The subcellular fractionation properties and function of insulin receptor substrate-1 (IRS-1) are independent of cytoskeletal integrity

Efficient insulin action requires spatial and temporal coordination of signaling cascades. The prototypical insulin receptor substrate, IRS-1 plays a central role in insulin signaling. By subcellular fractionation IRS-1 is enriched in a particulate fraction, termed the high speed pellet (HSP), and its redistribution from this fraction is associated with signal attenuation and insulin resistance. Anecdotal evidence suggests the cytoskeleton may underpin the localization of IRS-1 to the HSP. In the present study we have taken a systematic approach to examine whether the cytoskeleton contributes to the subcellular fractionation properties and function of IRS-1. By standard microscopy or immunoprecipitation we were unable to detect evidence to support a specific interaction between IRS-1 and the major cytoskeletal components actin (microfilaments), vimentin (intermediate filaments), and tubulin (microtubules) in 3T3-L1 adipocytes or in CHO.IR.IRS-1 cells. Pharmacological disruption of microfilaments and microtubules, individually or in combination, was without effect on the subcellular distribution of IRS-1 or insulin-stimulated tyrosine phosphorylation in either cell type. Phosphorylation of Akt was modestly reduced (20-35%) in 3T3-L1 adipocytes but not in CHO.IR.IRS-1 cells. In cells lacking intermediate filaments (Vim(-/-)) IRS-1 expression, distribution and insulin-stimulated phosphorylation appeared normal. Even after depolymerisation of microfilaments and microtubules, insulin-stimulated phosphorylation of IRS-1 and Akt were maintained in Vim-/- cells. Taken together these data indicate that the characteristic subcellular fractionation properties and function of IRS-1 are unlikely to be mediated by cytoskeletal networks and that proximal insulin signaling does not require an intact cytoskeleton. (c) 2006 Elsevier Ltd. All rights reserved.

IRS Looks Closely at Independent Contractors

The IRS is using various tools to attack the status of various so-called 'outside consultants" being used by hospitality firms. This article will provide some planning tips so that the hospitality firm can minimize its chances of having workers reclassified as employees.

The IRS Collection Division: Contacts and Settlements

In his study -The IRS Collection Division: Contacts and Settlements - by John M. Tarras, Assistant Professor School of Hotel, Restaurant and Institutional Management, Michigan State University, Tarras initially states: “The collection division of the internal revenue service is often the point of contact for many hospitality businesses. The author describes how the division operates, what the hospitality firm can expect when contacted by it, and what types of strategies firms might find helpful when negotiating a settlement with the IRS.” The author will have you know that even though most chance meetings with the IRS Collection Division are due to unfortunate tax payment circumstances, there are actually more benign reasons for close encounters of the IRS kind. This does not mean, however, that brushes with the IRS Collection Division will end on an ever friendlier note. “…the Tax Reform Act of 1986 with its added complexity will cause some hospitality firms to inadvertently fail to make proper payments on a timely basis,” Tarras affords in illustrating a perhaps less pugnacious side of IRS relations. Should a hospitality business owner represent himself/herself before the IRS? Never, says Tarras. “Too many taxpayers ruin their chances of a fair settlement by making what to them seem innocent remarks, but ones that turn out to be far different,” warns Professor Tarras. Tarras makes the distinction between IRS the Collection Division, and IRS the Audit Division. “While the Audit Division is interested in how the tax liability arose, the Collection Division is generally only interested in collecting the liability,” he informs you. Either sounds firmly in hostile territory. They don’t bluff. Tarras does want you to know that when the IRS threatens to levy on the assets of a hospitality business, they will do so. Those assets may extend to personal and real property as well, he says. The levy action is generally the final resort in an IRS collection effort. Professor Tarras explains the lien process and the due process attached to that IRS collection tactic. “The IRS can also levy a hospitality firm owner's wages. In this case, it is important to realize that you are allowed to exempt from levy $75 per week, along with $25 per week for each of your dependents (unless your spouse works),” Professor Tarras says with the appropriate citation. What are the options available to the hospitality business owner who finds himself on the wrong side of the IRS Collection Division? Negotiate in good faith says Professor Tarras. “In many cases, a visit to the IRS office will greatly reduce the chances that a simple problem will turn into a major one,” Tarras advises. He dedicates the last pages of the discussion to negotiation strategies.

Local luminous infrared galaxies: Spatially resolved mid-infrared observations with Spitzer/IRS

Luminous Infrared (IR) Galaxies (LIRGs, L_IR=10^11-10 L_⨀) are an important cosmological class of galaxies as they are the main contributors to the co-moving star formation rate density of the universe at z=1. In this paper we present a guaranteed time observation (GTO) Spitzer InfraRed Spectrograph (IRS) program aimed to obtain spectral mapping of a sample of 14 local d<76Mpc LIRGs. The data cubes map, at least, the central 20arcsec X 20arcsec to 30 arcsec X 30 arcsec regions of the galaxies, and use all four IRS modules covering the full 5-38 μ m spectral range. The final goal of this project is to characterize fully the mid-IR properties of local LIRGs as a first step to understanding their more distant counterparts. In this paper we present the first results of this GTO program. The IRS spectral mapping data allow us to build spectral maps of the bright mid-IR emission lines (e.g., [Ne II] 12.81 μ m, [Ne III]15.56 μ m, [S III] 18.71 μ m, H_2 at 17 μ m), continuum, the 6.2 and 11.3 μ m polycyclic aromatic hydrocarbon (PAH) features, and the 9.7 μ m silicate feature, as well as to extract 1D spectra for regions of interest in each galaxy. The IRS data are used to obtain spatially resolved measurements of the extinction using the 9.7 μ m silicate feature, and to trace star forming regions using the neon lines and the PAH features. We also investigate a number of active galactic nuclei (AGN) indicators, including the presence of high excitation emission lines and a strong dust continuum emission at around 6 9.7 μ m . We finally use the integrated Spitzer/IRS spectra as templates of local LIRGs. We discuss several possible uses for these templates, including the calibration of the star formation rate of IR-bright galaxies at high redshift. We also predict the intensities of the brightest mid-IR emission lines for LIRGs as a function of redshift, and compare them with the expected sensitivities of future space IR missions.

Response toolkit to provide an active response against intrusions using Ontology-Based IRS

Los sistemas de respuesta activa tienen por objetivo ejecutar una respuesta en contra de una intrusión de forma automática. Sin embargo, ejecutar una respuesta automáticamente no es una tarea trivial ya que el costo de ejecutar una respuesta podría ser más grande que el efecto que cause la intrusión propiamente dicha. También, el sistema debe contar con un amplio conjunto de acciones de respuesta y un algoritmo que seleccione la respuesta óptima. Este artículo propone un toolkit de respuestas que será integrado a un IRS basado en Ontologías para permitir la ejecución automática de la mejor respuesta cuando una intrusión es detectada. Se presenta un conjunto de respuestas basadas en host y basadas en red que pueden ser ejecutadas por el IRS, dicha ejecución es llevada a cabo mediante agentes basados en plugins que han sido distribuidos en la red. Finalmente, se realiza la verificación del sistema propuesto, tomando como caso de uso un ataque de defacement obteniéndose resultados satisfactorios.

A tributação dos trabalhadores destacados em sede de IRS e Segurança Social

O presente trabalho incide sobre a tributação (IRS e Segurança Social) dos trabalhadores destacados por uma empresa portuguesa a fim de exercerem a sua atividade num país estrangeiro. O destacamento de trabalhadores é um fenómeno cada vez maior, devido ao cotexto económico e social em que Portugal se encontra, pois as empresas portuguesas estão a expandir-se e a apostar nos mercados internacionais e consequentemente cresce a mobilidade de mão-de-obra para os territórios onde as empresas investem. É nesta conjuntura que se torna crucial abordar os vários cenários fiscais em que os trabalhadores destacados se podem enquadrar. Ou seja, há necessidade de entender como é o seu enquadramento fiscal no país de origem (Portugal) e no país de destino, onde devem efetuar as contribuições para a Segurança Social, onde estes trabalhadores de enquadram como residentes e naturalmente onde possuem as suas obrigações fiscais. Neste âmbito é feito um enquadramento fiscal de forma a abordar os diversos temas que envolvem esta questão, bem como todas as matérias ao nível de Segurança Social que estão relacionadas. Numa perspetiva prática e objetiva, são analisadas as disposições legais em matéria de tributação do trabalhado dependente e de Segurança Social, utilizando para isso três países como exemplo (Reino Unido, Brasil e Angola).

How do retailers from emerging markets internationalize? : The case of Chilean retailers

This paper explores how retail firms from emerging markets internationalize and compete with multinational retailers from developed markets. Drawing on interviews with company managers, industry data and corporate reports, this paper provides insights into the successful internationalization process of two Chilean retailers in the Latin American region.

Urban growth monitoring techniques for sustainable development

This paper discusses the role of advance techniques for monitoring urban growth and change for sustainable development of urban environment. It also presents results of a case study involving satellite data for land use/land cover classification of Lucknow city using IRS-1C multi-spectral features. Two classification algorithms have been used in the study. Experiments were conducted to see the level of improvement in digital classification of urban environment using Artificial Neural Network (ANN) technique.

Insulin-like growth factor-i : vitronectin complex-induced changes in gene expression effect breast cell survival and migration

Recent studies have demonstrated that IGF-I associates with VN through IGF-binding proteins (IGFBP) which in turn modulate IGF-stimulated biological functions such as cell proliferation, attachment and migration. Since IGFs play important roles in transformation and progression of breast tumours, we aimed to describe the effects of IGF-I:IGFBP:VN complexes on breast cell function and to dissect mechanisms underlying these responses. In this study we demonstrate that substrate-bound IGF-I:IGFBP:VN complexes are potent stimulators of MCF-7 breast cell survival, which is mediated by a transient activation of ERK/MAPK and sustained activation of PI3-K/AKT pathways. Furthermore, use of pharmacological inhibitors of the MAPK and PI3-K pathways confirms that both pathways are involved in IGF-I:IGFBP:VN complex-mediated increased cell survival. Microarray analysis of cells stimulated to migrate in response to IGF-I:IGFBP:VN complexes identified differential expression of genes with previously reported roles in migration, invasion and survival (Ephrin-B2, Sharp-2, Tissue-factor, Stratifin, PAI-1, IRS-1). These changes were not detected when the IGF-I analogue (\[L24]\[A31]-IGF-I), which fails to bind to the IGF-I receptor, was substituted; confirming the IGF-I-dependent differential expression of genes associated with enhanced cell migration. Taken together, these studies have established that IGF-I:IGFBP:VN complexes enhance breast cell migration and survival, processes central to facilitating metastasis. This study highlights the interdependence of ECM and growth factor interactions in biological functions critical for metastasis and identifies potential novel therapeutic targets directed at preventing breast cancer progression.

Insulin increases De Novo Steroidogenesis in prostate cancer cells

Androgen-dependent pathways regulate maintenance and growth of normal and malignant prostate tissues. Androgen deprivation therapy (ADT) exploits this dependence and is used to treat metastatic prostate cancer; however, regression initially seen with ADT gives way to development of incurable castration-resistant prostate cancer (CRPC). Although ADT generates a therapeutic response, it is also associated with a pattern of metabolic alterations consistent with metabolic syndrome including elevated circulating insulin. Because CRPC cells are capable of synthesizing androgens de novo, we hypothesized that insulin may also influence steroidogenesis in CRPC. In this study, we examined this hypothesis by evaluating the effect of insulin on steroid synthesis in prostate cancer cell lines. Treatment with 10 nmol/L insulin increased mRNA and protein expression of steroidogenesis enzymes and upregulated the insulin receptor substrate insulin receptor substrate 2 (IRS-2). Similarly, insulin treatment upregulated intracellular testosterone levels and secreted androgens, with the concentrations of steroids observed similar to the levels reported in prostate cancer patients. With similar potency to dihydrotestosterone, insulin treatment resulted in increased mRNA expression of prostate-specific antigen. CRPC progression also correlated with increased expression of IRS-2 and insulin receptor in vivo. Taken together, our findings support the hypothesis that the elevated insulin levels associated with therapeutic castration may exacerbate progression of prostate cancer to incurable CRPC in part by enhancing steroidogenesis.

IGF2 increases de novo steroidogenesis in prostate cancer cells

Androgen-dependent pathways regulate maintenance and growth of normal and malignant prostate tissues. Androgen deprivation therapy (ADT) exploits this dependence and is used to treat metastatic prostate cancer; however, regression initially seen with ADT gives way to development of incurable castration-resistant prostate cancer (CRPC). Although ADT generates a therapeutic response, it is also associated with a pattern of metabolic alterations consistent with metabolic syndrome including elevated circulating insulin. Because CRPC cells are capable of synthesizing androgens de novo, we hypothesized that insulin may also influence steroidogenesis in CRPC. In this study, we examined this hypothesis by evaluating the effect of insulin on steroid synthesis in prostate cancer cell lines. Treatment with 10 nmol/L insulin increased mRNA and protein expression of steroidogenesis enzymes and upregulated the insulin receptor substrate insulin receptor substrate 2 (IRS-2). Similarly, insulin treatment upregulated intracellular testosterone levels and secreted androgens, with the concentrations of steroids observed similar to the levels reported in prostate cancer patients. With similar potency to dihydrotestosterone, insulin treatment resulted in increased mRNA expression of prostate-specific antigen. CRPC progression also correlated with increased expression of IRS-2 and insulin receptor in vivo. Taken together, our findings support the hypothesis that the elevated insulin levels associated with therapeutic castration may exacerbate progression of prostate cancer to incurable CRPC in part by enhancing steroidogenesis.

The importance of mosquito behavioural adaptations to malaria control in Africa

Over the past decade the use of long-lasting insecticidal nets (LLINs), in combination with improved drug therapies, indoor residual spraying (IRS) and better health infrastructure, has helped reduce malaria in many African countries for the first time in a generation. However, insecticide resistance in the vector is an evolving threat to these gains. We review emerging and historical data on behavioural resistance in response to LLINs and IRS. Overall the current literature suggests behavioural and species changes may be emerging, but the data are sparse and, at times unconvincing. However, preliminary modelling has demonstrated that behavioural resistance could have significant impacts on the effectiveness of malaria control. We propose seven recommendations to improve understanding of resistance in malaria vectors. Determining the public health impact of physiological and behavioural insecticide resistance is an urgent priority if we are to maintain the significant gains made in reducing malaria morbidity and mortality.