Intrabursal administration of the antiangiopoietin 1 antibody produces a delay in rat follicular development associated with an increase in ovarian apoptosis mediated by changes in the expression of BCL2 related genes

The angiopoietin (ANGPT) receptor (TEK) system plays a crucial role in blood vessel development and regression. To date, no reports have addressed the actions of the anti-ANGPT1 antibody on gonadotropin-stimulated follicular development and atresia in the ovary. Therefore, in this study we specifically investigated whether ANGPT1 plays a critical intraovarian survival role for gonadotropin-dependent folliculogenesis. In particular, we examined the effect of local administration of anti-ANGPT1 antibody on follicular development, apoptosis, and expression of BCL2 protein family members (BAX, BCL2, and BCL2L1), TNFRSF6, and FASLG in ovarian follicles from prepubertal eCG-treated rats. The inhibition of ANGPT1 caused an increase in the number of atretic follicles and a decrease in the number of both antral follicles (AFs) and preovulatory follicles in gonadotropin-treated rat ovaries. Taking into account that follicular atresia is mediated by apoptosis, we analyzed the effect of the antibody against ANGPT1 on programmed cell death. The inhibition of the action of ANGPT1 caused an increase both in the number of apoptotic granulosa cells in AFs and in the spontaneous DNA fragmentation of AFs cultured in serum-free medium. Besides, AFs obtained from rats treated with intraovarian antibodies against ANGPT1 showed both a decrease in BCL2 and an increase in BAX protein levels. Moreover, a reduction in the BCL2L1L/BCL2L1S ratio was observed in this group, with a reduction of BCL2L1L greater than that of BCL2L1S, thus showing that the expression of these antiapoptotic proteins is lower in follicles from treated rats than in those from untreated ones. Our findings suggest that the inhibition of ANGPT1 activity causes an increase in the number of atretic follicles mediated by ovarian apoptosis through an imbalance in the ratio of antiapoptotic to proapoptotic proteins. This could take place through a paracrine effect on granulosa cells mediated by the TEK receptor in theca cells. Therefore, these data clearly indicate that ANGPT1 is necessary for follicular development induced by gonadotropins. © 2008 by the Society for the Study of Reproduction, Inc.Fil:Parborell, F. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.Fil:Abramovich, D. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.Fil:Tesone, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina

Peripheral and central mechanisms involved in hormonal control of male and female reproduction

Reproduction involves the integration of hormonal signals acting across multiple systems togenerate a synchronized physiological output. A critical component of reproduction is the luteinizinghormone (LH) surge, which is mediated by estradiol (E2) and neuroprogesterone interacting tostimulate kisspeptin release in the rostral periventricular nucleus of the third ventricle in rats. Recentevidence has shown that both classical and membrane E2 and progesterone signaling is involved inthis pathway. A metabolite of gonadotropin-releasing hormone (GnRH), GnRH-(1-5), has been shownto stimulate GnRH expression, secretion, and has a role in the regulation of lordosis. Additionally,gonadotropin-inhibitory hormone (GnIH) projects to and influences the activity of GnRH neurons inbirds. Stress-induced changes in GnIH have been shown to alter breeding behaviors in birds,demonstrating another molecular control of reproduction. Peripherally, paracrine and autocrineactions within the gonad have been suggested as therapeutic targets for infertility in both males andfemales. Dysfunction of testicular prostaglandin synthesis is a possible cause of idiopathic maleinfertility. Indeed, local production of melatonin and corticotropin-releasing hormone (CRH) couldinfluence spermatogenesis via immune pathways in the gonad. In females, vascular endothelialgrowth factor A (VEGF-A) has been implicated in an angiogenic process that mediates developmentof the corpus luteum and thus fertility via the Notch signaling pathway. Age-induced decreases infertility involve ovarian kisspeptin and its regulation of ovarian sympathetic innervation. Finally,morphological changes in the arcuate nucleus of the hypothalamus influence female sexualreceptivity in rats. The processes mediating these morphological changes have been shown toinvolve rapid effects of E2 controlling synaptogenesis in this hypothalamic nucleus. Together, thisreview highlights new research in these areas, focusing on recent findings in the molecularmechanisms of central and peripheral hormonal control of reproduction.Fil: Rudolph, L. M.. University of California at Los Angeles; Estados UnidosFil: Bentley, G. E.. University of California Berkeley; Estados UnidosFil: Calandra, Ricardo Saul. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Paredes, A. H.. Universidad de Chile; ChileFil: Tesone, Marta. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Wu, T. J.. Uniformed Services University; Estados UnidosFil: Micevych, P. E.. University of California at Los Angeles; Estados Unido

Satb1 overexpression drives tumor-promoting activities in cancer-associated dendritic cells

Special AT-rich sequence-binding protein 1 (Satb1) governs genome-wide transcriptional programs. Using a conditional knockout mouse, we find that Satb1 is required for normal differentiation of conventional dendritic cells (DCs). Furthermore, Satb1 governs the differentiation of inflammatory DCs by regulating major histocompatibility complex class II (MHC II) expression through Notch1 signaling. Mechanistically, Satb1 binds to the Notch1 promoter, activating Notch expression and driving RBPJ occupancy of the H2-Ab1 promoter, which activates MHC II transcription. However, tumor-driven, unremitting expression of Satb1 in activated Zbtb46(+) inflammatory DCs that infiltrate ovarian tumors results in an immunosuppressive phenotype characterized by increased secretion of tumor-promoting Galectin-1 and IL-6. In vivo silencing of Satb1 in tumor-associated DCs reverses their tumorigenic activity and boosts protective immunity. Therefore, dynamic fluctuations in Satb1 expression govern the generation and immunostimulatory activity of steady-state and inflammatory DCs, but continuous Satb1 overexpression in differentiated DCs converts them into tolerogenic/pro-inflammatory cells that contribute to malignant progression.Fil: Tesone, Amelia J.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Rutkowski, Melanie R.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Brencicova, Eva. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Svoronos, Nikolaos. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Perales Puchal, Alfredo. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Stephen, Tom L.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Allegrezza, Michael J.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Payne, Kyle K.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Nguyen, Jenny M.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Wickramasinghe, Jayamanna. The Wistar Institute. Center for Systems and Computational Biology; Estados UnidosFil: Tchou, Julia. University of Pennsylvania; Estados UnidosFil: Borowsky, Mark E.. Christiana Care Health System. Helen F. Graham Cancer Center; Estados UnidosFil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Kossenkov, Andrew V.. The Wistar Institute. Center for Systems and Computational Biology; Estados UnidosFil: Conejo Garcia, José R.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados Unido

Transformation-based Refactorings: a First Analysis

International audienceRefactorings are behavior preserving transformations. Little work exists on the analysis of their implementation and in particular how refactorings could be composed from smaller, reusable, parts (being simple transformations or other refactorings) and how (non behavior preserving) transformations could be used in isolation or to compose new refactoring operators. In this article we study the seminal implementation and evolution of Refactorings as proposed in the PhD of D. Roberts. Such an implementation is available as the Refactoring Browser package in Pharo. In particular we focus on the possibilities to reuse transformations independently from the behavior preserving aspect of a refactoring. The long term question we want to answer is: Is it possible to have more atomic transformations and refactorings composed out of such transformations? We study preconditions of existing refactorings and identify several families. We identify missed opportunities of reuse in the case of implicit composite refactorings. We analyze the refactorings that are explicitly composed out of other refactorings to understand whether the composition could be expressed at another level of abstraction. This analysis should be the basis for a more systematic expression of composable refactorings as well as the reuse of logic between transformations and refactorings

Remarkable Challenges of High-Performance Language Virtual Machines

Language Virtual Machines (VMs) are pervasive in every laptop, server, and smartphone, as is the case with Java or Javascript. They allow application portability between different platforms and better usage of resources. They are used in critical applications such as stock exchange, banking, insurance, and health [25]. Virtual machines are an important asset in companies because they allow the efficient execution of high-level programming languages. Nowadays, they even attract investments from large non-system companies, e.g., Netflix 1 , Meta 2 , Shopify 3 and Amazon 4. VMs achieve high-performance thanks to aggressive optimization techniques that observe and adapt the execution dynamically, either by doing just-in-time compilation [5] or by adapting the memory management strategies at runtime [90, 91]. For all these reasons Virtual Machines are highly-complex engineering pieces, often handcrafted by experts, that mix state-of-the-art compilation techniques with complex memory management that collaborate with the underlying operating systems and hardware. However, besides some well-known techniques that are published in research venues, most knowledge and technology around virtual machines are highly concentrated in large companies such as Microsoft, Google, and Oracle, making Virtual Machine construction difficult, and experiments difficult to reproduce and replicate. Language VMs present many multidisciplinary scientific challenges that appear at the intersection of fields such as hardware, system software, compiler, and software language engineering. This document aims to give a brief overview of the current challenges the VM community faces. To keep this document short, we selected remarkable challenges in managed execution, managed memory, performance evaluation, software engineering and security

ICMSF Methods Studies. XV. Comparison of Four Media and Methods for Enumerating Staphylococcus aureus in Powdered Milk.

Four media were examined for their usefulness in enumerating Staphylococcus aureus inoculated (a) into milk that was then dried or (b) directly into dried milk powder. In all, seven strains of S. aureus were inoculated individually into each preparation and were enumerated after two periods of storage (18 to 19 d and 60 to 61 d). Fourteen laboratories from twelve countries participated in the comparison which found that direct plating on agar medium in 14-cm petri dishes may be as useful as enrichment followed by streaking. Plating on Baird-Parker medium or on Hauschild pork plasma fibrinogen medium and a MPN method using Giolitti and Cantoni's broth with Tween 80 were equally sensitive for enumerating S. aureus in dried milk powder. The use of Hauschild medium may eliminate the need for supplementary tests to confirm colonies as S. aureus , but in some cases was found to fail in some laboratories. Giolitti and Cantoni's broth without Tween 80 generally was less useful than the three other media for enumerating S. aureus . S. aureus inoculated into milk that was then dried survived longer than when inoculated into dried milk

Sexuação, desejo e gozo: entre neurose e perversão

Este artigo retoma três perguntas lançadas por Freud em 1927, no seu excepcional texto intitulado "Fetichismo", para repensá-las a partir do ensino de Lacan dos anos 1970, conhecido como o campo do gozo. O artigo se serve das fórmulas quânticas da sexuação, para verificar a evidenciação lógica "a relação sexual não existe" na posição sexuada que um sujeito pode ocupar com seus parceiros nas estruturas neurótica e perversa. Interrogamos algumas variantes do sujeito com seu parceiro no gozo e no desejo. Para tanto, retomamos os três tipos de gozo verificados por Lacan na relação do sujeito com o parceiro na posição sexuada: o gozo feminino - também chamado de suplementar e gozo Outro -, o gozo místico e o gozo perverso. Revisitam-se os casos trabalhados por Lacan para questionar o que distingue fundamentalmente o neurótico do perverso, ou seja, retomando as questões introduzidas por Freud

“It’s Like Hating Puppies!” Employee Disengagement and Corporate Social Responsibility

Corporate social responsibility (CSR) has been linked with numerous organizational advantages, including recruitment, retention, productivity, and morale, which relate specifically to employees. However, despite specific benefits of CSR relating to employees and their importance as a stakeholder group, it is noteworthy that a lack of attention has been paid to the individual level of analysis with CSR primarily being studied at the organizational level. Both research and practice of CSR have largely treated the individual organization as a “black box,” failing to account for individual differences amongst employees and the resulting variations in antecedents to CSR engagement or disengagement. This is further exacerbated by the tendency in stakeholder theory to homogenize priorities within a single stakeholder group. In response, utilizing case study data drawn from three multinational tourism and hospitality organizations, combined with extensive interview data collected from CSR leaders, industry professionals, engaged, and disengaged employees, this exploratory research produces a finer-grained understanding of employees as a stakeholder group, identifying a number of opportunities and barriers for individual employee engagement in CSR interventions. This research proposes that employees are situated along a spectrum of engagement from actively engaged to actively disengaged. While there are some common drivers of engagement across the entire spectrum of employees, differences also exist depending on the degree to which employees, rather than senior management, support corporate responsibility within their organizations. Key antecedents to CSR engagement that vary depending on employees’ existing level of broader engagement include organizational culture, CSR intervention design, employee CSR perceptions, and the observed benefits of participation