A new population of Darwin's fox (Lycalopex fulvipes) in the Valdivian Coastal Range

Indexación: Web of Science; Scielo.Darwin's fox (Lycalopex fulvipes Martin, 1837) is an endemic of the temperate forests of the Coastal Range of southern Chile, that was reported by Charles Darwin in 1834 in southern Chiloé Island (42° S, 74° W; Martin 1837). Initially known exclusively from that island, it was considered both an insular subspecies of the chilla fox (Lycalopex griseus Gray, 1837) (Housse 1953; Clutton-Brock et al. 1976) and a valid species (Martin 1837; Gay 1947; Osgood 1943). In 1990, a mainland population was reported at Nahuelbuta National Park (ca. 450 km north of Chiloé Island, 37° 47′ S, 72° 59′ W; Figure 1a) in sympatry with the chilla and culpeo foxes (Lycalopex culpaeus Molina, 1782) (Jaksic et al. 1990; Medel et al. 1990; Jiménez et al. 1991). This supported its status as a valid species, later confirmed through genetic studies (Yahnke et al. 1996).http://ref.scielo.org/z7mmt

Circulatory immune cells in Cushing syndrome: bystanders or active contributors to atherometabolic injury? A study of adhesion and activation of cell surface markers.

Glucocorticoids (GC) induce cardiometabolic risk while atherosclerosis is a chronic inflammation involving immunity. GC are immune suppressors, and the adrenocorticotrophic hormone (ACTH) has immune modulator activities. Both may act in atherothrombotic inflammation involving immune cells (IMNC). Aim. To investigate adhesion and activation surface cell markers (CDs) of peripheral IMNC in endogenous Cushing syndrome (CS) and the immune modulator role of ACTH. Material and Methods. 16 ACTH-dependent CS (ACTH-D), 10 ACTH-independent (ACTH-ID) CS, and 16 healthy controls (C) were included. Leukocytes (Leuc), monocytes (MN), lymphocytes (Lym), and neutrophils (N) were analyzed by flow cytometry for atherosclerosis previously associated with CDs. Results. Leuc, N, and MN correlated with CS (p < 0.05), WC (p < 0.001), WHR (p = 0.003), BMI (p < 0.001), and hs-CRP (p < 0.001). CD14++CD16+ (p = 0.047); CD14+CD16++ (p = 0.053) MN; CD15+ (p = 0.027); CD15+CD16+ (p = 0.008) N; and NK-Lym (p = 0.019) were higher in CS. CD14+CD16++ MN were higher in ACTH-ID (8.9 ± 3.5%) versus ACTH-D CS (4.2 ± 1.9%) versus C (4.9 ± 2.3%). NK-Lym correlated with c-LDL (r = 0.433, p = 0.039) and CD15+ N with hs-CRP (r = 0.446, p = 0.037). In multivariate analysis, Leuc, N, and MN depended on BMI (p = 0.021), WC (p = 0.002), and WHR (p = 0.014), while CD15+ and CD15+CD16+ N on hypercortisolism and CS (p = 0.035). Conclusion. In CS, IMNC present changes in activation and adhesion CDs implicated in atherothrombotic inflammation. ACTH-IDCS presents a particular IMNC phenotype, possibly due to the absence of the immune modulator effect of ACTH

Soluble CD137 as a dynamic biomarker to monitor agonist CD137 immunotherapies

Background On the basis of efficacy in mouse tumor models, multiple CD137 (4-1BB) agonist agents are being preclinically and clinically developed. The costimulatory molecule CD137 is inducibly expressed as a transmembrane or as a soluble protein (sCD137). Moreover, the CD137 cytoplasmic signaling domain is a key part in approved chimeric antigen receptors (CARs). Reliable pharmacodynamic biomarkers for CD137 ligation and costimulation of T cells will facilitate clinical development of CD137 agonists in the clinic. Methods We used human and mouse CD8 T cells undergoing activation to measure CD137 transcription and protein expression levels determining both the membrane-bound and soluble forms. In tumor-bearing mice plasma sCD137 concentrations were monitored on treatment with agonist anti-CD137 monoclonal antibodies (mAbs). Human CD137 knock-in mice were treated with clinical-grade agonist anti-human CD137 mAb (Urelumab). Sequential plasma samples were collected from the first patients intratumorally treated with Urelumab in the INTRUST clinical trial. Anti-mesothelin CD137-encompassing CAR-transduced T cells were stimulated with mesothelin coated microbeads. sCD137 was measured by sandwich ELISA and Luminex. Flow cytometry was used to monitor CD137 surface expression. Results CD137 costimulation upregulates transcription and protein expression of CD137 itself including sCD137 in human and mouse CD8 T cells. Immunotherapy with anti-CD137 agonist mAb resulted in increased plasma sCD137 in mice bearing syngeneic tumors. sCD137 induction is also observed in human CD137 knock-in mice treated with Urelumab and in mice transiently humanized with T cells undergoing CD137 costimulation inside subcutaneously implanted Matrigel plugs. The CD137 signaling domain-containing CAR T cells readily released sCD137 and acquired CD137 surface expression on antigen recognition. Patients treated intratumorally with low dose Urelumab showed increased plasma concentrations of sCD137. Conclusion sCD137 in plasma and CD137 surface expression can be used as quantitative parameters dynamically reflecting therapeutic costimulatory activity elicited by agonist CD137-targeted agents

A Model of Continuous Improvement Programme Management

The aim of this study is to identify key management decisions that enable the sustainment of a continuous improvement (CI) initiative. To accomplish this aim, we examine the procedures and practices used by two manufacturing companies for the management of their CI initiatives; one that is successfully sustaining the effectiveness of its CI initiative and another failing to do the same. This research makes two contributions to the conceptual understanding of CI programme management. First, we identify five CI programme management factors that enable the sustainment of a CI initiative. Second, the five factors are incorporated into a new CI programme management model. The model details a ‘bottom-up’ procedure for the generation of manufacturing performance improvement ideas and the management of their implementation

Circulatory Immune Cells in Cushing Syndrome: Bystanders or Active Contributors to Atherometabolic Injury? A Study of Adhesion and Activation of Cell Surface Markers

Glucocorticoids (GC) induce cardiometabolic risk while atherosclerosis is a chronic inflammation involving immunity. GC are immune suppressors, and the adrenocorticotrophic hormone (ACTH) has immune modulator activities. Both may act in atherothrombotic inflammation involving immune cells (IMNC). Aim. To investigate adhesion and activation surface cell markers (CDs) of peripheral IMNC in endogenous Cushing syndrome (CS) and the immune modulator role of ACTH. Material and Methods. 16 ACTH-dependent CS (ACTH-D), 10 ACTH-independent (ACTH-ID) CS, and 16 healthy controls (C) were included. Leukocytes (Leuc), monocytes (MN), lymphocytes (Lym), and neutrophils (N) were analyzed by flow cytometry for atherosclerosis previously associated with CDs. Results. Leuc, N, and MN correlated with CS (p<0.05), WC (p<0.001), WHR (p=0.003), BMI (p<0.001), and hs-CRP (p<0.001). CD14++CD16+ (p=0.047); CD14+CD16++ (p=0.053) MN; CD15+ (p=0.027); CD15+CD16+ (p=0.008) N; and NK-Lym (p=0.019) were higher in CS. CD14+CD16++ MN were higher in ACTH-ID (8.9 ± 3.5%) versus ACTH-D CS (4.2 ± 1.9%) versus C (4.9 ± 2.3%). NK-Lym correlated with c-LDL (r = 0.433, p=0.039) and CD15+ N with hs-CRP (r = 0.446, p=0.037). In multivariate analysis, Leuc, N, and MN depended on BMI (p=0.021), WC (p=0.002), and WHR (p=0.014), while CD15+ and CD15+CD16+ N on hypercortisolism and CS (p=0.035). Conclusion. In CS, IMNC present changes in activation and adhesion CDs implicated in atherothrombotic inflammation. ACTH-IDCS presents a particular IMNC phenotype, possibly due to the absence of the immune modulator effect of ACTH

Heterogenous presence of neutrophil extracellular traps in human solid tumours is partially dependent on IL-8

Neutrophil extracellular traps (NETs) are webs of extracellular nuclear DNA extruded by dying neutrophils infiltrating tissue. NETs constitute a defence mechanism to entrap and kill fungi and bacteria. Tumours induce the formation of NETs to the advantage of the malignancy via a variety of mechanisms shown in mouse models. Here, we investigated the presence of NETs in a variety of human solid tumours and their association with IL-8 (CXCL8) protein expression and CD8+ T-cell density in the tumour microenvironment. Multiplex immunofluorescence panels were developed to identify NETs in human cancer tissues by co-staining with the granulocyte marker CD15, the neutrophil marker myeloperoxidase and citrullinated histone H3 (H3Cit), as well as IL-8 protein and CD8+ T cells. Three ELISA methods to detect and quantify circulating NETs in serum were optimised and utilised. Whole tumour sections and tissue microarrays from patients with non-small cell lung cancer (NSCLC; n = 14), bladder cancer (n = 14), melanoma (n = 11), breast cancer (n = 31), colorectal cancer (n = 20) and mesothelioma (n = 61) were studied. Also, serum samples collected retrospectively from patients with metastatic melanoma (n = 12) and NSCLC (n = 34) were ELISA assayed to quantify circulating NETs and IL-8. NETs were detected in six different human cancer types with wide individual variation in terms of tissue density and distribution. At least in NSCLC, bladder cancer and metastatic melanoma, NET density positively correlated with IL-8 protein expression and inversely correlated with CD8+ T-cell densities. In a series of serum samples from melanoma and NSCLC patients, a positive correlation between circulating NETs and IL-8 was found. In conclusion, NETs are detectable in formalin-fixed human biopsy samples from solid tumours and in the circulation of cancer patients with a considerable degree of individual variation. NETs show a positive association with IL-8 and a trend towards a negative association with CD8+ tumour-infiltrating lymphocytes

APC/C-Mediated Degradation of dsRNA-Binding Protein 4 (DRB4) Involved in RNA Silencing

Background: Selective protein degradation via the ubiquitin-26S proteasome is a major mechanism underlying DNA replication and cell division in all Eukaryotes. In particular, the APC/C (Anaphase Promoting Complex or Cyclosome) is a master ubiquitin protein ligase (E3) that targets regulatory proteins for degradation allowing sister chromatid separation and exit from mitosis. Interestingly, recent work also indicates that the APC/C remains active in differentiated animal and plant cells. However, its role in post-mitotic cells remains elusive and only a few substrates have been characterized. Methodology/Principal Findings: In order to identify novel APC/C substrates, we performed a yeast two-hybrid screen using as the bait Arabidopsis APC10/DOC1, one core subunit of the APC/C, which is required for substrate recruitment. This screen identified DRB4, a double-stranded RNA binding protein involved in the biogenesis of different classes of small RNA (sRNA). This protein interaction was further confirmed in vitro and in plant cells. Moreover, APC10 interacts with DRB4 through the second dsRNA binding motif (dsRBD2) of DRB4, which is also required for its homodimerization and binding to its Dicer partner DCL4. We further showed that DRB4 protein accumulates when the proteasome is inactivated and, most importantly, we found that DRB4 stability depends on APC/C activity. Hence, depletion of Arabidopsis APC/C activity by RNAi leads to a strong accumulation of endogenous DRB4, far beyond its normal level of accumulation. However, we could not detect any defects in sRNA production in lines where DRB4 was overexpressed

Arquitecturas multiprocesador en cómputo de altas prestaciones: software de base, métricas y aplicaciones

Caracterizar las arquitecturas multiprocesador distribuidas enfocadas especialmente a cluster y cloud computing, con énfasis en las que utilizan procesadores de múltiples núcleos (multicores y GPUs), con el objetivo de modelizarlas, estudiar su escalabilidad, analizar y predecir performance de aplicaciones paralelas y desarrollar esquemas de tolerancia a fallas en las mismas. Profundizar el estudio de arquitecturas basadas en GPUs y su comparación con clusters de multicores, así como el empleo combinado de GPUs y multicores en computadoras de alta perfomance. En particular estudiar perfomance en Clusters “híbridos”. Analizar la eficiencia energética en estas arquitecturas paralelas, considerando el impacto de la arquitectura, el sistema operativo, el modelo de programación y el algoritmo específico. Analizar y desarrollar software de base para clusters de multicores y GPUs, tratando de optimizar el rendimiento. En el año 2013 se han incorporado nuevas líneas de interés: - El desarrollo de aplicaciones sobre Cloud y en particular las aplicaciones de Big Data en Cloud. - La utilización de los registros de hardware de los procesadores para la toma de diferentes decisiones en tiempo de ejecución. - El desarrollo de herramientas para la transformación de código heredado, buscando su optimización sobre arquitecturas paralelas. Es de hacer notar que este proyecto se coordina con otros proyectos en curso en el III-LIDI, relacionados con Algoritmos Paralelos, Sistemas Distribuidos y Sistemas de Tiempo Real.Eje: Procesamiento Distribuido y ParaleloRed de Universidades con Carreras en Informática (RedUNCI

Arquitecturas multiprocesador en cómputo de altas prestaciones: software de base, métricas y aplicaciones

Caracterizar las arquitecturas multiprocesador distribuidas enfocadas especialmente a cluster y cloud computing, con énfasis en las que utilizan procesadores de múltiples núcleos (multicores y GPUs), con el objetivo de modelizarlas, estudiar su escalabilidad, analizar y predecir performance de aplicaciones paralelas y desarrollar esquemas de tolerancia a fallas en las mismas. Profundizar el estudio de arquitecturas basadas en GPUs y su comparación con clusters de multicores, así como el empleo combinado de GPUs y multicores en computadoras de alta perfomance. En particular estudiar perfomance en Clusters “híbridos”. Analizar la eficiencia energética en estas arquitecturas paralelas, considerando el impacto de la arquitectura, el sistema operativo, el modelo de programación y el algoritmo específico. Analizar y desarrollar software de base para clusters de multicores y GPUs, tratando de optimizar el rendimiento. En el año 2013 se han incorporado nuevas líneas de interés: - El desarrollo de aplicaciones sobre Cloud y en particular las aplicaciones de Big Data en Cloud. - La utilización de los registros de hardware de los procesadores para la toma de diferentes decisiones en tiempo de ejecución. - El desarrollo de herramientas para la transformación de código heredado, buscando su optimización sobre arquitecturas paralelas. Es de hacer notar que este proyecto se coordina con otros proyectos en curso en el III-LIDI, relacionados con Algoritmos Paralelos, Sistemas Distribuidos y Sistemas de Tiempo Real.Eje: Procesamiento Distribuido y ParaleloRed de Universidades con Carreras en Informática (RedUNCI

Software de base, métricas y aplicaciones en arquitecturas multiprocesador orientadas a cómputo de altas prestaciones

Caracterizar las arquitecturas multiprocesador distribuidas enfocadas especialmente a cluster y cloud computing, con énfasis en las que utilizan procesadores de múltiples núcleos (multicores y GPUs), con el objetivo de modelizarlas, estudiar su escalabilidad, analizar y predecir performance de aplicaciones paralelas, estudiar el consumo energético y su impacto en la perfomance así como desarrollar esquemas para detección y tolerancia a fallas en las mismas. Profundizar el estudio de arquitecturas basadas en GPUs y su comparación con clusters de multicores, así como el empleo combinado de GPUs y multicores en computadoras de alta perfomance. En particular estudiar perfomance en Clusters “híbridos”. Analizar y desarrollar software de base para clusters de multicores y GPUs, tratando de optimizar el rendimiento. Investigar arquitecturas multicore asimétricas, sus aplicaciones y el software de base de las mismas apuntando a optimizar el rendimiento de aplicaciones de propósito general. A partir del año 2013 se han incorporado nuevas líneas de interés: - Cloud computing, incluyendo aplicaciones de HPC sobre cloud. - El desarrollo de aplicaciones que integran Big Data y procesamiento sobre Cloud. - La utilización de los registros de hardware de los procesadores para la toma de diferentes decisiones en tiempo de ejecución. - El desarrollo de herramientas para la transformación de código heredado, buscando su optimización sobre arquitecturas paralelas. Es de hacer notar que este proyecto se coordina con otros proyectos en curso en el III-LIDI, relacionados con Algoritmos Paralelos, Sistemas Distribuidos y Sistemas de Tiempo Real.Eje: Procesamiento Distribuído y ParaleloRed de Universidades con Carreras en Informática (RedUNCI