Antileishmanial action of organometallic complexes of Pt(II) and Rh(I)

The three organometallic complexes [(Cis-PtII (DDH) (2,5-Dihidroxibenzensulfonic)2, RhI (CO)2 Cl(2-Aminobenzothiazole) and RhI (CO)2 Cl(5-Cl-2-Methilbenzothiazole)] used in this study had been previously found to have a high in vitro activity against promastigote and amastigote like forms of Leishmania donovani. Here, the cytotoxic effect of these new organometallic complexes on the J-774 macrophages were studied. Only the RhI(CO)2 Cl (2-Aminobenzothiazole) complex induced substantial toxicity in the cells. Also, we assayed the effect of this complex on the parasite's biosynthesis of macromolecules. The RhI(CO)2Cl (5-Cl-2-Methylbenzothiazole) complex inhibited DNA, RNA, and protein synthesis. On the other hand, the two other compounds tested did not inhibit the incorporation of radioactive precursors. Finally important ultrastructural alterations in the parasites treated with the two non-cytotoxic complexes were observed.

On the cellular site of two-pore channel TPC1 action in the Poaceae.

The slow vacuolar (SV) channel has been characterized in different dicots by patch-clamp recordings. This channel represents the major cation conductance of the largest organelle in most plant cells. Studies with the tpc1-2 mutant of the model dicot plant Arabidopsis thaliana identified the SV channel as the product of the TPC1 gene. By contrast, research on rice and wheat TPC1 suggested that the monocot gene encodes a plasma membrane calcium-permeable channel. To explore the site of action of grass TPC1 channels, we expressed OsTPC1 from rice (Oryza sativa) and TaTPC1 from wheat (Triticum aestivum) in the background of the Arabidopsis tpc1-2 mutant. Cross-species tpc1 complementation and patch-clamping of vacuoles using Arabidopsis and rice tpc1 null mutants documented that both monocot TPC1 genes were capable of rescuing the SV channel deficit. Vacuoles from wild-type rice but not the tpc1 loss-of-function mutant harbor SV channels exhibiting the hallmark properties of dicot TPC1/SV channels. When expressed in human embryonic kidney (HEK293) cells OsTPC1 was targeted to Lysotracker-Red-positive organelles. The finding that the rice TPC1, just like those from the model plant Arabidopsis and even animal cells, is localized and active in lyso-vacuolar membranes associates this cation channel species with endomembrane function.

Membrane interaction of polymyxin B and synthetic analogues studied in biomimetic systems: implications for antibacterial action

Membrane-active antimicrobial peptides, such as polymyxin B (PxB), are currently in the spotlight as potential candidates toovercome bacterial resistance. We have designed synthetic analogs ofPxB in order to determine the structural requirements for membraneaction. Since the mechanism of action of PxB involves interaction withboth the outer membrane and the cytoplasmic membrane of Gramnegative bacteria, we have used an approach based on mimicking theouter layers of these membranes using monolayers, Langmuir-Blodgettfilms and unilamelar vesicles, and applying a battery of biophysicalmethods in order to dissect the different events of membraneinteraction. Collectively, results indicate that the PxB analogues act inthe bacterial membrane by the same mechanism than PxB, and that cationic amphipathicity determines peptide activity.

Membrane interaction of polymyxin B and synthetic analogues studied in biomimetic systems: implications for antibacterial action

Membrane-active antimicrobial peptides, such as polymyxin B (PxB), are currently in the spotlight as potential candidates toovercome bacterial resistance. We have designed synthetic analogs ofPxB in order to determine the structural requirements for membraneaction. Since the mechanism of action of PxB involves interaction withboth the outer membrane and the cytoplasmic membrane of Gramnegative bacteria, we have used an approach based on mimicking theouter layers of these membranes using monolayers, Langmuir-Blodgettfilms and unilamelar vesicles, and applying a battery of biophysicalmethods in order to dissect the different events of membraneinteraction. Collectively, results indicate that the PxB analogues act inthe bacterial membrane by the same mechanism than PxB, and that cationic amphipathicity determines peptide activity.

Cultural Planning and community sustainability: The case of the Cultural Facilities Plan of Catalonia (PECCAT 2010-20)

The government of Catalonia has developed a planning framework that seeks to establish the provision of cultural facilities throughout the country. The Cultural Facilities Plan of Catalonia (PECCAT) is based on an analysis of historical gaps and establishes a minimum spatial scheme. The plan responds to problems associated with the absence of a former similar instrument, which has led to an inconsistent and inappropriate cultural infrastructure that fails to fulfill its fundamental mission of securing the cultural rights of the population. The paper sets forth the aims of this policy and describes the objectives and basic characteristics of the plan and the expected outcomes. With the plan, the government of Catalonia seeks to rebalance the infrastructure within the territory and to ensure universal access to basic cultural services, while avoiding a logic of standardization and taking local communities into account. With the development of local plans in the municipalities, local governments encourage community participation processes to adapt and decide on priorities for action based on needs assessments and cultural opportunities for local sustainable development. The local plans focus on local cultural strengths, take advantage of opportunities, and aim to realize the cultural dynamics of a place through establishing an infrastructure that can best respond to the needs and cultural demands of the local communities, taking into account economic, social, and environmental sustainability.

Combined drug action of 2-phenylimidazo[2,1-b]benzothiazole derivatives on cancer cells according to their oncogenic molecular signatures

The development of targeted molecular therapies has provided remarkable advances into the treatment of human cancers. However, in most tumors the selective pressure triggered by anticancer agents encourages cancer cells to acquire resistance mechanisms. The generation of new rationally designed targeting agents acting on the oncogenic path(s) at multiple levels is a promising approach for molecular therapies. 2-phenylimidazo[2,1-b]benzothiazole derivatives have been highlighted for their properties of targeting oncogenic Met receptor tyrosine kinase (RTK) signaling. In this study, we evaluated the mechanism of action of one of the most active imidazo[2,1-b]benzothiazol-2-ylphenyl moiety-based agents, Triflorcas, on a panel of cancer cells with distinct features. We show that Triflorcas impairs in vitro and in vivo tumorigenesis of cancer cells carrying Met mutations. Moreover, Triflorcas hampers survival and anchorage-independent growth of cancer cells characterized by 'RTK swapping' by interfering with PDGFRβ phosphorylation. A restrained effect of Triflorcas on metabolic genes correlates with the absence of major side effects in vivo. Mechanistically, in addition to targeting Met, Triflorcas alters phosphorylation levels of the PI3K-Akt pathway, mediating oncogenic dependency to Met, in addition to Retinoblastoma and nucleophosmin/B23, resulting in altered cell cycle progression and mitotic failure. Our findings show how the unusual binding plasticity of the Met active site towards structurally different inhibitors can be exploited to generate drugs able to target Met oncogenic dependency at distinct levels. Moreover, the disease-oriented NCI Anticancer Drug Screen revealed that Triflorcas elicits a unique profile of growth inhibitory-responses on cancer cell lines, indicating a novel mechanism of drug action. The anti-tumor activity elicited by 2-phenylimidazo[2,1-b]benzothiazole derivatives through combined inhibition of distinct effectors in cancer cells reveal them to be promising anticancer agents for further investigation.

Combined drug action of 2-phenylimidazo[2,1-b]benzothiazole derivatives on cancer cells according to their oncogenic molecular signatures

The development of targeted molecular therapies has provided remarkable advances into the treatment of human cancers. However, in most tumors the selective pressure triggered by anticancer agents encourages cancer cells to acquire resistance mechanisms. The generation of new rationally designed targeting agents acting on the oncogenic path(s) at multiple levels is a promising approach for molecular therapies. 2-phenylimidazo[2,1-b]benzothiazole derivatives have been highlighted for their properties of targeting oncogenic Met receptor tyrosine kinase (RTK) signaling. In this study, we evaluated the mechanism of action of one of the most active imidazo[2,1-b]benzothiazol-2-ylphenyl moiety-based agents, Triflorcas, on a panel of cancer cells with distinct features. We show that Triflorcas impairs in vitro and in vivo tumorigenesis of cancer cells carrying Met mutations. Moreover, Triflorcas hampers survival and anchorage-independent growth of cancer cells characterized by 'RTK swapping' by interfering with PDGFRβ phosphorylation. A restrained effect of Triflorcas on metabolic genes correlates with the absence of major side effects in vivo. Mechanistically, in addition to targeting Met, Triflorcas alters phosphorylation levels of the PI3K-Akt pathway, mediating oncogenic dependency to Met, in addition to Retinoblastoma and nucleophosmin/B23, resulting in altered cell cycle progression and mitotic failure. Our findings show how the unusual binding plasticity of the Met active site towards structurally different inhibitors can be exploited to generate drugs able to target Met oncogenic dependency at distinct levels. Moreover, the disease-oriented NCI Anticancer Drug Screen revealed that Triflorcas elicits a unique profile of growth inhibitory-responses on cancer cell lines, indicating a novel mechanism of drug action. The anti-tumor activity elicited by 2-phenylimidazo[2,1-b]benzothiazole derivatives through combined inhibition of distinct effectors in cancer cells reveal them to be promising anticancer agents for further investigation.

Dual Action of BPC194: A Membrane Active Peptide Killing Bacterial Cells

Membrane active peptides can perturb the lipid bilayer in several ways, such as poration and fusion of the target cell membrane, and thereby efficiently kill bacterial cells. We probe here the mechanistic basis of membrane poration and fusion caused by membrane-active, antimicrobial peptides. We show that the cyclic antimicrobial peptide, BPC194, inhibits growth of Gram-negative bacteria and ruptures the outer and inner membrane at the onset of killing, suggesting that not just poration is taking place at the cell envelope. To simplify the system and to better understand the mechanism of action, we performed Förster resonance energy transfer and cryogenic transmission electron microscopy studies in model membranes and show that the BPC194 causes fusion of vesicles. The fusogenic action is accompanied by leakage as probed by dual-color fluorescence burst analysis at a single liposome level. Atomistic molecular dynamics simulations reveal how the peptides are able to simultaneously perturb the membrane towards porated and fused states. We show that the cyclic antimicrobial peptides trigger both fusion and pore formation and that such large membrane perturbations have a similar mechanistic basis

Barriers of ESCO Service Business in Finland

The purpose of this study is to determine what are the key barriers hampering ESCO service business success in Finland. Research approach for this study is qualitative. Data was collected using Delphi method with two questionnaire rounds. Internet based tool was applied in carrying out questionnaires. Respondents of the questionnaires were ESCO service experts and researchers, and people working for ESCO service providers. Characteristics of ESCO service and ESCO project implementation are analyzed by using transaction costs theory of service business. In terms of ESCO service in Finland, uncertainty and asset specificity are relevant dimensions of TCE. General uncertainty in world’s economy hinders demand for ESCO service, and asset specificity of ESCO contracts induces slight problems for project financiers. Also bounded rationalism and opportunism are present in Finnish ESCO business. The most significant barriers of success of ESCO service in Finland are problems in legislative and political frameworks, and in customers’ investment processes. ESCO service providers should move more strongly towards service dominant business logic and improve understanding of customer needs. Political barriers are unsuitable procurement processes, unclear and unpredictable laws, and lack of compelling factors in subsidy system. Investment process hurdles are caused by customers’ lack of interest to change course of action. These are things in which ESCOs can have influence in.

An exploratory study of nurses' perceptions of their action learning experience /

Each year, the College of Nurses of Ontario (CNO) requires all registered nurses and registered practical nurses in Ontario to complete a Reflective Practice learning activity. In doing so, nurses are expected to perform a self- assessment, identify a practice problem or issue, create and implement a personal learning plan, and evaluate the learning and outcomes accomplished. The process and components of CNO's Reflective Practice program are very similar to an Action Learning activity. The purpose of this qualitative research was to explore the perceptions of 1 1 nurses who completed at least 1 Action Learning activity. Data analysis of their comments provided insight into their perceptions of the Action Learning experience, perceptions of the negative and positive characteristics of various activities within the Action Learning process, and perceptions of barriers or challenges within this experience. The author concluded that participants perceived their Action Learning activities to be a positive experience because the process focused on practice problems and issues, enhanced thinking about practice problems, and achieved practice-relevant outcomes. However, the results indicated that self-directed learning and journal writing were difficult activities for some participants, and some experienced negative emotional responses during reflection. The research concluded that barriers to implementation of Action Learning include a lack of understanding of the process and a perceived lack of support from employers.

Insurgency in a time of terrorism

Is it possible to separate terrorism from armed insurgency? Are all armed manifestations terrorism? Is terrorism a method of action or a logic for action? This article purports to analyze insurgency in the midst of the anti-terrorist era of the new century. By using Vietnam as an example, the author points out how armed insurgency has as of lately been called “terrorist”, yet stresses that this concept should be carefully and strategically looked through in order to better understand the violent nature of two very different phenomena: transactional and trans-national insurgencies-----¿Se puede escindir el terrorismo de la insurgencia armada? ¿Toda expresión armada es terrorismo? ¿El territorio es un método de acción o una lógica de acción? Este artículo presenta un análisis de la insurgencia a la luz de la era antiterrorista del nuevo siglo. Con la utilización del ejemplo de Vietnam el autor señala cómo la insurgencia armada ha sido señalada de “terrorista”; sin embargo, debe revisarse detenidamente de manera estratégica este concepto para entender mejor la naturaleza de la violencia de dos fenómenos diferentes: la insurgencia transnacional y el terrorismo transnacional.

The Construction of a State Peace Policy and the Process of Conflict Resolution

The academic literature specialized on processes of conflict resolution has focused on how third party intervention and mediation can contribute to end violent conflict, however it has also ignored the potential role of the state in countries affected by internal war. This article calls for a better understanding of the state, not only as a source of contemporary conflict but as a potential advocate of conflict resolution processes. It suggests that it is necessary and possible to involve the state in more effective processes of conflict resolution through the implementation of a State Peace Policy. The central argument is that some of the critical elements that should guide the state action when confronting the destructive logic of war and violence can be effectively undertaken through a public policy focused on building peace. After suggesting a general definition of State Peace Policy and highlighting some of its main attributes, the article recognizes that this sort of policy can also orientate the unfinished process of state consolidation in Colombia and other countries affected by internal conflict. The role of the state in the process of conflict resolution is crucial; however there are some issues normally ignored within the policy-making process, they must be seriously taken into account in order to eliminate the underlying structures that perpetuate conflict and delay the consolidation of sustainable peace.-----La literatura académica especializada en procesos de resolución de conflictos se ha centrado en el estudio de cómo la intervención de terceras partes y la labor de mediación pueden contribuir a poner fin a los conflictos violentos, sin embargo, también ha ignorado el rol potencial del estado en aquellos países afectados por la guerra interna. Este artículo llama la atención sobre la necesidad de estudiar al estado no sólo como la fuente de los conflictos contemporáneos, sino como un colaborador potencial en procesos de resolución de conflictos. Se sugiere que es necesario y también posible involucrar al estado en este tipo de procesos de una manera más efectiva a través de la implementación de una Política de Estado centrada en la Paz. El argumento central es que algunos de los elementos claves que deben guiar la acción del estado cuando éste se enfrenta a la lógica destructiva de la guerra y la violencia, pueden ser efectivamente tratados a través de una política pública que de prioridad a la construcción de la paz. Luego de sugerir una definición general y destacar algunos de los principales atributos de ésta clase de Política de Estado, el artículo reconoce que ésta podría también orientar el proceso inacabado de consolidación del estado en Colombia y en otros países afectados por conflictos internos. El rol del estado en el proceso para resolver los conflictos es crucial, sin embargo hay algunos aspectos normalmente ignorados durante el proceso de formulación de políticas que deben ser tomados en cuenta seriamente para eliminar las estructuras que perpetúan el conflicto y que retrasan la consolidación de la paz sostenible.

Publicness of goods and violent conflict : evidence from Colombia

How the degree of publicness of goods affect violent conflict? Based on the theoretical model in Esteban and Ray (2001) we find that the effect of the degree of publicness depends on the group size. When the group is small (large), the degree of publicness increases (decreases) the likelihood of conflict. This opens an empirical question that we tackle using microdata from the Colombian conflict at the municipality level. We use three goods with different publicness degree to identify the sign of the effect of publicness on conflict. These goods are coca crops (private good), road density (public good subject to congestion) and average education quality (a purer public good). After dealing with endogeneity issues using an IV approach, we find that the degree of publicness reduces the likelihood of both paramilitary and guerrilla attacks. Moreover, coca production exacerbates conflict and the provision of both public goods mitigates conflict. These results are robust to size, geographical, and welfare controls. Policies that improve public goods provision will help to fight the onset of conflict.

MEASUREMENT AND MODELING OF THE TOXICITY OF BINARY MIXTURES IN THE NEMATODE CAENORHABDITIS ELEGANS-A TEST OF INDEPENDENT ACTION

Ecological risk assessments must increasingly consider the effects of chemical mixtures on the environment as anthropogenic pollution continues to grow in complexity. Yet testing every possible mixture combination is impractical and unfeasible; thus, there is an urgent need for models that can accurately predict mixture toxicity from single-compound data. Currently, two models are frequently used to predict mixture toxicity from single-compound data: Concentration addition and independent action (IA). The accuracy of the predictions generated by these models is currently debated and needs to be resolved before their use in risk assessments can be fully justified. The present study addresses this issue by determining whether the IA model adequately described the toxicity of binary mixtures of five pesticides and other environmental contaminants (cadmium, chlorpyrifos, diuron, nickel, and prochloraz) each with dissimilar modes of action on the reproduction of the nematode Caenorhabditis elegans. In three out of 10 cases, the IA model failed to describe mixture toxicity adequately with significant or antagonism being observed. In a further three cases, there was an indication of synergy, antagonism, and effect-level-dependent deviations, respectively, but these were not statistically significant. The extent of the significant deviations that were found varied, but all were such that the predicted percentage effect seen on reproductive output would have been wrong by 18 to 35% (i.e., the effect concentration expected to cause a 50% effect led to an 85% effect). The presence of such a high number and variety of deviations has important implications for the use of existing mixture toxicity models for risk assessments, especially where all or part of the deviation is synergistic.

Teachers’ action research in a culture of performativity

In a culture of performativity, action research offers teachers an opportunity to step back and reflect on their practice. This paper reports on a collaborative project carried out between a university and a secondary school in England, in which the university staff supported an action research project within the school. Five school teachers volunteered to engage in this project. They were given an introduction to action research and were assigned a university researcher to support them. Despite the common input and a common school culture, the teachers engaged in very different models of action research. This article reports on two teachers whose approaches were dissimilar. It examines these differences and suggests that they can be explained by considering the teachers’ different responses to a performativity culture.