and effector cytokine production of bystander T cells in an IL-10–dependent manner. Taken together, our data suggest that robust CD26 costimulatory signaling induces preferential expression of EGR2 and IL-10 as a potential mechanism for regulating CD26-mediated activation.
Survival of Human Circulating Antigen-Induced Plasma Cells Is Supported by Plasma Cell–Niche Cytokines and T Follicular Helper Lymphocytes
Authors: Ramos-Amaya Ana , Rodríguez-Bayona Beatriz , López-Blanco Rubén , Andújar Eloisa , Pérez-Alegre Mónica , Campos-Caro Antonio , Brieva José A.
Published: December 2014

Human circulating Ag-induced plasma cells (PCs) contain a high proportion of cycling cells. This study reveals that these PCs spontaneously proliferate in culture during 72 h, as determined by BrdU-uptake detection. Transcriptome analysis indicates that, in comparison with tonsil and bone marrow (BM) PCs, these PCs distinctively upregulate genes involved in cell division. Blood PC proliferation occurs simultaneously with increasing apoptosis rates, and is associated with PC survival. In addition, the proliferating activity of these PCs is enhanced by the addition of cytokines present in PC survival niches. Moreover, blood Ag-induced, but not BM, PCs exhibit the expression of molecules involved in the interaction between memory B cells and T follicular helper (Tfh) cells. In fact, purified circulating and tonsil Tfh cells increased IgG secretion by blood Ag-induced, but not by BM, PCs. This effect is exerted by augmenting blood PC survival through a mechanism partly dependent on cell contact. These results strongly suggest that the proliferating capacity of circulating Ag-induced PCs contributes to their competitive migration to survival niches, either to long-living PC niches or to temporal niches present in reactive lymphoid organs and inflamed tissues, structures where Tfh cells appear to participate.
Complement Deficiency Promotes Cutaneous Wound Healing in Mice
Authors: Rafail Stavros , Kourtzelis Ioannis , Foukas Periklis G. , Markiewski Maciej M. , DeAngelis Robert A. , Guariento Mara , Ricklin Daniel , Grice Elizabeth A. , Lambris John D.
Published: December 2014

Wound healing is a complex homeostatic response to injury that engages numerous cellular activities, processes, and cell-to-cell interactions. The complement system, an intricate network of proteins with important roles in immune surveillance and homeostasis, has been implicated in many physiological processes; however, its role in wound healing remains largely unexplored. In this study, we employ a murine model of excisional cutaneous wound healing and show that C3−/− mice exhibit accelerated early stages of wound healing. Reconstitution of C3−/− mice with serum from C3+/+ mice or purified human C3 abrogated the accelerated wound-healing phenotype. Wound histology of C3−/− mice revealed a reduction in inflammatory infiltrate compared with C3+/+ mice. C3 deficiency also resulted in increased accumulation of mast cells and advanced angiogenesis. We further show that mice deficient in the downstream complement effector C5 exhibit a similar wound-healing phenotype, which is recapitulated in C5aR1−/− mice, but not C3aR−/− or C5aR2−/− mice. Taken together, these data suggest that C5a signaling through C5aR may in part play a pivotal role in recruitment and activation of inflammatory cells to the wound environment, which in turn could delay the early stages of cutaneous wound healing. These findings also suggest a previously underappreciated role for complement in wound healing, and may have therapeutic implications for conditions of delayed wound healing.
Endogenous Intracellular Cathelicidin Enhances TLR9 Activation in Dendritic Cells and Macrophages
Authors: Nakagawa Yukinobu , Gallo Richard L.
Published: December 2014

Cathelicidins are a gene family best known for their antimicrobial action, but the diverse mature peptides they encode also have other host defense functions. The human cathelicidin peptide LL-37 enhances recognition of nucleic acids, an action whose significance is seen in human diseases such as psoriasis where it is associated with increased type 1 IFN production. This function has been attributed to the extracellular action of the peptide to facilitate uptake of nucleic acids. In this study, we demonstrate that the murine mature cathelicidin peptide (CRAMP), encoded by the mouse gene (Camp), is functionally distinct from the human mature peptide (LL-37), as it does not facilitate CpG entry. However, mouse cathelicidin does influence recognition of CpG as bone marrow–derived dendritic cells from Camp−/− mice have impaired CpG responses and Camp−/− mice had impaired response to CpG given i.v. or s.c. We show that cathelicidin concentrates in Lamp1 positive compartments, is colocalized with CpG in the endolysosome, can be immunoprecipitated with TLR9, and binds to CpG intracellulary. Collectively, these results indicate that the functions of cathelicidin in control of TLR9 activation may include both intracellular and extracellular effects.
Distinct Cellular Sources of Hepoxilin A3 and Leukotriene B4 Are Used To Coordinate Bacterial-Induced Neutrophil Transepithelial Migration
Authors: Pazos Michael A. , Pirzai Waheed , Yonker Lael M. , Morisseau Christophe , Gronert Karsten , Hurley Bryan P.
Published: December 2014

Neutrophilic infiltration is a leading contributor to pathology in a number of pulmonary disease states, including cystic fibrosis. Hepoxilin A3 (HXA3) is a chemotactic eicosanoid shown to mediate the transepithelial passage of neutrophils in response to infection in several model systems and at multiple mucosal surfaces. Another well-known eicosanoid mediating general neutrophil chemotaxis is leukotriene B4 (LTB4). We sought to distinguish the roles of each eicosanoid in the context of infection of lung epithelial monolayers by Pseudomonas aeruginosa. Using human and mouse in vitro transwell model systems, we used a combination of biosynthetic inhibitors, receptor antagonists, as well as mutant sources of neutrophils to assess the contribution of each chemoattractant in driving neutrophil transepithelial migration. We found that following chemotaxis to epithelial-derived HXA3 signals, neutrophil-derived LTB4 is required to amplify the magnitude of neutrophil migration. LTB4 signaling is not required for migration to HXA3 signals, but LTB4 generation by migrated neutrophils plays a significant role in augmenting the initial HXA3-mediated migration. We conclude that HXA3 and LTB4 serve independent roles to collectively coordinate an effective neutrophilic transepithelial migratory response.
NF- κB Essential Modulator Deficiency Leading to Disseminated Cutaneous Atypical Mycobacteria
Authors: Braue Jonathan , Murugesan Vagishwari , Holland Steven , Patel Nishit , Naik Eknath , Leiding Jennifer , Yacoub Abraham Tareq , Prieto-Granada Carlos N , Greene John Norman
Published: December 2014

NF- κB essential modulator (NEMO) is a kinase integral to the macrophage TNF-α pathway, which leads to the intracellular destruction of Mycobacteria species. Defects in the NEMO pathway lead to a spectrum of diseases, including but not limited to ectodermal dysplasia, Mendelian susceptibility to mycobacterial diseases, and incontinentia pigmenti. In addition, paucity of NEMO can lead to the inability to mount a proper immune response against opportunistic pyogenic and mycobacterial infections, leading to dissemination to various organ systems. This manuscript will discuss the numerous clinical manifestations of NEMO deficiency, the differential diagnosis for atypical mycobacterial infections in immunocompetent adults, and feature a case report of rare isolated susceptibility to disseminated atypical mycobacteria due to a mutation in the first exon of the NEMO gene.
Biogenic amines in smear and mould-ripened cheeses
Authors: Pleva Pavel , Buňková Leona , Theimrová Eva , Bartošáková Vendula , Buňka František , Purevdorj Khatantuul
Published: December 2014

The aim of the study was the monitoring of six biogenic amines (histamine, tyramine, phenylethylamine, tryptamine, putrescine, and cadaverine) and two polyamines (spermidine and spermine) in 30 samples of dairy products purchased in the Czech Republic, namely in 15 samples of mould-ripened cheeses and in 15 samples of smear-ripened cheeses. A further goal was the microbiological analysis of the individual samples of cheeses (total count of microorganisms, number of enterobacteria, enterococci, lactic acid bacteria, yeasts and moulds). The monitored biogenic amines were analyzed by a high performance liquid chromatography equipped with a UV/VIS DAD detector. The amount of enterobacteria in fresh cheese exceeded 105 CFU.g‑1. In smear-ripened cheese flavourless (Romadur type), the amount was >103 CFU.g-1 and 104-105 CFU.g-1 in smear-ripened cheese with flavour. Biogenic amines were observed in two groups of blue cheeses (white veined cheese and blue veined cheese) and smear-ripened cheeses. In both groups, there is a possibility of the presence of biogenic amines because the number of microorganisms and concentration of free amino acids increase during ripening.In ten samples of soft smear-ripening acid cheese and in smear-ripened cheese, the total content of biogenic amines were 22-1000 mg.kg-1 and in 5 samples of these cheeses, it was in range 1000-6000 mg.kg-1. The total amount of biogenic amines in the blue cheeses were in range 40-600 mg.kg-1. The presense of the tyramine was observed in the all analysed cheeses. The tyramine producing strains generated more than 900 mg.kg-1 of this biogenic amine. The production of tryptamine in the analysed cheeses was not proved by this study. The results of this study show that biogenic amines and polyamines are common in cheese. However, in some cases, they can pose a significant health danger for consumers. Any legislative control authority does not monitor them, as they are secondary metabolites even though they are potential health risks.
Clinical Research Skills Development Program in Cell-Based Regenerative Medicine
Authors: Schulman Ivonne Hernandez , Suncion Viky , Karantalis Vasileios , Balkan Wayne , Hare Joshua M. ,   for the Cardiovascular Cell Therapy Research Network
Published: December 2014

Cell-based therapy aimed at restoring organ function is one of the most exciting and promising areas of medical research. However, a novel intervention like cell-based therapy requires physician education and training. An increasing number of physicians untrained in regenerative medicine are using cell-based therapy to treat patients for a wide variety of chronic illnesses. The current lack of training for physicians in this area combined with the sharply increasing practice of regenerative medicine is concerning for a number of reasons, namely potential harm to patients and avoidable conflicts between governmental regulatory agencies and physicians. Academic medical fellowship training programs are needed that specifically prepare physicians for treating patients with cell-based therapies for various organ systems and chronic diseases. The National Heart, Lung, and Blood Institute established the Cardiovascular Cell Therapy Network to design and conduct clinical trials that advance the field of cell-based therapy for patients with cardiovascular disease. As part of the network, a two-year Clinical Research Skills Development Program was supported at two centers with the goal of training early career investigators in cell-based clinical and translational research. In this review, we describe the implementation of this training program at our institution with the purpose of promoting the further development of academic fellowship programs in cell-based regenerative medicine.
Medical Group Visits: A Feasibility Study to Manage Patients with Chronic Pain in an Underserved Urban Clinic
Authors: Gardiner Paula , Dresner Danielle , Barnett Katherine Gergen , Sadikova Ekaterina , Saper Robert
Published: December 2014

Background:

Chronic pain affects millions of racially diverse Americans. Evidence suggests that group medical visits are effective for treating chronic pain; similarly, a number of studies demonstrate the effectiveness of certain evidence-based complementary therapies in managing pain.

Objectives:

The primary goal of this study is to evaluate the feasibility of the integrative medical group visit (IMGV) care model in an inner-city racially diverse outpatient clinic. IMGV combines patient-centered, non-pharmacologic strategies and principles of mindfulness-based stress-reduction with a group medical visit to reduce pain and associated symptoms.

Methods:

We surveyed patients pre and post an 8-session IMGV program to evaluate changes in pain in the last week (0—10 point scale) and comorbid symptoms including depression (Patient Health Questionaire-8 [PHQ-8]), perceived stress, and sleep quality. We also recorded referrals to the program, patients screened for eligibility, total enrollment, loss to follow-up, and attendance.

Results:

Seventy patients joined IMGV, and of these, 65 (93%) enrolled in the study. Over the course of 12 months, 7 groups met (median 9 patients/group; range 8—13 participants). Mean difference in pain level for all patients between baseline and 8 weeks was 0.7 (SD=2.0, P=.005). Mean diference in PHQ-8 depression score for patients with baseline score ≥5 was 2.6 (SD=4.6, P<.001). Statistically significant improvements were also seen in sleep quality and perceived stress.

Conclusion:

A group visits program combining conventional and integrative medicine for predominantly racially diverse patients is feasible.
Treating type-1 diabetes with an epigenetic drug
Authors: Kitagawa Yohko , Ohkura Naganari
Published: December 2014

A single drug treats type-1 diabetes in mice by dampening inflammation and enhancing insulin production.
Observed multivariable signals of late 20th and early 21st century volcanic activity
Authors: Santer Benjamin D. , Solomon Susan , Bonfils Céline , Zelinka Mark D. , Painter Jeffrey F. , Beltran Francisco , Fyfe John C. , Johannesson Gardar , Mears Carl , Ridley David A. , Vernier Jean‐Paul , Wentz Frank J.
Published: December 2014

The relatively muted warming of the surface and lower troposphere since 1998 has attracted considerable attention. One contributory factor to this “warming hiatus” is an increase in volcanically induced cooling over the early 21st century. Here we identify the signals of late 20th and early 21st century volcanic activity in multiple observed climate variables. Volcanic signals are statistically discernible in spatial averages of tropical and near‐global SST, tropospheric temperature, net clear‐sky short‐wave radiation, and atmospheric water vapor. Signals of late 20th and early 21st century volcanic eruptions are also detectable in near‐global averages of rainfall. In tropical average rainfall, however, only a Pinatubo‐caused drying signal is identifiable. Successful volcanic signal detection is critically dependent on removal of variability induced by the El Niño–Southern Oscillation.
Tidal modulation and triggering of low‐frequency earthquakes in northern Cascadia
Authors: Royer A. A. , Thomas A. M. , Bostock M. G.
Published: December 2014

We analyze the influence of Earth and ocean tides on the triggering of low‐frequency earthquakes (LFEs) in northern Cascadia using three LFE catalogs for southern Vancouver Island and Washington state from episodic tremor and slip events between 2003 and 2013. Sensitivities of LFE families to tidally induced fault normal stress, updip shear stress (UDSS), and corresponding time derivatives are computed and their geographic variability is mapped. We find localized areas showing higher sensitivity to UDSS than their surroundings, suggesting that tidal sensitivity depends on laterally heterogeneous physical properties such as variable pore fluid pressures and frictional properties along the plate interface. We observe that sensitivity of LFEs to UDSS rises dramatically from near zero on the first day of strong activity to a maximum ∼4 days later. In addition, the peak LFE rate transitions from a correlation with peak tidal shear stress rate to a correlation with peak tidal shear stress through large slow slip events. We identify 64 Rapid‐Tremor‐Reversals (RTRs) that start a few days after the main slip front. The RTRs have an average stress drop of ∼0.8 kPa and a majority (72%) occurs during periods of large positive UDSS. The combined observations imply that RTRs play an important role in slow slip processes and that modulation of creep rate due to tidal stress and tidal triggering of secondary events are jointly responsible for the observed tidal sensitivity.