3,018 research outputs found
Dimerization-Induced Fermi-Surface Reconstruction in IrTe2
We report a de Haas-van Alphen (dHvA) oscillation study on IrTe2 single crystals showing complex dimer formations. By comparing the angle dependence of dHvA oscillations with band structure calculations, we show distinct Fermi surface reconstruction induced by a 1/5-type and a 1/8-type dimerizations. This verifies that an intriguing quasi-two-dimensional conducting plane across the layers is induced by dimerization in both cases. A phase transition to the 1/8 phase with higher dimer density reveals that local instabilities associated with intra-and interdimer couplings are the main driving force for complex dimer formations in IrTe2.X11149sciescopu
The Goldbeter-Koshland switch in the first-order region and its response to dynamic disorder
In their classical work (Proc. Natl. Acad. Sci. USA, 1981, 78:6840-6844),
Goldbeter and Koshland mathematically analyzed a reversible covalent
modification system which is highly sensitive to the concentration of
effectors. Its signal-response curve appears sigmoidal, constituting a
biochemical switch. However, the switch behavior only emerges in the
"zero-order region", i.e. when the signal molecule concentration is much lower
than that of the substrate it modifies. In this work we showed that the
switching behavior can also occur under comparable concentrations of signals
and substrates, provided that the signal molecules catalyze the modification
reaction in cooperation. We also studied the effect of dynamic disorders on the
proposed biochemical switch, in which the enzymatic reaction rates, instead of
constant, appear as stochastic functions of time. We showed that the system is
robust to dynamic disorder at bulk concentration. But if the dynamic disorder
is quasi-static, large fluctuations of the switch response behavior may be
observed at low concentrations. Such fluctuation is relevant to many biological
functions. It can be reduced by either increasing the conformation
interconversion rate of the protein, or correlating the enzymatic reaction
rates in the network.Comment: 23 pages, 4 figures, accepted by PLOS ON
Activation of Human Stearoyl-Coenzyme A Desaturase 1 Contributes to the Lipogenic Effect of PXR in HepG2 Cells
The pregnane X receptor (PXR) was previously known as a xenobiotic receptor. Several recent studies suggested that PXR also played an important role in lipid homeostasis but the underlying mechanism remains to be clearly defined. In this study, we found that rifampicin, an agonist of human PXR, induced lipid accumulation in HepG2 cells. Lipid analysis showed the total cholesterol level increased. However, the free cholesterol and triglyceride levels were not changed. Treatment of HepG2 cells with rifampicin induced the expression of the free fatty acid transporter CD36 and ABCG1, as well as several lipogenic enzymes, including stearoyl-CoA desaturase-1 (SCD1), long chain free fatty acid elongase (FAE), and lecithin-cholesterol acyltransferase (LCAT), while the expression of acyl:cholesterol acetyltransferase(ACAT1) was not affected. Moreover, in PXR over-expressing HepG2 cells (HepG2-PXR), the SCD1 expression was significantly higher than in HepG2-Vector cells, even in the absence of rifampicin. Down-regulation of PXR by shRNA abolished the rifampicin-induced SCD1 gene expression in HepG2 cells. Promoter analysis showed that the human SCD1 gene promoter is activated by PXR and a novel DR-7 type PXR response element (PXRE) response element was located at -338 bp of the SCD1 gene promoter. Taken together, these results indicated that PXR activation promoted lipid synthesis in HepG2 cells and SCD1 is a novel PXR target gene. © 2013 Zhang et al
The Maximal Inverse Seesaw from Operator and Oscillating Asymmetric Sneutrino Dark Matter
The maximal supersymmetric inverse seesaw mechanism (MSIS)
provides a natural way to relate asymmetric dark matter (ADM) with neutrino
physics. In this paper we point out that, MSIS is a natural outcome if one
dynamically realizes the inverse seesaw mechanism in the next-to minimal
supersymmetric standard model (NMSSM) via the dimension-five operator
, with the NMSSM singlet developing TeV scale VEV; it
slightly violates lepton number due to the suppression by the fundamental scale
, thus preserving maximally. The resulting sneutrino is a
distinguishable ADM candidate, oscillating and favored to have weak scale mass.
A fairly large annihilating cross section of such a heavy ADM is available due
to the presence of singlet.Comment: journal versio
Extracellular Histone-Induced Protein Kinase C Alpha Activation and Troponin Phosphorylation Is a Potential Mechanism of Cardiac Contractility Depression in Sepsis
Reduction in cardiac contractility is common in severe sepsis. However, the pathological mechanism is still not fully understood. Recently it has been found that circulating histones released after extensive immune cell death play important roles in multiple organ injury and disfunction, particularly in cardiomyocyte injury and contractility reduction. How extracellular histones cause cardiac contractility depression is still not fully clear. In this work, using cultured cardiomyocytes and a histone infusion mouse model, we demonstrate that clinically relevant histone concentrations cause significant increases in intracellular calcium concentrations with subsequent activation and enriched localization of calcium-dependent protein kinase C (PKC) α and βII into the myofilament fraction of cardiomyocytes in vitro and in vivo. Furthermore, histones induced dose-dependent phosphorylation of cardiac troponin I (cTnI) at the PKC-regulated phosphorylation residues (S43 and T144) in cultured cardiomyocytes, which was also confirmed in murine cardiomyocytes following intravenous histone injection. Specific inhibitors against PKCα and PKCβII revealed that histone-induced cTnI phosphorylation was mainly mediated by PKCα activation, but not PKCβII. Blocking PKCα also significantly abrogated histone-induced deterioration in peak shortening, duration and the velocity of shortening, and re-lengthening of cardiomyocyte contractility. These in vitro and in vivo findings collectively indicate a potential mechanism of histone-induced cardiomyocyte dysfunction driven by PKCα activation with subsequent enhanced phosphorylation of cTnI. These findings also indicate a potential mechanism of clinical cardiac dysfunction in sepsis and other critical illnesses with high levels of circulating histones, which holds the potential translational benefit to these patients by targeting circulating histones and downstream pathways
Flagellin is a strong vaginal adjuvant of a therapeutic vaccine for genital cancer
Cervical cancer is a high-incidence female cancer most commonly caused by human papilloma virus (HPV) infection of the genital mucosa. Immunotherapy targeting HPV-derived tumor antigens (TAs) has been widely studied in animal models and in patients. Because the female genital tract is a portal for the entry of HPV and a highly compartmentalized system, the development of topical vaginal immunotherapy in an orthotopic cancer model would provide an ideal therapeutic. Thus, we examined whether flagellin, a potent mucosal immunomodulator, could be used as an adjuvant for a topical therapeutic vaccine for female genital cancer. Intravaginal (IVAG) co-administration of the E6/E7 peptides with flagellin resulted in tumor suppression and long-term survival of tumor-bearing mice. In contrast to IVAG vaccination, intranasal (IN) or subcutaneous (SC) immunization did not induce significant tumor suppression in the same model. The vaginal adjuvant effect of the flagellin was completely abolished in Toll-like receptor-5 (TLR5) knock-out mice. IVAG immunization with the E6/E7 peptides plus flagellin induced the accumulation of CD4(+) and CD8(+) cells and the expression of T cell activation-related genes in the draining genital lymph nodes (gLNs). The co-administered flagellin elicited antigen-specific IFN gamma production in the gLNs and spleen. The intravaginally administered flagellin was found in association with CD11c(+) cells in the gLNs. Moreover, after immunization with a flagellin and the E6/E7 peptides, the TLR5 expression in gLN cells was significantly upregulated. These results suggest that flagellin serves as a potent vaginal adjuvant for a therapeutic peptide cancer vaccine through the activation of TLR5 signaling.1166sciescopu
Salmonella typhimurium Suppresses Tumor Growth via the Pro-Inflammatory Cytokine Interleukin-1 beta
Although strains of attenuated Salmonella typhimurium and wild-type Escherichia coli show similar tumor-targeting capacities, only S. typhimurium significantly suppresses tumor growth in mice. The aim of the present study was to examine bacteria-mediated immune responses by conducting comparative analyses of the cytokine profiles and immune cell populations within tumor tissues colonized by E. coli or attenuated Salmonellae. CT26 tumor-bearing mice were treated with two different bacterial strains: S. typhimurium defective in ppGpp synthesis (Delta ppGpp Salmonellae) or wild-type E. coli MG1655. Cytokine profiles and immune cell populations in tumor tissue colonized by these two bacterial strains were examined at two time points based on the pattern of tumor growth after Delta ppGpp Salmonellae treatment: 1) when tumor growth was suppressed ('suppression stage') and 2) when they began to re-grow ('re-growing stage'). The levels of IL-1 beta and TNF-alpha were markedly increased in tumors colonized by Delta ppGpp Salmonellae. This increase was associated with tumor regression; the levels of both IL-1 beta and TNF-alpha returned to normal level when the tumors started to re-grow. To identify the immune cells primarily responsible for Salmonellae-mediated tumor suppression, we examined the major cell types that produce IL-1 beta and TNF-alpha. We found that macrophages and dendritic cells were the main producers of TNF-alpha and IL-1 beta. Inhibiting IL-1 beta production in Salmonellae-treated mice restored tumor growth, whereas tumor growth was suppressed for longer by local administration of recombinant IL-1 beta or TNF-alpha in conjunction with Salmonella therapy. These findings suggested that IL-1 beta and TNF-alpha play important roles in Salmonella-mediated cancer therapy. A better understanding of host immune responses in Salmonella therapy may increase the success of a given drug, particularly when various strategies are combined with bacteriotherapy.111715Ysciescopu
Predicting live birth, preterm and low birth weight infant after in-vitro fertilisation: a prospective study of 144018 treatment cycles
Background
The extent to which baseline couple characteristics affect the probability of live birth and adverse perinatal outcomes after assisted conception is unknown.
Methods and Findings
We utilised the Human Fertilisation and Embryology Authority database to examine the predictors of live birth in all in vitro fertilisation (IVF) cycles undertaken in the UK between 2003 and 2007 (n = 144,018). We examined the potential clinical utility of a validated model that pre-dated the introduction of intracytoplasmic sperm injection (ICSI) as compared to a novel model. For those treatment cycles that resulted in a live singleton birth (n = 24,226), we determined the associates of potential risk factors with preterm birth, low birth weight, and macrosomia. The overall rate of at least one live birth was 23.4 per 100 cycles (95% confidence interval [CI] 23.2–23.7). In multivariable models the odds of at least one live birth decreased with increasing maternal age, increasing duration of infertility, a greater number of previously unsuccessful IVF treatments, use of own oocytes, necessity for a second or third treatment cycle, or if it was not unexplained infertility. The association of own versus donor oocyte with reduced odds of live birth strengthened with increasing age of the mother. A previous IVF live birth increased the odds of future success (OR 1.58, 95% CI 1.46–1.71) more than that of a previous spontaneous live birth (OR 1.19, 95% CI 0.99–1.24); p-value for difference in estimate <0.001. Use of ICSI increased the odds of live birth, and male causes of infertility were associated with reduced odds of live birth only in couples who had not received ICSI. Prediction of live birth was feasible with moderate discrimination and excellent calibration; calibration was markedly improved in the novel compared to the established model. Preterm birth and low birth weight were increased if oocyte donation was required and ICSI was not used. Risk of macrosomia increased with advancing maternal age and a history of previous live births. Infertility due to cervical problems was associated with increased odds of all three outcomes—preterm birth, low birth weight, and macrosomia.
Conclusions
Pending external validation, our results show that couple- and treatment-specific factors can be used to provide infertile couples with an accurate assessment of whether they have low or high risk of a successful outcome following IVF
Top Quarks as a Window to String Resonances
We study the discovery potential of string resonances decaying to
final state at the LHC. We point out that top quark pair production is a
promising and an advantageous channel for studying such resonances, due to
their low Standard Model background and unique kinematics. We study the
invariant mass distribution and angular dependence of the top pair production
cross section via exchanges of string resonances. The mass ratios of these
resonances and the unusual angular distribution may help identify their
fundamental properties and distinguish them from other new physics. We find
that string resonances for a string scale below 4 TeV can be detected via the
channel, either from reconstructing the semi-leptonic
decay or recent techniques in identifying highly boosted tops.Comment: 22 pages, 6 figure
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