Limited redundancy in phosphorylation of retinoblastoma tumor suppressor protein by cyclin-dependent kinases in acute lymphoblastic leukemia

Cyclin-dependent kinases (CDKs) successively phosphorylate the retinoblastoma protein (RB) at the restriction point in G1 phase. Hyperphosphorylation results in functional inactivation of RB, activation of the E2F transcriptional program, and entry of cells into S phase. RB unphosphorylated at serine 608 has growth suppressive activity. Phosphorylation of serines 608/612 inhibits binding of E2F-1 to RB. In Nalm-6 acute lymphoblastic leukemia extracts, serine 608 is phosphorylated by CDK4/6 complexes but not by CDK2. We reasoned that phosphorylation of serines 608/612 by redundant CDKs could accelerate phospho group formation and determined which G1 CDK contributes to serine 612 phosphorylation. Here, we report that CDK4 complexes from Nalm-6 extracts phosphorylated in vitro the CDK2-preferred serine 612, which was inhibited by p16INK4a, and fascaplysin. In contrast, serine 780 and serine 795 were efficiently phosphorylated by CDK4 but not by CDK2. The data suggest that the redundancy in phosphorylation of RB by CDK2 and CDK4 in Nalm-6 extracts is limited. Serine 612 phosphorylation by CDK4 also occurred in extracts of childhood acute lymphoblastic leukemia cells but not in extracts of mobilized CD34+ hemopoietic progenitor cells. This phenomenon could contribute to the commitment of childhood acute lymphocytic leukemia cells to proliferate and explain their refractoriness to differentiation-inducing agents.

An Acceptance and Commitment Approach to Issues of Behavioral Health Care in Soldiers

For over a decade, the U.S. military has been engaged in two distinct, yet equally deadly conflicts: Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF). There are many physical and psychological effects of war necessitating the activation and interventions of a myriad of behavioral health professionals. The purpose of the paper was to understand how and if contemporary military culture may work to support or hinder application of an Acceptance and Commitment Therapy (ACT) approach to issues of psychological health among Soldiers. While the empirical research on efficacy with Soldiers is limited, a review of military culture revealed the promotion of rigid rule following, although effective in combat, influences the emotional control agenda and stigma while in garrison. However, empirical research demonstrating the clinical benefits and flexibility of ACT is rapidly emerging with civilian and Veteran populations. Suggested as a prevention technique utilized early in Soldier's training to increase psychological flexibility, ACT appears to demonstrate much promise in ameliorating the psychological consequences of war.

"High commitment" strategies:it ain't what you do; it's the way that you do it

Purpose: This paper sets out to contribute to the advancement of knowledge, particularly with regard to the processes of implementation and the role of managers engaged in such high commitment strategies and work practices. Design/methodology/approach: This study is part of a research project investigating the extent to which employee involvement predicts job performance (as well as job satisfaction, wellbeing and organisational commitment) in the NHS, using both quantitative and qualitative methods. The main focus of this paper is to present evidence from four of the 20 case studies to show the barriers to implementing employee involvement as well as highlighting the techniques and practices that have proven to be most successful. Findings: Employee involvement is used successfully by management and has enabled frontline staff to contribute their knowledge to their work. Research limitations/implications: The ethical issues of confidentiality and anonymity permeated the research process throughout. Practical implications: The link between "high commitment" strategies and organisational performance is of great interest to academics and practitioners alike. One of these "high commitment" strategies, namely employee involvement, has been an important HR strategy for the NHS in the UK. Originality/value: Other organisations can learn from the findings by implementing the successful parts. © Emerald Group Publishing Limited.

Revisiting the role stress-commitment relationship:can managerial interventions help?

Purpose: The purpose of this paper is to investigate the moderating influences of empowerment and professional development on role stress-commitment relationships, while examining and confirming the effects of role stress on organisational commitment. Design/methodology/approach: The results are drawn from a cross-sectional survey of 184 front-line employees (FLEs) from a travel service organization. Multiple and moderated regression analyses were employed to test the hypothesised direct and interaction effects. Findings: The results show that role stressors influence affective organizational commitment in FLEs negatively. Role ambiguity did not, unexpectedly, influence continuance commitment positively, but role conflict did. Professional development and empowerment are important management tools that can be used to combat the detrimental effect of role stress on organizational commitment. The paper finds empowerment to be particularly useful in combating the dysfunctional effects of role ambiguity on affective commitment, while professional development is a key tool that helps to combat the dysfunctional effects of role conflict on affective and continuance commitment. However, there are caveats associated with the implementation of these management tools. Practical implications: It is important for management to understand role stress from the FLE perspective, and strategically use intervention tools to help moderate the effects of role stress on organizational commitment components. Originality/value: This study adds further support to the literature that role ambiguity and role conflict should be studied as distinct components of role stress because treating role stress as a single construct may result in suboptimal outcomes for managers, and misleading findings for researchers. In this context, the paper contributes to literature by investigating the moderating impact of empowerment and professional development on the role stress-affective commitment/continuance commitment relationships. The findings suggest that different managerial strategies are required to combat the effect of each of these role stressors on the affective and continuance components of commitment respectively. © Emerald Group Publishing Limited.

Service employee clusters in banking:exploring Ind's typology considering behaviour, commitment and attitude about leadership

Purpose: Ind suggests front line employees can be segmented according to their level of brand-supporting performance. His employee typology has not been empirically tested. The paper aims to explore front line employee performance in retail banking, and profile employee types. Design/methodology/approach: Attitudinal and demographic data from a sample of 404 front line service employees in a leading Irish bank informs a typology of service employees. Findings: Champions, Outsiders and Disruptors exist within retail banking. The authors provide an employee profile for each employee type. They found Champions amongst males, and older employees. The highest proportion of female employees surveyed were Outsiders. Disruptors were more likely to complain, and rated their performance lower than any other employee type. Contrary to extant literature, Disruptors were more likely to hold a permanent contract than other employee types. Originality/value: The authors augment the literature by providing insights about the profile of three employee types: Brand Champions, Outsiders and Disruptors. Moreover, the authors postulate the influence of leadership and commitment on each employee type. The cluster profiles raise important questions for hiring, training and rewarding front line banking employees. The authors also provide guidelines for managers to encourage Champions, and curtail Disruptors. © Emerald Group Publishing Limited.

Petrofac International Limited: el mercadeo interno, una estrategia efectiva en el manejo de personal

Como futuros administrados es importante recordar que nuestra función no será únicamente crear una empresa y generar constantemente ingresos. Esto es una de tantas tareas que tiene una persona que se encamina por crear o ser parte de una empresa, sea grande o pequeña siempre existirán variables que con los años se han convertido más y más indispensables en los procesos de este recorrido. El tema principal de nuestro estudio de caso es entender el concepto del endomarketing o como muchos lo conocen marketing interno; en pocas palabras es algo que por años se ha visto su efectividad en la productividad y satisfacción de los empleados. Google es una de las multinacionales más grandes del mundo, que el ultimo reconocimiento fue por parte de uno de los ranking más influyentes “The World’s Billionaries” ocupando como el CEO de la compañía Larry Page el puesto #12 , que por años ha sabido invertir en su recurso más importante que son sus empleados. En una entrevista con la revista Fortune, Larry exclama que “es importante que la empresa sea una familia, que las personas sientan que son parte de la empresa, y que la empresa es como una familia para ellos. Cuando se trata a las personas de esa manera, se obtiene una mejor productividad”. Con este pequeño ejemplo e idea de cómo una de las marcas más influyentes en el mundo ha fortalecido su mejor recurso por años el cual le ha remunerado con el éxito que tiene hoy en día. Entonces es como el mercadeo interno o endomarketing siendo uno de los conceptos tratados en el mercadeo en general hoy en día, logrando meterse como un modelo de negocio en la mayoría de empresas que existen hoy. Este es uno de los motivos que nos motivó para desarrollar este estudio de caso que verán a continuación, el cual se basa en la investigación y análisis de variables que comprenden a la empresa Petrofac, y si bien ha sabido implementar el concepto en sus procesos diarios. El estudio de caso describe como a través de los años ha sabido implementar con éxito la herramienta de evaluación y análisis del mercado interno a los empleados que constituyen hoy en día Petrofac International Limited. Abarcaremos primero con los objetivos del estudio, seguido del inicio y crecimiento de la empresa en los últimos años, en que países tiene presencia y cuáles son sus proyectos más importantes hoy en día. El estudio de caso será implementado por un tipo de investigación descriptiva, que con la recopilación de suficiente información tanto cuantitativa como cualitativa nos ira fortaleciendo la hipótesis principal, usaremos datos estadísticos que serán recopilados de encuestas, entrevistas y focus group. Al final con el análisis y a las conclusiones que lleguemos se busca demostrar el impacto positivo que ha tenido los empleados de diferentes países y de diferentes culturas que poco a poco han influenciado a la empresa para alcanzar el éxito que ha logrado hasta ahora, y de la misma forma como la empresa ha influenciado en cada una de las vidas de estas personas sin importar el lugar en el que estén laborando, siempre la empresa busca que se sientan parte de ella. Como resultados generales, se obtienen argumentos que sustentan que la implementación del mercadeo interno le permite a la empresa generar ventajas competitivas y dinámicas, que son desarrolladas internamente para un futuro reflejarlas ante los clientes externos. El estudio permitió concluir que el mercadeo interno debe ser una estrategia de comunicación dentro de una empresa convirtiéndose de primera necesidad para la compañía, pues los beneficios que genera son cada vez más necesarios para cada área que abarca el negocio.

Plasmodium vivax circumsporozoite genotypes: a limited variation or new subspecies with major biological consequences?

Background: Plasmodium vivax circumsporozoite variants have been identified in several geographical areas. The real implication of the genetic variation in this region of the P. vivax genome has been questioned for a long time. Although previous studies have observed significant association between VK210 and the Duffy blood group, we present here that evidences of this variation are limited to the CSP central portion. Methods: The phylogenetic analyses were accomplished starting from the amplification of conserved domains of 18 SSU RNAr and Cyt B. The antibodies responses against the CSP peptides, MSP-1, AMA-1 and DBP were detected by ELISA, in plasma samples of individuals infected with two P. vivax CS genotypes: VK210 and P. vivax-like. Results: These analyses of the two markers demonstrate high similarity among the P. vivax CS genotypes and surprisingly showed diversity equal to zero between VK210 and P. vivax-like, positioning these CS genotypes in the same clade. A high frequency IgG antibody against the N- and C-terminal regions of the P. vivax CSP was found as compared to the immune response to the R- and V-repetitive regions (p = 0.0005, Fisher's Exact test). This difference was more pronounced when the P. vivax-like variant was present in the infection (p = 0.003, Fisher's Exact test). A high frequency of antibody response against MSP-1 and AMA-1 peptides was observed for all P. vivax CS genotypes in comparison to the same frequency for DBP. Conclusions: This results target that the differences among the P. vivax CS variants are restrict to the central repeated region of the protein, mostly nucleotide variation with important serological consequences.

The close circumstellar environment of Betelgeuse II. Diffraction-limited spectro-imaging from 7.76 to 19.50 mu m with VLT/VISIR

Context. Mass-loss occurring in red supergiants (RSGs) is a major contributor to the enrichment of the interstellar medium in dust and molecules. The physical mechanism of this mass loss is however relatively poorly known. Betelgeuse is the nearest RSG, and as such a prime object for high angular resolution observations of its surface (by interferometry) and close circumstellar environment. Aims. The goal of our program is to understand how the material expelled from Betelgeuse is transported from its surface to the interstellar medium, and how it evolves chemically in this process. Methods. We obtained diffraction-limited images of Betelgeuse and a calibrator (Aldebaran) in six filters in the N band (7.76 to 12.81 mu m) and two filters in the Q band (17.65 and 19.50 mu m), using the VLT/VISIR instrument. Results. Our images show a bright, extended and complex circumstellar envelope at all wavelengths. It is particularly prominent longwards of approximate to 9-10 mu m, pointing at the presence of O-rich dust, such as silicates or alumina. A partial circular shell is observed between 0.5 and 1.0 '' from the star, and could correspond to the inner radius of the dust envelope. Several knots and filamentary structures are identified in the nebula. One of the knots, located at a distance of 0.9 '' west of the star, is particularly bright and compact. Conclusions. The circumstellar envelope around Betelgeuse extends at least up to several tens of stellar radii. Its relatively high degree of clumpiness indicates an inhomogeneous spatial distribution of the material lost by the star. Its extension corresponds to an important intermediate scale, where most of the dust is probably formed, between the hot and compact gaseous envelope observed previously in the near infrared and the interstellar medium.

Limited ecoclinal variation found in Malva parviflora (small-flowered mallow) across the Mediterranean-climatic agricultural region of Western Australia

Malva parviflora L. populations were collected from 24 locations across the Mediterranean-climatic agricultural region of Western Australia and grown in Perth in a common garden experiment. Seventeen morphometric and taxonomic measurements were taken and genetic variation was investigated by performing principal components analysis (PCA). Taxonomic measurements confirmed that all plants used in the study were M. parviflora. Greater variation occurred within populations than between populations. Separation between populations was only evident between northern and southern populations along principal components 2 (PC2), which was due mainly to flowering time. Flowering time and consequently photoperiod were highly correlated with latitude and regression analysis revealed a close relationship (r(2) = 0.6). Additionally, the pollination system of M. parviflora was examined. Plants were able to self-pollinate without the need for external vectors and the pollen ovule ratio (31 +/- 1.3) revealed that M. parviflora is most likely to be an obligate inbreeder with a slight potential for outcrossing. The limited variation of M. parviflora enhances the likelihood of suitable control strategies being effective across a broad area.

Limited Ca(2+) and PKA-pathway dependent neurogenic differentiation of human adult mesenchymal stem cells as compared to fetal neuronal stem cells

The ability of mesenchymal stem cells to generate functional neurons in culture is still a matter of controversy. In order to assess this issue, we performed a functional comparison between neuronal differentiation of human MSCs and fetal-derived neural stem cells (NSCs) based on morphological, immunocytochemical, and electrophysiological criteria. Furthermore, possible biochemical mechanisms involved in this process were presented. NF200 immunostaining was used to quantify the yield of differentiated cells after exposure to CAMP. The addition of a PKA inhibitor and Ca(2+) blockers to the differentiation medium significantly reduced the yield of differentiated cells. Activation of CREB was also observed on MSCs during maturation. Na(+)-, K(+)-, and Ca(2+)-voltage-dependent currents were recorded from MSCs-derived cells. In contrast, significantly larger Na(+) currents, firing activity, and spontaneous synaptic currents were recorded from NSCs. Our results indicate that the initial neuronal differentiation of MSCs is induced by CAMP and seems to be dependent upon Ca(2+) and the PKA pathway. However, compared to fetal neural stem cells, adult mesenchymal counterparts are limited in their neurogenic potential. Despite the similar yield of neuronal cells, NSCs achieved a more mature functional state. Description of the underlying mechanisms that govern MSCs` differentiation toward a stable neuronal phenotype and their limitations provides a unique opportunity to enhance our understanding of stem cell plasticity. (C) 2009 Elsevier Inc. All rights reserved.

Low doses of silver nitrate induce pleurodesis with a limited systemic response

Background and objective: Both talc and 0.5% silver nitrate have been shown to induce effective pleurodesis. However, acute adverse systemic inflammatory effects have been described with both agents. The aim of this study was to assess in rabbits the systemic effects associated with a new technique of pleurodesis using repeated low doses of 0.1% silver nitrate. Methods: Rabbits were injected intrapleurally through a chest tube with 0.1% silver nitrate at 0, 24 and 48 h. Other groups received a single injection of 0.5% silver nitrate or 400 mg/kg of talc. Blood samples were collected at 24, 48 and 72 h, and at 7 days, and cytological and biochemical measurements were performed. After 28 days, the presence of macroscopic pleural adhesions and microscopic pleural fibrosis in the pleural cavity were evaluated. Results: Both talc and 0.5% silver nitrate caused significant increases in blood neutrophils, serum LDH, IL-8, transforming growth factor-beta and CRP in comparison with control at almost all time points, whereas sequential doses of 0.1% silver nitrate only increased LDH and CRP in the first 24 h and transforming growth factor-beta at all time points. All groups showed efficient pleurodesis, with no differences in pleural adhesions or fibrosis. Conclusions: Sequential doses of 0.1% silver nitrate produced efficient pleurodesis in rabbits, with a low systemic inflammatory response in comparison with 400 mg/kg of talc or 0.5% silver nitrate.

Factors involved in the T helper type 1 and type 2 cell commitment and osteoclast regulation in inflammatory apical diseases

Periapical chronic lesion formation involves activation of the immune response and alveolar bone resorption around the tooth apex. However, the overall roles of T helper type 1 (Th1), Th2, and T-regulatory cell (Treg) responses and osteoclast regulatory factors in periapical cysts and granulomas have not been fully determined. This study aimed to investigate whether different forms of apical periodontitis, namely cysts and granulomas, show different balances of Th1, Th2 regulators, Treg markers, and factors involved in osteoclast chemotaxis and activation. Gene expression of these factors was assessed using quantitative real-time polymerase chain reaction, in samples obtained from healthy gingiva (n = 8), periapical granulomas (n = 20), and cysts (n = 10). Periapical cysts exhibited a greater expression of GATA-3, while a greater expression of T-bet, Foxp3, and interleukin-10 (IL-10) was seen in granulomas. The expression of interferon-gamma, IL-4, and transforming growth factor-beta was similar in both lesions. Regarding osteoclastic factors, while the expression of SDF-1 alpha/CXCL12 and CCR1 was higher in cysts, the expression of RANKL was significantly higher in granulomas. Both lesions exhibited similar expression of CXCR4, CK beta 8/CCL23, and osteoprotegerin, which were significantly higher than in control. Our results showed a predominance of osteoclast activity in granulomas that was correlated with the Th1 response. The concomitant expression of Treg cell markers suggests a possible suppression of the Th1 response in granulomas. On the other hand, in cysts the Th2 activity is augmented. The mechanisms of periradicular lesion development are still not fully understood but the imbalance of immune and osteoclastic cell activity in cysts and granulomas seems to be critically regulated by Treg cells.

Long-term treatment of familial male-limited precocious puberty (testotoxicosis) with cyproterone acetate or ketoconazole

Background Familial male-limited precocious puberty (FMPP) or testotoxicosis is a rare gonadotrophin-independent form of sexual precocity caused by constitutively activating mutations of the LH receptor. Several clinical therapeutic approaches have been reported for this disorder, but with a paucity of long-term outcome data. Objective To evaluate the long-term treatment of testotoxicosis with cyproterone acetate or ketoconazole. Design A multicentric retrospective clinical study. Patients Ten boys from eight unrelated Brazilian families who carried known LH-receptor activating mutations were treated with 70 mg/m(2) cyproterone acetate (n = 5) or 10 mg/kg ketoconazole (n = 5) for a mean period of 5 and 8 years, respectively. Measurements Chronological and bone ages, bone age/chronological age ratio, target height (TH) range, adult height, basal and GnRH-stimulated gonadotrophin levels and basal testosterone levels were assessed. Results Growth velocity decreased significantly during treatment with cyproterone acetate or ketoconazole when compared to pretreatment value in each group (P < 0.05). Bone age/chronological age ratio decreased significantly after cyproterone acetate or ketoconazole therapy. Basal testosterone levels were significantly lower in patients undergoing ketoconazole compared to cyproterone acetate treatment [0.6 +/- 0.3 nmol/l (42 +/- 21 ng/dl) vs. 5.6 +/- 4.0 nmol/l (392 +/- 280 ng/dl); P < 0.05], as expected. Secondary gonadotrophin-dependent precocious puberty occurred at a similar frequency (40%) in both groups. Five patients have attained adult height and two patients have already reached 90% of their adult height. Two of them achieved their TH range and one patient, for whom TH was not available, had an adult height of 0.3 SDS. Four boys (two in each group) did not attain their TH range. Conclusion Long-term treatment with cyproterone acetate or ketoconazole resulted in similar outcomes without important side-effects in boys with testotoxicosis. However, both therapies showed limited efficacy in attaining normal adult height.