200 research outputs found
Quark-hadron duality, axial anomaly and mixing
Interplay between axial anomaly and quark-hadron duality in the presence of
strong mixing is considered. The anomaly sum rule for meson transition form
factors based on the dispersive representation of axial anomaly and
quark-hadron duality in octet channel is analyzed. The comparison of this sum
rule to the experimental data on and mesons transition form
factors shows that the interval of duality in this channel is rather small,
contradicting the usual understanding of quark-hadron duality. The same values
of interval of duality are supported by considering the two-point correlator in
the local duality limit. This contradiction may be resolved by introducing of
some nonperturbative non-OPE correction to the relevant spectral density. The
form and value of this correction are discussed.Comment: 9 pages, 1 figure, reference adde
Two photon decay of the pseudoscalars, the chiral symmetry breaking corrections
The extrapolation of the decay amplitudes of the pseudoscalar mesons into two
photons from the soft meson limit where it is obtained from the axial-anomaly
to the mass shell involves the contribution of the 0^ - continuum. These chiral
symmetry breaking corrections turn out to be large. The effects of these
corrections on the calculated pi ^0 decay rate, on the values of the
singlet-octet mixing angle and on the ratios f_8 / f_pi and f_0 / f_pi are
discussed. The implications for the transition form factors gamma gamma* -->
pseudoscalars are also evaluated and confronted with the available experimental
data.Comment: Computational errors straightened and study of the implications on
the form factors of the transitions gamma gamma* --> pseudoscalars adde
Symmetry preserving regularization with a cutoff
A Lorentz and gauge symmetry preserving regularization method is proposed in
4 dimension based on momentum cutoff. We use the conditions of gauge invariance
or freedom of shift of the loop-momentum to define the evaluation of the terms
carrying Lorentz indices, e.g. proportional to k_{\mu}k_{\nu}. The remaining
scalar integrals are calculated with a four dimensional momentum cutoff. The
finite terms (independent of the cutoff) are unambiguous and agree with the
result of dimensional regularization.Comment: 12 pages, 1 figure, v2 references adde
Expression of excess receptors and negative feedback control of signal pathways are required for rapid activation and prompt cessation of signal transduction
Cellular signal transduction is initiated by the binding of extracellular ligands to membrane receptors. Receptors are often expressed in excess, and cells are activated when a small number of receptors bind ligands. Intracellular signal proteins are act
A Novel ZAP-70 Dependent FRET Based Biosensor Reveals Kinase Activity at both the Immunological Synapse and the Antisynapse
Many hypotheses attempting to explain the speed and sensitivity with which a T-cell discriminates the antigens it encounters include a notion of relative spatial and temporal control of particular biochemical steps involved in the process. An essential step in T-cell receptor (TCR) mediated signalling is the activation of the protein tyrosine kinase ZAP-70. ZAP-70 is recruited to the TCR upon receptor engagement and, once activated, is responsible for the phosphorylation of the protein adaptor, Linker for Activation of T-cells, or LAT. LAT phosphorylation results in the recruitment of a signalosome including PLCγ1, Grb2/SOS, GADS and SLP-76. In order to examine the real time spatial and temporal evolution of ZAP-70 activity following TCR engagement in the immune synapse, we have developed ROZA, a novel FRET-based biosensor whose function is dependent upon ZAP-70 activity. This new probe not only provides a measurement of the kinetics of ZAP-70 activity, but also reveals the subcellular localization of the activity as well. Unexpectedly, ZAP-70 dependent FRET was observed not only at the T-cell -APC interface, but also at the opposite pole of the cell or “antisynapse”
The effects of violence and aggression from parents on child protection workers' personal, family and professional lives
Creative Commons CC-BY: This article is distributed under the terms of the Creative Commons Attribution 3.0 License (http://www.creativecommons.org/licenses/by/3.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).This article presents findings from a survey of the experiences of child protection workers in England when working with parents who exhibit aggression and violence. This work explores the effects on workers in their professional lives, and on themselves and their families in their private lives. The article examines workers’ thoughts and experiences about the effects of parental hostility on workers’ ability to protect children. The article also details workers’ experiences of the nature and effectiveness of training and support in this area. These findings are then examined in the light of the results of an analysis of the literature, including the findings from serious case review (SCR) reports in England (official inquiries into the causes of child deaths where the children are known to social and health services). The majority of the 590 respondents in the survey were social workers (n = 402; 68%), reflecting the fact that case management of child protection cases in the United Kingdom is the responsibility of social workers working in statutory agencies. This article addresses, from a consideration of the secondary analysis and the original research findings from the survey, how individual workers, managers, and agencies can best understand and then respond effectively to aggressive parental behaviors.Peer reviewe
Downregulation of TFPI in breast cancer cells induces tyrosine phosphorylation signaling and increases metastatic growth by stimulating cell motility
<p>Abstract</p> <p>Background</p> <p>Increased hemostatic activity is common in many cancer types and often causes additional complications and even death. Circumstantial evidence suggests that tissue factor pathway inhibitor-1 (TFPI) plays a role in cancer development. We recently reported that downregulation of TFPI inhibited apoptosis in a breast cancer cell line. In this study, we investigated the effects of TFPI on self-sustained growth and motility of these cells, and of another invasive breast cancer cell type (MDA-MB-231).</p> <p>Methods</p> <p>Stable cell lines with TFPI (both α and β) and only TFPIβ downregulated were created using RNA interference technology. We investigated the ability of the transduced cells to grow, when seeded at low densities, and to form colonies, along with metastatic characteristics such as adhesion, migration and invasion.</p> <p>Results</p> <p>Downregulation of TFPI was associated with increased self-sustained cell growth. An increase in cell attachment and spreading was observed to collagen type I, together with elevated levels of integrin α2. Downregulation of TFPI also stimulated migration and invasion of cells, and elevated MMP activity was involved in the increased invasion observed. Surprisingly, equivalent results were observed when TFPIβ was downregulated, revealing a novel function of this isoform in cancer metastasis.</p> <p>Conclusions</p> <p>Our results suggest an anti-metastatic effect of TFPI and may provide a novel therapeutic approach in cancer.</p
Signaling Signatures and Functional Properties of Anti-Human CD28 Superagonistic Antibodies
Superagonistic CD28 antibodies (CD28SAs) activate T lymphocytes without concomitant perturbation of the TCR/CD3-complex. In rodents these reagents induce the preferential expansion of regulatory T cells and can be used for the treatment of autoimmune diseases. Unexpectedly, the humanized CD28 superagonist TGN1412 caused severe and life threatening adverse effects during a recently conducted phase I clinical trail. The underlying molecular mechanisms are as yet unclear. We show that TGN1412 as well as the commercially available CD28 superagonist ANC28.1 induce a delayed but extremely sustained calcium response in human naïve and memory CD4+ T cells but not in cynomolgus T lymphocytes. The sustained Ca++-signal was associated with the activation of multiple intracellular signaling pathways and together these events culminated in the rapid de novo synthesis of high amounts of pro-inflammatory cytokines, most notably IFN-γ and TNF-α. Importantly, sustained transmembranous calcium flux, activation of Src-kinases as well as activation of PI3K were found to be absolutely required for CD28SA-mediated production of IFN-γ and IL-2. Collectively, our data suggest a molecular basis for the severe side effects caused by TGN1412 and impinge upon the relevance of non-human primates as preclinical models for reagents that are supposed to modify the function of human T cells
Genetic and Physical Interactions between Tel2 and the Med15 Mediator Subunit in Saccharomyces cerevisiae
International audienceBACKGROUND: In budding yeast, the highly conserved Tel2 protein is part of several complexes and its main function is now believed to be in the biogenesis of phosphatidyl inositol 3-kinase related kinases. PRINCIPAL FINDINGS: To uncover potentially novel functions of Tel2, we set out to isolate temperature-sensitive (ts) mutant alleles of TEL2 in order to perform genetic screenings. MED15/GAL11, a subunit of Mediator, a general regulator of transcription, was isolated as a suppressor of these mutants. The isolated tel2 mutants exhibited a short telomere phenotype that was partially rescued by MED15/GAL11 overexpression. The tel2-15 mutant was markedly deficient in the transcription of EST2, coding for the catalytic subunit of telomerase, potentially explaining the short telomere phenotype of this mutant. In parallel, a two-hybrid screen identified an association between Tel2 and Rvb2, a highly conserved member of the AAA+ family of ATPases further found by in vivo co-immunoprecipitation to be tight and constitutive. Transiently overproduced Tel2 and Med15/Gal11 associated together, suggesting a potential role for Tel2 in transcription. Other Mediator subunits, as well as SUA7/TFIIB, also rescued the tel2-ts mutants. SIGNIFICANCE: Altogether, the present data suggest the existence of a novel role for Tel2, namely in transcription, possibly in cooperation with Rvb2 and involving the existence of physical interactions with the Med15/Gal11 Mediator subunit
Increased Membrane Cholesterol in Lymphocytes Diverts T-Cells toward an Inflammatory Response
Cell signaling for T-cell growth, differentiation, and apoptosis is initiated in the cholesterol-rich microdomains of the plasma membrane known as lipid rafts. Herein, we investigated whether enrichment of membrane cholesterol in lipid rafts affects antigen-specific CD4 T-helper cell functions. Enrichment of membrane cholesterol by 40–50% following squalene administration in mice was paralleled by an increased number of resting CD4 T helper cells in periphery. We also observed sensitization of the Th1 differentiation machinery through co-localization of IL-2Rα, IL-4Rα, and IL-12Rβ2 subunits with GM1 positive lipid rafts, and increased STAT-4 and STAT-5 phosphorylation following membrane cholesterol enrichment. Antigen stimulation or CD3/CD28 polyclonal stimulation of membrane cholesterol-enriched, resting CD4 T-cells followed a path of Th1 differentiation, which was more vigorous in the presence of increased IL-12 secretion by APCs enriched in membrane cholesterol. Enrichment of membrane cholesterol in antigen-specific, autoimmune Th1 cells fostered their organ-specific reactivity, as confirmed in an autoimmune mouse model for diabetes. However, membrane cholesterol enrichment in CD4+
Foxp3+ T-reg cells did not alter their suppressogenic function. These findings revealed a differential regulatory effect of membrane cholesterol on the function of CD4 T-cell subsets. This first suggests that membrane cholesterol could be a new therapeutic target to modulate the immune functions, and second that increased membrane cholesterol in various physiopathological conditions may bias the immune system toward an inflammatory Th1 type response
- …