Temporal Regulation of Rapamycin on Memory CTL Programming by IL-12

Mammalian target of rapamycin (mTOR) is a master regulator of cell growth. Recent reports have defined its important role in memory cytotoxic T lymphocyte (CTL) differentiation in infections and memory programming. We report that rapamycin regulated memory CTL programming by IL-12 to a similar level in a wide range of concentrations, and the enhanced memory CTLs by rapamycin were functional and provided similar protection against Listeria Monocytogenes challenge compared to the control. In addition, rapamycin-experienced CTLs went through substantially enhanced proliferation after transfer into recipients. Furthermore, the regulatory function of rapamycin on CD62L expression in memory CTLs was mainly contributed by the presence of rapamycin in the first 24-hr of stimulation in vitro, whereas the effective window of rapamycin on the size of memory CTLs was determined between 24 to 72 hrs. In conclusion, rapamycin regulates IL-12-driven programming of CTLs to a similar level in a wide range of concentrations, and regulates the phenotype and the size of memory CTLs in different temporal windows

Direct and indirect interactions between ants ( Pheidole megacephala ), scales ( Coccus viridis ) and plants ( Pluchea indica )

This study investigated direct and indirect interactions between the ant, Pheidole megacephala (Fabr.), the green scale, Coccus viridis (Green), and the scale's host plant, Pluchea indica (L.). To examine the influence of ants on scales and host plants, scale population densities, scale mortality rates, and plant performance were studied on control host plants with ants and host plants from which ants had been removed. Plants with ants present had significantly greater scale population densities and scale reproductive rates than did plants without ants. Scale mortality from both parasitism and other causes was increased on plants without ants relative to plants with ants. Predator introduction experiments showed that P. megacephala removes predatory coccinellid larvae, even when they are covered with a protective coating. Host plants from which ants had been removed had significantly higher degrees of honeydew accumulation, which resulted in greater colonization by sooty mold and greater rates of leaf death and abscission. Ants also removed herbivorous lepidopteran larvae from plants. Results are discussed in terms of the potential of P. megacephala to exert direct and indirect positive effects on scale populations and an indirect positive effect on Pluchea indica .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47790/1/442_2004_Article_BF00325261.pd

Pioglitazone administration alters ovarian gene expression in aging obese lethal yellow mice

<p>Abstract</p> <p>Background</p> <p>Women with polycystic ovary syndrome (PCOS) are often treated with insulin-sensitizing agents, e.g. thiazolidinediones (TZD), which have been shown to reduce androgen levels and improved ovulatory function. Acting via peroxisome proliferator-activated receptor (PPAR) gamma, TZD alter the expression of a large variety of genes. Lethal yellow (LY; C57BL/6J Ay/a) mice, possessing a mutation (Ay) in the agouti gene locus, exhibit progressive obesity, reproductive dysfunction, and altered metabolic regulation similar to women with PCOS. The current study was designed to test the hypothesis that prolonged treatment of aging LY mice with the TZD, pioglitazone, alters the ovarian expression of genes that may impact reproduction.</p> <p>Methods</p> <p>Female LY mice received daily oral doses of either 0.01 mg pioglitazone (n = 4) or an equal volume of vehicle (DMSO; n = 4) for 8 weeks. At the end of treatment, ovaries were removed and DNA microarrays were used to analyze differential gene expression.</p> <p>Results</p> <p>Twenty-seven genes showed at least a two-fold difference in ovarian expression with pioglitazone treatment. These included leptin, angiopoietin, angiopoietin-like 4, Foxa3, PGE1 receptor, resistin-like molecule-alpha (RELM), and actin-related protein 6 homolog (ARP6). For most altered genes, pioglitazone changed levels of expression to those seen in untreated C57BL/6J(a/a) non-mutant lean mice.</p> <p>Conclusion</p> <p>TZD administration may influence ovarian function via numerous diverse mechanisms that may or may not be directly related to insulin/IGF signaling.</p

Temperature- and Touch-Sensitive Neurons Couple CNG and TRPV Channel Activities to Control Heat Avoidance in Caenorhabditis elegans

Background: Any organism depends on its ability to sense temperature and avoid noxious heat. The nematode Caenorhabditis elegans responds to noxious temperatures exceeding,35uC and also senses changes in its environmental temperature in the range between 15 and 25uC. The neural circuits and molecular mechanisms involved in thermotaxis have been successfully studied, whereas details of the thermal avoidance behavior remain elusive. In this work, we investigate neurological and molecular aspects of thermonociception using genetic, cell biological and physiological approaches. Methodology/Principal Findings: We show here that the thermosensory neurons AFD, in addition to sensing temperature within the range within which the animals can thrive, also contribute to the sensation of noxious temperatures resulting in a reflex-like escape reaction. Distinct sets of interneurons are involved in transmitting thermonociception and thermotaxis, respectively. Loss of AFD is partially compensated by the activity of a pair of multidendritic, polymodal neurons, FLP, whereas laser ablation of both types of neurons abrogated the heat response in the head of the animals almost completely. A third pair of heat sensory neurons, PHC, is situated in the tail. We find that the thermal avoidance response requires the cell autonomous function of cGMP dependent Cyclic Nucleotide-Gated (CNG) channels in AFD, and the heat- and capsaicinsensitive Transient Receptor Potential Vanilloid (TRPV) channels in the FLP and PHC sensory neurons. Conclusions/Significance: Our results identify distinct thermal responses mediated by a single neuron, but also show tha

Functional Polymorphism of the Mu-Opioid Receptor Gene (OPRM1) Influences Reinforcement Learning in Humans

Previous reports on the functional effects (i.e., gain or loss of function), and phenotypic outcomes (e.g., changes in addiction vulnerability and stress response) of a commonly occurring functional single nucleotide polymorphism (SNP) of the mu-opioid receptor (OPRM1 A118G) have been inconsistent. Here we examine the effect of this polymorphism on implicit reward learning. We used a probabilistic signal detection task to determine whether this polymorphism impacts response bias to monetary reward in 63 healthy adult subjects: 51 AA homozygotes and 12 G allele carriers. OPRM1 AA homozygotes exhibited typical responding to the rewarded response—that is, their bias to the rewarded stimulus increased over time. However, OPRM1 G allele carriers exhibited a decline in response to the rewarded stimulus compared to the AA homozygotes. These results extend previous reports on the heritability of performance on this task by implicating a specific polymorphism. Through comparison with other studies using this task, we suggest a possible mechanism by which the OPRM1 polymorphism may confer reduced response to natural reward through a dopamine-mediated decrease during positive reinforcement learning

Synergistic effects of various Her inhibitors in combination with IGF-1R, C-MET and Src targeting agents in breast cancer cell lines

Introduction: Overexpression of the receptor tyrosine kinase HER2 has been reported in around 25% of human breast cancers, usually indicating a poor prognosis. As a result, HER2 has become a popular target for therapy. However, despite recent advances in HER2 targeted therapy, many patients still experience primary and secondary resistance to such treatments. It is therefore important to understand the underlying mechanism of resistance and to develop more effective therapeutic interventions for breast cancer. Methods: The sensitivity of a panel of seven breast cancer cell lines to treatment with various types HER-family inhibitors alone, or in combination with a selection of other tyrosine kinase inhibitors (TKIs) or chemotherapeutic agents was determined using the Sulforhodamine B colorimetric assay. Receptor expression, cell-cycle distribution, cell signalling and cell migration were determined using flow cytometry, Western blot and Incucyte Zoom Live-Cell Analysis System respectively. Results: Overall, breast cancer cells were more sensitive to treatment with the irreversible pan-HER family inhibitors, particularly afatinib and neratinib, than treatment with the first-generation reversible inhibitors. Of three HER-2 overexpressing cell lines in this panel, SKBr3 and BT474 were highly sensitive to treatment with HER-family inhibitors (IC50s as low as 3 nM), while MDA-MB-453 was relatively resistant (lowest IC50 = 0.11 μM). When the HER-family inhibitors were combined with other agents such as NVP-AEW541 (an IGF-1R inhibitor), dasatinib (a Src inhibitor) or crizotinib (a c-Met/ALK inhibitor), such combination produced synergistic effects in some of the cell lines examined. Interestingly, co-targeting of Src and HER-family members in MDA-MB-453 cells led to synergistic growth inhibition, suggesting the importance of Src in mediating resistance to HER2-targeting agents. Finally, treatment with the irreversible HER family blockers and dasatinib were also most effective at inhibiting the migration of breast cancer cells. Conclusion: We concluded that the irreversible inhibitors of HER-family members are generally more effective at inhibiting growth, downstream signalling and migration compared with reversible inhibitors, and that combining HER-family inhibitors with other TKIs such as dasatinib may have therapeutic advantages in certain breast cancer subtypes and warrants further investigation

Common European Sales Law (CESL) and Private International Law: Some Critical Remarks

This article is an updated and revised version of the contribution published by the author in XI Anuario Español de Derecho Internacional Privado, 2011, 25-61, under the title: “La Propuesta de Reglamento relativo a una normativa común de compraventa europea y el Derecho internacional privado”.La Propuesta de Reglamento del Parlamento Europeo y del Consejo relativo a una normativa común de compraventa europea de 11 de octubre de 2011 (PCESL) introduce una reglamentación material para algunas compraventas transfronterizas que no desplaza la aplicación de las normas de conflicto (en particular de las contenidas de los Reglamentos “Roma I” y “Roma II”). Al contrario, el instrumento opcional contenido en la Propuesta de Reglamento (CESL) presupone la aplicación de la ley de un Estado miembro, como lex contractus. Una vez escogida por las partes, la CESL desplaza a las normas internas cobre compraventa de la ley del Estado miembro. Esta opción del legislador comunitario plantea numerosos problemas e interrogantes acerca de las relaciones entre la CESL y las normas de Derecho internacional privado y en torno a su coexistencia con otros convenios internacionales y el propio acervo comunitario. El análisis de estas relaciones es el objeto del presente estudio, que permite concluir con una valoración negativa de la competitividad internacional de este nuevo instrumento comunitario.The Proposal for a Regulation of the European Parliament and of the Council on a Common European Sales Law of 11 October 2011 (PCESL) introduces a substantive regulation for some cross-border sales contracts that does not displace the application of conflict-of-laws rules (especially those included in “Rome I” and “Rome II” Regulations). On the contrary, the optional instrument included in the Proposal (CESL) presupposes the application of the law of a Member State as lex contractus. Once the parties have chosen the CESL, this regime prevails over the internal rules on sales contracts of the law of that Member State. The formula used by the European legislator gives rise to many concerns and questions about the relationships between the CESL and the conflict-of-laws rules and about its cohabitation with other international conventions and the European acquis itself. The analysis of these relationships is the subject of this article, which concludes with a negative assessment on the international competitiveness of the new European instrument

Plasma CCN2/connective tissue growth factor is associated with right ventricular dysfunction in patients with neuroendocrine tumors

<p>Abstract</p> <p>Background</p> <p>Carcinoid heart disease, a known complication of neuroendocrine tumors, is characterized by right heart fibrotic lesions. Carcinoid heart disease has traditionally been defined by the degree of valvular involvement. Right ventricular (RV) dysfunction due to mural involvement may also be a manifestation. Connective tissue growth factor (CCN2) is elevated in many fibrotic disorders. Its role in carcinoid heart disease is unknown. We sought to investigate the relationship between plasma CCN2 and valvular and mural involvement in carcinoid heart disease.</p> <p>Methods</p> <p>Echocardiography was performed in 69 patients with neuroendocrine tumors. RV function was assessed using tissue Doppler analysis of myocardial systolic strain. Plasma CCN2 was analyzed using an enzyme-linked immunosorbent assay. Mann-Whitney U, Kruskal-Wallis, Chi-squared and Fisher's exact tests were used to compare groups where appropriate. Linear regression was used to evaluate correlation.</p> <p>Results</p> <p>Mean strain was -21% ± 5. Thirty-three patients had reduced RV function (strain > -20%, mean -16% ± 3). Of these, 8 had no or minimal tricuspid and/or pulmonary regurgitation (TR/PR). Thirty-six patients had normal or mildly reduced RV function (strain ≤ -20%, mean -25% ± 3). There was a significant inverse correlation between RV function and plasma CCN2 levels (r = 0.47, p < 0.001). Patients with reduced RV function had higher plasma CCN2 levels than those with normal or mildly reduced RV function (p < 0.001). Plasma CCN2 ≥ 77 μg/L was an independent predictor of reduced RV function (odds ratio 15.36 [95% CI 4.15;56.86]) and had 88% sensitivity and 69% specificity for its detection (p < 0.001). Plasma CCN2 was elevated in patients with mild or greater TR/PR compared to those with no or minimal TR/PR (p = 0.008), with the highest levels seen in moderate to severe TR/PR (p = 0.03).</p> <p>Conclusions</p> <p>Elevated plasma CCN2 levels are associated with RV dysfunction and valvular regurgitation in NET patients. CCN2 may play a role in neuroendocrine tumor-related cardiac fibrosis and may serve as a marker of its earliest stages.</p