Elicitation of Induced Resistance against Pectobacterium carotovorum and Pseudomonas syringae by Specific Individual Compounds Derived from Native Korean Plant Species

Directory of Open Access Journals (Sweden)

Choong-Min Ryu

2013-10-01

Full Text Available Plants have developed general and specific defense mechanisms for protection against various enemies. Among the general defenses, induced resistance has distinct characteristics, such as broad-spectrum resistance and long-lasting effectiveness. This study evaluated over 500 specific chemical compounds derived from native Korean plant species to determine whether they triggered induced resistance against Pectobacterium carotovorum supsp. carotovorum (Pcc in tobacco (Nicotiana tabacum and Pseudomonas syringae pv. tomato (Pst in Arabidopsis thaliana. To select target compound(s with direct and indirect (volatile effects, a new Petri-dish-based in vitro disease assay system with four compartments was developed. The screening assay showed that capsaicin, fisetin hydrate, jaceosidin, and farnesiferol A reduced the disease severity significantly in tobacco. Of these four compounds, capsaicin and jaceosidin induced resistance against Pcc and Pst, which depended on both salicylic acid (SA and jasmonic acid (JA signaling, using Arabidopsis transgenic and mutant lines, including npr1 and NahG for SA signaling and jar1 for JA signaling. The upregulation of the PR2 and PDF1.2 genes after Pst challenge with capsaicin pre-treatment indicated that SA and JA signaling were primed. These results demonstrate that capsaicin and jaceosidin can be effective triggers of strong induced resistance against both necrotrophic and biotrophic plant pathogens.

Vaccination with lipid core peptides fails to induce epitope-specific T cell responses but confers non-specific protective immunity in a malaria model.

Directory of Open Access Journals (Sweden)

Simon H Apte

Full Text Available Vaccines against many pathogens for which conventional approaches have failed remain an unmet public health priority. Synthetic peptide-based vaccines offer an attractive alternative to whole protein and whole organism vaccines, particularly for complex pathogens that cause chronic infection. Previously, we have reported a promising lipid core peptide (LCP vaccine delivery system that incorporates the antigen, carrier, and adjuvant in a single molecular entity. LCP vaccines have been used to deliver several peptide subunit-based vaccine candidates and induced high titre functional antibodies and protected against Group A streptococcus in mice. Herein, we have evaluated whether LCP constructs incorporating defined CD4(+ and/or CD8(+ T cell epitopes could induce epitope-specific T cell responses and protect against pathogen challenge in a rodent malaria model. We show that LCP vaccines failed to induce an expansion of antigen-specific CD8(+ T cells following primary immunization or by boosting. We further demonstrated that the LCP vaccines induced a non-specific type 2 polarized cytokine response, rather than an epitope-specific canonical CD8(+ T cell type 1 response. Cytotoxic responses of unknown specificity were also induced. These non-specific responses were able to protect against parasite challenge. These data demonstrate that vaccination with lipid core peptides fails to induce canonical epitope-specific T cell responses, at least in our rodent model, but can nonetheless confer non-specific protective immunity against Plasmodium parasite challenge.

The role of germline promoters and I exons in cytokine-induced gene-specific class switch recombination.

Science.gov (United States)

Dunnick, Wesley A; Shi, Jian; Holden, Victoria; Fontaine, Clinton; Collins, John T

2011-01-01

Germline transcription precedes class switch recombination (CSR). The promoter regions and I exons of these germline transcripts include binding sites for activation- and cytokine-induced transcription factors, and the promoter regions/I exons are essential for CSR. Therefore, it is a strong hypothesis that the promoter/I exons regions are responsible for much of cytokine-regulated, gene-specific CSR. We tested this hypothesis by swapping the germline promoter and I exons for the murine γ1 and γ2a H chain genes in a transgene of the entire H chain C-region locus. We found that the promoter/I exon for γ1 germline transcripts can direct robust IL-4-induced recombination to the γ2a gene. In contrast, the promoter/I exon for the γ2a germline transcripts works poorly in the context of the γ1 H chain gene, resulting in expression of γ1 H chains that is level. Nevertheless, the small amount of recombination to the chimeric γ1 gene is induced by IFN-γ. These results suggest that cytokine regulation of CSR, but not the magnitude of CSR, is regulated by the promoter/I exons.

Wolbachia symbiont infections induce strong cytoplasmic incompatibility in the tsetse fly Glossina morsitans.

Directory of Open Access Journals (Sweden)

Uzma Alam

2011-12-01

Full Text Available Tsetse flies are vectors of the protozoan parasite African trypanosomes, which cause sleeping sickness disease in humans and nagana in livestock. Although there are no effective vaccines and efficacious drugs against this parasite, vector reduction methods have been successful in curbing the disease, especially for nagana. Potential vector control methods that do not involve use of chemicals is a genetic modification approach where flies engineered to be parasite resistant are allowed to replace their susceptible natural counterparts, and Sterile Insect technique (SIT where males sterilized by chemical means are released to suppress female fecundity. The success of genetic modification approaches requires identification of strong drive systems to spread the desirable traits and the efficacy of SIT can be enhanced by identification of natural mating incompatibility. One such drive mechanism results from the cytoplasmic incompatibility (CI phenomenon induced by the symbiont Wolbachia. CI can also be used to induce natural mating incompatibility between release males and natural populations. Although Wolbachia infections have been reported in tsetse, it has been a challenge to understand their functional biology as attempts to cure tsetse of Wolbachia infections by antibiotic treatment damages the obligate mutualistic symbiont (Wigglesworthia, without which the flies are sterile. Here, we developed aposymbiotic (symbiont-free and fertile tsetse lines by dietary provisioning of tetracycline supplemented blood meals with yeast extract, which rescues Wigglesworthia-induced sterility. Our results reveal that Wolbachia infections confer strong CI during embryogenesis in Wolbachia-free (Gmm(Apo females when mated with Wolbachia-infected (Gmm(Wt males. These results are the first demonstration of the biological significance of Wolbachia infections in tsetse. Furthermore, when incorporated into a mathematical model, our results confirm that Wolbachia can

Specificity of herbivore-induced hormonal signaling and defensive traits in five closely related milkweeds (Asclepias spp.).

Science.gov (United States)

Agrawal, Anurag A; Hastings, Amy P; Patrick, Eamonn T; Knight, Anna C

2014-07-01

Despite the recognition that phytohormonal signaling mediates induced responses to herbivory, we still have little understanding of how such signaling varies among closely related species and may generate herbivore-specific induced responses. We studied closely related milkweeds (Asclepias) to link: 1) plant damage by two specialist chewing herbivores (milkweed leaf beetles Labidomera clivicolis and monarch caterpillars Danaus plexippus); 2) production of the phytohormones jasmonic acid (JA), salicylic acid (SA), and abscisic acid (ABA); 3) induction of defensive cardenolides and latex; and 4) impacts on Danaus caterpillars. We first show that A. syriaca exhibits induced resistance following monarch herbivory (i.e., reduced monarch growth on previously damaged plants), while the defensively dissimilar A. tuberosa does not. We next worked with a broader group of five Asclepias, including these two species, that are highly divergent in defensive traits yet from the same clade. Three of the five species showed herbivore-induced changes in cardenolides, while induced latex was found in four species. Among the phytohormones, JA and ABA showed specific responses (although they generally increased) to insect species and among the plant species. In contrast, SA responses were consistent among plant and herbivore species, showing a decline following herbivore attack. Jasmonic acid showed a positive quantitative relationship only with latex, and this was strongest in plants damaged by D. plexippus. Although phytohormones showed qualitative tradeoffs (i.e., treatments that enhanced JA reduced SA), the few significant individual plant-level correlations among hormones were positive, and these were strongest between JA and ABA in monarch damaged plants. We conclude that: 1) latex exudation is positively associated with endogenous JA levels, even among low-latex species; 2) correlations among milkweed hormones are generally positive, although herbivore damage induces a

Spin-orbit-induced strong coupling of a single spin to a nanomechanical resonator

DEFF Research Database (Denmark)

Pályi, András; Struck, P R; Rudner, Mark

2012-01-01

as a realization of the Jaynes-Cummings model of quantum electrodynamics in the strong-coupling regime. A quantized flexural mode of the suspended tube plays the role of the optical mode and we identify two distinct two-level subspaces, at small and large magnetic field, which can be used as qubits in this setup......We theoretically investigate the deflection-induced coupling of an electron spin to vibrational motion due to spin-orbit coupling in suspended carbon nanotube quantum dots. Our estimates indicate that, with current capabilities, a quantum dot with an odd number of electrons can serve...

Study of cancer-specific chimeric promoters induced by irradiation

International Nuclear Information System (INIS)

Xiong Jie; Zhou Yunfeng; Sun Wenjie; Wang Weifeng; Liao Zhengkai; Zhou Fuxiang; Xie Conghua

2010-01-01

Objective: To combine the radio-inducible CArG element with cancer-specific human telomerase reverse transcriptase (hTERT) gene promoter, and to construct the novel chimeric promoters. Methods: The synthetic hTERT promoters containing different number of radio-inducible CArG elements were constructed, and the activities of the promoters in the cancer cells (HeLa, A549, and MHCC97 cells) and nomal cells (hEL cells) were detected by using luciferase-reporter assays after the treatment of irradiation (a single or fractionated irradiation dose). Results: Synthetic promoter containing 6 repeated CArG units was better in radio-inducibility than any other promoters containing different number of CArG units, and nearly maximum levels obtained at 4-6 Gy. The very low activities of the chimeric promoters could be detected in normal hEL cells. A similar level of reporter gene expression was observed after 3 fractionated doses of 2 Gy compared with a single dose of 6 Gy in cancer cells. Conclusions: The cancer-specific chimeric promoter containing 6 CArG elements showes the best radio-response, and the chimeric promoter system has the potential in cancer gene therapy. (authors)

Construction and Development of a Cardiac Tissue-Specific and Hypoxia-Inducible Expression Vector

Directory of Open Access Journals (Sweden)

Shahrooz Ghaderi

2018-03-01

Full Text Available Purpose: Cardiovascular gene therapy is a sophisticated approach, thanks to the safety of vectors, stable transgene expression, delivery method, and different layers of the heart. To date, numerous expression vectors have been introduced in biotechnology and biopharmacy industries in relation to genetic manipulation. Despite the rapid growth of these modalities, they must be intelligently designed, addressing the cardiac-specific transgene expression and less side effects. Herein, we conducted a pilot project aiming to design a cardiac-specific hypoxia-inducible expression cassette. Methods: We explored a new approach to design an expression cassette containing cardiac specific enhancer, hypoxia response elements (HRE, cardiac specific promoter, internal ribosome entry site (IRES, and beta globin poly A sequence to elicit specific and inducible expression of the gene of interest. Enhanced green fluorescent protein (eGFP was sub-cloned by BglII and NotI into the cassette. The specificity and inducible expression of the cassette was determined in both mouse myoblast C2C12 and mammary glandular tumor 4T1 as ‘twin’ cells. eGFP expression was evaluated by immunofluorescence microscope and flow cytometry at 520 nm emission peak. Results: Our data revealed that the designed expression cassette provided tissue specific and hypoxia inducible (O2<1% transgene expression. Conclusion: It is suggested that cardiac-specific enhancer combined with cardiac-specific promoter are efficient for myoblast specific gene expression. As well, this is for the first time that HRE are derived from three well known hypoxia-regulated promoters. Therefore, there is no longer need to overlap PCR process for one repeated sequence just in one promoter.

The I kappa B kinase inhibitor ACHP strongly attenuates TGF beta 1-induced myofibroblast formation and collagen synthesis

NARCIS (Netherlands)

Mia, Masum M.; Bank, Ruud A.

2015-01-01

Excessive accumulation of a collagen-rich extracellular matrix (ECM) by myofibroblasts is a characteristic feature of fibrosis, a pathological state leading to serious organ dysfunction. Transforming growth factor beta1 (TGF beta 1) is a strong inducer of myofibroblast formation and subsequent

Adaptability and specificity of inhibition processes in distractor-induced blindness.

Science.gov (United States)

Winther, Gesche N; Niedeggen, Michael

2017-12-01

In a rapid serial visual presentation task, inhibition processes cumulatively impair processing of a target possessing distractor properties. This phenomenon-known as distractor-induced blindness-has thus far only been elicited using dynamic visual features, such as motion and orientation changes. In three ERP experiments, we used a visual object feature-color-to test for the adaptability and specificity of the effect. In Experiment I, participants responded to a color change (target) in the periphery whose onset was signaled by a central cue. Presentation of irrelevant color changes prior to the cue (distractors) led to reduced target detection, accompanied by a frontal ERP negativity that increased with increasing number of distractors, similar to the effects previously found for dynamic targets. This suggests that distractor-induced blindness is adaptable to color features. In Experiment II, the target consisted of coherent motion contrasting the color distractors. Correlates of distractor-induced blindness were found neither in the behavioral nor in the ERP data, indicating a feature specificity of the process. Experiment III confirmed the strict distinction between congruent and incongruent distractors: A single color distractor was embedded in a stream of motion distractors with the target consisting of a coherent motion. While behavioral performance was affected by the distractors, the color distractor did not elicit a frontal negativity. The experiments show that distractor-induced blindness is also triggered by visual stimuli predominantly processed in the ventral stream. The strict specificity of the central inhibition process also applies to these stimulus features. © 2017 Society for Psychophysiological Research.

Effects of intravenous hyperosmotic sodium bicarbonate on arterial and cerebrospinal fluid acid-base status and cardiovascular function in calves with experimentally induced respiratory and strong ion acidosis.

Science.gov (United States)

Berchtold, Joachim F; Constable, Peter D; Smith, Geoffrey W; Mathur, Sheerin M; Morin, Dawn E; Tranquilli, William J

2005-01-01

The objectives of this study were to determine the effects of hyperosmotic sodium bicarbonate (HSB) administration on arterial and cerebrospinal fluid (CSF) acid-base balance and cardiovascular function in calves with experimentally induced respiratory and strong ion (metabolic) acidosis. Ten healthy male Holstein calves (30-47 kg body weight) were instrumented under halothane anesthesia to permit cardiovascular monitoring and collection of blood samples and CSE Respiratory acidosis was induced by allowing the calves to spontaneously ventilate, and strong ion acidosis was subsequently induced by i.v. administration of L-lactic acid. Calves were then randomly assigned to receive either HSB (8.4% NaHCO3; 5 ml/kg over 5 minutes, i.v.; n=5) or no treatment (controls, n=5) and monitored for 1 hour. Mixed respiratory and strong ion acidosis was accompanied by increased heart rate, cardiac index, mean arterial pressure, cardiac contractility (maximal rate of change of left ventricular pressure), and mean pulmonary artery pressure. Rapid administration of HSB immediately corrected the strong ion acidosis, transiently increased arterial partial pressure of carbon dioxide (P(CO2)), and expanded the plasma volume. The transient increase in arterial P(CO2) did not alter CSF P(CO2) or induce paradoxical CSF acidosis. Compared to untreated control calves, HSB-treated calves had higher cardiac index and contractility and a faster rate of left ventricular relaxation for 1 hour after treatment, indicating that HSB administration improved myocardial systolic function. We conclude that rapid i.v. administration of HSB provided an effective and safe method for treating strong ion acidosis in normovolemic halothane-anesthetized calves with experimentally induced respiratory and strong ion acidosis. Fear of inducing paradoxical CSF acidosis is not a valid reason for withholding HSB administration in calves with mixed respiratory and strong ion acidosis.

Dynamic Test Method Based on Strong Electromagnetic Pulse for Electromagnetic Shielding Materials with Field-Induced Insulator-Conductor Phase Transition

Science.gov (United States)

Wang, Yun; Zhao, Min; Wang, Qingguo

2018-01-01

In order to measure the pulse shielding performance of materials with the characteristic of field-induced insulator-conductor phase transition when materials are used for electromagnetic shielding, a dynamic test method was proposed based on a coaxial fixture. Experiment system was built by square pulse source, coaxial cable, coaxial fixture, attenuator, and oscilloscope and insulating components. S11 parameter of the test system was obtained, which suggested that the working frequency ranges from 300 KHz to 7.36 GHz. Insulating performance is good enough to avoid discharge between conductors when material samples is exposed in the strong electromagnetic pulse field up to 831 kV/m. This method is suitable for materials with annular shape, certain thickness and the characteristic of field-induced insulator-conductor phase transition to get their shielding performances of strong electromagnetic pulse.

Radiation-induced structural transitions in composite materials with strong interaction of polymer components

International Nuclear Information System (INIS)

Zaikin, Yu.A.; Koztaeva, U.P.

2002-01-01

In earlier papers the internal friction (IF) method was applied to studies of structural relaxation in different types of polymer-based composite materials (glass-cloth, paper-based and foiled laminates impregnated by epoxy and phenolic resins) irradiated by 2 MeV electrons in the dose range of 0.1-50.0 MGy. Selectivity and high sensibility of the internal friction method allowed to distinguish glassy transitions in different structural components of the composites. The relaxation processes observed were identified and attributed to structural alterations in the polymer filler, the binder and the boundary layers. It was shown that changes in the parameters of relaxation maximums during irradiation can be considered as quantitative characteristics for the degree of radiation-induced degradation or cross-linking of polymer molecules. This paper deals with specific features of IF spectra in paper-based laminates where both the filler fibers and the binder are strongly interacting polymers. Anisotropy of viscous and elastic properties is very weak for this kind of materials, so that IF measurements give nearly the same result independently on the filler fiber orientation in the sample. The main reasons for it are the rigid chain structure of fillers (polyethylene-terephthalate and cellulose) and the good adhesion strengthened by diffusion of the epoxy or phenolic binder to defect regions of the filler.The IF temperature dependence observed in paper-based laminates is represented by superposition of two very broad relaxation maximums associated with transitions from glassy to high-elastic state in structural components, each based on one of the polymers. The inflection points characteristic for IF temperature dependence in paper-based laminates give a reason to treat them as a superposition of α-peaks associated with transitions from glassy to high-elastic state in structural components of a composite based on the binder and the filler, respectively. Another

Jet quenching parameters in strongly coupled nonconformal gauge theories

International Nuclear Information System (INIS)

Buchel, Alex

2006-01-01

Recently Liu, Rajagopal, and Wiedemann (LRW) [H. Liu, K. Rajagopal, and U. A. Wiedemann, hep-ph/0605178.] proposed a first principle, nonperturbative quantum field theoretic definition of 'jet quenching parameter' q-circumflex used in models of medium-induced radiative parton energy loss in nucleus-nucleus collisions at RHIC. Relating q-circumflex to a short-distance behavior of a certain lightlike Wilson loop, they used gauge theory-string theory correspondence to evaluate q-circumflex for the strongly coupled N=4 SU(N c ) gauge theory plasma. We generalize analysis of LRW to strongly coupled nonconformal gauge theory plasma. We find that a jet quenching parameter is gauge theory specific (not universal). Furthermore, it appears its value increases as the number of effective adjoint degrees of freedom of a gauge theory plasma increases

Strong mechanically induced effects in DC current-biased suspended Josephson junctions

Science.gov (United States)

McDermott, Thomas; Deng, Hai-Yao; Isacsson, Andreas; Mariani, Eros

2018-01-01

Superconductivity is a result of quantum coherence at macroscopic scales. Two superconductors separated by a metallic or insulating weak link exhibit the AC Josephson effect: the conversion of a DC voltage bias into an AC supercurrent. This current may be used to activate mechanical oscillations in a suspended weak link. As the DC-voltage bias condition is remarkably difficult to achieve in experiments, here we analyze theoretically how the Josephson effect can be exploited to activate and detect mechanical oscillations in the experimentally relevant condition with purely DC current bias. We unveil how changing the strength of the electromechanical coupling results in two qualitatively different regimes showing dramatic effects of the oscillations on the DC-voltage characteristic of the device. These include the appearance of Shapiro-type plateaus for weak coupling and a sudden mechanically induced retrapping for strong coupling. Our predictions, measurable in state-of-the-art experimental setups, allow the determination of the frequency and quality factor of the resonator using DC only techniques.

Self-induced steps in a small Josephson junction strongly coupled to a multimode resonator

DEFF Research Database (Denmark)

Larsen, A.; Jensen, H. Dalsgaard; Mygind, Jesper

1991-01-01

An equally spaced series of very large and nearly constant-voltage self-induced singularities has been observed in the dc I-V characteristics of a small Josephson tunnel junction strongly coupled to a resonant section of a superconducting transmission line. The system allows extremely high values...... of the coupling parameter. The current steps are due to subharmonic parametric excitation of the fundamental mode of the resonator loaded by the junction admittance. Using an applied magnetic field to vary the coupling parameter, we traced out half-integer steps as well as the mode steps known from more weakly...

Opiate-induced seizures: a study of mu and delta specific mechanisms.

Science.gov (United States)

Snead, O C

1986-08-01

Two groups of experiments were conducted to determine if morphine- and enkephalin-induced seizures are specifically mediated by the mu and delta receptor, respectively. In the first experiments, designed to assess the ontogeny of mu- or delta-seizures, rats from 6 h to 85 days of age received implanted cortical and depth electrodes as well as an indwelling cannula in the lateral ventricle. Various amounts of the mu-receptor agonists, morphine and morphiceptin, and the delta agonists, D-Ala2-D-Leu5-enkephalin (DADL) and Tyr-D-Ser-Gly-Phe-Leu-Thr (DSLET), were then administered intracerebroventricularly (icv) with continuous EEG monitoring. The second experiments entailed use of the nonspecific opiate antagonist, naloxone, as well as the specific delta antagonist, ICI 154,129, against seizures induced by icv-administered morphine, morphiceptin, DADL, or DSLET. Both morphine and morphiceptin produced electrical seizure activity in rats as young as 5 days after birth. The drugs produced similar seizure activity in terms of electrical morphology, observed behavior, ontogeny, threshold dose, and reversibility with small doses of naloxone. In the pharmacologic experiments, icv naloxone blocked all opiate-induced seizures. ICI 154,129 blocked DSLET seizure, had little effect on enkephalin or DADL seizures, and no effect on morphine or morphiceptin seizures. These data indicate that DSLET seizures are delta-specific but that all other opiate-induced seizures studied may involve multiple opiate receptor-mediated mechanisms.

The role of the endocrine system in feeding-induced tissue-specific circadian entrainment.

Science.gov (United States)

Sato, Miho; Murakami, Mariko; Node, Koichi; Matsumura, Ritsuko; Akashi, Makoto

2014-07-24

The circadian clock is entrained to environmental cycles by external cue-mediated phase adjustment. Although the light input pathway has been well defined, the mechanism of feeding-induced phase resetting remains unclear. The tissue-specific sensitivity of peripheral entrainment to feeding suggests the involvement of multiple pathways, including humoral and neuronal signals. Previous in vitro studies with cultured cells indicate that endocrine factors may function as entrainment cues for peripheral clocks. However, blood-borne factors that are well characterized in actual feeding-induced resetting have yet to be identified. Here, we report that insulin may be involved in feeding-induced tissue-type-dependent entrainment in vivo. In ex vivo culture experiments, insulin-induced phase shift in peripheral clocks was dependent on tissue type, which was consistent with tissue-specific insulin sensitivity, and peripheral entrainment in insulin-sensitive tissues involved PI3K- and MAPK-mediated signaling pathways. These results suggest that insulin may be an immediate early factor in feeding-mediated tissue-specific entrainment. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Specific inhibition of cytotoxic memory cells produced against uv-induced tumors in uv-irradiation mice

International Nuclear Information System (INIS)

Thorn, R.M.

1978-01-01

Cytotoxic responses of uv-irradiated mice against syngeneic uv-induced tumors were measured by using a 51 Cr-release assay to determine if uv treatment induced a specific reduction of cytotoxic activity. The in vivo and in vitro primary responses against syngeneic tumors and allogeneic cells were unaffected, as was the ''memory'' response (in vivo stimulation, in vitro restimulation) against alloantigens. In contrast, the memory response of uv-treated mice against syngeneic, uv-induced tumors was consistently and significantly depressed. The cytotoxicity generated by tumor cell stimulation in vivo or in vitro was tumor-specific and T cell-dependent. Since the primary response against syngeneic uv-induced tumors produces apparently normal amounts of tumor-specific cytotoxic activity, uv-treated mice may not reject transplanted syngeneic tumors because of too few T effector memory cells. These results imply that, at least in this system, tumor rejection depends mostly on the secondary responses against tumor antigens and that at least one carcinogen can, indirectly, specifically regulate immune responses

Semi-allogeneic dendritic cells can induce antigen-specific T-cell activation, which is not enhanced by concurrent alloreactivity.

Science.gov (United States)

Wells, James W; Cowled, Chris J; Darling, David; Guinn, Barbara-Ann; Farzaneh, Farzin; Noble, Alistair; Galea-Lauri, Joanna

2007-12-01

Alloreactive T-cell responses are known to result in the production of large amounts of proinflammatory cytokines capable of activating and maturing dendritic cells (DC). However, it is unclear whether these allogeneic responses could also act as an adjuvant for concurrent antigen-specific responses. To examine effects of simultaneous alloreactive and antigen-specific T-cell responses induced by semi-allogeneic DC. Semi-allogeneic DC were generated from the F(1) progeny of inbred strains of mice (C57BL/6 and C3H, or C57BL/6 and DBA). We directly primed antigen-specific CD8(+) and CD4(+) T-cells from OT-I and OT-II mice, respectively, in the absence of allogeneic responses, in vitro, and in the presence or absence of alloreactivity in vivo. In vitro, semi-allogeneic DC cross-presented ovalbumin (OVA) to naïve CD8(+) OT-I transgenic T-cells, primed naïve CD4(+) OT-II transgenic T-cells and could stimulate strong alloreactive T-cell proliferation in a primary mixed lymphocyte reaction (MLR). In vivo, semi-allogeneic DC migrated efficiently to regional lymph nodes but did not survive there as long as autologous DC. In addition, they were not able to induce cytotoxic T-lymphocyte (CTL) activity to a target peptide, and only weakly stimulated adoptively transferred OT-II cells. The CD4(+) response was unchanged in allo-tolerized mice, indicating that alloreactive T-cell responses could not provide help for concurrently activated antigen-specific responses. In an EL4 tumour-treatment model, vaccination with semi-allogeneic DC/EL4 fusion hybrids, but not allogeneic DC/EL4 hybrids, significantly increased mouse survival. Expression of self-Major histocompatibility complex (MHC) by semi-allogeneic DC can cause the induction of antigen-specific immunity, however, concurrently activated allogeneic bystander responses do not provide helper or adjuvant effects.

The construction of a library of synthetic promoters revealed some specific features of strong Streptomyces promoters

DEFF Research Database (Denmark)

Seghezzi, Nicolas; Amar, Patrick; Købmann, Brian

2011-01-01

Streptomyces are bacteria of industrial interest whose genome contains more than 73% of bases GC. In order to define, in these GC-rich bacteria, specific sequence features of strong promoters, a library of synthetic promoters of various sequence composition was constructed in Streptomyces. To do so...... cloned into the promoter-probe plasmid pIJ487 just upstream of the promoter-less aphII gene that confers resistance to neomycin. This synthetic promoter library was transformed into Streptomyces lividans, and the resulting transformants were screened for their ability to grow in the presence of different...... projects. Thirty-eight promoters were sequenced, and the sequences of the 14 weakest and 14 strongest promoters were compared using the WebLogo software with small sample correction. This comparison revealed that the −10 box, the −10 extended motif as well as the spacer of the strong Streptomyces promoters...

Propranolol–induced Impairment of Contextual Fear Memory Reconsolidation in Rats: A similar Effect on Weak and Strong Recent and Remote Memories

Science.gov (United States)

Taherian, Fatemeh; Vafaei, Abbas Ali; Vaezi, Gholam Hassan; Eskandarian, Sharaf; Kashef, Adel; Rashidy-Pour, Ali

2014-01-01

Introduction Previous studies have demonstrated that the β-adrenergic receptor antagonist propranolol impairs fear memory reconsolidation in experimental animals. There are experimental parameters such as the age and the strength of memory that can interact with pharmacological manipulations of memory reconsolidation. In this study, we investigated the ability of the age and the strength of memory to influence the disrupting effects of propranolol on fear memory reconsolidation in rats. Methods The rats were trained in a contextual fear conditioning using two (weak training) or five (strong training) footshocks (1mA). Propranolol (10mg/kg) injection was immediately followed retrieval of either a one-day recent (weak or strong) or 36-day remote (weak or strong) contextual fear memories. Results We found that propranolol induced a long-lasting impairment of subsequent expression of recent and remote memories with either weak or strong strength. We also found no memory recovery after a weak reminder shock. Furthermore, no significant differences were found on the amount of memory deficit induced by propranolol among memories with different age and strength. Discussion Our data suggest that the efficacy of propranolol in impairing fear memory reconsolidation is not limited to the age or strength of the memory. PMID:25337385

Strong braking of m = 1 impurity-induced ‘snake’ in EAST sawtoothing plasma

International Nuclear Information System (INIS)

Ma, Tianpeng; Xu, Liqing; Hu, Liqun

2014-01-01

Strong braking of the m = 1 impurity-induced (e.g. molybdenum emission) density perturbation ‘snake’ was observed in EAST sawtoothing plasma. The shift of the peak positions of soft x-ray emissions due to the snake can be as high as 7 cm. Notable electron density fluctuations (δn e /n e0 can be as high as 8%) originating from this m = 1 snake are measured by a hydrogen cyanide laser interferometer. Due to mode coupling, synchronous locking of the m = 2 tearing mode and m = 1 snakes is expected to happen when the width of the m = 2 island exceeds a critical value. A critical width value of m = 2 for mode locking is calculated. The forced reconnection in the q = 2 surface is induced by a toroidal sideband of the m = 1 mode. (paper)

Intramuscular Immunisation with Chlamydial Proteins Induces Chlamydia trachomatis Specific Ocular Antibodies.

Directory of Open Access Journals (Sweden)

Alexander Badamchi-Zadeh

Full Text Available Ocular infection with Chlamydia trachomatis can cause trachoma, which is the leading cause of blindness due to infection worldwide. Despite the large-scale implementation of trachoma control programmes in the majority of countries where trachoma is endemic, there remains a need for a vaccine. Since C. trachomatis infects the conjunctival epithelium and stimulates an immune response in the associated lymphoid tissue, vaccine regimens that enhance local antibody responses could be advantageous. In experimental infections of non-human primates (NHPs, antibody specificity to C. trachomatis antigens was found to change over the course of ocular infection. The appearance of major outer membrane protein (MOMP specific antibodies correlated with a reduction in ocular chlamydial burden, while subsequent generation of antibodies specific for PmpD and Pgp3 correlated with C. trachomatis eradication.We used a range of heterologous prime-boost vaccinations with DNA, Adenovirus, modified vaccinia Ankara (MVA and protein vaccines based on the major outer membrane protein (MOMP as an antigen, and investigated the effect of vaccine route, antigen and regimen on the induction of anti-chlamydial antibodies detectable in the ocular lavage fluid of mice.Three intramuscular vaccinations with recombinant protein adjuvanted with MF59 induced significantly greater levels of anti-MOMP ocular antibodies than the other regimens tested. Intranasal delivery of vaccines induced less IgG antibody in the eye than intramuscular delivery. The inclusion of the antigens PmpD and Pgp3, singly or in combination, induced ocular antigen-specific IgG antibodies, although the anti-PmpD antibody response was consistently lower and attenuated by combination with other antigens.If translatable to NHPs and/or humans, this investigation of the murine C. trachomatis specific ocular antibody response following vaccination provides a potential mouse model for the rapid and high throughput

Poly-ϵ-caprolactone/chitosan nanoparticles provide strong adjuvant effect for hepatitis B antigen.

Science.gov (United States)

Jesus, Sandra; Soares, Edna; Borchard, Gerrit; Borges, Olga

2017-10-01

This work aims to investigate the adjuvant effect of poly-ϵ-caprolactone/chitosan nanoparticles (NPs) for hepatitis B surface antigen (HBsAg) and the plasmid DNA encoding HBsAg (pRC/CMV-HBs). Both antigens were adsorbed onto preformed NPs. Vaccination studies were performed in C57BL/6 mice. Transfection efficiency was investigated in A549 cell line. HBsAg-adsorbed NPs generated strong anti-HBsAg IgG titers, mainly of IgG1 isotype, and induced antigen-specific IFN-γ and IL-17 secretion by spleen cells. The addition of pRC/CMV-HBs to the HBsAg-adsorbed NPs inhibited IL-17 secretion but had minor effect on IFN-γ levels. Lastly, pRC/CMV-HBs-loaded NPs generated a weak serum antibody response. Poly-ϵ-caprolactone/chitosan NPs provide a strong humoral adjuvant effect for HBsAg and induce a Th1/Th17-mediated cellular immune responses worth explore for hepatitis B virus vaccination.

Semi-strong split domination in graphs

Directory of Open Access Journals (Sweden)

Anwar Alwardi

2014-06-01

Full Text Available Given a graph $G = (V,E$, a dominating set $D subseteq V$ is called a semi-strong split dominating set of $G$ if $|V setminus D| geq 1$ and the maximum degree of the subgraph induced by $V setminus D$ is 1. The minimum cardinality of a semi-strong split dominating set (SSSDS of G is the semi-strong split domination number of G, denoted $gamma_{sss}(G$. In this work, we introduce the concept and prove several results regarding it.

The sequence specificity of UV-induced DNA damage in a systematically altered DNA sequence.

Science.gov (United States)

Khoe, Clairine V; Chung, Long H; Murray, Vincent

2018-06-01

The sequence specificity of UV-induced DNA damage was investigated in a specifically designed DNA plasmid using two procedures: end-labelling and linear amplification. Absorption of UV photons by DNA leads to dimerisation of pyrimidine bases and produces two major photoproducts, cyclobutane pyrimidine dimers (CPDs) and pyrimidine(6-4)pyrimidone photoproducts (6-4PPs). A previous study had determined that two hexanucleotide sequences, 5'-GCTC*AC and 5'-TATT*AA, were high intensity UV-induced DNA damage sites. The UV clone plasmid was constructed by systematically altering each nucleotide of these two hexanucleotide sequences. One of the main goals of this study was to determine the influence of single nucleotide alterations on the intensity of UV-induced DNA damage. The sequence 5'-GCTC*AC was designed to examine the sequence specificity of 6-4PPs and the highest intensity 6-4PP damage sites were found at 5'-GTTC*CC nucleotides. The sequence 5'-TATT*AA was devised to investigate the sequence specificity of CPDs and the highest intensity CPD damage sites were found at 5'-TTTT*CG nucleotides. It was proposed that the tetranucleotide DNA sequence, 5'-YTC*Y (where Y is T or C), was the consensus sequence for the highest intensity UV-induced 6-4PP adduct sites; while it was 5'-YTT*C for the highest intensity UV-induced CPD damage sites. These consensus tetranucleotides are composed entirely of consecutive pyrimidines and must have a DNA conformation that is highly productive for the absorption of UV photons. Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.

Rapid desensitization induces internalization of antigen-specific IgE on mouse mast cells.

Science.gov (United States)

Oka, Tatsuya; Rios, Eon J; Tsai, Mindy; Kalesnikoff, Janet; Galli, Stephen J

2013-10-01

Rapid desensitization transiently prevents severe allergic reactions, allowing administration of life-saving therapies in previously sensitized patients. However, the mechanisms underlying successful rapid desensitization are not fully understood. We sought to investigate whether the mast cell (MC) is an important target of rapid desensitization in mice sensitized to exhibit IgE-dependent passive systemic anaphylaxis in vivo and to investigate the antigen specificity and underlying mechanisms of rapid desensitization in our mouse model. C57BL/6 mice (in vivo) or primary isolated C57BL/6 mouse peritoneal mast cells (PMCs; in vitro) were passively sensitized with antigen-specific anti-2,4-dinitrophenyl IgE, anti-ovalbumin IgE, or both. MCs were exposed over a short period of time to increasing amounts of antigen (2,4-dinitrophenyl-human serum albumin or ovalbumin) in the presence of extracellular calcium in vitro or by means of intravenous administration to sensitized mice in vivo before challenging the mice with or exposing the PMCs to optimal amounts of specific or irrelevant antigen. Rapidly exposing mice or PMCs to progressively increasing amounts of specific antigen inhibited the development of antigen-induced hypothermia in sensitized mice in vivo and inhibited antigen-induced PMC degranulation and prostaglandin D2 synthesis in vitro. Such MC hyporesponsiveness was induced antigen-specifically and was associated with a significant reduction in antigen-specific IgE levels on MC surfaces. Rapidly exposing MCs to progressively increasing amounts of antigen can both enhance the internalization of antigen-specific IgE on the MC surface and also desensitize these cells in an antigen-specific manner in vivo and in vitro. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Tissue specific promoters improve the localization of radiation-inducible gene expression

International Nuclear Information System (INIS)

Hallahan, Dennis; Kataoka, Yasushi; Kuchibhotla, Jaya; Virudachalam, Subbu; Weichselbaum, Ralph

1996-01-01

Purpose: Site-specific activation of gene expression can be achieved by the use of a promoter that is induced by physical agents such as x-rays. The purpose of the present study was to determine whether site-specific activation of gene therapy can also be achieved within the vascular endothelium by use of radiation-inducible promoters. We studied induction of promoter-reporter gene constructs using previously identified radiation-promoters from c-jun, c-fos, Egr-1, ICAM-1, ELAM-1 after transfection into in the vascular endothelium. Methods: The following radiation-inducible genetic constructs were created: The ELAM-1 promoter fragment was cloned into pOGH to obtain the pE-sel(-587 +35)GH reporter construct. The ICAM-1 promoter fragment (-1162/+1) was cloned upstream of the CAT coding region of the pCAT-plasmid (Promega) after removal of the SV40 promoter by Bgl2/Stu1 digestion to create the pBS-CAT plasmid. The 132 to +170 bp segment of the 5' untranslated region of the c-jun promoter was cloned to the CAT reporter gene to create the -132/+170 cjun-CAT. The Egr-1 promoter fragment (-425/+75) was cloned upstream of the CAT coding region to create the pE425-CAT plasmid. Tandem repeats of the AP-1 binding site were cloned upstream of the CAT coding region (3 xTRE-CAT). Tandem repeats of the Egr binding site (EBS) were cloned upstream of the CAT coding region (EBS-CAT). Human vascular endothelial cells from both large vessel and small vessel origin (HUVEC and HMEC), as well as human tumor cell lines were transfected with plasmids -132/+170 cjun-CAT, pE425-CAT, 3 xTRE-CAT, EBS-CAT, pE-sel-GH and pBS-CAT by use of liposomes. Humor tumor cell lines included SQ20B (squamous), RIT3 (sarcoma), and HL525 (leukemia). Each plasmid was cotransfected with a plasmid containing a CMV promoter linked to the LacZ gene (1 μg). Transfected cells were treated with mock irradiation or x-rays. Cell extracts were assayed for reporter gene expression. Results: Radiation-induced gene

OBSERVATION OF STRONG - STRONG AND OTHER BEAM - BEAM EFFECTS IN RHIC

International Nuclear Information System (INIS)

FISCHER, W.; BLASKIEWICZ, M.; BRENNAN, J.M.; CAMERON, P.; CONNOLLY, R.; MONTAG, C.; PEGGS, S.; PILAT, F.; PTITSYN, V.; TEPIKIAN, S.; TRBOJEVIC, D.; VAN ZEIJTS, J.

2003-01-01

RHIC is currently the only hadron collider in which strong-strong beam-beam effects can be seen. For the first time, coherent beam-beam modes were observed in a bunched beam hadron collider. Other beam-beam effects in RHIC were observed in operation and in dedicated experiments with gold ions, deuterons and protons. Observations include measurements of beam-beam induced tune shifts, lifetime and emittance growth measurements with and without beam-beam interaction, and background rates as a function of tunes. During ramps unequal radio frequencies in the two rings cause the crossing points to move longitudinally. Thus bunches experience beam-beam interactions only in intervals and the tunes are modulated. In this article we summarize the most important beam-beam observations made so far

Rh-Catalyzed annulations of N-methoxybenzamides with ketenimines: synthesis of 3-aminoisoindolinones and 3-diarylmethyleneisoindolinones with strong aggregation induced emission properties.

Science.gov (United States)

Zhou, Xiaorong; Peng, Zhixing; Zhao, Hongyang; Zhang, Zhiyin; Lu, Ping; Wang, Yanguang

2016-08-23

Rhodium-catalyzed C-H activation/annulation reactions of ketenimines with N-methoxybenzamides furnished 3-aminoisoindolin-1-ones and 3-(diarylmethylene)isoindolin-1-ones. The synthesized 3-(diarylmethylene)isoindolin-1-ones exhibited aggregation induced emissions in aqueous tetrahydrofuran solution and strong green-yellow emissions in solids.

Oral Salmonella: malaria circumsporozoite recombinants induce specific CD8+ cytotoxic T cells

OpenAIRE

1990-01-01

Oral immunization with an attenuated Salmonella typhimurium recombinant containing the full-length Plasmodium berghei circumsporozoite (CS) gene induces protective immunity against P. berghei sporozoite challenge in the absence of antibody. We found that this immunity was mediated through the induction of specific CD8+ T cells since in vivo elimination of CD8+ cells abrogated protection. In vitro studies revealed that this Salmonella-P. berghei CS recombinant induced class I- restricted CD8+ ...

Benchmark studies of induced radioactivity produced in LHC materials, Part I: Specific activities.

Science.gov (United States)

Brugger, M; Khater, H; Mayer, S; Prinz, A; Roesler, S; Ulrici, L; Vincke, H

2005-01-01

Samples of materials which will be used in the LHC machine for shielding and construction components were irradiated in the stray radiation field of the CERN-EU high-energy reference field facility. After irradiation, the specific activities induced in the various samples were analysed with a high-precision gamma spectrometer at various cooling times, allowing identification of isotopes with a wide range of half-lives. Furthermore, the irradiation experiment was simulated in detail with the FLUKA Monte Carlo code. A comparison of measured and calculated specific activities shows good agreement, supporting the use of FLUKA for estimating the level of induced activity in the LHC.

Benchmark studies of induced radioactivity produced in LHC materials, part I: Specific activities

International Nuclear Information System (INIS)

Brugger, M.; Khater, H.; Mayer, S.; Prinz, A.; Roesler, S.; Ulrici, L.; Vincke, H.

2005-01-01

Samples of materials which will be used in the LHC machine for shielding and construction components were irradiated in the stray radiation field of the CERN-EU high-energy reference field facility. After irradiation, the specific activities induced in the various samples were analysed with a high-precision gamma spectrometer at various cooling times, allowing identification of isotopes with a wide range of half-lives. Furthermore, the irradiation experiment was simulated in detail with the FLUKA Monte Carlo code. A comparison of measured and calculated specific activities shows good agreement, supporting the use of FLUKA for estimating the level of induced activity in the LHC. (authors)

The effect of patient-specific factors on radiation-induced regional lung injury

International Nuclear Information System (INIS)

Garipagaoglu, Melahat; Munley, Michael T.; Hollis, Donna; Poulson, Jean M.; Bentel, Gunilla C.; Sibley, Gregory; Anscher, Mitchell S.; Fan Ming; Jaszczak, Ronald J.; Coleman, R. Edward; Marks, Lawrence B.

1999-01-01

Purpose: To assess the impact of patient-specific factors on radiation (RT)-induced reductions in regional lung perfusion. Methods: Fifty patients (32 lung carcinoma, 7 Hodgkin's disease, 9 breast carcinoma and 2 other thoracic tumors) had pre-RT and ≥24-week post-RT single photon emission computed tomography (SPECT) perfusion images to assess the dose dependence of RT-induced reductions in regional lung perfusion. The SPECT data were analyzed using a normalized and non-normalized approach. Furthermore, two different mathematical methods were used to assess the impact of patient-specific factors on the dose-response curve (DRC). First, DRCs for different patient subgroups were generated and compared. Second, in a more formal statistical approach, individual DRCs for regional lung injury for each patient were fit to a linear-quadratic model (reduction = coefficient 1 x dose + coefficient 2 x dose 2 ). Multiple patient-specific factors including tobacco history, pre-RT diffusion capacity to carbon monoxide (DLCO), transforming growth factor-beta (TGF-β), chemotherapy exposure, disease type, and mean lung dose were explored in a multivariate analysis to assess their impact on the coefficients. Results: None of the variables tested had a consistent impact on the radiation sensitivity of regional lung (i.e., the slope of the DRC). In the formal statistical analysis, there was a suggestion of a slight increase in radiation sensitivity in the dose range >40 Gy for nonsmokers (vs. smokers) and in those receiving chemotherapy (vs. no chemotherapy). However, this finding was very dependent on the specific statistical and normalization method used. Conclusion: Patient-specific factors do not have a dramatic effect on RT-induced reduction in regional lung perfusion. Additional studies are underway to better clarify this issue. We continue to postulate that patient-specific factors will impact on how the summation of regional injury translates into whole organ injury

A multi-subunit Chlamydia vaccine inducing neutralizing antibodies and strong IFN-γ(+) CMI responses protects against a genital infection in minipigs

DEFF Research Database (Denmark)

Bøje, Sarah; Olsen, Anja Weinreich; Erneholm, Karin

2016-01-01

Chlamydia is the most widespread sexually transmitted bacterial disease and a prophylactic vaccine is highly needed. Ideally, this vaccine is required to induce a combined response of Th1 cell-mediated immune (CMI) response in concert with neutralizing antibodies. Using a novel Göttingen minipig...... animal model, we evaluated the immunogenicity and efficacy of a multi-subunit vaccine formulated in the strong Th1-inducing adjuvant CAF01. We evaluated a mixture of two fusion proteins (Hirep1 and CTH93) designed to promote either neutralizing antibodies or cell-mediated immunity, respectively. Hirep1...

Cell type-specific roles of Jak3 in IL-2-induced proliferative signal transduction

International Nuclear Information System (INIS)

Fujii, Hodaka

2007-01-01

Binding of interleukin-2 (IL-2) to its specific receptor induces activation of two members of Jak family protein tyrosine kinases, Jak1 and Jak3. An IL-2 receptor (IL-2R)-reconstituted NIH 3T3 fibroblast cell line proliferates in response to IL-2 only when hematopoietic lineage-specific Jak3 is ectopically expressed. However, the mechanism of Jak3-dependent proliferation in the fibroblast cell line is not known. Here, I showed that Jak3 expression is dispensable for IL-2-induced activation of Jak1 and Stat proteins and expression of nuclear proto-oncogenes in the IL-2R-reconstituted fibroblast cell line. Jak3 expression markedly enhanced these IL-2-induced signaling events. In contrast, Jak3 expression was essential for induction of cyclin genes involved in the G1-S transition. These data suggest a critical role of Jak3 in IL-2 signaling in the fibroblast cell line and may provide further insight into the cell type-specific mechanism of cytokine signaling

Cell type-specific roles of Jak3 in IL-2-induced proliferative signal transduction

Science.gov (United States)

Fujii, Hodaka

2007-01-01

Binding of IL-2 to its specific receptor induces activation of two members of Jak family protein tyrosine kinases, Jak1 and Jak3. An IL-2R-reconstituted NIH 3T3 fibroblast cell line proliferates in response to IL-2 only when hematopoietic lineage-specific Jak3 is ectopically expressed. However, the mechanism of Jak3-dependent proliferation in the fibroblast cell line is not known. Here, I showed that Jak3 expression is dispensable for IL-2-induced activation of Jak1 and Stat proteins and expression of nuclear proto-oncogenes in the IL-2R-reconstituted fibroblast cell line. However, Jak3 expression markedly enhanced these IL-2-induced signaling events. In contrast, Jak3 expression was essential for induction of cyclin genes involved in the G1-S transition. These data suggest a critical role of Jak3 in IL-2 signaling in the fibroblast cell line and may provide further insight into the cell type-specific mechanism of cytokine signaling. PMID:17266928

Plasmodium falciparum parasites expressing pregnancy-specific variant surface antigens adhere strongly to the choriocarcinoma cell line BeWo

DEFF Research Database (Denmark)

Haase, Rikke N; Megnekou, Rosette; Lundquist, Maja

2006-01-01

Placenta-sequestering Plasmodium falciparum parasites causing pregnancy-associated malaria express pregnancy-specific variant surface antigens (VSA(PAM)). We report here that VSA(PAM)-expressing patient isolates adhere strongly to the choriocarcinoma cell line BeWo and that the BeWo line can...... be used to efficiently select for VSA(PAM) expression in vitro....

Selective organ specific inflammation in offspring harbouring microchimerism from strongly alloreactive mothers.

Science.gov (United States)

Leveque, Lucie; Hodgson, Samantha; Peyton, Stephen; Koyama, Motoko; MacDonald, Kelli P A; Khosrotehrani, Kiarash

2014-05-01

The origins of autoimmunity are not yet understood despite significant advances in immunology. The trafficking of maternal cells to the offspring represents the very first immunological event in foetal life and is reinforced during lactation. The persistence of maternal cells in offspring's tissues and circulation has been associated with several autoimmune disorders. However a direct causal effect has never been demonstrated. Maternal T cells specifically targeting foetal insulin producing cells have been shown to generate islet inflammation without directly participating in this process. Our objective was to evaluate if alloreactive maternal cells could directly trigger a graft-versus host like reaction or indirectly influence the development of the offspring's regulatory T cells favouring autoimmunity. We adopted a breeding strategy comparing genetically identical offspring from either strongly alloreactive transgenic mothers compared to immunodeficient mothers. We detected maternal alloreactive T cells in the offspring and early signs of inflammation in small intestine of 6 weeks old offspring. Interestingly, CD4(+) Foxp3(+) regulatory T cell frequency was diminished in mesenteric lymph nodes from eight months old offspring born of alloreactive mothers compared to offspring of immunodeficient mothers. Our study favours a hypothesis where highly alloreactive maternal cell microchimerism indirectly predisposes offspring to autoimmunity. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

Dynamic high pressure induced strong and weak hydrogen bonds enhanced by pre-resonance stimulated Raman scattering in liquid water.

Science.gov (United States)

Wang, Shenghan; Fang, Wenhui; Li, Fabing; Gong, Nan; Li, Zhanlong; Li, Zuowei; Sun, Chenglin; Men, Zhiwei

2017-12-11

355 nm pulsed laser is employed to excite pre-resonance forward stimulated Raman scattering (FSRS) of liquid water at ambient temperature. Due to the shockwave induced dynamic high pressure, the obtained Raman spectra begin to exhibit double peaks distribution at 3318 and 3373 cm -1 with the input energy of 17 mJ,which correspond with OH stretching vibration with strong and weak hydrogen (H) bonds. With laser energy rising from 17 to 27 mJ, the Stokes line at 3318 cm -1 shifts to 3255 and 3230 cm -1 because of the high pressure being enlarged. When the energy is up to 32 mJ, only 3373 cm -1 peak exists. The strong and weak H bond exhibit quite different energy dependent behaviors.

Human leukemia antigen-A*0201-restricted epitopes of human endogenous retrovirus W family envelope (HERV-W env) induce strong cytotoxic T lymphocyte responses.

Science.gov (United States)

Tu, Xiaoning; Li, Shan; Zhao, Lijuan; Xiao, Ran; Wang, Xiuling; Zhu, Fan

2017-08-01

Human endogenous retrovirus W family (HERV-W) envelope (env) has been reported to be related to several human diseases, including autoimmune disorders, and it could activate innate immunity. However, there are no reports investigating whether human leukemia antigen (HLA)-A*0201 + restriction is involved in the immune response caused by HERV-W env in neuropsychiatric diseases. In the present study, HERV-W env-derived epitopes presented by HLA-A*0201 are described with the potential for use in adoptive immunotherapy. Five peptides displaying HLA-A*0201-binding motifs were predicted using SYFEPITHI and BIMAS, and synthesized. A CCK-8 assay showed peptides W, Q and T promoted lymphocyte proliferation. Stimulation of peripheral blood mononuclear cells from HLA-A*0201 + donors with each of these peptides induced peptide-specific CD8 + T cells. High numbers of IFN-γ-secreting T cells were also detectable after several weekly stimulations with W, Q and T. Besides lysis of HERV-W env-loaded target cells, specific apoptosis was also observed. These data demonstrate that human T cells can be sensitized toward HERV-W env peptides (W, Q and T) and, moreover, pose a high killing potential toward HERV-W env-expressing U251 cells. In conclusion, peptides W Q and T, which are HERV-W env antigenic epitopes, have both antigenicity and immunogenicity, and can cause strong T cell immune responses. Our data strengthen the view that HERV-W env should be considered as an autoantigen that can induce autoimmunity in neuropsychiatric diseases, such as multiple sclerosis and schizophrenia. These data might provide an experimental foundation for a HERV-W env peptide vaccine and new insight into the treatment of neuropsychiatric diseases.

Strong interaction effects in hadronic atoms

International Nuclear Information System (INIS)

Kaufmann, W.B.

1977-01-01

The WKB method is applied to the calculation of strong interaction-induced level widths and shifts of hadronic atoms. The calculation, while elementary enough for undergraduate quantum mechanics students, gives a good account of kaonic and antiprotonic atom data

Radically altered T cell receptor signaling in glycopeptide-specific T cell hybridoma induced by antigen with minimal differences in the glycan group

DEFF Research Database (Denmark)

Jensen, T; Nielsen, M; Gad, Monika

2001-01-01

A T cell hybridoma raised against the synthetic glycopeptide T(72)(Tn) was used to study whether the initial TCR signaling events are markedly different when the hybridoma is stimulated with glycopeptides closely related to the cognate glycopeptide antigen. T(72)(Tn) has an alpha-D-GalNAc group O......)(alpha-D-GlcNAc), which differs from T(72)(Tn) solely by the orientation of a hydroxy group in the carbohydrate structure, completely failed to induce detectable tyrosine phosphorylation and IL-2 secretion. APC pulsed with S(72)(Tn), which differs from T(72)(Tn) by not having a methyl group in the serine......-linked to the central threonine in the decapeptide VITAFTEGLK, and the hybridoma is known to be highly specific for this carbohydrate group. T(72)(Tn)-pulsed APC induced tyrosine phosphorylation of the TCR-zeta 21- and 23-kDa proteins and the downstream p42/44 MAP kinase and strong IL-2 secretion. APC pulsed with T(72...

Specificity of mutations induced by carbon ions in budding yeast Saccharomyces cerevisiae

International Nuclear Information System (INIS)

Matuo, Youichirou; Nishijima, Shigehiro; Hase, Yoshihiro; Sakamoto, Ayako; Tanaka, Atsushi; Shimizu, Kikuo

2006-01-01

To investigate the nature of mutations induced by accelerated ions in eukaryotic cells, the effects of carbon-ion irradiation were compared with those of γ-ray irradiation in the budding yeast Saccharomyces cerevisiae. The mutational effect and specificity of carbon-ion beams were studied in the URA3 gene of the yeast. Our experiments showed that the carbon ions generated more than 10 times the number of mutations induced by γ-rays, and that the types of base changes induced by carbon ions include transversions (68.7%), transitions (13.7%) and deletions/insertions (17.6%). The transversions were mainly G:C → T:A, and all the transitions were G:C → A:T. In comparison with the surrounding sequence context of mutational base sites, the C residues in the 5'-AC(A/T)-3' sequence were found to be easily changed. Large deletions and duplications were not observed, whereas ion-induced mutations in Arabidopsis thaliana were mainly short deletions and rearrangements. The remarkable feature of yeast mutations induced by carbon ions was that the mutation sites were localized near the linker regions of nucleosomes, whereas mutations induced by γ-ray irradiation were located uniformly throughout the gene

Similar cold stress induces sex-specific neuroendocrine and working memory responses.

Science.gov (United States)

Solianik, Rima; Skurvydas, Albertas; Urboniene, Daiva; Eimantas, Nerijus; Daniuseviciute, Laura; Brazaitis, Marius

2015-01-01

Men have higher cold-induced neuroendocrine response than women; nevertheless, it is not known whether a different stress hormone rise elicits different effects on cognition during whole body cooling. The objective was to compare the effect of cold-induced neuroendocrine responses on the performance of working memory sensitive tasks between men and women. The cold stress continued until rectal temperature reached 35.5 degree C or for a maximum of 170 min. Working memory performance and stress hormone concentrations were monitored. During cold stress, body temperature variables dropped in all subjects (P < 0.001) and did not differ between sexes. Cold stress raised plasma epinephrine and serum cortisol levels only in men (P < 0.05). Cold stress adversely affected memory performance in men but not in women (P < 0.05). The present study indicated that similar moderate cold stress in men and women induces sex-specific neuroendocrine and working memory responses.

A Comprehensive, Ethnically Diverse Library of Sickle Cell Disease-Specific Induced Pluripotent Stem Cells

Directory of Open Access Journals (Sweden)

Seonmi Park

2017-04-01

Full Text Available Summary: Sickle cell anemia affects millions of people worldwide and is an emerging global health burden. As part of a large NIH-funded NextGen Consortium, we generated a diverse, comprehensive, and fully characterized library of sickle-cell-disease-specific induced pluripotent stem cells (iPSCs from patients of different ethnicities, β-globin gene (HBB haplotypes, and fetal hemoglobin (HbF levels. iPSCs stand to revolutionize the way we study human development, model disease, and perhaps eventually, treat patients. Here, we describe this unique resource for the study of sickle cell disease, including novel haplotype-specific polymorphisms that affect disease severity, as well as for the development of patient-specific therapeutics for this phenotypically diverse disorder. As a complement to this library, and as proof of principle for future cell- and gene-based therapies, we also designed and employed CRISPR/Cas gene editing tools to correct the sickle hemoglobin (HbS mutation. : In this resource article, Mostoslavsky, Murphy, and colleagues of the NextGen consortium describe a diverse, comprehensive, and characterized library of sickle cell disease-specific induced pluripotent stem cells (iPSCs from patients of different ethnicities, β-globin gene (HBB haplotypes and fetal hemoglobin (HbF levels. This bank is readily available and accessible to all investigators. Keywords: induced pluripotent stem cells, iPSCs, sickle cell disease, disease modeling, directed differentiation, gene correction

Dietary determinants of pregnancy induced hypertension in Isfahan

Directory of Open Access Journals (Sweden)

Zamzam Paknahad

2008-02-01

Full Text Available

• <strong>BACKGROUND>: Pregnancy-induced hypertension (PIH is a pregnancy-specific condition that occurs after the 20th week of gestation. These physiologic changes can be aggravated by undernutrition. There are some evidence based on the importance of nutrient deficiency in developing this syndrome. Therefore, the aim of present study was to determine the nutritional risk factors for pregnancy induced hypertension in a group of pregnant women in Isfahan.
• <strong>METHODS>: In this case-control study, we recruited 46 Isfahanian pregnant women in two groups (with and without PIH. They were 19 to 45 year-old and they did not consume any antihypertensive or diuretic medications. Demographic questionnaire and food frequency questionnaire were filled in both groups.
• <strong>RESULTS>: There were no significant differences in energy and vitamin E and C intakes between the two groups. Zinc and calcium intakes were lower in women with PIH compared to those without PIH (P = 0.04 and P = 0.007, respectively. Riboflavin and protein intakes were lower in women with PIH compared to subjects without PIH (P = 0.03 and P = 0.01, respectively.
• <strong>CONCLUSIONS>: Lower intake of calcium, zinc, riboflavin and protein should be considered as possible risk factors for PIH. Adequate intake of dairy products which are good sources of mentioned nutrients are recommended to prevent PIH.
• <strong>KEYWORDS>: Pregnancy induced hypertension, diet, nutrient.

Mixed chimerism and permanent specific transplantation tolerance induced by a nonlethal preparative regimen

International Nuclear Information System (INIS)

Sharabi, Y.; Sachs, D.H.

1989-01-01

The use of allogeneic bone marrow transplantation as a means of inducing donor-specific tolerance across MHC barriers could provide an immunologically specific conditioning regimen for organ transplantation. However, a major limitation to this approach is the toxicity of whole body irradiation as currently used to abrogate host resistance and permit marrow engraftment. The present study describes methodology for abrogating host resistance and permitting marrow engraftment without lethal irradiation. Our preparative protocol involves administration of anti-CD4 and anti-CD8 mAbs in vivo, 300-rad WBI, 700-rad thymic irradiation, and unmanipulated fully MHC-disparate bone marrow. B10 mice prepared by this regimen developed stable mixed lymphohematopoetic chimerism without any clinical evidence of graft-vs.-host disease. Engraftment was accompanied by induction of specific tolerance to donor skin grafts (B10.D2), while third-party skin grafts (B10.BR) were promptly rejected. Mice treated with the complete regimen without bone marrow transplantation appeared healthy and enjoyed long-term survival. This study therefore demonstrates that stable mixed chimerism with donor-specific tolerance can be induced across an MHC barrier after a nonlethal preparative regimen, without clinical GVHD and without the risk of aplasia

Transgenerational effects of mild heat in Arabidopsis thaliana show strong genotype specificity that is explained by climate at origin.

Science.gov (United States)

Groot, Maartje P; Kubisch, Alexander; Ouborg, N Joop; Pagel, Jörn; Schmid, Karl J; Vergeer, Philippine; Lampei, Christian

2017-08-01

Transgenerational environmental effects can trigger strong phenotypic variation. However, it is unclear how cues from different preceding generations interact. Also, little is known about the genetic variation for these life history traits. Here, we present the effects of grandparental and parental mild heat, and their combination, on four traits of the third-generation phenotype of 14 Arabidopsis thaliana genotypes. We tested for correlations of these effects with climate and constructed a conceptual model to identify the environmental conditions that favour the parental effect on flowering time. We observed strong evidence for genotype-specific transgenerational effects. On average, A. thaliana accustomed to mild heat produced more seeds after two generations. Parental effects overruled grandparental effects in all traits except reproductive biomass. Flowering was generally accelerated by all transgenerational effects. Notably, the parental effect triggered earliest flowering in genotypes adapted to dry summers. Accordingly, this parental effect was favoured in the model when early summer heat terminated the growing season and environments were correlated across generations. Our results suggest that A. thaliana can partly accustom to mild heat over two generations and genotype-specific parental effects show non-random evolutionary divergence across populations that may support climate change adaptation in the Mediterranean. © 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.

Strong resilience of soil respiration components to drought-induced die-off resulting in forest secondary succession.

Science.gov (United States)

Barba, Josep; Curiel Yuste, Jorge; Poyatos, Rafael; Janssens, Ivan A; Lloret, Francisco

2016-09-01

How forests cope with drought-induced perturbations and how the dependence of soil respiration on environmental and biological drivers is affected in a warming and drying context are becoming key questions. The aims of this study were to determine whether drought-induced die-off and forest succession were reflected in soil respiration and its components and to determine the influence of climate on the soil respiration components. We used the mesh exclusion method to study seasonal variations in soil respiration (R S) and its components: heterotrophic (R H) and autotrophic (R A) [further split into fine root (R R) and mycorrhizal respiration (R M)] in a mixed Mediterranean forest where Scots pine (Pinus sylvestris L.) is undergoing a drought-induced die-off and is being replaced by holm oak (Quercus ilex L.). Drought-induced pine die-off was not reflected in R S nor in its components, which denotes a high functional resilience of the plant and soil system to pine die-off. However, the succession from Scots pine to holm oak resulted in a reduction of R H and thus in an important decrease of total respiration (R S was 36 % lower in holm oaks than in non-defoliated pines). Furthermore, R S and all its components were strongly regulated by soil water content-and-temperature interaction. Since Scots pine die-off and Quercus species colonization seems to be widely occurring at the driest limit of the Scots pine distribution, the functional resilience of the soil system over die-off and the decrease of R S from Scots pine to holm oak could have direct consequences for the C balance of these ecosystems.

Antigen-specific cytotoxic T cell and antigen-specific proliferating T cell clones can be induced to cytolytic activity by monoclonal antibodies against T3

NARCIS (Netherlands)

Spits, H.; Yssel, H.; Leeuwenberg, J.; de Vries, J. E.

1985-01-01

T3 is a human differentiation antigen expressed exclusively on mature T cells. In this study it is shown that anti-T3 monoclonal antibodies, in addition to their capacity to induce T cells to proliferate, are able to induce antigen-specific cytotoxic T lymphocyte clones to mediate antigen

Noise-induced extinction for a ratio-dependent predator-prey model with strong Allee effect in prey

Science.gov (United States)

Mandal, Partha Sarathi

2018-04-01

In this paper, we study a stochastically forced ratio-dependent predator-prey model with strong Allee effect in prey population. In the deterministic case, we show that the model exhibits the stable interior equilibrium point or limit cycle corresponding to the co-existence of both species. We investigate a probabilistic mechanism of the noise-induced extinction in a zone of stable interior equilibrium point. Computational methods based on the stochastic sensitivity function technique are applied for the analysis of the dispersion of random states near stable interior equilibrium point. This method allows to construct a confidence domain and estimate the threshold value of the noise intensity for a transition from the coexistence to the extinction.

Proteomic identification of an embryo-specific 1Cys-Prx promoter and analysis of its activity in transgenic rice.

Science.gov (United States)

Kim, Je Hein; Jung, In Jung; Kim, Dool Yi; Fanata, Wahyu Indra; Son, Bo Hwa; Yoo, Jae Yong; Harmoko, Rikno; Ko, Ki Seong; Moon, Jeong Chan; Jang, Ho Hee; Kim, Woe Yeon; Kim, Jae-Yean; Lim, Chae Oh; Lee, Sang Yeol; Lee, Kyun Oh

2011-04-29

Proteomic analysis of a rice callus led to the identification of 10 abscisic acid (ABA)-induced proteins as putative products of the embryo-specific promoter candidates. 5'-flanking sequence of 1 Cys-Prx, a highly-induced protein gene, was cloned and analyzed. The transcription initiation site of 1 Cys-Prx maps 96 nucleotides upstream of the translation initiation codon and a TATA-box and putative seed-specific cis-acting elements, RYE and ABRE, are located 26, 115 and 124 bp upstream of the transcription site, respectively. β-glucuronidase (GUS) expression driven by the 1 Cys-Prx promoters was strong in the embryo and aleurone layer and the activity reached up to 24.9 ± 3.3 and 40.5 ± 2.1 pmol (4 MU/min/μg protein) in transgenic rice seeds and calluses, respectively. The activity of the 1 Cys-Prx promoters is much higher than that of the previously-identified embryo-specific promoters, and comparable to that of strong endosperm-specific promoters in rice. GUS expression driven by the 1 Cys-Prx promoters has been increased by ABA treatment and rapidly induced by wounding in callus and at the leaf of the transgenic plants, respectively. Furthermore, ectopic expression of the GUS construct in Arabidopsis suggested that the 1 Cys-Prx promoter also has strong activity in seeds of dicot plants. Copyright © 2011 Elsevier Inc. All rights reserved.

A test of genotypic variation in specificity of herbivore-induced responses in Solidago altissima L. (Asteraceae)

NARCIS (Netherlands)

Uesugi, A.; Poelman, E.H.; Kessler, A.

2013-01-01

Plant-induced responses to multiple herbivores can mediate ecological interactions among herbivore species, thereby influencing herbivore community composition in nature. Several studies have indicated high specificity of induced responses to different herbivore species. In addition, there may be

Strong Selective Adsorption of Polymers.

Science.gov (United States)

Ge, Ting; Rubinstein, Michael

2015-06-09

A scaling theory is developed for selective adsorption of polymers induced by the strong binding between specific monomers and complementary surface adsorption sites. By "selective" we mean specific attraction between a subset of all monomers, called "sticky", and a subset of surface sites, called "adsorption sites". We demonstrate that, in addition to the expected dependence on the polymer volume fraction ϕ bulk in the bulk solution, selective adsorption strongly depends on the ratio between two characteristic length scales, the root-mean-square distance l between neighboring sticky monomers along the polymer, and the average distance d between neighboring surface adsorption sites. The role of the ratio l / d arises from the fact that a polymer needs to deform to enable the spatial commensurability between its sticky monomers and the surface adsorption sites for selective adsorption. We study strong selective adsorption of both telechelic polymers with two end monomers being sticky and multisticker polymers with many sticky monomers between sticky ends. For telechelic polymers, we identify four adsorption regimes at l / d 1, we expect that the adsorption layer at exponentially low ϕ bulk consists of separated unstretched loops, while as ϕ bulk increases the layer crosses over to a brush of extended loops with a second layer of weakly overlapping tails. For multisticker chains, in the limit of exponentially low ϕ bulk , adsorbed polymers are well separated from each other. As l / d increases, the conformation of an individual polymer changes from a single-end-adsorbed "mushroom" to a random walk of loops. For high ϕ bulk , adsorbed polymers at small l / d are mushrooms that cover all the adsorption sites. At sufficiently large l / d , adsorbed multisticker polymers strongly overlap. We anticipate the formation of a self-similar carpet and with increasing l / d a two-layer structure with a brush of loops covered by a self-similar carpet. As l / d exceeds the

Repletion of zinc in zinc-deficient cells strongly up-regulates IL-1β-induced IL-2 production in T-cells.

Science.gov (United States)

Daaboul, Doha; Rosenkranz, Eva; Uciechowski, Peter; Rink, Lothar

2012-10-01

Mild zinc deficiency in humans negatively affects IL-2 production resulting in declined percentages of cytolytic T cells and decreased NK cell lytic activity, which enhances the susceptibility to infections and malignancies. T-cell activation is critically regulated by zinc and the normal physiological zinc level in T-cells slightly lies below the optimal concentration for T-cell functions. A further reduction in zinc level leads to T-cell dysfunction and autoreactivity, whereas high zinc concentrations (100 μM) were shown to inhibit interleukin-1 (IL-1)-induced IL-1 receptor kinase (IRAK) activation. In this study, we investigated the molecular mechanism by which zinc regulates the IL-1β-induced IL-2 expression in T-cells. Zinc supplementation to zinc-deficient T-cells increased intracellular zinc levels by altering the expression of zinc transporters, particularly Zip10 and Zip12. A zinc signal was observed in the murine T-cell line EL-4 6.1 after 1 h of stimulation with IL-1β, measured by specific zinc sensors FluoZin-3 and ZinPyr-1. This signal is required for the phosphorylation of MAPK p38 and NF-κB subunit p65, which triggers the transcription of IL-2 and strongly increases its production. These results indicate that short-term zinc supplementation to zinc-deficient T-cells leads to a fast rise in zinc levels which subsequently enhance cytokine production. In conclusion, low and excessive zinc levels might be equally problematic for zinc-deficient subjects, and stabilized zinc levels seem to be essential to avoid negative concentration-dependent zinc effects on T-cell activation.

Specificity of mutations induced by carbon ions in budding yeast Saccharomyces cerevisiae

Energy Technology Data Exchange (ETDEWEB)

Matuo, Youichirou [Graduate School of Engineering, Osaka University, Yamada-oka 2-1, Suita, Osaka 565-0871 (Japan); Nishijima, Shigehiro [Graduate School of Engineering, Osaka University, Yamada-oka 2-1, Suita, Osaka 565-0871 (Japan); Hase, Yoshihiro [Radiation-Applied Biology Division, Quantum Beam Science Directorate, Japan Atomic Energy Agency (JAEA), Watanuki-machi 1233, Takasaki, Gunma 370-1292 (Japan); Sakamoto, Ayako [Radiation-Applied Biology Division, Quantum Beam Science Directorate, Japan Atomic Energy Agency (JAEA), Watanuki-machi 1233, Takasaki, Gunma 370-1292 (Japan); Tanaka, Atsushi [Radiation-Applied Biology Division, Quantum Beam Science Directorate, Japan Atomic Energy Agency (JAEA), Watanuki-machi 1233, Takasaki, Gunma 370-1292 (Japan); Shimizu, Kikuo [Radioisotope Research Center, Osaka University, Yamada-oka 2-4, Suita, Osaka 565-0871 (Japan)]. E-mail: shimizu@rirc.osaka-u.ac.jp

2006-12-01

To investigate the nature of mutations induced by accelerated ions in eukaryotic cells, the effects of carbon-ion irradiation were compared with those of {gamma}-ray irradiation in the budding yeast Saccharomyces cerevisiae. The mutational effect and specificity of carbon-ion beams were studied in the URA3 gene of the yeast. Our experiments showed that the carbon ions generated more than 10 times the number of mutations induced by {gamma}-rays, and that the types of base changes induced by carbon ions include transversions (68.7%), transitions (13.7%) and deletions/insertions (17.6%). The transversions were mainly G:C {sup {yields}} T:A, and all the transitions were G:C {sup {yields}} A:T. In comparison with the surrounding sequence context of mutational base sites, the C residues in the 5'-AC(A/T)-3' sequence were found to be easily changed. Large deletions and duplications were not observed, whereas ion-induced mutations in Arabidopsis thaliana were mainly short deletions and rearrangements. The remarkable feature of yeast mutations induced by carbon ions was that the mutation sites were localized near the linker regions of nucleosomes, whereas mutations induced by {gamma}-ray irradiation were located uniformly throughout the gene.

Nephron segment specific microRNA biomarkers of pre-clinical drug-induced renal toxicity: Opportunities and challenges

Energy Technology Data Exchange (ETDEWEB)

Nassirpour, Rounak, E-mail: Rounak.nassirpour@pfizer.com [Drug Safety, Pfizer Worldwide Research and Development, 1 Burtt Rd, Andover, MA 01810 (United States); Ramaiah, Shashi K. [Drug Safety, Pfizer Worldwide Research and Development, 610 Main Street, Cambridge, MA 02139 (United States); Whiteley, Laurence O. [Drug Safety, Pfizer Worldwide Research and Development, 1 Burtt Rd, Andover, MA 01810 (United States)

2016-12-01

Drug-induced nephrotoxicity is a common drug development complication for pharmaceutical companies. Sensitive, specific, translatable and non-invasive biomarkers of renal toxicity are urgently needed to diagnose nephron segment specific injury. The currently available gold standard biomarkers for nephrotoxicity are not kidney-specific, lack sensitivity for early detection, and are not suitable for renal damage localization (glomerular vs tubulointerstitial injury). MicroRNAs (miRNAs) are increasingly gaining momentum as promising biomarkers of various organ toxicities, including drug induced renal injury. This is mostly due to their stability in easily accessible biofluids, ease of developing nucleic acids detection compared to protein detection assays, as well as their interspecies translatability. Increasing concordance of miRNA findings by standardizing methodology most suitable for their detection and quantitation, as well as characterization of their expression pattern in a cell type specific manner, will accelerate progress toward validation of these miRNAs as biomarkers in pre-clinical, and clinical settings. This review aims to highlight the current pre-clinical findings surrounding miRNAs as biomarkers in two important segments of the nephron, the glomerulus and tubules. - Highlights: • miRNAs are promising biomarkers of drug-induced kidney injury. • Summarized pre-clinical miRNA biomarkers of drug-induced nephrotoxicity. • Described the strengths and challenges associated with miRNAs as biomarkers.

A multi-subunit Chlamydia vaccine inducing neutralizing antibodies and strong IFN-γ(+) CMI responses protects against a genital infection in minipigs

DEFF Research Database (Denmark)

Bøje, Sarah; Olsen, Anja Weinreich; Erneholm, Karin

2016-01-01

Chlamydia is the most widespread sexually transmitted bacterial disease and a prophylactic vaccine is highly needed. Ideally, this vaccine is required to induce a combined response of Th1 cell-mediated immune (CMI) response in concert with neutralizing antibodies. Using a novel Göttingen minipig...... trachomatis SvD bacteria (UV-SvD/CAF01) or CAF01. The Hirep1+CTH93/CAF01 vaccine induced a strong CMI response against the vaccine antigens and high titers of antibodies, particularly against the VD4 region of MOMP. Sera from Hirep1+CTH93/CAF01 immunized pigs neutralized C. trachomatis SvD and SvF infectivity...

Sex specific effects of heat induced hormesis in Hsf-deficient Drosophila melanogaster

DEFF Research Database (Denmark)

Sørensen, J G; Kristensen, Torsten Nygård; Kristensen, K V

2007-01-01

In insects mild heat stress early in life has been reported to increase life span and heat resistance later in life, a phenomenon termed hormesis. Here, we test if the induction of the heat shock response by mild heat stress is mediating hormesis in longevity and heat resistance at older age...... line, seemingly mediated by the production of heat shock proteins (Hsps). The results indicate that heat inducible Hsps are important for heat induced hormesis in longevity and heat stress resistance. However, the results also suggest that other processes are involved and that different mechanisms...... might have marked sex specific impact...

Site-specific effects of apolipoprotein E expression on diet-induced obesity and white adipose tissue metabolic activation.

Science.gov (United States)

Hatziri, Aikaterini; Kalogeropoulou, Christina; Xepapadaki, Eva; Birli, Eleni; Karavia, Eleni A; Papakosta, Eugenia; Filou, Serafoula; Constantinou, Caterina; Kypreos, Kyriakos E

2018-02-01

Apolipoprotein E (APOE) has been strongly implicated in the development of diet induced obesity. In the present study, we investigated the contribution of brain and peripherally expressed human apolipoprotein E3 (APOE3), the most common human isoform, to diet induced obesity. In our studies APOE3 knock-in (Apoe3 knock-in ), Apoe-deficient (apoe -/- ) and brain-specific expressing APOE3 (Apoe3 brain ) mice were fed western-type diet for 12week and biochemical analyses were performed. Moreover, AAV-mediated gene transfer of APOE3 to apoe -/- mice was employed, as a means to achieve APOE3 expression selectively in periphery, since peripherally expressed APOE does not cross blood brain barrier (BBB) or blood-cerebrospinal fluid barrier (BCSFB). Our data suggest a bimodal role of APOE3 in visceral white adipose tissue (WAT) mitochondrial metabolic activation that is highly dependent on its site of expression and independent of postprandial dietary lipid deposition. Our findings indicate that brain APOE3 expression is associated with a potent inhibition of visceral WAT mitochondrial oxidative phosphorylation, leading to significantly reduced substrate oxidation, increased fat accumulation and obesity. In contrast, peripherally expressed APOE3 is associated with a notable shift of substrate oxidation towards non-shivering thermogenesis in visceral WAT mitochondria, leading to resistance to obesity. Copyright © 2017 Elsevier B.V. All rights reserved.

Sequence-Specific Model for Peptide Retention Time Prediction in Strong Cation Exchange Chromatography.

Science.gov (United States)

Gussakovsky, Daniel; Neustaeter, Haley; Spicer, Victor; Krokhin, Oleg V

2017-11-07

The development of a peptide retention prediction model for strong cation exchange (SCX) separation on a Polysulfoethyl A column is reported. Off-line 2D LC-MS/MS analysis (SCX-RPLC) of S. cerevisiae whole cell lysate was used to generate a retention dataset of ∼30 000 peptides, sufficient for identifying the major sequence-specific features of peptide retention mechanisms in SCX. In contrast to RPLC/hydrophilic interaction liquid chromatography (HILIC) separation modes, where retention is driven by hydrophobic/hydrophilic contributions of all individual residues, SCX interactions depend mainly on peptide charge (number of basic residues at acidic pH) and size. An additive model (incorporating the contributions of all 20 residues into the peptide retention) combined with a peptide length correction produces a 0.976 R 2 value prediction accuracy, significantly higher than the additive models for either HILIC or RPLC. Position-dependent effects on peptide retention for different residues were driven by the spatial orientation of tryptic peptides upon interaction with the negatively charged surface functional groups. The positively charged N-termini serve as a primary point of interaction. For example, basic residues (Arg, His, Lys) increase peptide retention when located closer to the N-terminus. We also found that hydrophobic interactions, which could lead to a mixed-mode separation mechanism, are largely suppressed at 20-30% of acetonitrile in the eluent. The accuracy of the final Sequence-Specific Retention Calculator (SSRCalc) SCX model (∼0.99 R 2 value) exceeds all previously reported predictors for peptide LC separations. This also provides a solid platform for method development in 2D LC-MS protocols in proteomics and peptide retention prediction filtering of false positive identifications.

Bone-Inspired Spatially Specific Piezoelectricity Induces Bone Regeneration.

Science.gov (United States)

Yu, Peng; Ning, Chengyun; Zhang, Yu; Tan, Guoxin; Lin, Zefeng; Liu, Shaoxiang; Wang, Xiaolan; Yang, Haoqi; Li, Kang; Yi, Xin; Zhu, Ye; Mao, Chuanbin

2017-01-01

The extracellular matrix of bone can be pictured as a material made of parallel interspersed domains of fibrous piezoelectric collagenous materials and non-piezoelectric non-collagenous materials. To mimic this feature for enhanced bone regeneration, a material made of two parallel interspersed domains, with higher and lower piezoelectricity, respectively, is constructed to form microscale piezoelectric zones (MPZs). The MPZs are produced using a versatile and effective laser-irradiation technique in which K 0.5 Na 0.5 NbO 3 (KNN) ceramics are selectively irradiated to achieve microzone phase transitions. The phase structure of the laser-irradiated microzones is changed from a mixture of orthorhombic and tetragonal phases (with higher piezoelectricity) to a tetragonal dominant phase (with lower piezoelectricity). The microzoned piezoelectricity distribution results in spatially specific surface charge distribution, enabling the MPZs to bear bone-like microscale electric cues. Hence, the MPZs induce osteogenic differentiation of stem cells in vitro and bone regeneration in vivo even without being seeded with stem cells. The concept of mimicking the spatially specific piezoelectricity in bone will facilitate future research on the rational design of tissue regenerative materials.

Transcript-specific effects of adrenalectomy on seizure-induced BDNF expression in rat hippocampus

DEFF Research Database (Denmark)

Lauterborn, J C; Poulsen, F R; Stinis, C T

1998-01-01

Activity-induced brain-derived neurotrophic factor (BDNF) expression is negatively modulated by circulating adrenal steroids. The rat BDNF gene gives rise to four major transcript forms that each contain a unique 5' exon (I-IV) and a common 3' exon (V) that codes for BDNF protein. Exon-specific i......Activity-induced brain-derived neurotrophic factor (BDNF) expression is negatively modulated by circulating adrenal steroids. The rat BDNF gene gives rise to four major transcript forms that each contain a unique 5' exon (I-IV) and a common 3' exon (V) that codes for BDNF protein. Exon...... and in exon II-containing mRNA with 30-days survival. In the dentate gyrus granule cells, adrenalectomy markedly potentiated increases in exon I and II cRNA labeling, but not increases in exon III and IV cRNA labeling, elicited by one hippocampal afterdischarge. Similarly, for the granule cells and CA1...... no effect on exon IV-containing mRNA content. These results demonstrate that the negative effects of adrenal hormones on activity-induced BDNF expression are by far the greatest for transcripts containing exons I and II. Together with evidence for region-specific transcript expression, these results suggest...

Depot-specific differences in angiogenic capacity of adipose tissue in differential susceptibility to diet-induced obesity

Directory of Open Access Journals (Sweden)

Mun-Gyu Song

2016-11-01

Full Text Available Objective: Adipose tissue (AT expansion requires AT remodeling, which depends on AT angiogenesis. Modulation of AT angiogenesis could have therapeutic promise for the treatment of obesity. However, it is unclear how the capacity of angiogenesis in each adipose depot is affected by over-nutrition. Therefore, we investigated the angiogenic capacity (AC of subcutaneous and visceral fats in lean and obese mice. Methods: We compared the AC of epididymal fat (EF and inguinal fat (IF using an angiogenesis assay in diet-induced obese (DIO mice and diet-resistant (DR mice fed a high-fat diet (HFD. Furthermore, we compared the expression levels of genes related to angiogenesis, macrophage recruitment, and inflammation using RT-qPCR in the EF and IF of lean mice fed a low-fat diet (LFD, DIO mice, and DR mice fed a HFD. Results: DIO mice showed a significant increase in the AC of EF only at 22 weeks of age compared to DR mice. The expression levels of genes related to angiogenesis, macrophage recruitment, and inflammation were significantly higher in the EF of DIO mice than in those of LFD mice and DR mice, while expression levels of genes related to macrophages and their recruitment were higher in the IF of DIO mice than in those of LFD and DR mice. Expression of genes related to angiogenesis (including Hif1a, Vegfa, Fgf1, Kdr, and Pecam1, macrophage recruitment, and inflammation (including Emr1, Ccr2, Itgax, Ccl2, Tnf, and Il1b correlated more strongly with body weight in the EF of HFD-fed obese mice compared to that of IF. Conclusions: These results suggest depot-specific differences in AT angiogenesis and a potential role in the susceptibility to diet-induced obesity. Keywords: Angiogenesis, Inflammation, Adipose tissue, Diet-induced obese mice, Diet-resistant mice, High-fat diet

Inhibitory Effect of Endostar on Specific Angiogenesis Induced by Human Hepatocellular Carcinoma

Directory of Open Access Journals (Sweden)

Qing Ye

2015-01-01

Full Text Available To investigate the effect of endostar on specific angiogenesis induced by human hepatocellular carcinoma, this research systematically elucidated the inhibitory effect on HepG2-induced angiogenesis by endostar from 50 ng/mL to 50000 ng/mL. We employed fluorescence quantitative Boyden chamber analysis, wound-healing assay, flow cytometry examination using a coculture system, quantitative analysis of tube formation, and in vivo Matrigel plug assay induced by HCC conditioned media (HCM and HepG2 compared with normal hepatocyte conditioned media (NCM and L02. Then, we found that endostar as a tumor angiogenesis inhibitor could potently inhibit human umbilical vein endothelial cell (HUVEC migration in response to HCM after four- to six-hour action, inhibit HCM-induced HUVEC migration to the lesion part in a dose-dependent manner between 50 ng/mL and 5000 ng/mL at 24 hours, and reduce HUVEC proliferation in a dose-dependent fashion. Endostar inhibited HepG2-induced tube formation of HUVECs which peaked at 50 ng/mL. In vivo Matrigel plug formation was also significantly reduced by endostar in HepG2 inducing system rather than in L02 inducing system. It could be concluded that, at cell level, endostar inhibited the angiogenesis-related biological behaviors of HUVEC in response to HCC, including migration, adhesion proliferation, and tube formation. At animal level, endostar inhibited the angiogenesis in response to HCC in Matrigel matrix.

Dichloroacetate induces tumor-specific radiosensitivity in vitro but attenuates radiation-induced tumor growth delay in vivo

Energy Technology Data Exchange (ETDEWEB)

Zwicker, F.; Roeder, F.; Debus, J.; Huber, P.E. [University Hospital Center Heidelberg, Heidelberg (Germany). Dept. of Radiation Oncology; Deutsches Krebsforschungszentrum (DKFZ), Heidelberg (Germany). Clinical Cooperation Unit Molecular Radiation Oncology; Kirsner, A.; Weber, K.J. [University Hospital Center Heidelberg, Heidelberg (Germany). Dept. of Radiation Oncology; Peschke, P. [Deutsches Krebsforschungszentrum (DKFZ), Heidelberg (Germany). Clinical Cooperation Unit Molecular Radiation Oncology

2013-08-15

Background: Inhibition of pyruvate dehydrogenase kinase (PDK) by dichloroacetate (DCA) can shift tumor cell metabolism from anaerobic glycolysis to glucose oxidation, with activation of mitochondrial activity and chemotherapy-dependent apoptosis. In radiotherapy, DCA could thus potentially enhance the frequently moderate apoptotic response of cancer cells that results from their mitochondrial dysfunction. The aim of this study was to investigate tumor-specific radiosensitization by DCA in vitro and in a human tumor xenograft mouse model in vivo. Materials and methods: The interaction of DCA with photon beam radiation was investigated in the human tumor cell lines WIDR (colorectal) and LN18 (glioma), as well as in the human normal tissue cell lines HUVEC (endothelial), MRC5 (lung fibroblasts) and TK6 (lymphoblastoid). Apoptosis induction in vitro was assessed by DAPI staining and sub-G1 flow cytometry; cell survival was quantified by clonogenic assay. The effect of DCA in vivo was investigated in WIDR xenograft tumors growing subcutaneously on BALB/c-nu/nu mice, with and without fractionated irradiation. Histological examination included TUNEL and Ki67 staining for apoptosis and proliferation, respectively, as well as pinomidazole labeling for hypoxia. Results: DCA treatment led to decreased clonogenic survival and increased specific apoptosis rates in tumor cell lines (LN18, WIDR) but not in normal tissue cells (HUVEC, MRC5, TK6). However, this significant tumor-specific radiosensitization by DCA in vitro was not reflected by the situation in vivo: The growth suppression of WIDR xenograft tumors after irradiation was reduced upon additional DCA treatment (reflected by Ki67 expression levels), although early tumor cell apoptosis rates were significantly increased by DCA. This apparently paradoxical effect was accompanied by a marked DCA-dependent induction of hypoxia in tumor-tissue. Conclusion: DCA induced tumor-specific radiosensitization in vitro but not in vivo

Effect of initial perturbation amplitude on Richtmyer-Meshkov flows induced by strong shocks

Energy Technology Data Exchange (ETDEWEB)

Dell, Z.; Abarzhi, S. I., E-mail: snezhana.abarzhi@gmail.com, E-mail: sabarji@andrew.cmu.edu [Mellon College of Science and Carnegie Mellon University – Qatar, Carnegie Mellon University, Pittsburgh, Pennsylvania 15231 (United States); Stellingwerf, R. F. [Stellingwerf Consulting, Huntsville, Alabama 35803 (United States)

2015-09-15

We systematically study the effect of the initial perturbation on Richtmyer-Meshkov (RM) flows induced by strong shocks in fluids with contrasting densities. Smooth Particle Hydrodynamics simulations are employed. A broad range of shock strengths and density ratios is considered. The amplitude of the initial single mode sinusoidal perturbation of the interface varies from 0% to 100% of its wavelength. The simulations results are compared, wherever possible, with four rigorous theories, and with other experiments and simulations, achieving good quantitative and qualitative agreement. Our study is focused on early time dynamics of the Richtmyer-Meshkov instability (RMI). We analyze the initial growth-rate of RMI immediately after the shock passage, when the perturbation amplitude increases linearly with time. For the first time, to the authors' knowledge, we find that the initial growth-rate of RMI is a non-monotone function of the initial perturbation amplitude, thus restraining the amount of energy that can be deposited by the shock at the interface. The maximum value of the initial growth-rate depends on the shock strength and the density ratio, whereas the corresponding value of the initial perturbation amplitude depends only slightly on the shock strength and density ratio.

Epidermal Expression and Regulation of Interleukin-33 during Homeostasis and Inflammation: Strong Species Differences.

Science.gov (United States)

Sundnes, Olav; Pietka, Wojciech; Loos, Tamara; Sponheim, Jon; Rankin, Andrew L; Pflanz, Stefan; Bertelsen, Vibeke; Sitek, Jan C; Hol, Johanna; Haraldsen, Guttorm; Khnykin, Denis

2015-07-01

IL-33 is a novel IL-1 family member with a putative role in inflammatory skin disorders and a complex biology. Therefore, recent conflicting data regarding its function in experimental models justify a close assessment of its tissue expression and regulation. Indeed, we report here that there are strong species differences in the expression and regulation of epidermal IL-33. In murine epidermis, IL-33 behaved similar to an alarmin, being constitutively expressed in keratinocyte nuclei and rapidly lost during acute inflammation. By contrast, human and porcine IL-33 were weakly expressed or absent in keratinocytes of noninflamed skin but induced during acute inflammation. To this end, we observed that expression of IL-33 in human keratinocytes but not murine keratinocytes was strongly induced by IFN-γ, and this upregulation completely depended on the presence of EGFR ligands. Accordingly, IFN-γ increased the expression of IL-33 in the basal layers of the epidermis in human ex vivo skin cultures only, despite good evidence of IFN-γ activity in cultures from both species. Together these findings demonstrate that a full understanding of IL-33 function in clinical settings must take species-specific differences into account.

Strong adhesion by regulatory T cells induces dendritic cell cytoskeletal polarization and contact-dependent lethargy.

Science.gov (United States)

Chen, Jiahuan; Ganguly, Anutosh; Mucsi, Ashley D; Meng, Junchen; Yan, Jiacong; Detampel, Pascal; Munro, Fay; Zhang, Zongde; Wu, Mei; Hari, Aswin; Stenner, Melanie D; Zheng, Wencheng; Kubes, Paul; Xia, Tie; Amrein, Matthias W; Qi, Hai; Shi, Yan

2017-02-01

Dendritic cells are targeted by regulatory T (T reg) cells, in a manner that operates as an indirect mode of T cell suppression. In this study, using a combination of single-cell force spectroscopy and structured illumination microscopy, we analyze individual T reg cell-DC interaction events and show that T reg cells exhibit strong intrinsic adhesiveness to DCs. This increased DC adhesion reduces the ability of contacted DCs to engage other antigen-specific cells. We show that this unusually strong LFA-1-dependent adhesiveness of T reg cells is caused in part by their low calpain activities, which normally release integrin-cytoskeleton linkage, and thereby reduce adhesion. Super resolution imaging reveals that such T reg cell adhesion causes sequestration of Fascin-1, an actin-bundling protein essential for immunological synapse formation, and skews Fascin-1-dependent actin polarization in DCs toward the T reg cell adhesion zone. Although it is reversible upon T reg cell disengagement, this sequestration of essential cytoskeletal components causes a lethargic state of DCs, leading to reduced T cell priming. Our results reveal a dynamic cytoskeletal component underlying T reg cell-mediated DC suppression in a contact-dependent manner. © 2017 Chen et al.

Induction of complex immune responses and strong protection against retrovirus challenge by adenovirus-based immunization depends on the order of vaccine delivery.

Science.gov (United States)

Kaulfuß, Meike; Wensing, Ina; Windmann, Sonja; Hrycak, Camilla Patrizia; Bayer, Wibke

2017-02-06

In the Friend retrovirus mouse model we developed potent adenovirus-based vaccines that were designed to induce either strong Friend virus GagL 85-93 -specific CD8 + T cell or antibody responses, respectively. To optimize the immunization outcome we evaluated vaccination strategies using combinations of these vaccines. While the vaccines on their own confer strong protection from a subsequent Friend virus challenge, the simple combination of the vaccines for the establishment of an optimized immunization protocol did not result in a further improvement of vaccine effectivity. We demonstrate that the co-immunization with GagL 85-93 /leader-gag encoding vectors together with envelope-encoding vectors abrogates the induction of GagL 85-93 -specific CD8 + T cells, and in successive immunization protocols the immunization with the GagL 85-93 /leader-gag encoding vector had to precede the immunization with an envelope encoding vector for the efficient induction of GagL 85-93 -specific CD8 + T cells. Importantly, the antibody response to envelope was in fact enhanced when the mice were adenovirus-experienced from a prior immunization, highlighting the expedience of this approach. To circumvent the immunosuppressive effect of envelope on immune responses to simultaneously or subsequently administered immunogens, we developed a two immunizations-based vaccination protocol that induces strong immune responses and confers robust protection of highly Friend virus-susceptible mice from a lethal Friend virus challenge.

Mesoporous TiO{sub 2} aggregate photoanode with high specific surface area and strong light scattering for dye-sensitized solar cells

Energy Technology Data Exchange (ETDEWEB)

Li, Chunhui; Luo, Yanhong; Guo, Xiaozhi; Li, Dongmei [Key Laboratory for Renewable Energy, Chinese Academy of Sciences, Beijing Key Laboratory for New Energy Materials and Devices, Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190 (China); Mi, Jianli; So, Lasse; Hald, Peter [Center for Materials Crystallography, Department of Chemistry and Interdisciplinary Nanoscience Center, Aarhus University, DK-8000 Aarhus (Denmark); Meng, Qingbo, E-mail: qbmeng@iphy.ac.cn [Key Laboratory for Renewable Energy, Chinese Academy of Sciences, Beijing Key Laboratory for New Energy Materials and Devices, Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190 (China); Iversen, Bo B., E-mail: bo@chem.au.dk [Center for Materials Crystallography, Department of Chemistry and Interdisciplinary Nanoscience Center, Aarhus University, DK-8000 Aarhus (Denmark)

2012-12-15

Phase-pure anatase TiO{sub 2} nanocrystallite aggregates synthesized by a continuous supercritical fluid process have been first used for fabricating mesoporous photoanodes of dye-sensitized solar cells (DSCs). Due to the small size (11 nm) of the TiO{sub 2} nanocrystallites in the aggregates, the mesoporous photoanode provides a high specific surface area, 80 m{sup 2}/g, which ensures high dye loading. At the same time, the submicrometer-sized aggregates endow the mesoporous photoanode with strong light scattering effect. Therefore, the light harvesting efficiency of the photoanode is increased. With an improved short-circuit current density, a high overall power conversion efficiency of 8.65% (100 mW/cm{sup 2}, AM 1.5) is achieved without additional scattering layers, 12% enhanced compared with the DSCs fabricated from commercial Degussa P25 with exactly the same procedures. In addition, this supercritical fluid process is scalable and rapid (less than one minute) for TiO{sub 2} aggregates synthesis, which will push the commercialization of DSCs in the future. - Graphical abstract: Due to the special morphology and structure, the photoanode of DSCs provides high specific surface area and strong light scattering at the same time, which results in high conversion efficiencies of the DSCs. Table of contents: Thanks to the synchronous realization of high specific surface area and strong light scattering, a high efficiency of 8.65% was achieved based on a novel mesoporous TiO{sub 2} aggregates photoanode for DSCs. Highlights: Black-Right-Pointing-Pointer The TiO{sub 2} aggregate photoanode provides a possible route for highly efficient DSCs. Black-Right-Pointing-Pointer Photoanode with high dye loading and light scattering is successfully fabricated. Black-Right-Pointing-Pointer TiO{sub 2} synthesized by a supercritical fluid process is first applied to DSCs. Black-Right-Pointing-Pointer The synthesis method and high efficiency will push the commercialization of DSCs.

Spontaneous dressed-state polarization in the strong driving regime of cavity QED.

Science.gov (United States)

Armen, Michael A; Miller, Anthony E; Mabuchi, Hideo

2009-10-23

We utilize high-bandwidth phase-quadrature homodyne measurement of the light transmitted through a Fabry-Perot cavity, driven strongly and on resonance, to detect excess phase noise induced by a single intracavity atom. We analyze the correlation properties and driving-strength dependence of the atom-induced phase noise to establish that it corresponds to the long-predicted phenomenon of spontaneous dressed-state polarization. Our experiment thus provides a demonstration of cavity quantum electrodynamics in the strong-driving regime in which one atom interacts strongly with a many-photon cavity field to produce novel quantum stochastic behavior.

External application of gametophyte-specific ZmPMEI1 induces pollen tube burst in maize.

Science.gov (United States)

Woriedh, Mayada; Wolf, Sebastian; Márton, Mihaela L; Hinze, Axel; Gahrtz, Manfred; Becker, Dirk; Dresselhaus, Thomas

2013-09-01

Regulated demethylesterification of homogalacturonan, a major component of plant cell walls, by the activity of pectin methylesterases (PMEs), plays a critical role for cell wall stability and integrity. Especially fast growing plant cells such as pollen tubes secrete large amounts of PMEs toward their apoplasmic space. PME activity itself is tightly regulated by its inhibitor named as PME inhibitor and is thought to be required especially at the very pollen tube tip. We report here the identification and functional characterization of PMEI1 from maize (ZmPMEI1). We could show that the protein acts as an inhibitor of PME but not of invertases and found that its gene is strongly expressed in both gametophytes (pollen grain and embryo sac). Promoter reporter studies showed gene activity also during pollen tube growth toward and inside the transmitting tract. All embryo sac cells except the central cell displayed strong expression. Weaker signals were visible at sporophytic cells of the micropylar region. ZmPMEI1-EGFP fusion protein is transported within granules inside the tube and accumulates at the pollen tube tip as well as at sites where pollen tubes bend and/or change growth directions. The female gametophyte putatively influences pollen tube growth behavior by exposing it to ZmPMEI1. We therefore simulated this effect by applying recombinant protein at different concentrations on growing pollen tubes. ZmPMEI1 did not arrest growth, but destabilized the cell wall inducing burst. Compared with female gametophyte secreted defensin-like ZmES4, which induces burst at the very pollen tube tip, ZmPMEI1-induced burst occurs at the subapical region. These findings indicate that ZmPMEI1 secreted by the embryo sac likely destabilizes the pollen tube wall during perception and together with other proteins such as ZmES4 leads to burst and thus sperm release.

Human lactoferricin derived di-peptides deploying loop structures induce apoptosis specifically in cancer cells through targeting membranous phosphatidylserine.

Science.gov (United States)

Riedl, Sabrina; Leber, Regina; Rinner, Beate; Schaider, Helmut; Lohner, Karl; Zweytick, Dagmar

2015-11-01

Host defense-derived peptides have emerged as a novel strategy for the development of alternative anticancer therapies. In this study we report on characteristic features of human lactoferricin (hLFcin) derivatives which facilitate specific killing of cancer cells of melanoma, glioblastoma and rhabdomyosarcoma compared with non-specific derivatives and the synthetic peptide RW-AH. Changes in amino acid sequence of hLFcin providing 9-11 amino acids stretched derivatives LF11-316, -318 and -322 only yielded low antitumor activity. However, the addition of the repeat (di-peptide) and the retro-repeat (di-retro-peptide) sequences highly improved cancer cell toxicity up to 100% at 20 μM peptide concentration. Compared to the complete parent sequence hLFcin the derivatives showed toxicity on the melanoma cell line A375 increased by 10-fold and on the glioblastoma cell line U-87mg by 2-3-fold. Reduced killing velocity, apoptotic blebbing, activation of caspase 3/7 and formation of apoptotic DNA fragments proved that the active and cancer selective peptides, e.g. R-DIM-P-LF11-322, trigger apoptosis, whereas highly active, though non-selective peptides, such as DIM-LF11-318 and RW-AH seem to kill rapidly via necrosis inducing membrane lyses. Structural studies revealed specific toxicity on cancer cells by peptide derivatives with loop structures, whereas non-specific peptides comprised α-helical structures without loop. Model studies with the cancer membrane mimic phosphatidylserine (PS) gave strong evidence that PS only exposed by cancer cells is an important target for specific hLFcin derivatives. Other negatively charged membrane exposed molecules as sialic acid, heparan and chondroitin sulfate were shown to have minor impact on peptide activity. Copyright © 2015. Published by Elsevier B.V.

Grass immunotherapy induces inhibition of allergen-specific human peripheral blood mononuclear cell proliferation.

Science.gov (United States)

Baskar, S; Hamilton, R G; Norman, P S; Ansari, A A

1997-02-01

The peripheral blood mononuclear cells (PBMC) from humans allergic to grass pollens (GR+ subjects) show strong in vitro proliferative responses to purified allergens from Lolium perenne pollen Lol p 1, and to a lesser extent to Lol p 2 and Lol p 3. By contrast, PBMC from grass allergic patients undergoing immunotherapy (GR + IT subjects) exhibit a very poor Lol p-specific proliferative response, similar to that observed in nongrass allergic subjects (GR-subjects). Unlike GR-subjects, both GR+ and GR + IT subjects have high levels of antigen-specific serum IgG and IgE antibodies to Lol p 1, Lol p 2 and Lol p 3. While GR+ subjects exhibit a significant correlation between antigen-specific serum antibody and PBMC responses, GR + IT subjects do not show a correlation between the two responses. The possible mechanisms by which immunotherapy may modulate allergen-specific T cell proliferative response are discussed.

Specific histone modification responds to arsenic-induced oxidative stress

Energy Technology Data Exchange (ETDEWEB)

Ma, Lu [Department of Toxicology, Guangzhou Key Laboratory of Environmental Pollution and Health Risk Assessment, School of Public Health, Sun Yat-sen University, Guangzhou (China); Li, Jun [Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang, Guizhou (China); Zhan, Zhengbao; Chen, Liping; Li, Daochuan; Bai, Qing; Gao, Chen; Li, Jie; Zeng, Xiaowen; He, Zhini; Wang, Shan; Xiao, Yongmei [Department of Toxicology, Guangzhou Key Laboratory of Environmental Pollution and Health Risk Assessment, School of Public Health, Sun Yat-sen University, Guangzhou (China); Chen, Wen, E-mail: chenwen@mail.sysu.edu.cn [Department of Toxicology, Guangzhou Key Laboratory of Environmental Pollution and Health Risk Assessment, School of Public Health, Sun Yat-sen University, Guangzhou (China); Zhang, Aihua, E-mail: aihuagzykd@163.com [Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang, Guizhou (China)

2016-07-01

To explore whether specific histone modifications are associated with arsenic-induced oxidative damage, we recruited 138 arsenic-exposed and arsenicosis subjects from Jiaole Village, Xinren County of Guizhou province, China where the residents were exposed to arsenic from indoor coal burning. 77 villagers from Shang Batian Village that were not exposed to high arsenic coal served as the control group. The concentrations of urine and hair arsenic in the arsenic-exposure group were 2.4-fold and 2.1-fold (all P < 0.001) higher, respectively, than those of the control group. Global histone modifications in human peripheral lymphocytes (PBLCs) were examined by ELISA. The results showed that altered global levels of H3K18ac, H3K9me2, and H3K36me3 correlated with both urinary and hair-arsenic levels of the subjects. Notably, H3K36me3 and H3K18ac modifications were associated with urinary 8-OHdG (H3K36me3: β = 0.16; P = 0.042, H3K18ac: β = − 0.24; P = 0.001). We also found that the modifications of H3K18ac and H3K36me3 were enriched in the promoters of oxidative stress response (OSR) genes in human embryonic kidney (HEK) cells and HaCaT cells, providing evidence that H3K18ac and H3K36me3 modifications mediate transcriptional regulation of OSR genes in response to NaAsO{sub 2} treatment. Particularly, we found that reduced H3K18ac modification correlated with suppressed expression of OSR genes in HEK cells with long term arsenic treatment and in PBLCs of all the subjects. Taken together, we reveal a critical role for specific histone modification in response to arsenic-induced oxidative damage. - Highlights: • H3K18ac, H3K9me2 and H3K36me3 were associated with arsenic exposed levels. • H3K18ac and H3K36me3 were correlated with oxidative damage induced by arsenic. • H3K18ac and H3K36me3 might involve in transcriptional regulation of OSR genes. • Dysregulation of H3K18ac and H3K36me3 might be biomarkers of arsenic toxicity.

Specific histone modification responds to arsenic-induced oxidative stress

International Nuclear Information System (INIS)

Ma, Lu; Li, Jun; Zhan, Zhengbao; Chen, Liping; Li, Daochuan; Bai, Qing; Gao, Chen; Li, Jie; Zeng, Xiaowen; He, Zhini; Wang, Shan; Xiao, Yongmei; Chen, Wen; Zhang, Aihua

2016-01-01

To explore whether specific histone modifications are associated with arsenic-induced oxidative damage, we recruited 138 arsenic-exposed and arsenicosis subjects from Jiaole Village, Xinren County of Guizhou province, China where the residents were exposed to arsenic from indoor coal burning. 77 villagers from Shang Batian Village that were not exposed to high arsenic coal served as the control group. The concentrations of urine and hair arsenic in the arsenic-exposure group were 2.4-fold and 2.1-fold (all P < 0.001) higher, respectively, than those of the control group. Global histone modifications in human peripheral lymphocytes (PBLCs) were examined by ELISA. The results showed that altered global levels of H3K18ac, H3K9me2, and H3K36me3 correlated with both urinary and hair-arsenic levels of the subjects. Notably, H3K36me3 and H3K18ac modifications were associated with urinary 8-OHdG (H3K36me3: β = 0.16; P = 0.042, H3K18ac: β = − 0.24; P = 0.001). We also found that the modifications of H3K18ac and H3K36me3 were enriched in the promoters of oxidative stress response (OSR) genes in human embryonic kidney (HEK) cells and HaCaT cells, providing evidence that H3K18ac and H3K36me3 modifications mediate transcriptional regulation of OSR genes in response to NaAsO 2 treatment. Particularly, we found that reduced H3K18ac modification correlated with suppressed expression of OSR genes in HEK cells with long term arsenic treatment and in PBLCs of all the subjects. Taken together, we reveal a critical role for specific histone modification in response to arsenic-induced oxidative damage. - Highlights: • H3K18ac, H3K9me2 and H3K36me3 were associated with arsenic exposed levels. • H3K18ac and H3K36me3 were correlated with oxidative damage induced by arsenic. • H3K18ac and H3K36me3 might involve in transcriptional regulation of OSR genes. • Dysregulation of H3K18ac and H3K36me3 might be biomarkers of arsenic toxicity.

Current-horn suppression for reduced coherent-synchrotron-radiation-induced emittance growth in strong bunch compression

Directory of Open Access Journals (Sweden)

T. K. Charles

2017-03-01

Full Text Available Control of coherent synchrotron radiation (CSR-induced emittance growth is essential in linear accelerators designed to deliver very high brightness electron beams. Extreme current values at the head and tail of the electron bunch, resulting from strong bunch compression, are responsible for large CSR production leading to significant transverse projected emittance growth. The Linac Coherent Light Source (LCLS truncates the head and tail current spikes which greatly improves free electron laser (FEL performance. Here we consider the underlying dynamics that lead to formation of current spikes (also referred to as current horns, which has been identified as caustics forming in electron trajectories. We present a method to analytically determine conditions required to avoid the caustic formation and therefore prevent the current spikes from forming. These required conditions can be easily met, without increasing the transverse slice emittance, through inclusion of an octupole magnet in the middle of a bunch compressor.

Distinct susceptibility of HIV vaccine vector-induced CD4 T cells to HIV infection

Science.gov (United States)

Niu, Qingli; Hou, Wei; Churchyard, Gavin; Nitayaphan, Sorachai; Pitisuthithum, Punnee; Rerks-Ngarm, Supachai; Franchini, Genoveffa

2018-01-01

The concerns raised from adenovirus 5 (Ad5)-based HIV vaccine clinical trials, where excess HIV infections were observed in some vaccine recipients, have highlighted the importance of understanding host responses to vaccine vectors and the HIV susceptibility of vector-specific CD4 T cells in HIV vaccination. Our recent study reported that human Ad5-specific CD4 T cells induced by Ad5 vaccination (RV156A trial) are susceptible to HIV. Here we further investigated the HIV susceptibility of vector-specific CD4 T cells induced by ALVAC, a canarypox viral vector tested in the Thai trial RV144, as compared to Ad5 vector-specific CD4 T cells in the HVTN204 trial. We showed that while Ad5 vector-specific CD4 T cells were readily susceptible to HIV, ALVAC-specific CD4 T cells in RV144 PBMC were substantially less susceptible to both R5 and X4 HIV in vitro. The lower HIV susceptibility of ALVAC-specific CD4 T cells was associated with the reduced surface expression of HIV entry co-receptors CCR5 and CXCR4 on these cells. Phenotypic analyses identified that ALVAC-specific CD4 T cells displayed a strong Th1 phenotype, producing higher levels of IFN-γ and CCL4 (MIP-1β) but little IL-17. Of interest, ALVAC and Ad5 vectors induced distinct profiles of vector-specific CD8 vs. CD4 T-cell proliferative responses in PBMC, with ALVAC preferentially inducing CD8 T-cell proliferation, while Ad5 vector induced CD4 T-cell proliferation. Depletion of ALVAC-, but not Ad5-, induced CD8 T cells in PBMC led to a modest increase in HIV infection of vector-specific CD4 T cells, suggesting a role of ALVAC-specific CD8 T cells in protecting ALVAC-specific CD4 T cells from HIV. Taken together, our data provide strong evidence for distinct HIV susceptibility of CD4 T cells induced by different vaccine vectors and highlight the importance of better evaluating anti-vector responses in HIV vaccination. PMID:29474461

Strain-Induced Enhancement of the Electron Energy Relaxation in Strongly Correlated Superconductors

Directory of Open Access Journals (Sweden)

C. Gadermaier

2014-03-01

Full Text Available We use femtosecond optical spectroscopy to systematically measure the primary energy relaxation rate Γ_{1} of photoexcited carriers in cuprate and pnictide superconductors. We find that Γ_{1} increases monotonically with increased negative strain in the crystallographic a axis. Generally, the Bardeen-Shockley deformation potential theorem and, specifically, pressure-induced Raman shifts reported in the literature suggest that increased negative strain enhances electron-phonon coupling, which implies that the observed direct correspondence between a and Γ_{1} is consistent with the canonical assignment of Γ_{1} to the electron-phonon interaction. The well-known nonmonotonic dependence of the superconducting critical temperature T_{c} on the a-axis strain is also reflected in a systematic dependence T_{c} on Γ_{1}, with a distinct maximum at intermediate values (∼16  ps^{−1} at room temperature. The empirical nonmonotonic systematic variation of T_{c} with the strength of the electron-phonon interaction provides us with unique insight into the role of electron-phonon interaction in relation to the mechanism of high-T_{c} superconductivity as a crossover phenomenon.

Generation of an inducible colon-specific Cre enzyme mouse line for colon cancer research

NARCIS (Netherlands)

Tetteh, Paul W.; Kretzschmar, Kai; Begthel, Harry; Van Den Born, Maaike; Korving, Jeroen; Morsink, Folkert; Farin, Henner; Van Es, Johan H.; Offerhaus, G. Johan A; Clevers, Hans

2016-01-01

Current mouse models for colorectal cancer often differ significantly from human colon cancer, being largely restricted to the small intestine. Here, we aim to develop a colon-specific inducible mouse model that can faithfully recapitulate human colon cancer initiation and progression. Carbonic

Strong interband Faraday rotation in 3D topological insulator Bi2Se3.

Science.gov (United States)

Ohnoutek, L; Hakl, M; Veis, M; Piot, B A; Faugeras, C; Martinez, G; Yakushev, M V; Martin, R W; Drašar, Č; Materna, A; Strzelecka, G; Hruban, A; Potemski, M; Orlita, M

2016-01-11

The Faraday effect is a representative magneto-optical phenomenon, resulting from the transfer of angular momentum between interacting light and matter in which time-reversal symmetry has been broken by an externally applied magnetic field. Here we report on the Faraday rotation induced in the prominent 3D topological insulator Bi2Se3 due to bulk interband excitations. The origin of this non-resonant effect, extraordinarily strong among other non-magnetic materials, is traced back to the specific Dirac-type Hamiltonian for Bi2Se3, which implies that electrons and holes in this material closely resemble relativistic particles with a non-zero rest mass.

Strongly interacting matter in magnetic fields

CERN Document Server

Landsteiner, Karl; Schmitt, Andreas; Yee, Ho-Ung

2013-01-01

The physics of strongly interacting matter in an external magnetic field is presently emerging as a topic of great cross-disciplinary interest for particle, nuclear, astro- and condensed matter physicists. It is known that strong magnetic fields are created in heavy ion collisions, an insight that has made it possible to study a variety of surprising and intriguing phenomena that emerge from the interplay of quantum anomalies, the topology of non-Abelian gauge fields, and the magnetic field. In particular, the non-trivial topological configurations of the gluon field induce a non-dissipative electric current in the presence of a magnetic field. These phenomena have led to an extended formulation of relativistic hydrodynamics, called chiral magnetohydrodynamics. Hitherto unexpected applications in condensed matter physics include graphene and topological insulators. Other fields of application include astrophysics, where strong magnetic fields exist in magnetars and pulsars. Last but not least, an important ne...

MgB2 superconducting particles in a strong electric field

International Nuclear Information System (INIS)

Tao, R.; Xu, X.; Amr, E.

2003-01-01

The electric-field induced ball formation has been observed with MgB 2 powder in a strong static or quasi-static electric field. The effect of temperature and magnetic field on the ball formation shows surprising features. For quite a wide range of temperature from T c =39 K and below, the ball size is proportional to (1-T/T c ). As the temperature further goes below 20 K, the ball size becomes almost a constant. If MgB 2 particles are in a strong electric field and a moderate magnetic field, the electric-field induced balls align in the magnetic-field direction to form ball chains

A single-strand specific lesion drives MMS-induced hyper-mutability at a double-strand break in yeast.

Science.gov (United States)

Yang, Yong; Gordenin, Dmitry A; Resnick, Michael A

2010-08-05

Localized hyper-mutability (LHM) can be important in evolution, immunity, and genetic diseases. We previously reported that single-strand DNA (ssDNA) can be an important source of damage-induced LHM in yeast. Here, we establish that the generation of LHM by methyl methanesulfonate (MMS) during repair of a chromosomal double-strand break (DSB) can result in over 0.2 mutations/kb, which is approximately 20,000-fold higher than the MMS-induced mutation density without a DSB. The MMS-induced mutations associated with DSB repair were primarily due to substitutions via translesion DNA synthesis at damaged cytosines, even though there are nearly 10 times more MMS-induced lesions at other bases. Based on this mutation bias, the promutagenic lesion dominating LHM is likely 3-methylcytosine, which is single-strand specific. Thus, the dramatic increase in mutagenesis at a DSB is concluded to result primarily from the generation of non-repairable lesions in ssDNA associated with DSB repair along with efficient induction of highly mutagenic ssDNA-specific lesions. These findings with MMS-induced LHM have broad biological implications for unrepaired damage generated in ssDNA and possibly ssRNA. Published by Elsevier B.V.

New frontier in regenerative medicine: site-specific gene correction in patient-specific induced pluripotent stem cells.

Science.gov (United States)

Garate, Zita; Davis, Brian R; Quintana-Bustamante, Oscar; Segovia, Jose C

2013-06-01

Advances in cell and gene therapy are opening up new avenues for regenerative medicine. Because of their acquired pluripotency, human induced pluripotent stem cells (hiPSCs) are a promising source of autologous cells for regenerative medicine. They show unlimited self-renewal while retaining the ability, in principle, to differentiate into any cell type of the human body. Since Yamanaka and colleagues first reported the generation of hiPSCs in 2007, significant efforts have been made to understand the reprogramming process and to generate hiPSCs with potential for clinical use. On the other hand, the development of gene-editing platforms to increase homologous recombination efficiency, namely DNA nucleases (zinc finger nucleases, TAL effector nucleases, and meganucleases), is making the application of locus-specific gene therapy in human cells an achievable goal. The generation of patient-specific hiPSC, together with gene correction by homologous recombination, will potentially allow for their clinical application in the near future. In fact, reports have shown targeted gene correction through DNA-Nucleases in patient-specific hiPSCs. Various technologies have been described to reprogram patient cells and to correct these patient hiPSCs. However, no approach has been clearly more efficient and safer than the others. In addition, there are still significant challenges for the clinical application of these technologies, such as inefficient differentiation protocols, genetic instability resulting from the reprogramming process and hiPSC culture itself, the efficacy and specificity of the engineered DNA nucleases, and the overall homologous recombination efficiency. To summarize advances in the generation of gene corrected patient-specific hiPSCs, this review focuses on the available technological platforms, including their strengths and limitations regarding future therapeutic use of gene-corrected hiPSCs.

Modeling retinal degeneration using patient-specific induced pluripotent stem cells.

Directory of Open Access Journals (Sweden)

Zi-Bing Jin

Full Text Available Retinitis pigmentosa (RP is the most common inherited human eye disease resulting in night blindness and visual defects. It is well known that the disease is caused by rod photoreceptor degeneration; however, it remains incurable, due to the unavailability of disease-specific human photoreceptor cells for use in mechanistic studies and drug screening. We obtained fibroblast cells from five RP patients with distinct mutations in the RP1, RP9, PRPH2 or RHO gene, and generated patient-specific induced pluripotent stem (iPS cells by ectopic expression of four key reprogramming factors. We differentiated the iPS cells into rod photoreceptor cells, which had been lost in the patients, and found that they exhibited suitable immunocytochemical features and electrophysiological properties. Interestingly, the number of the patient-derived rod cells with distinct mutations decreased in vitro; cells derived from patients with a specific mutation expressed markers for oxidation or endoplasmic reticulum stress, and exhibited different responses to vitamin E than had been observed in clinical trials. Overall, patient-derived rod cells recapitulated the disease phenotype and expressed markers of cellular stresses. Our results demonstrate that the use of patient-derived iPS cells will help to elucidate the pathogenic mechanisms caused by genetic mutations in RP.

Prebiotic inulin-type fructans induce specific changes in the human gut microbiota.

Science.gov (United States)

Vandeputte, Doris; Falony, Gwen; Vieira-Silva, Sara; Wang, Jun; Sailer, Manuela; Theis, Stephan; Verbeke, Kristin; Raes, Jeroen

2017-11-01

Contrary to the long-standing prerequisite of inducing selective (ie, bifidogenic) effects, recent findings suggest that prebiotic interventions lead to ecosystem-wide microbiota shifts. Yet, a comprehensive characterisation of this process is still lacking. Here, we apply 16S rDNA microbiota profiling and matching (gas chromatography mass spectrometry) metabolomics to assess the consequences of inulin fermentation both on the composition of the colon bacterial ecosystem and faecal metabolites profiles. Faecal samples collected during a double-blind, randomised, cross-over intervention study set up to assess the effect of inulin consumption on stool frequency in healthy adults with mild constipation were analysed. Faecal microbiota composition and metabolite profiles were linked to the study's clinical outcome as well as to quality-of-life measurements recorded. While faecal metabolite profiles were not significantly altered by inulin consumption, our analyses did detect a modest effect on global microbiota composition and specific inulin-induced changes in relative abundances of Anaerostipes , Bilophila and Bifidobacterium were identified. The observed decrease in Bilophila abundances following inulin consumption was associated with both softer stools and a favourable change in constipation-specific quality-of-life measures. Ecosystem-wide analysis of the effect of a dietary intervention with prebiotic inulin-type fructans on the colon microbiota revealed that this effect is specifically associated with three genera, one of which ( Bilophila ) representing a promising novel target for mechanistic research. NCT02548247. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Specificity of induced defenses, growth, and reproduction in lima bean (Phaseolus lunatus) in response to multispecies herbivory.

Science.gov (United States)

Moreira, Xoaquín; Abdala-Roberts, Luis; Hernández-Cumplido, Johnattan; Cuny, Maximilien A C; Glauser, Gaetan; Benrey, Betty

2015-08-01

• Following herbivore attack, plants can either reduce damage by inducing defenses or mitigate herbivory effects through compensatory growth and reproduction. It is increasingly recognized that such induced defenses in plants are herbivore-specific, but less is known about the specificity of compensatory responses. Damage by multiple herbivores may also lead to synergistic effects on induction and plant fitness that differ from those caused by a single herbivore species. Although largely unstudied, the order of arrival and damage by different herbivore species might also play an important role in the impacts of herbivory on plants.• We investigated the specificity of defense induction (phenolics) and effects on growth (number of stems and leaves) and reproduction (number of seeds, seed mass, and germination rate) from feeding by two generalist leaf-chewing herbivores (Spodoptera eridania and Diabrotica balteata) on Phaseolus lunatus plants and evaluated whether simultaneous attack by both herbivores and their order of arrival influenced such dynamics.• Herbivory increased levels of leaf phenolics, but such effects were not herbivore-specific. In contrast, herbivory enhanced seed germination in an herbivore-specific manner. For all variables measured, the combined effects of both herbivore species did not differ from their individual effects. Finally, the order of herbivore arrival did not influence defense induction, plant growth, or seed number but did influence seed mass and germination.• Overall, this study highlights novel aspects of the specificity of plant responses induced by damage from multiple species of herbivores and uniquely associates such effects with plant lifetime fitness. © 2015 Botanical Society of America, Inc.

Norepinephrine induces pathway-specific long-lasting potentiation and depression in the hippocampal dentate gyrus.

Science.gov (United States)

Dahl, D; Sarvey, J M

1989-01-01

The study presented here indicates that norepinephrine (NE) selectively induces long-lasting modifications of synaptically mediated responses in the dentate gyrus of the rat hippocampal slice. A low concentration of NE (1.0 microM; in the presence of 50 microM phentolamine, an alpha-adrenergic antagonist) or a 1.0 microM concentration of the specific beta-adrenergic agonist isoproterenol induced long-lasting pathway-specific alterations of granule cell electrophysiological responses. Excitatory postsynaptic potentials and population spikes evoked by stimulation of the medial perforant pathway (PP) were potentiated for more than 45 min. In contrast, responses to lateral PP stimulation were depressed for the same period. Both potentiation and depression were blocked by the beta-adrenergic antagonist propranolol (1.0 microM). These results indicate that NE can act differentially on projections to the dentate gyrus arising in the entorhinal cortex. Such selective persistent modifications of cortical circuits may be involved in processes in the mammalian brain underlying attention, learning, and memory. PMID:2734319

Tissue-specific and pathogen-inducible expression of a fusion protein containing a Fusarium-specific antibody and a fungal chitinase protects wheat against Fusarium pathogens and mycotoxins.

Science.gov (United States)

Cheng, Wei; Li, He-Ping; Zhang, Jing-Bo; Du, Hong-Jie; Wei, Qi-Yong; Huang, Tao; Yang, Peng; Kong, Xian-Wei; Liao, Yu-Cai

2015-06-01

Fusarium head blight (FHB) in wheat and other small grain cereals is a globally devastating disease caused by toxigenic Fusarium pathogens. Controlling FHB is a challenge because germplasm that is naturally resistant against these pathogens is inadequate. Current control measures rely on fungicides. Here, an antibody fusion comprised of the Fusarium spp.-specific recombinant antibody gene CWP2 derived from chicken, and the endochitinase gene Ech42 from the biocontrol fungus Trichoderma atroviride was introduced into the elite wheat cultivar Zhengmai9023 by particle bombardment. Expression of this fusion gene was regulated by the lemma/palea-specific promoter Lem2 derived from barley; its expression was confirmed as lemma/palea-specific in transgenic wheat. Single-floret inoculation of independent transgenic wheat lines of the T3 to T6 generations revealed significant resistance (type II) to fungal spreading, and natural infection assays in the field showed significant resistance (type I) to initial infection. Gas chromatography-mass spectrometry analysis revealed marked reduction of mycotoxins in the grains of the transgenic wheat lines. Progenies of crosses between the transgenic lines and the FHB-susceptible cultivar Huamai13 also showed significantly enhanced FHB resistance. Quantitative real-time PCR analysis revealed that the tissue-specific expression of the antibody fusion was induced by salicylic acid drenching and induced to a greater extent by F. graminearum infection. Histochemical analysis showed substantial restriction of mycelial growth in the lemma tissues of the transgenic plants. Thus, the combined tissue-specific and pathogen-inducible expression of this Fusarium-specific antibody fusion can effectively protect wheat against Fusarium pathogens and reduce mycotoxin content in grain. © 2014 Society for Experimental Biology, Association of Applied Biologists and John Wiley & Sons Ltd.

Strong-interaction nonuniversality

International Nuclear Information System (INIS)

Volkas, R.R.; Foot, R.; He, X.; Joshi, G.C.

1989-01-01

The universal QCD color theory is extended to an SU(3) 1 direct product SU(3) 2 direct product SU(3) 3 gauge theory, where quarks of the ith generation transform as triplets under SU(3)/sub i/ and singlets under the other two factors. The usual color group is then identified with the diagonal subgroup, which remains exact after symmetry breaking. The gauge bosons associated with the 16 broken generators then form two massive octets under ordinary color. The interactions between quarks and these heavy gluonlike particles are explicitly nonuniversal and thus an exploration of their physical implications allows us to shed light on the fundamental issue of strong-interaction universality. Nonuniversality and weak flavor mixing are shown to generate heavy-gluon-induced flavor-changing neutral currents. The phenomenology of these processes is studied, as they provide the major experimental constraint on the extended theory. Three symmetry-breaking scenarios are presented. The first has color breaking occurring at the weak scale, while the second and third divorce the two scales. The third model has the interesting feature of radiatively induced off-diagonal Kobayashi-Maskawa matrix elements

Strongly Correlated Systems Theoretical Methods

CERN Document Server

Avella, Adolfo

2012-01-01

The volume presents, for the very first time, an exhaustive collection of those modern theoretical methods specifically tailored for the analysis of Strongly Correlated Systems. Many novel materials, with functional properties emerging from macroscopic quantum behaviors at the frontier of modern research in physics, chemistry and materials science, belong to this class of systems. Any technique is presented in great detail by its own inventor or by one of the world-wide recognized main contributors. The exposition has a clear pedagogical cut and fully reports on the most relevant case study where the specific technique showed to be very successful in describing and enlightening the puzzling physics of a particular strongly correlated system. The book is intended for advanced graduate students and post-docs in the field as textbook and/or main reference, but also for other researchers in the field who appreciates consulting a single, but comprehensive, source or wishes to get acquainted, in a as painless as po...

Strongly correlated systems numerical methods

CERN Document Server

Mancini, Ferdinando

2013-01-01

This volume presents, for the very first time, an exhaustive collection of those modern numerical methods specifically tailored for the analysis of Strongly Correlated Systems. Many novel materials, with functional properties emerging from macroscopic quantum behaviors at the frontier of modern research in physics, chemistry and material science, belong to this class of systems. Any technique is presented in great detail by its own inventor or by one of the world-wide recognized main contributors. The exposition has a clear pedagogical cut and fully reports on the most relevant case study where the specific technique showed to be very successful in describing and enlightening the puzzling physics of a particular strongly correlated system. The book is intended for advanced graduate students and post-docs in the field as textbook and/or main reference, but also for other researchers in the field who appreciate consulting a single, but comprehensive, source or wishes to get acquainted, in a as painless as possi...

<strong>Low dose transdermal estradiol induces breast density and heterogeneity changes comparable to those of raloxifenestrong>

DEFF Research Database (Denmark)

Nielsen, Mads; Raundahl, Jakob; Pettersen, Paola

2009-01-01

Objective: To investigate whether transdermal low dose estradiol treatment induces changes in mammographic density or heterogeneity compared to raloxifene. Secondarily, if these changes relate to changes in bone formation/resorption markers, and if these findings indicate elevation of breast canc...

Radiation-induced bystander effects in vivo are sex specific

International Nuclear Information System (INIS)

Koturbash, Igor; Kutanzi, Kristy; Hendrickson, Karl; Rodriguez-Juarez, Rocio; Kogosov, Dmitry; Kovalchuk, Olga

2008-01-01

Ionizing radiation (IR) effects span beyond the area of direct exposure and can be observed in neighboring and distant naive cells and organs. This phenomenon is termed a 'bystander effect'. IR effects in directly exposed tissue in vivo are epigenetically mediated and distinct in males and females. Yet, IR-induced bystander effects have never been explored in a sex-specificity domain. We used an in vivo mouse model, whereby the bystander effects are studied in spleen of male and female animals subjected to head exposure when the rest of the body is protected by a medical-grade lead shield. We analyzed the induction of DNA damage and alterations in global DNA methylation. Molecular parameters were correlated with cellular proliferation and apoptosis levels. The changes observed in bystander organs are compared to the changes in unexposed animals and animals exposed to predicted and measured scatter doses. We have found the selective induction of DNA damage levels, global DNA methylation, cell proliferation and apoptosis in exposed and bystander spleen tissue of male and female mice. Sex differences were significantly diminished in animals subjected to a surgical removal of gonads. These data constitute the first evidence of sex differences in radiation-induced bystander effects in mouse spleen in vivo. We show the role of sex hormones in spleen bystander responses and discuss implications of the observed changes

Radiation-induced bystander effects in vivo are sex specific

Energy Technology Data Exchange (ETDEWEB)

Koturbash, Igor; Kutanzi, Kristy; Hendrickson, Karl; Rodriguez-Juarez, Rocio; Kogosov, Dmitry [Department of Biological Sciences, University of Lethbridge, Alberta T1K 3M4 (Canada); Kovalchuk, Olga [Department of Biological Sciences, University of Lethbridge, Alberta T1K 3M4 (Canada)], E-mail: olga.kovalchuk@uleth.ca

2008-07-03

Ionizing radiation (IR) effects span beyond the area of direct exposure and can be observed in neighboring and distant naive cells and organs. This phenomenon is termed a 'bystander effect'. IR effects in directly exposed tissue in vivo are epigenetically mediated and distinct in males and females. Yet, IR-induced bystander effects have never been explored in a sex-specificity domain. We used an in vivo mouse model, whereby the bystander effects are studied in spleen of male and female animals subjected to head exposure when the rest of the body is protected by a medical-grade lead shield. We analyzed the induction of DNA damage and alterations in global DNA methylation. Molecular parameters were correlated with cellular proliferation and apoptosis levels. The changes observed in bystander organs are compared to the changes in unexposed animals and animals exposed to predicted and measured scatter doses. We have found the selective induction of DNA damage levels, global DNA methylation, cell proliferation and apoptosis in exposed and bystander spleen tissue of male and female mice. Sex differences were significantly diminished in animals subjected to a surgical removal of gonads. These data constitute the first evidence of sex differences in radiation-induced bystander effects in mouse spleen in vivo. We show the role of sex hormones in spleen bystander responses and discuss implications of the observed changes.

Radiation-induced bystander effects in vivo are sex specific.

Science.gov (United States)

Koturbash, Igor; Kutanzi, Kristy; Hendrickson, Karl; Rodriguez-Juarez, Rocio; Kogosov, Dmitry; Kovalchuk, Olga

2008-07-03

Ionizing radiation (IR) effects span beyond the area of direct exposure and can be observed in neighboring and distant naïve cells and organs. This phenomenon is termed a 'bystander effect'. IR effects in directly exposed tissue in vivo are epigenetically mediated and distinct in males and females. Yet, IR-induced bystander effects have never been explored in a sex-specificity domain. We used an in vivo mouse model, whereby the bystander effects are studied in spleen of male and female animals subjected to head exposure when the rest of the body is protected by a medical-grade lead shield. We analyzed the induction of DNA damage and alterations in global DNA methylation. Molecular parameters were correlated with cellular proliferation and apoptosis levels. The changes observed in bystander organs are compared to the changes in unexposed animals and animals exposed to predicted and measured scatter doses. We have found the selective induction of DNA damage levels, global DNA methylation, cell proliferation and apoptosis in exposed and bystander spleen tissue of male and female mice. Sex differences were significantly diminished in animals subjected to a surgical removal of gonads. These data constitute the first evidence of sex differences in radiation-induced bystander effects in mouse spleen in vivo. We show the role of sex hormones in spleen bystander responses and discuss implications of the observed changes.

Skin cancer induced by ultraviolet radiation and immunity

International Nuclear Information System (INIS)

Sado, Toshihiko

1977-01-01

It was clarified that an immunological mechanism, in which the resistance against ultraviolet radiation (UV)-induced neoplasm with strong antigenicity in the body disappeared, was introduced, when the mouse was exposed to UV for two to five weeks. It was also suggested that the immunological mechanism was an induction of T lymphocyte (inhibitive T cells) which had a function to specifically inhibit proliferation of lymphocyte clone which had anti-UV-induced neoplasm activity contained in lymphocyte mass of normal mouse. It can be thought that the action mechanism of this cells may inhibit a process of differentiation of T precursor cells of cell damage, which has anti-UV-induced neoplasm activity, into cell damage T cells. As a mechanism in which such inhibitive T cells are induced, the possibility that specific inhibitive T cells against antigens which are changed by UV would be induced after proteins, which receives some changes in consequence of skin injuries due to UV, are separated from cells as soluble antigens, is thought. Reports of experiments on these problems performed by many researchers were also described. (Tsunoda, M.)

Epicutaneous Immunization with Type II Collagen Inhibits both Onset and Progression of Chronic Collagen-Induced Arthritis

OpenAIRE

Strid, Jessica; Tan, Lee Aun; Strobel, Stephan; Londei, Marco; Callard, Robin

2007-01-01

Epicutaneous immunization is a potential non-invasive technique for antigen-specific immune-modulation. Topical application of protein antigens to barrier-disrupted skin induces potent antigen-specific immunity with a strong Th2-bias. In this study, we investigate whether the autoimmune inflammatory response of chronic collagen-induced arthritis (CCIA) in DBA/1-TCR-beta Tg mice can be modified by epicutaneous immunization. We show that epicutaneous immunization with type II collagen (CII) inh...

Current induced multi-mode propagating spin waves in a spin transfer torque nano-contact with strong perpendicular magnetic anisotropy

Science.gov (United States)

Mohseni, S. Morteza; Yazdi, H. F.; Hamdi, M.; Brächer, T.; Mohseni, S. Majid

2018-03-01

Current induced spin wave excitations in spin transfer torque nano-contacts are known as a promising way to generate exchange-dominated spin waves at the nano-scale. It has been shown that when these systems are magnetized in the film plane, broken spatial symmetry of the field around the nano-contact induced by the Oersted field opens the possibility for spin wave mode co-existence including a non-linear self-localized spin-wave bullet and a propagating mode. By means of micromagnetic simulations, here we show that in systems with strong perpendicular magnetic anisotropy (PMA) in the free layer, two propagating spin wave modes with different frequency and spatial distribution can be excited simultaneously. Our results indicate that in-plane magnetized spin transfer nano-contacts in PMA materials do not host a solitonic self-localized spin-wave bullet, which is different from previous studies for systems with in plane magnetic anisotropy. This feature renders them interesting for nano-scale magnonic waveguides and crystals since magnon transport can be configured by tuning the applied current.

Induced Pluripotent Stem Cell Models of Progranulin-Deficient Frontotemporal Dementia Uncover Specific Reversible Neuronal Defects

Directory of Open Access Journals (Sweden)

Sandra Almeida

2012-10-01

Full Text Available The pathogenic mechanisms of frontotemporal dementia (FTD remain poorly understood. Here we generated multiple induced pluripotent stem cell lines from a control subject, a patient with sporadic FTD, and an FTD patient with a novel heterozygous GRN mutation (progranulin [PGRN] S116X. In neurons and microglia differentiated from PGRN S116X induced pluripotent stem cells, the levels of intracellular and secreted PGRN were reduced, establishing patient-specific cellular models of PGRN haploinsufficiency. Through a systematic screen of inducers of cellular stress, we found that PGRN S116X neurons, but not sporadic FTD neurons, exhibited increased sensitivity to staurosporine and other kinase inhibitors. Moreover, the serine/threonine kinase S6K2, a component of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways, was specifically downregulated in PGRN S116X neurons. Both increased sensitivity to kinase inhibitors and reduced S6K2 were rescued by PGRN expression. Our findings identify cell-autonomous, reversible defects in patient neurons with PGRN deficiency, and provide a compelling model for studying PGRN-dependent pathogenic mechanisms and testing potential therapies.

HLA Association with Drug-Induced Adverse Reactions

Directory of Open Access Journals (Sweden)

Wen-Lang Fan

2017-01-01

Full Text Available Adverse drug reactions (ADRs remain a common and major problem in healthcare. Severe cutaneous adverse drug reactions (SCARs, such as Stevens–Johnson syndrome (SJS/toxic epidermal necrolysis (TEN with mortality rate ranges from 10% to more than 30%, can be life threatening. A number of recent studies demonstrated that ADRs possess strong genetic predisposition. ADRs induced by several drugs have been shown to have significant associations with specific alleles of human leukocyte antigen (HLA genes. For example, hypersensitivity to abacavir, a drug used for treating of human immunodeficiency virus (HIV infection, has been proposed to be associated with allele 57:01 of HLA-B gene (terms HLA-B∗57:01. The incidences of abacavir hypersensitivity are much higher in Caucasians compared to other populations due to various allele frequencies in different ethnic populations. The antithyroid drug- (ATDs- induced agranulocytosis are strongly associated with two alleles: HLA-B∗38:02 and HLA-DRB1∗08:03. In addition, HLA-B∗15:02 allele was reported to be related to carbamazepine-induced SJS/TEN, and HLA-B∗57:01 in abacavir hypersensitivity and flucloxacillin induced drug-induced liver injury (DILI. In this review, we summarized the alleles of HLA genes which have been proposed to have association with ADRs caused by different drugs.

17AAG-induced internalisation of HER2-specific Affibody molecules.

Science.gov (United States)

Göstring, Lovisa; Lindegren, Sture; Gedda, Lars

2016-10-01

The geldanamycin derivative 17-allylamino-17-demethoxygeldanamycin (17-AAG) is known to induce internalisation and degradation of the otherwise internalisation-resistant human epidermal growth factor receptor 2 (HER2) receptor. In the present study, 17-AAG was used to increase internalisation of the HER2-specific Affibody molecule ABY-025. The cellular redistribution of halogen-labelled 211 At-ABY-025 and radiometal-labelled 111 In-ABY-025 following treatment with 17-AAG was studied. 17-AAG treatment of SKOV-3 human ovarian carcinoma and SKBR-3 human breast carcinoma cells to some extent shifted the localisation of 111 In-ABY-025 from the cell surface to intracellular compartments in the two cell lines. ABY-025 labelled with the high-linear energy transfer α emitter 211 At was also internalised to a higher degree; however, due to its physiological properties, this nuclide was excreted faster. The results indicate that 17-AAG may be used to facilitate cell-specific intracellular localisation of a suitable cytotoxic or radioactive agent coupled to ABY-025 in HER2-overexpressing cells.

Mechanically induced strong red emission in samarium ions doped piezoelectric semiconductor CaZnOS for dynamic pressure sensing and imaging

Science.gov (United States)

Wang, Wei; Peng, Dengfeng; Zhang, Hanlu; Yang, Xiaohong; Pan, Caofeng

2017-07-01

Piezoelectric semiconductor with optical, electrical and mechanical multifunctions has great potential applications in future optoelectronic devices. The rich properties and applications mainly encompass the intrinsic structures and their coupling effects. Here, we report that lanthanide ions doped piezoelectric semiconductor CaZnOS:Sm3+ showing strong red emission induced by dynamic mechanical stress. Under moderate mechanical load, the doped piezoelectric semiconductor exhibits strong visible red emission to the naked eyes even under the day light. A flexible dynamic pressure sensor device is fabricated based on the prepared CaZnOS:Sm3+ powders. The mechanical-induced emission properties of the device are investigated by the optical fiber spectrometer. The linear characteristic emissions are attributed to the 4G5/2→6H5/2 (566 nm), 4G5/2→6H7/2 (580-632 nm), 4G5/2→6H9/2 (653-673 nm) and 4G5/2→6H11/2 (712-735 nm) f-f transitions of Sm3+ ions. The integral emission intensity is proportional to the value of applied pressure. By using the linear relationship between integrated emission intensity and the dynamic pressure, the real-time pressure distribution is visualized and recorded. Our results highlight that the incorporation of lanthanide luminescent ions into piezoelectric semiconductors as smart materials could be applied into the flexible mechanical-optical sensor device without additional auxiliary power, which has great potential for promising applications such as mapping of personalized handwriting, smart display, and human machine interface.

Induction of antigen-specific immunity by pH-sensitive carbonate apatite as a potent vaccine carrier

International Nuclear Information System (INIS)

Hebishima, Takehisa; Tada, Seiichi; Takeshima, Shin-nosuke; Akaike, Toshihiro; Ito, Yoshihiro; Aida, Yoko

2011-01-01

Highlights: ► To develop effective vaccine, we examined the effects of CO 3 Ap as an antigen carrier. ► OVA contained in CO 3 Ap was taken up by BMDCs more effectively than free OVA. ► OVA-immunized splenocytes was activated by OVA contained in CO 3 Ap effectively. ► OVA contained in CO 3 Ap induced strong OVA-specific immune responses to C57BL/6 mice. ► CO 3 Ap is promising antigen carrier for the achievement of effective vaccine. -- Abstract: The ability of carbonate apatite (CO 3 Ap) to enhance antigen-specific immunity was examined in vitro and in vivo to investigate its utility as a vaccine carrier. Murine bone marrow-derived dendritic cells took up ovalbumin (OVA) containing CO 3 Ap more effectively than free OVA. Interestingly, mice immunized with OVA-containing CO 3 Ap produced OVA-specific antibodies more effectively than mice immunized with free OVA. Furthermore, immunization of C57BL/6 mice with OVA-containing CO 3 Ap induced the proliferation and antigen-specific production of IFN-γ by splenocytes more strongly than immunization with free OVA. Moreover, no significant differences were detected in the induction of delayed-type hypersensitivity responses, an immune reaction involving an antigen-specific, cell-mediated immune response between OVA-containing CO 3 Ap and OVA-containing alumina salt (Alum), suggesting that CO 3 Ap induced cell-mediated immune response to the same degree as Alum, which is commonly used for clinical applications. This study is the first to demonstrate the induction of antigen-specific immune responses in vivo by CO 3 Ap.

Mixtures of Strongly Interacting Bosons in Optical Lattices

International Nuclear Information System (INIS)

Buonsante, P.; Penna, V.; Giampaolo, S. M.; Illuminati, F.; Vezzani, A.

2008-01-01

We investigate the properties of strongly interacting heteronuclear boson-boson mixtures loaded in realistic optical lattices, with particular emphasis on the physics of interfaces. In particular, we numerically reproduce the recent experimental observation that the addition of a small fraction of 41 K induces a significant loss of coherence in 87 Rb, providing a simple explanation. We then investigate the robustness against the inhomogeneity typical of realistic experimental realizations of the glassy quantum emulsions recently predicted to occur in strongly interacting boson-boson mixtures on ideal homogeneous lattices

Strongly correlated photons generated by coupling a three- or four-level system to a waveguide

Science.gov (United States)

Zheng, Huaixiu; Gauthier, Daniel J.; Baranger, Harold U.

2012-04-01

We study the generation of strongly correlated photons by coupling an atom to photonic quantum fields in a one-dimensional waveguide. Specifically, we consider a three-level or four-level system for the atom. Photon-photon bound states emerge as a manifestation of the strong photon-photon correlation mediated by the atom. Effective repulsive or attractive interaction between photons can be produced, causing either suppressed multiphoton transmission (photon blockade) or enhanced multiphoton transmission (photon-induced tunneling). As a result, nonclassical light sources can be generated on demand by sending coherent states into the proposed system. We calculate the second-order correlation function of the transmitted field and observe bunching and antibunching caused by the bound states. Furthermore, we demonstrate that the proposed system can produce photon pairs with a high degree of spectral entanglement, which have a large capacity for carrying information and are important for large-alphabet quantum communication.

Electrophoresis in strong electric fields.

Science.gov (United States)

Barany, Sandor

2009-01-01

Two kinds of non-linear electrophoresis (ef) that can be detected in strong electric fields (several hundred V/cm) are considered. The first ("classical" non-linear ef) is due to the interaction of the outer field with field-induced ionic charges in the electric double layer (EDL) under conditions, when field-induced variations of electrolyte concentration remain to be small comparatively to its equilibrium value. According to the Shilov theory, the non-linear component of the electrophoretic velocity for dielectric particles is proportional to the cubic power of the applied field strength (cubic electrophoresis) and to the second power of the particles radius; it is independent of the zeta-potential but is determined by the surface conductivity of particles. The second one, the so-called "superfast electrophoresis" is connected with the interaction of a strong outer field with a secondary diffuse layer of counterions (space charge) that is induced outside the primary (classical) diffuse EDL by the external field itself because of concentration polarization. The Dukhin-Mishchuk theory of "superfast electrophoresis" predicts quadratic dependence of the electrophoretic velocity of unipolar (ionically or electronically) conducting particles on the external field gradient and linear dependence on the particle's size in strong electric fields. These are in sharp contrast to the laws of classical electrophoresis (no dependence of V(ef) on the particle's size and linear dependence on the electric field gradient). A new method to measure the ef velocity of particles in strong electric fields is developed that is based on separation of the effects of sedimentation and electrophoresis using videoimaging and a new flowcell and use of short electric pulses. To test the "classical" non-linear electrophoresis, we have measured the ef velocity of non-conducting polystyrene, aluminium-oxide and (semiconductor) graphite particles as well as Saccharomice cerevisiae yeast cells as a

Transgenic Expression of the piRNA-Resistant Masculinizer Gene Induces Female-Specific Lethality and Partial Female-to-Male Sex Reversal in the Silkworm, Bombyx mori.

Science.gov (United States)

Sakai, Hiroki; Sumitani, Megumi; Chikami, Yasuhiko; Yahata, Kensuke; Uchino, Keiro; Kiuchi, Takashi; Katsuma, Susumu; Aoki, Fugaku; Sezutsu, Hideki; Suzuki, Masataka G

2016-08-01

In Bombyx mori (B. mori), Fem piRNA originates from the W chromosome and is responsible for femaleness. The Fem piRNA-PIWI complex targets and cleaves mRNAs transcribed from the Masc gene. Masc encodes a novel CCCH type zinc-finger protein and is required for male-specific splicing of B. mori doublesex (Bmdsx) transcripts. In the present study, several silkworm strains carrying a transgene, which encodes a Fem piRNA-resistant Masc mRNA (Masc-R), were generated. Forced expression of the Masc-R transgene caused female-specific lethality during the larval stages. One of the Masc-R strains weakly expressed Masc-R in various tissues. Females heterozygous for the transgene expressed male-specific isoform of the Bombyx homolog of insulin-like growth factor II mRNA-binding protein (ImpM) and Bmdsx. All examined females showed a lower inducibility of vitellogenin synthesis and exhibited abnormalities in the ovaries. Testis-like tissues were observed in abnormal ovaries and, notably, the tissues contained considerable numbers of sperm bundles. Homozygous expression of the transgene resulted in formation of the male-specific abdominal segment in adult females and caused partial male differentiation in female genitalia. These results strongly suggest that Masc is an important regulatory gene of maleness in B. mori.

Carnauba wax nanoparticles enhance strong systemic and mucosal cellular and humoral immune responses to HIV-gp140 antigen.

Science.gov (United States)

Arias, Mauricio A; Loxley, Andrew; Eatmon, Christy; Van Roey, Griet; Fairhurst, David; Mitchnick, Mark; Dash, Philip; Cole, Tom; Wegmann, Frank; Sattentau, Quentin; Shattock, Robin

2011-02-01

Induction of humoral responses to HIV at mucosal compartments without inflammation is important for vaccine design. We developed charged wax nanoparticles that efficiently adsorb protein antigens and are internalized by DC in the absence of inflammation. HIV-gp140-adsorbed nanoparticles induced stronger in vitro T-cell proliferation responses than antigen alone. Such responses were greatly enhanced when antigen was co-adsorbed with TLR ligands. Immunogenicity studies in mice showed that intradermal vaccination with HIV-gp140 antigen-adsorbed nanoparticles induced high levels of specific IgG. Importantly, intranasal immunization with HIV-gp140-adsorbed nanoparticles greatly enhanced serum and vaginal IgG and IgA responses. Our results show that HIV-gp140-carrying wax nanoparticles can induce strong cellular/humoral immune responses without inflammation and may be of potential use as effective mucosal adjuvants for HIV vaccine candidates. Copyright © 2010 Elsevier Ltd. All rights reserved.

Patient-specific cardiovascular progenitor cells derived from integration-free induced pluripotent stem cells for vascular tissue regeneration.

Science.gov (United States)

Hu, Jiang; Wang, Yongyu; Jiao, Jiao; Liu, Zhongning; Zhao, Chao; Zhou, Zhou; Zhang, Zhanpeng; Forde, Kaitlynn; Wang, Lunchang; Wang, Jiangang; Baylink, David J; Zhang, Xiao-Bing; Gao, Shaorong; Yang, Bo; Chen, Y Eugene; Ma, Peter X

2015-12-01

Tissue-engineered blood vessels (TEBVs) are promising in regenerating a live vascular replacement. However, the vascular cell source is limited, and it is crucial to develop a scaffold that accommodates new type of vascular progenitor cells and facilitates in vivo lineage specification of the cells into functional vascular smooth muscle cells (VSMCs) to regenerate vascular tissue. In the present study, integration-free human induced pluripotent stem cells (hiPSCs) were established from patient peripheral blood mononuclear cells through episomal vector nucleofection of reprogramming factors. The established hiPSCs were then induced into mesoderm-originated cardiovascular progenitor cells (CVPCs) with a highly efficient directed lineage specification method. The derived CVPCs were demonstrated to be able to differentiate into functional VSMCs. Subcutaneous implantation of CVPCs seeded on macroporous nanofibrous poly(l-lactide) scaffolds led to in vivo VSMC lineage specification and matrix deposition inside the scaffolds. In summary, we established integration-free patient-specific hiPSCs from peripheral blood mononuclear cells, derived CVPCs through directed lineage specification, and developed an advanced scaffold for these progenitor cells to further differentiate in vivo into VSMCs and regenerate vascular tissue in a subcutaneous implantation model. This study has established an efficient patient-specific approach towards in vivo regeneration of vascular tissue. Copyright © 2015 Elsevier Ltd. All rights reserved.

Comment on “Drug Screening for ALS Using Patient-Specific Induced Pluripotent Stem Cells”

Science.gov (United States)

Bilican, Bilada; Serio, Andrea; Barmada, Sami J.; Nishimura, Agnes Lumi; Sullivan, Gareth J.; Carrasco, Monica; Phatnani, Hemali P.; Puddifoot, Clare A.; Story, David; Fletcher, Judy; Park, In-Hyun; Friedman, Brad A.; Daley, George Q.; Wyllie, David J. A.; Hardingham, Giles E.; Wilmut, Ian; Finkbeiner, Steven; Maniatis, Tom; Shaw, Christopher E.; Chandran, Siddharthan

2014-01-01

Egawa et al. recently showed the value of patient-specific induced pluripotent stem cells (iPSCs) for modeling amyotrophic lateral sclerosis in vitro. Their study and our work highlight the need for complementary assays to detect small, but potentially important, phenotypic differences between control iPSC lines and those carrying disease mutations. PMID:23740897

Histone deacetylase inhibitors strongly sensitise neuroblastoma cells to TRAIL-induced apoptosis by a caspases-dependent increase of the pro- to anti-apoptotic proteins ratio

International Nuclear Information System (INIS)

Mühlethaler-Mottet, Annick; Flahaut, Marjorie; Bourloud, Katia Balmas; Auderset, Katya; Meier, Roland; Joseph, Jean-Marc; Gross, Nicole

2006-01-01

Neuroblastoma (NB) is the second most common solid childhood tumour, an aggressive disease for which new therapeutic strategies are strongly needed. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in most tumour cells, but not in normal tissues and therefore represents a valuable candidate in apoptosis-inducing therapies. Caspase-8 is silenced in a subset of highly malignant NB cells, which results in full TRAIL resistance. In addition, despite constitutive caspase-8 expression, or its possible restoration by different strategies, NB cells remain weakly sensitive to TRAIL indicating a need to develop strategies to sensitise NB cells to TRAIL. Histone deacetylase inhibitors (HDACIs) are a new class of anti-cancer agent inducing apoptosis or cell cycle arrest in tumour cells with very low toxicity toward normal cells. Although HDACIs were recently shown to increase death induced by TRAIL in weakly TRAIL-sensitive tumour cells, the precise involved sensitisation mechanisms have not been fully identified. NB cell lines were treated with various doses of HDACIs and TRAIL, then cytotoxicity was analysed by MTS/PMS proliferation assays, apoptosis was measured by the Propidium staining method, caspases activity by colorimetric protease assays, and (in)activation of apoptotic proteins by immunoblotting. Sub-toxic doses of HDACIs strongly sensitised caspase-8 positive NB cell lines to TRAIL induced apoptosis in a caspases dependent manner. Combined treatments increased the activation of caspases and Bid, and the inactivation of the anti-apoptotic proteins XIAP, Bcl-x, RIP, and survivin, thereby increasing the pro- to anti-apoptotic protein ratio. It also enhanced the activation of the mitochondrial pathway. Interestingly, the kinetics of caspases activation and inactivation of anti-apoptotic proteins is accelerated by combined treatment with TRAIL and HDACIs compared to TRAIL alone. In contrast, cell surface expression of TRAIL

[Mutants of the yeast Saccharomyces cerevisiae characterized by enhanced induced mutagenesis. III. Effect of the him mutation on the effectiveness and specificity of UF-induced mutagenesis].

Science.gov (United States)

Ivanov, E L; Koval'tsova, S V; Korolev, V G

1987-09-01

We have studied the influence of him1-1, him2-1, him3-1 and himX mutations on induction frequency and specificity of UV-induced adenine-dependent mutations in the yeast Saccharomyces cerevisiae. Him mutations do not render haploid cells more sensitive to the lethal action of UV-light; however, in him strains adenine-dependent mutations (ade1, ade2) were induced more frequently (1.5--2-fold), as compared to the HIM strain. An analysis of the molecular nature of ade2 mutants revealed that him1-1, him2-1 and himX mutations increase specifically the yield of transitions (AT----GC and GC----AT), whereas in the him3-1 strain the yield of transversions was enhanced as well. We suggest him mutations analysed to affect specific repair pathway for mismatch correction.

Interferon-β gene transfer induces a strong cytotoxic bystander effect on melanoma cells.

Science.gov (United States)

Rossi, Úrsula A; Gil-Cardeza, María L; Villaverde, Marcela S; Finocchiaro, Liliana M E; Glikin, Gerardo C

2015-05-01

A local gene therapy scheme for the delivery of type I interferons could be an alternative for the treatment of melanoma. We evaluated the cytotoxic effects of interferon-β (IFNβ) gene lipofection on tumor cell lines derived from three human cutaneous and four canine mucosal melanomas. The cytotoxicity of human IFNβ gene lipofection resulted higher or equivalent to that of the corresponding addition of the recombinant protein (rhIFNβ) to human cells. IFNβ gene lipofection was not cytotoxic for only one canine melanoma cell line. When cultured as monolayers, three human and three canine IFNβ-lipofected melanoma cell lines displayed a remarkable bystander effect. As spheroids, the same six cell lines were sensitive to IFNβ gene transfer, two displaying a significant multicell resistance phenotype. The effects of conditioned IFNβ-lipofected canine melanoma cell culture media suggested the release of at least one soluble thermolabile cytotoxic factor that could not be detected in human melanoma cells. By using a secretion signal-free truncated human IFNβ, we showed that its intracellular expression was enough to induce cytotoxicity in two human melanoma cell lines. The lower cytoplasmatic levels of reactive oxygen species detected after intracellular IFNβ expression could be related to the resistance displayed by one human melanoma cell line. As IFNβ gene transfer was effective against most of the assayed melanomas in a way not limited by relatively low lipofection efficiencies, the clinical potential of this approach is strongly supported. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Generation of an inducible colon-specific Cre enzyme mouse line for colon cancer research.

Science.gov (United States)

Tetteh, Paul W; Kretzschmar, Kai; Begthel, Harry; van den Born, Maaike; Korving, Jeroen; Morsink, Folkert; Farin, Henner; van Es, Johan H; Offerhaus, G Johan A; Clevers, Hans

2016-10-18

Current mouse models for colorectal cancer often differ significantly from human colon cancer, being largely restricted to the small intestine. Here, we aim to develop a colon-specific inducible mouse model that can faithfully recapitulate human colon cancer initiation and progression. Carbonic anhydrase I (Car1) is a gene expressed uniquely in colonic epithelial cells. We generated a colon-specific inducible Car1 CreER knock-in (KI) mouse with broad Cre activity in epithelial cells of the proximal colon and cecum. Deletion of the tumor suppressor gene Apc using the Car1 CreER KI caused tumor formation in the cecum but did not yield adenomas in the proximal colon. Mutation of both Apc and Kras yielded microadenomas in both the cecum and the proximal colon, which progressed to macroadenomas with significant morbidity. Aggressive carcinomas with some invasion into lymph nodes developed upon combined induction of oncogenic mutations of Apc, Kras, p53, and Smad4 Importantly, no adenomas were observed in the small intestine. Additionally, we observed tumors from differentiated Car1-expressing cells with Apc/Kras mutations, suggesting that a top-down model of intestinal tumorigenesis can occur with multiple mutations. Our results establish the Car1 CreER KI as a valuable mouse model to study colon-specific tumorigenesis and metastasis as well as cancer-cell-of-origin questions.

Cardiovascular Disease Modeling Using Patient-Specific Induced Pluripotent Stem Cells

Directory of Open Access Journals (Sweden)

Atsushi Tanaka

2015-08-01

Full Text Available The generation of induced pluripotent stem cells (iPSCs has opened up a new scientific frontier in medicine. This technology has made it possible to obtain pluripotent stem cells from individuals with genetic disorders. Because iPSCs carry the identical genetic anomalies related to those disorders, iPSCs are an ideal platform for medical research. The pathophysiological cellular phenotypes of genetically heritable heart diseases such as arrhythmias and cardiomyopathies, have been modeled on cell culture dishes using disease-specific iPSC-derived cardiomyocytes. These model systems can potentially provide new insights into disease mechanisms and drug discoveries. This review focuses on recent progress in cardiovascular disease modeling using iPSCs, and discusses problems and future perspectives concerning their use.

A BAC-based transgenic mouse specifically expresses an inducible Cre in the urothelium.

Directory of Open Access Journals (Sweden)

Tian Huai Shen

Full Text Available Cre-loxp mediated conditional knockout strategy has played critical roles for revealing functions of many genes essential for development, as well as the causal relationships between gene mutations and diseases in the postnatal adult mice. One key factor of this strategy is the availability of mice with tissue- or cell type-specific Cre expression. However, the success of the traditional molecular cloning approach to generate mice with tissue specific Cre expression often depends on luck. Here we provide a better alternative by using bacterial artificial chromosome (BAC-based recombineering to insert iCreERT2 cDNA at the ATG start of the Upk2 gene. The BAC-based transgenic mice express the inducible Cre specifically in the urothelium as demonstrated by mRNA expression and staining for LacZ expression after crossing with a Rosa26 reporter mouse. Taking into consideration the size of the gene of interest and neighboring genes included in a BAC, this method should be widely applicable for generation of mice with tissue specific gene expression or deletions in a more specific manner than previously reported.

Ubiquitin-dependent system controls radiation induced apoptosis

International Nuclear Information System (INIS)

Delic, J.; Magdelenat, H.; Glaisner, S.; Magdelenat, H.; Maciorowski, Z.

1997-01-01

The selective proteolytic pathway, dependent upon 'N-end rule' protein recognition/ubiquitination and on the subsequent proteasome dependent processing of ubiquitin conjugates, operates in apoptosis induced by γ-irradiation. The proteasome inhibitor peptide aldehyde, MG132, efficiently induced apoptosis and was also able (at doses lower than those required for apoptosis induction) to potentiate apoptosis induced by DNA damage. Its specificity is suggested by the induction of the ubiquitin (UbB and UbC) and E1 (ubiquitin activating enzyme) genes and by an altered ubiquitination pattern. More selectively, a di-peptide competitor of the 'N-end rule' of ubiquitin dependent protein processing inhibited radiation induced apoptosis. This inhibition is also followed by an altered ubiquitination pattern and by activation of Poly (ADP-ribose) polymerase (PARP). These data strongly suggest that early apoptosis radiation induced events are controlled by ubiquitin-dependent proteolytic processing. (author)

Angular-momentum-assisted dissociation of CO in strong optical fields

Science.gov (United States)

Mullin, Amy; Ogden, Hannah; Murray, Matthew; Liu, Qingnan; Toro, Carlos

2017-04-01

Filaments are produced in CO gas by intense, chirped laser pulses. Visible emission from C2 is observed as a result of chemical reactions of highly excited CO. At laser intensities greater than 1014 W cm-2, the C2 emission shows a strong dependence on laser polarization. Oppositely chirped pulses of light with ω0 = 800 nm are recombined spatially and temporally to generate angularly accelerating electric fields (up to 30 THz) that either have an instantaneous linear polarization or act as a dynamic polarization grating that oscillates among linear and circular polarizations. The angularly accelerating linear polarization corresponds to an optical centrifuge that concurrently drives molecules into high rotational states (with J 50) and induces strong-field dissociation. Higher order excitation is observed for the time-varying laser polarization configuration that does not induce rotational excitation. The results indicate that the presence of rotational angular momentum lowers the threshold for CO dissociation in strong optical fields by coupling nuclear and electronic degrees of freedom. Support from NSF CHE-1058721 and the University of Maryland.

Dendritic cells exposed to MVA-based HIV-1 vaccine induce highly functional HIV-1-specific CD8(+ T cell responses in HIV-1-infected individuals.

Directory of Open Access Journals (Sweden)

Núria Climent

Full Text Available Currently, MVA virus vectors carrying HIV-1 genes are being developed as HIV-1/AIDS prophylactic/therapeutic vaccines. Nevertheless, little is known about the impact of these vectors on human dendritic cells (DC and their capacity to present HIV-1 antigens to human HIV-specific T cells. This study aimed to characterize the interaction of MVA and MVA expressing the HIV-1 genes Env-Gag-Pol-Nef of clade B (referred to as MVA-B in human monocyte-derived dendritic cells (MDDC and the subsequent processes of HIV-1 antigen presentation and activation of memory HIV-1-specific T lymphocytes. For these purposes, we performed ex vivo assays with MDDC and autologous lymphocytes from asymptomatic HIV-infected patients. Infection of MDDC with MVA-B or MVA, at the optimal dose of 0.3 PFU/MDDC, induced by itself a moderate degree of maturation of MDDC, involving secretion of cytokines and chemokines (IL1-ra, IL-7, TNF-α, IL-6, IL-12, IL-15, IL-8, MCP-1, MIP-1α, MIP-1β, RANTES, IP-10, MIG, and IFN-α. MDDC infected with MVA or MVA-B and following a period of 48 h or 72 h of maturation were able to migrate toward CCL19 or CCL21 chemokine gradients. MVA-B infection induced apoptosis of the infected cells and the resulting apoptotic bodies were engulfed by the uninfected MDDC, which cross-presented HIV-1 antigens to autologous CD8(+ T lymphocytes. MVA-B-infected MDDC co-cultured with autologous T lymphocytes induced a highly functional HIV-specific CD8(+ T cell response including proliferation, secretion of IFN-γ, IL-2, TNF-α, MIP-1β, MIP-1α, RANTES and IL-6, and strong cytotoxic activity against autologous HIV-1-infected CD4(+ T lymphocytes. These results evidence the adjuvant role of the vector itself (MVA and support the clinical development of prophylactic and therapeutic anti-HIV vaccines based on MVA-B.

Sex-specific metabolic interactions between liver and adipose tissue in MCD diet-induced non-alcoholic fatty liver disease.

Science.gov (United States)

Lee, Yun-Hee; Kim, Sou Hyun; Kim, Sang-Nam; Kwon, Hyun-Jung; Kim, Jeong-Dong; Oh, Ji Youn; Jung, Young-Suk

2016-07-26

Higher susceptibility to metabolic disease in male exemplifies the importance of sexual dimorphism in pathogenesis. We hypothesized that the higher incidence of non-alcoholic fatty liver disease in males involves sex-specific metabolic interactions between liver and adipose tissue. In the present study, we used a methionine-choline deficient (MCD) diet-induced fatty liver mouse model to investigate sex differences in the metabolic response of the liver and adipose tissue. After 2 weeks on an MCD-diet, fatty liver was induced in a sex-specific manner, affecting male mice more severely than females. The MCD-diet increased lipolytic enzymes in the gonadal white adipose tissue (gWAT) of male mice, whereas it increased expression of uncoupling protein 1 and other brown adipocyte markers in the gWAT of female mice. Moreover, gWAT from female mice demonstrated higher levels of oxygen consumption and mitochondrial content compared to gWAT from male mice. FGF21 expression was increased in liver tissue by the MCD diet, and the degree of upregulation was significantly higher in the livers of female mice. The endocrine effect of FGF21 was responsible, in part, for the sex-specific browning of gonadal white adipose tissue. Collectively, these data demonstrated that distinctively female-specific browning of white adipose tissue aids in protecting female mice against MCD diet-induced fatty liver disease.

Fusarium oxysporum Triggers Tissue-Specific Transcriptional Reprogramming in Arabidopsis thaliana

Science.gov (United States)

Lyons, Rebecca; Stiller, Jiri; Powell, Jonathan; Rusu, Anca; Manners, John M.; Kazan, Kemal

2015-01-01

Some of the most devastating agricultural diseases are caused by root-infecting pathogens, yet the majority of studies on these interactions to date have focused on the host responses of aerial tissues rather than those belowground. Fusarium oxysporum is a root-infecting pathogen that causes wilt disease on several plant species including Arabidopsis thaliana. To investigate and compare transcriptional changes triggered by F. oxysporum in different Arabidopsis tissues, we infected soil-grown plants with F. oxysporum and subjected root and leaf tissue harvested at early and late timepoints to RNA-seq analyses. At least half of the genes induced or repressed by F. oxysporum showed tissue-specific regulation. Regulators of auxin and ABA signalling, mannose binding lectins and peroxidases showed strong differential expression in root tissue. We demonstrate that ARF2 and PRX33, two genes regulated in the roots, promote susceptibility to F. oxysporum. In the leaves, defensins and genes associated with the response to auxin, cold and senescence were strongly regulated while jasmonate biosynthesis and signalling genes were induced throughout the plant. PMID:25849296

Fusarium oxysporum triggers tissue-specific transcriptional reprogramming in Arabidopsis thaliana.

Directory of Open Access Journals (Sweden)

Rebecca Lyons

Full Text Available Some of the most devastating agricultural diseases are caused by root-infecting pathogens, yet the majority of studies on these interactions to date have focused on the host responses of aerial tissues rather than those belowground. Fusarium oxysporum is a root-infecting pathogen that causes wilt disease on several plant species including Arabidopsis thaliana. To investigate and compare transcriptional changes triggered by F. oxysporum in different Arabidopsis tissues, we infected soil-grown plants with F. oxysporum and subjected root and leaf tissue harvested at early and late timepoints to RNA-seq analyses. At least half of the genes induced or repressed by F. oxysporum showed tissue-specific regulation. Regulators of auxin and ABA signalling, mannose binding lectins and peroxidases showed strong differential expression in root tissue. We demonstrate that ARF2 and PRX33, two genes regulated in the roots, promote susceptibility to F. oxysporum. In the leaves, defensins and genes associated with the response to auxin, cold and senescence were strongly regulated while jasmonate biosynthesis and signalling genes were induced throughout the plant.

ALKBH7 drives a tissue and sex-specific necrotic cell death response following alkylation-induced damage

Science.gov (United States)

Jordan, Jennifer J; Chhim, Sophea; Margulies, Carrie M; Allocca, Mariacarmela; Bronson, Roderick T; Klungland, Arne; Samson, Leona D; Fu, Dragony

2017-01-01

Regulated necrosis has emerged as a major cell death mechanism in response to different forms of physiological and pharmacological stress. The AlkB homolog 7 (ALKBH7) protein is required for regulated cellular necrosis in response to chemotherapeutic alkylating agents but its role within a whole organism is unknown. Here, we show that ALKBH7 modulates alkylation-induced cellular death through a tissue and sex-specific mechanism. At the whole-animal level, we find that ALKBH7 deficiency confers increased resistance to MMS-induced toxicity in male but not female mice. Moreover, ALKBH7-deficient mice exhibit protection against alkylation-mediated cytotoxicity in retinal photoreceptor and cerebellar granule cells, two cell types that undergo necrotic death through the initiation of the base excision repair pathway and hyperactivation of the PARP1/ARTD1 enzyme. Notably, the protection against alkylation-induced cerebellar degeneration is specific to ALKBH7-deficient male but not female mice. Our results uncover an in vivo role for ALKBH7 in mediating a sexually dimorphic tissue response to alkylation damage that could influence individual responses to chemotherapies based upon alkylating agents. PMID:28726787

Mode Specific Electronic Friction in Dissociative Chemisorption on Metal Surfaces: H2 on Ag(111)

Science.gov (United States)

Maurer, Reinhard J.; Jiang, Bin; Guo, Hua; Tully, John C.

2017-06-01

Electronic friction and the ensuing nonadiabatic energy loss play an important role in chemical reaction dynamics at metal surfaces. Using molecular dynamics with electronic friction evaluated on the fly from density functional theory, we find strong mode dependence and a dominance of nonadiabatic energy loss along the bond stretch coordinate for scattering and dissociative chemisorption of H2 on the Ag(111) surface. Exemplary trajectories with varying initial conditions indicate that this mode specificity translates into modulated energy loss during a dissociative chemisorption event. Despite minor nonadiabatic energy loss of about 5%, the directionality of friction forces induces dynamical steering that affects individual reaction outcomes, specifically for low-incidence energies and vibrationally excited molecules. Mode-specific friction induces enhanced loss of rovibrational rather than translational energy and will be most visible in its effect on final energy distributions in molecular scattering experiments.

Induced photoassociation in the field of a strong electomagnetic wave

International Nuclear Information System (INIS)

Zaretskij, D.F.; Lomonosov, V.V.; Lyul'ka, V.A.

1979-01-01

The quantum-mechanical problem of the stimulated transition of a system in the field of a strong electromagnetic wave from the continuous spectrum to a bound state possessing a finite lifetime is considered. The expressions obtained are employed to calculate stimulated production of mesic atoms and mesic molecules (ddμ). It is demonstrated that in an external electromagnetic field the probability for production of this type may considerably increase

Experiments on plasma turbulence induced by strong, steady electric fields

International Nuclear Information System (INIS)

Hamberger, S.M.

1975-01-01

The author discusses the effect of applying a strong electric field to collisionless plasma. In particular are compared what some ideas and prejudices lead one to expect to happen, what computer simulation experiments tell one ought to happen, and what actually does happen in two laboratory experiments which have been designed to allow the relevant instability and turbulent processes to occur unobstructed and which have been studied in sufficient detail. (Auth.)

Confinining properties of QCD in strong magnetic backgrounds

Directory of Open Access Journals (Sweden)

Bonati Claudio

2017-01-01

Full Text Available Strong magnetic backgrounds are known to modify QCD properties at a nonperturbative level. We discuss recent lattice results, obtained for Nf = 2 + 1 QCD with physical quark masses, concerning in particular the modifications and the anisotropies induced at the level of the static quark-antiquark potential, both at zero and finite temperature.

Strong coupling electroweak symmetry breaking

Energy Technology Data Exchange (ETDEWEB)

Barklow, T.L. [Stanford Linear Accelerator Center, Menlo Park, CA (United States); Burdman, G. [Univ. of Wisconsin, Madison, WI (United States). Dept. of Physics; Chivukula, R.S. [Boston Univ., MA (United States). Dept. of Physics

1997-04-01

The authors review models of electroweak symmetry breaking due to new strong interactions at the TeV energy scale and discuss the prospects for their experimental tests. They emphasize the direct observation of the new interactions through high-energy scattering of vector bosons. They also discuss indirect probes of the new interactions and exotic particles predicted by specific theoretical models.

Strong coupling electroweak symmetry breaking

International Nuclear Information System (INIS)

Barklow, T.L.; Burdman, G.; Chivukula, R.S.

1997-04-01

The authors review models of electroweak symmetry breaking due to new strong interactions at the TeV energy scale and discuss the prospects for their experimental tests. They emphasize the direct observation of the new interactions through high-energy scattering of vector bosons. They also discuss indirect probes of the new interactions and exotic particles predicted by specific theoretical models

Semiallogenic fusions of MSI+ tumor cells and activated B cells induce MSI-specific T cell responses

International Nuclear Information System (INIS)

Garbe, Yvette; Klier, Ulrike; Linnebacher, Michael

2011-01-01

Various strategies have been developed to transfer tumor-specific antigens into antigen presenting cells in order to induce cytotoxic T cell responses against tumor cells. One approach uses cellular vaccines based on fusions of autologous antigen presenting cells and allogeneic tumor cells. The fusion cells combine antigenicity of the tumor cell with optimal immunostimulatory capacity of the antigen presenting cells. Microsatellite instability caused by mutational inactivation of DNA mismatch repair genes results in translational frameshifts when affecting coding regions. It has been shown by us and others that these mutant proteins lead to the presentation of immunogenic frameshift peptides that are - in principle - recognized by a multiplicity of effector T cells. We chose microsatellite instability-induced frameshift antigens as ideal to test for induction of tumor specific T cell responses by semiallogenic fusions of microsatellite instable carcinoma cells with CD40-activated B cells. Two fusion clones of HCT116 with activated B cells were selected for stimulation of T cells autologous to the B cell fusion partner. Outgrowing T cells were phenotyped and tested in functional assays. The fusion clones expressed frameshift antigens as well as high amounts of MHC and costimulatory molecules. Autologous T cells stimulated with these fusions were predominantly CD4 + , activated, and reacted specifically against the fusion clones and also against the tumor cell fusion partner. Interestingly, a response toward 6 frameshift-derived peptides (of 14 tested) could be observed. Cellular fusions of MSI + carcinoma cells and activated B cells combine the antigen-presenting capacity of the B cell with the antigenic repertoire of the carcinoma cell. They present frameshift-derived peptides and can induce specific and fully functional T cells recognizing not only fusion cells but also the carcinoma cells. These hybrid cells may have great potential for cellular immunotherapy and

Nucleic acid-induced antiviral immunity in invertebrates: an evolutionary perspective.

Science.gov (United States)

Wang, Pei-Hui; Weng, Shao-Ping; He, Jian-Guo

2015-02-01

Nucleic acids derived from viral pathogens are typical pathogen associated molecular patterns (PAMPs). In mammals, the recognition of viral nucleic acids by pattern recognition receptors (PRRs), which include Toll-like receptors (TLRs) and retinoic acid-inducible gene (RIG)-I-like receptors (RLRs), induces the release of inflammatory cytokines and type I interferons (IFNs) through the activation of nuclear factor κB (NF-κB) and interferon regulatory factor (IRF) 3/7 pathways, triggering the host antiviral state. However, whether nucleic acids can induce similar antiviral immunity in invertebrates remains ambiguous. Several studies have reported that nucleic acid mimics, especially dsRNA mimic poly(I:C), can strongly induce non-specific antiviral immune responses in insects, shrimp, and oyster. This behavior shows multiple similarities to the hallmarks of mammalian IFN responses. In this review, we highlight the current understanding of nucleic acid-induced antiviral immunity in invertebrates. We also discuss the potential recognition and regulatory mechanisms that confer non-specific antiviral immunity on invertebrate hosts. Copyright © 2014 Elsevier Ltd. All rights reserved.

Activation of Kupffer Cells Is Associated with a Specific Dysbiosis Induced by Fructose or High Fat Diet in Mice.

Directory of Open Access Journals (Sweden)

Gladys Ferrere

Full Text Available The increase consumption of fructose in diet is associated with liver inflammation. As a specific fructan substrate, fructose may modify the gut microbiota which is involved in obesity-induced liver disease. Here, we aimed to assess whether fructose-induced liver damage was associated with a specific dysbiosis, especially in mice fed a high fat diet (HFD. To this end, four groups of mice were fed with normal and HFD added or not with fructose. Body weight and glucose sensitivity, liver inflammation, dysbiosis and the phenotype of Kupffer cells were determined after 16 weeks of diet. Food intake was increased in the two groups of mice fed with the HFD. Mice fed with HFD and fructose showed a higher infiltration of lymphocytes into the liver and a lower inflammatory profile of Kupffer cells than mice fed with the HFD without fructose. The dysbiosis associated with diets showed that fructose specifically prevented the decrease of Mouse intestinal bacteria in HFD fed mice and increased Erysipelotrichi in mice fed with fructose, independently of the amount of fat. In conclusion, fructose, used as a sweetener, induced a dysbiosis which is different in presence of fat in the diet. Consequently, the activation of Kupffer cells involved in mice model of HFD-induced liver inflammation was not observed in an HFD/fructose combined diet. These data highlight that the complexity of diet composition could highly impact the development of liver lesions during obesity. Specific dysbiosis associated with the diet could explain that the progressions of liver damage are different.

Development of inducer-free expression plasmids based on IPTG-inducible promoters for Bacillus subtilis.

Science.gov (United States)

Tran, Dinh Thi Minh; Phan, Trang Thi Phuong; Huynh, Thanh Kieu; Dang, Ngan Thi Kim; Huynh, Phuong Thi Kim; Nguyen, Tri Minh; Truong, Tuom Thi Tinh; Tran, Thuoc Linh; Schumann, Wolfgang; Nguyen, Hoang Duc

2017-07-25

the inducible vector using the same promoter. Finally, we used gfp as a reporter gene in combination with the two promoters Pgrac01 and Pgrac100 to test the new vector types. The GFP expression levels could be repressed at least 1.5 times for the Pgrac01-gfp+ inducer-free construct in E. coli. The inducer-free constructs Pgrac01-gfp+ and Pgrac100-gfp+ allowed GFP expression at high levels from 23 × 10 4 to 32 × 10 4 RFU units and 9-13% of total intracellular proteins. We could reconfirm the two major advantages of the new inducer-free expression plasmids: (1) Strong repression of the target gene expression in the E. coli cloning strain, and (2) production of the target protein at high levels in B. subtilis in the absence of the inducer. We propose a general strategy to generate inducer-free expression vector by using IPTG-inducible vectors, and more specifically we developed inducer-free expression plasmids using IPTG-inducible promoters in the absence of the LacI repressor. These plasmids could be an excellent choice for high-level production of recombinant proteins in B. subtilis without the addition of inducer and at the same time maintaining a low basal level of the recombinant proteins in E. coli. The repression of the recombinant gene expression would facilitate cloning of genes that potentially inhibit the growth of E. coli cloning strains. The inducer-free expression plasmids will be extended versions of the current available IPTG-inducible expression vectors for B. subtilis, in which all these vectors use the same cognate promoters. These inducer-free and previously developed IPTG-inducible expression plasmids will be a useful cassette to study gene expression at a small scale up to a larger scale up for the production of recombinant proteins.

Precisely Molded Nanoparticle Displaying DENV-E Proteins Induces Robust Serotype-Specific Neutralizing Antibody Responses.

Directory of Open Access Journals (Sweden)

Stefan W Metz

2016-10-01

Full Text Available Dengue virus (DENV is the causative agent of dengue fever and dengue hemorrhagic fever. The virus is endemic in over 120 countries, causing over 350 million infections per year. Dengue vaccine development is challenging because of the need to induce simultaneous protection against four antigenically distinct DENV serotypes and evidence that, under some conditions, vaccination can enhance disease due to specific immunity to the virus. While several live-attenuated tetravalent dengue virus vaccines display partial efficacy, it has been challenging to induce balanced protective immunity to all 4 serotypes. Instead of using whole-virus formulations, we are exploring the potentials for a particulate subunit vaccine, based on DENV E-protein displayed on nanoparticles that have been precisely molded using Particle Replication in Non-wetting Template (PRINT technology. Here we describe immunization studies with a DENV2-nanoparticle vaccine candidate. The ectodomain of DENV2-E protein was expressed as a secreted recombinant protein (sRecE, purified and adsorbed to poly (lactic-co-glycolic acid (PLGA nanoparticles of different sizes and shape. We show that PRINT nanoparticle adsorbed sRecE without any adjuvant induces higher IgG titers and a more potent DENV2-specific neutralizing antibody response compared to the soluble sRecE protein alone. Antigen trafficking indicate that PRINT nanoparticle display of sRecE prolongs the bio-availability of the antigen in the draining lymph nodes by creating an antigen depot. Our results demonstrate that PRINT nanoparticles are a promising platform for delivering subunit vaccines against flaviviruses such as dengue and Zika.

Commensal Bacteroides species induce colitis in host-genotype-specific fashion in a mouse model of inflammatory bowel disease.

Science.gov (United States)

Bloom, Seth M; Bijanki, Vinieth N; Nava, Gerardo M; Sun, Lulu; Malvin, Nicole P; Donermeyer, David L; Dunne, W Michael; Allen, Paul M; Stappenbeck, Thaddeus S

2011-05-19

The intestinal microbiota is important for induction of inflammatory bowel disease (IBD). IBD is associated with complex shifts in microbiota composition, but it is unclear whether specific bacterial subsets induce IBD and, if so, whether their proportions in the microbiota are altered during disease. Here, we fulfilled Koch's postulates in host-genotype-specific fashion using a mouse model of IBD with human-relevant disease-susceptibility mutations. From screening experiments we isolated common commensal Bacteroides species, introduced them into antibiotic-pretreated mice, and quantitatively reisolated them in culture. The bacteria colonized IBD-susceptible and -nonsusceptible mice equivalently, but induced disease exclusively in susceptible animals. Conversely, commensal Enterobacteriaceae were >100-fold enriched during spontaneous disease, but an Enterobacteriaceae isolate failed to induce disease in antibiotic-pretreated mice despite robust colonization. We thus demonstrate that IBD-associated microbiota alterations do not necessarily reflect underlying disease etiology. These findings establish important experimental criteria and a conceptual framework for understanding microbial contributions to IBD. Copyright © 2011 Elsevier Inc. All rights reserved.

Commensal Bacteroides species induce colitis in host-genotype-specific fashion in a mouse model of inflammatory bowel disease

Science.gov (United States)

Bloom, Seth M.; Bijanki, Vinieth N.; Nava, Gerardo M.; Sun, Lulu; Malvin, Nicole P.; Donermeyer, David L.; Dunne, W. Michael; Allen, Paul M.; Stappenbeck, Thaddeus S.

2011-01-01

SUMMARY The intestinal microbiota is important for induction of inflammatory bowel disease (IBD). IBD is associated with complex shifts in microbiota composition, but it is unclear whether specific bacterial subsets induce IBD and, if so, whether their proportions in the microbiota are altered during disease. Here we fulfilled Koch’s postulates in host-genotype-specific fashion using a mouse model of IBD with human-relevant disease-susceptibility mutations. From screening experiments we isolated common commensal Bacteroides species, introduced them into antibiotic-pretreated mice, and quantitatively re-isolated them in culture. The bacteria colonized IBD-susceptible and non-susceptible mice equivalently, but induced disease exclusively in susceptible animals. Conversely, commensal Enterobacteriaceae were >100-fold enriched during spontaneous disease but an Enterobacteriaceae isolate failed to induce disease in antibiotic-pretreated mice despite robust colonization. We thus demonstrate that IBD-associated microbiota alterations do not necessarily reflect underlying disease etiology. These findings establish important experimental criteria and a conceptual framework for understanding microbial contributions to IBD. PMID:21575910

Targeted delivery of TLR ligands to human and mouse dendritic cells strongly enhances adjuvanticity.

Science.gov (United States)

Tacken, Paul J; Zeelenberg, Ingrid S; Cruz, Luis J; van Hout-Kuijer, Maaike A; van de Glind, Gerline; Fokkink, Remco G; Lambeck, Annechien J A; Figdor, Carl G

2011-12-22

Effective vaccines consist of 2 components: immunodominant antigens and effective adjuvants. Whereas it has been demonstrated that targeted delivery of antigens to dendritic cells (DCs) improves vaccine efficacy, we report here that co-targeting of TLR ligands (TLRLs) to DCs strongly enhances adjuvanticity and immunity. We encapsulated ligands for intracellular TLRs within biodegradable nanoparticles coated with Abs recognizing DC-specific receptors. Targeted delivery of TLRLs to human DCs enhanced the maturation and production of immune stimulatory cytokines and the Ag-specific activation of naive CD8(+) T cells. In vivo studies demonstrated that nanoparticles carrying Ag induced cytotoxic T-lymphocyte responses at 100-fold lower adjuvant dose when TLRLs were co-encapsulated instead of administered in soluble form. Moreover, the efficacy of these targeted TLRLs reduced the serum cytokine storm and related toxicity that is associated with administration of soluble TLRLs. We conclude that the targeted delivery of adjuvants may improve the efficacy and safety of DC-based vaccines.

Subcycle dynamics of Coulomb asymmetry in strong elliptical laser fields.

Science.gov (United States)

Li, Min; Liu, Yunquan; Liu, Hong; Ning, Qicheng; Fu, Libin; Liu, Jie; Deng, Yongkai; Wu, Chengyin; Peng, Liang-You; Peng, Liangyou; Gong, Qihuang

2013-07-12

We measure photoelectron angular distributions of noble gases in intense elliptically polarized laser fields, which indicate strong structure-dependent Coulomb asymmetry. Using a dedicated semiclassical model, we have disentangled the contribution of direct ionization and multiple forward scattering on Coulomb asymmetry in elliptical laser fields. Our theory quantifies the roles of the ionic potential and initial transverse momentum on Coulomb asymmetry, proving that the small lobes of asymmetry are induced by direct ionization and the strong asymmetry is induced by multiple forward scattering in the ionic potential. Both processes are distorted by the Coulomb force acting on the electrons after tunneling. Lowering the ionization potential, the relative contribution of direct ionization on Coulomb asymmetry substantially decreases and Coulomb focusing on multiple rescattering is more important. We do not observe evident initial longitudinal momentum spread at the tunnel exit according to our simulation.

Efficient generation of lens progenitor cells from cataract patient-specific induced pluripotent stem cells.

Directory of Open Access Journals (Sweden)

Xiaodi Qiu

Full Text Available The development of a technique to induce the transformation of somatic cells to a pluripotent state via the ectopic expression of defined transcription factors was a transformational event in the field of regenerative medicine. The development of this technique also impacted ophthalmology, as patient-specific induced pluripotent stemcells (iPSCs may be useful resources for some ophthalmological diseases. The lens is a key refractive element in the eye that focuses images of the visual world onto the retina. To establish a new model for drug screening to treat lens diseases and investigating lens aging and development, we examined whether human lens epithelial cells (HLECs could be induced into iPSCs and if lens-specific differentiation of these cells could be achieved under defined chemical conditions. We first efficiently reprogrammed HLECs from age-related cataract patients to iPSCs with OCT-4, SOX-2, and KLF-4. The resulting HLEC-derived iPS (HLE-iPS colonies were indistinguishable from human ES cells with respect to morphology, gene expression, pluripotent marker expression and their ability to generate all embryonic germ-cell layers. Next, we performed a 3-step induction procedure: HLE-iPS cells were differentiated into large numbers of lens progenitor-like cells with defined factors (Noggin, BMP and FGF2, and we determined that these cells expressed lens-specific markers (PAX6, SOX2, SIX3, CRYAB, CRYAA, BFSP1, and MIP. In addition, HLE-iPS-derived lens cells exhibited reduced expression of epithelial mesenchymal transition (EMT markers compared with human embryonic stem cells (hESCs and fibroblast-derived iPSCs. Our study describes a highly efficient procedure for generating lens progenitor cells from cataract patient HLEC-derived iPSCs. These patient-derived pluripotent cells provide a valuable model for studying the developmental and molecular biological mechanisms that underlie cell determination in lens development and cataract

The chloroindole auxins of pea, strong plant growth hormones or endogenous herbicides

International Nuclear Information System (INIS)

Engvild, K.C.

1994-02-01

In this work the three theses below are discussed: 1) Identification and quantitative determination of the very strong plant hormone, the auxin 4-chloroindole-3-acetic acid methyl ester, in immature seeds of Pisum, Vicia, Lathyrus, and Lens spp. by incorporation of radioactive 36 Cl, thin layer chromatography, autoradiography, colour reactions, and gas chromatography/mass spectrometry. 2) The strong biological activity of 4-chloroindole-3-acetic acid and its analogues and its ability to induce strong, almost irreversible, ethylene evolution. 3) The possible role of chloroindole auxin in plants, particularly if it might be the hypothetical death hormone, secreted from developing seeds, which induces senescence and kills the mother plant at maturity; if plants generally have several auxin types, growth promoters and endogenous herbicides; and if other chlorine-containing plant hormones occur in developing seeds of other crop species. (au) (7 tabs., 8 ills., 144 refs.)

Neutrino oscillations in strong magnetic fields

International Nuclear Information System (INIS)

Likhachev, G.G.; Studenikin, A.I.

1994-07-01

Neutrino conversion processes between two neutrino species and the corresponding oscillations induced by strong magnetic fields are considered. The value of the critical strength of magnetic field B cr as a function of characteristics of neutrinos in vacuum (Δm 2 ν , mixing angle θ), effective particle density of matter n eff , neutrino (transition) magnetic moment μ-tilde and energy E is introduced. It is shown that the neutrino conversion and oscillations effects induced by magnetic fields B ≥ B cr are important and may result in the depletion of the initial type of ν's in the bunch. A possible increase of these effects in the case when neutrinos pass through a sudden decrease of density of matter (''cross-boundary effect'') and applications to neutrinos from neutron stars and supernova are discussed. (author). 25 refs

Design specifications to ensure flow-induced vibration and fretting-wear performance in CANDU steam generators and heat exchangers

International Nuclear Information System (INIS)

Janzen, V.P.; Han, Y.; Pettigrew, M.J.

2009-01-01

Preventing flow-induced vibration and fretting-wear problems in steam generators and heat exchangers requires design specifications that bring together specific guidelines, analysis methods, requirements and appropriate performance criteria. This paper outlines the steps required to generate and support such design specifications for CANDU nuclear steam generators and heat exchangers, and relates them to typical steam-generator design features and computer modeling capabilities. It also describes current issues that are driving changes to flow-induced vibration and fretting-wear specifications that can be applied to the design process for component refurbishment, replacement or new designs. These issues include recent experimental or field evidence for new excitation mechanisms, e.g., the possibility of in-plane fluidelastic instability of U-tubes, the demand for longer reactor and component lifetimes, the need for better predictions of dynamic properties and vibration response, e.g., two-phase random-turbulence excitation, and requirements to consider system 'excursions' or abnormal scenarios, e.g., a main steam line break in the case of steam generators. The paper describes steps being taken to resolve these issues. (author)

Activation-induced cytidine deaminase deficiency causes organ-specific autoimmune disease.

Directory of Open Access Journals (Sweden)

Koji Hase

Full Text Available Activation-induced cytidine deaminase (AID expressed by germinal center B cells is a central regulator of somatic hypermutation (SHM and class switch recombination (CSR. Humans with AID mutations develop not only the autosomal recessive form of hyper-IgM syndrome (HIGM2 associated with B cell hyperplasia, but also autoimmune disorders by unknown mechanisms. We report here that AID-/- mice spontaneously develop tertiary lymphoid organs (TLOs in non-lymphoid tissues including the stomach at around 6 months of age. At a later stage, AID-/- mice develop a severe gastritis characterized by loss of gastric glands and epithelial hyperplasia. The disease development was not attenuated even under germ-free (GF conditions. Gastric autoantigen -specific serum IgM was elevated in AID-/- mice, and the serum levels correlated with the gastritis pathological score. Adoptive transfer experiments suggest that autoimmune CD4+ T cells mediate gastritis development as terminal effector cells. These results suggest that abnormal B-cell expansion due to AID deficiency can drive B-cell autoimmunity, and in turn promote TLO formation, which ultimately leads to the propagation of organ-specific autoimmune effector CD4+ T cells. Thus, AID plays an important role in the containment of autoimmune diseases by negative regulation of autoreactive B cells.

Cardiac-specific catalase overexpression rescues anthrax lethal toxin-induced cardiac contractile dysfunction: role of oxidative stress and autophagy

OpenAIRE

Kandadi, Machender R; Yu, Xuejun; Frankel, Arthur E; Ren, Jun

2012-01-01

Abstract Background Lethal and edema toxins secreted by Bacillus anthracis during anthrax infection were found to incite serious cardiovascular complications. However, the underlying mechanisms in anthrax lethal toxin-induced cardiac anomalies remain unknown. This study was designed to evaluate the impact of antioxidant enzyme catalase in anthrax lethal toxin-induced cardiomyocyte contractile dysfunction. Methods Wild type (WT) and cardiac-specific catalase overexpression mice were challenged...

Echicetin coated polystyrene beads: a novel tool to investigate GPIb-specific platelet activation and aggregation.

Directory of Open Access Journals (Sweden)

Alexey Navdaev

Full Text Available von Willebrand factor/ristocetin (vWF/R induces GPIb-dependent platelet agglutination and activation of αIIbβ3 integrin, which also binds vWF. These conditions make it difficult to investigate GPIb-specific signaling pathways in washed platelets. Here, we investigated the specific mechanisms of GPIb signaling using echicetin-coated polystyrene beads, which specifically activate GPIb. We compared platelet activation induced by echicetin beads to vWF/R. Human platelets were stimulated with polystyrene beads coated with increasing amounts of echicetin and platelet activation by echicetin beads was then investigated to reveal GPIb specific signaling. Echicetin beads induced αIIbβ3-dependent aggregation of washed platelets, while under the same conditions vWF/R treatment led only to αIIbβ3-independent platelet agglutination. The average distance between the echicetin molecules on the polystyrene beads must be less than 7 nm for full platelet activation, while the total amount of echicetin used for activation is not critical. Echicetin beads induced strong phosphorylation of several proteins including p38, ERK and PKB. Synergistic signaling via P2Y12 and thromboxane receptor through secreted ADP and TxA2, respectively, were important for echicetin bead triggered platelet activation. Activation of PKG by the NO/sGC/cGMP pathway inhibited echicetin bead-induced platelet aggregation. Echicetin-coated beads are powerful and reliable tools to study signaling in human platelets activated solely via GPIb and GPIb-triggered pathways.

Echicetin Coated Polystyrene Beads: A Novel Tool to Investigate GPIb-Specific Platelet Activation and Aggregation

Science.gov (United States)

Petunin, Alexey; Clemetson, Kenneth J.; Gambaryan, Stepan; Walter, Ulrich

2014-01-01

von Willebrand factor/ristocetin (vWF/R) induces GPIb-dependent platelet agglutination and activation of αIIbβ3 integrin, which also binds vWF. These conditions make it difficult to investigate GPIb-specific signaling pathways in washed platelets. Here, we investigated the specific mechanisms of GPIb signaling using echicetin-coated polystyrene beads, which specifically activate GPIb. We compared platelet activation induced by echicetin beads to vWF/R. Human platelets were stimulated with polystyrene beads coated with increasing amounts of echicetin and platelet activation by echicetin beads was then investigated to reveal GPIb specific signaling. Echicetin beads induced αIIbβ3-dependent aggregation of washed platelets, while under the same conditions vWF/R treatment led only to αIIbβ3-independent platelet agglutination. The average distance between the echicetin molecules on the polystyrene beads must be less than 7 nm for full platelet activation, while the total amount of echicetin used for activation is not critical. Echicetin beads induced strong phosphorylation of several proteins including p38, ERK and PKB. Synergistic signaling via P2Y12 and thromboxane receptor through secreted ADP and TxA2, respectively, were important for echicetin bead triggered platelet activation. Activation of PKG by the NO/sGC/cGMP pathway inhibited echicetin bead-induced platelet aggregation. Echicetin-coated beads are powerful and reliable tools to study signaling in human platelets activated solely via GPIb and GPIb-triggered pathways. PMID:24705415

Induced Pluripotent Stem Cell Models of Progranulin-Deficient Frontotemporal Dementia Uncover Specific Reversible Neuronal Defects

Science.gov (United States)

Almeida, Sandra; Zhang, Zhijun; Coppola, Giovanni; Mao, Wenjie; Futai, Kensuke; Karydas, Anna; Geschwind, Michael D.; Tartaglia, M. Carmela; Gao, Fuying; Gianni, Davide; Sena-Esteves, Miguel; Geschwind, Daniel H.; Miller, Bruce L.; Farese, Robert V.; Gao, Fen-Biao

2012-01-01

SUMMARY The pathogenic mechanisms of frontotemporal dementia (FTD) remain poorly understood. Here we generated multiple induced pluripotent stem cell (iPSC) lines from a control subject, a patient with sporadic FTD, and an FTD patient with a novel GRN mutation (PGRN S116X). In neurons and microglia differentiated from PGRN S116X iPSCs, the levels of intracellular and secreted progranulin were reduced, establishing patient-specific cellular models of progranulin haploinsufficiency. Through a systematic screen of inducers of cellular stress, we found that PGRN S116X neurons, but not sporadic FTD neurons, exhibited increased sensitivity to staurosporine and other kinase inhibitors. Moreover, the serine/threonine kinase S6K2, a component of the PI3K and MAPK pathways, was specifically downregulated in PGRN S116X neurons. Both increased sensitivity to kinase inhibitors and reduced S6K2 were rescued by progranulin expression. Our findings identify cell-autonomous, reversible defects in patient neurons with progranulin deficiency and provide a new model for studying progranulin-dependent pathogenic mechanisms and testing potential therapies. PMID:23063362

Radiation-induced malignant tumours: a specific cytogenetic profile?

International Nuclear Information System (INIS)

Chauveinc, L.; Gaboriaux, G.; Dutrillaux, A. M.; Dutrillaux, B.; Chauveinc, L.; Ricoul, M.; Sabatier, L.; Dutrillaux, B.

1997-01-01

To date, there is no criterion enabling to determine the spontaneous or radio-induced origin of malignant tumour occurring in a previously irradiated patient. Biological studies are rare. The cytogenetic data which could be found in the literature for eleven radio-induced tumours suggest that aneuploidies and polyclonality are frequent events. We studied, by R-Banding cytogenetic technique, five patients with short-term cultures (3 cases), short and long-term cultures (1 case) and xeno-grafting on nude pattern a high rate of balanced translocations, numerous random break points and a polyclonal evolution (10 clones). All other tumours, including the xeno-grafting sarcoma, had a monoclonal profile with complex karyotypes, hypo-diploid formulas and many deletions. These results show that the mechanism of radiation-induced tumours frequently involves chromosomes losses and deletions. The most likely explanation is that these alterations unmask radiation induced recessive mutations of tumour suppressor genes. (authors)

Strong dietary restrictions protect Drosophila against anoxia/reoxygenation injuries.

Directory of Open Access Journals (Sweden)

Paul Vigne

Full Text Available Reoxygenation of ischemic tissues is a major factor that determines the severity of cardiovascular diseases. This paper describes the consequences of anoxia/reoxygenation (A/R stresses on Drosophila, a useful, anoxia tolerant, model organism.Newly emerged adult male flies were exposed to anoxic conditions (<1% O2 for 1 to 6 hours, reoxygenated and their survival was monitored.A/R stresses induced a transient increase in mortality which peaked at the time of reoxygenation. Then flies recovered low mortality rates similar to those of control flies. A/R induced mortality was strongly dependent on dietary conditions during the 48 h that preceded anoxia. Well fed flies were anoxia sensitive. Strong dietary restrictions and starvation conditions protected flies against A/R injuries. The tolerance to anoxia was associated to large decreases in glycogen, protein, and ATP contents. During anoxia, anoxia tolerant flies produced more lactate, less phosphate and they maintained more stable ATP levels than anoxia sensitive flies. Moderate dietary restrictions, which increased the longevity of normoxic flies, did not promote resistance to A/R stresses. Diet dependent A/R injuries were still observed in sigma loss of function mutants and they were insensitive to dietary rapamycin or resveratrol. AICAR (5-aminoimidazole-4-carboxamide-1-beta-D-ribose-furanoside, an activator AMP kinase decreased A/R injuries. Mutants in the insulin signalling pathway were more anoxia tolerant in a fed state.Long A/R stresses induce a transient increase in mortality in Drosophila. This mortality is highly dependent on dietary conditions prior to the stress. Strong dietary restrictions and starvation conditions protect flies against A/R injuries, probably by inducing a major remodelling of energy metabolism. The results also indicate that mechanistically different responses develop in response to dietary restrictions of different strengths. AMP kinase and the insulin signalling

Generation of healthy mice from gene-corrected disease-specific induced pluripotent stem cells.

Directory of Open Access Journals (Sweden)

Guangming Wu

2011-07-01

Full Text Available Using the murine model of tyrosinemia type 1 (fumarylacetoacetate hydrolase [FAH] deficiency; FAH⁻/⁻ mice as a paradigm for orphan disorders, such as hereditary metabolic liver diseases, we evaluated fibroblast-derived FAH⁻/⁻-induced pluripotent stem cells (iPS cells as targets for gene correction in combination with the tetraploid embryo complementation method. First, after characterizing the FAH⁻/⁻ iPS cell lines, we aggregated FAH⁻/⁻-iPS cells with tetraploid embryos and obtained entirely FAH⁻/⁻-iPS cell-derived mice that were viable and exhibited the phenotype of the founding FAH⁻/⁻ mice. Then, we transduced FAH cDNA into the FAH⁻/⁻-iPS cells using a third-generation lentiviral vector to generate gene-corrected iPS cells. We could not detect any chromosomal alterations in these cells by high-resolution array CGH analysis, and after their aggregation with tetraploid embryos, we obtained fully iPS cell-derived healthy mice with an astonishing high efficiency for full-term development of up to 63.3%. The gene correction was validated functionally by the long-term survival and expansion of FAH-positive cells of these mice after withdrawal of the rescuing drug NTBC (2-(2-nitro-4-fluoromethylbenzoyl-1,3-cyclohexanedione. Furthermore, our results demonstrate that both a liver-specific promoter (transthyretin, TTR-driven FAH transgene and a strong viral promoter (from spleen focus-forming virus, SFFV-driven FAH transgene rescued the FAH-deficiency phenotypes in the mice derived from the respective gene-corrected iPS cells. In conclusion, our data demonstrate that a lentiviral gene repair strategy does not abrogate the full pluripotent potential of fibroblast-derived iPS cells, and genetic manipulation of iPS cells in combination with tetraploid embryo aggregation provides a practical and rapid approach to evaluate the efficacy of gene correction of human diseases in mouse models.

Evaluation of Cytochalasin B-Induced Membrane Vesicles Fusion Specificity with Target Cells

Directory of Open Access Journals (Sweden)

Marina Gomzikova

2018-01-01

Full Text Available Extracellular vesicles (EV represent a promising vector system for biomolecules and drug delivery due to their natural origin and participation in intercellular communication. As the quantity of EVs is limited, it was proposed to induce the release of membrane vesicles from the surface of human cells by treatment with cytochalasin B. Cytochalasin B-induced membrane vesicles (CIMVs were successfully tested as a vector for delivery of dye, nanoparticles, and a chemotherapeutic. However, it remained unclear whether CIMVs possess fusion specificity with target cells and thus might be used for more targeted delivery of therapeutics. To answer this question, CIMVs were obtained from human prostate cancer PC3 cells. The diameter of obtained CIMVs was 962,13 ± 140,6 nm. We found that there is no statistically significant preference in PC3 CIMVs fusion with target cells of the same type. According to our observations, the greatest impact on CIMVs entry into target cells is by the heterophilic interaction of CIMV membrane receptors with the surface proteins of target cells.

Strong homeostatic TCR signals induce formation of self-tolerant virtual memory CD8 T cells.

Science.gov (United States)

Drobek, Ales; Moudra, Alena; Mueller, Daniel; Huranova, Martina; Horkova, Veronika; Pribikova, Michaela; Ivanek, Robert; Oberle, Susanne; Zehn, Dietmar; McCoy, Kathy D; Draber, Peter; Stepanek, Ondrej

2018-05-11

Virtual memory T cells are foreign antigen-inexperienced T cells that have acquired memory-like phenotype and constitute 10-20% of all peripheral CD8 + T cells in mice. Their origin, biological roles, and relationship to naïve and foreign antigen-experienced memory T cells are incompletely understood. By analyzing T-cell receptor repertoires and using retrogenic monoclonal T-cell populations, we demonstrate that the virtual memory T-cell formation is a so far unappreciated cell fate decision checkpoint. We describe two molecular mechanisms driving the formation of virtual memory T cells. First, virtual memory T cells originate exclusively from strongly self-reactive T cells. Second, the stoichiometry of the CD8 interaction with Lck regulates the size of the virtual memory T-cell compartment via modulating the self-reactivity of individual T cells. Although virtual memory T cells descend from the highly self-reactive clones and acquire a partial memory program, they are not more potent in inducing experimental autoimmune diabetes than naïve T cells. These data underline the importance of the variable level of self-reactivity in polyclonal T cells for the generation of functional T-cell diversity. © 2018 The Authors. Published under the terms of the CC BY 4.0 license.

Investigation on Flow-Induced Noise due to Backflow in Low Specific Speed Centrifugal Pumps

Directory of Open Access Journals (Sweden)

Qiaorui Si

2013-01-01

Full Text Available Flow-induced noise causes disturbances during the operation of centrifugal pumps and also affects their performance. The pumps often work at off-design conditions, mainly at part-load conditions, because of frequent changes in the pump device system. Consequently numerous unstable phenomena occur. In low specific speed centrifugal pumps the main disturbance is the inlet backflow, which is considered as one of the most important factors of flow-induced noise and vibration. In this study, a test rig of the flow-induced noise and vibration of the centrifugal pump was built to collect signals under various operating conditions. The three-dimensional unsteady flow of centrifugal pumps was calculated based on the Reynolds-averaged equations that resemble the shear stress transport (SST k-ω turbulence model. The results show that the blade passing frequency and shaft frequency are dominant in the spectrum of flow-induced noise, whereas the shaft component, amplitude value at shaft frequency, and peak frequencies around the shaft increase with decreasing flow. Through flow field analysis, the inlet backflow of the impeller occurs under 0.7 times the design flow. The pressure pulsation spectrum with backflow conditions validates the flow-induced noise findings. The velocity characteristics of the backflow zone at the inlet pipe were analyzed, and the dynamic characteristics of the backflow eddy during one impeller rotating period were simultaneously obtained by employing the backflow conditions. A flow visualization experiment was performed to confirm the numerical calculations.

Cardiac-Specific Overexpression of Catalase Attenuates Lipopolysaccharide-Induced Myocardial Contractile Dysfunction: Role of Autophagy

OpenAIRE

Turdi, Subat; Han, Xuefeng; Huff, Anna F.; Roe, Nathan D.; Hu, Nan; Gao, Feng; Ren, Jun

2012-01-01

Lipopolysaccharide (LPS) from Gram-negative bacteria is a major initiator of sepsis, leading to cardiovascular collapse. Accumulating evidence has indicated a role of reactive oxygen species (ROS) in cardiovascular complication in sepsis. This study was designed to examine the effect of cardiac-specific overexpression of catalase in LPS-induced cardiac contractile dysfunction and the underlying mechanism(s) with a focus on autophagy. Catalase transgenic and wild-type FVB mice were challenged ...

Cadmium induces the expression of specific stress proteins in sea urchin embryos

International Nuclear Information System (INIS)

Roccheri, Maria Carmela; Agnello, Maria; Bonaventura, Rosa; Matranga, Valeria

2004-01-01

Marine organisms are highly sensitive to many environmental stresses, and consequently, the analysis of their bio-molecular responses to different stress agents is very important for the understanding of putative repair mechanisms. Sea urchin embryos represent a simple though significant model system to test how specific stress can simultaneously affect development and protein expression. Here, we used Paracentrotus lividus sea urchin embryos to study the effects of time-dependent continuous exposure to subacute/sublethal cadmium concentrations. We found that, between 15 and 24 h of exposure, the synthesis of a specific set of stress proteins (90, 72-70, 56, 28, and 25 kDa) was induced, with an increase in the rate of synthesis of 72-70 kDa (hsps), 56 kDa (hsp), and 25 kDa, which was dependent on the lengths of treatment. Recovery experiments in which cadmium was removed showed that while stress proteins continued to be synthesized, embryo development was resumed only after short lengths of exposure

Site-specific analysis of UV-induced cyclobutane pyrimidine dimers in nucleotide excision repair-proficient and -deficient hamster cells: Lack of correlation with mutational spectra

International Nuclear Information System (INIS)

Vreeswijk, Maaike P.G.; Meijers, Caro M.; Giphart-Gassler, Micheline; Vrieling, Harry; Zeeland, Albert A. van; Mullenders, Leon H.F.; Loenen, Wil A.M.

2009-01-01

Irradiation of cells with UVC light induces two types of mutagenic DNA photoproducts, i.e. cyclobutane pyrimidine dimers (CPD) and pyrimidine (6-4) pyrimidone photoproducts (6-4PP). To investigate the relationship between the frequency of UV-induced photolesions at specific sites and their ability to induce mutations, we quantified CPD formation at the nucleotide level along exons 3 and 8 of the hprt gene using ligation-mediated PCR, and determined the mutational spectrum of 132 UV-induced hprt mutants in the AA8 hamster cell line and of 165 mutants in its nucleotide excision repair-defective derivative UV5. In AA8 cells, transversions predominated with a strong strand bias towards thymine-containing photolesions in the non-transcribed strand. As hamster AA8 cells are proficient in global genome repair of 6-4PP but selectively repair CPD from the transcribed strand of active genes, most mutations probably resulted from erroneous bypass of CPD in the non-transcribed strand. However, the relative incidence of CPD and the positions where mutations most frequently arose do not correlate. In fact some major damage sites hardly gave rise to the formation of mutations. In the repair-defective UV5 cells, mutations were almost exclusively C > T transitions caused by photoproducts at PyC sites in the transcribed strand. Even though CPD were formed at high frequencies at some TT sites in UV5, these photoproducts did not contribute to mutation induction at all. We conclude that, even in the absence of repair, large variations in the level of induction of CPD at different sites throughout the two exons do not correspond to frequencies of mutation induction.

Strong Electroweak Symmetry Breaking

CERN Document Server

Grinstein, Benjamin

2011-01-01

Models of spontaneous breaking of electroweak symmetry by a strong interaction do not have fine tuning/hierarchy problem. They are conceptually elegant and use the only mechanism of spontaneous breaking of a gauge symmetry that is known to occur in nature. The simplest model, minimal technicolor with extended technicolor interactions, is appealing because one can calculate by scaling up from QCD. But it is ruled out on many counts: inappropriately low quark and lepton masses (or excessive FCNC), bad electroweak data fits, light scalar and vector states, etc. However, nature may not choose the minimal model and then we are stuck: except possibly through lattice simulations, we are unable to compute and test the models. In the LHC era it therefore makes sense to abandon specific models (of strong EW breaking) and concentrate on generic features that may indicate discovery. The Technicolor Straw Man is not a model but a parametrized search strategy inspired by a remarkable generic feature of walking technicolor,...

Disruption of NBS1 gene leads to early embryonic lethality in homozygous null mice and induces specific cancer in heterozygous mice

Energy Technology Data Exchange (ETDEWEB)

Kurimasa, Akihiro; Burma, Sandeep; Henrie, Melinda; Ouyang, Honghai; Osaki, Mitsuhiko; Ito, Hisao; Nagasawa, Hatsumi; Little, John B.; Oshimura, Mitsuo; Li, Gloria C.; Chen, David J.

2002-04-15

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive chromosome instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition, with cellular features similar to that of ataxia telangiectasia (AT). NBS results from mutations in the mammalian gene Nbs1 that codes for a 95-kDa protein called nibrin, NBS1, or p95. To establish an animal model for NBS, we attempted to generate NBS1 knockout mice. However, NBS1 gene knockouts were lethal at an early embryonic stage. NBS1 homozygous(-/-) blastocyst cells cultured in vitro showed retarded growth and subsequently underwent growth arrest within 5 days of culture. Apoptosis, assayed by TUNEL staining, was observed in NBSI homozygous(-/-) blastocyst cells cultured for four days. NBSI heterozygous(+/-) mice were normal, and exhibited no specific phenotype for at least one year. However, fibroblast cells from NBSI heterozygous(+/-) mice displayed an enhanced frequency of spontaneous transformation to anchorage-independent growth as compared to NBS1 wild-type(+/+) cells. Furthermore, heterozygous(+/-) mice exhibited a high incidence of hepatocellular carcinoma after one year compared to wild-type mice, even though no significant differences in the incidence of other tumors such as lung adenocarcinoma and lymphoma were observed. Taken together, these results strongly suggest that NBS1 heterozygosity and reduced NBSI expression induces formation of specific tumors in mice.

Dysfunction of different cellular degradation pathways contributes to specific β-amyloid42-induced pathologies.

Science.gov (United States)

Ji, Xuan-Ru; Cheng, Kuan-Chung; Chen, Yu-Ru; Lin, Tzu-Yu; Cheung, Chun Hei Antonio; Wu, Chia-Lin; Chiang, Hsueh-Cheng

2018-03-01

The endosomal-lysosomal system (ELS), autophagy, and ubiquitin-proteasome system (UPS) are cellular degradation pathways that each play a critical role in the removal of misfolded proteins and the prevention of the accumulation of abnormal proteins. Recent studies on Alzheimer's disease (AD) pathogenesis have suggested that accumulation of aggregated β-amyloid (Aβ) peptides in the AD brain results from a dysfunction in these cellular clearance systems. However, the specific roles of these pathways in the removal of Aβ peptides and the pathogenesis underlying AD are unclear. Our in vitro and in vivo genetic approaches revealed that ELS mainly removed monomeric β-amyloid42 (Aβ42), while autophagy and UPS clear oligomeric Aβ42. Although overproduction of phosphatidylinositol 4-phosphate-5 increased Aβ42 clearance, it reduced the life span of Aβ42 transgenic flies. Our behavioral studies further demonstrated impaired autophagy and UPS-enhanced Aβ42-induced learning and memory deficits, but there was no effect on Aβ42-induced reduction in life span. Results from genetic fluorescence imaging showed that these pathways were damaged in the following order: UPS, autophagy, and finally ELS. The results of our study demonstrate that different degradation pathways play distinct roles in the removal of Aβ42 aggregates and in disease progression. These findings also suggest that pharmacologic treatments that are designed to stimulate cellular degradation pathways in patients with AD should be used with caution.-Ji, X.-R., Cheng, K.-C., Chen, Y.-R., Lin, T.-Y., Cheung, C. H. A., Wu, C.-L., Chiang, H.-C. Dysfunction of different cellular degradation pathways contributes to specific β-amyloid42-induced pathologies.

Antigen-specific tolerance of human alpha1-antitrypsin induced by helper-dependent adenovirus.

Science.gov (United States)

Cerullo, V; McCormack, W; Seiler, M; Mane, V; Cela, R; Clarke, C; Rodgers, J R; Lee, B

2007-12-01

As efficient and less toxic virus-derived gene therapy vectors are developed, a pressing problem is to avoid immune response to the therapeutic gene product. Secreted therapeutic proteins potentially represent a special problem, as they are readily available to professional antigen-presenting cells throughout the body. Some studies suggest that immunity to serum proteins can be avoided in some mouse strains by using tissue-specific promoters. Here we show that expression of human alpha1-antitrypsin (AAT) was nonimmunogenic in the immune-responsive strain C3H/HeJ, when expressed from helper-dependent (HD) vectors using ubiquitous as well as tissue-specific promoters. Coadministration of less immunogenic HD vectors with an immunogenic first-generation vector failed to immunize, suggesting immune suppression rather than immune stealth. Indeed, mice primed with HD vectors were tolerant to immune challenge with hAAT emulsified in complete Freund's adjuvant. Such animals developed high-titer antibodies to coemulsified human serum albumin, showing that tolerance was antigen specific. AAT-specific T cell responses were depressed in tolerized animals, suggesting that tolerance affects both T and B cells. These results are consistent with models of high-dose tolerance of B cells and certain other suppressive mechanisms, and suggest that a high level of expression from HD vectors can be sufficient to induce specific immune tolerance to serum proteins.

Supper strong nanostructured TWIP steels for automotive applications

Directory of Open Access Journals (Sweden)

G.W. Yuan

2014-02-01

Full Text Available A ductile and super strong nanostructured twinning-induced plasticity (TWIP steels were fabricated by cold rolling and recovery treatment. This strong and ductile nanostructured alloy can be used for the anti-intrusion part of body-in-white. Cold rolling was used to produce intensive nano-twins so that the microstructure was greatly refined. Recovery is employed to anneal dislocations for improving the ductility. A physical model is proposed to describe the relationship between the yield stress and the twin density. Furthermore, the present work also found that the activation energy for recovery is ~160 J/mol, which implies that the recovery mechanism is governed by dislocation core diffusion.

Atom-Pair Kinetics with Strong Electric-Dipole Interactions.

Science.gov (United States)

Thaicharoen, N; Gonçalves, L F; Raithel, G

2016-05-27

Rydberg-atom ensembles are switched from a weakly to a strongly interacting regime via adiabatic transformation of the atoms from an approximately nonpolar into a highly dipolar quantum state. The resultant electric dipole-dipole forces are probed using a device akin to a field ion microscope. Ion imaging and pair-correlation analysis reveal the kinetics of the interacting atoms. Dumbbell-shaped pair-correlation images demonstrate the anisotropy of the binary dipolar force. The dipolar C_{3} coefficient, derived from the time dependence of the images, agrees with the value calculated from the permanent electric-dipole moment of the atoms. The results indicate many-body dynamics akin to disorder-induced heating in strongly coupled particle systems.

Insula-specific responses induced by dental pain. A proton magnetic resonance spectroscopy study

International Nuclear Information System (INIS)

Gutzeit, A.; Weymarn, C. von; Froehlich, J.M.; Binkert, C.A.; Meier, D.; Meier, M.L.; Bruegger, M.; Ettlin, D.A.; Graf, N.

2011-01-01

To evaluate whether induced dental pain leads to quantitative changes in brain metabolites within the left insular cortex after stimulation of the right maxillary canine and to examine whether these metabolic changes and the subjective pain intensity perception correlate. Ten male volunteers were included in the pain group and compared with a control group of 10 other healthy volunteers. The pain group received a total of 87-92 electrically induced pain stimuli over 15 min to the right maxillary canine tooth. Contemporaneously, they evaluated the subjective pain intensity of every stimulus using an analogue scale. Neurotransmitter changes within the left insular cortex were evaluated by MR spectroscopy. Significant metabolic changes in glutamine (+55.1%), glutamine/glutamate (+16.4%) and myo-inositol (-9.7%) were documented during pain stimulation. Furthermore, there was a significant negative correlation between the subjective pain intensity perception and the metabolic levels of Glx, Gln, glutamate and N-acetyl aspartate. The insular cortex is a metabolically active region in the processing of acute dental pain. Induced dental pain leads to quantitative changes in brain metabolites within the left insular cortex resulting in significant alterations in metabolites. Negative correlation between subjective pain intensity rating and specific metabolites could be observed. (orig.)

Insula-specific responses induced by dental pain. A proton magnetic resonance spectroscopy study

Energy Technology Data Exchange (ETDEWEB)

Gutzeit, A.; Weymarn, C. von; Froehlich, J.M.; Binkert, C.A. [Cantonal Hospital Winterthur, Department of Radiology, Winterthur (Switzerland); Meier, D. [University and ETH Zurich, Institute for Biomedical Engineering, Zurich (Switzerland); Meier, M.L.; Bruegger, M. [University of Zurich, Institute of Psychology, Division Neuropsychology, Zurich (Switzerland); Ettlin, D.A. [University of Zuerich, Center for Dental and Oral Medicine and Cranio-Maxillofacial Surgery, Clinic for Removable Prosthodontics, Masticatory Disorders and Special Care Dentistry, Zuerich (Switzerland); Graf, N. [University Hospital of Zurich, Clinical Trials Center, Center for Clinical Research, Zurich (Switzerland)

2011-04-15

To evaluate whether induced dental pain leads to quantitative changes in brain metabolites within the left insular cortex after stimulation of the right maxillary canine and to examine whether these metabolic changes and the subjective pain intensity perception correlate. Ten male volunteers were included in the pain group and compared with a control group of 10 other healthy volunteers. The pain group received a total of 87-92 electrically induced pain stimuli over 15 min to the right maxillary canine tooth. Contemporaneously, they evaluated the subjective pain intensity of every stimulus using an analogue scale. Neurotransmitter changes within the left insular cortex were evaluated by MR spectroscopy. Significant metabolic changes in glutamine (+55.1%), glutamine/glutamate (+16.4%) and myo-inositol (-9.7%) were documented during pain stimulation. Furthermore, there was a significant negative correlation between the subjective pain intensity perception and the metabolic levels of Glx, Gln, glutamate and N-acetyl aspartate. The insular cortex is a metabolically active region in the processing of acute dental pain. Induced dental pain leads to quantitative changes in brain metabolites within the left insular cortex resulting in significant alterations in metabolites. Negative correlation between subjective pain intensity rating and specific metabolites could be observed. (orig.)

The role of myostatin and activin receptor IIB in the regulation of unloading-induced myofiber type-specific skeletal muscle atrophy.

Science.gov (United States)

Babcock, Lyle W; Knoblauch, Mark; Clarke, Mark S F

2015-09-15

Chronic unloading induces decrements in muscle size and strength. This adaptation is governed by a number of molecular factors including myostatin, a potent negative regulator of muscle mass. Myostatin must first be secreted into the circulation and then bind to the membrane-bound activin receptor IIB (actRIIB) to exert its atrophic action. Therefore, we hypothesized that myofiber type-specific atrophy observed after hindlimb suspension (HLS) would be related to myofiber type-specific expression of myostatin and/or actRIIB. Wistar rats underwent HLS for 10 days, after which the tibialis anterior was harvested for frozen cross sectioning. Simultaneous multichannel immunofluorescent staining combined with differential interference contrast imaging was employed to analyze myofiber type-specific expression of myostatin and actRIIB and myofiber type cross-sectional area (CSA) across fiber types, myonuclei, and satellite cells. Hindlimb suspension (HLS) induced significant myofiber type-specific atrophy in myosin heavy chain (MHC) IIx (P Myostatin staining associated with myonuclei was less in HLS rats compared with controls, while satellite cell staining for myostatin remained unchanged. In contrast, the total number myonuclei and satellite cells per myofiber was reduced in HLS compared with ambulatory control rats (P myostatin-induced myofiber type-selective atrophy observed during chronic unloading. Copyright © 2015 the American Physiological Society.

Cell-type-specific roles for COX-2 in UVB-induced skin cancer

Science.gov (United States)

Herschman, Harvey

2014-01-01

In human tumors, and in mouse models, cyclooxygenase-2 (COX-2) levels are frequently correlated with tumor development/burden. In addition to intrinsic tumor cell expression, COX-2 is often present in fibroblasts, myofibroblasts and endothelial cells of the tumor microenvironment, and in infiltrating immune cells. Intrinsic cancer cell COX-2 expression is postulated as only one of many sources for prostanoids required for tumor promotion/progression. Although both COX-2 inhibition and global Cox-2 gene deletion ameliorate ultraviolet B (UVB)-induced SKH-1 mouse skin tumorigenesis, neither manipulation can elucidate the cell type(s) in which COX-2 expression is required for tumorigenesis; both eliminate COX-2 activity in all cells. To address this question, we created Cox-2 flox/flox mice, in which the Cox-2 gene can be eliminated in a cell-type-specific fashion by targeted Cre recombinase expression. Cox-2 deletion in skin epithelial cells of SKH-1 Cox-2 flox/flox;K14Cre + mice resulted, following UVB irradiation, in reduced skin hyperplasia and increased apoptosis. Targeted epithelial cell Cox-2 deletion also resulted in reduced tumor incidence, frequency, size and proliferation rate, altered tumor cell differentiation and reduced tumor vascularization. Moreover, Cox-2 flox/flox;K14Cre + papillomas did not progress to squamous cell carcinomas. In contrast, Cox-2 deletion in SKH-1 Cox-2 flox/flox; LysMCre + myeloid cells had no effect on UVB tumor induction. We conclude that (i) intrinsic epithelial COX-2 activity plays a major role in UVB-induced skin cancer, (ii) macrophage/myeloid COX-2 plays no role in UVB-induced skin cancer and (iii) either there may be another COX-2-dependent prostanoid source(s) that drives UVB skin tumor induction or there may exist a COX-2-independent pathway(s) to UVB-induced skin cancer. PMID:24469308

Differentiation of Induced Pluripotent Stem Cells to Lentoid Bodies Expressing a Lens Cell-Specific Fluorescent Reporter.

Directory of Open Access Journals (Sweden)

Taruna Anand

Full Text Available Curative approaches for eye cataracts and other eye abnormalities, such as myopia and hyperopia currently suffer from a lack of appropriate models. Here, we present a new approach for in vitro growth of lentoid bodies from induced pluripotent stem (iPS cells as a tool for ophthalmological research. We generated a transgenic mouse line with lens-specific expression of a fluorescent reporter driven by the alphaA crystallin promoter. Fetal fibroblasts were isolated from transgenic fetuses, reprogrammed to iPS cells, and differentiated to lentoid bodies exploiting the specific fluorescence of the lens cell-specific reporter. The employment of cell type-specific reporters for establishing and optimizing differentiation in vitro seems to be an efficient and generally applicable approach for developing differentiation protocols for desired cell populations.

Manipulation of resonant Auger processes with strong optical fields

Science.gov (United States)

Picón, Antonio; Buth, Christian; Doumy, Gilles; Krässig, Bertold; Young, Linda; Southworth, Stephen

2013-05-01

We recently reported on the optical control of core-excited states of a resonant Auger process in neon. We have focused on the resonant excitation 1 s --> 1s-1 3 p , while a strong optical field may resonantly couple two core-excited states (1s-1 3 p and 1s-1 3 s) in the Rydberg manifold as well as dressing the continuum. There is a clear signature in the Auger electron spectrum of the inner-shell dynamics induced by the strong optical field: i) the Auger electron spectrum is modified by the rapid optical-induced population transfer from the 1s-1 3 p state to the 1s-1 3 s state during their decay. ii) The angular anisotropy parameter, defining the angular distribution of the Auger electron, is manifested in the envelope of the (angle-integrated) sidebands. This work is funded by the Office of Basic Energy Sciences, Office of Science, U.S. Department of Energy, under Contract No. DE-AC02-06CH11357.

Clinical and immunologic findings of methylene diphenyl diisocyanate-induced occupational asthma in a car upholstery factory.

Science.gov (United States)

Hur, G-Y; Koh, D-H; Choi, G-S; Park, H-J; Choi, S-J; Ye, Y-M; Kim, K-S; Park, H-S

2008-04-01

Although methylene diphenyl diisocyanate (MDI) is widely used in many industries, there have been few immunological studies of MDI-induced occupational asthma. We investigated the effects of MDI exposure on the clinical and immunologic condition of workers in a single car upholstery factory. Fifty-eight MDI-exposed workers were studied. Work-related lower-respiratory symptoms (WRRS) were identified using a questionnaire. Serum-specific IgE and IgG antibodies to MDI-human serum albumin conjugate were detected by ELISA. Atopy was evaluated using a skin prick test. MDI-induced occupational asthma was confirmed in the symptomatic workers with a positive result on an MDI-specific inhalation test. Thirteen (22.4%) of the subjects complained of WRRS. MDI-induced occupational asthma was confirmed in five (8.6%) of the workers, and occupational eosinophilic bronchitis was confirmed in two (3.5%). The prevalence of specific IgG antibodies (20.7%) was higher than that of specific IgE antibodies (8.6%). The prevalence of MDI-induced occupational asthma/eosinophilic bronchitis was strongly associated with the presence of both WRRS and serum-specific IgG antibodies to an MDI-human serum albumin conjugate (Pworkers. The prevalence of MDI-induced occupational asthma was 8.6%, and MDI-induced eosinophilic bronchitis was confirmed in two workers. The presence of work-related lower-respiratory symptoms and serum-specific IgG antibodies to an MDI-human serum albumin conjugate may be used to predict MDI-induced occupational asthma/eosinophilic bronchitis in MDI-exposed workers.

Cell-stage-specific enhancement by caffeine of the frequency of chromatid aberrations induced by X-rays in neutral ganglia of Drosophila melanogaster

International Nuclear Information System (INIS)

De Marco, A.; Polani, S.

1981-01-01

Caffeine (10 -2 M) induced a high level of chromatid aberrations in neural ganglia of third-instar larvae of Drosophila melanogaster only when it was added to cells in late G 2 and mitotic prophase. No aberrations were observed after treatment in late S-middle G 2 or C-mitosis. We observed that, in these stages, caffeine strongly increased X-ray-induced damage (500 R). This potentiation was quantitatively similar. But it involved all types of aberration after treatment in C-mitosis, and essentially isochromatid deletions and chromatid exhanges after treatment in S-G 2 . Some hypotheses are put forth to explain the possible mechanism of action of caffeine in the potentiation of X-ray-induced damage. (orig.)

Aerosol-Induced Changes of Convective Cloud Anvils Produce Strong Climate Warming

Science.gov (United States)

Koren, I.; Remer, L. A.; Altaratz, O.; Martins, J. V.; Davidi, A.

2010-01-01

The effect of aerosol on clouds poses one of the largest uncertainties in estimating the anthropogenic contribution to climate change. Small human-induced perturbations to cloud characteristics via aerosol pathways can create a change in the top-of-atmosphere radiative forcing of hundreds of Wm(exp-2) . Here we focus on links between aerosol and deep convective clouds of the Atlantic and Pacific Intertropical Convergence Zones, noting that the aerosol environment in each region is entirely different. The tops of these vertically developed clouds consisting of mostly ice can reach high levels of the atmosphere, overshooting the lower stratosphere and reaching altitudes greater than 16 km. We show a link between aerosol, clouds and the free atmosphere wind profile that can change the magnitude and sign of the overall climate radiative forcing. We find that increased aerosol loading is associated with taller cloud towers and anvils. The taller clouds reach levels of enhanced wind speeds that act to spread and thin the anvi1 clouds, increasing areal coverage and decreasing cloud optical depth. The radiative effect of this transition is to create a positive radiative forcing (warming) at top-of-atmosphere. Furthermore we introduce the cloud optical depth (r), cloud height (Z) forcing space and show that underestimation of radiative forcing is likely to occur in cases of non homogenous clouds. Specifically, the mean radiative forcing of towers and anvils in the same scene can be several times greater than simply calculating the forcing from the mean cloud optical depth in the scene. Limitations of the method are discussed, alternative sources of aerosol loading are tested and meteorological variance is restricted, but the trend of taller clouds; increased and thinner anvils associated with increased aerosol loading remains robust through all the different tests and perturbations.

Aerosol-induced changes of convective cloud anvils produce strong climate warming

Directory of Open Access Journals (Sweden)

I. Koren

2010-05-01

Full Text Available The effect of aerosol on clouds poses one of the largest uncertainties in estimating the anthropogenic contribution to climate change. Small human-induced perturbations to cloud characteristics via aerosol pathways can create a change in the top-of-atmosphere radiative forcing of hundreds of Wm⁻². Here we focus on links between aerosol and deep convective clouds of the Atlantic and Pacific Intertropical Convergence Zones, noting that the aerosol environment in each region is entirely different. The tops of these vertically developed clouds consisting of mostly ice can reach high levels of the atmosphere, overshooting the lower stratosphere and reaching altitudes greater than 16 km. We show a link between aerosol, clouds and the free atmosphere wind profile that can change the magnitude and sign of the overall climate radiative forcing.

We find that increased aerosol loading is associated with taller cloud towers and anvils. The taller clouds reach levels of enhanced wind speeds that act to spread and thin the anvil clouds, increasing areal coverage and decreasing cloud optical depth. The radiative effect of this transition is to create a positive radiative forcing (warming at top-of-atmosphere.

Furthermore we introduce the cloud optical depth (τ, cloud height (Z forcing space and show that underestimation of radiative forcing is likely to occur in cases of non homogenous clouds. Specifically, the mean radiative forcing of towers and anvils in the same scene can be several times greater than simply calculating the forcing from the mean cloud optical depth in the scene.

Limitations of the method are discussed, alternative sources of aerosol loading are tested and meteorological variance is restricted, but the trend of taller clouds, increased and thinner anvils associated with increased aerosol loading remains robust through all the different tests and perturbations.

Human and Animal Isolates of Yersinia enterocolitica Show Significant Serotype-Specific Colonization and Host-Specific Immune Defense Properties

Science.gov (United States)

Schaake, Julia; Kronshage, Malte; Uliczka, Frank; Rohde, Manfred; Knuuti, Tobias; Strauch, Eckhard; Fruth, Angelika; Wos-Oxley, Melissa

2013-01-01

Yersinia enterocolitica is a human pathogen that is ubiquitous in livestock, especially pigs. The bacteria are able to colonize the intestinal tract of a variety of mammalian hosts, but the severity of induced gut-associated diseases (yersiniosis) differs significantly between hosts. To gain more information about the individual virulence determinants that contribute to colonization and induction of immune responses in different hosts, we analyzed and compared the interactions of different human- and animal-derived isolates of serotypes O:3, O:5,27, O:8, and O:9 with murine, porcine, and human intestinal cells and macrophages. The examined strains exhibited significant serotype-specific cell binding and entry characteristics, but adhesion and uptake into different host cells were not host specific and were independent of the source of the isolate. In contrast, survival and replication within macrophages and the induced proinflammatory response differed between murine, porcine, and human macrophages, suggesting a host-specific immune response. In fact, similar levels of the proinflammatory cytokine macrophage inflammatory protein 2 (MIP-2) were secreted by murine bone marrow-derived macrophages with all tested isolates, but the equivalent interleukin-8 (IL-8) response of porcine bone marrow-derived macrophages was strongly serotype specific and considerably lower in O:3 than in O:8 strains. In addition, all tested Y. enterocolitica strains caused a considerably higher level of secretion of the anti-inflammatory cytokine IL-10 by porcine than by murine macrophages. This could contribute to limiting the severity of the infection (in particular of serotype O:3 strains) in pigs, which are the primary reservoir of Y. enterocolitica strains pathogenic to humans. PMID:23959720

Institutionalizing Strong Sustainability: A Rawlsian Perspective

Directory of Open Access Journals (Sweden)

Konrad Ott

2014-02-01

Full Text Available The article aims to provide some ethical orientation on how sustainability might be actualized by institutions. Since institutionalization is about rules and organization, it presupposes ideas and concepts by which institutions can be substantiated. After outlining terminology, the article deals with underlying ethical and conceptual problems which are highly relevant for any suggestions concerning institutionalization. These problems are: (a the ethical scope of the sustainability perspective (natural capital, poverty, sentient animals, (b the theory of justice on which ideas about sustainability are built (capability approach, Rawlsianism, and (c the favored concept of sustainability (weak, intermediate, and strong sustainability. These problems are analyzed in turn. As a result, a Rawlsian concept of rule-based strong sustainability is proposed. The specific problems of institutionalization are addressed by applying Rawls’s concept of branches. The article concludes with arguments in favor of three transnational duties which hold for states that have adopted Rawlsian strong sustainability.

A Comprehensive, Ethnically Diverse Library of Sickle Cell Disease-Specific Induced Pluripotent Stem Cells.

Science.gov (United States)

Park, Seonmi; Gianotti-Sommer, Andreia; Molina-Estevez, Francisco Javier; Vanuytsel, Kim; Skvir, Nick; Leung, Amy; Rozelle, Sarah S; Shaikho, Elmutaz Mohammed; Weir, Isabelle; Jiang, Zhihua; Luo, Hong-Yuan; Chui, David H K; Figueiredo, Maria Stella; Alsultan, Abdulraham; Al-Ali, Amein; Sebastiani, Paola; Steinberg, Martin H; Mostoslavsky, Gustavo; Murphy, George J

2017-04-11

Sickle cell anemia affects millions of people worldwide and is an emerging global health burden. As part of a large NIH-funded NextGen Consortium, we generated a diverse, comprehensive, and fully characterized library of sickle-cell-disease-specific induced pluripotent stem cells (iPSCs) from patients of different ethnicities, β-globin gene (HBB) haplotypes, and fetal hemoglobin (HbF) levels. iPSCs stand to revolutionize the way we study human development, model disease, and perhaps eventually, treat patients. Here, we describe this unique resource for the study of sickle cell disease, including novel haplotype-specific polymorphisms that affect disease severity, as well as for the development of patient-specific therapeutics for this phenotypically diverse disorder. As a complement to this library, and as proof of principle for future cell- and gene-based therapies, we also designed and employed CRISPR/Cas gene editing tools to correct the sickle hemoglobin (HbS) mutation. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Dynamics of valence-shell electrons and nuclei probed by strong-field holography and rescattering

Science.gov (United States)

Walt, Samuel G.; Bhargava Ram, Niraghatam; Atala, Marcos; Shvetsov-Shilovski, Nikolay I; von Conta, Aaron; Baykusheva, Denitsa; Lein, Manfred; Wörner, Hans Jakob

2017-01-01

Strong-field photoelectron holography and laser-induced electron diffraction (LIED) are two powerful emerging methods for probing the ultrafast dynamics of molecules. However, both of them have remained restricted to static systems and to nuclear dynamics induced by strong-field ionization. Here we extend these promising methods to image purely electronic valence-shell dynamics in molecules using photoelectron holography. In the same experiment, we use LIED and photoelectron holography simultaneously, to observe coupled electronic-rotational dynamics taking place on similar timescales. These results offer perspectives for imaging ultrafast dynamics of molecules on femtosecond to attosecond timescales. PMID:28643771

Time-resolved pulse-counting lock-in detection of laser induced fluorescence in the presence of a strong background emission

Science.gov (United States)

Pelissier, B.; Sadeghi, N.

1996-10-01

We describe a time-resolved pulse-counting system well adapted for the detection of continuous laser induced fluorescence (LIF) signals in repetitive phenomena, when a strong background emission is present. It consists of 256 channels coupled to a first in first out memory and interfaced to a 486 DX 33 PC, for data storage. It accepts time-averaged count rates up to 450 kcount/s. Time between channels can be set from 12.5 ns to several μs and the dead time between two consecutive cycles of the physical phenomena is less than 20 ns. In phase with a chopper, which modulates the laser beam, it adds the observed photon signal to the channel memories when the beam is on and substracts it when the beam is stopped, acting like a lock-in amplifier which detect only the modulated part of the signal. The minimum detectivity on the LIF signal is only limited by the shot noise of the plasma induced emission signal. As an application, we studied the time variation of the Ar+*(2G9/2) metastable ions, detected by LIF, in two types of plasmas. Their radiative lifetime and collisional quenching frequencies were deduced from their decay rate in the afterglow of a pulsed Helicon reactor. We also observed the evolution of their density in a 455 kHz capacitively coupled argon discharge.

The CO/NOx emissions of swirled, strongly pulsed jet diffusion flames

KAUST Repository

Liao, Ying-Hao; Hermanson, James C.

2014-01-01

recirculation within the swirl-induced recirculation zone. Scaling relations, when taking into account the impact of air dilution over an injection cycle on the flame length, reveal a strong correlation between the CO emissions and the global residence time

The role of hypoxia inducible factor-1 alpha in bypassing oncogene-induced senescence.

Directory of Open Access Journals (Sweden)

Mehtap Kilic Eren

Full Text Available Oncogene induced senescence (OIS is a sustained anti-proliferative response acutely induced in primary cells via activation of mitogenic oncogenes such as Ras/BRAF. This mechanism acts as an initial barrier preventing normal cells transformation into malignant cell. Besides oncogenic activation and DNA damage response (DDR, senescence is modulated by a plethora of other factors, and one of the most important one is oxygen tension of the tissue. The aim of this study was to determine the impact of hypoxia on RasV12-induced senescence in human diploid fibroblasts (HDFs. We showed here that hypoxia prevents execution of oncogene induced senescence (OIS, through a strong down-regulation of senescence hallmarks, such as SA- β-galactosidase, H3K9me3, HP1γ, p53, p21CIP1 and p16INK4a in association with induction of hypoxia inducible factor-1α (HIF-1α. In addition, hypoxia also decreased marks of H-RasV12-induced DDR in both cell lines through down-regulation of ATM/ATR, Chk1 and Chk2 phosphorylation as well as decreased γ-H2AX positivity. Utilizing shRNA system targeting HIF-1α we show that HIF-1α is directly involved in down regulation of p53 and its target p21CIP1 but not p16INK4a. In line with this finding we found that knock down of HIF-1α leads to a strong induction of apoptotic response, but not restoration of senescence in Ras expressing HDFs in hypoxia. This indicates that HIF-1α is an important player in early steps of tumorigenesis, leading to suppression of senescence through its negative regulation of p53 and p21CIP1. In our work we describe a mechanism through which hypoxia and specifically HIF-1α preclude cells from maintaining senescence-driven anti proliferative response. These findings indicate the possible mechanism through which hypoxic environment helps premalignant cells to evade impingement of cellular failsafe pathways.

Specific Oral Tolerance Induction Using IFN-Gamma in 2 Cases of Food-Dependent Exercise-Induced Anaphylaxis

Directory of Open Access Journals (Sweden)

Geunwoong Noh

2013-01-01

Full Text Available Anaphylaxis induced by exercise after the intake of certain foods is referred to as food-dependent exercise-induced anaphylaxis (FDEIA. Only the preventive medication such as oral sodium cromoglycate and oral combined cetirizine-montelukast was tried in FDEIA. Specific oral tolerance induction (SOTI using IFN-gamma was tried in 2 cases of FDEIA for wheat. Merely, exercise accompanied every treatment just after the intake of allergenic foods during treatment. Patients acquired tolerance for wheat in both cases successfully. After treatment, two patients take wheat in their food living freely. Conclusively, SOTI using IFN-gamma was effective as the causative treatment for allergenic foods in FDEIA.

Intramuscular Priming and Intranasal Boosting Induce Strong Genital Immunity Through Secretory IgA in Minipigs Infected with Chlamydia trachomatis

DEFF Research Database (Denmark)

Lorenzen, Emma; Follmann, Frank; Bøje, Sarah

2015-01-01

with a reproductive system very similar to humans. The vaccine was composed of C. trachomatis subunit antigens formulated in the Th1/Th17 promoting CAF01 adjuvant. IM priming immunizations with CAF01 induced a significant cell-mediated interferon gamma and interleukin 17A response and a significant systemic high......-titered neutralizing IgG response. Following genital challenge, intranasally boosted groups mounted an accelerated, highly significant genital IgA response that correlated with enhanced bacterial clearance on day 3 post infection. By detecting antigen-specific secretory component (SC), we showed that the genital Ig...

Evidence for a glassy state in strongly driven carbon

International Nuclear Information System (INIS)

Brown, C.R.D.; Gericke, D.O.; Wunsch, K.; Cammarata, M.; Fritz, D.; Glenzer, S.H.; Heimann, P.; Lee, H.J.; Lemke, H.; Nagler, B.; Zhu, D.; Galtier, E.; Moinard, A.; Rosmej, F.B.

2014-01-01

Here, we report results of an experiment creating a transient, highly correlated carbon state using a combination of optical and x-ray lasers. Scattered x-rays reveal a highly ordered state with an electrostatic energy significantly exceeding the thermal energy of the ions. Strong Coulomb forces are predicted to induce nucleation into a crystalline ion structure within a few picoseconds. However, we observe no evidence of such phase transition after several tens of picoseconds but strong indications for an over-correlated fluid state. The experiment suggests a much slower nucleation and points to an intermediate glassy state where the ions are frozen close to their original positions in the fluid. (authors)

Transcriptome Analysis of Mycobacteria-Specific CD4+ T Cells Identified by Activation-Induced Expression of CD154.

Science.gov (United States)

Kunnath-Velayudhan, Shajo; Goldberg, Michael F; Saini, Neeraj K; Johndrow, Christopher T; Ng, Tony W; Johnson, Alison J; Xu, Jiayong; Chan, John; Jacobs, William R; Porcelli, Steven A

2017-10-01

Analysis of Ag-specific CD4 + T cells in mycobacterial infections at the transcriptome level is informative but technically challenging. Although several methods exist for identifying Ag-specific T cells, including intracellular cytokine staining, cell surface cytokine-capture assays, and staining with peptide:MHC class II multimers, all of these have significant technical constraints that limit their usefulness. Measurement of activation-induced expression of CD154 has been reported to detect live Ag-specific CD4 + T cells, but this approach remains underexplored and, to our knowledge, has not previously been applied in mycobacteria-infected animals. In this article, we show that CD154 expression identifies adoptively transferred or endogenous Ag-specific CD4 + T cells induced by Mycobacterium bovis bacillus Calmette-Guérin vaccination. We confirmed that Ag-specific cytokine production was positively correlated with CD154 expression by CD4 + T cells from bacillus Calmette-Guérin-vaccinated mice and show that high-quality microarrays can be performed from RNA isolated from CD154 + cells purified by cell sorting. Analysis of microarray data demonstrated that the transcriptome of CD4 + CD154 + cells was distinct from that of CD154 - cells and showed major enrichment of transcripts encoding multiple cytokines and pathways of cellular activation. One notable finding was the identification of a previously unrecognized subset of mycobacteria-specific CD4 + T cells that is characterized by the production of IL-3. Our results support the use of CD154 expression as a practical and reliable method to isolate live Ag-specific CD4 + T cells for transcriptomic analysis and potentially for a range of other studies in infected or previously immunized hosts. Copyright © 2017 by The American Association of Immunologists, Inc.

Calculation of induced current densities and specific absorption rates (SAR) for pregnant women exposed to hand-held metal detectors

International Nuclear Information System (INIS)

Kainz, Wolfgang; Chan, Dulciana D; Casamento, Jon P; Bassen, Howard I

2003-01-01

The finite difference time domain (FDTD) method in combination with a well established frequency scaling method was used to calculate the internal fields and current densities induced in a simple model of a pregnant woman and her foetus, when exposed to hand-held metal detectors. The pregnant woman and foetus were modelled using a simple semi-heterogeneous model in 10 mm resolution, consisting of three different types of tissue. The model is based on the scanned shape of a pregnant woman in the 34th gestational week. Nine different representative models of hand-held metal detectors operating in the frequency range from 8 kHz to 2 MHz were evaluated. The metal detectors were placed directly on the abdomen of the computational model with a spacing of 1 cm. Both the induced current density and the specific absorption rate (SAR) are well below the recommended limits for exposure of the general public published in the ICNIRP Guidelines and the IEEE C95.1 Standard. The highest current density is 8.3 mA m -2 and the highest SAR is 26.5 μW kg -1 . Compared to the limits for the induced current density recommended in the ICNIRP Guidelines, a minimum safety factor of 3 exists. Compared to the IEEE C95.1 Standard, a safety factor of 60,000 for the specific absorption rate was found. Based on the very low specific absorption rate and an induced current density below the recommended exposure limits, significant temperature rise or nerve stimulation in the pregnant woman or in the foetus can be excluded

On the role of sound in the strong Langmuir turbulence

International Nuclear Information System (INIS)

Malkin, V.M.

1989-01-01

The main directions in the precision of the theory of strong Langmuir turbulence caused by the necessity of account of sound waves in plasma are preseted. In particular the effect of conversion of short-wave modulations in Langmuir waves induced by sound waves, are briefly described. 8 refs

Association of HLA-BFNx011502 allele and carbamazepine-induced Stevens-Johnson syndrome among Indians

Directory of Open Access Journals (Sweden)

Mehta Timir

2009-01-01

Full Text Available Background: Stevens-Johnson Syndrome (SJS and toxic epidermal necrolysis are severe cutaneous reactions caused by certain drugs, including antiepileptic carbamazepine. A strong association has been reported between human leucocyte antigen (HLA-BFNx011502 and carbamazepine-induced SJS in Han Chinese patients. European studies suggested that HLA-BFNx011502 is not a universal marker but is ethnicity-specific for Asians. Aim: To study the association between HLA-BFNx011502 and carbamazepine-induced SJS in Indian patients. Methods: Eight individuals who fulfilled the diagnostic criteria of SJS induced by carbamazepine were identified and HLA-B molecular typing was performed. HLA-B genotyping was carried out by polymerase chain reaction using sequence-specific primers. Results: Out of eight patients studied for genotype, six patients were found to have the HLA-BFNx011502 allele. Conclusion: This study suggests an association between HLA-BFNx011502 and carbamazepine-induced SJS in Indian patients.

The QCD mass gap and quark deconfinement scales as mass bounds in strong gravity

Energy Technology Data Exchange (ETDEWEB)

Burikham, Piyabut [Chulalongkorn University, High Energy Physics Theory Group, Department of Physics, Faculty of Science, Bangkok (Thailand); Harko, Tiberiu [Babes-Bolyai University, Department of Physics, Cluj-Napoca (Romania); University College London, Department of Mathematics, London (United Kingdom); Lake, Matthew J. [Sun Yat-Sen University, School of Physics, Guangzhou (China); Nanyang Technological University, School of Physical and Mathematical Sciences, Singapore (Singapore); Naresuan University, The Institute for Fundamental Study, ' ' The Tah Poe Academia Institute' ' , Phitsanulok (Thailand); Thailand Center of Excellence in Physics, Ministry of Education, Bangkok (Thailand)

2017-11-15

Though not a part of mainstream physics, Salam's theory of strong gravity remains a viable effective model for the description of strong interactions in the gauge singlet sector of QCD, capable of producing particle confinement and asymptotic freedom, but not of reproducing interactions involving SU(3) color charge. It may therefore be used to explore the stability and confinement of gauge singlet hadrons, though not to describe scattering processes that require color interactions. It is a two-tensor theory of both strong interactions and gravity, in which the strong tensor field is governed by equations formally identical to the Einstein equations, apart from the coupling parameter, which is of order 1 GeV{sup -1}. We revisit the strong gravity theory and investigate the strong gravity field equations in the presence of a mixing term which induces an effective strong cosmological constant, Λ{sub f}. This introduces a strong de Sitter radius for strongly interacting fermions, producing a confining bubble, which allows us to identify Λ{sub f} with the 'bag constant' of the MIT bag model, B ≅ 2 x 10{sup 14} g cm{sup -3}. Assuming a static, spherically symmetric geometry, we derive the strong gravity TOV equation, which describes the equilibrium properties of compact hadronic objects. From this, we determine the generalized Buchdahl inequalities for a strong gravity 'particle', giving rise to upper and lower bounds on the mass/radius ratio of stable, compact, strongly interacting objects. We show, explicitly, that the existence of the lower mass bound is induced by the presence of Λ{sub f}, producing a mass gap, and that the upper bound corresponds to a deconfinement phase transition. The physical implications of our results for holographic duality in the context of the AdS/QCD and dS/QCD correspondences are also discussed. (orig.)

PWR control rods wear by vibrations induced by coolant fluid

International Nuclear Information System (INIS)

Reynier, R.

1997-01-01

Flow induced vibrations in pressurised water reactors generate the wear of control rods against their guidance systems. Alternate sliding (at 320 deg. C in water) and impact-sliding tests (at room temperature in air) were carried out on 304 L austenitic stainless steel control rods' claddings. Microstructural analysis were made on the wear scars of the tube specimen using Scanning ELectron Microscopy, microhardness measurements and X-ray diffractometry. The alternate sliding leads to an important mass loss, a strong plastic deformation due to the strain hardening of the surface layers and generates strong compressive residual stresses. These results are specific to a severe wear case. Therefore, the impact-sliding mode induces martensitic phase, a cracked oxide layer and a compressive residual stresses weaker than those created in the alternate sliding case. This type of motion leads to a milder wear of the control rods

Site-specific strong ground motion prediction using 2.5-D modelling

Science.gov (United States)

Narayan, J. P.

2001-08-01

An algorithm was developed using the 2.5-D elastodynamic wave equation, based on the displacement-stress relation. One of the most significant advantages of the 2.5-D simulation is that the 3-D radiation pattern can be generated using double-couple point shear-dislocation sources in the 2-D numerical grid. A parsimonious staggered grid scheme was adopted instead of the standard staggered grid scheme, since this is the only scheme suitable for computing the dislocation. This new 2.5-D numerical modelling avoids the extensive computational cost of 3-D modelling. The significance of this exercise is that it makes it possible to simulate the strong ground motion (SGM), taking into account the energy released, 3-D radiation pattern, path effects and local site conditions at any location around the epicentre. The slowness vector (py) was used in the supersonic region for each layer, so that all the components of the inertia coefficient are positive. The double-couple point shear-dislocation source was implemented in the numerical grid using the moment tensor components as the body-force couples. The moment per unit volume was used in both the 3-D and 2.5-D modelling. A good agreement in the 3-D and 2.5-D responses for different grid sizes was obtained when the moment per unit volume was further reduced by a factor equal to the finite-difference grid size in the case of the 2.5-D modelling. The components of the radiation pattern were computed in the xz-plane using 3-D and 2.5-D algorithms for various focal mechanisms, and the results were in good agreement. A comparative study of the amplitude behaviour of the 3-D and 2.5-D wavefronts in a layered medium reveals the spatial and temporal damped nature of the 2.5-D elastodynamic wave equation. 3-D and 2.5-D simulated responses at a site using a different strike direction reveal that strong ground motion (SGM) can be predicted just by rotating the strike of the fault counter-clockwise by the same amount as the azimuth of

HCV-specific immune responses induced by CIGB-230 in combination with IFN-α plus ribavirin

Science.gov (United States)

Amador-Cañizares, Yalena; Martínez-Donato, Gillian; Álvarez-Lajonchere, Liz; Vasallo, Claudia; Dausá, Mariacarla; Aguilar-Noriega, Daylen; Valenzuela, Carmen; Raíces, Ivette; Dubuisson, Jean; Wychowski, Czeslaw; Cinza-Estévez, Zurina; Castellanos, Marlén; Núñez, Magdalys; Armas, Anny; González, Yaimé; Revé, Ismariley; Guerra, Ivis; Pérez Aguiar, Ángel; Dueñas-Carrera, Santiago

2014-01-01

AIM: To analyze hepatitis C virus (HCV)-specific immune responses in chronically infected patients under triple therapy with interferon-α (IFN-α) plus ribavirin and CIGB-230. METHODS: CIGB-230 was administered in different schedules with respect to IFN-α plus ribavirin therapy. Paired serum and peripheral blood mononuclear cells (PBMC) samples from baseline and end of treatment were analyzed. The HCV-specific humoral response was tested by enzyme-linked immunosorbent assay, neutralizing antibodies were evaluated by cell culture HCV neutralization assays, PBMC proliferation was assayed by carboxyfluorescein succinimidyl ester staining and IFN-γ secretion was assessed by enzyme-linked immunospot. Data on virological and histological response and their association with immune variables are also provided. RESULTS: From week 12 to week 48, all groups of patients showed a significant reduction in mean leukocyte counts. Statistically significant reductions in antibody titers were frequent, but only individuals immunized with CIGB-230 as early add-on treatment sustained the core-IgG response, and the neutralizing antibody response was enhanced only in patients receiving CIGB-230. Cell-mediated immune responses also tended to decline, but significant reductions in IFN-γ secretion and total absence of core-specific lymphoproliferation were exclusive of the control group. Only CIGB-230-immunized individuals showed de novo induced lymphoproliferative responses against the structural antigens. Importantly, it was demonstrated that the quality of the CIGB-230-induced immune response depended on the number of doses and timing of administration in relation to the antiviral therapy. Specifically, the administration of 6 doses of CIGB-230 as late add-on to therapy increased the neutralizing antibody activity and the de novo core-specific IFN-γ secretion, both of which were associated with the sustained virological response. CONCLUSION: CIGB-230, combined with IFN

IL-36γ Is a Strong Inducer of IL-23 in Psoriatic Cells and Activates Angiogenesis

Directory of Open Access Journals (Sweden)

Charlie Bridgewood

2018-02-01

Full Text Available The IL-1 family member cytokine IL-36γ is recognised as key mediator in the immunopathology of psoriasis, hallmarks of which involve the activation of both resident and infiltrating inflammatory myeloid cells and aberrant angiogenesis. This research demonstrates a role for IL-36γ in both myeloid activation and angiogenesis. We show that IL-36γ induces the production of psoriasis-associated cytokines from macrophages (IL-23 and TNFα and that this response is enhanced in macrophages from psoriasis patients. This effect is specific for IL-36γ and could not be mimicked by other IL-1 family cytokines such as IL-1α. IL-36γ was also demonstrated to induce endothelial tube formation and branching, in a VEGF-A-dependent manner. Furthermore, IL-36γ-stimulated macrophages potently activated endothelial cells and led to increased adherence of monocytes, effects that were markedly more pronounced for psoriatic macrophages. Interestingly, regardless of stimulus, psoriasis monocytes showed increased adherence to both the stimulated and unstimulated endothelium when compared with monocytes from healthy individuals. Collectively, these findings show that IL-36γ has the potential to enhance endothelium directed leucocyte infiltration into the skin and strengthen the IL-23/IL-17 pathway adding to the growing evidence of pathogenetic roles for IL-36γ in psoriatic responses. Our findings also point to a cellular response, which could potentially explain cardiovascular comorbidities in psoriasis in the form of endothelial activation and increased monocyte adherence.

IL-36γ Is a Strong Inducer of IL-23 in Psoriatic Cells and Activates Angiogenesis.

Science.gov (United States)

Bridgewood, Charlie; Fearnley, Gareth W; Berekmeri, Anna; Laws, Philip; Macleod, Tom; Ponnambalam, Sreenivasan; Stacey, Martin; Graham, Anne; Wittmann, Miriam

2018-01-01

The IL-1 family member cytokine IL-36γ is recognised as key mediator in the immunopathology of psoriasis, hallmarks of which involve the activation of both resident and infiltrating inflammatory myeloid cells and aberrant angiogenesis. This research demonstrates a role for IL-36γ in both myeloid activation and angiogenesis. We show that IL-36γ induces the production of psoriasis-associated cytokines from macrophages (IL-23 and TNFα) and that this response is enhanced in macrophages from psoriasis patients. This effect is specific for IL-36γ and could not be mimicked by other IL-1 family cytokines such as IL-1α. IL-36γ was also demonstrated to induce endothelial tube formation and branching, in a VEGF-A-dependent manner. Furthermore, IL-36γ-stimulated macrophages potently activated endothelial cells and led to increased adherence of monocytes, effects that were markedly more pronounced for psoriatic macrophages. Interestingly, regardless of stimulus, psoriasis monocytes showed increased adherence to both the stimulated and unstimulated endothelium when compared with monocytes from healthy individuals. Collectively, these findings show that IL-36γ has the potential to enhance endothelium directed leucocyte infiltration into the skin and strengthen the IL-23/IL-17 pathway adding to the growing evidence of pathogenetic roles for IL-36γ in psoriatic responses. Our findings also point to a cellular response, which could potentially explain cardiovascular comorbidities in psoriasis in the form of endothelial activation and increased monocyte adherence.

Nuclear receptor CAR specifically activates the two-pore K+ channel Kcnk1 gene in male mouse livers, which attenuates phenobarbital-induced hepatic hyperplasia.

Science.gov (United States)

Saito, Kosuke; Moore, Rick; Negishi, Masahiko

2013-03-01

KCNK1, a member of the family of two-pore K(+) ion channels, is specifically induced in the livers of male mice after phenobarbital treatment. Here, we have determined the molecular mechanism of this male-specific activation of the Kcnk1 gene and characterized KCNK1 as a phenobarbital-inducible antihyperplasia factor. Upon activation by phenobarbital, nuclear receptor CAR binds the 97-bp response element (-2441/-2345) within the Kcnk1 promoter. This binding is observed in the livers of male mice, but not in the livers of female mice and requires the pituitary gland, because hypophysectomy abrogates it. Hyperplasia further progressed in the livers of Kcnk1 ( -/- ) male mice compared with those of Kcnk1 ( +/+ ) males after phenobarbital treatment. Thus, KCNK1 suppresses phenobarbital-induced hyperplasia. These results indicate that phenobarbital treatment induces KCNK1 to elicit a male-specific and growth-suppressing signal. Thus, KCNK1 and Kcnk1 ( -/- ) mice provide an experimental tool for further investigation into the molecular mechanism of CAR-mediated promotion of the development of hepatocellular carcinoma in mice.

Human-induced geomorphic change across environmental gradients

Science.gov (United States)

Vanacker, V.; Molina, A.; Bellin, N.; Christl, M.

2016-12-01

Human-induced land cover changes are causing important adverse effects on the ecological services rendered by mountain ecosystems, and the number of case-studies of the impact of humans on soil erosion and sediment yield has mounted rapidly. Anthropogenic disturbance of natural vegetation can profoundly alter the physical, chemical and biological processes within soils. Rapid removal of topsoil during intense farming can result in an imbalance between soil production through chemical weathering and physical soil erosion, with direct implications on nutrient cycling, soil fertility and agricultural production. In this study, we present a conceptual model for assessing human-induced erosion for a wide variety of environmental settings and pose that human-induced geomorphic change cannot be assessed solely based on modern erosion rates as natural or baseline erosion rates can be important in e.g. mountainous terrain. As such, we assess the vulnerability of a given ecosystem to human-induced land cover change by quantifying the change in catchment-wide erosion rates resulting from anthropogenic changes in vegetation cover. Human-induced erosion is here approximated by the ratio of the total specific sediment yield to the natural erosional mass flux, and is dimensionless. The conceptual model is applied to three contrasting environmental settings where data on soil production, physical soil erosion and long-term denudation are available: the tropical Andes, subtropical southern Brazil, and semi-arid Spanish Cordillera. The magnitude of human-induced geomorphic change strongly differs between the three regions. The data suggest that the sensitivity to human-induced erosion is ecosystem dependent, and related to soil erosivity and potential vegetation cover disturbances as a result of human impact. It may therefore be expected that the potential for erosion regulation is larger in well-vegetated ecosystem where strong differences may exist in vegetation cover between

Silver nanoparticles induce developmental stage-specific embryonic phenotypes in zebrafish

Science.gov (United States)

Lee, Kerry J.; Browning, Lauren M.; Nallathamby, Prakash D.; Osgood, Christopher J.; Xu, Xiao-Hong Nancy

2013-11-01

Much is anticipated from the development and deployment of nanomaterials in biological organisms, but concerns remain regarding their biocompatibility and target specificity. Here we report our study of the transport, biocompatibility and toxicity of purified and stable silver nanoparticles (Ag NPs, 13.1 +/- 2.5 nm in diameter) upon the specific developmental stages of zebrafish embryos using single NP plasmonic spectroscopy. We find that single Ag NPs passively diffuse into five different developmental stages of embryos (cleavage, early-gastrula, early-segmentation, late-segmentation, and hatching stages), showing stage-independent diffusion modes and diffusion coefficients. Notably, the Ag NPs induce distinctive stage and dose-dependent phenotypes and nanotoxicity, upon their acute exposure to the Ag NPs (0-0.7 nM) for only 2 h. The late-segmentation embryos are most sensitive to the NPs with the lowest critical concentration (CNP,c nanotoxicity, upon their acute exposure to the Ag NPs (0-0.7 nM) for only 2 h. The late-segmentation embryos are most sensitive to the NPs with the lowest critical concentration (CNP,c << 0.02 nM) and highest percentages of cardiac abnormalities, followed by early-segmentation embryos (CNP,c < 0.02 nM), suggesting that disruption of cell differentiation by the NPs causes the most toxic effects on embryonic development. The cleavage-stage embryos treated with the NPs develop into a wide variety of phenotypes (abnormal finfold, tail/spinal cord flexure, cardiac malformation/edema, yolk sac edema, and acephaly). These organ structures are not yet developed in cleavage-stage embryos, suggesting that the earliest determinative events to create these structures are ongoing, and disrupted by NPs, which leads to the downstream effects. In contrast, the hatching embryos are most resistant to the Ag NPs, and majority of embryos (94%) develop normally, and none of them develop abnormally. Interestingly, early-gastrula embryos are less sensitive

Mycobacterium vaccae induces a strong Th1 response that subsequently declines in C57BL/6 mice.

Science.gov (United States)

Zhang, Lijiao; Jiang, Yanlong; Cui, Ziyin; Yang, Wentao; Yue, Limin; Ma, Yingcong; Shi, Shaohua; Wang, Chunfang; Wang, Chunfeng; Qian, Aidong

2016-12-30

Mycobacterium (M.) vaccae is a fast-growing species of saprophytic bacteria that is widely distributed. To understand the host immune responses induced by M. vaccae isolated from bovine submaxillary lymph nodes, C57BL/6 mice were infected with reference strain M. bovis Bacillus Calmette-Guérin (BCG) and isolated M. vaccae using intraperitoneal injections. Comparison of the bacterial replication and organ pathology between M. vaccae and M. bovis BCG revealed that M. vaccae was more malignant than M. bovis in mice. We also demonstrated that serum from the M. vaccae -infected mice contained a higher expression level of gamma-interferon (IFN-γ), tumor necrosis factor alpha, monocyte chemoattractant protein-1, interleukin (IL)-4, IL-12, IL-10 and transforming growth factor beta than did the other groups, especially after week 4. Furthermore, when the numbers of CD3⁺CD4⁺IFN-γ⁺ and CD3⁺CD4⁺IL4⁺cells in the infected mice were observed by flow cytometry, we found that a powerful T helper 1 (Th1) response was induced by M. vaccae infection, which was associated with the emergence of CD3⁺CD4⁺IFN-γ⁺cells. However, the Th1 response declined over time, which was associated with appearance of the CD4⁺CD25⁺FoxP3⁺ and CD4⁺CD25⁺CD152⁺Treg cell reaction. In addition, a strong Th2 response was found. Finally, we found that M. vaccae infection increased the production of type I IFNs, which was associated with a reduced Th1 response.

Bifidobacterium longum CCM 7952 Promotes Epithelial Barrier Function and Prevents Acute DSS-Induced Colitis in Strictly Strain-Specific Manner.

Directory of Open Access Journals (Sweden)

Dagmar Srutkova

Full Text Available Reduced microbial diversity has been associated with inflammatory bowel disease (IBD and probiotic bacteria have been proposed for its prevention and/or treatment. Nevertheless, comparative studies of strains of the same subspecies for specific health benefits are scarce. Here we compared two Bifidobacterium longum ssp. longum strains for their capacity to prevent experimental colitis.Immunomodulatory properties of nine probiotic bifidobacteria were assessed by stimulation of murine splenocytes. The immune responses to B. longum ssp. longum CCM 7952 (Bl 7952 and CCDM 372 (Bl 372 were further characterized by stimulation of bone marrow-derived dendritic cell, HEK293/TLR2 or HEK293/NOD2 cells. A mouse model of dextran sulphate sodium (DSS-induced colitis was used to compare their beneficial effects in vivo.The nine bifidobacteria exhibited strain-specific abilities to induce cytokine production. Bl 372 induced higher levels of both pro- and anti-inflammatory cytokines in spleen and dendritic cell cultures compared to Bl 7952. Both strains engaged TLR2 and contain ligands for NOD2. In a mouse model of DSS-induced colitis, Bl 7952, but not Bl 372, reduced clinical symptoms and preserved expression of tight junction proteins. Importantly, Bl 7952 improved intestinal barrier function as demonstrated by reduced FITC-dextran levels in serum.We have shown that Bl 7952, but not Bl 372, protected mice from the development of experimental colitis. Our data suggest that although some immunomodulatory properties might be widespread among the genus Bifidobacterium, others may be rare and characteristic only for a specific strain. Therefore, careful selection might be crucial in providing beneficial outcome in clinical trials with probiotics in IBD.

Strongly interacting W's and Z's

International Nuclear Information System (INIS)

Gaillard, M.K.

1984-01-01

The study focussed primarily on the dynamics of a strongly interacting W, Z(SIW) sector, with the aim of sharpening predictions for total W, Z yield and W, Z multiplicities expected from WW fusion for various scenarios. Specific issues raised in the context of the general problem of modeling SIW included the specificity of the technicolor (or, equivalently, QCD) model, whether or not a composite scalar model can be evaded, and whether the standard model necessarily implies an I = J = O state (≅ Higgs particle) that is relatively ''light'' (M ≤ hundreds of TeV). The consensus on the last issue was that existing arguments are inconclusive. While the author shall briefly address compositeness and alternatives to the technicolor model, quantitative estimates will be of necessity based on technicolor or an extrapolation of pion data

Robust mesoscopic superposition of strongly correlated ultracold atoms

International Nuclear Information System (INIS)

Hallwood, David W.; Ernst, Thomas; Brand, Joachim

2010-01-01

We propose a scheme to create coherent superpositions of annular flow of strongly interacting bosonic atoms in a one-dimensional ring trap. The nonrotating ground state is coupled to a vortex state with mesoscopic angular momentum by means of a narrow potential barrier and an applied phase that originates from either rotation or a synthetic magnetic field. We show that superposition states in the Tonks-Girardeau regime are robust against single-particle loss due to the effects of strong correlations. The coupling between the mesoscopically distinct states scales much more favorably with particle number than in schemes relying on weak interactions, thus making particle numbers of hundreds or thousands feasible. Coherent oscillations induced by time variation of parameters may serve as a 'smoking gun' signature for detecting superposition states.

Time-resolved pulse-counting lock-in detection of laser induced fluorescence in the presence of a strong background emission

International Nuclear Information System (INIS)

Pelissier, B.; Sadeghi, N.

1996-01-01

We describe a time-resolved pulse-counting system well adapted for the detection of continuous laser induced fluorescence (LIF) signals in repetitive phenomena, when a strong background emission is present. It consists of 256 channels coupled to a first in first out memory and interfaced to a 486 DX 33 PC, for data storage. It accepts time-averaged count rates up to 450 kcount/s. Time between channels can be set from 12.5 ns to several μs and the dead time between two consecutive cycles of the physical phenomena is less than 20 ns. In phase with a chopper, which modulates the laser beam, it adds the observed photon signal to the channel memories when the beam is on and substracts it when the beam is stopped, acting like a lock-in amplifier which detect only the modulated part of the signal. The minimum detectivity on the LIF signal is only limited by the shot noise of the plasma induced emission signal. As an application, we studied the time variation of the Ar + *( 2 G 9/2 ) metastable ions, detected by LIF, in two types of plasmas. Their radiative lifetime and collisional quenching frequencies were deduced from their decay rate in the afterglow of a pulsed Helicon reactor. We also observed the evolution of their density in a 455 kHz capacitively coupled argon discharge. copyright 1996 American Institute of Physics

Strong consistency of nonparametric Bayes density estimation on compact metric spaces with applications to specific manifolds.

Science.gov (United States)

Bhattacharya, Abhishek; Dunson, David B

2012-08-01

This article considers a broad class of kernel mixture density models on compact metric spaces and manifolds. Following a Bayesian approach with a nonparametric prior on the location mixing distribution, sufficient conditions are obtained on the kernel, prior and the underlying space for strong posterior consistency at any continuous density. The prior is also allowed to depend on the sample size n and sufficient conditions are obtained for weak and strong consistency. These conditions are verified on compact Euclidean spaces using multivariate Gaussian kernels, on the hypersphere using a von Mises-Fisher kernel and on the planar shape space using complex Watson kernels.

Myxoviruses do not induce non-specific alterations in membrane permeability early on in infection

International Nuclear Information System (INIS)

Foster, K.A.; Micklem, K.J.; Bogomolova, N.N.; Boriskin, Y.S.; Pasternak, C.A.

1983-01-01

The permeability characteristics of cells infected with myxoviruses have been studied by measuring the concentrative uptake of nutrients, the concentration of intracellular K + , and the maintenance of the Na + gradient across the plasma membrane. Cells either show no change at all (Sendai virus-infected BHK cells and measles virus-infected Vero cells) or they show a decreased ability to concentrate nutrients, while intracellular K + and the Na + gradient remain unchanged (Sendai and influenza virus-infected L-1210 cells, measles virus-infected lymphocytes and mumps virus-infected L-41 cells). In no case, therefore, was a change observed that resembles the non-specific increase in membrane permeability induced by haemolytic paramyxoviruses (35, 42) or the non-specific membrane leakiness postulated to take place in infected cells (8, 9). A preliminary account of some of these findings has been presented (39)

Non-verbal emotion communication training induces specific changes in brain function and structure.

Science.gov (United States)

Kreifelts, Benjamin; Jacob, Heike; Brück, Carolin; Erb, Michael; Ethofer, Thomas; Wildgruber, Dirk

2013-01-01

The perception of emotional cues from voice and face is essential for social interaction. However, this process is altered in various psychiatric conditions along with impaired social functioning. Emotion communication trainings have been demonstrated to improve social interaction in healthy individuals and to reduce emotional communication deficits in psychiatric patients. Here, we investigated the impact of a non-verbal emotion communication training (NECT) on cerebral activation and brain structure in a controlled and combined functional magnetic resonance imaging (fMRI) and voxel-based morphometry study. NECT-specific reductions in brain activity occurred in a distributed set of brain regions including face and voice processing regions as well as emotion processing- and motor-related regions presumably reflecting training-induced familiarization with the evaluation of face/voice stimuli. Training-induced changes in non-verbal emotion sensitivity at the behavioral level and the respective cerebral activation patterns were correlated in the face-selective cortical areas in the posterior superior temporal sulcus and fusiform gyrus for valence ratings and in the temporal pole, lateral prefrontal cortex and midbrain/thalamus for the response times. A NECT-induced increase in gray matter (GM) volume was observed in the fusiform face area. Thus, NECT induces both functional and structural plasticity in the face processing system as well as functional plasticity in the emotion perception and evaluation system. We propose that functional alterations are presumably related to changes in sensory tuning in the decoding of emotional expressions. Taken together, these findings highlight that the present experimental design may serve as a valuable tool to investigate the altered behavioral and neuronal processing of emotional cues in psychiatric disorders as well as the impact of therapeutic interventions on brain function and structure.

Controlling the alignment of neutral molecules by a strong laser field

DEFF Research Database (Denmark)

Sakai, H.; Hilligsøe, Karen Marie; Hald, K.

1999-01-01

by lowering the initial rotational energy of the molecules or by increasing the laser intensity. The alignment is measured by photodissociating the molecules with a femtosecond laser pulse and detecting the direction of the photofragments by imaging techniques. The strongest degree of alignment observed......A strong nonresonant nanosecond laser pulse is used to align neutral iodine molecules. The technique, applicable to both polar and nonpolar molecules, relies on the interaction between the strong laser field and the induced dipole moment of the molecules. The degree of alignment is enhanced...

Pellet feed adsorbed with the recombinant Lactococcus lactis BFE920 expressing SiMA antigen induced strong recall vaccine effects against Streptococcus iniae infection in olive flounder (Paralichthys olivaceus).

Science.gov (United States)

Kim, Daniel; Beck, Bo Ram; Lee, Sun Min; Jeon, Jongsu; Lee, Dong Wook; Lee, Jae Il; Song, Seong Kyu

2016-08-01

The aim of this study was to develop a fish feed vaccine that provides effective disease prevention and convenient application. A lactic acid bacterium (LAB), Lactococcus lactis BFE920, was modified to express the SiMA antigen, a membrane protein of Streptococcus iniae. The antigen was engineered to be expressed under the nisin promoter, which is induced by nisin produced naturally by the host LAB. Various sizes (40 ± 3.5 g, 80 ± 2.1 g, and 221 ± 2.4 g) of olive flounder (Paralichthys olivaceus) were vaccinated by feeding the extruded pellet feed, onto which the SiMA-expressing L. lactis BFE920 (1.0 × 10(7) CFU/g) was adsorbed. Vaccine-treated feed was administered twice a day for 1 week, and priming and boosting were performed with a 1-week interval in between. The vaccinated fish had significantly elevated levels of antigen-specific serum antibodies and T cell marker mRNAs: CD4-1, CD4-2, and CD8a. In addition, the feed vaccine significantly induced T cell effector functions, such as the production of IFN-γ and activation of the transcription factor that induces its expression, T-bet. When the flounder were challenged by intraperitoneal infection and bath immersion with S. iniae, the vaccinated fish showed 84% and 82% relative percent survival (RPS), respectively. Furthermore, similar protective effects were confirmed even 3 months after vaccination in a field study (n = 4800), indicating that this feed vaccine elicited prolonged duration of immunopotency. In addition, the vaccinated flounder gained 21% more weight and required 16% less feed to gain a unit of body weight compared to the control group. The data clearly demonstrate that the L. lactis BFE920-SiMA feed vaccine has strong protective effects, induces prolonged vaccine efficacy, and has probiotic effects. In addition, this LAB-based fish feed vaccine can be easily used to target many different pathogens of diverse fish species. Copyright © 2016 Elsevier Ltd. All rights reserved.

Strongly anisotropic spin-orbit splitting in a two-dimensional electron gas

DEFF Research Database (Denmark)

Michiardi, Matteo; Bianchi, Marco; Dendzik, Maciej

2015-01-01

Near-surface two-dimensional electron gases on the topological insulator Bi$_2$Te$_2$Se are induced by electron doping and studied by angle-resolved photoemission spectroscopy. A pronounced spin-orbit splitting is observed for these states. The $k$-dependent splitting is strongly anisotropic to a...

Strongly correlated systems experimental techniques

CERN Document Server

Mancini, Ferdinando

2015-01-01

The continuous evolution and development of experimental techniques is at the basis of any fundamental achievement in modern physics. Strongly correlated systems (SCS), more than any other, need to be investigated through the greatest variety of experimental techniques in order to unveil and crosscheck the numerous and puzzling anomalous behaviors characterizing them. The study of SCS fostered the improvement of many old experimental techniques, but also the advent of many new ones just invented in order to analyze the complex behaviors of these systems. Many novel materials, with functional properties emerging from macroscopic quantum behaviors at the frontier of modern research in physics, chemistry and materials science, belong to this class of systems. The volume presents a representative collection of the modern experimental techniques specifically tailored for the analysis of strongly correlated systems. Any technique is presented in great detail by its own inventor or by one of the world-wide recognize...

Endurance exercise training induces fat depot-specific differences in basal autophagic activity

Energy Technology Data Exchange (ETDEWEB)

Tanaka, Goki; Kato, Hisashi; Izawa, Tetsuya, E-mail: tizawa@mail.doshisha.ac.jp

2015-10-23

autophagosome associated LC3-II in WAT. • Exercise-induced changes in p62 and ATG7 were WAT-type specific. • Exercise-induced basal autophagic activity shows fat depot-specific differences.

Endurance exercise training induces fat depot-specific differences in basal autophagic activity

International Nuclear Information System (INIS)

Tanaka, Goki; Kato, Hisashi; Izawa, Tetsuya

2015-01-01

autophagosome associated LC3-II in WAT. • Exercise-induced changes in p62 and ATG7 were WAT-type specific. • Exercise-induced basal autophagic activity shows fat depot-specific differences.

Beta decay and other processes in strong electromagnetic fields

International Nuclear Information System (INIS)

Akhmedov, E. Kh.

2011-01-01

We consider effects of the fields of strong electromagnetic waves on various characteristics of quantum processes. After a qualitative discussion of the effects of external fields on the energy spectra and angular distributions of the final-state particles as well as on the total probabilities of the processes (such as decay rates and total cross sections), we present a simple method of calculating the total probabilities of processes with production of nonrelativistic charged particles. Using nuclear β decay as an example, we study the weak- and strong-field limits, as well as the field-induced β decay of nuclei stable in the absence of the external fields, both in the tunneling and multiphoton regimes. We also consider the possibility of accelerating forbidden nuclear β decays by lifting the forbiddeness due to the interaction of the parent or daughter nuclei with the field of a strong electromagnetic wave. It is shown that for currently attainable electromagnetic fields all effects on total β-decay rates are unobservably small.

Cardiac-Specific Overexpression of Catalase Attenuates Lipopolysaccharide-Induced Myocardial Contractile Dysfunction: Role of Autophagy

Science.gov (United States)

Turdi, Subat; Han, Xuefeng; Huff, Anna F.; Roe, Nathan D.; Hu, Nan; Gao, Feng; Ren, Jun

2012-01-01

Lipopolysaccharide (LPS) from Gram-negative bacteria is a major initiator of sepsis, leading to cardiovascular collapse. Accumulating evidence has indicated a role of reactive oxygen species (ROS) in cardiovascular complication in sepsis. This study was designed to examine the effect of cardiac-specific overexpression of catalase in LPS-induced cardiac contractile dysfunction and the underlying mechanism(s) with a focus on autophagy. Catalase transgenic and wild-type FVB mice were challenged with LPS (6 mg/kg) and cardiac function was evaluated. Levels of oxidative stress, autophagy, apoptosis and protein damage were examined using fluorescence microscopy, Western blot, TUNEL assay, caspase-3 activity and carbonyl formation. Kaplan-Meier curve was constructed for survival following LPS treatment. Our results revealed a lower mortality in catalase mice compared with FVB mice following LPS challenge. LPS injection led to depressed cardiac contractile capacity as evidenced by echocardiography and cardiomyocyte contractile function, the effect of which was ablated by catalase overexpression. LPS treatment induced elevated TNF-α level, autophagy, apoptosis (TUNEL, caspase-3 activation, cleaved caspase-3), production of ROS and O2−, and protein carbonyl formation, the effects of which were significantly attenuated by catalase overexpression. Electron microscopy revealed focal myocardial damage characterized by mitochondrial injury following LPS treatment, which was less severe in catalase mice. Interestingly, LPS-induced cardiomyocyte contractile dysfunction was prevented by antioxidant NAC and the autophagy inhibitor 3-methyladenine. Taken together, our data revealed that catalase protects against LPS-induced cardiac dysfunction and mortality, which may be associated with inhibition of oxidative stress and autophagy. PMID:22902401

Novel strong tissue specific promoter for gene expression in human germ cells

Directory of Open Access Journals (Sweden)

Kuzmin Denis

2010-08-01

Full Text Available Abstract Background Tissue specific promoters may be utilized for a variety of applications, including programmed gene expression in cell types, tissues and organs of interest, for developing different cell culture models or for use in gene therapy. We report a novel, tissue-specific promoter that was identified and engineered from the native upstream regulatory region of the human gene NDUFV1 containing an endogenous retroviral sequence. Results Among seven established human cell lines and five primary cultures, this modified NDUFV1 upstream sequence (mNUS was active only in human undifferentiated germ-derived cells (lines Tera-1 and EP2102, where it demonstrated high promoter activity (~twice greater than that of the SV40 early promoter, and comparable to the routinely used cytomegaloviral promoter. To investigate the potential applicability of the mNUS promoter for biotechnological needs, a construct carrying a recombinant cytosine deaminase (RCD suicide gene under the control of mNUS was tested in cell lines of different tissue origin. High cytotoxic effect of RCD with a cell-death rate ~60% was observed only in germ-derived cells (Tera-1, whereas no effect was seen in a somatic, kidney-derived control cell line (HEK293. In further experiments, we tested mNUS-driven expression of a hyperactive Sleeping Beauty transposase (SB100X. The mNUS-SB100X construct mediated stable transgene insertions exclusively in germ-derived cells, thereby providing further evidence of tissue-specificity of the mNUS promoter. Conclusions We conclude that mNUS may be used as an efficient promoter for tissue-specific gene expression in human germ-derived cells in many applications. Our data also suggest that the 91 bp-long sequence located exactly upstream NDUFV1 transcriptional start site plays a crucial role in the activity of this gene promoter in vitro in the majority of tested cell types (10/12, and an important role - in the rest two cell lines.

Resveratrol strongly enhances the retinoic acid-induced superoxide generating activity via up-regulation of gp91-phox gene expression in U937 cells.

Science.gov (United States)

Kikuchi, Hidehiko; Mimuro, Hitomi; Kuribayashi, Futoshi

2018-01-01

The membrane bound cytochrome b 558 composed of gp91-phox and p22-phox proteins, and cytosolic proteins p40-, p47-and p67-phox are important components of superoxide (O 2 - )-generating system in phagocytes. Here, we describe that resveratrol, a pleiotropic phytochemical belonging to the stilbenoids, dramatically activates the O 2 - -generating system during retinoic acid (RA)-induced differentiation of human monoblastic leukemia U937 cells to macrophage-like cells. When U937 cells were cultured in the presence of RA and resveratrol, the O 2 - -generating activity increased more than 5-fold compared with that in the absence of the latter. Semiquantitative RT-PCR showed that co-treatment with RA and resveratrol strongly enhanced transcription of the gp91-phox compared with those of the RA-treatment only. On the other hand, immunoblot analysis revealed that co-treatment with RA and resveratrol caused remarkable accumulation of protein levels of gp91-phox (to 4-fold), p22-phox (to 5-fold) and p47-phox (to 4-fold) compared with those of the RA-treatment alone. In addition, ChIP assay suggested that resveratrol participates in enhancing the gene expression of gp91-phox via promoting acetylation of Lys-9 residues and Lys-14 residues of histone H3 within chromatin around the promoter regions of the gene. These results suggested that resveratrol strongly enhances the RA-induced O 2 - -generating activity via up-regulation of gp91-phox gene expression in U937 cells. Copyright © 2017 Elsevier Inc. All rights reserved.

Diabetes-specific genetic effects on obesity traits in American Indian populations: the Strong Heart Family Study

Directory of Open Access Journals (Sweden)

Howard Barbara V

2008-10-01

Full Text Available Abstract Background Body fat mass distribution and deposition are determined by multiple environmental and genetic factors. Obesity is associated with insulin resistance, hyperinsulinemia, and type 2 diabetes. We previously identified evidence for genotype-by-diabetes interaction on obesity traits in Strong Heart Family Study (SHFS participants. To localize these genetic effects, we conducted genome-wide linkage scans of obesity traits in individuals with and without type 2 diabetes, and in the combined sample while modeling interaction with diabetes using maximum likelihood methods (SOLAR 2.1.4. Methods SHFS recruited American Indians from Arizona, North and South Dakota, and Oklahoma. Anthropometric measures and diabetes status were obtained during a clinic visit. Marker allele frequencies were derived using maximum likelihood methods estimated from all individuals and multipoint identity by descent sharing was estimated using Loki. We used variance component linkage analysis to localize quantitative trait loci (QTLs influencing obesity traits. We tested for evidence of additive and QTL-specific genotype-by-diabetes interactions using the regions identified in the diabetes-stratified analyses. Results Among 245 diabetic and 704 non-diabetic American Indian individuals, we detected significant additive gene-by-diabetes interaction for weight and BMI (P P Conclusion These results suggest distinct genetic effects on body mass in individuals with diabetes compared to those without diabetes, and a possible role for one or more genes on chromosome 1 in the pathogenesis of obesity.

Generation of patient-specific induced pluripotent stem cells from Leber's hereditary optic neuropathy

Directory of Open Access Journals (Sweden)

Huai-En Lu

2018-04-01

Full Text Available Leber's hereditary optic neuropathy (LHON is a maternally inherited mitochondrial disease caused by homoplasmic point mutations in complex I subunit genes of mitochondrial DNA. In this report, we generated an induced pluripotent stem cell (iPSCs line, TVGH-iPSC-010-09, from the peripheral blood mononuclear cells of a female patient with Leber's hereditary optic neuropathy (LHON by using the Sendai-virus delivery system. The resulting iPSCs retained the disease-causing mitochondrial DNA mutation, expressed pluripotent markers and could differentiate into the three germ layers. We believe LHON patient-specific iPSCs provide a powerful in vitro model for evaluating the pathological phenotypes of the disease.

Coxsackievirus A 16 infection does not interfere with the specific immune response induced by an enterovirus 71 inactivated vaccine in rhesus monkeys.

Science.gov (United States)

Wang, Jingjing; Qi, Sudong; Zhang, Xiaolong; Zhang, Ying; Liu, Longding; Che, Yanchun; He, Zhanlong; Zhao, Yuan; Lu, Shuaiyao; Yu, Wenhai; Li, Qihan

2014-07-31

Hand, foot and mouth disease is usually caused by enterovirus 71 (EV71) and coxsackievirus A 16 (CA16), which are members of the Picornaviridae family. In the present study, the characteristics of the immune response induced by an EV71 inactivated vaccine (made from human diploid cells) were explored in the presence of CA16 infection, based on the previously established neonatal rhesus monkey model. The typical clinical manifestations, including body temperature, viral viremia and virus shedding in the mouth, pharynx and feces, were characterized. A specific neutralizing antibody assay showed that the specific immune response induced by the EV71 inactivated vaccine was active against EV71 but not against CA16. No remarkable fluctuation in proinflammatory cytokine release was identified in the serum of immunized monkeys with EV71 vaccine and CA16 infections subsequently. The results showed that the specific immune response induced by the EV71 inactivated vaccine is effective against EV71 infection but is not affected by CA16 infection. Copyright © 2014 Elsevier Ltd. All rights reserved.

Specific Conditions for Resveratrol Neuroprotection against Ethanol-Induced Toxicity

Directory of Open Access Journals (Sweden)

Brigitte Gonthier

2012-01-01

Full Text Available Aims. 3,5,4′-Trihydroxy-trans-stilbene, a natural polyphenolic compound present in wine and grapes and better known as resveratrol, has free radical scavenging properties and is a potent protector against oxidative stress induced by alcohol metabolism. Today, the mechanism by which ethanol exerts its toxicity is still not well understood, but it is generally considered that free radical generation plays an important role in the appearance of structural and functional alterations in cells. The aim of this study was to evaluate the protective action of resveratrol against ethanol-induced brain cell injury. Methods. Primary cultures of rat astrocytes were exposed to ethanol, with or without a pretreatment with resveratrol. We examined the dose-dependent effects of this resveratrol pretreatment on cytotoxicity and genotoxicity induced by ethanol. Cytotoxicity was assessed using the MTT reduction test. Genotoxicity was evidenced using single cell gel electrophoresis. In addition, DNA staining with fluorescent dyes allowed visualization of nuclear damage using confocal microscopy. Results. Cell pretreatment with low concentrations of trans-resveratrol (0.1–10 μM slowed down cell death and DNA damage induced by ethanol exposure, while higher concentrations (50–100 μM enhanced these same effects. No protection by cis-resveratrol was observed. Conclusion. Protection offered by trans-resveratrol against ethanol-induced neurotoxicity was only effective for low concentrations of this polyphenol.

The CO/NOx emissions of swirled, strongly pulsed jet diffusion flames

KAUST Repository

Liao, Ying-Hao

2014-05-28

The CO and NOx exhaust emissions of swirled, strongly pulsed, turbulent jet diffusion flames were studied experimentally in a coflow swirl combustor. Measurements of emissions were performed on the combustor centerline using standard emission analyzers combined with an aspirated sampling probe located downstream of the visible flame tip. The highest levels of CO emissions are generally found for compact, isolated flame puffs, which is consistent with the quenching due to rapid dilution with excess air. The imposition of swirl generally results in a decrease in CO levels by up to a factor of 2.5, suggesting more rapid and compete fuel/air mixing by imposing swirl in the coflow stream. The levels of NO emissions for most cases are generally below the steady-flame value. The NO levels become comparable to the steady-flame value for sufficiently short jet-off times. The swirled coflow air can, in some cases, increase the NO emissions due to a longer combustion residence time due to the flow recirculation within the swirl-induced recirculation zone. Scaling relations, when taking into account the impact of air dilution over an injection cycle on the flame length, reveal a strong correlation between the CO emissions and the global residence time. However, the NO emissions do not successfully correlate with the global residence time. For some specific cases, a compact flame with a simultaneous decrease in both CO and NO emissions compared to the steady flames was observed. © Copyright © Taylor & Francis Group, LLC.

Fractional Transport in Strongly Turbulent Plasmas

Science.gov (United States)

Isliker, Heinz; Vlahos, Loukas; Constantinescu, Dana

2017-07-01

We analyze statistically the energization of particles in a large scale environment of strong turbulence that is fragmented into a large number of distributed current filaments. The turbulent environment is generated through strongly perturbed, 3D, resistive magnetohydrodynamics simulations, and it emerges naturally from the nonlinear evolution, without a specific reconnection geometry being set up. Based on test-particle simulations, we estimate the transport coefficients in energy space for use in the classical Fokker-Planck (FP) equation, and we show that the latter fails to reproduce the simulation results. The reason is that transport in energy space is highly anomalous (strange), the particles perform Levy flights, and the energy distributions show extended power-law tails. Newly then, we motivate the use and derive the specific form of a fractional transport equation (FTE), we determine its parameters and the order of the fractional derivatives from the simulation data, and we show that the FTE is able to reproduce the high energy part of the simulation data very well. The procedure for determining the FTE parameters also makes clear that it is the analysis of the simulation data that allows us to make the decision whether a classical FP equation or a FTE is appropriate.

X-ray-induced specific-locus mutations in the ad-3 region of two-component heterokaryons of Neurospora crassa

International Nuclear Information System (INIS)

Serres, F.J. de

1989-01-01

More extensive genetic tests have been preformed on a series of 832 X-ray-induced specific-locus mutations in the ad-3 region of a 2-component heterokaryon of Neurospora crassa, reported earlier. Using new tester strains and techniques for performing large-scale genetic tests to characterize ad-3 mutants induced in 2-component heterokaryons, new data have been obtained on this sample of X-ray-induced mutants. These new data show that unexpectedly high frequencies of both single-locus mutations and multilocus deletions in the ad-3 region have addition, but separate, sites of recessive lethal damage in the imeediately adjacent genetic regions. The frequencies of these X-ray-induced multiple-locus mutants in the ad-3 region are orders of magnitude higher than expected on the basis of target theory and classical models of chromosome structure during interphase. Current models of interphase chromosome structure in higher eukaryotes as revealed by chromosome 'painting' offer a possible explanation of the Neurospora data. (author). 25 refs.; 5 figs

Vγ9Vδ2 T cell activation by strongly agonistic nucleotidic phosphoantigens.

Science.gov (United States)

Moulin, Morgane; Alguacil, Javier; Gu, Siyi; Mehtougui, Asmaa; Adams, Erin J; Peyrottes, Suzanne; Champagne, Eric

2017-12-01

Human Vγ9Vδ2 T cells can sense through their TCR tumor cells producing the weak endogenous phosphorylated antigen isopentenyl pyrophosphate (IPP), or bacterially infected cells producing the strong agonist hydroxyl dimethylallyl pyrophosphate (HDMAPP). The recognition of the phosphoantigen is dependent on its binding to the intracellular B30.2 domain of butyrophilin BTN3A1. Most studies have focused on pyrophosphate phosphoantigens. As triphosphate nucleotide derivatives are naturally co-produced with IPP and HDMAPP, we analyzed their specific properties using synthetic nucleotides derived from HDMAPP. The adenylated, thymidylated and uridylated triphosphate derivatives were found to activate directly Vγ9Vδ2 cell lines as efficiently as HDMAPP in the absence of accessory cells. These antigens were inherently resistant to terminal phosphatases, but apyrase, when added during a direct stimulation of Vγ9Vδ2 cells, abrogated their stimulating activity, indicating that their activity required transformation into strong pyrophosphate agonists by a nucleotide pyrophosphatase activity which is present in serum. Tumor cells can be sensitized with nucleotide phosphoantigens in the presence of apyrase to become stimulatory, showing that this can occur before their hydrolysis into pyrophosphates. Whereas tumors sensitized with HDMAPP rapidly lost their stimulatory activity, sensitization with nucleotide derivatives, in particular with the thymidine derivative, induced long-lasting stimulating ability. Using isothermal titration calorimetry, binding of some nucleotide derivatives to BTN3A1 intracellular domain was found to occur with an affinity similar to that of IPP, but much lower than that of HDMAPP. Thus, nucleotide phosphoantigens are precursors of pyrophosphate antigens which can deliver strong agonists intracellularly resulting in prolonged and strengthened activity.

Irradiation strongly reduces tumorigenesis of human induced pluripotent stem cells

International Nuclear Information System (INIS)

Inui, Shoki; Minami, Kazumasa; Ito, Emiko; Imaizumi, Hiromasa; Mori, Seiji; Koizumi, Masahiko; Fukushima, Satsuki; Miyagawa, Shigeru; Sawa, Yoshiki; Matsuura, Nariaki

2017-01-01

Induced pluripotent stem (iPS) cells have demonstrated they can undergo self-renewal, attain pluripotency, and differentiate into various types of functional cells. In clinical transplantation of iPS cells, however, a major problem is the prevention of tumorigenesis. We speculated that tumor formation could be inhibited by means of irradiation. Since the main purpose of this study was to explore the prevention of tumor formation in human iPS (hiPS) cells, we tested the effects of irradiation on tumor-associated factors such as radiosensitivity, pluripotency and cell death in hiPS cells. The irradiated hiPS cells showed much higher radiosensitivity, because the survival fraction of hiPS cells irradiated with 2 Gy was < 10%, and there was no change of pluripotency. Irradiation with 2 and 4 Gy caused substantial cell death, which was mostly the result of apoptosis. Irradiation with 2 Gy was detrimental enough to cause loss of proliferation capability and trigger substantial cell death in vitro. The hiPS cells irradiated with 2 Gy were injected into NOG mice (NOD/Shi-scid, IL-2 Rγnull) for the analysis of tumor formation. The group of mice into which hiPS cells irradiated with 2 Gy was transplanted showed significant suppression of tumor formation in comparison with that of the group into which non-irradiated hiPS cells were transplanted. It can be presumed that this diminished rate of tumor formation was due to loss of proliferation and cell death caused by irradiation. Our findings suggest that tumor formation following cell therapy or organ transplantation induced by hiPS cells may be prevented by irradiation.

Generation of Patient-Specific induced Pluripotent Stem Cell from Peripheral Blood Mononuclear Cells by Sendai Reprogramming Vectors.

Science.gov (United States)

Quintana-Bustamante, Oscar; Segovia, Jose C

2016-01-01

Induced pluripotent stem cells (iPSC) technology has changed preclinical research since their generation was described by Shinya Yamanaka in 2006. iPSCs are derived from somatic cells after being reprogrammed back to an embryonic state by specific combination of reprogramming factors. These reprogrammed cells resemble all the characteristic of embryonic stem cells (ESC). The reprogramming technology is even more valuable to research diseases biology and treatment by opening gene and cell therapies in own patient's iPSC. Patient-specific iPSC can be generated from a large variety of patient cells by any of the myriad of reprogramming platforms described. Here, we describe the generation of patient-specific iPSC from patient peripheral blood mononuclear cells by Sendai Reprogramming vectors.

Inward transport of a toroidally confined plasma subject to strong radial electric fields

Science.gov (United States)

Roth, J. R.; Krawczonek, W. M.; Powers, E. J.; Hong, J.; Kim, Y.

1977-01-01

The paper aims at showing that the density and confinement time of a toroidal plasma can be enhanced by radial electric fields far stronger than the ambipolar values, and that, if such electric fields point into the plasma, radially inward transport can result. The investigation deals with low-frequency fluctuation-induced transport using digitally implemented spectral analysis techniques and with the role of strong applied radial electric fields and weak vertical magnetic fields on plasma density and particle confinement times in a Bumpy Torus geometry. Results indicate that application of sufficiently strong radially inward electric fields results in radially inward fluctuation-induced transport into the toroidal electrostatic potential well; this inward transport gives rise to higher average electron densities and longer particle confinement times in the toroidal plasma.

Complex dynamics induced by strong confinement - From tracer diffusion in strongly heterogeneous media to glassy relaxation of dense fluids in narrow slits

Science.gov (United States)

Mandal, Suvendu; Spanner-Denzer, Markus; Leitmann, Sebastian; Franosch, Thomas

2017-08-01

We provide an overview of recent advances of the complex dynamics of particles in strong confinements. The first paradigm is the Lorentz model where tracers explore a quenched disordered host structure. Such systems naturally occur as limiting cases of binary glass-forming systems if the dynamics of one component is much faster than the other. For a certain critical density of the host structure the tracers undergo a localization transition which constitutes a critical phenomenon. A series of predictions in the vicinity of the transition have been elaborated and tested versus computer simulations. Analytical progress is achieved for small obstacle densities. The second paradigm is a dense strongly interacting liquid confined to a narrow slab. Then the glass transition depends nonmonotonically on the separation of the plates due to an interplay of local packing and layering. Very small slab widths allow to address certain features of the statics and dynamics analytically.

<strong>Akt is transferred to the nucleus of cells treated with apoptin, and it participates in apoptin-induced cell deathstrong>

DEFF Research Database (Denmark)

Maddika, S; Bay, GH; Kroczak, TJ

2007-01-01

OBJECTIVES: The phosphatidylinositol 3-kinase (PI3-K)/Akt pathway is well known for the regulation of cell survival, proliferation, and some metabolic routes. MATERIALS AND METHODS: In this study, we document a novel role for the PI3-K/Akt pathway during cell death induced by apoptin, a tumour-selective....... Downstream of PI3-K, Akt is activated and translocated to the nucleus together with apoptin. Direct interaction between apoptin and Akt is documented. Co-expression of nuclear Akt significantly potentiates cell death induced by apoptin. Thus, apoptin-facilitated nuclear Akt, in contrast to when in its......, as it likely gains access to a new set of substrates in the nucleus. The implicated link between survival and cell death pathways during apoptosis opens new pharmacological opportunities to modulate apoptosis in cancer, for example through the manipulation of Akt's cellular localization....

Olanzapine Reverses MK-801-Induced Cognitive Deficits and Region-Specific Alterations of NMDA Receptor Subunits

Science.gov (United States)

Liu, Xiao; Li, Jitao; Guo, Chunmei; Wang, Hongli; Sun, Yaxin; Wang, Han; Su, Yun-Ai; Li, Keqing; Si, Tianmei

2018-01-01

Cognitive dysfunction constitutes an essential component in schizophrenia for its early presence in the pathophysiology of the disease and close relatedness to life quality of patients. To develop effective treatment of cognitive deficits, it is important to understand their neurobiological causes and to identify potential therapeutic targets. In this study, adopting repeated MK-801 treatment as an animal model of schizophrenia, we investigated whether antipsychotic drugs, olanzapine and haloperidol, can reverse MK-801-induced cognitive deficits and how the reversal processes recruited proteins involved in glutamate neurotransmission in rat medial prefrontal cortex (mPFC) and hippocampus. We found that low-dose chronic MK-801 treatment impaired object-in-context recognition memory and reversal learning in the Morris water maze, leaving reference memory relatively unaffected, and that these cognitive deficits can be partially reversed by olanzapine, not haloperidol, treatment. At the molecular level, chronic MK-801 treatment resulted in the reduction of multiple N-methyl-D-aspartate (NMDA) receptor subunits in rat mPFC and olanzapine, not haloperidol, treatment restored the levels of GluN1 and phosphorylated GluN2B in this region. Taken together, MK-801-induced cognitive deficits may be associated with region-specific changes in NMDA receptor subunits and the reversal of specific NMDA receptor subunits may underlie the cognition-enhancing effects of olanzapine. PMID:29375333

Clozapine-induced agranulocytosis: Evidence for an immune-mediated mechanism from a patient-specific in-vitro approach

Energy Technology Data Exchange (ETDEWEB)

Regen, Francesca; Herzog, Irmelin; Hahn, Eric; Ruehl, Claudia; Le Bret, Nathalie; Dettling, Michael; Heuser, Isabella [Dept. of Psychiatry, Campus Benjamin Franklin, Charité, University Medicine Berlin (Germany); Hellmann-Regen, Julian, E-mail: julian.hellmann@charite.de [Dept. of Psychiatry, Campus Benjamin Franklin, Charité, University Medicine Berlin (Germany); Berlin Institute of Health (BIH), Berlin (Germany)

2017-02-01

Use of the atypical antipsychotic clozapine (CZP) is compromised by the risk of potentially fatal agranulocytosis/granulocytopenia (CIAG). To address this, we have established a simple, personalized cell culture-based strategy to identify CIAG-susceptible patients, hypothesizing that an immunogenic and possibly haptene-based mechanism underlies CIAG pathophysiology. To detect a putative haptene-induced response to CZP in vitro exposure, a traditional lymphocyte stimulation assay was adapted and applied to patient-specific peripheral blood-derived mononuclear cells (PBMC). 6 patients with a history of CIAG, 6 patients under CZP treatment (without CIAG) and 12 matched healthy controls were studied. In vitro CZP exposure, even at strikingly low levels, resulted in significantly increased proliferation rates only in CIAG patients' PBMC. Other parameters including cell viability and mitogen-induced proliferation were also affected by in vitro CZP exposure, yet there was no significant difference between the groups. This personalized approach is a starting point for further investigations into a putative haptene-based mechanism underlying CIAG development, and may facilitate the future development of predictive testing. - Highlights: • Clozapine induces proliferation in PBMCs from patients with a history of CIAG. • Simple, PBMC-based assay results in robust effects of physiological clozapine levels. • Haptene-based mechanisms discussed to underlie clozapine-induced proliferation.

Hot colors: the nature and specificity of color-induced nasal thermal sensations.

Science.gov (United States)

Michael, George A; Galich, Hélène; Relland, Solveig; Prud'hon, Sabine

2010-03-05

The nature of the recently discovered color-induced nasal thermal sensations was investigated in four Experiments. Subjects were required to fixate a bottle containing a red or green solution presented centrally (Exp1 and Exp4) or laterally (Exp2) and to sniff another bottle, always the same one, but which they were not allowed to see, containing 10 ml of a colorless, odorless and trigeminal-free solution. Each nostril was tested separately, and subjects were asked whether the sniffed solution induced warming or cooling sensations (plus an ambient sensation in Exp4) in the nasal cavity. The results of Experiments 1 and 2 confirmed the warming/left nostril-cooling/right nostril dissociation, suggesting the existence of different lateralized processes for thermal processing. However, Experiment 2 failed to demonstrate dominance of warming responses when subjects' eyes were directed to the left or cooling responses when they were directed to the right. Nor did gaze direction interact with the tested nostril. This suggests that the color-induced thermal sensations are specifically related to the nasal trigeminal system, rather than a general process related to general hemispheric activity. When the exposed bottles were colorless (Exp3), no lateralized patterns were observed, suggesting, in combination with the results of Experiments 1 and 2, that both color cues and nasal stimulations are necessary for lateralized patterns to arise. Rendering the temperature judgment even more difficult (Exp4), made the lateralized patterns shift towards the associated (i.e., ambient) responses. The results are discussed in a general framework which considers that, even in the absence of real thermal stimulus, preparing to process thermal stimuli in the nasal cavity may activate the underlying lateralized neural mechanisms, and that those mechanisms are reflected in the responses. Copyright 2009 Elsevier B.V. All rights reserved.

Interleukin-1β-induced iNOS expression in human lung carcinoma A549 cells: involvement of STAT and MAPK pathways

International Nuclear Information System (INIS)

Ravichandran, Kameswaran; Tyagi, Alpna; Deep, Gagan; Agarwal, Chapla; Agarwal, Rajesh

2011-01-01

For understanding of signaling molecules important in lung cancer growth and progression, IL-1β effect was analyzed on iNOS expression and key signaling molecules in human lung carcinoma A549 cells and established the role of specific signaling molecules by using specific chemical inhibitors. IL-1β exposure (10 ng/ml) induced strong iNOS expression in serum starved A549 cells. Detailed molecular analyses showed that IL-1β increased expression of phosphorylated STAT1 (Tyr701 and Ser727) and STAT3 (Tyr705 and Ser727) both in total cell lysates and nuclear lysates. Further, IL-1β exposure strongly activated MAPKs (ERK1/2, JNK1/2 and p38) and Akt as well as increased nuclear levels of NF-κB and HIF-1α in A549 cells. Use of specific chemical inhibitors for JAK1 kinase (piceatannol), JAK2 kinase (AG-490), MEK1/2 (PD98059) and JNK1/2 (SP600125) revealed that IL-1β-induced iNOS expression involved signaling pathways in addition to JAKSTAT and ERK1/2-JNK1/2 activation. Overall, these results suggested that instead of specific pharmacological inhibitors, use of chemopreventive agents with broad spectrum efficacy to inhibit IL-1β-induced signaling cascades and iNOS expression would be a better strategy towards lung cancer prevention and/or treatment. (author)

Enterovirus strain and type-specific differences in growth kinetics and virus-induced cell destruction in human pancreatic duct epithelial HPDE cells.

Science.gov (United States)

Smura, Teemu; Natri, Olli; Ylipaasto, Petri; Hellman, Marika; Al-Hello, Haider; Piemonti, Lorenzo; Roivainen, Merja

2015-12-02

Enterovirus infections have been suspected to be involved in the development of type 1 diabetes. However, the pathogenetic mechanism of enterovirus-induced type 1 diabetes is not known. Pancreatic ductal cells are closely associated with pancreatic islets. Therefore, enterovirus infections in ductal cells may also affect beta-cells and be involved in the induction of type 1 diabetes. The aim of this study was to assess the ability of different enterovirus strains to infect, replicate and produce cytopathic effect in human pancreatic ductal cells. Furthermore, the viral factors that affect these capabilities were studied. The pancreatic ductal cells were highly susceptible to enterovirus infections. Both viral growth and cytolysis were detected for several enterovirus serotypes. However, the viral growth and capability to induce cytopathic effect (cpe) did not correlate completely. Some of the virus strains replicated in ductal cells without apparent cpe. Furthermore, there were strain-specific differences in the growth kinetics and the ability to cause cpe within some serotypes. Viral adaptation experiments were carried out to study the potential genetic determinants behind these phenotypic differences. The blind-passage of non-lytic CV-B6-Schmitt strain in HPDE-cells resulted in lytic phenotype and increased progeny production. This was associated with the substitution of a single amino acid (K257E) in the virus capsid protein VP1 and the viral ability to use decay accelerating factor (DAF) as a receptor. This study demonstrates considerable plasticity in the cell tropism, receptor usage and cytolytic properties of enteroviruses and underlines the strong effect of single or few amino acid substitutions in cell tropism and lytic capabilities of a given enterovirus. Since ductal cells are anatomically close to pancreatic islets, the capability of enteroviruses to infect and destroy pancreatic ductal cells may also implicate in respect to enterovirus induced type 1

Immunizations with hepatitis B viral antigens and a TLR7/8 agonist adjuvant induce antigen-specific immune responses in HBV-transgenic mice

Directory of Open Access Journals (Sweden)

Ying Wang

2014-12-01

Conclusions: Immunization with CL097-conjugated HBV-Ag reversed immune tolerance in HBV-Tg mice and induced antigen-specific immune responses. TLR7/8 agonists appear to be potent adjuvants for the induction of antigen-specific Th1 responses in an immune tolerant state.

Precision cancer immunotherapy: optimizing dendritic cell-based strategies to induce tumor antigen-specific T-cell responses against individual patient tumors.

Science.gov (United States)

Osada, Takuya; Nagaoka, Koji; Takahara, Masashi; Yang, Xiao Yi; Liu, Cong-Xiao; Guo, Hongtao; Roy Choudhury, Kingshuk; Hobeika, Amy; Hartman, Zachary; Morse, Michael A; Lyerly, H Kim

2015-05-01

Most dendritic cell (DC)-based vaccines have loaded the DC with defined antigens, but loading with autologos tumor-derived antigens would generate DCs that activate personalized tumor-specific T-cell responses. We hypothesized that DC matured with an optimized combination of reagents and loaded with tumor-derived antigens using a clinically feasible electroporation strategy would induce potent antitumor immunity. We first studied the effects on DC maturation and antigen presentation of the addition of picibanil (OK432) to a combination of zoledronic acid, tumor necrosis factor-α, and prostaglandin E2. Using DC matured with the optimized combination, we tested 2 clinically feasible sources of autologous antigen for electroloading, total tumor mRNA or total tumor lysate, to determine which stimulated more potent antigen-specific T cells in vitro and activated more potent antitumor immunity in vivo. The combination of tumor necrosis factor-α/prostaglandin E2/zoledronic acid/OK432 generated DC with high expression of maturation markers and antigen-specific T-cell stimulatory function in vitro. Mature DC electroloaded with tumor-derived mRNA [mRNA electroporated dendritic cell (EPDC)] induced greater expansion of antigen-specific T cells in vitro than DC electroloaded with tumor lysate (lysate EPDC). In a therapeutic model of MC38-carcinoembryonic antigen colon cancer-bearing mice, vaccination with mRNA EPDC induced the most efficient anti-carcinoembryonic antigen cellular immune response, which significantly suppressed tumor growth. In conclusion, mature DC electroloaded with tumor-derived mRNA are a potent cancer vaccine, especially useful when specific tumor antigens for vaccination have not been identified, allowing autologous tumor, and if unavailable, allogeneic cell lines to be used as an unbiased source of antigen. Our data support clinical testing of this strategy.

The Contribution of Transactivation Subdomains 1 and 2 to p53-Induced Gene Expression Is Heterogeneous But Not Subdomain-Specific

Directory of Open Access Journals (Sweden)

Jennifer M. Smith

2007-12-01

Full Text Available Two adjacent regions within the transactivation domain of p53 are sufficient to support sequence-specific transactivation when fused to a heterologous DNA binding domain. It has been hypothesized that these two subdomains of p53 may contribute to the expression of distinct p53-responsive genes. Here we have used oligonucleotide microarrays to identify transcripts induced by variants of p53 with point mutations within subdomains 1, 2, or 1 and 2 (QS1, QS2, QS1/QS2, respectively. The expression of 254 transcripts was increased in response to wild-type p53 expression but most of these transcripts were poorly induced by these variants of p53. Strikingly, a number of known p53regulated transcripts including TNFRSF10B, BAX, BTG2, POLH were increased to wild-type levels by p53QS1 and p53QS2 but not p53QS1/QS2, indicating that either sub domain 1 or 2 is sufficient for p53-dependent expression of a small subset of p53-responsive genes. Unexpectedly, there was no evidence for p53QS1- or p53QS2-specific gene expression. Taken together, we found heterogeneity in the requirement for transactivation subdomains 1 and 2 of p53 without any subdomain-specific contribution to p53-induced gene expression.

<strong>Mini-project>

DEFF Research Database (Denmark)

Katajainen, Jyrki

2008-01-01

In this project the goal is to develop the safe * family of containers for the CPH STL. The containers to be developed should be safer and more reliable than any of the existing implementations. A special focus should be put on strong exception safety since none of the existing prototypes available...

Cardiac-specific overexpression of catalase attenuates lipopolysaccharide-induced myocardial contractile dysfunction: role of autophagy.

Science.gov (United States)

Turdi, Subat; Han, Xuefeng; Huff, Anna F; Roe, Nathan D; Hu, Nan; Gao, Feng; Ren, Jun

2012-09-15

Lipopolysaccharide (LPS) from gram-negative bacteria is a major initiator of sepsis, leading to cardiovascular collapse. Accumulating evidence has indicated a role of reactive oxygen species (ROS) in cardiovascular complications in sepsis. This study was designed to examine the effect of cardiac-specific overexpression of catalase in LPS-induced cardiac contractile dysfunction and the underlying mechanism(s) with a focus on autophagy. Catalase transgenic and wild-type FVB mice were challenged with LPS (6 mg/kg) and cardiac function was evaluated. Levels of oxidative stress, autophagy, apoptosis, and protein damage were examined using fluorescence microscopy, Western blot, TUNEL assay, caspase-3 activity, and carbonyl formation. A Kaplan-Meier curve was constructed for survival after LPS treatment. Our results revealed a lower mortality in catalase mice compared with FVB mice after LPS challenge. LPS injection led to depressed cardiac contractile capacity as evidenced by echocardiography and cardiomyocyte contractile function, the effect of which was ablated by catalase overexpression. LPS treatment induced elevated TNF-α level, autophagy, apoptosis (TUNEL, caspase-3 activation, cleaved caspase-3), production of ROS and O(2)(-), and protein carbonyl formation, the effects of which were significantly attenuated by catalase overexpression. Electron microscopy revealed focal myocardial damage characterized by mitochondrial injury after LPS treatment, which was less severe in catalase mice. Interestingly, LPS-induced cardiomyocyte contractile dysfunction was prevented by the antioxidant N-acetylcysteine and the autophagy inhibitor 3-methyladenine. Taken together, our data revealed that catalase protects against LPS-induced cardiac dysfunction and mortality, which may be associated with inhibition of oxidative stress and autophagy. Copyright © 2012 Elsevier Inc. All rights reserved.

A robust approach to identifying tissue-specific gene expression regulatory variants using personalized human induced pluripotent stem cells.

Directory of Open Access Journals (Sweden)

Je-Hyuk Lee

2009-11-01

Full Text Available Normal variation in gene expression due to regulatory polymorphisms is often masked by biological and experimental noise. In addition, some regulatory polymorphisms may become apparent only in specific tissues. We derived human induced pluripotent stem (iPS cells from adult skin primary fibroblasts and attempted to detect tissue-specific cis-regulatory variants using in vitro cell differentiation. We used padlock probes and high-throughput sequencing for digital RNA allelotyping and measured allele-specific gene expression in primary fibroblasts, lymphoblastoid cells, iPS cells, and their differentiated derivatives. We show that allele-specific expression is both cell type and genotype-dependent, but the majority of detectable allele-specific expression loci remains consistent despite large changes in the cell type or the experimental condition following iPS reprogramming, except on the X-chromosome. We show that our approach to mapping cis-regulatory variants reduces in vitro experimental noise and reveals additional tissue-specific variants using skin-derived human iPS cells.

Rare sugar D-allose strongly induces thioredoxin-interacting protein and inhibits osteoclast differentiation in Raw264 cells.

Science.gov (United States)

Yamada, Kana; Noguchi, Chisato; Kamitori, Kazuyo; Dong, Youyi; Hirata, Yuko; Hossain, Mohammad A; Tsukamoto, Ikuko; Tokuda, Masaaki; Yamaguchi, Fuminori

2012-02-01

Oxidative stress modulates the osteoclast differentiation via redox systems, and thioredoxin 1 (Trx) promotes the osteoclast formation by regulating the activity of transcription factors. The function of Trx is known to be regulated by its binding partner, thioredoxin-interacting protein (TXNIP). We previously reported that the expression of TXNIP gene is strongly induced by a rare sugar D-allose. In this study, we tested the hypothesis that D-allose could inhibit the osteoclast differentiation by regulating the Trx function. We used a murine Raw264 cell line that differentiates to the osteoclast by the receptor activator of nuclear factor-κB ligand (RANKL) treatment. The effect of sugars was evaluated by tartrate-resistant acid phosphatase staining. The expression and localization of TXNIP and Trx protein were examined by Western blotting and immunohistochemisty. The activity of the nuclear factor-κB, nuclear factor of activated T cells, and activator protein 1 transcription factors was measured by the luciferase reporter assay. The addition of D-allose (25 mmol/L) inhibited the osteoclast differentiation down to 9.53% ± 1.27% of a receptor activator of nuclear factor-κB ligand-only treatment. During the osteoclast differentiation, a significant increase of TNXIP was observed by D-allose treatment. The immunohistochemical analysis showed that both Trx and TXNIP existed in the nucleus in preosteoclasts and osteoclasts. Overexpression of TXNIP by plasmid transfection also inhibited the osteoclast formation, indicating the functional importance of TXNIP for the osteoclast differentiation. Transcriptional activity of the activator protein 1, nuclear factor-κB, and nuclear factor of activated T cells, known to be modulated by Trx, were inhibited by D-allose. In conclusion, our data indicate that D-allose is a strong inhibitor of the osteoclast differentiation, and this effect could be caused by TXNIP induction and a resulting inhibition of the Trx function

Integration of genome-scale metabolic networks into whole-body PBPK models shows phenotype-specific cases of drug-induced metabolic perturbation.

Science.gov (United States)

Cordes, Henrik; Thiel, Christoph; Baier, Vanessa; Blank, Lars M; Kuepfer, Lars

2018-01-01

Drug-induced perturbations of the endogenous metabolic network are a potential root cause of cellular toxicity. A mechanistic understanding of such unwanted side effects during drug therapy is therefore vital for patient safety. The comprehensive assessment of such drug-induced injuries requires the simultaneous consideration of both drug exposure at the whole-body and resulting biochemical responses at the cellular level. We here present a computational multi-scale workflow that combines whole-body physiologically based pharmacokinetic (PBPK) models and organ-specific genome-scale metabolic network (GSMN) models through shared reactions of the xenobiotic metabolism. The applicability of the proposed workflow is illustrated for isoniazid, a first-line antibacterial agent against Mycobacterium tuberculosis , which is known to cause idiosyncratic drug-induced liver injuries (DILI). We combined GSMN models of a human liver with N-acetyl transferase 2 (NAT2)-phenotype-specific PBPK models of isoniazid. The combined PBPK-GSMN models quantitatively describe isoniazid pharmacokinetics, as well as intracellular responses, and changes in the exometabolome in a human liver following isoniazid administration. Notably, intracellular and extracellular responses identified with the PBPK-GSMN models are in line with experimental and clinical findings. Moreover, the drug-induced metabolic perturbations are distributed and attenuated in the metabolic network in a phenotype-dependent manner. Our simulation results show that a simultaneous consideration of both drug pharmacokinetics at the whole-body and metabolism at the cellular level is mandatory to explain drug-induced injuries at the patient level. The proposed workflow extends our mechanistic understanding of the biochemistry underlying adverse events and may be used to prevent drug-induced injuries in the future.

Low-dose tryptophan depletion in recovered depressed women induces impairments in autobiographical memory specificity.

Science.gov (United States)

Haddad, Anneke D M; Williams, J Mark G; McTavish, Sarah F B; Harmer, Catherine J

2009-12-01

Depressed patients perform poorly on tests of autobiographical memory specificity (AMS); this may have negative consequences for other important cognitive abilities, delays recovery from mood episodes, and, in recovered patients, may mediate vulnerability to future episodes. Although the cognitive mechanisms underlying AMS deficits are beginning to be understood, the neurobiological mechanisms remain unclear. Serotonin is implicated in both depression and long-term memory; therefore, temporary lowering of brain serotonin function via acute tryptophan depletion (ATD) offers a means of studying the role of serotonin in autobiographical memory specificity. In this study, 24 previously depressed women underwent low-dose ATD or sham depletion and completed tests of initial and delayed memory, recollection- and familiarity-based recognition, and AMS. ATD did not differentially affect state mood. Compared with sham depletion, ATD impaired immediate recall on the Auditory Verbal Learning Test. Although ATD did not differentially impair recollection- and familiarity-based recognition, it did slow recognition of positive words. ATD also reduced autobiographical memory specificity in response to negative cue words. The results confirm previous findings that low-dose ATD can reinstate depression-congruent biases in cognition without causing depressive mood in vulnerable populations. The ATD-induced reduction in memory specificity suggests that serotonergic dysfunction may mediate depressive deficits in autobiographical memory; the interaction of cognitive and neurobiological vulnerability mechanisms is discussed.

Performance analysis of relay-assisted all-optical FSO networks over strong atmospheric turbulence channels with pointing errors

KAUST Repository

Yang, Liang

2014-12-01

In this study, we consider a relay-assisted free-space optical communication scheme over strong atmospheric turbulence channels with misalignment-induced pointing errors. The links from the source to the destination are assumed to be all-optical links. Assuming a variable gain relay with amplify-and-forward protocol, the electrical signal at the source is forwarded to the destination with the help of this relay through all-optical links. More specifically, we first present a cumulative density function (CDF) analysis for the end-to-end signal-to-noise ratio. Based on this CDF, the outage probability, bit-error rate, and average capacity of our proposed system are derived. Results show that the system diversity order is related to the minimum value of the channel parameters.

HY-Specific Induced Regulatory T Cells Display High Specificity and Efficacy in the Prevention of Acute Graft-versus-Host Disease.

Science.gov (United States)

Li, Jun; Heinrichs, Jessica; Haarberg, Kelley; Semple, Kenrick; Veerapathran, Anandharaman; Liu, Chen; Anasetti, Claudio; Yu, Xue-Zhong

2015-07-15

Naturally derived regulatory T cells (Tregs) may prevent graft-versus-host disease (GVHD) while preserving graft-versus-leukemia (GVL) activity. However, clinical application of naturally derived regulatory T cells has been severely hampered by their scarce availability and nonselectivity. To overcome these limitations, we took alternative approaches to generate Ag-specific induced Tregs (iTregs) and tested their efficacy and selectivity in the prevention of GVHD in preclinical models of bone marrow transplantation. We selected HY as a target Ag because it is a naturally processed, ubiquitously expressed minor histocompatibility Ag (miHAg) with a proven role in GVHD and GVL effect. We generated HY-specific iTregs (HY-iTregs) from resting CD4 T cells derived from TCR transgenic mice, in which CD4 cells specifically recognize HY peptide. We found that HY-iTregs were highly effective in preventing GVHD in male (HY(+)) but not female (HY(-)) recipients using MHC II-mismatched, parent→F1, and miHAg-mismatched murine bone marrow transplantation models. Interestingly, the expression of target Ag (HY) on the hematopoietic or nonhematopoietic compartment alone was sufficient for iTregs to prevent GVHD. Furthermore, treatment with HY-iTregs still preserved the GVL effect even against pre-established leukemia. We found that HY-iTregs were more stable in male than in female recipients. Furthermore, HY-iTregs expanded extensively in male but not female recipients, which in turn significantly reduced donor effector T cell expansion, activation, and migration into GVHD target organs, resulting in effective prevention of GVHD. This study demonstrates that iTregs specific for HY miHAgs are highly effective in controlling GVHD in an Ag-dependent manner while sparing the GVL effect. Copyright © 2015 by The American Association of Immunologists, Inc.

The combination of BH3-mimetic ABT-737 with the alkylating agent temozolomide induces strong synergistic killing of melanoma cells independent of p53.

Directory of Open Access Journals (Sweden)

Steven N Reuland

Full Text Available Metastatic melanoma has poor prognosis and is refractory to most conventional chemotherapies. The alkylating agent temozolomide (TMZ is commonly used in treating melanoma but has a disappointing response rate. Agents that can act cooperatively with TMZ and improve its efficacy are thus highly sought after. The BH3 mimetic ABT-737, which can induce apoptosis by targeting pro-survival Bcl-2 family members, has been found to enhance the efficacy of many conventional chemotherapeutic agents in multiple cancers. We found that combining TMZ and ABT-737 induced strong synergistic apoptosis in multiple human melanoma cell lines. When the drugs were used in combination in a mouse xenograft model, they drastically reduced tumor growth at concentrations where each individual drug had no significant effect. We found that TMZ treatment elevated p53 levels, and that the pro-apoptotic protein Noxa was elevated in TMZ/ABT-737 treated cells. Experiments with shRNA demonstrated that the synergistic effect of TMZ and ABT-737 was largely dependent on Noxa. Experiments with nutlin-3, a p53 inducer, demonstrated that p53 induction was sufficient for synergistic cell death with ABT-737 in a Noxa-dependent fashion. However, p53 was not necessary for TMZ/ABT-737 synergy as demonstrated by a p53-null line, indicating that TMZ and ABT-737 together induce Noxa in a p53-independent fashion. These results demonstrate that targeting anti-apoptotic Bcl-2 members is a promising method for treating metastatic melanoma, and that clinical trials with TMZ and Bcl-2 inhibitors are warranted.

Early-Life Experience Decreases Drug-Induced Reinstatement of Morphine CPP in Adulthood via Microglial-Specific Epigenetic Programming of Anti-Inflammatory IL-10 Expression

Science.gov (United States)

Schwarz, Jaclyn M.; Hutchinson, Mark R.; Bilbo, Staci D.

2012-01-01

A critical component of drug addiction research involves identifying novel biological mechanisms and environmental predictors of risk or resilience to drug addiction and associated relapse. Increasing evidence suggests microglia and astrocytes can profoundly affect the physiological and addictive properties of drugs of abuse, including morphine. We report that glia within the rat Nucleus Accumbens (NAcc) respond to morphine with an increase in cytokine/chemokine expression, which predicts future reinstatement of morphine conditioned place preference (CPP) following a priming dose of morphine. This glial response to morphine is influenced by early-life experience. A neonatal handling paradigm that increases the quantity and quality of maternal care significantly increases baseline expression of the anti-inflammatory cytokine IL-10 within the NAcc, attenuates morphine-induced glial activation, and prevents the subsequent reinstatement of morphine CPP in adulthood. IL-10 expression within the NAcc and reinstatement of CPP are negatively correlated, suggesting a protective role for this specific cytokine against morphine-induced glial reactivity and drug-induced reinstatement of morphine CPP. Neonatal handling programs the expression of IL-10 within the NAcc early in development, and this is maintained into adulthood via decreased methylation of the IL-10 gene specifically within microglia. The effect of neonatal handling is mimicked by pharmacological modulation of glia in adulthood with Ibudilast, which increases IL-10 expression, inhibits morphine-induced glial activation within the NAcc, and prevents reinstatement of morphine CPP. Taken together, we have identified a novel gene X early-life environment interaction on morphine-induced glial activation, and a specific role for glial activation in drug-induced reinstatement of drug-seeking behavior. PMID:22159099

A virosomal formulated Her-2/neu multi-peptide vaccine induces Her-2/neu-specific immune responses in patients with metastatic breast cancer: a phase I study.

Science.gov (United States)

Wiedermann, Ursula; Wiltschke, C; Jasinska, J; Kundi, M; Zurbriggen, R; Garner-Spitzer, E; Bartsch, R; Steger, G; Pehamberger, H; Scheiner, O; Zielinski, C C

2010-02-01

We have previously shown in mice that vaccination with three Her-2-peptides representing B-cell epitopes of the extracellular domain of Her-2/neu induces Her-2/neu-specific IgG antibodies with strong anti-tumor activity in vitro and in vivo. We have now finalized a phase I clinical trial with an anti-Her-2/neu vaccine-construct of immunopotentiating reconstituted influenza virosomes with the three peptides in patients with metastatic breast cancer (MBC). Ten MBC patients with low protein overexpression of Her-2/neu of MBC (+ or ++ upon immunohistochemistry, FISH negative) and positive hormone receptor status were enrolled in a single center phase I study. The virosomal formulated vaccine, consisting of 10 microg/peptide, was intramuscularly applied three times on days 1, 28, and 56. The primary endpoint of the study, which lasted 12 weeks, was safety, the secondary endpoint immunogenicity. Local erythema at the injection site was the only vaccine-related side effect occurring in four patients. In 8 of 10 patients an increase in peptide-specific antibody titer measured by ELISA was found. Importantly, the induced antibodies were also directed against the native Her-2/neu protein. Cellular immune responses, as measured by in vitro production of IL-2, IFN-c, and TNF-a of PBMCs showed a marked increase after vaccination in the majority of vaccinees. Notably, the number of CD4+CD25+Foxp3+T regulatory cells, which were significantly increased compared to healthy controls prior to vaccination, was markedly reduced following vaccination. In all, the immunological responses after vaccination indicated that the patients in stage IV of disease were immunocompetent and susceptible to vaccination. The Her-2/neu multipeptide vaccine was safe, well tolerated and effective in overcoming immunological tolerance to Her-2/neu. The induction of anti-Her-2-specific antibodies could result in clinical benefit comparable to passive anti-Her-2 antibody therapy.

Tumor-specific CD4+ T cells develop cytotoxic activity and eliminate virus-induced tumor cells in the absence of regulatory T cells.

Science.gov (United States)

Akhmetzyanova, Ilseyar; Zelinskyy, Gennadiy; Schimmer, Simone; Brandau, Sven; Altenhoff, Petra; Sparwasser, Tim; Dittmer, Ulf

2013-02-01

The important role of tumor-specific cytotoxic CD8(+) T cells is well defined in the immune control of the tumors, but the role of effector CD4(+) T cells is poorly understood. In the current research, we have used a murine retrovirus-induced tumor cell line of C57BL/6 mouse origin, namely FBL-3 cells, as a model to study basic mechanisms of immunological control and escape during tumor formation. This study shows that tumor-specific CD4(+) T cells are able to protect against virus-induced tumor cells. We show here that there is an expansion of tumor-specific CD4(+) T cells producing cytokines and cytotoxic molecule granzyme B (GzmB) in the early phase of tumor growth. Importantly, we demonstrate that in vivo depletion of regulatory T cells (Tregs) and CD8(+) T cells in FBL-3-bearing DEREG transgenic mice augments IL-2 and GzmB production by CD4(+) T cells and increases FV-specific CD4(+) T-cell effector and cytotoxic responses leading to the complete tumor regression. Therefore, the capacity to reject tumor acquired by tumor-reactive CD4(+) T cells largely depends on the direct suppressive activity of Tregs. We suggest that a cytotoxic CD4(+) T-cell immune response may be induced to enhance resistance against oncovirus-associated tumors.

First-principles study of strong correlation effects in pyrochlore iridates

Energy Technology Data Exchange (ETDEWEB)

Shinaoka, Hiroshi [Department of Physics, Saitama University (Japan); Hoshino, Shintaro [Department of Basic Science, The University of Tokyo (Japan); Troyer, Matthias [Theoretische Physik, ETH Zuerich (Switzerland); Werner, Philipp [Department of Physics, University of Fribourg (Switzerland)

2016-07-01

The pyrochlore iridates A{sub 2}Ir{sub 2}O{sub 7} (A=Pr, Nd, Y, etc.) are an ideal system to study fascinating phenomena induced by strong electron correlations and spin-orbit coupling. In this talk, we study strong correlation effects in the prototype compound Y{sub 2}Ir{sub 2}O{sub 7} using the local density approximation and dynamical mean-field theory (LDA+DMFT). We map out the phase diagram in the space of temperature, onsite Coulomb repulsion U, and filling. Consistent with experiments, we find that an all-in/all-out ordered insulating phase is stable for realistic values of U. We reveal the importance of the hybridization between j{sub eff} = 1/2 and j{sub eff} = 3/2 states under the Coulomb interaction and trigonal crystal field. We demonstrate a substantial band narrowing in the paramagnetic metallic phase and non-Fermi liquid behavior in the electron/hole doped system originating from long-lived quasi-spin moments induced by nearly flat bands. We further compare our results with recent experimental results of Eu{sub 2}Ir{sub 2}O{sub 7} under hydrostatic pressure.

Regionally strong feedbacks between the atmosphere and terrestrial biosphere

Science.gov (United States)

Green, Julia K.; Konings, Alexandra G.; Alemohammad, Seyed Hamed; Berry, Joseph; Entekhabi, Dara; Kolassa, Jana; Lee, Jung-Eun; Gentine, Pierre

2017-06-01

The terrestrial biosphere and atmosphere interact through a series of feedback loops. Variability in terrestrial vegetation growth and phenology can modulate fluxes of water and energy to the atmosphere, and thus affect the climatic conditions that in turn regulate vegetation dynamics. Here we analyse satellite observations of solar-induced fluorescence, precipitation, and radiation using a multivariate statistical technique. We find that biosphere-atmosphere feedbacks are globally widespread and regionally strong: they explain up to 30% of precipitation and surface radiation variance in regions where feedbacks occur. Substantial biosphere-precipitation feedbacks are often found in regions that are transitional between energy and water limitation, such as semi-arid or monsoonal regions. Substantial biosphere-radiation feedbacks are often present in several moderately wet regions and in the Mediterranean, where precipitation and radiation increase vegetation growth. Enhancement of latent and sensible heat transfer from vegetation accompanies this growth, which increases boundary layer height and convection, affecting cloudiness, and consequently incident surface radiation. Enhanced evapotranspiration can increase moist convection, leading to increased precipitation. Earth system models underestimate these precipitation and radiation feedbacks mainly because they underestimate the biosphere response to radiation and water availability. We conclude that biosphere-atmosphere feedbacks cluster in specific climatic regions that help determine the net CO2 balance of the biosphere.

NATO Advanced Study Institute on Atoms in Strong Fields

CERN Document Server

Clark, Charles; Nayfeh, Munir

1990-01-01

This book collects the lectures given at the NATO Advanced Study Institute on "Atoms in Strong Fields", which took place on the island of Kos, Greece, during the two weeks of October 9-21,1988. The designation "strong field" applies here to an external electromagnetic field that is sufficiently strong to cause highly nonlinear alterations in atomic or molecular struc­ ture and dynamics. The specific topics treated in this volume fall into two general cater­ gories, which are those for which strong field effects can be studied in detail in terrestrial laboratories: the dynamics of excited states in static or quasi-static electric and magnetic fields; and the interaction of atoms and molecules with intense laser radiation. In both areas there exist promising opportunities for research of a fundamental nature. An electric field of even a few volts per centimeter can be very strong on the atom­ ic scale, if it acts upon a weakly bound state. The study of Rydberg states with high reso­ lution laser spectroscop...

Sex-specific effects of a parasite evolving in a female-biased host population.

Science.gov (United States)

Duneau, David; Luijckx, Pepijn; Ruder, Ludwig F; Ebert, Dieter

2012-12-18

Males and females differ in many ways and might present different opportunities and challenges to their parasites. In the same way that parasites adapt to the most common host type, they may adapt to the characteristics of the host sex they encounter most often. To explore this hypothesis, we characterized host sex-specific effects of the parasite Pasteuria ramosa, a bacterium evolving in naturally, strongly, female-biased populations of its host Daphnia magna. We show that the parasite proliferates more successfully in female hosts than in male hosts, even though males and females are genetically identical. In addition, when exposure occurred when hosts expressed a sexual dimorphism, females were more infected. In both host sexes, the parasite causes a similar reduction in longevity and leads to some level of castration. However, only in females does parasite-induced castration result in the gigantism that increases the carrying capacity for the proliferating parasite. We show that mature male and female Daphnia represent different environments and reveal one parasite-induced symptom (host castration), which leads to increased carrying capacity for parasite proliferation in female but not male hosts. We propose that parasite induced host castration is a property of parasites that evolved as an adaptation to specifically exploit female hosts.

Sex-specific effects of a parasite evolving in a female-biased host population

Directory of Open Access Journals (Sweden)

Duneau David

2012-12-01

Full Text Available Abstract Background Males and females differ in many ways and might present different opportunities and challenges to their parasites. In the same way that parasites adapt to the most common host type, they may adapt to the characteristics of the host sex they encounter most often. To explore this hypothesis, we characterized host sex-specific effects of the parasite Pasteuria ramosa, a bacterium evolving in naturally, strongly, female-biased populations of its host Daphnia magna. Results We show that the parasite proliferates more successfully in female hosts than in male hosts, even though males and females are genetically identical. In addition, when exposure occurred when hosts expressed a sexual dimorphism, females were more infected. In both host sexes, the parasite causes a similar reduction in longevity and leads to some level of castration. However, only in females does parasite-induced castration result in the gigantism that increases the carrying capacity for the proliferating parasite. Conclusions We show that mature male and female Daphnia represent different environments and reveal one parasite-induced symptom (host castration, which leads to increased carrying capacity for parasite proliferation in female but not male hosts. We propose that parasite induced host castration is a property of parasites that evolved as an adaptation to specifically exploit female hosts.

Sex-specific effects of a parasite evolving in a female-biased host population

Science.gov (United States)

2012-01-01

Background Males and females differ in many ways and might present different opportunities and challenges to their parasites. In the same way that parasites adapt to the most common host type, they may adapt to the characteristics of the host sex they encounter most often. To explore this hypothesis, we characterized host sex-specific effects of the parasite Pasteuria ramosa, a bacterium evolving in naturally, strongly, female-biased populations of its host Daphnia magna. Results We show that the parasite proliferates more successfully in female hosts than in male hosts, even though males and females are genetically identical. In addition, when exposure occurred when hosts expressed a sexual dimorphism, females were more infected. In both host sexes, the parasite causes a similar reduction in longevity and leads to some level of castration. However, only in females does parasite-induced castration result in the gigantism that increases the carrying capacity for the proliferating parasite. Conclusions We show that mature male and female Daphnia represent different environments and reveal one parasite-induced symptom (host castration), which leads to increased carrying capacity for parasite proliferation in female but not male hosts. We propose that parasite induced host castration is a property of parasites that evolved as an adaptation to specifically exploit female hosts. PMID:23249484

Preconception paternal bisphenol A exposure induces sex-specific anxiety and depression behaviors in adult rats.

Directory of Open Access Journals (Sweden)

Ying Fan

Full Text Available Bisphenol A (BPA, an environmental endocrine-disrupting compound, has drawn a great attention for its adverse effect on behavioral development. Maternal exposure to this compound has been reported to induce anxiety and depression in offspring, but the effect of its paternal exposure is rarely discussed. This study investigated whether preconception paternal BPA exposure can affect the emotions of male rats and their offspring. Eighteen adult male rats (F0 received either a vehicle or 50 μg/kg/day BPA diet for 21 weeks and were then mated with non-exposed females to produce offspring (F1. The affective behaviors of F0 and F1 rats were evaluated in the open-field test, the elevated-plus maze and the forced swimming test, and their serum corticosterone were then examined. BPA exposure induced increased anxiety behaviors along with increased serum corticosterone in F0 rats. This paternal exposure also led to increased anxiety behaviors in F1 females and aggravated depression behaviors in both sexes of F1 rats. Furthermore, only F1 females exhibited increased serum corticosterone. Overall, these data indicate that preconception paternal exposure to a low dose of BPA may induce transgenerational sex-specific impairments in the affection of adult rats.

The interferon-induced antiviral protein PML (TRIM19) promotes the restriction and transcriptional silencing of lentiviruses in a context-specific, isoform-specific fashion.

Science.gov (United States)

Masroori, Nasser; Merindol, Natacha; Berthoux, Lionel

2016-03-22

The promyelocytic leukemia (PML) protein, a type I interferon (IFN-I)-induced gene product and a member of the tripartite motif (TRIM) family, modulates the transcriptional activity of viruses belonging to various families. Whether PML has an impact on the replication of HIV-1 has not been fully addressed, but recent studies point to its possible involvement in the restriction of HIV-1 in human cells and in the maintenance of transcriptional latency in human cell lines in which HIV-1 is constitutively repressed. We investigated further the restriction of HIV-1 and a related lentivirus, SIVmac, by PML in murine cells and in a lymphocytic human cell line. In particular, we studied the relevance of PML to IFN-I-mediated inhibition and the role of individual human isoforms. We demonstrate that both human PML (hPML) and murine PML (mPML) inhibit the early post-entry stages of the replication of HIV-1 and a related lentivirus, SIVmac. In addition, HIV-1 was transcriptionally silenced by mPML and by hPML isoforms I, II, IV and VI in MEFs. This PML-mediated transcriptional repression was attenuated in presence of the histone deacetylase inhibitor SAHA. In contrast, depletion of PML had no effect on HIV-1 gene expression in a human T cell line. PML was found to contribute to the inhibition of HIV-1 by IFN-I. Specifically, IFN-α and IFN-β treatments of MEFs enhanced the PML-dependent inhibition of HIV-1 early replication stages. We show that PML can inhibit HIV-1 and other lentiviruses as part of the IFN-I-mediated response. The restriction takes place at two distinct steps, i.e. reverse transcription and transcription, and in an isoform-specific, cellular context-specific fashion. Our results support a model in which PML activates innate immune antilentiviral effectors. These data are relevant to the development of latency reversal-inducing pharmacological agents, since PML was previously proposed as a pharmacological target for such inhibitors. This study also has

Sensitivity analysis of uranium solubility under strongly oxidizing conditions

International Nuclear Information System (INIS)

Liu, L.; Neretnieks, I.

1999-01-01

To evaluate the effect of geochemical conditions in the repository on the solubility of uranium under strongly oxidizing conditions, a mathematical model has been developed to determine the solubility, by utilizing a set of nonlinear algebraic equations to describe the chemical equilibria in the groundwater environment. The model takes into account the predominant precipitation-dissolution reactions, hydrolysis reactions and complexation reactions that may occur under strongly oxidizing conditions. The model also includes the solubility-limiting solids induced by the presence of carbonate, phosphate, silicate, calcium, and sodium in the groundwater. The thermodynamic equilibrium constants used in the solubility calculations are essentially taken from the NEA Thermochemical Data Base of Uranium, with some modification and some uranium minerals added, such as soddyite, rutherfordite, uranophane, uranyl orthophosphate, and becquerelite. By applying this model, the sensitivities of uranium solubility to variations in the concentrations of various groundwater component species are systematically investigated. The results show that the total analytical concentrations of carbonate, phosphate, silicate, and calcium in deep groundwater play the most important role in determining the solubility of uranium under strongly oxidizing conditions

X-ray-induced specific-locus mutations in the ad-3 region of two-component heterokaryons of Neurospora crass

International Nuclear Information System (INIS)

De Serres, F.J.

1990-01-01

More extensive complementation tests than those performed initially on a series of 832 X-ray-induced specific-locus mutations in the adenine-4 (ad-3) region of a two-component heterokaryon (H-12) of Neurospora crassa showed that unexpectedly high frequencies of specific-locus mutations in the ad-3 region have additional, but separate, sites of recessive lethal damage in the immediately adjacent genetic regions. In the present paper, X-ray-induced irreparable ad-3 mutants of the folowing genotypes and numbers (ad-3A ad-3B, ad-3A ad-3B nic-2, and ad-3B nic-2) have also subjected to the same genetic fine structure analysis. These experiments, in the previous and present papers, were designed to determine the extent of the functional inactivation in the ad-3 and immediately adjacent genetic regions in individual mutants classified as presumptive multilocus deletions or multiplelocus mutations. The data in the present paper have shown that in Neurospora crassa most X-ray-induced irreparable mutants of genotype ad-3A ad-3B, ad-3A ad-3B nic-2, and ad-3 nic-2 map as a series of overlapping multilocus deletions. In addition, genetic fine structure analysis has shown that some of the mutants classified, initially, as multilocus deletions, are actually multiple-locus mutations: multilocus deletions with closely linked, and separate, sites of recessive lethal damage with a wide variety of genotyes. Combining data from the present experiments with previously published date, the frequency of multiple-locus mutations among X-ray-induced gene/point mutations and multilocus deletions in the ad-3 region is 6.2%. (author). 27 refs.; 4 figs.; 7 tab

Transport phenomena in strongly correlated Fermi liquids

International Nuclear Information System (INIS)

Kontani, Hiroshi

2013-01-01

Comprehensive overview. Written by an expert of this topic. Provides the reader with current developments in the field. In conventional metals, various transport coefficients are scaled according to the quasiparticle relaxation time, τ, which implies that the relaxation time approximation (RTA) holds well. However, such a simple scaling does not hold in many strongly correlated electron systems, reflecting their unique electronic states. The most famous example would be cuprate high-Tc superconductors (HTSCs), where almost all the transport coefficients exhibit a significant deviation from the RTA results. To better understand the origin of this discrepancy, we develop a method for calculating various transport coefficients beyond the RTA by employing field theoretical techniques. Near the magnetic quantum critical point, the current vertex correction (CVC), which describes the electron-electron scattering beyond the relaxation time approximation, gives rise to various anomalous transport phenomena. We explain anomalous transport phenomena in cuprate HTSCs and other metals near their magnetic or orbital quantum critical point using a uniform approach. We also discuss spin related transport phenomena in strongly correlated systems. In many d- and f-electron systems, the spin current induced by the spin Hall effect is considerably greater because of the orbital degrees of freedom. This fact attracts much attention due to its potential application in spintronics. We discuss various novel charge, spin and heat transport phenomena in strongly correlated metals.

Strong-Field Control of Laser Filamentation Mechanisms

Science.gov (United States)

Levis, Robert; Romanov, Dmitri; Filin, Aleskey; Compton, Ryan

2008-05-01

The propagation of short strong-file laser pulses in gas and solution phases often result in formation of filaments. This phenomenon involves many nonlinear processes including Kerr lensing, group velocity dispersion, multi-photon ionization, plasma defocusing, intensity clamping, and self-steepening. Of these, formation and dynamics of pencil-shape plasma areas plays a crucial role. The fundamental understanding of these laser-induced plasmas requires additional effort, because the process is highly nonlinear and complex. We studied the ultrafast laser-generated plasma dynamics both experimentally and theoretically. Ultrafast plasma dynamics was probed using Coherent Anti-Stokes Raman Scattering. The measurements were made in a room temperature gas maintained at 1 atm in a flowing cell. The time dependent scattering was measured by delaying the CARS probe with respect to the intense laser excitation pulse. A general trend is observed between the spacing of the ground state and the first allowed excited state with the rise time for the noble gas series and the molecular gases. This trend is consistent with our theoretical model, which considers the ultrafast dynamics of the strong field generated plasma as a three-step process; (i) strong-field ionization followed by the electron gaining considerable kinetic energy during the pulse; (ii) immediate post-pulse dynamics: fast thermalization, impact-ionization-driven electron multiplication and cooling; (iii) ensuing relaxation: evolution to electron-ion equilibrium and eventual recombination.

Defective Lipoprotein Sorting Induces lolA Expression through the Rcs Stress Response Phosphorelay System

OpenAIRE

Tao, Kazuyuki; Narita, Shin-ichiro; Tokuda, Hajime

2012-01-01

The Escherichia coli LolA protein is a lipoprotein-specific chaperone that carries lipoproteins from the inner to the outer membrane. A dominant negative LolA mutant, LolA(I93C/F140C), in which both 93Ile and 140Phe are replaced by Cys, binds tightly to the lipoprotein-dedicated ABC transporter LolCDE complex on the inner membrane and therefore inhibits the detachment of outer membrane-specific lipoproteins from the inner membrane. We found that the expression of this mutant strongly induced ...

The Bekenstein bound in strongly coupled O(N) scalar field theory

International Nuclear Information System (INIS)

Magalhaes, T. Santos; Svaiter, N.F.; Menezes, G.

2009-09-01

We discuss the O(N) self-interacting scalar field theory, in the strong-coupling regime and also in the limit of large N. Considering that the system is in thermal equilibrium with a reservoir at temperature β -1 , we assume the presence of macroscopic boundaries conning the field in a hypercube of side L. Using the strong-coupling perturbative expansion, we generalize previous results, i.e., we obtain the renormalized mean energy E and entropy S for the system in rst order of the strong-coupling perturbative expansion, presenting an analytical proof that the specific entropy also satisfies in some situations a quantum bound. When considering the low temperature behavior of the specific entropy, the sign of the renormalized zero-point energy can invalidate this quantum bound. If the renormalized zero point-energy is a positive quantity, at intermediate temperatures and in the low temperature limit, there is a quantum bound. (author)

PPARγ partial agonist GQ-16 strongly represses a subset of genes in 3T3-L1 adipocytes

Energy Technology Data Exchange (ETDEWEB)

Milton, Flora Aparecida [Faculdade de Ciências da Saúde, Laboratório de Farmacologia Molecular, Universidade de Brasília (Brazil); Genomic Medicine, Houston Methodist Research Institute, Houston, TX (United States); Cvoro, Aleksandra [Genomic Medicine, Houston Methodist Research Institute, Houston, TX (United States); Amato, Angelica A. [Faculdade de Ciências da Saúde, Laboratório de Farmacologia Molecular, Universidade de Brasília (Brazil); Sieglaff, Douglas H.; Filgueira, Carly S.; Arumanayagam, Anithachristy Sigamani [Genomic Medicine, Houston Methodist Research Institute, Houston, TX (United States); Caro Alves de Lima, Maria do; Rocha Pitta, Ivan [Laboratório de Planejamento e Síntese de Fármacos – LPSF, Universidade Federal de Pernambuco (Brazil); Assis Rocha Neves, Francisco de [Faculdade de Ciências da Saúde, Laboratório de Farmacologia Molecular, Universidade de Brasília (Brazil); Webb, Paul, E-mail: pwebb@HoustonMethodist.org [Genomic Medicine, Houston Methodist Research Institute, Houston, TX (United States)

2015-08-28

Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor gamma (PPARγ) agonists that improve insulin resistance but trigger side effects such as weight gain, edema, congestive heart failure and bone loss. GQ-16 is a PPARγ partial agonist that improves glucose tolerance and insulin sensitivity in mouse models of obesity and diabetes without inducing weight gain or edema. It is not clear whether GQ-16 acts as a partial agonist at all PPARγ target genes, or whether it displays gene-selective actions. To determine how GQ-16 influences PPARγ activity on a gene by gene basis, we compared effects of rosiglitazone (Rosi) and GQ-16 in mature 3T3-L1 adipocytes using microarray and qRT-PCR. Rosi changed expression of 1156 genes in 3T3-L1, but GQ-16 only changed 89 genes. GQ-16 generally showed weak effects upon Rosi induced genes, consistent with partial agonist actions, but a subset of modestly Rosi induced and strongly repressed genes displayed disproportionately strong GQ-16 responses. PPARγ partial agonists MLR24 and SR1664 also exhibit disproportionately strong effects on transcriptional repression. We conclude that GQ-16 displays a continuum of weak partial agonist effects but efficiently represses some negatively regulated PPARγ responsive genes. Strong repressive effects could contribute to physiologic actions of GQ-16. - Highlights: • GQ-16 is an insulin sensitizing PPARγ ligand with reduced harmful side effects. • GQ-16 displays a continuum of weak partial agonist activities at PPARγ-induced genes. • GQ-16 exerts strong repressive effects at a subset of genes. • These inhibitor actions should be evaluated in models of adipose tissue inflammation.

PPARγ partial agonist GQ-16 strongly represses a subset of genes in 3T3-L1 adipocytes

International Nuclear Information System (INIS)

Milton, Flora Aparecida; Cvoro, Aleksandra; Amato, Angelica A.; Sieglaff, Douglas H.; Filgueira, Carly S.; Arumanayagam, Anithachristy Sigamani; Caro Alves de Lima, Maria do; Rocha Pitta, Ivan; Assis Rocha Neves, Francisco de; Webb, Paul

2015-01-01

Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor gamma (PPARγ) agonists that improve insulin resistance but trigger side effects such as weight gain, edema, congestive heart failure and bone loss. GQ-16 is a PPARγ partial agonist that improves glucose tolerance and insulin sensitivity in mouse models of obesity and diabetes without inducing weight gain or edema. It is not clear whether GQ-16 acts as a partial agonist at all PPARγ target genes, or whether it displays gene-selective actions. To determine how GQ-16 influences PPARγ activity on a gene by gene basis, we compared effects of rosiglitazone (Rosi) and GQ-16 in mature 3T3-L1 adipocytes using microarray and qRT-PCR. Rosi changed expression of 1156 genes in 3T3-L1, but GQ-16 only changed 89 genes. GQ-16 generally showed weak effects upon Rosi induced genes, consistent with partial agonist actions, but a subset of modestly Rosi induced and strongly repressed genes displayed disproportionately strong GQ-16 responses. PPARγ partial agonists MLR24 and SR1664 also exhibit disproportionately strong effects on transcriptional repression. We conclude that GQ-16 displays a continuum of weak partial agonist effects but efficiently represses some negatively regulated PPARγ responsive genes. Strong repressive effects could contribute to physiologic actions of GQ-16. - Highlights: • GQ-16 is an insulin sensitizing PPARγ ligand with reduced harmful side effects. • GQ-16 displays a continuum of weak partial agonist activities at PPARγ-induced genes. • GQ-16 exerts strong repressive effects at a subset of genes. • These inhibitor actions should be evaluated in models of adipose tissue inflammation

Control of dynamical self-assembly of strongly Brownian nanoparticles through convective forces induced by ultrafast laser

Science.gov (United States)

Ilday, Serim; Akguc, Gursoy B.; Tokel, Onur; Makey, Ghaith; Yavuz, Ozgun; Yavuz, Koray; Pavlov, Ihor; Ilday, F. Omer; Gulseren, Oguz

We report a new dynamical self-assembly mechanism, where judicious use of convective and strong Brownian forces enables effective patterning of colloidal nanoparticles that are almost two orders of magnitude smaller than the laser beam. Optical trapping or tweezing effects are not involved, but the laser is used to create steep thermal gradients through multi-photon absorption, and thereby guide the colloids through convective forces. Convective forces can be thought as a positive feedback mechanism that helps to form and reinforce pattern, while Brownian motion act as a competing negative feedback mechanism to limit the growth of the pattern, as well as to increase the possibilities of bifurcation into different patterns, analogous to the competition observed in reaction-diffusion systems. By steering stochastic processes through these forces, we are able to gain control over the emergent pattern such as to form-deform-reform of a pattern, to change its shape and transport it spatially within seconds. This enables us to dynamically initiate and control large patterns comprised of hundreds of colloids. Further, by not relying on any specific chemical, optical or magnetic interaction, this new method is, in principle, completely independent of the material type being assembled.

Lack of specificity of chromosome breaks resulting from radiation-induced genomic instability in Chinese hamster cells

International Nuclear Information System (INIS)

Trott, K.-R.; Teibe, A.

1998-01-01

In V79 Chinese hamster cells, radiation-induced genomic instability results in a persistently increased frequency of micronuclei, dicentric chromosomes and apoptosis and in decreased colony-forming ability. These manifestations of radiation-induced genomic instability may be attributed to an increased rate of chromosome breakage events many generations after irradiation. This chromosomal instability does not seem to be a property which has been inflicted on individual chromosomes at the time of irradiation. Rather, it appears to be secondary to an increased level of non-specific clastogenic factors in the progeny of most if not all irradiated cells. This conclusion is drawn from the observations presented here, that all the chromosomes in surviving V79 cells are involved in the formation of dicentric chromosome aberrations 1 or 2 weeks after irradiation with about equal probability if corrections are made for chromosome length. (orig.)

Substrate specificity of glucose dehydrogenase and carbon source utilization pattern of pantoea dispersa strain P2 and its radiation induced mutants

International Nuclear Information System (INIS)

Lee, Young Keun; Murugesan, Senthilkumar

2009-01-01

Mineral phosphate solubilizing pantoea dispersa strain P2 produced 5.5 mM and 42.6 mM of gluconic acid on 24 h and 72 h incubation, respectively. Strain P2 exhibited glucose dehydrogenase (GDH) specific activity of 0.32 IU mg -1 protein. We have studied the substrate specificity of GDH as well as carbon source utilization pattern of strain P2. GDH of strain P2 did not use ribose as substrate. Utilization of lactose with specific activity of 0.65 IU mg -1 protein indicated that the enzyme belongs to GDH type B isozyme. Arabinose, galactose, ribose, sucrose and xylose did not induce the synthesis of GDH enzyme while mannose induced the synthesis of GDH with highest specific activity of 0.58 IU mg -1 protein. Through radiation mutagenesis, the substrate specificity of GDH was modified in order to utilize side range of sugars available in root exudates. Ribose, originally not a substrate for GDH of strain P2 was utilized as substrate by mutants P2-M5 with specific activity of 0.44 and 0.57 IU mg -1 protein, respectively. Specific activity of GDH on the media containing lactose and galactose was also improved to 1.2 and 0.52 IU mg -1 protein in P2-M5 and P2-M6 respectively. Based on the carbon source availability in root exudate, the mutants can be selected and utilized as efficient biofertilizer under P-deficient soil conditions

Oral Vaccination with the Porcine Rotavirus VP4 Outer Capsid Protein Expressed by Lactococcus lactis Induces Specific Antibody Production

Directory of Open Access Journals (Sweden)

Yi-jing Li

2010-01-01

Full Text Available The objective of this study to design a delivery system resistant to the gastrointestinal environment for oral vaccine against porcine rotavirus. Lactococcus lactis NZ9000 was transformed with segments of vP4 of the porcine rotavirus inserted into the pNZ8112 surface-expression vector, and a recombinant L. lactis expressing VP4 protein was constructed. An approximately 27 kDa VP4 protein was confirmed by SDS-PAGE , Western blot and immunostaining analysis. BALB/c mice were immunized orally with VP4-expression recombinant L. lactis and cellular, mucosal and systemic humoral immune responses were examined. Specific anti-VP4 secretory IgA and IgG were found in feces, ophthalmic and vaginal washes and in serum. The induced antibodies demonstrated neutralizing effects on porcine rotavirus infection on MA104 cells. Our findings suggest that oral immunization with VP4-expressing L. lactis induced both specific local and systemic humoral and cellular immune responses in mice.

Unexpected strong magnetism of Cu doped single-layer MoS₂ and its origin.

Science.gov (United States)

Yun, Won Seok; Lee, J D

2014-05-21

The magnetism of the 3d transition-metal (TM) doped single-layer (1L) MoS2, where the Mo atom is partially replaced by the 3d TM atom, is investigated using the first-principles density functional calculations. In a series of 3d TM doped 1L-MoS2's, the induced spin polarizations are negligible for Sc, Ti, and Cr dopings, while the induced spin polarizations are confirmed for V, Mn, Fe, Co, Ni, Cu, and Zn dopings and the systems become magnetic. Especially, the Cu doped system shows unexpectedly strong magnetism although Cu is nonmagnetic in its bulk state. The driving force is found to be a strong hybridization between Cu 3d states and 3p states of neighboring S, which results in an extreme unbalanced spin-population in the spin-split impurity bands near the Fermi level. Finally, we also discuss further issues of the Cu induced magnetism of 1L-MoS2 such as investigation of additional charge states, the Cu doping at the S site instead of the Mo site, and the Cu adatom on the layer (i.e., 1L-MoS2).

Strong coupling strategy for fluid-structure interaction problems in supersonic regime via fixed point iteration

Science.gov (United States)

Storti, Mario A.; Nigro, Norberto M.; Paz, Rodrigo R.; Dalcín, Lisandro D.

2009-03-01

In this paper some results on the convergence of the Gauss-Seidel iteration when solving fluid/structure interaction problems with strong coupling via fixed point iteration are presented. The flow-induced vibration of a flat plate aligned with the flow direction at supersonic Mach number is studied. The precision of different predictor schemes and the influence of the partitioned strong coupling on stability is discussed.

Identifying Candidate Reprogramming Genes in Mouse Induced Pluripotent Stem Cells.

Science.gov (United States)

Gao, Fang; Li, Jingyu; Zhang, Heng; Yang, Xu; An, Tiezhu

2017-08-01

Factor-based induced reprogramming approaches have tremendous potential for human regenerative medicine, but the efficiencies of these approaches are still low. In this study, we analyzed the global transcriptional profiles of mouse induced pluripotent stem cells (miPSCs) and mouse embryonic stem cells (mESCs) from seven different labs and present here the first successful clustering according to cell type, not by lab of origin. We identified 2131 different expression genes (DEs) as candidate pluripotency-associated genes by comparing mESCs/miPSCs with somatic cells and 720 DEs between miPSCs and mESCs. Interestingly, there was a significant overlap between the two DE sets. Therefore, we defined the overlap DEs as "consensus DEs" including 313 miPSC-specific genes expressed at a higher level in miPSCs versus mESCs and 184 mESC-specific genes in total and reasoned that these may contribute to the differences in pluripotency between mESCs and miPSCs. A classification of "consensus DEs" according to their different expression levels between somatic cells and mESCs/miPSCs shows that 86% of the miPSC-specific genes are more highly expressed in somatic cells, while 73% of mESC-specific genes are highly expressed in mESCs/miPSCs, indicating that the miPSCs have not efficiently silenced the expression pattern of the somatic cells from which they are derived and failed to completely induce the genes with high expression levels in mESCs. We further revealed a strong correlation between oocyte-enriched factors and insufficiently induced mESC-specific genes and identified 11 hub genes via network analysis. In light of these findings, we postulated that these key hub genes might not only drive somatic cell nuclear transfer (SCNT) reprogramming but also augment the efficiency and quality of miPSC reprogramming.

EDITORIAL: Strongly correlated electron systems Strongly correlated electron systems

Science.gov (United States)

Ronning, Filip; Batista, Cristian

2011-03-01

Strongly correlated electrons is an exciting and diverse field in condensed matter physics. This special issue aims to capture some of that excitement and recent developments in the field. Given that this issue was inspired by the 2010 International Conference on Strongly Correlated Electron Systems (SCES 2010), we briefly give some history in order to place this issue in context. The 2010 International Conference on Strongly Correlated Electron Systems was held in Santa Fe, New Mexico, a reunion of sorts from the 1989 International Conference on the Physics of Highly Correlated Electron Systems that also convened in Santa Fe. SCES 2010—co-chaired by John Sarrao and Joe Thompson—followed the tradition of earlier conferences, in this century, hosted by Buzios (2008), Houston (2007), Vienna (2005), Karlsruhe (2004), Krakow (2002) and Ann Arbor (2001). Every three years since 1997, SCES has joined the International Conference on Magnetism (ICM), held in Recife (2000), Rome (2003), Kyoto (2006) and Karlsruhe (2009). Like its predecessors, SCES 2010 topics included strongly correlated f- and d-electron systems, heavy-fermion behaviors, quantum-phase transitions, non-Fermi liquid phenomena, unconventional superconductivity, and emergent states that arise from electronic correlations. Recent developments from studies of quantum magnetism and cold atoms complemented the traditional subjects and were included in SCES 2010. 2010 celebrated the 400th anniversary of Santa Fe as well as the birth of astronomy. So what's the connection to SCES? The Dutch invention of the first practical telescope and its use by Galileo in 1610 and subsequent years overturned dogma that the sun revolved about the earth. This revolutionary, and at the time heretical, conclusion required innovative combinations of new instrumentation, observation and mathematics. These same combinations are just as important 400 years later and are the foundation of scientific discoveries that were discussed

Individual Differences in the Speed of Facial Emotion Recognition Show Little Specificity but Are Strongly Related with General Mental Speed: Psychometric, Neural and Genetic Evidence

Directory of Open Access Journals (Sweden)

Xinyang Liu

2017-08-01

Full Text Available Facial identity and facial expression processing are crucial socio-emotional abilities but seem to show only limited psychometric uniqueness when the processing speed is considered in easy tasks. We applied a comprehensive measurement of processing speed and contrasted performance specificity in socio-emotional, social and non-social stimuli from an individual differences perspective. Performance in a multivariate task battery could be best modeled by a general speed factor and a first-order factor capturing some specific variance due to processing emotional facial expressions. We further tested equivalence of the relationships between speed factors and polymorphisms of dopamine and serotonin transporter genes. Results show that the speed factors are not only psychometrically equivalent but invariant in their relation with the Catechol-O-Methyl-Transferase (COMT Val158Met polymorphism. However, the 5-HTTLPR/rs25531 serotonin polymorphism was related with the first-order factor of emotion perception speed, suggesting a specific genetic correlate of processing emotions. We further investigated the relationship between several components of event-related brain potentials with psychometric abilities, and tested emotion specific individual differences at the neurophysiological level. Results revealed swifter emotion perception abilities to go along with larger amplitudes of the P100 and the Early Posterior Negativity (EPN, when emotion processing was modeled on its own. However, after partialling out the shared variance of emotion perception speed with general processing speed-related abilities, brain-behavior relationships did not remain specific for emotion. Together, the present results suggest that speed abilities are strongly interrelated but show some specificity for emotion processing speed at the psychometric level. At both genetic and neurophysiological levels, emotion specificity depended on whether general cognition is taken into account

Individual Differences in the Speed of Facial Emotion Recognition Show Little Specificity but Are Strongly Related with General Mental Speed: Psychometric, Neural and Genetic Evidence

Science.gov (United States)

Liu, Xinyang; Hildebrandt, Andrea; Recio, Guillermo; Sommer, Werner; Cai, Xinxia; Wilhelm, Oliver

2017-01-01

Facial identity and facial expression processing are crucial socio-emotional abilities but seem to show only limited psychometric uniqueness when the processing speed is considered in easy tasks. We applied a comprehensive measurement of processing speed and contrasted performance specificity in socio-emotional, social and non-social stimuli from an individual differences perspective. Performance in a multivariate task battery could be best modeled by a general speed factor and a first-order factor capturing some specific variance due to processing emotional facial expressions. We further tested equivalence of the relationships between speed factors and polymorphisms of dopamine and serotonin transporter genes. Results show that the speed factors are not only psychometrically equivalent but invariant in their relation with the Catechol-O-Methyl-Transferase (COMT) Val158Met polymorphism. However, the 5-HTTLPR/rs25531 serotonin polymorphism was related with the first-order factor of emotion perception speed, suggesting a specific genetic correlate of processing emotions. We further investigated the relationship between several components of event-related brain potentials with psychometric abilities, and tested emotion specific individual differences at the neurophysiological level. Results revealed swifter emotion perception abilities to go along with larger amplitudes of the P100 and the Early Posterior Negativity (EPN), when emotion processing was modeled on its own. However, after partialling out the shared variance of emotion perception speed with general processing speed-related abilities, brain-behavior relationships did not remain specific for emotion. Together, the present results suggest that speed abilities are strongly interrelated but show some specificity for emotion processing speed at the psychometric level. At both genetic and neurophysiological levels, emotion specificity depended on whether general cognition is taken into account or not. These

Novel engineered HIV-1 East African Clade-A gp160 plasmid construct induces strong humoral and cell-mediated immune responses in vivo

International Nuclear Information System (INIS)

Muthumani, Karuppiah; Zhang Donghui; Dayes, Nathanael S.; Hwang, Daniel S.; Calarota, Sandra A.; Choo, Andrew Y.; Boyer, Jean D.; Weiner, David B.

2003-01-01

HIV-1 sequences are highly diverse due to the inaccuracy of the viral reverse transcriptase. This diversity has been studied and used to categorize HIV isolates into subtypes or clades, which are geographically distinct. To develop effective vaccines against HIV-1, immunogens representing different subtypes may be important for induction of cross-protective immunity, but little data exist describing and comparing the immunogenicity induced by different subtype-based vaccines. This issue is further complicated by poor expression of HIV structural antigens due to rev dependence. One costly approach is to codon optimize each subtype construct to be examined. Interestingly, cis-acting transcriptional elements (CTE) can also by pass rev restriction by a rev independent export pathway. We reasoned that rev+CTE constructs might have advantages for such expression studies. A subtype A envelope sequence from a viral isolate from east Africa was cloned into a eukaryotic expression vector under the control of the CMV-IE promoter. The utility of inclusion of the Mason-Pfizer monkey virus (MPV)-CTE with/without rev for driving envelope expression and immunogenicity was examined. Expression of envelope (gp120) was confirmed by immunoblot analysis and by pseudotype virus infectivity assays. The presence of rev and the CTE together increased envelope expression and viral infection. Furthermore the CTE+rev construct was significantly more immunogenic then CTE alone vector. Isotype analysis and cytokine profiles showed strong Th1 response in plasmid-immunized mice, which also demonstrated the superior nature of the rev+CTE construct. These responses were of similar or greater magnitude to a codon-optimized construct. The resulting cellular immune responses were highly cross-reactive with a HIV-1 envelope subtype B antigen. This study suggests a simple strategy for improving the expression and immunogenicity of HIV subtype-specific envelope antigens as plasmid or vector

iPSC-Derived Regulatory Dendritic Cells Inhibit Allograft Rejection by Generating Alloantigen-Specific Regulatory T Cells

Directory of Open Access Journals (Sweden)

Songjie Cai

2017-05-01

Full Text Available Regulatory dendritic cell (DCregs-based immunotherapy is a potential therapeutic tool for transplant rejection. We generated DCregs from murine induced pluripotent stem cells (iPSCs, which could remain in a “stable immature stage” even under strong stimulation. Harnessing this characteristic, we hypothesized that iPS-DCregs worked as a negative vaccine to generate regulatory T cells (Tregs, and induced donor-specific allograft acceptance. We immunized naive CBA (H-2Kk mice with B6 (H-2Kb iPS-DCregs and found that Tregs (CD4+CD25+FOXP3+ significantly increased in CBA splenocytes. Moreover, immunized CBA recipients permanently accepted B6 cardiac grafts in a donor-specific pattern. We demonstrated mechanistically that donor-type iPS-DCregs triggered transforming growth factor β1 secretion, under which the donor-antigen peptides directed naive CD4+ T cells to differentiate into donor-specific FOXP3+ Tregs instead of into effector T cells in vivo. These findings highlight the potential of iPS-DCregs as a key cell therapy resource in clinical transplantation.

Gravitational leptogenesis, C, CP and strong equivalence

International Nuclear Information System (INIS)

McDonald, Jamie I.; Shore, Graham M.

2015-01-01

The origin of matter-antimatter asymmetry is one of the most important outstanding problems at the interface of particle physics and cosmology. Gravitational leptogenesis (baryogenesis) provides a possible mechanism through explicit couplings of spacetime curvature to appropriate lepton (or baryon) currents. In this paper, the idea that these strong equivalence principle violating interactions could be generated automatically through quantum loop effects in curved spacetime is explored, focusing on the realisation of the discrete symmetries C, CP and CPT which must be broken to induce matter-antimatter asymmetry. The related issue of quantum corrections to the dispersion relation for neutrino propagation in curved spacetime is considered within a fully covariant framework.

Gravitational leptogenesis, C, CP and strong equivalence

Energy Technology Data Exchange (ETDEWEB)

McDonald, Jamie I.; Shore, Graham M. [Department of Physics, Swansea University,Swansea, SA2 8PP (United Kingdom)

2015-02-12

The origin of matter-antimatter asymmetry is one of the most important outstanding problems at the interface of particle physics and cosmology. Gravitational leptogenesis (baryogenesis) provides a possible mechanism through explicit couplings of spacetime curvature to appropriate lepton (or baryon) currents. In this paper, the idea that these strong equivalence principle violating interactions could be generated automatically through quantum loop effects in curved spacetime is explored, focusing on the realisation of the discrete symmetries C, CP and CPT which must be broken to induce matter-antimatter asymmetry. The related issue of quantum corrections to the dispersion relation for neutrino propagation in curved spacetime is considered within a fully covariant framework.

Strong enhancement of streaming current power by application of two phase flow

NARCIS (Netherlands)

Xie, Yanbo; Sherwood, John D.; Shui, Lingling; van den Berg, Albert; Eijkel, Jan C.T.

2011-01-01

We show that the performance of a streaming-potential based microfluidic energy conversion system can be strongly en-hanced by the use of two phase flow. In single-phase systems, the internal conduction current induced by the streaming poten-tial limits the output power, while in a two-phase system

Flow-induced vibration and fretting-wear specifications to ensure steam-generator and heat exchanger lifetime performance

International Nuclear Information System (INIS)

Janzen, V.P.; Han, Y.; Pettigrew, M.J.

2008-01-01

The current interest in refurbishment, life extension and new-build activity has meant a renewed emphasis on technical specifications that will ensure improved reliability and longer life. Preventing vibration and fretting-wear problems in steam generators and heat exchangers requires design specifications that bring together specific guidelines, analysis methods, requirements and appropriate performance criteria. The specifications must be firmly based on experimental data and field inspections. In addition, the specifications must be supported by theoretical analyses and fundamental scaling correlations, to cover conditions and geometries over the wide range applicable to existing components and probable future designs. The specifications are expected to evolve to meet changing industry requirements. This paper outlines the steps required to generate and support design specifications, and relates them to typical steam-generator design features and computer modeling capabilities. It also describes current issues that are driving changes to flow-induced vibration and fretting-wear specifications that can be applied to the design process for component refurbishment, replacement or new designs. These issues include recent experimental or field evidence for new excitation mechanisms, e.g., the possibility of in-plane fluidelastic instability of U-tubes, the demand for longer reactor and component lifetimes, the need for better predictions of dynamic properties and vibration response, e.g., two-phase random-turbulence excitation, and requirements to consider system 'excursions' or abnormal scenarios, e.g., a main steam line break in the case of steam generators. The paper describes steps being taken to resolve these issues. (author)

Attosecond Electron Wave Packet Dynamics in Strong Laser Fields

International Nuclear Information System (INIS)

Johnsson, P.; Remetter, T.; Varju, K.; L'Huillier, A.; Lopez-Martens, R.; Valentin, C.; Balcou, Ph.; Kazamias, S.; Mauritsson, J.; Gaarde, M. B.; Schafer, K. J.; Mairesse, Y.; Wabnitz, H.; Salieres, P.

2005-01-01

We use a train of sub-200 attosecond extreme ultraviolet (XUV) pulses with energies just above the ionization threshold in argon to create a train of temporally localized electron wave packets. We study the energy transfer from a strong infrared (IR) laser field to the ionized electrons as a function of the delay between the XUV and IR fields. When the wave packets are born at the zero crossings of the IR field, a significant amount of energy (∼20 eV) is transferred from the field to the electrons. This results in dramatically enhanced above-threshold ionization in conditions where the IR field alone does not induce any significant ionization. Because both the energy and duration of the wave packets can be varied independently of the IR laser, they are valuable tools for studying and controlling strong-field processes

Cold suppresses agonist-induced activation of TRPV1.

Science.gov (United States)

Chung, M-K; Wang, S

2011-09-01

Cold therapy is frequently used to reduce pain and edema following acute injury or surgery such as tooth extraction. However, the neurobiological mechanisms of cold therapy are not completely understood. Transient receptor potential vanilloid 1 (TRPV1) is a capsaicin- and heat-gated nociceptive ion channel implicated in thermosensation and pathological pain under conditions of inflammation or injury. Although capsaicin-induced nociception, neuropeptide release, and ionic currents are suppressed by cold, it is not known if cold suppresses agonist-induced activation of recombinant TRPV1. We demonstrate that cold strongly suppressed the activation of recombinant TRPV1 by multiple agonists and capsaicin-evoked currents in trigeminal ganglia neurons under normal and phosphorylated conditions. Cold-induced suppression was partially impaired in a TRPV1 mutant that lacked heat-mediated activation and potentiation. These results suggest that cold-induced suppression of TRPV1 may share a common molecular basis with heat-induced potentiation, and that allosteric inhibition may contribute, in part, to the cold-induced suppression. We also show that combination of cold and a specific antagonist of TRPV1 can produce an additive suppression. Our results provide a mechanistic basis for cold therapy and may enhance anti-nociceptive approaches that target TRPV1 for managing pain under inflammation and tissue injury, including that from tooth extraction.

Is nutrient intake a gender-specific cause for enhanced susceptibility to alcohol-induced liver disease in women?

DEFF Research Database (Denmark)

Wagnerberger, S.; Schäfer, C.; Schwarz, E.

2008-01-01

AIM: Women have a higher susceptibility to alcohol-induced liver disease (ALD) than men. Gender-related differences in food preference were described in previous studies for several populations, but not in alcohol abusers. As certain micronutrients are reported to take influence on the development......, the data of calculated daily macro- and micronutrient intake do not suggest any explicit influence of gender-specific nutrition in the development of ALD....

Cardiac-specific catalase overexpression rescues anthrax lethal toxin-induced cardiac contractile dysfunction: role of oxidative stress and autophagy.

Science.gov (United States)

Kandadi, Machender R; Yu, Xuejun; Frankel, Arthur E; Ren, Jun

2012-11-07

Lethal and edema toxins secreted by Bacillus anthracis during anthrax infection were found to incite serious cardiovascular complications. However, the underlying mechanisms in anthrax lethal toxin-induced cardiac anomalies remain unknown. This study was designed to evaluate the impact of antioxidant enzyme catalase in anthrax lethal toxin-induced cardiomyocyte contractile dysfunction. Wild type (WT) and cardiac-specific catalase overexpression mice were challenged with lethal toxin (2 μg/g, intraperotineally (i.p.)). Cardiomyocyte contractile and intracellular Ca(2+) properties were assessed 18 h later using an IonOptix edge-detection system. Proteasome function was assessed using chymotrypsin-like and caspase-like activities. GFP-LC3 puncta and Western blot analysis were used to evaluate autophagy and protein ubiquitination. Lethal toxin exposure suppressed cardiomyocyte contractile function (suppressed peak shortening, maximal velocity of shortening/re-lengthening, prolonged duration of shortening/re-lengthening, and impaired intracellular Ca(2+) handling), the effects of which were alleviated by catalase. In addition, lethal toxin triggered autophagy, mitochondrial and ubiquitin-proteasome defects, the effects of which were mitigated by catalase. Pretreatment of cardiomyocytes from catalase mice with the autophagy inducer rapamycin significantly attenuated or ablated catalase-offered protection against lethal toxin-induced cardiomyocyte dysfunction. On the other hand, the autophagy inhibitor 3-MA ablated or significantly attenuated lethal toxin-induced cardiomyocyte contractile anomalies. Our results suggest that catalase is protective against anthrax lethal toxin-induced cardiomyocyte contractile and intracellular Ca(2+) anomalies, possibly through regulation of autophagy and mitochondrial function.

Human-specific subcellular compartmentalization of P-element induced wimpy testis-like (PIWIL) granules during germ cell development and spermatogenesis

NARCIS (Netherlands)

Gomes Fernandes, Maria; He, Nannan; Wang, Fang; Van Iperen, Liesbeth; Eguizabal, Cristina; Matorras, Roberto; Roelen, Bernard A J; Chuva de Sousa Lopes, Susana M

2018-01-01

STUDY QUESTION: What is the dynamics of expression of P-element induced wimpy testis-like (PIWIL) proteins in the germline during human fetal development and spermatogenesis? SUMMARY ANSWER: PIWIL1, PIWIL2, PIWIL3 and PIWIL4 were expressed in a sex-specific fashion in human germ cells (GC) during

Sensitive and specific detection of classical scrapie prions in the brain of goats by real-time quaking-induced conversion

Science.gov (United States)

The real-time quaking-induced conversion (RT-QuIC) is a rapid, specific, and sensitive prion seeding activity detection assay that uses recombinant prion protein (rPrPSen) to detect sub-infectious levels of the abnormal isoforms of the prion protein (PrPSc). Although RT-QuIC has been successfully us...

Direct current (DC) resistivity and Induced Polarization (IP) monitoring of active layer dynamics at high temporal resolution

DEFF Research Database (Denmark)

Doetsch, J.; Fiandaca, G.; Ingeman-Nielsen, Thomas

2015-01-01

With permafrost thawing and changes in active layer dynamics induced by climate change, interactions between biogeochemical and thermal processes in the ground are of great importance. Here, active layer dynamics have been monitored using direct current (DC) resistivity and induced polarization (IP...... the soil freezing as a strong increase in resistivity. While the freezing horizon generally moves deeper with time, some variations in the freezing depth are observed along the profile. Comparison with depth-specific soil temperature indicates an exponential relationship between resistivity and below...

Specific estrogen-induced cell proliferation of cultured Syrian hamster renal proximal tubular cells in serum-free chemically defined media

International Nuclear Information System (INIS)

Oberley, T.D.; Lauchner, L.J.; Pugh, T.D.; Gonzalez, A.; Goldfarb, S.; Li, S.A.; Li, J.J.

1989-01-01

It has long been recognized that the renal proximal tubular epithelium of the hamster is a bona fide estrogen target tissue. The effect of estrogens on the growth of proximal tubule cell explants and dissociated single cells derived from these explant outgrowths has been studied in culture. Renal tubular cells were grown on a PF-HR-9 basement membrane under serum-free chemically defined culture conditions. At 7-14 days in culture, cell number was enhanced 3-fold in the presence of either 17β-estradiol or diethylstilbestrol. A similar 3-fold increase in cell number was also seen at 1 nM 17β-estradiol in subcultured dissociated single tubular cells derived from hamster renal tubular explant outgrowths at 21 days in culture. Concomitant exposure of tamoxifen at 3-fold molar excess in culture completely abolished the increase in cell number seen with 17β-estradiol. The proliferation effect of estrogens on proximal tubular cell growth appears to be species specific since 17β-estradiol did not alter the growth of either rat or guinea pig proximal tubules in culture. In addition, at 7-10 days in culture in the presence of 17β-estradiol, [ 3 H]thymidine labeling of hamster tubular cells was enhanced 3-fold. These results clearly indicate that estrogens can directly induce primary epithelial cell proliferation at physiologic concentrations and provide strong additional evidence for an important hormonal role in the neoplastic transformation of the hamster kidney

Cell Type-Specific Chromatin Signatures Underline Regulatory DNA Elements in Human Induced Pluripotent Stem Cells and Somatic Cells.

Science.gov (United States)

Zhao, Ming-Tao; Shao, Ning-Yi; Hu, Shijun; Ma, Ning; Srinivasan, Rajini; Jahanbani, Fereshteh; Lee, Jaecheol; Zhang, Sophia L; Snyder, Michael P; Wu, Joseph C

2017-11-10

Regulatory DNA elements in the human genome play important roles in determining the transcriptional abundance and spatiotemporal gene expression during embryonic heart development and somatic cell reprogramming. It is not well known how chromatin marks in regulatory DNA elements are modulated to establish cell type-specific gene expression in the human heart. We aimed to decipher the cell type-specific epigenetic signatures in regulatory DNA elements and how they modulate heart-specific gene expression. We profiled genome-wide transcriptional activity and a variety of epigenetic marks in the regulatory DNA elements using massive RNA-seq (n=12) and ChIP-seq (chromatin immunoprecipitation combined with high-throughput sequencing; n=84) in human endothelial cells (CD31 + CD144 + ), cardiac progenitor cells (Sca-1 + ), fibroblasts (DDR2 + ), and their respective induced pluripotent stem cells. We uncovered 2 classes of regulatory DNA elements: class I was identified with ubiquitous enhancer (H3K4me1) and promoter (H3K4me3) marks in all cell types, whereas class II was enriched with H3K4me1 and H3K4me3 in a cell type-specific manner. Both class I and class II regulatory elements exhibited stimulatory roles in nearby gene expression in a given cell type. However, class I promoters displayed more dominant regulatory effects on transcriptional abundance regardless of distal enhancers. Transcription factor network analysis indicated that human induced pluripotent stem cells and somatic cells from the heart selected their preferential regulatory elements to maintain cell type-specific gene expression. In addition, we validated the function of these enhancer elements in transgenic mouse embryos and human cells and identified a few enhancers that could possibly regulate the cardiac-specific gene expression. Given that a large number of genetic variants associated with human diseases are located in regulatory DNA elements, our study provides valuable resources for deciphering

SUMO Signaling by Hypoxic Inactivation of SUMO-Specific Isopeptidases

Directory of Open Access Journals (Sweden)

Kathrin Kunz

2016-09-01

Full Text Available Post-translational modification of proteins with ubiquitin-like SUMO modifiers is a tightly regulated and highly dynamic process. The SENP family of SUMO-specific isopeptidases comprises six cysteine proteases. They are instrumental in counterbalancing SUMO conjugation, but their regulation is not well understood. We demonstrate that in hypoxic cell extracts, the catalytic activity of SENP family members, in particular SENP1 and SENP3, is inhibited in a rapid and fully reversible process. Comparative mass spectrometry from normoxic and hypoxic cells defines a subset of hypoxia-induced SUMO1 targets, including SUMO ligases RanBP2 and PIAS2, glucose transporter 1, and transcriptional regulators. Among the most strongly induced targets, we identified the transcriptional co-repressor BHLHE40, which controls hypoxic gene expression programs. We provide evidence that SUMOylation of BHLHE40 is reversed by SENP1 and contributes to transcriptional repression of the metabolic master regulator gene PGC-1α. We propose a pathway that connects oxygen-controlled SENP activity to hypoxic reprogramming of metabolism.

An inducible model of abacterial prostatitis induces antigen specific inflammatory and proliferative changes in the murine prostate

Science.gov (United States)

Haverkamp, Jessica M.; Charbonneau, Bridget; Meyerholz, David K.; Cohen, Michael B.; Snyder, Paul W.; Svensson, Robert U.; Henry, Michael D.; Wang, Hsing- Hui

2011-01-01

Background Prostatitis is a poorly understood disease and increasing evidence suggests inflammation is involved in other prostatic diseases, including prostate cancer. Methods The ability of pre-activated CD8 T cells to induce prostatitis was examined by adoptive transfer into POET-3 mice or POET-3/Luc/Pten−/+ mice. Characterization of the inflammatory response was determined by examining leukocyte infiltration by histological analysis, flow cytometry and by evaluating cytokine and chemokine levels in prostate tissue. The impact of inflammation on the prostate was evaluated by monitoring epithelial cell proliferation over time. Results Initiation of inflammation by ovalbumin specific CD8+ T cells (OT-I cells) resulted in development of acute prostatitis in the anterior, dorsolateral and anterior prostate of POET-3 and POET-3/Luc/Pten−/+ mice. Acute prostatitis was characterized by recruitment of adoptively transferred OT-I cells and importantly, autologous CD4+ and CD8+ T cells, myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg). In concert with leukocyte infiltration elevated levels of pro-inflammatory cytokines and chemokines were observed. Inflammation also resulted in marked epithelial cell proliferation that was sustained up to 80 days post adoptive-transfer of OT-I cells. Conclusions The POET-3 model represents a novel mouse model to study both acute and chronic prostate inflammation in an antigen-specific system. Further, the POET-3 mouse model can be crossed with other genetic models of disease such as the C57/Luc/Pten−/− model of prostate cancer, allowing the impact of prostatitis on other prostatic diseases to be evaluated. PMID:21656824

Fireworks induced particle pollution: A spatio-temporal analysis

Science.gov (United States)

Kumar, M.; Singh, R. K.; Murari, V.; Singh, A. K.; Singh, R. S.; Banerjee, T.

2016-11-01

Diwali-specific firework induced particle pollution was measured in terms of aerosol mass loading, type, optical properties and vertical distribution. Entire nation exhibited an increase in particulate concentrations specifically in Indo-Gangetic Plain (IGP). Aerosol surface mass loading at middle IGP revealed an increase of 56-121% during festival days in comparison to their background concentrations. Space-borne measurements (Aqua and Terra-MODIS) typically identified IGP with moderate to high AOD (0.3-0.8) during pre-festive days which transmutes to very high AOD (0.4-1.8) during Diwali-day with accumulation of aerosol fine mode fractions (0.3-1.0). Most of the aerosol surface monitoring stations exhibited increase in PM2.5 especially on Diwali-day while PM10 exhibited increase on subsequent days. Elemental compositions strongly support K, Ba, Sr, Cd, S and P to be considered as firework tracers. The upper and middle IGP revealed dominance of absorbing aerosols (OMI-AI: 0.80-1.40) while CALIPSO altitude-orbit-cross-section profiles established the presence of polluted dust which eventually modified with association of smoke and polluted continental during extreme fireworks. Diwali-specific these observations have implications on associating fireworks induced particle pollution and human health while inclusion of these observations should improve regional air quality model.

Liver-Specific Deletion of Protein-Tyrosine Phosphatase 1B (PTP1B) Improves Metabolic Syndrome and Attenuates Diet-Induced Endoplasmic Reticulum Stress

Science.gov (United States)

Delibegovic, Mirela; Zimmer, Derek; Kauffman, Caitlin; Rak, Kimberly; Hong, Eun-Gyoung; Cho, You-Ree; Kim, Jason K.; Kahn, Barbara B.; Neel, Benjamin G.; Bence, Kendra K.

2009-01-01

OBJECTIVE—The protein tyrosine phosphatase PTP1B is a negative regulator of insulin signaling; consequently, mice deficient in PTP1B are hypersensitive to insulin. Because PTP1B−/− mice have diminished fat stores, the extent to which PTP1B directly regulates glucose homeostasis is unclear. Previously, we showed that brain-specific PTP1B−/− mice are protected against high-fat diet–induced obesity and glucose intolerance, whereas muscle-specific PTP1B−/− mice have increased insulin sensitivity independent of changes in adiposity. Here we studied the role of liver PTP1B in glucose homeostasis and lipid metabolism. RESEARCH DESIGN AND METHODS—We analyzed body mass/adiposity, insulin sensitivity, glucose tolerance, and lipid metabolism in liver-specific PTP1B−/− and PTP1Bfl/fl control mice, fed a chow or high-fat diet. RESULTS—Compared with normal littermates, liver-specific PTP1B−/− mice exhibit improved glucose homeostasis and lipid profiles, independent of changes in adiposity. Liver-specific PTP1B−/− mice have increased hepatic insulin signaling, decreased expression of gluconeogenic genes PEPCK and G-6-Pase, enhanced insulin-induced suppression of hepatic glucose production, and improved glucose tolerance. Liver-specific PTP1B−/− mice exhibit decreased triglyceride and cholesterol levels and diminished expression of lipogenic genes SREBPs, FAS, and ACC. Liver-specific PTP1B deletion also protects against high-fat diet–induced endoplasmic reticulum stress response in vivo, as evidenced by decreased phosphorylation of p38MAPK, JNK, PERK, and eIF2α and lower expression of the transcription factors C/EBP homologous protein and spliced X box-binding protein 1. CONCLUSIONS—Liver PTP1B plays an important role in glucose and lipid metabolism, independent of alterations in adiposity. Inhibition of PTP1B in peripheral tissues may be useful for the treatment of metabolic syndrome and reduction of cardiovascular risk in addition to

Substrate specificity of glucose dehydrogenase and carbon source utilization pattern of pantoea dispersa strain P2 and its radiation induced mutants

Energy Technology Data Exchange (ETDEWEB)

Lee, Young Keun; Murugesan, Senthilkumar [Korea Atomic Energy Research Institute, Jeongeup (Korea, Republic of)

2009-06-15

Mineral phosphate solubilizing pantoea dispersa strain P2 produced 5.5 mM and 42.6 mM of gluconic acid on 24 h and 72 h incubation, respectively. Strain P2 exhibited glucose dehydrogenase (GDH) specific activity of 0.32 IU mg{sup -1} protein. We have studied the substrate specificity of GDH as well as carbon source utilization pattern of strain P2. GDH of strain P2 did not use ribose as substrate. Utilization of lactose with specific activity of 0.65 IU mg{sup -1} protein indicated that the enzyme belongs to GDH type B isozyme. Arabinose, galactose, ribose, sucrose and xylose did not induce the synthesis of GDH enzyme while mannose induced the synthesis of GDH with highest specific activity of 0.58 IU mg{sup -1} protein. Through radiation mutagenesis, the substrate specificity of GDH was modified in order to utilize side range of sugars available in root exudates. Ribose, originally not a substrate for GDH of strain P2 was utilized as substrate by mutants P2-M5 with specific activity of 0.44 and 0.57 IU mg{sup -1} protein, respectively. Specific activity of GDH on the media containing lactose and galactose was also improved to 1.2 and 0.52 IU mg{sup -1} protein in P2-M5 and P2-M6 respectively. Based on the carbon source availability in root exudate, the mutants can be selected and utilized as efficient biofertilizer under P-deficient soil conditions.

Surface-Induced Hybridization between Graphene and Titanium

Energy Technology Data Exchange (ETDEWEB)

Hsu, Allen L. [MIT (Massachusetts Inst. of Technology), Cambridge, MA (United States).; Koch, Roland J. [Technische Universitat, Chemnitz (Germany); Ong, Mitchell T. [Stanford Univ., CA (United States); Fang, Wenjing [MIT (Massachusetts Inst. of Technology), Cambridge, MA (United States); Hofmann, Mario [MIT (Massachusetts Inst. of Technology), Cambridge, MA (United States); Kim, Ki Kang [MIT (Massachusetts Inst. of Technology), Cambridge, MA (United States).; Seyller, Thomas [Technische Universitat, Chemnitz (Germany); Dresselhaus, Mildred S. [MIT (Massachusetts Inst. of Technology), Cambridge, MA (United States); Reed, Evan J. [Stanford Univ., CA (United States); Kong, Jing [MIT (Massachusetts Inst. of Technology), Cambridge, MA (United States); Palacios, Tomás [MIT (Massachusetts Inst. of Technology), Cambridge, MA (United States)

2014-08-26

Carbon-based materials such as graphene sheets and carbon nanotubes have inspired a broad range of applications ranging from high-speed flexible electronics all the way to ultrastrong membranes. However, many of these applications are limited by the complex interactions between carbon-based materials and metals. In this work, we experimentally investigate the structural interactions between graphene and transition metals such as palladium (Pd) and titanium (Ti), which have been confirmed by density functional simulations. We find that the adsorption of titanium on graphene is more energetically favorable than in the case of most metals, and density functional theory shows that a surface induced p-d hybridization occurs between atomic carbon and titanium orbitals. This strong affinity between the two materials results in a short-range ordered crystalline deposition on top of graphene as well as chemical modifications to graphene as seen by Raman and X-ray photoemission spectroscopy (XPS). This induced hybridization is interface-specific and has major consequences for contacting graphene nanoelectronic devices as well as applications toward metal-induced chemical functionalization of graphene.

TCR Signal Strength Regulates Akt Substrate Specificity To Induce Alternate Murine Th and T Regulatory Cell Differentiation Programs.

Science.gov (United States)

Hawse, William F; Boggess, William C; Morel, Penelope A

2017-07-15

The Akt/mTOR pathway is a key driver of murine CD4 + T cell differentiation, and induction of regulatory T (Treg) cells results from low TCR signal strength and low Akt/mTOR signaling. However, strong TCR signals induce high Akt activity that promotes Th cell induction. Yet, it is unclear how Akt controls alternate T cell fate decisions. We find that the strength of the TCR signal results in differential Akt enzymatic activity. Surprisingly, the Akt substrate networks associated with T cell fate decisions are qualitatively different. Proteomic profiling of Akt signaling networks during Treg versus Th induction demonstrates that Akt differentially regulates RNA processing and splicing factors to drive T cell differentiation. Interestingly, heterogeneous nuclear ribonucleoprotein (hnRNP) L or hnRNP A1 are Akt substrates during Treg induction and have known roles in regulating the stability and splicing of key mRNAs that code for proteins in the canonical TCR signaling pathway, including CD3ζ and CD45. Functionally, inhibition of Akt enzymatic activity results in the dysregulation of splicing during T cell differentiation, and knockdown of hnRNP L or hnRNP A1 results in the lower induction of Treg cells. Together, this work suggests that a switch in substrate specificity coupled to the phosphorylation status of Akt may lead to alternative cell fates and demonstrates that proteins involved with alternative splicing are important factors in T cell fate decisions. Copyright © 2017 by The American Association of Immunologists, Inc.

Non-specific immunization against parasites

International Nuclear Information System (INIS)

Cox, F.E.G.

1981-01-01

Non-specific resistance to tumours can be induced by pretreating animals with micro-organisms, microbial extracts or various synthetic substances. Mycobacterium bovis, Corynebacterium parvum and a number of other micro-organisms also protect mice against rodent piroplasms and there is evidence that they are also protective against other parasites including Schistosoma mansoni. The actual mechanisms of non-specific immunity are still unclear but it is influenced by both the genetic make-up of the host and the nature of the parasite. Non-specific immunization may be a possible alternative to specific immunization and may avoid many of the potential immunopathological changes induced during parasite infections. Irradiated vaccines (Dictyocaulus viviparus, schistomiasis) are mentioned marginally only

Disease-specific induced pluripotent stem cells: a platform for human disease modeling and drug discovery.

Science.gov (United States)

Jang, Jiho; Yoo, Jeong-Eun; Lee, Jeong-Ah; Lee, Dongjin R; Kim, Ji Young; Huh, Yong Jun; Kim, Dae-Sung; Park, Chul-Yong; Hwang, Dong-Youn; Kim, Han-Soo; Kang, Hoon-Chul; Kim, Dong-Wook

2012-03-31

The generation of disease-specific induced pluripotent stem cell (iPSC) lines from patients with incurable diseases is a promising approach for studying disease mechanisms and drug screening. Such innovation enables to obtain autologous cell sources in regenerative medicine. Herein, we report the generation and characterization of iPSCs from fibroblasts of patients with sporadic or familial diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), juvenile-onset, type I diabetes mellitus (JDM), and Duchenne type muscular dystrophy (DMD), as well as from normal human fibroblasts (WT). As an example to modeling disease using disease-specific iPSCs, we also discuss the previously established childhood cerebral adrenoleukodystrophy (CCALD)- and adrenomyeloneuropathy (AMN)-iPSCs by our group. Through DNA fingerprinting analysis, the origins of generated disease-specific iPSC lines were identified. Each iPSC line exhibited an intense alkaline phosphatase activity, expression of pluripotent markers, and the potential to differentiate into all three embryonic germ layers: the ectoderm, endoderm, and mesoderm. Expression of endogenous pluripotent markers and downregulation of retrovirus-delivered transgenes [OCT4 (POU5F1), SOX2, KLF4, and c-MYC] were observed in the generated iPSCs. Collectively, our results demonstrated that disease-specific iPSC lines characteristically resembled hESC lines. Furthermore, we were able to differentiate PD-iPSCs, one of the disease-specific-iPSC lines we generated, into dopaminergic (DA) neurons, the cell type mostly affected by PD. These PD-specific DA neurons along with other examples of cell models derived from disease-specific iPSCs would provide a powerful platform for examining the pathophysiology of relevant diseases at the cellular and molecular levels and for developing new drugs and therapeutic regimens.

Ascaroside expression in Caenorhabditis elegans is strongly dependent on diet and developmental stage.

Directory of Open Access Journals (Sweden)

Fatma Kaplan

2011-03-01

Full Text Available The ascarosides form a family of small molecules that have been isolated from cultures of the nematode Caenorhabditis elegans. They are often referred to as "dauer pheromones" because most of them induce formation of long-lived and highly stress resistant dauer larvae. More recent studies have shown that ascarosides serve additional functions as social signals and mating pheromones. Thus, ascarosides have multiple functions. Until now, it has been generally assumed that ascarosides are constitutively expressed during nematode development.Cultures of C. elegans were developmentally synchronized on controlled diets. Ascarosides released into the media, as well as stored internally, were quantified by LC/MS. We found that ascaroside biosynthesis and release were strongly dependent on developmental stage and diet. The male attracting pheromone was verified to be a blend of at least four ascarosides, and peak production of the two most potent mating pheromone components, ascr#3 and asc#8 immediately preceded or coincided with the temporal window for mating. The concentration of ascr#2 increased under starvation conditions and peaked during dauer formation, strongly supporting ascr#2 as the main population density signal (dauer pheromone. After dauer formation, ascaroside production largely ceased and dauer larvae did not release any ascarosides. These findings show that both total ascaroside production and the relative proportions of individual ascarosides strongly correlate with these compounds' stage-specific biological functions.Ascaroside expression changes with development and environmental conditions. This is consistent with multiple functions of these signaling molecules. Knowledge of such differential regulation will make it possible to associate ascaroside production to gene expression profiles (transcript, protein or enzyme activity and help to determine genetic pathways that control ascaroside biosynthesis. In conjunction with findings

Epitope-Specific Tolerance Modes Differentially Specify Susceptibility to Proteolipid Protein-Induced Experimental Autoimmune Encephalomyelitis

Directory of Open Access Journals (Sweden)

Lei Wang

2017-11-01

Full Text Available Immunization with myelin components can elicit experimental autoimmune encephalomyelitis (EAE. EAE susceptibility varies between mouse strains, depending on the antigen employed. BL/6 mice are largely resistant to EAE induction with proteolipid protein (PLP, probably a reflection of antigen-specific tolerance. However, the extent and mechanism(s of tolerance to PLP remain unclear. Here, we identified three PLP epitopes in PLP-deficient BL/6 mice. PLP-sufficient mice did not respond against two of these, whereas tolerance was “leaky” for an epitope with weak predicted MHCII binding, and only this epitope was encephalitogenic. In TCR transgenic mice, the “EAE-susceptibility-associated” epitope was “ignored” by specific CD4 T cells, whereas the “resistance-associated” epitope induced clonal deletion and Treg induction in the thymus. Central tolerance was autoimmune regulator dependent and required expression and presentation of PLP by thymic epithelial cells (TECs. TEC-specific ablation of PLP revealed that peripheral tolerance, mediated by dendritic cells through recessive tolerance mechanisms (deletion and anergy, could largely compensate for a lack of central tolerance. However, adoptive EAE was exacerbated in mice lacking PLP in TECs, pointing toward a non-redundant role of the thymus in dominant tolerance to PLP. Our findings reveal multiple layers of tolerance to a central nervous system autoantigen that vary among epitopes and thereby specify disease susceptibility. Understanding how different modalities of tolerance apply to distinct T cell epitopes of a target in autoimmunity has implications for antigen-specific strategies to therapeutically interfere with unwanted immune reactions against self.

Particle Production in Strong Electromagnetic Fields in Relativistic Heavy-Ion Collisions

Directory of Open Access Journals (Sweden)

Kirill Tuchin

2013-01-01

Full Text Available I review the origin and properties of electromagnetic fields produced in heavy-ion collisions. The field strength immediately after a collision is proportional to the collision energy and reaches ~mπ2 at RHIC and ~10mπ2 at LHC. I demonstrate by explicit analytical calculation that after dropping by about one-two orders of magnitude during the first fm/c of plasma expansion, it freezes out and lasts for as long as quark-gluon plasma lives as a consequence of finite electrical conductivity of the plasma. Magnetic field breaks spherical symmetry in the direction perpendicular to the reaction plane, and therefore all kinetic coefficients are anisotropic. I examine viscosity of QGP and show that magnetic field induces azimuthal anisotropy on plasma flow even in spherically symmetric geometry. Very strong electromagnetic field has an important impact on particle production. I discuss the problem of energy loss and polarization of fast fermions due to synchrotron radiation, consider photon decay induced by magnetic field, elucidate J/ψ dissociation via Lorentz ionization mechanism, and examine electromagnetic radiation by plasma. I conclude that all processes in QGP are affected by strong electromagnetic field and call for experimental investigation.

Depleted uranium induces sex- and tissue-specific methylation patterns in adult zebrafish

International Nuclear Information System (INIS)

Gombeau, Kewin; Pereira, Sandrine; Ravanat, Jean-Luc; Camilleri, Virginie; Cavalie, Isabelle; Bourdineaud, Jean-Paul; Adam-Guillermin, Christelle

2016-01-01

We examined the effects of chronic exposure to different concentrations (2 and 20 μg L"−"1) of environmentally relevant waterborne depleted uranium (DU) on the DNA methylation patterns both at HpaII restriction sites (5′-CCGG-3′) and across the whole genome in the zebrafish brain, gonads, and eyes. We first identified sex-dependent differences in the methylation level of HpaII sites after exposure. In males, these effects were present as early as 7 days after exposure to 20 μg L"−"1 DU, and were even more pronounced in the brain, gonads, and eyes after 24 days. However, in females, hypomethylation was only observed in the gonads after exposure to 20 μg L"−"1 DU for 24 days. Sex-specific effects of DU were also apparent at the whole-genome level, because in males, exposure to 20 μg L"−"1 DU for 24 days resulted in cytosine hypermethylation in the brain and eyes and hypomethylation in the gonads. In contrast, in females, hypermethylation was observed in the brain after exposure to both concentrations of DU for 7 days. Based on our current knowledge of uranium toxicity, several hypotheses are proposed to explain these findings, including the involvement of oxidative stress, alteration of demethylation enzymes and the calcium signaling pathway. This study reports, for the first time, the sex- and tissue-specific epigenetic changes that occur in a nonhuman organism after exposure to environmentally relevant concentrations of uranium, which could induce transgenerational epigenetic effects. - Highlights: • This study demonstrates a sex-related effect of DU exposure on DNA methylation patterns. • Impacts on DNA methylation patterns revealed a tissue-specific effect of DU exposure. • The MS–AFLP and HPLC–MS/MS sensitively and complementarily demonstrated the responses to environmental concentrations of DU.

[Detection of fps tumor antigen with mono-specific anti-fps serum in tumors induced by acute transforming ALV].

Science.gov (United States)

Wang, Yixin; Chen, Hao; Zhao, Peng; Li, Jianliang; Cui, Zhizhong

2013-03-04

To prepare anti-fps mono-specific serum, and detect the fps antigen in tumors induced by acute transforming avian leukosis/sarcoma virus containing v-fps oncogene. Two part of v-fps gene was amplified by RT-PCR using the Fu-J viral RNA as the template. Mono-specific serum was prepared by immuning Kunming white mouse with both two recombinant infusion proteins expressed by the prokaryotic expression system. Indirect immunofluorescent assay was used to detect fps antigen in tumor tissue suspension cells and CEF infected by sarcoma supernatant. Immunohistochemical method was used to detect fps antigen in tumor tissue. The mouse mono-specific serum was specific as it had no cross reaction with classical ALV-J strains. The result reveals that the tumor tissue suspension cells, the CEF infected by sarcoma supernatant, and the slice immunohistochemistry of the sarcoma showed positive results. The anti-fps mono-specific serum was prepared, and the detection method was established, which laid the foundation for the study of viral biological characteristics and mechanism of tumourgenesis of acute transforming avian leukosis/sarcoma virus containing v-fps oncogene.

The characterization of six auxin-induced tomato GH3 genes uncovers a member, SlGH3.4, strongly responsive to arbuscular mycorrhizal symbiosis.

Science.gov (United States)

Liao, Dehua; Chen, Xiao; Chen, Aiqun; Wang, Huimin; Liu, Jianjian; Liu, Junli; Gu, Mian; Sun, Shubin; Xu, Guohua

2015-04-01

In plants, the GH3 gene family is widely considered to be involved in a broad range of plant physiological processes, through modulation of hormonal homeostasis. Multiple GH3 genes have been functionally characterized in several plant species; however, to date, limited works to study the GH3 genes in tomato have been reported. Here, we characterize the expression and regulatory profiles of six tomato GH3 genes, SlGH3.2, SlGH3.3, SlGH3.4, SlGH3.7, SlGH3.9 and SlGH3.15, in response to different phytohormone applications and arbuscular mycorrhizal (AM) fungal colonization. All six GH3 genes showed inducible responses to external IAA, and three members were significantly up-regulated in response to AM symbiosis. In particular, SlGH3.4, the transcripts of which were barely detectable under normal growth conditions, was strongly activated in the IAA-treated and AM fungal-colonized roots. A comparison of the SlGH3.4 expression in wild-type plants and M161, a mutant with a defect in AM symbiosis, confirmed that SlGH3.4 expression is highly correlated to mycorrhizal colonization. Histochemical staining demonstrated that a 2,258 bp SlGH3.4 promoter fragment could drive β-glucuronidase (GUS) expression strongly in root tips, steles and cortical cells of IAA-treated roots, but predominantly in the fungal-colonized cells of mycorrhizal roots. A truncated 654 bp promoter failed to direct GUS expression in IAA-treated roots, but maintained the symbiosis-induced activity in mycorrhizal roots. In summary, our results suggest that a mycorrhizal signaling pathway that is at least partially independent of the auxin signaling pathway has evolved for the co-regulation of the auxin- and mycorrhiza-activated GH3 genes in plants. © The Author 2014. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Quantum simulation of strongly correlated condensed matter systems

Science.gov (United States)

Hofstetter, W.; Qin, T.

2018-04-01

We review recent experimental and theoretical progress in realizing and simulating many-body phases of ultracold atoms in optical lattices, which gives access to analog quantum simulations of fundamental model Hamiltonians for strongly correlated condensed matter systems, such as the Hubbard model. After a general introduction to quantum gases in optical lattices, their preparation and cooling, and measurement techniques for relevant observables, we focus on several examples, where quantum simulations of this type have been performed successfully during the past years: Mott-insulator states, itinerant quantum magnetism, disorder-induced localization and its interplay with interactions, and topological quantum states in synthetic gauge fields.

Charging-delay effect on longitudinal dust acoustic shock wave in strongly coupled dusty plasma

International Nuclear Information System (INIS)

Ghosh, Samiran; Gupta, M.R.

2005-01-01

Taking into account the charging-delay effect, the nonlinear propagation characteristics of longitudinal dust acoustic wave in strongly coupled collisional dusty plasma described by generalized hydrodynamic model have been investigated. In the 'hydrodynamic limit', a Korteweg-de Vries Burger (KdVB) equation with a damping term arising due to dust-neutral collision is derived in which the Burger term is proportional to the dissipation due to dust viscosity through dust-dust correlation and charging-delay-induced anomalous dissipation. On the other hand, in the 'kinetic limit', a KdVB equation with a damping term and a nonlocal nonlinear forcing term arising due to memory-dependent strong correlation effect of dust fluid is derived in which the Burger term depends only on the charging-delay-induced dissipation. Numerical solution of integrodifferential equations reveals that (i) dissipation due to dust viscosity and principally due to charging delay causes excitation of the longitudinal dust acoustic shock wave in strongly coupled dusty plasma and (ii) dust-neutral collision does not appear to play any direct role in shock formation. The condition for the generation of shock is also discussed briefly

Induced Seismicity

Science.gov (United States)

Keranen, Katie M.; Weingarten, Matthew

2018-05-01

The ability of fluid-generated subsurface stress changes to trigger earthquakes has long been recognized. However, the dramatic rise in the rate of human-induced earthquakes in the past decade has created abundant opportunities to study induced earthquakes and triggering processes. This review briefly summarizes early studies but focuses on results from induced earthquakes during the past 10 years related to fluid injection in petroleum fields. Study of these earthquakes has resulted in insights into physical processes and has identified knowledge gaps and future research directions. Induced earthquakes are challenging to identify using seismological methods, and faults and reefs strongly modulate spatial and temporal patterns of induced seismicity. However, the similarity of induced and natural seismicity provides an effective tool for studying earthquake processes. With continuing development of energy resources, increased interest in carbon sequestration, and construction of large dams, induced seismicity will continue to pose a hazard in coming years.

Region-specific chromatin decondensation and micronucleus formation induced by 5-azacytidine in human TIG-7 cells.

Science.gov (United States)

Satoh, T; Yamamoto, K; Miura, K F; Sofuni, T

2004-01-01

A human diploid lung fibroblast cell strain, TIG-7, has a heteromorphic chromosome 15 with an extra short arm carrying a homogeneously staining region (15p+hsr). We demonstrated previously that the 15p+hsr consists of an inactive and G+C-rich rDNA cluster characterized by fluorescence in situ hybridization (FISH) and various chromosome banding techniques. Thus, it was suggested that the region could contain highly methylated DNA. To observe methylation status on the target region directly under the microscope, we used a demethylating agent, 5-azacytidine (5-azaC), to induce decondensation of the chromatin containing methylated DNA. At 24 h after treatment with 0.5 microM 5-azaC, marked decondensation of the 15p+hsr was observed in almost all of the metaphases. Furthermore, we observed micronuclei, which were equivalent to the rDNA of the 15p+hsr demonstrated by FISH in the same preparation. In contrast, the DNA cross-linking agent mitomycin C (MMC) preferentially induced 15p+hsr-negative micronuclei. These findings indicated that chromatin decondensation and subsequent DNA strand breakage induced by the demethylating effect of 5-azaC led specifically to 15p+hsr-positive micronuclei. Copyright 2003 S. Karger AG, Basel

Field measurement of wind pressure and wind-induced vibration of large-span spatial cable-truss system under strong wind or typhoon

Directory of Open Access Journals (Sweden)

ZHANG Zhihong

2013-10-01

Full Text Available In order to ensure wind-resistance safety of large-span pre-stressed flexible system in southeast coast area of China,and to prepare something for revising of current codes of practice or technical standards,the present paper conducts field measurement of wind pressure and wind-induced vibration of a practical and typical large-span spatial cable-truss system-lunar stadium in Yueqing city.Wind loading and wind effects on full-scale structure under strong wind or typhoon in real architectural environment can be obtained directly and effectively.Field measurement is the best way to investigate the wind loading property,wind effects,and wind-structure interactions of large-span flexible system.Measured data will be highly valuable for scientific research and practical design.On the other hand,it also provides the basis of wind-resistance safety design of this kind of tension structures.If any creative development,it would dramatically improve the research level of large-span pre-stressed flexible system in our country.

A novel immunotherapy of Brucellosis in cows monitored non invasively through a specific biomarker.

Directory of Open Access Journals (Sweden)

Hari Mohan Saxena

2018-04-01

Full Text Available Brucellosis is an important zoonotic disease causing huge economic losses worldwide. Currently no effective immunotherapy for Brucellosis or any biomarker to monitor the efficacy of therapy is available. Treatment is ineffective and animals remain carrier lifelong. S19 and RB51 are live attenuated vaccine strains of Brucella abortus. However, S19 induces only antibody, ineffective for intracellular pathogen. RB51 induces cell mediated immunity (CMI but it is Rifampicin resistant. Both organisms are secreted in milk and can infect humans and cause abortions in animals. Phage lysed bacteria (lysates retain maximum immunogenicity as opposed to killing by heat or chemicals. We report here the successful immunotherapy of bovine Brucellosis by phage lysates of RB51 (RL and S19 (SL. The SL induced strong antibody response and RL stimulated CMI. In vitro restimulation of leukocytes from RL immunized cattle induced interferon gamma production. A single subcutaneous dose of 2 ml of cocktail lysate (both RL and SL, eliminated live virulent Brucella from Brucellosis affected cattle with plasma level of Brucella specific 223 bp amplicon undetectable by RT-PCR and blood negative for live Brucella by culture in 3 months post-immunization. This is the first report on minimally invasive monitoring of the efficacy of antibacterial therapy employing plasma RNA specific for live bacteria as a biomarker as well as on the use of RB51 phage lysate for successful immunotherapy of Brucellosis in cattle.

Evidence for a second 'Prereplicative G2' repair mechanism, specific for γ-induced damage, in wild-type schizosaccharomyces pombe

International Nuclear Information System (INIS)

Gentner, N.E.; Atomic Energy of Canada Ltd., Chalk River, Ontario. Chalk River Nuclear Labs.)

1977-01-01

The major part of the substantial γ-resistance of wild-type Schizosaccharomyces pombe appears to be due to prereplicative recombinational repair mechanisms. The existence of a second 'prereplicative G2' repair pathway, specific for γ-induced damage, has now been deduced from studies of the effect of the repair inhibitor caffeine on γ-irradiated G1 phase and G2 phase cells. Only G2 cells are additionally inactivated on exposure to caffeine after γ-irradiation. This shows that both known caffeine-sensitive γ-repair processes (Genter and Werner, Molec. gen. Genet. 145, 1-5 [1976]) are dependent on the presence of a duplicated genome (2c) at the time of radiation exposure. Pathway I is the known 'prereplicative G2' repair process (Fabre, Radiation Res. 56, 528-539 [1973]) which is involved in both UV- and γ-repair, and which requires post-irradiation protein synthesis for activity. Pathway II represents a second distinct 'prereplicative G2' repair mechanism; it differs from the first in that it is specific for repair of γ-induced damage and appears to be constitutive. (orig.) [de

Strong dynamics and lattice gauge theory

Science.gov (United States)

Schaich, David

and other properties of the new particles predicted by these theories. I find S ≳ 0.1 in the specific theories I study. Although this result still disagrees with experiment, it is much closer to the experimental value than is the conventional wisdom S ≳ 0.3. These results encourage further lattice studies to search for experimentally viable strongly-interacting theories of EWSB.

Synthetic strong ground motions for engineering design utilizing empirical Green`s functions

Energy Technology Data Exchange (ETDEWEB)

Hutchings, L.J.; Jarpe, S.P.; Kasameyer, P.W.; Foxall, W.

1996-04-11

We present a methodology for developing realistic synthetic strong ground motions for specific sites from specific earthquakes. We analyzed the possible ground motion resulting from a M = 7.25 earthquake that ruptures 82 km of the Hayward fault for a site 1.4 km from the fault in the eastern San Francisco Bay area. We developed a suite of 100 rupture scenarios for the Hayward fault earthquake and computed the corresponding strong ground motion time histories. We synthesized strong ground motion with physics-based solutions of earthquake rupture and applied physical bounds on rupture parameters. By having a suite of rupture scenarios of hazardous earthquakes for a fixed magnitude and identifying the hazard to the site from the statistical distribution of engineering parameters, we introduce a probabilistic component into the deterministic hazard calculation. Engineering parameters of synthesized ground motions agree with those recorded from the 1995 Kobe, Japan and the 1992 Landers, California earthquakes at similar distances and site geologies.

TRAIL enhances paracetamol-induced liver sinusoidal endothelial cell death in a Bim- and Bid-dependent manner

Science.gov (United States)

Badmann, A; Langsch, S; Keogh, A; Brunner, T; Kaufmann, T; Corazza, N

2012-01-01

Paracetamol (acetaminophen, APAP) is a universally used analgesic and antipyretic agent. Considered safe at therapeutic doses, overdoses cause acute liver damage characterized by centrilobular hepatic necrosis. One of the major clinical problems of paracetamol-induced liver disease is the development of hemorrhagic alterations. Although hepatocytes represent the main target of the cytotoxic effect of paracetamol overdose, perturbations within the endothelium involving morphological changes of liver sinusoidal endothelial cells (LSECs) have also been described in paracetamol-induced liver disease. Recently, we have shown that paracetamol-induced liver damage is synergistically enhanced by the TRAIL signaling pathway. As LSECs are constantly exposed to activated immune cells expressing death ligands, including TRAIL, we investigated the effect of TRAIL on paracetamol-induced LSEC death. We here demonstrate for the first time that TRAIL strongly enhances paracetamol-mediated LSEC death with typical features of apoptosis. Inhibition of caspases using specific inhibitors resulted in a strong reduction of cell death. TRAIL appears to enhance paracetamol-induced LSEC death via the activation of the pro-apoptotic BH3-only proteins Bid and Bim, which initiate the mitochondrial apoptotic pathway. Taken together this study shows that the liver endothelial layer, mainly LSECs, represent a direct target of the cytotoxic effect of paracetamol and that activation of TRAIL receptor synergistically enhances paracetamol-induced LSEC death via the mitochondrial apoptotic pathway. TRAIL-mediated acceleration of paracetamol-induced cell death may thus contribute to the pathogenesis of paracetamol-induced liver damage. PMID:23254290

Cardiac-specific catalase overexpression rescues anthrax lethal toxin-induced cardiac contractile dysfunction: role of oxidative stress and autophagy

Directory of Open Access Journals (Sweden)

Kandadi Machender R

2012-11-01

Full Text Available Abstract Background Lethal and edema toxins secreted by Bacillus anthracis during anthrax infection were found to incite serious cardiovascular complications. However, the underlying mechanisms in anthrax lethal toxin-induced cardiac anomalies remain unknown. This study was designed to evaluate the impact of antioxidant enzyme catalase in anthrax lethal toxin-induced cardiomyocyte contractile dysfunction. Methods Wild type (WT and cardiac-specific catalase overexpression mice were challenged with lethal toxin (2 μg/g, intraperotineally (i.p.. Cardiomyocyte contractile and intracellular Ca2+ properties were assessed 18 h later using an IonOptix edge-detection system. Proteasome function was assessed using chymotrypsin-like and caspase-like activities. GFP-LC3 puncta and Western blot analysis were used to evaluate autophagy and protein ubiquitination. Results Lethal toxin exposure suppressed cardiomyocyte contractile function (suppressed peak shortening, maximal velocity of shortening/re-lengthening, prolonged duration of shortening/re-lengthening, and impaired intracellular Ca2+ handling, the effects of which were alleviated by catalase. In addition, lethal toxin triggered autophagy, mitochondrial and ubiquitin-proteasome defects, the effects of which were mitigated by catalase. Pretreatment of cardiomyocytes from catalase mice with the autophagy inducer rapamycin significantly attenuated or ablated catalase-offered protection against lethal toxin-induced cardiomyocyte dysfunction. On the other hand, the autophagy inhibitor 3-MA ablated or significantly attenuated lethal toxin-induced cardiomyocyte contractile anomalies. Conclusions Our results suggest that catalase is protective against anthrax lethal toxin-induced cardiomyocyte contractile and intracellular Ca2+ anomalies, possibly through regulation of autophagy and mitochondrial function.

Upregulation of PEDF expression by PARP inhibition contributes to the decrease in hyperglycemia-induced apoptosis in HUVECs

International Nuclear Information System (INIS)

Chen Haibing; Jia Weiping; Xu Xun; Fan Ying; Zhu Dongqing; Wu Haixiang; Xie Zhenggao; Zheng Zhi

2008-01-01

Poly(ADP-ribose)polymerase (PARP) inhibitors decrease angiogenesis through reducing vascular endothelium growth factor (VEGF) induced proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs). In contrast to VEGF, pigment epithelium-derived factor (PEDF) has been demonstrated to act as a strong endogenous inhibitor of angiogenesis. Here, we show that PARP inhibition with a specific inhibitor PJ-34 or specific PARP antisense oligonucleotide upregulates hyperglycemia-induced PEDF expression in HUVECs in a dose-dependent manner. This results in the retard of activation of p38 MAP kinase and the concomitant decrease in cell apoptosis. These results give the first direct demonstration that PEDF might represent a target for PARP inhibition treatment and the effects of PEDF on endothelial cells growth are context dependent

Fibroblast-Specific Deletion of Hypoxia Inducible Factor-1 Critically Impairs Murine Cutaneous Neovascularization and Wound Healing.

Science.gov (United States)

Duscher, Dominik; Maan, Zeshaan N; Whittam, Alexander J; Sorkin, Michael; Hu, Michael S; Walmsley, Graham G; Baker, Hutton; Fischer, Lauren H; Januszyk, Michael; Wong, Victor W; Gurtner, Geoffrey C

2015-11-01

Diabetes and aging are known risk factors for impaired neovascularization in response to ischemic insult, resulting in chronic wounds, and poor outcomes following myocardial infarction and cerebrovascular injury. Hypoxia-inducible factor (HIF)-1α, has been identified as a critical regulator of the response to ischemic injury and is dysfunctional in diabetic and elderly patients. To better understand the role of this master hypoxia regulator within cutaneous tissue, the authors generated and evaluated a fibroblast-specific HIF-1α knockout mouse model. The authors generated floxed HIF-1 mice (HIF-1) by introducing loxP sites around exon 1 of the HIF-1 allele in C57BL/6J mice. Fibroblast-restricted HIF-1α knockout (FbKO) mice were generated by breeding our HIF-1 with tamoxifen-inducible Col1a2-Cre mice (Col1a2-CreER). HIF-1α knockout was evaluated on a DNA, RNA, and protein level. Knockout and wild-type mice were subjected to ischemic flap and wound healing models, and CD31 immunohistochemistry was performed to assess vascularity of healed wounds. Quantitative real-time polymerase chain reaction of FbKO skin demonstrated significantly reduced Hif1 and Vegfa expression compared with wild-type. This finding was confirmed at the protein level (p wound closure and vascularity (p wound healing, reduced wound vascularity, and significant impairment in the ischemic neovascular response. These findings provide new insight into the importance of cell-specific responses to hypoxia during cutaneous neovascularization.

Non-specific immunization against babesiosis

International Nuclear Information System (INIS)

Cox, F.E.G.

1980-01-01

The rodent babesias, Babesia rodhaini and the less virulent B. microti, are useful models with which to study immunity to and immunization against babesiosis. In contrast with the difficulty in inducing specific immunity to these parasites it is comparatively easy to induce non-specific immunity by prior exposure to related and unrelated intra-erythrocytic protozoa, micro-organisms such as Mycobacterium bovis (BCG) and Corynebacterium parvum, microbial extracts and muramyl dipeptide. This non-specific immunity is long lasting and extremely effective. It is characterized by the facts that (a) it occurs early in the infection at the height of the first peak of parasitaemia, and (b) it involves the intra-erythrocytic death of the parasites. After the primary parasitaemia has resolved, some parasites continue to persist at a low level and when introduced into clean mice produce only low-level 'attenuated' infections in these. Non-specific immunity is not equally effective in all strains of mice. It is suggested that immunity to babesiosis, and infections caused by other intra-erythrocytic protozoa, involves two mechanisms, the first non-specific and the second specific. The actual balance between these two mechanisms varies from parasite to parasite and from host to host. An effective vaccine would have to be based on an understanding of the roles of non-specific immunity in the actual disease under consideration, and would ideally combine an adjuvant that would also stimulate non-specific immunity and an attenuated strain of parasite that would induce a specific response. (author)

Metabolic rate in different rat brain areas during seizures induced by a specific delta opiate receptor agonist.

Science.gov (United States)

Haffmans, J; De Kloet, R; Dzoljic, M R

1984-06-04

The glucose utilization during specific delta opiate agonist-induced epileptiform phenomena, determined by the [14C]2-deoxyglucose technique (2-DG), was examined in various rat brain areas at different time intervals. The peak in EEG spiking response and the most intensive 2-DG uptake occurred 5 min after intraventricular (i.v.t.) administration of the delta opiate receptor agonist. The most pronounced 2-DG uptake at this time interval can be observed in the subiculum, including the CA1 hippocampal area, frontal cortex and central amygdala. A general decrease of glucose consumption, compared to control values, is observed after 10 min, in all regions, with exception of the subiculum. Since functional activity and 2-DG uptake are correlated, we suggest that the subiculum and/or CA1 area, are probably the brain regions most involved in the enkephalin-induced epileptic phenomena.

Data base for site specific migration analysis of radioactive elements in repositories

Energy Technology Data Exchange (ETDEWEB)

Hadermann, J

1982-01-01

Migration analysis is of considerable importance in long-term safety aspects of radioactive waste repositories. The present work gives the data base for a selected part of a comprehensive geosphere transport calculation. We restrict ourselves to a critical evaluation of parameters pertinent to the migration analysis of the /sup 245/Cm chain. This includes the important nuclide /sup 237/Np. With these we are able to perform a site specific calculation for repositories planned in deep geologic formations in Switzerland. It is shown that the granitic basement induces strong time delays in nuclide migration. In contrast to that, the overlaying sedimentary layers cause primarily a dilution of the radionuclide concentrations.

Theory of strong hybridization-induced relaxation in uranium systems

International Nuclear Information System (INIS)

Hu, G.; Cooper, B.R.

1988-01-01

Commonly, for metallic uranium systems, sharp magnetic excitations are not observed in neutron inelastic scattering experiments, but rather there is a continuous spectrum of magnetic response. By extending our earlier theory for partially delocalized cerium systems, we can understand this behavior. The band-f hybridization is transformed to resonant scattering in our theory, where the exchange part of the scattering gives both a two-ion interaction (physically corresponding to cooperative hybridization, giving anisotropic magnetic ordering with unusual excitation dispersion for cerium systems) and a hybridization coupling of each ion to the band sea (giving relaxation and strong energy renormalization of the excitations for cerium systems). For uranium the f delocalization (and hence the hybridization) is much stronger than for cerium. The two-ion interaction (giving quasi-ionic energy level splitting) grows by an order of magnitude or more, as evidenced by greatly increased magnetic ordering temperatures. On the other hand, the single-site hybridization strength parameter J-script characterizing the f-to-band-bath coupling grows more moderately as the f levels move toward the Fermi energy, because of the renormalizing effect of the direct scattering which broadens the f levels. The increased energy scale of the quasi-ionic level splitting for uranium as compared to cerium or plutonium is the major contributor to the greatly increased width of magnetic scattering distributions, while the moderate increase in coupling of each uranium quasi-ion to the band sea gives a lesser contribution. We apply this theory to UP and UAs and compare our results with experiment

Vitamin C induces specific demethylation of H3K9me2 in mouse embryonic stem cells via Kdm3a/b.

Science.gov (United States)

Ebata, Kevin T; Mesh, Kathryn; Liu, Shichong; Bilenky, Misha; Fekete, Alexander; Acker, Michael G; Hirst, Martin; Garcia, Benjamin A; Ramalho-Santos, Miguel

2017-01-01

Histone methylation patterns regulate gene expression and are highly dynamic during development. The erasure of histone methylation is carried out by histone demethylase enzymes. We had previously shown that vitamin C enhances the activity of Tet enzymes in embryonic stem (ES) cells, leading to DNA demethylation and activation of germline genes. We report here that vitamin C induces a remarkably specific demethylation of histone H3 lysine 9 dimethylation (H3K9me2) in naïve ES cells. Vitamin C treatment reduces global levels of H3K9me2, but not other histone methylation marks analyzed, as measured by western blot, immunofluorescence and mass spectrometry. Vitamin C leads to widespread loss of H3K9me2 at large chromosomal domains as well as gene promoters and repeat elements. Vitamin C-induced loss of H3K9me2 occurs rapidly within 24 h and is reversible. Importantly, we found that the histone demethylases Kdm3a and Kdm3b are required for vitamin C-induced demethylation of H3K9me2. Moreover, we show that vitamin C-induced Kdm3a/b-mediated H3K9me2 demethylation and Tet-mediated DNA demethylation are independent processes at specific loci. Lastly, we document Kdm3a/b are partially required for the upregulation of germline genes by vitamin C. These results reveal a specific role for vitamin C in histone demethylation in ES cells and document that DNA methylation and H3K9me2 cooperate to silence germline genes in pluripotent cells.

A Drosophila immune response against Ras-induced overgrowth

Directory of Open Access Journals (Sweden)

Thomas Hauling

2014-03-01

Full Text Available Our goal is to characterize the innate immune response against the early stage of tumor development. For this, animal models where genetic changes in specific cells and tissues can be performed in a controlled way have become increasingly important, including the fruitfly Drosophila melanogaster. Many tumor mutants in Drosophila affect the germline and, as a consequence, also the immune system itself, making it difficult to ascribe their phenotype to a specific tissue. Only during the past decade, mutations have been induced systematically in somatic cells to study the control of tumorous growth by neighboring cells and by immune cells. Here we show that upon ectopic expression of a dominant-active form of the Ras oncogene (RasV12, both imaginal discs and salivary glands are affected. Particularly, the glands increase in size, express metalloproteinases and display apoptotic markers. This leads to a strong cellular response, which has many hallmarks of the granuloma-like encapsulation reaction, usually mounted by the insect against larger foreign objects. RNA sequencing of the fat body reveals a characteristic humoral immune response. In addition we also identify genes that are specifically induced upon expression of RasV12. As a proof-of-principle, we show that one of the induced genes (santa-maria, which encodes a scavenger receptor, modulates damage to the salivary glands. The list of genes we have identified provides a rich source for further functional characterization. Our hope is that this will lead to a better understanding of the earliest stage of innate immune responses against tumors with implications for mammalian immunity.

Characterization of a cis-acting element involved in cell-specific expression of the zebrafish brain aromatase gene.

Science.gov (United States)

Le Page, Yann; Menuet, Arnaud; Kah, Olivier; Pakdel, Farzad

2008-10-01

The cytochrome P450 Aromatase is the key enzyme catalyzing the conversion of androgens into estrogens. In zebrafish, the brain aromatase is encoded by cyp19b. Expression of cyp19b is restricted to radial glial cells bordering forebrain ventricles and is strongly stimulated by estrogens during development. At the promoter level, we have previously shown that an estrogen responsive element (ERE) is required for induction by estrogens. Here, we investigated the role of ERE flanking regions in the control of cell-specific expression. First, we show that a 20 bp length motif, named G x RE (glial x responsive element), acts in synergy with the ERE to mediate the estrogenic induction specifically in glial cells. Second, we demonstrate that, in vitro, this sequence binds factors exclusively present in glial or neuro-glial cells and is able to confer a glial specificity to an artificial estrogen-dependent gene. Taken together, these results contribute to the understanding of the molecular mechanisms allowing cyp19b regulation by estrogens and allowed to identify a promoter sequence involved in the strong estrogen inducibility of cyp19b which is specific for glial cells. The exceptional aromatase activity measured in the brain of teleost fish could rely on such mechanisms.

Isolation of a strong Arabidopsis guard cell promoter and its potential as a research tool

Science.gov (United States)

Yang, Yingzhen; Costa, Alex; Leonhardt, Nathalie; Siegel, Robert S; Schroeder, Julian I

2008-01-01

Background A common limitation in guard cell signaling research is that it is difficult to obtain consistent high expression of transgenes of interest in Arabidopsis guard cells using known guard cell promoters or the constitutive 35S cauliflower mosaic virus promoter. An additional drawback of the 35S promoter is that ectopically expressing a gene throughout the organism could cause pleiotropic effects. To improve available methods for targeted gene expression in guard cells, we isolated strong guard cell promoter candidates based on new guard cell-specific microarray analyses of 23,000 genes that are made available together with this report. Results A promoter, pGC1(At1g22690), drove strong and relatively specific reporter gene expression in guard cells including GUS (beta-glucuronidase) and yellow cameleon YC3.60 (GFP-based calcium FRET reporter). Reporter gene expression was weaker in immature guard cells. The expression of YC3.60 was sufficiently strong to image intracellular Ca2+ dynamics in guard cells of intact plants and resolved spontaneous calcium transients in guard cells. The GC1 promoter also mediated strong reporter expression in clustered stomata in the stomatal development mutant too-many-mouths (tmm). Furthermore, the same promoter::reporter constructs also drove guard cell specific reporter expression in tobacco, illustrating the potential of this promoter as a method for high level expression in guard cells. A serial deletion of the promoter defined a guard cell expression promoter region. In addition, anti-sense repression using pGC1 was powerful for reducing specific GFP gene expression in guard cells while expression in leaf epidermal cells was not repressed, demonstrating strong cell-type preferential gene repression. Conclusion The pGC1 promoter described here drives strong reporter expression in guard cells of Arabidopsis and tobacco plants. It provides a potent research tool for targeted guard cell expression or gene silencing. It is also

Cardiac Glycoside Glucoevatromonoside Induces Cancer Type-Specific Cell Death

Directory of Open Access Journals (Sweden)

Naira F. Z. Schneider

2018-03-01

Full Text Available Cardiac glycosides (CGs are natural compounds used traditionally to treat congestive heart diseases. Recent investigations repositioned CGs as potential anticancer agents. To discover novel cytotoxic CG scaffolds, we selected the cardenolide glucoevatromonoside (GEV out of 46 CGs for its low nanomolar anti-lung cancer activity. GEV presented reduced toxicity toward non-cancerous cell types (lung MRC-5 and PBMC and high-affinity binding to the Na+/K+-ATPase α subunit, assessed by computational docking. GEV-induced cell death was caspase-independent, as investigated by a multiparametric approach, and culminates in severe morphological alterations in A549 cells, monitored by transmission electron microscopy, live cell imaging and flow cytometry. This non-canonical cell death was not preceded or accompanied by exacerbation of autophagy. In the presence of GEV, markers of autophagic flux (e.g. LC3I-II conversion were impacted, even in presence of bafilomycin A1. Cell death induction remained unaffected by calpain, cathepsin, parthanatos, or necroptosis inhibitors. Interestingly, GEV triggered caspase-dependent apoptosis in U937 acute myeloid leukemia cells, witnessing cancer-type specific cell death induction. Differential cell cycle modulation by this CG led to a G2/M arrest, cyclin B1 and p53 downregulation in A549, but not in U937 cells. We further extended the anti-cancer potential of GEV to 3D cell culture using clonogenic and spheroid formation assays and validated our findings in vivo by zebrafish xenografts. Altogether, GEV shows an interesting anticancer profile with the ability to exert cytotoxic effects via induction of different cell death modalities.

BaP-metals co-exposure induced tissue-specific antioxidant defense in marine mussels Mytilus coruscus.

Science.gov (United States)

Chen, Siyu; Qu, Mengjie; Ding, Jiawei; Zhang, Yifei; Wang, Yi; Di, Yanan

2018-04-18

Both benzo(α)pyrene (BaP) and metals are frequently found in marine ecosystem and can cause detrimental effects in marine organism, especially the filter feeder-marine mussels. Although the biological responses in mussels have been well-studied upon the single metal or BaP exposure, the information about antioxidant defense, especially in different tissues of mussels, are still limited. Considering the variety of contaminants existing in the actual marine environment, single BaP (56 μg/L) and the co-exposure with Cu, Cd and Pb (50 μg/L, 50 μg/L and 3 mg/L respectively) were applied in a 6 days exposure followed by 6 days depuration experiment. The alterations of superoxide dismutase (SOD), catalase (CAT) activities and total antioxidant capacity (TAC) level were assessed in haemolymph, gills and digestive glands of marine mussels, Mytilus coruscus. An unparalleled change in antioxidant biomarkers was observed in all cells/tissues, with the SOD activity showing higher sensitivity to exposure. A tissue-specific response showing unique alteration in gill was investigated, indicating the different function of tissues during stress responses. Depressed antioxidant effects were induced by BaP-metals co-exposure, indicating the interaction may alter the intact properties of BaP. To our knowledge, this is the first research to explore the antioxidant defense induced by combined exposure of BaP-metals regarding to tissue-specific responses in marine mussels. The results and experimental model will provide valuable information and can be utilized in the investigation of stress response mechanisms, especially in relation to tissue functions in marine organism in the future. Copyright © 2018 Elsevier Ltd. All rights reserved.

Combined treatment with cotylenin A and phenethyl isothiocyanate induces strong antitumor activity mainly through the induction of ferroptotic cell death in human pancreatic cancer cells.

Science.gov (United States)

Kasukabe, Takashi; Honma, Yoshio; Okabe-Kado, Junko; Higuchi, Yusuke; Kato, Nobuo; Kumakura, Shunichi

2016-08-01

The treatment of pancreatic cancer, one of the most aggressive gastrointestinal tract malignancies, with current chemotherapeutic drugs has had limited success due to its chemoresistance and poor prognosis. Therefore, the development of new drugs or effective combination therapies is urgently needed. Cotylenin A (CN-A) (a plant growth regulator) is a potent inducer of differentiation in myeloid leukemia cells and exhibits potent antitumor activities in several cancer cell lines. In the present study, we demonstrated that CN-A and phenethyl isothiocyanate (PEITC), an inducer of reactive oxygen species (ROS) and a dietary anticarcinogenic compound, synergistically inhibited the proliferation of MIAPaCa-2, PANC-1 and gemcitabine-resistant PANC-1 cells. A combined treatment with CN-A and PEITC also effectively inhibited the anchorage-independent growth of these cancer cells. The combined treatment with CN-A and PEITC strongly induced cell death within 1 day at concentrations at which CN-A or PEITC alone did not affect cell viability. A combined treatment with synthetic CN-A derivatives (ISIR-005 and ISIR-042) or fusicoccin J (CN-A-related natural product) and PEITC did not have synergistic effects on cell death. The combined treatment with CN-A and PEITC synergistically induced the generation of ROS. Antioxidants (N-acetylcysteine and trolox), ferroptosis inhibitors (ferrostatin-1 and liproxstatin), and the lysosomal iron chelator deferoxamine canceled the synergistic cell death. Apoptosis inhibitors (Z-VAD-FMK and Q-VD-OPH) and the necrosis inhibitor necrostatin-1s did not inhibit synergistic cell death. Autophagy inhibitors (3-metyladenine and chloroquine) partially prevented cell death. These results show that synergistic cell death induced by the combined treatment with CN-A and PEITC is mainly due to the induction of ferroptosis. Therefore, the combination of CN-A and PEITC has potential as a novel therapeutic strategy against pancreatic cancer.

Chimeric SV40 virus-like particles induce specific cytotoxicity and protective immunity against influenza A virus without the need of adjuvants

International Nuclear Information System (INIS)

Kawano, Masaaki; Morikawa, Katsuma; Suda, Tatsuya; Ohno, Naohito; Matsushita, Sho; Akatsuka, Toshitaka; Handa, Hiroshi; Matsui, Masanori

2014-01-01

Virus-like particles (VLPs) are a promising vaccine platform due to the safety and efficiency. However, it is still unclear whether polyomavirus-based VLPs are useful for this purpose. Here, we attempted to evaluate the potential of polyomavirus VLPs for the antiviral vaccine using simian virus 40 (SV40). We constructed chimeric SV40-VLPs carrying an HLA-A ⁎ 02:01-restricted, cytotoxic T lymphocyte (CTL) epitope derived from influenza A virus. HLA-A ⁎ 02:01-transgenic mice were then immunized with the chimeric SV40-VLPs. The chimeric SV40-VLPs effectively induced influenza-specific CTLs and heterosubtypic protection against influenza A viruses without the need of adjuvants. Because DNase I treatment of the chimeric SV40-VLPs did not disrupt CTL induction, the intrinsic adjuvant property may not result from DNA contaminants in the VLP preparation. In addition, immunization with the chimeric SV40-VLPs generated long-lasting memory CTLs. We here propose that the chimeric SV40-VLPs harboring an epitope may be a promising CTL-based vaccine platform with self-adjuvant properties. - Highlights: • We constructed chimeric SV40-VLPs carrying an influenza virus-derived CTL epitope. • Chimeric SV40-VLPs induce influenza-specific CTLs in mice without adjuvants. • Chimeric SV40-VLPs induce heterosubtypic protection against influenza A viruses. • Chimeric SV40-VLPs induce long-lasting memory CTLs. • Chimeric SV40-VLPs is a promising vaccine platform with self-adjuvant properties

Chimeric SV40 virus-like particles induce specific cytotoxicity and protective immunity against influenza A virus without the need of adjuvants

Energy Technology Data Exchange (ETDEWEB)

Kawano, Masaaki [Department of Allergy and Immunology, Faculty of Medicine, Saitama Medical University, Moroyama-cho, Iruma-gun, Saitama 350-0495 (Japan); Morikawa, Katsuma [Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501 (Japan); Suda, Tatsuya [Department of Microbiology, Faculty of Medicine, Saitama Medical University, Moroyama-cho, Iruma-gun, Saitama 350-0495 (Japan); Laboratory for Immunopharmacology of Microbial Products, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392 (Japan); Ohno, Naohito [Laboratory for Immunopharmacology of Microbial Products, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392 (Japan); Matsushita, Sho [Department of Allergy and Immunology, Faculty of Medicine, Saitama Medical University, Moroyama-cho, Iruma-gun, Saitama 350-0495 (Japan); Allergy Center, Saitama Medical University, Moroyama-cho, Iruma-gun, Saitama 350-0495 (Japan); Akatsuka, Toshitaka [Department of Microbiology, Faculty of Medicine, Saitama Medical University, Moroyama-cho, Iruma-gun, Saitama 350-0495 (Japan); Handa, Hiroshi, E-mail: handa.h.aa@m.titech.ac.jp [Solutions Research Laboratory, Tokyo Institute of Technology, Midori-ku, Yokohama 226-8503 (Japan); Matsui, Masanori, E-mail: mmatsui@saitama-med.ac.jp [Department of Microbiology, Faculty of Medicine, Saitama Medical University, Moroyama-cho, Iruma-gun, Saitama 350-0495 (Japan)

2014-01-05

Virus-like particles (VLPs) are a promising vaccine platform due to the safety and efficiency. However, it is still unclear whether polyomavirus-based VLPs are useful for this purpose. Here, we attempted to evaluate the potential of polyomavirus VLPs for the antiviral vaccine using simian virus 40 (SV40). We constructed chimeric SV40-VLPs carrying an HLA-A{sup ⁎}02:01-restricted, cytotoxic T lymphocyte (CTL) epitope derived from influenza A virus. HLA-A{sup ⁎}02:01-transgenic mice were then immunized with the chimeric SV40-VLPs. The chimeric SV40-VLPs effectively induced influenza-specific CTLs and heterosubtypic protection against influenza A viruses without the need of adjuvants. Because DNase I treatment of the chimeric SV40-VLPs did not disrupt CTL induction, the intrinsic adjuvant property may not result from DNA contaminants in the VLP preparation. In addition, immunization with the chimeric SV40-VLPs generated long-lasting memory CTLs. We here propose that the chimeric SV40-VLPs harboring an epitope may be a promising CTL-based vaccine platform with self-adjuvant properties. - Highlights: • We constructed chimeric SV40-VLPs carrying an influenza virus-derived CTL epitope. • Chimeric SV40-VLPs induce influenza-specific CTLs in mice without adjuvants. • Chimeric SV40-VLPs induce heterosubtypic protection against influenza A viruses. • Chimeric SV40-VLPs induce long-lasting memory CTLs. • Chimeric SV40-VLPs is a promising vaccine platform with self-adjuvant properties.

Analyzing quantum jumps of one and two atoms strongly coupled to an optical cavity

DEFF Research Database (Denmark)

Reick, Sebastian; Mølmer, Klaus; Alt, Wolfgang

2010-01-01

We induce quantum jumps between the hyperfine ground states of one and two cesium atoms, strongly coupled to the mode of a high-finesse optical resonator, and analyze the resulting random telegraph signals. We identify experimental parameters to deduce the atomic spin state nondestructively from ...

Mixed allogeneic reconstitution (A+B----A) to induce donor-specific transplantation tolerance. Permanent acceptance of a simultaneous donor skin graft

International Nuclear Information System (INIS)

Ildstad, S.T.; Wren, S.M.; Oh, E.; Hronakes, M.L.

1991-01-01

Mixed allogeneic reconstitution, in which a mixture of T-cell-depleted bone marrow of syngeneic host and allogeneic donor type is transplanted into a lethally irradiated recipient (A+B----A), results in mixed lymphopoietic chimerism with engraftment of a mixture of both host and donor bone marrow elements. Recipients are specifically tolerant to donor both in vitro and in vivo. Donor-specific skin grafts survive indefinitely when they are placed after full bone marrow repopulation at 28 days, while third-party grafts are rapidly rejected. To determine whether a delay of a month or more for full bone marrow repopulation is required before a donor-specific graft can be placed, we have now examined whether tolerance induction can be achieved if a graft is placed at the time of bone marrow transplantation. Permanent acceptance of donor-specific B10.BR skin grafts occurred when mixed allogeneic chimerism (B10+B10.BR----B10) was induced and a simultaneous allogeneic donor graft placed. In vitro, mixed reconstituted recipients were specifically tolerant to the B10.BR donor lymphoid cells but fully reactive to MHC-disparate third-party (BALB/c; H-2dd) when assessed by mixed lymphocyte reaction (MLR) and cell-mediated lympholysis (CML) assays. These data therefore indicate that a donor-specific graft placed at the time of mixed allogeneic reconstitution is permanently accepted without rejection. To determine whether an allogeneic skin graft alone without allogeneic bone marrow would be sufficient to induce tolerance, syngeneic reconstitution (B10----B10) was carried out, and a simultaneous B10.BR allogeneic skin graft placed. Although skin grafts were prolonged in all recipients, all grafts rejected when full lymphopoietic repopulation occurred at 28 days

Metallization of a Rashba wire by a superconducting layer in the strong-proximity regime

Science.gov (United States)

Reeg, Christopher; Loss, Daniel; Klinovaja, Jelena

2018-04-01

Semiconducting quantum wires defined within two-dimensional electron gases and strongly coupled to thin superconducting layers have been extensively explored in recent experiments as promising platforms to host Majorana bound states. We study numerically such a geometry, consisting of a quasi-one-dimensional wire coupled to a disordered three-dimensional superconducting layer. We find that, in the strong-coupling limit of a sizable proximity-induced superconducting gap, all transverse subbands of the wire are significantly shifted in energy relative to the chemical potential of the wire. For the lowest subband, this band shift is comparable in magnitude to the spacing between quantized levels that arises due to the finite thickness of the superconductor (which typically is ˜500 meV for a 10-nm-thick layer of aluminum); in higher subbands, the band shift is much larger. Additionally, we show that the width of the system, which is usually much larger than the thickness, and moderate disorder within the superconductor have almost no impact on the induced gap or band shift. We provide a detailed discussion of the ramifications of our results, arguing that a huge band shift and significant renormalization of semiconducting material parameters in the strong-coupling limit make it challenging to realize a topological phase in such a setup, as the strong coupling to the superconductor essentially metallizes the semiconductor. This metallization of the semiconductor can be tested experimentally through the measurement of the band shift.

strong>PRAYER INDUCED ANALGESIAstrong>

DEFF Research Database (Denmark)

Jegindø, Else-Marie Elmholdt

, 40 healthy subjects (20 highly religious protestants and 20 non-religious men and women) received painful electrical stimulation during prayer to God, ‘secular prayer’ and a ‘pain only’ condition. Subjects were continuously monitored with a Task Force Monitor (heart rate variability, blood pressure...

Phase transition transistors based on strongly-correlated materials

Science.gov (United States)

Nakano, Masaki

2013-03-01

The field-effect transistor (FET) provides electrical switching functions through linear control of the number of charges at a channel surface by external voltage. Controlling electronic phases of condensed matters in a FET geometry has long been a central issue of physical science. In particular, FET based on a strongly correlated material, namely ``Mott transistor,'' has attracted considerable interest, because it potentially provides gigantic and diverse electronic responses due to a strong interplay between charge, spin, orbital and lattice. We have investigated electric-field effects on such materials aiming at novel physical phenomena and electronic functions originating from strong correlation effects. Here we demonstrate electrical switching of bulk state of matter over the first-order metal-insulator transition. We fabricated FETs based on VO2 with use of a recently developed electric-double-layer transistor technique, and found that the electrostatically induced carriers at a channel surface drive all preexisting localized carriers of 1022 cm-3 even inside a bulk to motion, leading to bulk carrier delocalization beyond the electrostatic screening length. This non-local switching of bulk phases is achieved with just around 1 V, and moreover, a novel non-volatile memory like character emerges in a voltage-sweep measurement. These observations are apparently distinct from those of conventional FETs based on band insulators, capturing the essential feature of collective interactions in strongly correlated materials. This work was done in collaboration with K. Shibuya, D. Okuyama, T. Hatano, S. Ono, M. Kawasaki, Y. Iwasa, and Y. Tokura. This work was supported by the Japan Society for the Promotion of Science (JSAP) through its ``Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program).''

Functional, Antigen-Specific Stem Cell Memory (TSCM CD4+ T Cells Are Induced by Human Mycobacterium tuberculosis Infection

Directory of Open Access Journals (Sweden)

Cheleka A. M. Mpande

2018-03-01

Full Text Available BackgroundMaintenance of long-lasting immunity is thought to depend on stem cell memory T cells (TSCM, which have superior self-renewing capacity, longevity and proliferative potential compared with central memory (TCM or effector (TEFF T cells. Our knowledge of TSCM derives primarily from studies of virus-specific CD8+ TSCM. We aimed to determine if infection with Mycobacterium tuberculosis (M. tb, the etiological agent of tuberculosis, generates antigen-specific CD4+ TSCM and to characterize their functional ontology.MethodsWe studied T cell responses to natural M. tb infection in a longitudinal adolescent cohort of recent QuantiFERON-TB Gold (QFT converters and three cross-sectional QFT+ adult cohorts; and to bacillus Calmette–Guerin (BCG vaccination in infants. M. tb and/or BCG-specific CD4 T cells were detected by flow cytometry using major histocompatibility complex class II tetramers bearing Ag85, CFP-10, or ESAT-6 peptides, or by intracellular cytokine staining. Transcriptomic analyses of M. tb-specific tetramer+ CD4+ TSCM (CD45RA+ CCR7+ CD27+ were performed by microfluidic qRT-PCR, and functional and phenotypic characteristics were confirmed by measuring expression of chemokine receptors, cytotoxic molecules and cytokines using flow cytometry.ResultsM. tb-specific TSCM were not detected in QFT-negative persons. After QFT conversion frequencies of TSCM increased to measurable levels and remained detectable thereafter, suggesting that primary M. tb infection induces TSCM cells. Gene expression (GE profiling of tetramer+ TSCM showed that these cells were distinct from bulk CD4+ naïve T cells (TN and shared features of bulk TSCM and M. tb-specific tetramer+ TCM and TEFF cells. These TSCM were predominantly CD95+ and CXCR3+, markers typical of CD8+ TSCM. Tetramer+ TSCM expressed significantly higher protein levels of CCR5, CCR6, CXCR3, granzyme A, granzyme K, and granulysin than bulk TN and TSCM cells. M. tb-specific TSCM were also

The role of direct parameter specification and attentional capture in near-threshold priming of motor reactions

Directory of Open Access Journals (Sweden)

Rob H. J. van der Lubbe

2006-01-01

Full Text Available The priming of motor responses can be induced by preceding visual stimuli that have been made invisible by metacontrast masking ('primes'. According to the concept of direct parameter specification (DPS;Neumann,1990, strong similarity between prime and target results in the processing operations that are to be applied to the target being also induced by the prime. As targets have to be attended to, this also implies that attention is captured by the location of a prime, thereby facilitating motor priming effects. This hypothetical effect may be viewed as a form of top-down attentional capture. In some subliminal priming experiments (e.g. Jaśkowski, Skalska, & Verleger, 2003, however, attentional capture may have been unrelated to target identity, as stimuli with unique features (singletons are known to induce bottom-up attentional capture. Three experiments were performed that largely confirmed the view that the result sof these earlier experiments were due to top-down attentional capture, in line with DPS. However, the priming effect was also evoked by a singleton irrelevant to the participants' task, although this effect was weaker than in case of strong similarity between prime and target. Priming effects remained when singletons were absent from one side of the visual field,suggesting that the presence of singletons is not a requirement for the observation of motor priming effects.

A specific glycerol kinase induces rapid cold hardening of the diamondback moth, Plutella xylostella.

Science.gov (United States)

Park, Youngjin; Kim, Yonggyun

2014-08-01

Insects in temperate zones survive low temperatures by migrating or tolerating the cold. The diamondback moth, Plutella xylostella, is a serious insect pest on cabbage and other cruciferous crops worldwide. We showed that P. xylostella became cold-tolerant by expressing rapid cold hardiness (RCH) in response to a brief exposure to moderately low temperature (4°C) for 7h along with glycerol accumulation in hemolymph. Glycerol played a crucial role in the cold-hardening process because exogenously supplying glycerol significantly increased the cold tolerance of P. xylostella larvae without cold acclimation. To determine the genetic factor(s) responsible for RCH and the increase of glycerol, four glycerol kinases (GKs), and glycerol-3-phosphate dehydrogenase (PxGPDH) were predicted from the whole P. xylostella genome and analyzed for their function associated with glycerol biosynthesis. All predicted genes were expressed, but differed in their expression during different developmental stages and in different tissues. Expression of the predicted genes was individually suppressed by RNA interference (RNAi) using double-stranded RNAs specific to target genes. RNAi of PxGPDH expression significantly suppressed RCH and glycerol accumulation. Only PxGK1 among the four GKs was responsible for RCH and glycerol accumulation. Furthermore, PxGK1 expression was significantly enhanced during RCH. These results indicate that a specific GK, the terminal enzyme to produce glycerol, is specifically inducible during RCH to accumulate the main cryoprotectant. Copyright © 2014 Elsevier Ltd. All rights reserved.

Steps in Modular Specifications for Concurrent Modules

DEFF Research Database (Denmark)

Da Rocha Pinto, Pedro; Dinsdale-Young, Thomas; Gardner, Philippa

2015-01-01

The specification of a concurrent program module is a difficult problem. The specifications must be strong enough to enable reasoning about the intended clients without reference to the underlying module implementation. We survey a range of verification techniques for specifying concurrent module......, in particular highlighting four key concepts: auxiliary state, interference abstraction, resource ownership and atomicity. We show how these concepts combine to provide powerful approaches to specifying concurrent modules.......The specification of a concurrent program module is a difficult problem. The specifications must be strong enough to enable reasoning about the intended clients without reference to the underlying module implementation. We survey a range of verification techniques for specifying concurrent modules...

Strong coupling electrostatics for randomly charged surfaces: antifragility and effective interactions.

Science.gov (United States)

Ghodrat, Malihe; Naji, Ali; Komaie-Moghaddam, Haniyeh; Podgornik, Rudolf

2015-05-07

We study the effective interaction mediated by strongly coupled Coulomb fluids between dielectric surfaces carrying quenched, random monopolar charges with equal mean and variance, both when the Coulomb fluid consists only of mobile multivalent counterions and when it consists of an asymmetric ionic mixture containing multivalent and monovalent (salt) ions in equilibrium with an aqueous bulk reservoir. We analyze the consequences that follow from the interplay between surface charge disorder, dielectric and salt image effects, and the strong electrostatic coupling that results from multivalent counterions on the distribution of these ions and the effective interaction pressure they mediate between the surfaces. In a dielectrically homogeneous system, we show that the multivalent counterions are attracted towards the surfaces with a singular, disorder-induced potential that diverges logarithmically on approach to the surfaces, creating a singular but integrable counterion density profile that exhibits an algebraic divergence at the surfaces with an exponent that depends on the surface charge (disorder) variance. This effect drives the system towards a state of lower thermal 'disorder', one that can be described by a renormalized temperature, exhibiting thus a remarkable antifragility. In the presence of an interfacial dielectric discontinuity, the singular behavior of counterion density at the surfaces is removed but multivalent counterions are still accumulated much more strongly close to randomly charged surfaces as compared with uniformly charged ones. The interaction pressure acting on the surfaces displays in general a highly non-monotonic behavior as a function of the inter-surface separation with a prominent regime of attraction at small to intermediate separations. This attraction is caused directly by the combined effects from charge disorder and strong coupling electrostatics of multivalent counterions, which dominate the surface-surface repulsion due to

The Differences in Serum Quantitative Specific IgE Levels Induced by Dermatophagoides pteronyssinus, Dermatophagoides farinae and Blomia tropicalis Sensitization in Intermittent and Persistent Allergic Asthma

Directory of Open Access Journals (Sweden)

Agus Joko Susanto

2018-01-01

Full Text Available Background: house dust mites (HDM are an important inhalant allergen in allergic asthma. However, molecular diagnostic study of specific IgE to HDM allergens has not been done in Indonesia. In addition, the association of quantitative specific IgE measurement with asthma severity has not been investigatedd. This study aimed to investigate the difference of serum quantitative specific IgE levels induced by Dermatophagoides (D. pteronyssinus, D. farinae and Blomia tropicalis sensitization in intermittent and persistent allergic asthma. Methods: this was a cross-sectional study on adult allergic asthma patients who were invited for serum specific IgE testing. This study was a part of a larger study within the Division of Allergy and Immunology, Cipto Mangunkusumo Hospital. Asthma severity was defined based on Global Initiative on Asthma (GINA 2015 criteria and were grouped as intermittent or persistent. Quantitative specific IgE testing was done on blood serum using a multiple allergosorbent test (Polycheck Allergy, Biocheck GmbH, Munster, Germany. The HDM allergens tested were D. pteronyssinus, D. farinae, and Blomia tropicalis. Difference between two groups were analyze using Mann-Whitney test. Results: a total of 87 subjects were enrolled in this study; 69 (79.3% were women. Mean patients’ age was 40, 2 years. Sixty-three (72.4% subjects had asthma and allergic rhinitis. Fifty-eight (66.7% subjects were classified as persistent asthma. The prevalence of sensitization was 62.1% for D. farinae, 51.7% for D. pteronyssinus, and 48.3% for Blomia tropicalis. The median of specific IgE levels were significantly higher in persistent asthma compares to intermittent asthma induced by D. farinae (median 1.30 vs. 0.0 kU/L; p=0.024 and B. tropicalis (median 0.57 vs. 0.0 kU/L; p=0.015 sensitization. Level of Specific IgE  D. pteronyssinus was also to be higher in persistent asthma than the level measured in intermittent asthma (0.67 vs. 0.00 kU/L; p=0

JC Polyomavirus Infection Is Strongly Controlled by Human Leucocyte Antigen Class II Variants

DEFF Research Database (Denmark)

Sundqvist, Emilie; Buck, Dorothea; Warnke, Clemens

2014-01-01

sequence-specific oligonucleotide (PCR-SSO) method. An initial GWAS screen displayed a strong HLA class II region signal. The HLA-DRB1*15 haplotype was strongly negatively associated to JCV sero-status in Scandinavian MS cases (OR = 0.42, p = 7×10(-15)) and controls (OR = 0.53, p = 2×10(-5)). In contrast...

Selective Destruction of Interleukin 23–Induced Expansion of a Major Antigen–Specific γδ T-Cell Subset in Patients With Tuberculosis

Science.gov (United States)

Gu, Jin; Xiao, Heping; Liang, Shanshan; Yang, Enzhuo; Yang, Rui; Huang, Dan; Chen, Crystal; Wang, Feifei; Shen, Ling; Chen, Zheng W.

2017-01-01

Abstract A loss of antigen-specific T-cell responses due to defective cytokine signaling during infections has not been reported. We hypothesize that tuberculosis can destroy signaling effects of selective cytokine(s) and induce exhaustion of antigen-specific T cells. To test this hypothesis, mechanistic studies were performed to examine whether and how tuberculosis blocked interleukin 23 (IL-23) and interleukin 2 (IL-2) signaling effects on a major human γδ T-cell subpopulation, phosphoantigen HMBPP–specific Vγ2Vδ2 T cells. IL-23 and IL-2 significantly expanded HMBPP-stimulated Vγ2Vδ2 T cells from subjects with latent tuberculosis infection, and IL-2 synergized the effect of IL-23. IL-23–induced expansion of Vγ2Vδ2 T cells involved STAT3. Surprisingly, patients with tuberculosis exhibited a selective destruction of IL-23–induced expansion of these cells. The tuberculosis-driven destruction of IL-23 signaling coincided with decreases of expression and phosphorylation of STAT3. Interestingly, impairing of STAT3 was linked to marked increases in the microRNAs (miRNAs) hsa-miR-337-3p and hsa-miR-125b-5p in Vγ2Vδ2 T cells from patients with tuberculosis. Downregulation of hsa-miR-337-3p and hsa-miR-125b-5p by miRNA sponges improved IL-23–mediated expansion of Vγ2Vδ2 T cells and restored the ability of these cells to produce anti–tuberculosis cytokines. These results support our hypothesis that tuberculosis can selectively impair a cytokine effect while sparing another and can induce exhaustion of T cells in response to the respective cytokine. PMID:27789724

Circuit electromechanics with single photon strong coupling

Energy Technology Data Exchange (ETDEWEB)

Xue, Zheng-Yuan, E-mail: zyxue@scnu.edu.cn; Yang, Li-Na [Guangdong Provincial Key Laboratory of Quantum Engineering and Quantum Materials, and School of Physics and Telecommunication Engineering, South China Normal University, Guangzhou 510006 (China); Zhou, Jian, E-mail: jianzhou8627@163.com [Department of Electronic Communication Engineering, Anhui Xinhua University, Hefei 230088 (China); Guangdong Provincial Key Laboratory of Quantum Engineering and Quantum Materials, and School of Physics and Telecommunication Engineering, South China Normal University, Guangzhou 510006 (China)

2015-07-13

In circuit electromechanics, the coupling strength is usually very small. Here, replacing the capacitor in circuit electromechanics by a superconducting flux qubit, we show that the coupling among the qubit and the two resonators can induce effective electromechanical coupling which can attain the strong coupling regime at the single photon level with feasible experimental parameters. We use dispersive couplings among two resonators and the qubit while the qubit is also driven by an external classical field. These couplings form a three-wave mixing configuration among the three elements where the qubit degree of freedom can be adiabatically eliminated, and thus results in the enhanced coupling between the two resonators. Therefore, our work constitutes the first step towards studying quantum nonlinear effect in circuit electromechanics.

In silico and cell-based analyses reveal strong divergence between prediction and observation of T-cell-recognized tumor antigen T-cell epitopes.

Science.gov (United States)

Schmidt, Julien; Guillaume, Philippe; Dojcinovic, Danijel; Karbach, Julia; Coukos, George; Luescher, Immanuel

2017-07-14

Tumor exomes provide comprehensive information on mutated, overexpressed genes and aberrant splicing, which can be exploited for personalized cancer immunotherapy. Of particular interest are mutated tumor antigen T-cell epitopes, because neoepitope-specific T cells often are tumoricidal. However, identifying tumor-specific T-cell epitopes is a major challenge. A widely used strategy relies on initial prediction of human leukocyte antigen-binding peptides by in silico algorithms, but the predictive power of this approach is unclear. Here, we used the human tumor antigen NY-ESO-1 (ESO) and the human leukocyte antigen variant HLA-A*0201 (A2) as a model and predicted in silico the 41 highest-affinity, A2-binding 8-11-mer peptides and assessed their binding, kinetic complex stability, and immunogenicity in A2-transgenic mice and on peripheral blood mononuclear cells from ESO-vaccinated melanoma patients. We found that 19 of the peptides strongly bound to A2, 10 of which formed stable A2-peptide complexes and induced CD8 + T cells in A2-transgenic mice. However, only 5 of the peptides induced cognate T cells in humans; these peptides exhibited strong binding and complex stability and contained multiple large hydrophobic and aromatic amino acids. These results were not predicted by in silico algorithms and provide new clues to improving T-cell epitope identification. In conclusion, our findings indicate that only a small fraction of in silico -predicted A2-binding ESO peptides are immunogenic in humans, namely those that have high peptide-binding strength and complex stability. This observation highlights the need for improving in silico predictions of peptide immunogenicity. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Supporting aboriginal knowledge and practice in health care: lessons from a qualitative evaluation of the strong women, strong babies, strong culture program.

Science.gov (United States)

Lowell, Anne; Kildea, Sue; Liddle, Marlene; Cox, Barbara; Paterson, Barbara

2015-02-05

The Strong Women, Strong Babies, Strong Culture Program (the Program) evolved from a recognition of the value of Aboriginal knowledge and practice in promoting maternal and child health (MCH) in remote communities of the Northern Territory (NT) of Australia. Commencing in 1993 it continues to operate today. In 2008, the NT Department of Health commissioned an evaluation to identify enabling factors and barriers to successful implementation of the Program, and to identify potential pathways for future development. In this paper we focus on the evaluation findings related specifically to the role of Aborignal cultural knowledge and practice within the Program. A qualitative evaluation utilised purposive sampling to maximise diversity in program history and Aboriginal culture. Semi-structured, in-depth interviews with 76 participants were recorded in their preferred language with a registered Interpreter when required. Thematic analysis of data was verified or modified through further discussions with participants and members of the evaluation team. Although the importance of Aboriginal knowledge and practice as a fundamental component of the Program is widely acknowledged, there has been considerable variation across time and location in the extent to which these cultural dimensions have been included in practice. Factors contributing to this variation are complex and relate to a number of broad themes including: location of control over Program activities; recognition and respect for Aboriginal knowledge and practice as a legitimate component of health care; working in partnership; communication within and beyond the Program; access to transport and working space; and governance and organisational support. We suggest that inclusion of Aboriginal knowledge and practice as a fundamental component of the Program is key to its survival over more than twenty years despite serious challenges. Respect for the legitimacy of Aboriginal knowledge and practice within health

A truncated receptor-binding domain of MERS-CoV spike protein potently inhibits MERS-CoV infection and induces strong neutralizing antibody responses: implication for developing therapeutics and vaccines.

Directory of Open Access Journals (Sweden)

Lanying Du

Full Text Available An emerging respiratory infectious disease with high mortality, Middle East respiratory syndrome (MERS, is caused by a novel coronavirus (MERS-CoV. It was first reported in 2012 in Saudi Arabia and has now spread to eight countries. Development of effective therapeutics and vaccines is crucial to save lives and halt the spread of MERS-CoV. Here, we show that a recombinant protein containing a 212-amino acid fragment (residues 377-588 in the truncated receptor-binding domain (RBD: residues 367-606 of MERS-CoV spike (S protein fused with human IgG Fc fragment (S377-588-Fc is highly expressed in the culture supernatant of transfected 293T cells. The purified S377-588-Fc protein efficiently binds to dipeptidyl peptidase 4 (DPP4, the receptor of MERS-CoV, and potently inhibited MERS-CoV infection, suggesting its potential to be further developed as a therapeutic modality for treating MERS-CoV infection and saving the patients' lives. The recombinant S377-588-Fc is able to induce in the vaccinated mice strong MERS-CoV S-specific antibodies, which blocks the binding of RBD to DPP4 receptor and effectively neutralizes MERS-CoV infection. These findings indicate that this truncated RBD protein shows promise for further development as an effective and safe vaccine for the prevention of MERS-CoV infection.

Kinetics and regional specificity of irinotecan-induced gene expression in the gastrointestinal tract

International Nuclear Information System (INIS)

Bowen, Joanne M.; Tsykin, Anna; Stringer, Andrea M.; Logan, Richard M.; Gibson, Rachel J.; Keefe, Dorothy M.K.

2010-01-01

Gastrointestinal toxicity remains a significant and dose-limiting complication of cancer treatment. While the pathophysiology is becoming clearer, considerable gaps in the knowledge remain surrounding the timing and site-specific gene changes which occur in response to insult. As such, this study aimed to assess gene expression profiles in a number of regions along the gastrointestinal tract following treatment with the chemotherapy agent, irinotecan, and correlate them with markers of cell death and tissue damage. Data analysis of microarray results found that genes involved in apoptosis, mitogen activated kinase (MAPK) signalling and inflammation were upregulated within 6 h, while genes involved in cell proliferation, wound healing and blood vessel formation were upregulated at later time points up to 72 h. Cell death was significantly increased at 6 and 24 h, and the stomach showed the lowest severity of overt tissue damage. Real time PCR of MAPK signalling pathway genes found that the jejunum and colon had significantly increased expression in a number of genes at 72 h, where as the stomach was unchanged. These results indicate that overall severity of tissue damage may be determined by precisely timed target gene responses specific to each region. Therapeutic targeting of key gene responses at the appropriate time point may prove to be effective for prevention of chemotherapy-induced gastrointestinal damage.

Oral administration of type-II collagen peptide 250-270 suppresses specific cellular and humoral immune response in collagen-induced arthritis.

Science.gov (United States)

Zhu, Ping; Li, Xiao-Yan; Wang, Hong-Kun; Jia, Jun-Feng; Zheng, Zhao-Hui; Ding, Jin; Fan, Chun-Mei

2007-01-01

Oral antigen is an attractive approach for the treatment of autoimmune and inflammatory diseases. Establishment of immune markers and methods in evaluating the effects of antigen-specific cellular and humoral immune responses will help the application of oral tolerance in the treatment of human diseases. The present article observed the effects of chicken collagen II (CII), the recombinant polymerized human collagen II 250-270 (rhCII 250-270) peptide and synthesized human CII 250-270 (syCII 250-270) peptide on the induction of antigen-specific autoimmune response in rheumatoid arthritis (RA) peripheral blood mononuclear cells (PBMC) and on the specific cellular and humoral immune response in collagen-induced arthritis (CIA) and mice fed with CII (250-270) prior to immunization with CII. In the study, proliferation, activation and intracellular cytokine production of antigen-specific T lymphocytes were simultaneously analyzed by bromodeoxyuridine (BrdU) incorporation and flow cytometry at the single-cell level. The antigen-specific antibody and antibody-forming cells were detected by ELISA and ELISPOT, respectively. CII (250-270) was found to have stimulated the response of specific lymphocytes in PBMC from RA patients, including the increase expression of surface activation antigen marker CD69 and CD25, and DNA synthesis. Mice, fed with CII (250-270) before CII immunization, had significantly lower arthritic scores than the mice immunized with CII alone, and the body weight of the former increased during the study period. Furthermore, the specific T cell activity, proliferation and secretion of interferon (IFN)-gamma in spleen cells were actively suppressed in CII (250-270)-fed mice, and the serum anti-CII, anti-CII (250-270) antibody activities and the frequency of specific antibody-forming spleen cells were significantly lower in CII (250-270)-fed mice than in mice immunized with CII alone. These observations suggest that oral administration of CII (250-270) can

Transgenic over-expression of YY1 induces pathologic cardiac hypertrophy in a sex-specific manner

Science.gov (United States)

Stauffer, Brian L.; Dockstader, Karen; Russell, Gloria; Hijmans, Jamie; Walker, Lisa; Cecil, Mackenzie; Demos-Davies, Kimberly; Medway, Allen; McKinsey, Timothy A.; Sucharov, Carmen C.

2015-01-01

YY1 can activate or repress transcription of various genes. In cardiac myocytes in culture YY1 has been shown to regulate expression of several genes involved in myocyte pathology. YY1 can also acutely protect the heart against detrimental changes in gene expression. In this study we show that cardiac over-expression of YY1 induces pathologic cardiac hypertrophy in male mice, measured by changes in gene expression and lower ejection fraction/fractional shortening. In contrast, female animals are protected against pathologic gene expression changes and cardiac dysfunction. Furthermore, we show that YY1 regulates, in a sex-specific manner, the expression of mammalian enable (Mena), a factor that regulates cytoskeletal actin dynamics and whose expression is increased in several models of cardiac pathology, and that Mena expression in humans with heart failure is sex-dependent. Finally, we show that sex differences in YY1 expression are also observed in human heart failure. In summary, this is the first work to show that YY1 has a sex-specific effect in the regulation of cardiac pathology. PMID:25935483

Strong asymmetry for surface modes in nonlinear lattices with long-range coupling

International Nuclear Information System (INIS)

Martinez, Alejandro J.; Vicencio, Rodrigo A.; Molina, Mario I.

2010-01-01

We analyze the formation of localized surface modes on a nonlinear cubic waveguide array in the presence of exponentially decreasing long-range interactions. We find that the long-range coupling induces a strong asymmetry between the focusing and defocusing cases for the topology of the surface modes and also for the minimum power needed to generate them. In particular, for the defocusing case, there is an upper power threshold for exciting staggered modes, which depends strongly on the long-range coupling strength. The power threshold for dynamical excitation of surface modes increases (decreases) with the strength of long-range coupling for the focusing (defocusing) cases. These effects seem to be generic for discrete lattices with long-range interactions.

Fluoxetine induces input-specific hippocampal dendritic spine remodeling along the septotemporal axis in adulthood and middle age.

Science.gov (United States)

McAvoy, Kathleen; Russo, Craig; Kim, Shannen; Rankin, Genelle; Sahay, Amar

2015-11-01

Fluoxetine, a selective serotonin-reuptake inhibitor (SSRI), is known to induce structural rearrangements and changes in synaptic transmission in hippocampal circuitry. In the adult hippocampus, structural changes include neurogenesis, dendritic, and axonal plasticity of pyramidal and dentate granule neurons, and dedifferentiation of dentate granule neurons. However, much less is known about how chronic fluoxetine affects these processes along the septotemporal axis and during the aging process. Importantly, studies documenting the effects of fluoxetine on density and distribution of spines along different dendritic segments of dentate granule neurons and CA1 pyramidal neurons along the septotemporal axis of hippocampus in adulthood and during aging are conspicuously absent. Here, we use a transgenic mouse line in which mature dentate granule neurons and CA1 pyramidal neurons are genetically labeled with green fluorescent protein (GFP) to investigate the effects of chronic fluoxetine treatment (18 mg/kg/day) on input-specific spine remodeling and mossy fiber structural plasticity in the dorsal and ventral hippocampus in adulthood and middle age. In addition, we examine levels of adult hippocampal neurogenesis, maturation state of dentate granule neurons, neuronal activity, and glutamic acid decarboxylase-67 expression in response to chronic fluoxetine in adulthood and middle age. Our studies reveal that while chronic fluoxetine fails to augment adult hippocampal neurogenesis in middle age, the middle-aged hippocampus retains high sensitivity to changes in the dentate gyrus (DG) such as dematuration, hypoactivation, and increased glutamic acid decarboxylase 67 (GAD67) expression. Interestingly, the middle-aged hippocampus shows greater sensitivity to fluoxetine-induced input-specific synaptic remodeling than the hippocampus in adulthood with the stratum-oriens of CA1 exhibiting heightened structural plasticity. The input-specific changes and circuit

Histone peptide AKRHRK enhances H2O2-induced DNA damage and alters its site specificity

International Nuclear Information System (INIS)

Midorikawa, Kaoru; Murata, Mariko; Kawanishi, Shosuke

2005-01-01

Histone proteins are involved in compaction of DNA and the protection of cells from oxygen toxicity. However, several studies have demonstrated that the metal-binding histone reacts with H 2 O 2 , leading to oxidative damage to a nucleobase. We investigated whether histone can accelerate oxidative DNA damage, using a minimal model for the N-terminal tail of histone H4, CH 3 CO-AKRHRK-CONH 2 , which has a metal-binding site. This histone peptide enhanced DNA damage induced by H 2 O 2 and Cu(II), especially at cytosine residues, and induced additional DNA cleavage at the 5'-guanine of GGG sequences. The peptide also enhanced the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine and ESR spin-trapping signal from H 2 O 2 and Cu(II). Cyclic redox reactions involving histone-bound Cu(II) and H 2 O 2 , may give rise to multiple production of radicals leading to multiple hits in DNA. It is noteworthy that the histone H4 peptide with specific sequence AKRHRK can cause DNA damage rather than protection under metal-overloaded condition

Utility of the ceftazidime-imipenem antagonism test (CIAT to detect and confirm the presence of inducible AmpC beta-lactamases among enterobacteriaceae

Directory of Open Access Journals (Sweden)

Vlademir Vicente Cantarelli

Full Text Available Detection of AmpC beta-lactamase production by enterobacteria has been problematic. Contrary to ESBLs, no specific guidelines are available for detection and confirmation of AmpC production by clinical relevant microorganisms. Moreover, some bacterial species may produce inducible AmpC beta-lactamases that can be easily overlooked by routine susceptibility tests. We reported here a new test based on the strong inducible effect of imipenem on AmpC genes and the consequent antagonism with ceftazidime. This test is very simple and proved to be helpful in detecting AmpC-inducible enzymes among several species of clinical isolates.

Electromotive force in strongly compressible magnetohydrodynamic turbulence

Science.gov (United States)

Yokoi, N.

2017-12-01

Variable density fluid turbulence is ubiquitous in geo-fluids, not to mention in astrophysics. Depending on the source of density variation, variable density fluid turbulence may be divided into two categories: the weak compressible (entropy mode) turbulence for slow flow and the strong compressible (acoustic mode) turbulence for fast flow. In the strong compressible turbulence, the pressure fluctuation induces a strong density fluctuation ρ ', which is represented by the density variance ( denotes the ensemble average). The turbulent effect on the large-scale magnetic-field B induction is represented by the turbulent electromotive force (EMF) (u': velocity fluctuation, b': magnetic-field fluctuation). In the usual treatment in the dynamo theory, the expression for the EMF has been obtained in the framework of incompressible or weak compressible turbulence, where only the variation of the mean density , if any, is taken into account. We see from the equation of the density fluctuation ρ', the density variance is generated by the large mean density variation ∂ coupled with the turbulent mass flux . This means that in the region where the mean density steeply changes, the density variance effect becomes relevant for the magnetic field evolution. This situation is typically the case for phenomena associated with shocks and compositional discontinuities. With the aid of the analytical theory of inhomogeneous compressible magnetohydrodynamic (MHD) turbulence, the expression for the turbulent electromotive force is investigated. It is shown that, among others, an obliqueness (misalignment) between the mean density gradient ∂ and the mean magnetic field B may contribute to the EMF as ≈χ B×∂ with the turbulent transport coefficient χ proportional to the density variance (χ ). This density variance effect is expected to strongly affect the EMF near the interface, and changes the transport properties of turbulence. In the case of an interface under the MHD slow

Mitochondrial control of cell death induced by hyperosmotic stress.

Science.gov (United States)

Criollo, Alfredo; Galluzzi, Lorenzo; Maiuri, M Chiara; Tasdemir, Ezgi; Lavandero, Sergio; Kroemer, Guido

2007-01-01

HeLa and HCT116 cells respond differentially to sorbitol, an osmolyte able to induce hypertonic stress. In these models, sorbitol promoted the phenotypic manifestations of early apoptosis followed by complete loss of viability in a time-, dose-, and cell type-specific fashion, by eliciting distinct yet partially overlapping molecular pathways. In HCT116 but not in HeLa cells, sorbitol caused the mitochondrial release of the caspase-independent death effector AIF, whereas in both cell lines cytochrome c was retained in mitochondria. Despite cytochrome c retention, HeLa cells exhibited the progressive activation of caspase-3, presumably due to the prior activation of caspase-8. Accordingly, caspase inhibition prevented sorbitol-induced killing in HeLa, but only partially in HCT116 cells. Both the knock-out of Bax in HCT116 cells and the knock-down of Bax in A549 cells by RNA interference reduced the AIF release and/or the mitochondrial alterations. While the knock-down of Bcl-2/Bcl-X(L) sensitized to sorbitol-induced killing, overexpression of a Bcl-2 variant that specifically localizes to mitochondria (but not of the wild-type nor of a endoplasmic reticulum-targeted form) strongly inhibited sorbitol effects. Thus, hyperosmotic stress kills cells by triggering different molecular pathways, which converge at mitochondria where pro- and anti-apoptotic members of the Bcl-2 family exert their control.

Isolation of a strong Arabidopsis guard cell promoter and its potential as a research tool

Directory of Open Access Journals (Sweden)

Siegel Robert S

2008-02-01

Full Text Available Abstract Background A common limitation in guard cell signaling research is that it is difficult to obtain consistent high expression of transgenes of interest in Arabidopsis guard cells using known guard cell promoters or the constitutive 35S cauliflower mosaic virus promoter. An additional drawback of the 35S promoter is that ectopically expressing a gene throughout the organism could cause pleiotropic effects. To improve available methods for targeted gene expression in guard cells, we isolated strong guard cell promoter candidates based on new guard cell-specific microarray analyses of 23,000 genes that are made available together with this report. Results A promoter, pGC1(At1g22690, drove strong and relatively specific reporter gene expression in guard cells including GUS (beta-glucuronidase and yellow cameleon YC3.60 (GFP-based calcium FRET reporter. Reporter gene expression was weaker in immature guard cells. The expression of YC3.60 was sufficiently strong to image intracellular Ca2+ dynamics in guard cells of intact plants and resolved spontaneous calcium transients in guard cells. The GC1 promoter also mediated strong reporter expression in clustered stomata in the stomatal development mutant too-many-mouths (tmm. Furthermore, the same promoter::reporter constructs also drove guard cell specific reporter expression in tobacco, illustrating the potential of this promoter as a method for high level expression in guard cells. A serial deletion of the promoter defined a guard cell expression promoter region. In addition, anti-sense repression using pGC1 was powerful for reducing specific GFP gene expression in guard cells while expression in leaf epidermal cells was not repressed, demonstrating strong cell-type preferential gene repression. Conclusion The pGC1 promoter described here drives strong reporter expression in guard cells of Arabidopsis and tobacco plants. It provides a potent research tool for targeted guard cell expression or

Distinct lipid a moieties contribute to pathogen-induced site-specific vascular inflammation.

Directory of Open Access Journals (Sweden)

Connie Slocum

2014-07-01

Full Text Available Several successful pathogens have evolved mechanisms to evade host defense, resulting in the establishment of persistent and chronic infections. One such pathogen, Porphyromonas gingivalis, induces chronic low-grade inflammation associated with local inflammatory bone loss and systemic inflammation manifested as atherosclerosis. P. gingivalis expresses an atypical lipopolysaccharide (LPS structure containing heterogeneous lipid A species, that exhibit Toll-like receptor-4 (TLR4 agonist or antagonist activity, or are non-activating at TLR4. In this study, we utilized a series of P. gingivalis lipid A mutants to demonstrate that antagonistic lipid A structures enable the pathogen to evade TLR4-mediated bactericidal activity in macrophages resulting in systemic inflammation. Production of antagonistic lipid A was associated with the induction of low levels of TLR4-dependent proinflammatory mediators, failed activation of the inflammasome and increased bacterial survival in macrophages. Oral infection of ApoE(-/- mice with the P. gingivalis strain expressing antagonistic lipid A resulted in vascular inflammation, macrophage accumulation and atherosclerosis progression. In contrast, a P. gingivalis strain producing exclusively agonistic lipid A augmented levels of proinflammatory mediators and activated the inflammasome in a caspase-11-dependent manner, resulting in host cell lysis and decreased bacterial survival. ApoE(-/- mice infected with this strain exhibited diminished vascular inflammation, macrophage accumulation, and atherosclerosis progression. Notably, the ability of P. gingivalis to induce local inflammatory bone loss was independent of lipid A expression, indicative of distinct mechanisms for induction of local versus systemic inflammation by this pathogen. Collectively, our results point to a pivotal role for activation of the non-canonical inflammasome in P. gingivalis infection and demonstrate that P. gingivalis evades immune

Expression of manganese superoxide dismutase in rat blood, heart and brain during induced systemic hypoxia

Directory of Open Access Journals (Sweden)

Septelia I. Wanandi

2011-02-01

Full Text Available Background: Hypoxia results in an increased generation of ROS. Until now, little is known about the role of MnSOD - a major endogenous antioxidant enzyme - on the cell adaptation response against hypoxia. The aim of this study was to  determine the MnSOD mRNA expression and levels of specific activity in blood, heart and brain of rats during induced systemic hypoxia.Methods: Twenty-five male Sprague Dawley rats were subjected to systemic hypoxia in an hypoxic chamber (at 8-10% O2 for 0, 1, 7, 14 and 21 days, respectively. The mRNA relative expression of MnSOD was analyzed using Real Time RT-PCR. MnSOD specific activity was determined using xanthine oxidase inhibition assay.Results: The MnSOD mRNA relative expression in rat blood and heart was decreased during early induced systemic hypoxia (day 1 and increased as hypoxia continued, whereas the mRNA expression in brain was increased since day 1 and reached its maximum level at day 7. The result of MnSOD specific activity during early systemic hypoxia was similar to the mRNA expression. Under very late hypoxic condition (day 21, MnSOD specific activity in blood, heart and brain was significantly decreased. We demonstrate a positive correlation between MnSOD mRNA expression and specific activity in these 3 tissues during day 0-14 of induced systemic hypoxia. Furthermore, mRNA expression and specific activity levels in heart strongly correlate with those in blood.Conclusion: The MnSOD expression at early and late phases of induced systemic hypoxia is distinctly regulated. The MnSOD expression in brain differs from that in blood and heart revealing that brain tissue can  possibly survive better from induced systemic hypoxia than heart and blood. The determination of MnSOD expression in blood can be used to describe its expression in heart under systemic hypoxic condition. (Med J Indones 2011; 20:27-33Keywords: MnSOD, mRNA expression, ROS, specific activity, systemic hypoxia

Monovalent Strep-Tactin for strong and site-specific tethering in nanospectroscopy.

Science.gov (United States)

Baumann, Fabian; Bauer, Magnus S; Milles, Lukas F; Alexandrovich, Alexander; Gaub, Hermann E; Pippig, Diana A

2016-01-01

Strep-Tactin, an engineered form of streptavidin, binds avidly to the genetically encoded peptide Strep-tag II in a manner comparable to streptavidin binding to biotin. These interactions have been used in protein purification and detection applications. However, in single-molecule studies, for example using atomic force microscopy-based single-molecule force spectroscopy (AFM-SMFS), the tetravalency of these systems impedes the measurement of monodispersed data. Here, we introduce a monovalent form of Strep-Tactin that harbours a unique binding site for Strep-tag II and a single cysteine that allows Strep-Tactin to specifically attach to the atomic force microscope cantilever and form a consistent pulling geometry to obtain homogeneous rupture data. Using AFM-SMFS, the mechanical properties of the interaction between Strep-tag II and monovalent Strep-Tactin were characterized. Rupture forces comparable to biotin:streptavidin unbinding were observed. Using titin kinase and green fluorescent protein, we show that monovalent Strep-Tactin is generally applicable to protein unfolding experiments. We expect monovalent Strep-Tactin to be a reliable anchoring tool for a range of single-molecule studies.

Pairing from strong repulsion in triangular lattice Hubbard model

Science.gov (United States)

Zhang, Shang-Shun; Zhu, Wei; Batista, Cristian D.

2018-04-01

We propose a pairing mechanism between holes in the dilute limit of doped frustrated Mott insulators. Hole pairing arises from a hole-hole-magnon three-body bound state. This pairing mechanism has its roots on single-hole kinetic energy frustration, which favors antiferromagnetic (AFM) correlations around the hole. We demonstrate that the AFM polaron (hole-magnon bound state) produced by a single hole propagating on a field-induced polarized background is strong enough to bind a second hole. The effective interaction between these three-body bound states is repulsive, implying that this pairing mechanism is relevant for superconductivity.

Pancreatic Endoderm-Derived From Diabetic Patient-Specific Induced Pluripotent Stem Cell Generates Glucose-Responsive Insulin-Secreting Cells.

Science.gov (United States)

Rajaei, Bahareh; Shamsara, Mehdi; Amirabad, Leila Mohammadi; Massumi, Mohammad; Sanati, Mohammad Hossein

2017-10-01

Human-induced pluripotent stem cells (hiPSCs) can potentially serve as an invaluable source for cell replacement therapy and allow the creation of patient- and disease-specific stem cells without the controversial use of embryos and avoids any immunological incompatibility. The generation of insulin-producing pancreatic β-cells from pluripotent stem cells in vitro provides an unprecedented cell source for personal drug discovery and cell transplantation therapy in diabetes. A new five-step protocol was introduced in this study, effectively induced hiPSCs to differentiate into glucose-responsive insulin-producing cells. This process mimics in vivo pancreatic organogenesis by directing cells through stages resembling definitive endoderm, primitive gut-tube endoderm, posterior foregut, pancreatic endoderm, and endocrine precursor. Each stage of differentiation were characterized by stage-specific markers. The produced cells exhibited many properties of functional β-cells, including expression of critical β-cells transcription factors, the potency to secrete C-peptide in response to high levels of glucose and the presence of mature endocrine secretory granules. This high efficient differentiation protocol, established in this study, yielded 79.18% insulin-secreting cells which were responsive to glucose five times higher than the basal level. These hiPSCs-derived glucose-responsive insulin-secreting cells might provide a promising approach for the treatment of type I diabetes mellitus. J. Cell. Physiol. 232: 2616-2625, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Strong-back safety latch

International Nuclear Information System (INIS)

DeSantis, G.N.

1995-01-01

The calculation decides the integrity of the safety latch that will hold the strong-back to the pump during lifting. The safety latch will be welded to the strong-back and will latch to a 1.5-in. dia cantilever rod welded to the pump baseplate. The static and dynamic analysis shows that the safety latch will hold the strong-back to the pump if the friction clamps fail and the pump become free from the strong-back. Thus, the safety latch will meet the requirements of the Lifting and Rigging Manual for under the hook lifting for static loading; it can withstand shock loads from the strong-back falling 0.25 inch

Pentacene Excitons in Strong Electric Fields.

Science.gov (United States)

Kuhnke, Klaus; Turkowski, Volodymyr; Kabakchiev, Alexander; Lutz, Theresa; Rahman, Talat S; Kern, Klaus

2018-02-05

Electroluminescence spectroscopy of organic semiconductors in the junction of a scanning tunneling microscope (STM) provides access to the polarizability of neutral excited states in a well-characterized molecular geometry. We study the Stark shift of the self-trapped lowest singlet exciton at 1.6 eV in a pentacene nanocrystal. Combination of density functional theory (DFT) and time-dependent DFT (TDDFT) with experiment allows for assignment of the observation to a charge-transfer (CT) exciton. Its charge separation is perpendicular to the applied field, as the measured polarizability is moderate and the electric field in the STM junction is strong enough to dissociate a CT exciton polarized parallel to the applied field. The calculated electric-field-induced anisotropy of the exciton potential energy surface will also be of relevance to photovoltaic applications. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Nanoparticles modify dendritic cell homeostasis and induce non-specific effects on immunity to malaria.

Science.gov (United States)

Xiang, Sue D; Kong, Ying Y; Hanley, Jennifer; Fuchsberger, Martina; Crimeen-Irwin, Blessing; Plebanski, Magdalena

2015-01-01

Many current vaccines to a specific pathogen influence responses to other pathogens in a process called heterologous immunity. We propose that their particulate nature contributes to non-specific effects. Herein, we demonstrate polystyrene nanoparticles modulate dendritic cell (DC) homeostasis, thereby promoting a persistent enhanced state of immune readiness to a subsequent infectious challenge. Particles (approximately 40 nm and 500 nm carboxylated polystyrene nanoparticles; PSNPs) alone or conjugated to a model antigen were injected in mice, and DCs in draining lymph nodes (dLNs) and bone-marrow (BM) quantified by flow cytometry. BM cells were tested for capacity to generate DCs upon culture with granulocyte and macrophage colony stimulating factor. Mice were challenged with Plasmodium yoelli. Blood parasitaemias were monitored by GIEMSA. Sera was analyzed for antibodies by ELISA. Intradermal administration of 40 nm PSNPs induced anti-inflammatory cytokines, chemokines and growth factors, increased numbers and proportions of DCs in the dLN, and increased the capacity of BM to generate DCs. Consistent with these unexpected changes, 40 nm PSNPs pre-injected mice had enhanced ability to generate immunity to a subsequent malarial infection. Intradermal administration of 40 nm PSNPs modifies DC homeostasis, which may at least in part explain the observed beneficial heterologous effects of current particulate vaccines. Further nanotechnological developments may exploit such strategies to promote beneficial non-specific effects. © The Author 2015. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

The NKG2D ligand ULBP2 is specifically regulated through an invariant chain-dependent endosomal pathway

DEFF Research Database (Denmark)

Uhlenbrock, Franziska Katharina; Hagemann-Jensen, Michael Henrik; Kehlet, Stephanie

2014-01-01

by affecting endosomal/lysosomal integrity and protein kinase C activity. The invariant chain was further essential for endosomal transport of ULBP2. This novel pathway was identified through screening experiments by which methylselenic acid was found to possess notable NKG2D ligand regulatory properties....... The protein kinase C inhibitor methylselenic acid induced MICA/B surface expression but dominantly blocked ULBP2 surface transport. Remarkably, by targeting this novel pathway we could specifically block the production of soluble ULBP2 from different, primary melanomas. Our findings strongly suggest...

Postzygotic isolation involves strong mitochondrial and sex-specific effects in Tigriopus californicus, a species lacking heteromorphic sex chromosomes.

Science.gov (United States)

Foley, B R; Rose, C G; Rundle, D E; Leong, W; Edmands, S

2013-11-01

Detailed studies of the genetics of speciation have focused on a few model systems, particularly Drosophila. The copepod Tigriopus californicus offers an alternative that differs from standard animal models in that it lacks heteromorphic chromosomes (instead, sex determination is polygenic) and has reduced opportunities for sexual conflict, because females mate only once. Quantitative trait loci (QTL) mapping was conducted on reciprocal F2 hybrids between two strongly differentiated populations, using a saturated linkage map spanning all 12 autosomes and the mitochondrion. By comparing sexes, a possible sex ratio distorter was found but no sex chromosomes. Although studies of standard models often find an excess of hybrid male sterility factors, we found no QTL for sterility and multiple QTL for hybrid viability (indicated by non-Mendelian adult ratios) and other characters. Viability problems were found to be stronger in males, but the usual explanations for weaker hybrid males (sex chromosomes, sensitivity of spermatogenesis, sexual selection) cannot fully account for these male viability problems. Instead, higher metabolic rates may amplify deleterious effects in males. Although many studies of standard speciation models find the strongest genetic incompatibilities to be nuclear-nuclear (specifically X chromosome-autosome), we found the strongest deleterious interaction in this system was mito-nuclear. Consistent with the snowball theory of incompatibility accumulation, we found that trigenic interactions in this highly divergent cross were substantially more frequent (>6×) than digenic interactions. This alternative system thus allows important comparisons to studies of the genetics of reproductive isolation in more standard model systems.

Anomalous transport phenomena in Fermi liquids with strong magnetic fluctuations

International Nuclear Information System (INIS)

Kontani, Hiroshi

2008-01-01

In this paper, we present recent developments in the theory of transport phenomena based on the Fermi liquid theory. In conventional metals, various transport coefficients are scaled according to the quasiparticles relaxation time, τ, which implies that the relaxation time approximation (RTA) holds well. However, such a simple scaling does not hold in many strongly correlated electron systems. The most famous example would be high-T c superconductors (HTSCs), where almost all the transport coefficients exhibit a significant deviation from the RTA results. This issue has been one of the most significant unresolved problems in HTSCs for a long time. Similar anomalous transport phenomena have been observed in metals near their antiferromagnetic (AF) quantum critical point (QCP). The main goal of this study is to demonstrate whether the anomalous transport phenomena in HTSC is evidence of a non-Fermi liquid ground state, or just RTA violation in strongly correlated Fermi liquids. Another goal is to establish a unified theory of anomalous transport phenomena in metals with strong magnetic fluctuations. For these purposes, we develop a method for calculating various transport coefficients beyond the RTA by employing field theoretical techniques. In a Fermi liquid, an excited quasiparticle induces other excited quasiparticles by collision, and current due to these excitations is called a current vertex correction (CVC). Landau noticed the existence of CVC first, which is indispensable for calculating transport coefficients in accord with the conservation laws. Here, we develop a transport theory involving resistivity and the Hall coefficient on the basis of the microscopic Fermi liquid theory, by considering the CVC. In nearly AF Fermi liquids, we find that the strong backward scattering due to AF fluctuations induces the CVC with prominent momentum dependence. This feature of the CVC can account for the significant enhancement in the Hall coefficient, magnetoresistance

Inhibitors of dual-specificity tyrosine phosphorylation-regulated kinases (DYRK) exert a strong anti-herpesviral activity.

Science.gov (United States)

Hutterer, Corina; Milbradt, Jens; Hamilton, Stuart; Zaja, Mirko; Leban, Johann; Henry, Christophe; Vitt, Daniel; Steingruber, Mirjam; Sonntag, Eric; Zeitträger, Isabel; Bahsi, Hanife; Stamminger, Thomas; Rawlinson, William; Strobl, Stefan; Marschall, Manfred

2017-07-01

Infection with human cytomegalovirus (HCMV) is a serious medical problem, particularly in immunocompromised individuals and neonates. The success of (val)ganciclovir therapy is hampered by low drug compatibility and induction of viral resistance. A novel strategy of antiviral treatment is based on the exploitation of cell-directed signaling, e. g. pathways with a known relevance for carcinogenesis and tumor drug development. Here we describe a principle for putative antiviral drugs based on targeting dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs). DYRKs constitute an evolutionarily conserved family of protein kinases with key roles in the control of cell proliferation and differentiation. Members of the DYRK family are capable of phosphorylating a number of substrate proteins, including regulators of the cell cycle, e.g. DYRK1B can induce cell cycle arrest, a critical step for the regulation of HCMV replication. Here we provide first evidence for a critical role of DYRKs during viral replication and the high antiviral potential of DYRK inhibitors (SC84227, SC97202 and SC97208, Harmine and AZ-191). Using established replication assays for laboratory and clinically relevant strains of HCMV, concentration-dependent profiles of inhibition were obtained. Mean inhibitory concentrations (EC50) of 0.98 ± 0.08 μM/SC84227, 0.60 ± 0.02 μM/SC97202, 6.26 ± 1.64 μM/SC97208, 0.71 ± 0.019 μM/Harmine and 0.63 ± 0.23 μM/AZ-191 were determined with HCMV strain AD169-GFP for the infection of primary human fibroblasts. A first analysis of the mode of antiviral action suggested a block of viral replication at the early-late stage of HCMV gene expression. Moreover, rhesus macaque cytomegalovirus (RhCMV), varicella-zoster virus (VZV) and herpes simplex virus (HSV-1) showed a similarly high sensitivity to these compounds. Thus, we conclude that DYRK signaling represents a promising target pathway for the development of novel anti

Diverse and Tissue Specific Mitochondrial Respiratory Response in A Mouse Model of Sepsis-Induced Multiple Organ Failure

DEFF Research Database (Denmark)

Karlsson, Michael; Hara, Naomi; Morata, Saori

2016-01-01

control ratio was also significantly increased. Maximal Protonophore-induced respiratory (uncoupled) capacity was similar between the two treatment groups.The present study suggests a diverse and tissue specific mitochondrial respiratory response to sepsis. The brain displayed an early impaired...... C57BL/6 mice were analyzed at either 6 hours or 24 hours. ROS-production was simultaneously measured in brain samples using fluorometry.Septic brain tissue exhibited an early increased uncoupling of respiration. Temporal changes between the two time points were diminutive and no difference in ROS...

CD8+ T Cells Induce Fatal Brainstem Pathology during Cerebral Malaria via Luminal Antigen-Specific Engagement of Brain Vasculature.

Directory of Open Access Journals (Sweden)

Phillip A Swanson

2016-12-01

Full Text Available Cerebral malaria (CM is a severe complication of Plasmodium falciparum infection that results in thousands of deaths each year, mostly in African children. The in vivo mechanisms underlying this fatal condition are not entirely understood. Using the animal model of experimental cerebral malaria (ECM, we sought mechanistic insights into the pathogenesis of CM. Fatal disease was associated with alterations in tight junction proteins, vascular breakdown in the meninges / parenchyma, edema, and ultimately neuronal cell death in the brainstem, which is consistent with cerebral herniation as a cause of death. At the peak of ECM, we revealed using intravital two-photon microscopy that myelomonocytic cells and parasite-specific CD8+ T cells associated primarily with the luminal surface of CNS blood vessels. Myelomonocytic cells participated in the removal of parasitized red blood cells (pRBCs from cerebral blood vessels, but were not required for the disease. Interestingly, the majority of disease-inducing parasite-specific CD8+ T cells interacted with the lumen of brain vascular endothelial cells (ECs, where they were observed surveying, dividing, and arresting in a cognate peptide-MHC I dependent manner. These activities were critically dependent on IFN-γ, which was responsible for activating cerebrovascular ECs to upregulate adhesion and antigen-presenting molecules. Importantly, parasite-specific CD8+ T cell interactions with cerebral vessels were impaired in chimeric mice rendered unable to present EC antigens on MHC I, and these mice were in turn resistant to fatal brainstem pathology. Moreover, anti-adhesion molecule (LFA-1 / VLA-4 therapy prevented fatal disease by rapidly displacing luminal CD8+ T cells from cerebrovascular ECs without affecting extravascular T cells. These in vivo data demonstrate that parasite-specific CD8+ T cell-induced fatal vascular breakdown and subsequent neuronal death during ECM is associated with luminal, antigen

Re-analysis of radiation-induced specific locus mutations in the mouse

International Nuclear Information System (INIS)

Abrahamson, S.; Wolff, S.

1976-01-01

It is stated that a re-analysis of published data on mouse mutation rates induced by x-and gamma rays suggests that the kinetics of induction can be analysed by fitting that data to a parabolic curve. This is interpreted to mean that a substantial proportion of the induced mutations results from gross chromosomal changes such as deletions, some of which are one-track and some of which are two-track. This analysis is based on the assumption that the shape of the dose curve, which in the female is concave upward, reflects the manner in which the mutations are induced rather than representing a one-track (linear) curve whose shape has been modified by differential repair. (author)

Polarized X-Ray Emission from Magnetized Neutron Stars: Signature of Strong-Field Vacuum Polarization

Science.gov (United States)

Lai, Dong; Ho, Wynn C.

2003-08-01

In the atmospheric plasma of a strongly magnetized neutron star, vacuum polarization can induce a Mikheyev-Smirnov-Wolfenstein type resonance across which an x-ray photon may (depending on its energy) convert from one mode into the other, with significant changes in opacities and polarizations. We show that this vacuum resonance effect gives rise to a unique energy-dependent polarization signature in the surface emission from neutron stars. The detection of polarized x rays from neutron stars can provide a direct probe of strong-field quantum electrodynamics and constrain the neutron star magnetic field and geometry.

Polarized x-ray emission from magnetized neutron stars: signature of strong-field vacuum polarization.

Science.gov (United States)

Lai, Dong; Ho, Wynn C G

2003-08-15

In the atmospheric plasma of a strongly magnetized neutron star, vacuum polarization can induce a Mikheyev-Smirnov-Wolfenstein type resonance across which an x-ray photon may (depending on its energy) convert from one mode into the other, with significant changes in opacities and polarizations. We show that this vacuum resonance effect gives rise to a unique energy-dependent polarization signature in the surface emission from neutron stars. The detection of polarized x rays from neutron stars can provide a direct probe of strong-field quantum electrodynamics and constrain the neutron star magnetic field and geometry.

Taxon- and Site-Specific Melatonin Catabolism

Directory of Open Access Journals (Sweden)

Rüdiger Hardeland

2017-11-01

Full Text Available Melatonin is catabolized both enzymatically and nonenzymatically. Nonenzymatic processes mediated by free radicals, singlet oxygen, other reactive intermediates such as HOCl and peroxynitrite, or pseudoenzymatic mechanisms are not species- or tissue-specific, but vary considerably in their extent. Higher rates of nonenzymatic melatonin metabolism can be expected upon UV exposure, e.g., in plants and in the human skin. Additionally, melatonin is more strongly nonenzymatically degraded at sites of inflammation. Typical products are several hydroxylated derivatives of melatonin and N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK. Most of these products are also formed by enzymatic catalysis. Considerable taxon- and site-specific differences are observed in the main enzymatic routes of catabolism. Formation of 6-hydroxymelatonin by cytochrome P450 subforms are prevailing in vertebrates, predominantly in the liver, but also in the brain. In pineal gland and non-mammalian retina, deacetylation to 5-methoxytryptamine (5-MT plays a certain role. This pathway is quantitatively prevalent in dinoflagellates, in which 5-MT induces cyst formation and is further converted to 5-methoxyindole-3-acetic acid, an end product released to the water. In plants, the major route is catalyzed by melatonin 2-hydroxylase, whose product is tautomerized to 3-acetamidoethyl-3-hydroxy-5-methoxyindolin-2-one (AMIO, which exceeds the levels of melatonin. Formation and properties of various secondary products are discussed.

Polarization-induced Zener tunnel diodes in GaN/InGaN/GaN heterojunctions

Energy Technology Data Exchange (ETDEWEB)

Yan, Xiaodong; Li, Wenjun; Islam, S. M.; Pourang, Kasra; Fay, Patrick [Department of Electrical Engineering, University of Notre Dame, Notre Dame, Indiana 46556 (United States); Xing, Huili; Jena, Debdeep, E-mail: djena@cornell.edu [Department of Electrical Engineering, University of Notre Dame, Notre Dame, Indiana 46556 (United States); Departments of ECE and MSE, Cornell University, Ithaca, New York 14853 (United States)

2015-10-19

By the insertion of thin In{sub x}Ga{sub 1−x}N layers into Nitrogen-polar GaN p-n junctions, polarization-induced Zener tunnel junctions are studied. The reverse-bias interband Zener tunneling current is found to be weakly temperature dependent, as opposed to the strongly temperature-dependent forward bias current. This indicates tunneling as the primary reverse-bias current transport mechanism. The Indium composition in the InGaN layer is systematically varied to demonstrate the increase in the interband tunneling current. Comparing the experimentally measured tunneling currents to a model helps identify the specific challenges in potentially taking such junctions towards nitride-based polarization-induced tunneling field-effect transistors.

Polarization-induced Zener tunnel diodes in GaN/InGaN/GaN heterojunctions

International Nuclear Information System (INIS)

Yan, Xiaodong; Li, Wenjun; Islam, S. M.; Pourang, Kasra; Fay, Patrick; Xing, Huili; Jena, Debdeep

2015-01-01

By the insertion of thin In x Ga 1−x N layers into Nitrogen-polar GaN p-n junctions, polarization-induced Zener tunnel junctions are studied. The reverse-bias interband Zener tunneling current is found to be weakly temperature dependent, as opposed to the strongly temperature-dependent forward bias current. This indicates tunneling as the primary reverse-bias current transport mechanism. The Indium composition in the InGaN layer is systematically varied to demonstrate the increase in the interband tunneling current. Comparing the experimentally measured tunneling currents to a model helps identify the specific challenges in potentially taking such junctions towards nitride-based polarization-induced tunneling field-effect transistors

Immunotherapy with a HER2-Targeting Listeria Induces HER2-Specific Immunity and Demonstrates Potential Therapeutic Effects in a Phase I Trial in Canine Osteosarcoma.

Science.gov (United States)

Mason, Nicola J; Gnanandarajah, Josephine S; Engiles, Julie B; Gray, Falon; Laughlin, Danielle; Gaurnier-Hausser, Anita; Wallecha, Anu; Huebner, Margie; Paterson, Yvonne

2016-09-01

Recombinant Listeria vaccines induce tumor-specific T-cell responses that eliminate established tumors and prevent metastatic disease in murine cancer models. We used dogs with HER2/neu(+) appendicular osteosarcoma, a well-recognized spontaneous model for pediatric osteosarcoma, to determine whether a highly attenuated, recombinant Listeria monocytogenes expressing a chimeric human HER2/neu fusion protein (ADXS31-164) could safely induce HER2/neu-specific immunity and prevent metastatic disease. Eighteen dogs that underwent limb amputation or salvage surgery and adjuvant chemotherapy were enrolled in a phase I dose escalation clinical trial and received either 2 × 10(8), 5 × 10(8), 1 × 10(9), or 3.3 × 10(9) CFU of ADXS31-164 intravenously every 3 weeks for 3 administrations. Only low-grade, transient toxicities were observed. ADXS31-164 broke peripheral tolerance and induced antigen-specific IFNγ responses against the intracellular domain of HER2/neu in 15 of 18 dogs within 6 months of treatment. Furthermore, ADXS31-164 reduced the incidence of metastatic disease and significantly increased duration of survival time and 1-, 2-, and 3-year survival rates when compared with a historical control group with HER2/neu(+) appendicular osteosarcoma treated with amputation and chemotherapy alone. These findings demonstrate that ADXS31-164 administered in the setting of minimal residual disease can induce HER2/neu-specific immunity and may reduce the incidence of metastatic disease and prolong overall survival in a clinically relevant, spontaneous, large animal model of cancer. These findings, therefore, have important translational relevance for children with osteosarcoma and adults with other HER2/neu(+) cancers. Clin Cancer Res; 22(17); 4380-90. ©2016 AACR. ©2016 American Association for Cancer Research.

Standard test methods for the strong-base resins used in the recovery of uranium

International Nuclear Information System (INIS)

Ford, M.A.; Lombaard, L.R.

1986-01-01

There are no detailed specifications for the strong-base ion-exchange resins used in continuous ion-exchange plants, and it was considered that a very useful purpose would be served by the publication of a series of standard laboratory tests on which such specifications could be based. This report describes test methods that are relevant to the ion-exchange recovery of uranium. They include tests of the physical properties of strong-base resins (relative density, particle-size distribution, and moisture content) and of their chemical properties (theoretical capacity, equilibrium capacity, kinetics of loading and elution). Included are several supporting procedures that are used in conjunction with these methods

Evaluation of ferromagnetic fluids and suspensions for the site-specific radiofrequency-induced hyperthermia of MX11 sarcoma cells in vitro

Energy Technology Data Exchange (ETDEWEB)

Brusentsov, Nikolai A.; Gogosov, V.V.; Brusentsova, T.N.; Sergeev, A.V.; Jurchenko, N.Y.; Kuznetsov, Anatoly A.; Kuznetsov, Oleg A. E-mail: oleg@louisiana.edu; Shumakov, L.I

2001-07-01

Seventeen different ferromagnetic fluids and suspensions were prepared and evaluated for application in radiofrequency-induced hyperthermia. Specific power absorption rates were measured at 0.88 MHz to range from 0 to 240 W per gram of iron for different preparations. Survival of MX11 cells mixed with ferrofluids and subjected to radiofrequency was much lower than with RF without ferrofluid or ferrofluid alone.

Evaluation of ferromagnetic fluids and suspensions for the site-specific radiofrequency-induced hyperthermia of MX11 sarcoma cells in vitro

International Nuclear Information System (INIS)

Brusentsov, Nikolai A.; Gogosov, V.V.; Brusentsova, T.N.; Sergeev, A.V.; Jurchenko, N.Y.; Kuznetsov, Anatoly A.; Kuznetsov, Oleg A.; Shumakov, L.I.

2001-01-01

Seventeen different ferromagnetic fluids and suspensions were prepared and evaluated for application in radiofrequency-induced hyperthermia. Specific power absorption rates were measured at 0.88 MHz to range from 0 to 240 W per gram of iron for different preparations. Survival of MX11 cells mixed with ferrofluids and subjected to radiofrequency was much lower than with RF without ferrofluid or ferrofluid alone

Interplay of Anderson localization and strong interaction in disordered systems

Energy Technology Data Exchange (ETDEWEB)

Henseler, Peter

2010-01-15

We study the interplay of disorder localization and strong local interactions within the Anderson-Hubbard model. Taking into account local Mott-Hubbard physics and static screening of the disorder potential, the system is mapped onto an effective single-particle Anderson model, which is studied within the self-consistent theory of electron localization. For fermions, we find rich nonmonotonic behavior of the localization length {xi}, particularly in two-dimensional systems, including an interaction-induced exponential enhancement of {xi} for small and intermediate disorders and a strong reduction of {xi} due to hopping suppression by strong interactions. In three dimensions, we identify for half filling a Mott-Hubbard-assisted Anderson localized phase existing between the metallic and the Mott-Hubbard-gapped phases. For small U there is re-entrant behavior from the Anderson localized phase to the metallic phase. For bosons, the unrestricted particle occupation number per lattice site yields a monotonic enhancement of {xi} as a function of decreasing interaction, which we assume to persist until the superfluid Bose-Einstein condensate phase is entered. Besides, we study cold atomic gases expanding, by a diffusion process, in a weak random potential. We show that the density-density correlation function of the expanding gas is strongly affected by disorder and we estimate the typical size of a speckle spot, i.e., a region of enhanced or depleted density. Both a Fermi gas and a Bose-Einstein condensate (in a mean-field approach) are considered. (orig.)

Interplay of Anderson localization and strong interaction in disordered systems

International Nuclear Information System (INIS)

Henseler, Peter

2010-01-01

We study the interplay of disorder localization and strong local interactions within the Anderson-Hubbard model. Taking into account local Mott-Hubbard physics and static screening of the disorder potential, the system is mapped onto an effective single-particle Anderson model, which is studied within the self-consistent theory of electron localization. For fermions, we find rich nonmonotonic behavior of the localization length ξ, particularly in two-dimensional systems, including an interaction-induced exponential enhancement of ξ for small and intermediate disorders and a strong reduction of ξ due to hopping suppression by strong interactions. In three dimensions, we identify for half filling a Mott-Hubbard-assisted Anderson localized phase existing between the metallic and the Mott-Hubbard-gapped phases. For small U there is re-entrant behavior from the Anderson localized phase to the metallic phase. For bosons, the unrestricted particle occupation number per lattice site yields a monotonic enhancement of ξ as a function of decreasing interaction, which we assume to persist until the superfluid Bose-Einstein condensate phase is entered. Besides, we study cold atomic gases expanding, by a diffusion process, in a weak random potential. We show that the density-density correlation function of the expanding gas is strongly affected by disorder and we estimate the typical size of a speckle spot, i.e., a region of enhanced or depleted density. Both a Fermi gas and a Bose-Einstein condensate (in a mean-field approach) are considered. (orig.)

Prolonged activation of virus-specific CD8+T cells after acute B19 infection.

Directory of Open Access Journals (Sweden)

Adiba Isa

2005-12-01

Full Text Available Human parvovirus B19 (B19 is a ubiquitous and clinically significant pathogen, causing erythema infectiosum, arthropathy, transient aplastic crisis, and intrauterine fetal death. The phenotype of CD8+ T cells in acute B19 infection has not been studied previously.The number and phenotype of B19-specific CD8+ T cell responses during and after acute adult infection was studied using HLA-peptide multimeric complexes. Surprisingly, these responses increased in magnitude over the first year post-infection despite resolution of clinical symptoms and control of viraemia, with T cell populations specific for individual epitopes comprising up to 4% of CD8+ T cells. B19-specific T cells developed and maintained an activated CD38+ phenotype, with strong expression of perforin and CD57 and downregulation of CD28 and CD27. These cells possessed strong effector function and intact proliferative capacity. Individuals tested many years after infection exhibited lower frequencies of B19-specific cytotoxic T lymphocytes, typically 0.05%-0.5% of CD8+ T cells, which were perforin, CD38, and CCR7 low.This is the first example to our knowledge of an "acute" human viral infection inducing a persistent activated CD8+ T cell response. The likely explanation--analogous to that for cytomegalovirus infection--is that this persistent response is due to low-level antigen exposure. CD8+ T cells may contribute to the long-term control of this significant pathogen and should be considered during vaccine development.

Prolonged activation of virus-specific CD8+T cells after acute B19 infection.

Directory of Open Access Journals (Sweden)

2005-12-01

Full Text Available BACKGROUND: Human parvovirus B19 (B19 is a ubiquitous and clinically significant pathogen, causing erythema infectiosum, arthropathy, transient aplastic crisis, and intrauterine fetal death. The phenotype of CD8+ T cells in acute B19 infection has not been studied previously. METHODS AND FINDINGS: The number and phenotype of B19-specific CD8+ T cell responses during and after acute adult infection was studied using HLA-peptide multimeric complexes. Surprisingly, these responses increased in magnitude over the first year post-infection despite resolution of clinical symptoms and control of viraemia, with T cell populations specific for individual epitopes comprising up to 4% of CD8+ T cells. B19-specific T cells developed and maintained an activated CD38+ phenotype, with strong expression of perforin and CD57 and downregulation of CD28 and CD27. These cells possessed strong effector function and intact proliferative capacity. Individuals tested many years after infection exhibited lower frequencies of B19-specific cytotoxic T lymphocytes, typically 0.05%-0.5% of CD8+ T cells, which were perforin, CD38, and CCR7 low. CONCLUSION: This is the first example to our knowledge of an "acute" human viral infection inducing a persistent activated CD8+ T cell response. The likely explanation--analogous to that for cytomegalovirus infection--is that this persistent response is due to low-level antigen exposure. CD8+ T cells may contribute to the long-term control of this significant pathogen and should be considered during vaccine development.

Non-equilibrium magnetic interactions in strongly correlated systems

Energy Technology Data Exchange (ETDEWEB)

Secchi, A., E-mail: a.secchi@science.ru.nl [Institute for Molecules and Materials, Radboud University Nijmegen, 6525 AJ Nijmegen (Netherlands); Brener, S.; Lichtenstein, A.I. [Institut für Theoretische Physik, Universitat Hamburg, Jungiusstraße 9, D-20355 Hamburg (Germany); Katsnelson, M.I. [Institute for Molecules and Materials, Radboud University Nijmegen, 6525 AJ Nijmegen (Netherlands)

2013-06-15

We formulate a low-energy theory for the magnetic interactions between electrons in the multi-band Hubbard model under non-equilibrium conditions determined by an external time-dependent electric field which simulates laser-induced spin dynamics. We derive expressions for dynamical exchange parameters in terms of non-equilibrium electronic Green functions and self-energies, which can be computed, e.g., with the methods of time-dependent dynamical mean-field theory. Moreover, we find that a correct description of the system requires, in addition to exchange, a new kind of magnetic interaction, that we name twist exchange, which formally resembles Dzyaloshinskii–Moriya coupling, but is not due to spin–orbit, and is actually due to an effective three-spin interaction. Our theory allows the evaluation of the related time-dependent parameters as well. -- Highlights: •We develop a theory for magnetism of strongly correlated systems out of equilibrium. •Our theory is suitable for laser-induced ultrafast magnetization dynamics. •We write time-dependent exchange parameters in terms of electronic Green functions. •We find a new magnetic interaction, a “twist exchange”. •We give general expressions for magnetic noise in itinerant-electron systems.

A non-lethal traumatic/hemorrhagic insult strongly modulates the compartment-specific PAI-1 response in the subsequent polymicrobial sepsis.

Directory of Open Access Journals (Sweden)

Pierre Raeven

Full Text Available INTRODUCTION: Plasminogen activator inhibitor 1 (PAI-1 is a key factor in trauma- and sepsis-induced coagulopathy. We examined how trauma-hemorrhage (TH modulates PAI-1 responses in subsequent cecal ligation and puncture (CLP-induced sepsis, and the association of PAI-1 with septic outcomes. METHODS: Mice underwent TH and CLP 48 h later in three separate experiments. In experiment 1, mice were sacrificed pre- and post-CLP to characterize the trajectory of PAI-1 in plasma (protein and tissues (mRNA. Post-CLP dynamics in TH-CLP (this study and CLP-Only mice (prior study were then compared for modulatory effects of TH. In experiment 2, to relate PAI-1 changes to outcome, mice underwent TH-CLP and were sampled daily and followed for 14 days to compare non-survivors (DEAD and survivors (SUR. In experiment 3, plasma and tissue PAI-1 expression were compared between mice predicted to die (P-DIE and to live (P-LIVE. RESULTS: In experiment 1, an early post-TH rise of circulating PAI-1 was contrasted by a delayed (post-TH decrease of PAI-1 mRNA in organs. In the post-CLP phase, profiles of circulating PAI-1 were similar between TH-CLP and CLP-Only mice. Conversely, PAI-1 mRNA declined in the liver and heart of TH-CLP mice versus CLP-Only. In experiment 2, there were no DEAD/SUR differences in circulating PAI-1 prior to CLP. Post-CLP, circulating PAI-1 in DEAD was 2-4-fold higher than in SUR. PAI-1 increase heralded septic deaths up to 48 h prior but DEAD/SUR thrombomodulin (endothelial injury marker levels were identical. In experiment 3, levels of circulating PAI-1 and its hepatic gene expression were higher in P-DIE versus P-LIVE mice and those increases closely correlated with liver dysfunction. CONCLUSIONS: Trauma modulated septic PAI-1 responses in a compartment-specific fashion. Only post-CLP increases in circulating PAI-1 predicted septic outcomes. In posttraumatic sepsis, pre-lethal release of PAI-1 was mostly of hepatic origin and was independent

Numerical analysis of the thermally induced flow in a strongly rotating gas centrifuge

Energy Technology Data Exchange (ETDEWEB)

Novelli, P.

1982-04-01

The present work is concerned with the numerical analysis of the thermally induced flow in a rapidly gas centrifuge. The primary purpose for this work is to investigate the dependence of the flow field on the thermal boundary conditions, angular speed, aspect ratio of the cylinder, holdup. Some of our results are compared with the predictions of asymptotic theories, particularly those of Sakurai-Mtsuda and Brouwers, and with the numerical results of Dickinson-Jones.

Probing strong-field electron-nuclear dynamics of polyatomic molecules using proton motion

International Nuclear Information System (INIS)

Markevitch, Alexei N.; Smith, Stanley M.; Levis, Robert J.; Romanov, Dmitri A.

2007-01-01

Proton ejection during Coulomb explosion is studied for several structure-related organic molecules (anthracene, anthraquinone, and octahydroanthracene) subjected to 800 nm, 60 fs laser pulses at intensities from 0.50 to 4.0x10 14 W cm -2 . The proton kinetic energy distributions are found to be markedly structure specific. The distributions are bimodal for anthracene and octahydroanthracene and trimodal for anthraquinone. Maximum (cutoff) energies of the distributions range from 50 eV for anthracene to 83 eV for anthraquinone. The low-energy mode (∼10 eV) is most pronounced in octahydroanthracene. The dependence of the characteristic features of the distributions on the laser intensity provides insights into molecular specificity of such strong-field phenomena as (i) nonadiabatic charge localization and (ii) field-mediated restructuring of polyatomic molecules polarized by a strong laser field

Tissue Specific Promoters in Colorectal Cancer

Directory of Open Access Journals (Sweden)

A. R. Rama

2015-01-01

Full Text Available Colorectal carcinoma is the third most prevalent cancer in the world. In the most advanced stages, the use of chemotherapy induces a poor response and is usually accompanied by other tissue damage. Significant progress based on suicide gene therapy has demonstrated that it may potentiate the classical cytotoxic effects in colorectal cancer. The inconvenience still rests with the targeting and the specificity efficiency. The main target of gene therapy is to achieve an effective vehicle to hand over therapeutic genes safely into specific cells. One possibility is the use of tumor-specific promoters overexpressed in cancers. They could induce a specific expression of therapeutic genes in a given tumor, increasing their localized activity. Several promoters have been assayed into direct suicide genes to cancer cells. This review discusses the current status of specific tumor-promoters and their great potential in colorectal carcinoma treatment.

An Antibody Blocking Activin Type II Receptors Induces Strong Skeletal Muscle Hypertrophy and Protects from Atrophy

Science.gov (United States)

Minetti, Giulia C.; Sheppard, KellyAnn; Ibebunjo, Chikwendu; Feige, Jerome N.; Hartmann, Steffen; Brachat, Sophie; Rivet, Helene; Koelbing, Claudia; Morvan, Frederic; Hatakeyama, Shinji

2014-01-01

The myostatin/activin type II receptor (ActRII) pathway has been identified to be critical in regulating skeletal muscle size. Several other ligands, including GDF11 and the activins, signal through this pathway, suggesting that the ActRII receptors are major regulatory nodes in the regulation of muscle mass. We have developed a novel, human anti-ActRII antibody (bimagrumab, or BYM338) to prevent binding of ligands to the receptors and thus inhibit downstream signaling. BYM338 enhances differentiation of primary human skeletal myoblasts and counteracts the inhibition of differentiation induced by myostatin or activin A. BYM338 prevents myostatin- or activin A-induced atrophy through inhibition of Smad2/3 phosphorylation, thus sparing the myosin heavy chain from degradation. BYM338 dramatically increases skeletal muscle mass in mice, beyond sole inhibition of myostatin, detected by comparing the antibody with a myostatin inhibitor. A mouse version of the antibody induces enhanced muscle hypertrophy in myostatin mutant mice, further confirming a beneficial effect on muscle growth beyond myostatin inhibition alone through blockade of ActRII ligands. BYM338 protects muscles from glucocorticoid-induced atrophy and weakness via prevention of muscle and tetanic force losses. These data highlight the compelling therapeutic potential of BYM338 for the treatment of skeletal muscle atrophy and weakness in multiple settings. PMID:24298022

Strong Langmuir turbulence

International Nuclear Information System (INIS)

Goldman, M.V.

1984-01-01

After a brief discussion of beam-excited Langmuir turbulence in the solar wind, we explain the criteria for wave-particle, three-wave and strong turbulence interactions. We then present the results of a numerical integration of the Zakharov equations, which describe the strong turbulence saturation of a weak (low-density) high energy, bump-on-tail beam instability. (author)

Vortex dynamics in type-II superconductors under strong pinning conditions

Science.gov (United States)

Thomann, A. U.; Geshkenbein, V. B.; Blatter, G.

2017-10-01

We study effects of pinning on the dynamics of a vortex lattice in a type-II superconductor in the strong-pinning situation and determine the force-velocity (or current-voltage) characteristic combining analytical and numerical methods. Our analysis deals with a small density np of defects that act with a large force fp on the vortices, thereby inducing bistable configurations that are a characteristic feature of strong pinning theory. We determine the velocity-dependent average pinning-force density 〈Fp(v ) 〉 and find that it changes on the velocity scale vp˜fp/η a03 , where η is the viscosity of vortex motion and a0 the distance between vortices. In the small pin-density limit, this velocity is much larger than the typical flow velocity vc˜Fc/η of the free vortex system at drives near the critical force density Fc=〈Fp(v =0 ) 〉 ∝npfp . As a result, we find a generic excess-force characteristic, a nearly linear force-velocity characteristic shifted by the critical force density Fc; the linear flux-flow regime is approached only at large drives. Our analysis provides a derivation of Coulomb's law of dry friction for the case of strong vortex pinning.

Strong Motion Earthquake Data Values of Digitized Strong-Motion Accelerograms, 1933-1994

Data.gov (United States)

National Oceanic and Atmospheric Administration, Department of Commerce — The Strong Motion Earthquake Data Values of Digitized Strong-Motion Accelerograms is a database of over 15,000 digitized and processed accelerograph records from...

Strong-Field Physics with Mid-IR Fields

Directory of Open Access Journals (Sweden)

Benjamin Wolter

2015-06-01

Full Text Available Strong-field physics is currently experiencing a shift towards the use of mid-IR driving wavelengths. This is because they permit conducting experiments unambiguously in the quasistatic regime and enable exploiting the effects related to ponderomotive scaling of electron recollisions. Initial measurements taken in the mid-IR immediately led to a deeper understanding of photoionization and allowed a discrimination among different theoretical models. Ponderomotive scaling of rescattering has enabled new avenues towards time-resolved probing of molecular structure. Essential for this paradigm shift was the convergence of two experimental tools: (1 intense mid-IR sources that can create high-energy photons and electrons while operating within the quasistatic regime and (2 detection systems that can detect the generated high-energy particles and image the entire momentum space of the interaction in full coincidence. Here, we present a unique combination of these two essential ingredients, namely, a 160-kHz mid-IR source and a reaction microscope detection system, to present an experimental methodology that provides an unprecedented three-dimensional view of strong-field interactions. The system is capable of generating and detecting electron energies that span a 6 order of magnitude dynamic range. We demonstrate the versatility of the system by investigating electron recollisions, the core process that drives strong-field phenomena, at both low (meV and high (hundreds of eV energies. The low-energy region is used to investigate recently discovered low-energy structures, while the high-energy electrons are used to probe atomic structure via laser-induced electron diffraction. Moreover, we present, for the first time, the correlated momentum distribution of electrons from nonsequential double ionization driven by mid-IR pulses.

Alterations in regulatory T cells induced by specific oligosaccharides improve vaccine responsiveness in mice.

Directory of Open Access Journals (Sweden)

Marcel A Schijf

Full Text Available Prophylactic vaccinations are generally performed to protect naïve individuals with or without suppressed immune responsiveness. In a mouse model for Influenza vaccinations the specific alterations of CD4(+CD25(+Foxp3(+ regulatory T-cells (Tregs in the immune modulation induced by orally supplied oligosaccharides containing scGOS/lcFOS/pAOS was assessed. This dietary intervention increased vaccine specific DTH responses. In addition, a significant increased percentage of T-bet(+ (Th1 activated CD69(+CD4(+ T cells (p<0.001 and reduced percentage of Gata-3(+ (Th2 activated CD69(+CD4(+T cells (p<0.001 was detected in the mesenteric lymph nodes (MLN of mice receiving scGOS/lcFOS/pAOS compared to control mice. Although no difference in the number or percentage of Tregs (CD4(+Foxp3(+ could be determined after scGOS/lcFOS/pAOS intervention, the percentage of CXCR3 (+ /T-bet(+ (Th1-Tregs was significantly reduced (p<0.05 in mice receiving scGOS/lcFOS/pAOS as compared to mice receiving placebo diets. Moreover, although no absolute difference in suppressive capacity could be detected, an alteration in cytokine profile suggests a regulatory T cell shift towards a reducing Th1 suppression profile, supporting an improved vaccination response.These data are indicative for improved vaccine responsiveness due to reduced Th1 suppressive capacity in the Treg population of mice fed the oligosaccharide specific diet, showing compartmentalization within the Treg population. The modulation of Tregs to control immune responses provides an additional arm of intervention using alternative strategies possibly leading to the development of improved vaccines.

Fluoxetine induces input-specific hippocampal dendritic spine remodeling along the septo-temporal axis in adulthood and middle age

Science.gov (United States)

McAvoy, Kathleen; Russo, Craig; Kim, Shannen; Rankin, Genelle; Sahay, Amar

2015-01-01

Fluoxetine, a selective serotonin-reuptake inhibitor (SSRI), is known to induce structural rearrangements and changes in synaptic transmission in hippocampal circuitry. In the adult hippocampus, structural changes include neurogenesis, dendritic and axonal plasticity of pyramidal and dentate granule neurons, and dedifferentiation of dentate granule neurons. However, much less is known about how chronic fluoxetine affects these processes along the septo-temporal axis and during the aging process. Importantly, studies documenting the effects of fluoxetine on density and distribution of spines along different dendritic segments of dentate granule neurons and CA1 pyramidal neurons along the septo-temporal axis of hippocampus in adulthood and during aging are conspicuously absent. Here, we use a transgenic mouse line in which mature dentate granule neurons and CA1 pyramidal neurons are genetically labeled with green fluorescent protein (GFP) to investigate the effects of chronic fluoxetine treatment (18mg/kg/day) on input-specific spine remodeling and mossy fiber structural plasticity in the dorsal and ventral hippocampus in adulthood and middle age. In addition, we examine levels of adult hippocampal neurogenesis, maturation state of dentate granule neurons, neuronal activity and glutamic acid decarboxylase-67 expression in response to chronic fluoxetine in adulthood and middle age. Our studies reveal that while chronic fluoxetine fails to augment adult hippocampal neurogenesis in middle age, the middle-aged hippocampus retains high sensitivity to changes in the dentate gyrus (DG) such as dematuration, hypoactivation, and increased glutamic acid decarboxylase 67 (GAD67) expression. Interestingly, the middle-aged hippocampus shows greater sensitivity to fluoxetine-induced input-specific synaptic remodeling than the hippocampus in adulthood with the stratum-oriens of CA1 exhibiting heightened structural plasticity. The input-specific changes and circuit

Strongly first-order electroweak phase transition and classical scale invariance

Science.gov (United States)

Farzinnia, Arsham; Ren, Jing

2014-10-01

In this work, we examine the possibility of realizing a strongly first-order electroweak phase transition within the minimal classically scale-invariant extension of the standard model (SM), previously proposed and analyzed as a potential solution to the hierarchy problem. By introducing one complex gauge-singlet scalar and three (weak scale) right-handed Majorana neutrinos, the scenario was successfully rendered capable of achieving a radiative breaking of the electroweak symmetry (by means of the Coleman-Weinberg mechanism), inducing nonzero masses for the SM neutrinos (via the seesaw mechanism), presenting a pseudoscalar dark matter candidate (protected by the CP symmetry of the potential), and predicting the existence of a second CP-even boson (with suppressed couplings to the SM content) in addition to the 125 GeV scalar. In the present treatment, we construct the full finite-temperature one-loop effective potential of the model, including the resummed thermal daisy loops, and demonstrate that finite-temperature effects induce a first-order electroweak phase transition. Requiring the thermally driven first-order phase transition to be sufficiently strong at the onset of the bubble nucleation (corresponding to nucleation temperatures TN˜100-200 GeV) further constrains the model's parameter space; in particular, an O(0.01) fraction of the dark matter in the Universe may be simultaneously accommodated with a strongly first-order electroweak phase transition. Moreover, such a phase transition disfavors right-handed Majorana neutrino masses above several hundreds of GeV, confines the pseudoscalar dark matter masses to ˜1-2 TeV, predicts the mass of the second CP-even scalar to be ˜100-300 GeV, and requires the mixing angle between the CP-even components of the SM doublet and the complex singlet to lie within the range 0.2≲sinω ≲0.4. The obtained results are displayed in comprehensive exclusion plots, identifying the viable regions of the parameter space

Handedness and "Open-Earedness": Strong Right-Handers Are Less Likely to Prefer Less Popular Musical Genres

Science.gov (United States)

Christman, Stephen D.

2013-01-01

Research shows that strong right-handedness is associated with decreased cognitive flexibility and decreased tendencies to update beliefs, arising from decreased interhemispheric interaction. In the current study, strong right-handedness was associated with decreased overall liking of less popular musical genres (with the specific genres of…

Strongly coupled SU(2v boson and LEP1 versus LEP2

Directory of Open Access Journals (Sweden)

M. Bilenky

1993-10-01

Full Text Available If new strong interactions exist in the electroweak bosonic sector (e.g., strong Higgs sector, dynamical electroweak breaking, etc., it is natural to expect new resonances, with potentially strong couplings. We consider an additional vector-boson triplet, V+-, V0, associated with an SU(2v local symmetry under the specific (but rather natural assumption that ordinary fermions are SU(2v singlets. Mixing of the V triplet with the W+-, Z0 bosons effectively leads to an SU(2L×U(1Y violating vector-boson-fermion interaction which is strongly bounded by LEP1 data. In contrast, the potentially large deviation of the Z0W+W- coupling from its SU(2L×U(1Y value is hardly constrained by LEP1 data. Results from experiments with direct access to the trilinear Z0W+W− coupling (LEP200, NLC are urgently needed.

Stage-Specific Human Induced Pluripotent Stem Cells Map the Progression of Myeloid Transformation to Transplantable Leukemia.

Science.gov (United States)

Kotini, Andriana G; Chang, Chan-Jung; Chow, Arthur; Yuan, Han; Ho, Tzu-Chieh; Wang, Tiansu; Vora, Shailee; Solovyov, Alexander; Husser, Chrystel; Olszewska, Malgorzata; Teruya-Feldstein, Julie; Perumal, Deepak; Klimek, Virginia M; Spyridonidis, Alexandros; Rampal, Raajit K; Silverman, Lewis; Reddy, E Premkumar; Papaemmanuil, Elli; Parekh, Samir; Greenbaum, Benjamin D; Leslie, Christina S; Kharas, Michael G; Papapetrou, Eirini P

2017-03-02

Myeloid malignancy is increasingly viewed as a disease spectrum, comprising hematopoietic disorders that extend across a phenotypic continuum ranging from clonal hematopoiesis to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In this study, we derived a collection of induced pluripotent stem cell (iPSC) lines capturing a range of disease stages encompassing preleukemia, low-risk MDS, high-risk MDS, and secondary AML. Upon their differentiation, we found hematopoietic phenotypes of graded severity and/or stage specificity that together delineate a phenotypic roadmap of disease progression culminating in serially transplantable leukemia. We also show that disease stage transitions, both reversal and progression, can be modeled in this system using genetic correction or introduction of mutations via CRISPR/Cas9 and that this iPSC-based approach can be used to uncover disease-stage-specific responses to drugs. Our study therefore provides insight into the cellular events demarcating the initiation and progression of myeloid transformation and a new platform for testing genetic and pharmacological interventions. Copyright © 2017 Elsevier Inc. All rights reserved.

Improved Activation toward Primary Colorectal Cancer Cells by Antigen-Specific Targeting Autologous Cytokine-Induced Killer Cells

Directory of Open Access Journals (Sweden)

Claudia Schlimper

2012-01-01

Full Text Available Adoptive therapy of malignant diseases with cytokine-induced killer (CIK cells showed promise in a number of trials; the activation of CIK cells from cancer patients towards their autologous cancer cells still needs to be improved. Here, we generated CIK cells ex vivo from blood lymphocytes of colorectal cancer patients and engineered those cells with a chimeric antigen receptor (CAR with an antibody-defined specificity for carcinoembryonic antigen (CEA. CIK cells thereby gained a new specificity as defined by the CAR and showed increase in activation towards CEA+ colon carcinoma cells, but less in presence of CEA− cells, indicated by increased secretion of proinflammatory cytokines. Redirected CIK activation was superior by CAR-mediated CD28-CD3ζ than CD3ζ signaling only. CAR-engineered CIK cells from colon carcinoma patients showed improved activation against their autologous, primary carcinoma cells from biopsies resulting in more efficient tumour cell lysis. We assume that adoptive therapy with CAR-modified CIK cells shows improved selectivity in targeting autologous tumour lesions.

Low dose decitabine treatment induces CD80 expression in cancer cells and stimulates tumor specific cytotoxic T lymphocyte responses.

Directory of Open Access Journals (Sweden)

Li-Xin Wang

Full Text Available Lack of immunogenicity of cancer cells has been considered a major reason for their failure in induction of a tumor specific T cell response. In this paper, we present evidence that decitabine (DAC, a DNA methylation inhibitor that is currently used for the treatment of myelodysplastic syndrome (MDS, acute myeloid leukemia (AML and other malignant neoplasms, is capable of eliciting an anti-tumor cytotoxic T lymphocyte (CTL response in mouse EL4 tumor model. C57BL/6 mice with established EL4 tumors were treated with DAC (1.0 mg/kg body weight once daily for 5 days. We found that DAC treatment resulted in infiltration of IFN-γ producing T lymphocytes into tumors and caused tumor rejection. Depletion of CD8(+, but not CD4(+ T cells resumed tumor growth. DAC-induced CTL response appeared to be elicited by the induction of CD80 expression on tumor cells. Epigenetic evidence suggests that DAC induces CD80 expression in EL4 cells via demethylation of CpG dinucleotide sites in the promoter of CD80 gene. In addition, we also showed that a transient, low-dose DAC treatment can induce CD80 gene expression in a variety of human cancer cells. This study provides the first evidence that epigenetic modulation can induce the expression of a major T cell co-stimulatory molecule on cancer cells, which can overcome immune tolerance, and induce an efficient anti-tumor CTL response. The results have important implications in designing DAC-based cancer immunotherapy.

Low Dose Decitabine Treatment Induces CD80 Expression in Cancer Cells and Stimulates Tumor Specific Cytotoxic T Lymphocyte Responses

Science.gov (United States)

Zhou, Ji-Hao; Yao, Yu-Shi; Li, Yong-Hui; Xu, Yi-Han; Li, Jing-Xin; Gao, Xiao-Ning; Zhou, Min-Hang; Jiang, Meng-Meng; Gao, Li; Ding, Yi; Lu, Xue-Chun; Shi, Jin-Long; Luo, Xu-Feng; Wang, Jia; Wang, Li-Li; Qu, Chunfeng; Bai, Xue-Feng; Yu, Li

2013-01-01

Lack of immunogenicity of cancer cells has been considered a major reason for their failure in induction of a tumor specific T cell response. In this paper, we present evidence that decitabine (DAC), a DNA methylation inhibitor that is currently used for the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and other malignant neoplasms, is capable of eliciting an anti-tumor cytotoxic T lymphocyte (CTL) response in mouse EL4 tumor model. C57BL/6 mice with established EL4 tumors were treated with DAC (1.0 mg/kg body weight) once daily for 5 days. We found that DAC treatment resulted in infiltration of IFN-γ producing T lymphocytes into tumors and caused tumor rejection. Depletion of CD8+, but not CD4+ T cells resumed tumor growth. DAC-induced CTL response appeared to be elicited by the induction of CD80 expression on tumor cells. Epigenetic evidence suggests that DAC induces CD80 expression in EL4 cells via demethylation of CpG dinucleotide sites in the promoter of CD80 gene. In addition, we also showed that a transient, low-dose DAC treatment can induce CD80 gene expression in a variety of human cancer cells. This study provides the first evidence that epigenetic modulation can induce the expression of a major T cell co-stimulatory molecule on cancer cells, which can overcome immune tolerance, and induce an efficient anti-tumor CTL response. The results have important implications in designing DAC-based cancer immunotherapy. PMID:23671644

Low dose decitabine treatment induces CD80 expression in cancer cells and stimulates tumor specific cytotoxic T lymphocyte responses.

Science.gov (United States)

Wang, Li-Xin; Mei, Zhen-Yang; Zhou, Ji-Hao; Yao, Yu-Shi; Li, Yong-Hui; Xu, Yi-Han; Li, Jing-Xin; Gao, Xiao-Ning; Zhou, Min-Hang; Jiang, Meng-Meng; Gao, Li; Ding, Yi; Lu, Xue-Chun; Shi, Jin-Long; Luo, Xu-Feng; Wang, Jia; Wang, Li-Li; Qu, Chunfeng; Bai, Xue-Feng; Yu, Li

2013-01-01

Lack of immunogenicity of cancer cells has been considered a major reason for their failure in induction of a tumor specific T cell response. In this paper, we present evidence that decitabine (DAC), a DNA methylation inhibitor that is currently used for the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and other malignant neoplasms, is capable of eliciting an anti-tumor cytotoxic T lymphocyte (CTL) response in mouse EL4 tumor model. C57BL/6 mice with established EL4 tumors were treated with DAC (1.0 mg/kg body weight) once daily for 5 days. We found that DAC treatment resulted in infiltration of IFN-γ producing T lymphocytes into tumors and caused tumor rejection. Depletion of CD8(+), but not CD4(+) T cells resumed tumor growth. DAC-induced CTL response appeared to be elicited by the induction of CD80 expression on tumor cells. Epigenetic evidence suggests that DAC induces CD80 expression in EL4 cells via demethylation of CpG dinucleotide sites in the promoter of CD80 gene. In addition, we also showed that a transient, low-dose DAC treatment can induce CD80 gene expression in a variety of human cancer cells. This study provides the first evidence that epigenetic modulation can induce the expression of a major T cell co-stimulatory molecule on cancer cells, which can overcome immune tolerance, and induce an efficient anti-tumor CTL response. The results have important implications in designing DAC-based cancer immunotherapy.

Lipid-protein interaction induced domains: Kinetics and conformational changes in multicomponent vesicles

Science.gov (United States)

Sreeja, K. K.; Sunil Kumar, P. B.

2018-04-01

The spatio-temporal organization of proteins and the associated morphological changes in membranes are of importance in cell signaling. Several mechanisms that promote the aggregation of proteins at low cell surface concentrations have been investigated in the past. We show, using Monte Carlo simulations, that the affinity of proteins for specific lipids can hasten their aggregation kinetics. The lipid membrane is modeled as a dynamically triangulated surface with the proteins defined as in-plane fields at the vertices. We show that, even at low protein concentrations, strong lipid-protein interactions can result in large protein clusters indicating a route to lipid mediated signal amplification. At high protein concentrations, the domains form buds similar to that seen in lipid-lipid interaction induced phase separation. Protein interaction induced domain budding is suppressed when proteins act as anisotropic inclusions and exhibit nematic orientational order. The kinetics of protein clustering and resulting conformational changes are shown to be significantly different for the isotropic and anisotropic curvature inducing proteins.

Curcumin and synthetic analogs induce reactive oxygen species and decreases specificity protein (Sp) transcription factors by targeting microRNAs

International Nuclear Information System (INIS)

Gandhy, Shruti U; Kim, KyoungHyun; Larsen, Lesley; Rosengren, Rhonda J; Safe, Stephen

2012-01-01

Curcumin inhibits growth of several cancer cell lines, and studies in this laboratory in bladder and pancreatic cancer cells show that curcumin downregulates specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 and pro-oncogenic Sp-regulated genes. In this study, we investigated the anticancer activity of curcumin and several synthetic cyclohexanone and piperidine analogs in colon cancer cells. The effects of curcumin and synthetic analogs on colon cancer cell proliferation and apoptosis were determined using standardized assays. The changes in Sp proteins and Sp-regulated gene products were analysed by western blots, and real time PCR was used to determine microRNA-27a (miR-27a), miR-20a, miR-17-5p and ZBTB10 and ZBTB4 mRNA expression. The IC 50 (half-maximal) values for growth inhibition (24 hr) of colon cancer cells by curcumin and synthetic cyclohexanone and piperidine analogs of curcumin varied from 10 μM for curcumin to 0.7 μM for the most active synthetic piperidine analog RL197, which was used along with curcumin as model agents in this study. Curcumin and RL197 inhibited RKO and SW480 colon cancer cell growth and induced apoptosis, and this was accompanied by downregulation of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 and Sp-regulated genes including the epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (c-MET), survivin, bcl-2, cyclin D1 and NFκB (p65 and p50). Curcumin and RL197 also induced reactive oxygen species (ROS), and cotreatment with the antioxidant glutathione significantly attenuated curcumin- and RL197-induced growth inhibition and downregulation of Sp1, Sp3, Sp4 and Sp-regulated genes. The mechanism of curcumin-/RL197-induced repression of Sp transcription factors was ROS-dependent and due to induction of the Sp repressors ZBTB10 and ZBTB4 and downregulation of microRNAs (miR)-27a, miR-20a and miR-17-5p that regulate these repressors. These results identify a new and highly potent

Curcumin and synthetic analogs induce reactive oxygen species and decreases specificity protein (Sp transcription factors by targeting microRNAs

Directory of Open Access Journals (Sweden)

Gandhy Shruti U

2012-11-01

Full Text Available Abstract Background Curcumin inhibits growth of several cancer cell lines, and studies in this laboratory in bladder and pancreatic cancer cells show that curcumin downregulates specificity protein (Sp transcription factors Sp1, Sp3 and Sp4 and pro-oncogenic Sp-regulated genes. In this study, we investigated the anticancer activity of curcumin and several synthetic cyclohexanone and piperidine analogs in colon cancer cells. Methods The effects of curcumin and synthetic analogs on colon cancer cell proliferation and apoptosis were determined using standardized assays. The changes in Sp proteins and Sp-regulated gene products were analysed by western blots, and real time PCR was used to determine microRNA-27a (miR-27a, miR-20a, miR-17-5p and ZBTB10 and ZBTB4 mRNA expression. Results The IC50 (half-maximal values for growth inhibition (24 hr of colon cancer cells by curcumin and synthetic cyclohexanone and piperidine analogs of curcumin varied from 10 μM for curcumin to 0.7 μM for the most active synthetic piperidine analog RL197, which was used along with curcumin as model agents in this study. Curcumin and RL197 inhibited RKO and SW480 colon cancer cell growth and induced apoptosis, and this was accompanied by downregulation of specificity protein (Sp transcription factors Sp1, Sp3 and Sp4 and Sp-regulated genes including the epidermal growth factor receptor (EGFR, hepatocyte growth factor receptor (c-MET, survivin, bcl-2, cyclin D1 and NFκB (p65 and p50. Curcumin and RL197 also induced reactive oxygen species (ROS, and cotreatment with the antioxidant glutathione significantly attenuated curcumin- and RL197-induced growth inhibition and downregulation of Sp1, Sp3, Sp4 and Sp-regulated genes. The mechanism of curcumin-/RL197-induced repression of Sp transcription factors was ROS-dependent and due to induction of the Sp repressors ZBTB10 and ZBTB4 and downregulation of microRNAs (miR-27a, miR-20a and miR-17-5p that regulate these repressors

Motivational incentives lead to a strong increase in lateral prefrontal activity after self-control exertion.

Science.gov (United States)

Luethi, Matthias S; Friese, Malte; Binder, Julia; Boesiger, Peter; Luechinger, Roger; Rasch, Björn

2016-10-01

Self-control is key to success in life. Initial acts of self-control temporarily impair subsequent self-control performance. Why such self-control failures occur is unclear, with prominent models postulating a loss of a limited resource vs a loss of motivation, respectively. Here, we used functional magnetic resonance imaging to identify the neural correlates of motivation-induced benefits on self-control. Participants initially exerted or did not exert self-control. In a subsequent Stroop task, participants performed worse after exerting self-control, but not if they were motivated to perform well by monetary incentives. On the neural level, having exerted self-control resulted in decreased activation in the left inferior frontal gyrus. Increasing motivation resulted in a particularly strong activation of this area specifically after exerting self-control. Thus, after self-control exertion participants showed more prefrontal neural activity without improving performance beyond baseline level. These findings suggest that impaired performance after self-control exertion may not exclusively be due to a loss of motivation. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Ubiquitin-fusion degradation pathway: A new strategy for inducing CD8 cells specific for mycobacterial HSP65

International Nuclear Information System (INIS)

Shen Jianying; Hisaeda, Hajime; Chou Bin; Yu Qingsheng; Tu Liping; Himeno, Kunisuke

2008-01-01

The ubiquitin-proteasome system (UPS) plays an indispensable role in inducing MHC class I-restricted CD8 + T cells. In this study, we exploited UPS to induce CD8 + T cells specific for mycobacterial HSP65 (mHSP65), one of the leading vaccine candidates against infection with Mycobacterium tuberculosis. A chimeric DNA termed pU-HSP65 encoding a fusion protein between murine ubiquitin and mHSP65 was constructed, and C57BL/6 (B6) mice were immunized with the DNA using gene gun bombardment. Mice immunized with the chimeric DNA acquired potent resistance against challenge with the syngeneic B16F1 melanoma cells transfected with the mHSP65 gene (HSP65/B16F1), compared with those immunized with DNA encoding only mHSP65. Splenocytes from the former group of mice showed a higher grade of cytotoxic activity against HSP65/B16F1 cells and contained a larger number of granzyme B- or IFN-γ-producing CD8 + T cells compared with those from the latter group of mice

Polymeric membranes modulate human keratinocyte differentiation in specific epidermal layers.

Science.gov (United States)

Salerno, Simona; Morelli, Sabrina; Giordano, Francesca; Gordano, Amalia; Bartolo, Loredana De

2016-10-01

In vitro models of human bioengineered skin substitutes are an alternative to animal experimentation for testing the effects and toxicity of drugs, cosmetics and pollutants. For the first time specific and distinct human epidermal strata were engineered by using membranes and keratinocytes. To this purpose, biodegradable membranes of chitosan (CHT), polycaprolactone (PCL) and a polymeric blend of CHT-PCL were prepared by phase-inversion technique and characterized in order to evaluate their morphological, physico-chemical and mechanical properties. The capability of membranes to modulate keratinocyte differentiation inducing specific interactions in epidermal membrane systems was investigated. The overall results demonstrated that the membrane properties strongly influence the cell morpho-functional behaviour of human keratinocytes, modulating their terminal differentiation, with the creation of specific epidermal strata or a fully proliferative epidermal multilayer system. In particular, human keratinocytes adhered on CHT and CHT-PCL membranes, forming the structure of the epidermal top layers, such as the corneum and granulosum strata, characterized by withdrawal or reduction from the cell cycle and cell proliferation. On the PCL membrane, keratinocytes developed an epidermal basal lamina, with high proliferating cells that stratified and migrated over time to form a complete differentiating epidermal multilayer system. Copyright © 2016 Elsevier B.V. All rights reserved.

Doubly excited helium. From strong correlation to chaos

International Nuclear Information System (INIS)

Jiang, Yuhai

2006-03-01

In the present dissertation, the double excitation states of helium including the autoionization decay of these states were studied experimentally and theoretically in a broad energy region, which includes the transition from strong correlation below the low single ionization thresholds (SIT) to the region of quantum chaos at energies very close to the double-ionization threshold. Two kind of experiments were performed, namely total-ion-yield measurements with the aim to observe total cross sections (TCS) and electron time-of-flight (TOF) measurements to obtain partial cross sections (PCS) as well as angular distribution parameters (ADP). Both types of measurements were performed at the third generation synchrotron radiation facility BESSY II in Berlin. The TCSs were recorded up to the SIT I 15 , and they were found to be in in excellent agreement with state-of-the-art complex-rotation calculations performed recently by D. Delande. These experimental and theoretical data on the TCSs were analyzed in order to study quantum chaos in doubly excited helium, and interesting signatures of quantum chaos were found. The TOF technique allowed to measure PCSs and ADPs in the energy regions from I 5 to I 9 and I 7 , respectively. These experimental data provide a critical assessment of theoretical models that can be used to explore the dynamics of strong correlation as well as quantum chaos in helium. In the theoretical part of this dissertation, the n- and l-specific PCSs and ADPs below I 4 were calculated employing the R-matrix method. The present theoretical results agree well with a recent experimental study of l-specific PCSs below I 4 by J.R. Harries et al. An analysis of patterns in the PCSs and ADPs on the basis of the present experimental and theoretical l-specific data allowed to improve the present understanding of autoionization decay dynamics in this two-electron atom. (orig.)

Controlled self-assembly of multiferroic core-shell nanoparticles exhibiting strong magneto-electric effects

Energy Technology Data Exchange (ETDEWEB)

Sreenivasulu, Gollapudi; Hamilton, Sean L.; Lehto, Piper R.; Srinivasan, Gopalan, E-mail: srinivas@oakland.edu [Physics Department, Oakland University, Rochester, Michigan 48309-4401 (United States); Popov, Maksym [Physics Department, Oakland University, Rochester, Michigan 48309-4401 (United States); Radiophysics Department, Taras Shevchenko National University of Kyiv, Kyiv 01601 (Ukraine); Chavez, Ferman A. [Chemistry Department, Oakland University, Rochester, Michigan 48309-4401 (United States)

2014-02-03

Ferromagnetic-ferroelectric composites show strain mediated coupling between the magnetic and electric sub-systems due to magnetostriction and piezoelectric effects associated with the ferroic phases. We have synthesized core-shell multiferroic nano-composites by functionalizing 10–100 nm barium titanate and nickel ferrite nanoparticles with complementary coupling groups and allowing them to self-assemble in the presence of a catalyst. The core-shell structure was confirmed by electron microscopy and magnetic force microscopy. Evidence for strong strain mediated magneto-electric coupling was obtained by static magnetic field induced variations in the permittivity over 16–18 GHz and polarization and by electric field induced by low-frequency ac magnetic fields.

BAF53b, a Neuron-Specific Nucleosome Remodeling Factor, Is Induced after Learning and Facilitates Long-Term Memory Consolidation.

Science.gov (United States)

Yoo, Miran; Choi, Kwang-Yeon; Kim, Jieun; Kim, Mujun; Shim, Jaehoon; Choi, Jun-Hyeok; Cho, Hye-Yeon; Oh, Jung-Pyo; Kim, Hyung-Su; Kaang, Bong-Kiun; Han, Jin-Hee

2017-03-29

Although epigenetic mechanisms of gene expression regulation have recently been implicated in memory consolidation and persistence, the role of nucleosome-remodeling is largely unexplored. Recent studies show that the functional loss of BAF53b, a postmitotic neuron-specific subunit of the BAF nucleosome-remodeling complex, results in the deficit of consolidation of hippocampus-dependent memory and cocaine-associated memory in the rodent brain. However, it is unclear whether BAF53b expression is regulated during memory formation and how BAF53b regulates fear memory in the amygdala, a key brain site for fear memory encoding and storage. To address these questions, we used viral vector approaches to either decrease or increase BAF53b function specifically in the lateral amygdala of adult mice in auditory fear conditioning paradigm. Knockdown of Baf53b before training disrupted long-term memory formation with no effect on short-term memory, basal synaptic transmission, and spine structures. We observed in our qPCR analysis that BAF53b was induced in the lateral amygdala neurons at the late consolidation phase after fear conditioning. Moreover, transient BAF53b overexpression led to persistently enhanced memory formation, which was accompanied by increase in thin-type spine density. Together, our results provide the evidence that BAF53b is induced after learning, and show that such increase of BAF53b level facilitates memory consolidation likely by regulating learning-related spine structural plasticity. SIGNIFICANCE STATEMENT Recent works in the rodent brain begin to link nucleosome remodeling-dependent epigenetic mechanism to memory consolidation. Here we show that BAF53b, an epigenetic factor involved in nucleosome remodeling, is induced in the lateral amygdala neurons at the late phase of consolidation after fear conditioning. Using specific gene knockdown or overexpression approaches, we identify the critical role of BAF53b in the lateral amygdala neurons for

Iterative solutions of nonlinear equations with strongly accretive or strongly pseudocontractive maps

International Nuclear Information System (INIS)

Chidume, C.E.

1994-03-01

Let E be a real q-uniformly smooth Banach space. Suppose T is a strongly pseudo-contractive map with open domain D(T) in E. Suppose further that T has a fixed point in D(T). Under various continuity assumptions on T it is proved that each of the Mann iteration process or the Ishikawa iteration method converges strongly to the unique fixed point of T. Related results deal with iterative solutions of nonlinear operator equations involving strongly accretive maps. Explicit error estimates are also provided. (author). 38 refs

Specific reactions of different striatal neuron types in morphology induced by quinolinic acid in rats.

Directory of Open Access Journals (Sweden)

Qiqi Feng

Full Text Available Huntington's disease (HD is a neurological degenerative disease and quinolinic acid (QA has been used to establish HD model in animals through the mechanism of excitotoxicity. Yet the specific pathological changes and the underlying mechanisms are not fully elucidated. We aimed to reveal the specific morphological changes of different striatal neurons in the HD model. Sprague-Dawley (SD rats were subjected to unilaterally intrastriatal injections of QA to mimic the HD model. Behavioral tests, histochemical and immunhistochemical stainings as well as Western blots were applied in the present study. The results showed that QA-treated rats had obvious motor and cognitive impairments when compared with the control group. Immunohistochemical detection showed a great loss of NeuN+ neurons and Darpp32+ projection neurons in the transition zone in the QA group when compared with the control group. The numbers of parvalbumin (Parv+ and neuropeptide Y (NPY+ interneurons were both significantly reduced while those of calretinin (Cr+ and choline acetyltransferase (ChAT+ were not changed notably in the transition zone in the QA group when compared to the controls. Parv+, NPY+ and ChAT+ interneurons were not significantly increased in fiber density while Cr+ neurons displayed an obvious increase in fiber density in the transition zone in QA-treated rats. The varicosity densities of Parv+, Cr+ and NPY+ interneurons were all raised in the transition zone after QA treatment. In conclusion, the present study revealed that QA induced obvious behavioral changes as well as a general loss of striatal projection neurons and specific morphological changes in different striatal interneurons, which may help further explain the underlying mechanisms and the specific functions of various striatal neurons in the pathological process of HD.

Core OCD Symptoms: Exploration of Specificity and Relations with Psychopathology

Science.gov (United States)

Stasik, Sara M.; Naragon-Gainey, Kristin; Chmielewski, Michael; Watson, David

2012-01-01

Obsessive-compulsive disorder (OCD) is a heterogeneous condition, comprised of multiple symptom domains. This study used aggregate composite scales representing three core OCD dimensions (Checking, Cleaning, Rituals), as well as Hoarding, to examine the discriminant validity, diagnostic specificity, and predictive ability of OCD symptom scales. The core OCD scales demonstrated strong patterns of convergent and discriminant validity – suggesting that these dimensions are distinct from other self-reported symptoms – whereas hoarding symptoms correlated just as strongly with OCD and non-OCD symptoms in most analyses. Across analyses, our results indicated that Checking is a particularly strong, specific marker of OCD diagnosis, whereas the specificity of Cleaning and Hoarding to OCD was less strong. Finally, the OCD Checking scale was the only significant predictor of OCD diagnosis in logistic regression analyses. Results are discussed with regard to the importance of assessing OCD symptom dimensions separately and implications for classification. PMID:23026094

Strong coupling between a single nitrogen-vacancy spin and the rotational mode of diamonds levitating in an ion trap

Science.gov (United States)

Delord, T.; Nicolas, L.; Chassagneux, Y.; Hétet, G.

2017-12-01

A scheme for strong coupling between a single atomic spin and the rotational mode of levitating nanoparticles is proposed. The idea is based on spin readout of nitrogen-vacancy centers embedded in aspherical nanodiamonds levitating in an ion trap. We show that the asymmetry of the diamond induces a rotational confinement in the ion trap. Using a weak homogeneous magnetic field and a strong microwave driving we then demonstrate that the spin of the nitrogen-vacancy center can be strongly coupled to the rotational mode of the diamond.

Radiochemical study of Re/W adsorption behavior on a strongly basic anion exchange resin

International Nuclear Information System (INIS)

Gott, Matthew D.; Missouri Univ., Columbia, MO; Ballard, Beau D.; Redman, Lindsay N.

2014-01-01

Rhenium-186g is a radionuclide with a high potential for therapeutic applications. It emits therapeutic β - particles accompanied by low energy γ-rays, which allows for in-vivo tracking of the radiolabeled compound and dosimetry estimates. The current reactor production pathway 185 Re(n,γ) 186g Re produces low specific activity 186g Re, thereby limiting its therapeutic application. Work is underway to develop an accelerator-based, charged particle induced production method for high specific activity 186g Re from targets of enriched 186 W. To optimize the chemical 186g Re recovery method, batch studies have been performed to characterize the adsorption behavior of Re and W on a strongly basic anion exchange resin. An in-depth physicochemical profile was developed for the interaction of Re with resin material, which showed the reaction to be endothermic and spontaneous. Basic (NaOH) and acidic (HNO 3 ) matrices were used to determine the equilibrium distribution coefficients for Re and W. The resin exhibits the best affinity for Re at slightly basic conditions and little affinity above moderately acidic concentrations. Tungsten has low affinity for the resin above moderately basic concentrations. A study was performed to examine the effect of W concentration on Re adsorption, which showed that even a high ionic WO 4 2- strength of up to 1.9 mol kg -1 does not significantly compromise ReO 4 - retention on the resin. (orig.)

Site specific X-ray induced changes in organic and metal organic compounds and their influence on global radiation damage

International Nuclear Information System (INIS)

Heintz, Desiree Ellen

2012-07-01

The aim of this work was to systematically investigate the effects of specific and global X-ray radiation damage to biological samples and obtain a conclusive model to describe the underlying principles. Based on the systematic studies performed in this work, it was possible to propose two conclusive mechanisms to describe X-ray induced photoreduction and global radiation damage. The influence of chemical composition, temperature and solvent on X-ray induced photoreduction was investigated by X-ray Absorption Near Edge Spectroscopy and single crystal X-ray diffraction of two B12 cofactors - cyano- and methylcobalamin - as well as iron(II) and iron(III) complexes. The obtained results revealed that X-ray induced photoreduction is a ligand dependent process, with a redox reaction taking place within the complex. It could further be shown that selective hydrogen abstraction plays an important role in the process of X-ray induced photoreduction. Based on the experimental results of this work, a model to describe X-ray induced photoreduction of metal organic complexes could be proposed. The process of X-ray induced hydrogen abstraction was further investigated in a combined X-ray and neutron diffraction study on the amino acids L-serine and L-alanine, which were used as model compounds for proteins, and the nucleoside deoxythymidine (thymidine) as a model for DNA. A damage mechanism for L-serine could be found. It involves the abstraction of two hydrogen atoms, one from the hydroxyl group and one from the adjacent methylene group. Such a hydrogen abstraction results in the formation of a carbonyl group. X-ray diffraction measurements on cyano- and methylcobalamin as well as on three metal amino acid complexes, containing nickel(II) and copper(II), respectively, were conducted to investigate the contribution of X-ray induced photoreduction to global radiation damage. Results from these measurements combined with the results from L-serine, L-alanine and thymidine allowed

Site specific X-ray induced changes in organic and metal organic compounds and their influence on global radiation damage

Energy Technology Data Exchange (ETDEWEB)

Heintz, Desiree Ellen

2012-07-15

The aim of this work was to systematically investigate the effects of specific and global X-ray radiation damage to biological samples and obtain a conclusive model to describe the underlying principles. Based on the systematic studies performed in this work, it was possible to propose two conclusive mechanisms to describe X-ray induced photoreduction and global radiation damage. The influence of chemical composition, temperature and solvent on X-ray induced photoreduction was investigated by X-ray Absorption Near Edge Spectroscopy and single crystal X-ray diffraction of two B12 cofactors - cyano- and methylcobalamin - as well as iron(II) and iron(III) complexes. The obtained results revealed that X-ray induced photoreduction is a ligand dependent process, with a redox reaction taking place within the complex. It could further be shown that selective hydrogen abstraction plays an important role in the process of X-ray induced photoreduction. Based on the experimental results of this work, a model to describe X-ray induced photoreduction of metal organic complexes could be proposed. The process of X-ray induced hydrogen abstraction was further investigated in a combined X-ray and neutron diffraction study on the amino acids L-serine and L-alanine, which were used as model compounds for proteins, and the nucleoside deoxythymidine (thymidine) as a model for DNA. A damage mechanism for L-serine could be found. It involves the abstraction of two hydrogen atoms, one from the hydroxyl group and one from the adjacent methylene group. Such a hydrogen abstraction results in the formation of a carbonyl group. X-ray diffraction measurements on cyano- and methylcobalamin as well as on three metal amino acid complexes, containing nickel(II) and copper(II), respectively, were conducted to investigate the contribution of X-ray induced photoreduction to global radiation damage. Results from these measurements combined with the results from L-serine, L-alanine and thymidine allowed

Highly Tissue Substructure-Specific Effects of Human Papilloma Virus in Mucosa of HIV-Infected Patients Revealed by Laser-Dissection Microscopy-Assisted Gene Expression Profiling

Science.gov (United States)

Baumgarth, Nicole; Szubin, Richard; Dolganov, Greg M.; Watnik, Mitchell R.; Greenspan, Deborah; Da Costa, Maria; Palefsky, Joel M.; Jordan, Richard; Roederer, Mario; Greenspan, John S.

2004-01-01

Human papilloma virus (HPV) causes focal infections of epithelial layers in skin and mucosa. HIV-infected patients on highly active antiretroviral therapy (HAART) appear to be at increased risk of developing HPV-induced oral warts. To identify the mechanisms that allow long-term infection of oral epithelial cells in these patients, we used a combination of laser-dissection microscopy (LDM) and highly sensitive and quantitative, non-biased, two-step multiplex real-time RT-PCR to study pathogen-induced alterations of specific tissue subcompartments. Expression of 166 genes was compared in three distinct epithelial and subepithelial compartments isolated from biopsies of normal mucosa from HIV-infected and non-infected patients and of HPV32-induced oral warts from HIV-infected patients. In contrast to the underlying HIV infection and/or HAART, which did not significantly elaborate tissue substructure-specific effects, changes in oral warts were strongly tissue substructure-specific. HPV 32 seems to establish infection by selectively enhancing epithelial cell growth and differentiation in the stratum spinosum and to evade the immune system by actively suppressing inflammatory responses in adjacent underlying tissues. With this highly sensitive and quantitative method tissue-specific expression of hundreds of genes can be studied simultaneously in a few cells. Because of its large dynamic measurement range it could also become a method of choice to confirm and better quantify results obtained by microarray analysis. PMID:15331396

Specific macrophage subtypes influence the progression of rhabdomyolysis-induced kidney injury.

Science.gov (United States)

Belliere, Julie; Casemayou, Audrey; Ducasse, Laure; Zakaroff-Girard, Alexia; Martins, Frédéric; Iacovoni, Jason S; Guilbeau-Frugier, Céline; Buffin-Meyer, Bénédicte; Pipy, Bernard; Chauveau, Dominique; Schanstra, Joost P; Bascands, Jean-Loup

2015-06-01

Rhabdomyolysis can be life threatening if complicated by AKI. Macrophage infiltration has been observed in rat kidneys after glycerol-induced rhabdomyolysis, but the role of macrophages in rhabdomyolysis-induced AKI remains unknown. Here, in a patient diagnosed with rhabdomyolysis, we detected substantial macrophage infiltration in the kidney. In a mouse model of rhabdomyolysis-induced AKI, diverse renal macrophage phenotypes were observed depending on the stage of the disease. Two days after rhabdomyolysis, F4/80(low)CD11b(high)Ly6b(high)CD206(low) kidney macrophages were dominant, whereas by day 8, F4/80(high)CD11b(+)Ly6b(low)CD206(high) cells became the most abundant. Single-cell gene expression analyses of FACS-sorted macrophages revealed that these subpopulations were heterogeneous and that individual cells simultaneously expressed both M1 and M2 markers. Liposomal clodronate-mediated macrophage depletion significantly reduced the early infiltration of F4/80(low)CD11b(high)Ly6b(high)CD206(low) macrophages. Furthermore, transcriptionally regulated targets potentially involved in disease progression, including fibronectin, collagen III, and chemoattractants that were identified via single-cell analysis, were verified as macrophage-dependent in situ. In vitro, myoglobin treatment induced proximal tubular cells to secrete chemoattractants and macrophages to express proinflammatory markers. At day 30, liposomal clodronate-mediated macrophage depletion reduced fibrosis and improved both kidney repair and mouse survival. Seven months after rhabdomyolysis, histologic lesions were still present but were substantially reduced with prior depletion of macrophages. These results suggest an important role for macrophages in rhabdomyolysis-induced AKI progression and advocate the utility of long-term follow-up for patients with this disease. Copyright © 2015 by the American Society of Nephrology.

Immobilization induced osteopenia is strain specific in mice

Directory of Open Access Journals (Sweden)

Andreas Lodberg

2015-06-01

Full Text Available Immobilization causes rapid and massive bone loss. By comparing Botulinum Toxin A (BTX-induced bone loss in mouse strains with different genetic backgrounds we investigated whether the genetic background had an influence on the severity of the osteopenia. Secondly, we investigated whether BTX had systemic effects on bone. Female mice from four inbred mouse strains (BALB/cJ, C57BL/6 J, DBA/2 J, and C3H/HeN were injected unilaterally with BTX (n = 10/group or unilaterally with saline (n = 10/group. Mice were euthanized after 21 days, and the bone properties evaluated using μCT, DXA, bone histomorphometry, and mechanical testing. BTX resulted in substantially lower trabecular bone volume fraction (BV/TV and trabecular thickness in all mouse strains. The deterioration of BV/TV was significantly greater in C57BL/6 J (−57% and DBA/2 J (−60% than in BALB/cJ (−45% and C3H/HeN (−34% mice. The loss of femoral neck fracture strength was significantly greater in C57BL/6 J (−47% and DBA/2 J (−45% than in C3H (−25% mice and likewise the loss of mid-femoral fracture strength was greater in C57BL/6 J (−17%, DBA/2 J (−12%, and BALB/cJ (−9% than in C3H/HeN (−1% mice, which were unaffected. Using high resolution μCT we found no evidence of a systemic effect on any of the microstructural parameters of the contralateral limb. Likewise, there was no evidence of a systemic effect on the bone strength in any mouse strain. We did, however, find a small systemic effect on aBMD in DBA/2 J and C3H/HeN mice. The present study shows that BTX-induced immobilization causes the greatest loss of cortical and trabecular bone in C57BL/6 J and DBA/2 J mice. A smaller loss of bone microstructure and fracture strength was seen in BALB/cJ mice, while the bone microstructure and fracture strength of C3H/HeN mice were markedly less affected. This indicates that BTX-induced loss of bone is mouse strain dependent. We found only minimal systemic

Strong intrinsic motivation

OpenAIRE

Dessi, Roberta; Rustichini, Aldo

2015-01-01

A large literature in psychology, and more recently in economics, has argued that monetary rewards can reduce intrinsic motivation. We investigate whether the negative impact persists when intrinsic motivation is strong, and test this hypothesis experimentally focusing on the motivation to undertake interesting and challenging tasks, informative about individual ability. We find that this type of task can generate strong intrinsic motivation, that is impervious to the effect of monetary incen...

Elongation Factor Tu and Heat Shock Protein 70 Are Membrane-Associated Proteins from Mycoplasma ovipneumoniae Capable of Inducing Strong Immune Response in Mice.

Directory of Open Access Journals (Sweden)

Fei Jiang

Full Text Available Chronic non-progressive pneumonia, a disease that has become a worldwide epidemic has caused considerable loss to sheep industry. Mycoplasma ovipneumoniae (M. ovipneumoniae is the causative agent of interstitial pneumonia in sheep, goat and bighorn. We here have identified by immunogold and immunoblotting that elongation factor Tu (EF-Tu and heat shock protein 70 (HSP 70 are membrane-associated proteins on M. ovipneumonaiea. We have evaluated the humoral and cellular immune responses in vivo by immunizing BALB/c mice with both purified recombinant proteins rEF-Tu and rHSP70. The sera of both rEF-Tu and rHSP70 treated BALB/c mice demonstrated increased levels of IgG, IFN-γ, TNF-α, IL-12(p70, IL-4, IL-5 and IL-6. In addition, ELISPOT assay showed significant increase in IFN-γ+ secreting lymphocytes in the rHSP70 group when compared to other groups. Collectively our study reveals that rHSP70 induces a significantly better cellular immune response in mice, and may act as a Th1 cytokine-like adjuvant in immune response induction. Finally, growth inhibition test (GIT of M. ovipneumoniae strain Y98 showed that sera from rHSP70 or rEF-Tu-immunized mice inhibited in vitro growth of M. ovipneumoniae. Our data strongly suggest that EF-Tu and HSP70 of M. ovipneumoniae are membrane-associated proteins capable of inducing antibody production, and cytokine secretion. Therefore, these two proteins may be potential candidates for vaccine development against M. ovipneumoniae infection in sheep.

X-Ray-Induced Damage to the Submandibular Salivary Glands in Mice: An Analysis of Strain-Specific Responses

Science.gov (United States)

Kamiya, Mana; Kawase, Tomoyuki; Hayama, Kazuhide; Tsuchimochi, Makoto; Okuda, Kazuhiro; Yoshie, Hiromasa

2015-01-01

Abstract Radiation therapy for head and neck cancers often causes xerostomia (dry mouth) by acutely damaging the salivary glands through the induction of severe acute inflammation. By contrast, the mechanism underlying the X-ray-induced delayed salivary dysfunction is unknown and has attracted increasing attention. To identify and develop a mouse model that distinguishes the delayed from the acute effects, we examined three different mouse strains (C57BL/6, ICR, and ICR-nu/nu) that showed distinct T-cell activities to comparatively analyze their responses to X-ray irradiation. Three strains were irradiated with X-rays (25 Gy), and functional changes of the submandibular glands were examined by determining pilocarpine-induced saliva secretion. Structural changes were evaluated using histopathological and immunohistochemical examinations of CD3, cleaved poly (ADP-ribose) polymerase (PARP), and Bcl-xL. In C57BL/6 mice, the X-ray irradiation induced acute inflammation accompanied by severe inflammatory cell infiltration at 4 days postirradiation, causing substantial destruction and significant dysfunction at 2 weeks. Fibrotic repair was observed at 16 weeks. In ICR-nu/nu mice, the inflammation and organ destruction were much milder than in the other mice strains, but increased apoptotic cells and a significant reduction in salivary secretion were observed at 4 and 8 weeks and beyond, respectively. These results suggest that in C57BL/6 mice, X-ray-induced functional and structural damage to the salivary glands is caused mainly by acute inflammation. By contrast, although neither acute inflammation nor organ destruction was observed in ICR-nu/nu mice, apoptotic cell death preceded the dysfunction in salivary secretion in the later phase. These data suggest that the X-ray-irradiated ICR-nu/nu mouse may be a useful animal model for developing more specific therapeutic methods for the delayed dysfunction of salivary glands. PMID:26309806

STRONG FIELD EFFECTS ON PULSAR ARRIVAL TIMES: GENERAL ORIENTATIONS

International Nuclear Information System (INIS)

Wang Yan; Creighton, Teviet; Price, Richard H.; Jenet, Frederick A.

2009-01-01

A pulsar beam passing close to a black hole can provide a probe of very strong gravitational fields even if the pulsar itself is not in a strong field region. In the case that the spin of the hole can be ignored, we have previously shown that all strong field effects on the beam can be understood in terms of two 'universal' functions: F(φ in ) and T(φ in ) of the angle of beam emission φ in ; these functions are universal in that they depend only on a single parameter, the pulsar/black hole distance from which the beam is emitted. Here we apply this formalism to general pulsar-hole-observer geometries, with arbitrary alignment of the pulsar spin axis and arbitrary pulsar beam direction and angular width. We show that the analysis of the observational problem has two distinct elements: (1) the computation of the location and trajectory of an observer-dependent 'keyhole' direction of emission in which a signal can be received by the observer; and (2) the determination of an annulus that represents the set of directions containing beam energy. Examples of each are given along with an example of a specific observational scenario.

Earthquake Intensity and Strong Motion Analysis Within SEISCOMP3

Science.gov (United States)

Becker, J.; Weber, B.; Ghasemi, H.; Cummins, P. R.; Murjaya, J.; Rudyanto, A.; Rößler, D.

2017-12-01

Measuring and predicting ground motion parameters including seismic intensities for earthquakes is crucial and subject to recent research in engineering seismology.gempa has developed the new SIGMA module for Seismic Intensity and Ground Motion Analysis. The module is based on the SeisComP3 framework extending it in the field of seismic hazard assessment and engineering seismology. SIGMA may work with or independently of SeisComP3 by supporting FDSN Web services for importing earthquake or station information and waveforms. It provides a user-friendly and modern graphical interface for semi-automatic and interactive strong motion data processing. SIGMA provides intensity and (P)SA maps based on GMPE's or recorded data. It calculates the most common strong motion parameters, e.g. PGA/PGV/PGD, Arias intensity and duration, Tp, Tm, CAV, SED and Fourier-, power- and response spectra. GMPE's are configurable. Supporting C++ and Python plug-ins, standard and customized GMPE's including the OpenQuake Hazard Library can be easily integrated and compared. Originally tailored to specifications by Geoscience Australia and BMKG (Indonesia) SIGMA has become a popular tool among SeisComP3 users concerned with seismic hazard and strong motion seismology.

Wolbachia-induced cytoplasmic incompatibility is associated with decreased Hira expression in male Drosophila.

Directory of Open Access Journals (Sweden)

Ya Zheng

Full Text Available BACKGROUND: Wolbachia are obligate endosymbiotic bacteria that infect numerous species of arthropods and nematodes. Wolbachia can induce several reproductive phenotypes in their insect hosts including feminization, male-killing, parthenogenesis and cytoplasmic incompatibility (CI. CI is the most common phenotype and occurs when Wolbachia-infected males mate with uninfected females resulting in no or very low numbers of viable offspring. However, matings between males and females infected with the same strain of Wolbachia result in viable progeny. Despite substantial scientific effort, the molecular mechanisms underlying CI are currently unknown. METHODOLOGY/PRINCIPAL FINDINGS: Gene expression studies were undertaken in Drosophila melanogaster and D. simulans which display differential levels of CI using quantitative RT-PCR. We show that Hira expression is correlated with the induction of CI and occurs in a sex-specific manner. Hira expression is significantly lower in males which induce strong CI when compared to males inducing no CI or Wolbachia-uninfected males. A reduction in Hira expression is also observed in 1-day-old males that induce stronger CI compared to 5-day-old males that induce weak or no CI. In addition, Hira mutated D. melanogaster males mated to uninfected females result in significantly decreased hatch rates comparing with uninfected crosses. Interestingly, wMel-infected females may rescue the hatch rates. An obvious CI phenotype with chromatin bridges are observed in the early embryo resulting from Hira mutant fertilization, which strongly mimics the defects associated with CI. CONCLUSIONS/SIGNIFICANCE: Our results suggest Wolbachia-induced CI in Drosophila occurs due to a reduction in Hira expression in Wolbachia-infected males leading to detrimental effects on sperm fertility resulting in embryo lethality. These results may help determine the underlying mechanism of CI and provide further insight in to the important role

Is It Possible to Predict Strong Earthquakes?

Science.gov (United States)

Polyakov, Y. S.; Ryabinin, G. V.; Solovyeva, A. B.; Timashev, S. F.

2015-07-01

The possibility of earthquake prediction is one of the key open questions in modern geophysics. We propose an approach based on the analysis of common short-term candidate precursors (2 weeks to 3 months prior to strong earthquake) with the subsequent processing of brain activity signals generated in specific types of rats (kept in laboratory settings) who reportedly sense an impending earthquake a few days prior to the event. We illustrate the identification of short-term precursors using the groundwater sodium-ion concentration data in the time frame from 2010 to 2014 (a major earthquake occurred on 28 February 2013) recorded at two different sites in the southeastern part of the Kamchatka Peninsula, Russia. The candidate precursors are observed as synchronized peaks in the nonstationarity factors, introduced within the flicker-noise spectroscopy framework for signal processing, for the high-frequency component of both time series. These peaks correspond to the local reorganizations of the underlying geophysical system that are believed to precede strong earthquakes. The rodent brain activity signals are selected as potential "immediate" (up to 2 weeks) deterministic precursors because of the recent scientific reports confirming that rodents sense imminent earthquakes and the population-genetic model of K irshvink (Soc Am 90, 312-323, 2000) showing how a reliable genetic seismic escape response system may have developed over the period of several hundred million years in certain animals. The use of brain activity signals, such as electroencephalograms, in contrast to conventional abnormal animal behavior observations, enables one to apply the standard "input-sensor-response" approach to determine what input signals trigger specific seismic escape brain activity responses.

Anti-idiotypic antibodies against UV-induced tumor-specific CTL clones. Preparation in syngeneic combination

International Nuclear Information System (INIS)

Kuribayashi, K.; Tanaka, C.; Matsubayashi, Y.; Masuda, T.; Udono, H.; Abe, M.; Nakayama, E.; Shiku, H.

1988-01-01

In this study, we first established several CTL clones of (BALB/c x C57BL/6)F1 origin that were specific for either syngeneic UV female 1 or UV male 1 fibrosarcoma cell lines. All the CTL clones had Thy-1+ Lyt-2+ L3T4- phenotypes and showed Kd restriction when lysing the corresponding target cells. Sera obtained from syngeneic animals immunized with three CTL clones, 10B-5 for UV female 1, and CTL9 and CTL10 for UV male 1, showed specific inhibition of target cell lysis with the corresponding CTL clones. The inhibitory activities were found in sera of the majority of immunized animals. Because the inhibitory activity resides in protein A-binding fraction, mAb were produced by hybridizing spleen cells of hyperimmune animals. N1-56 was thus obtained from a mouse immunized with 10B-5 CTL clone reactive with UV female 1. N1-56 was clonotype specific, reacting with 10B-5 but not with other CTL lines or leukemia cell lines. No N1-56+ cells were detectable in thymocytes, lymph node cells, or spleen cells of either naive or UV female 1-immune CB6F1 mice. Immunoprecipitation showed that N1-56 reacts with 90,000 Mr molecules on 10B-5 CTL clone under nonreducing conditions and 45,000 Mr molecules under reducing conditions, indicating its reactivities with idiotypic determinants of TCR on the CTL clone. N1-56 inhibited lytic activity of 10B-5, but neither N1-56 nor alpha-10B-5 hyperimmune serum inhibited that of alpha-UV female 1 mixed lymphocyte tumor cell culture cells. N1-56 induced proliferation of 10B-5 without addition of Ag

Effects of nasal corticosteroids on boosts of systemic allergen-specific IgE production induced by nasal allergen exposure.

Directory of Open Access Journals (Sweden)

Cornelia Egger