Anti-malarial ozonides OZ439 and OZ609 tested at clinically relevant compound exposure parameters in a novel ring-stage survival assay

BACKGROUND: Drug efficacy against kelch 13 mutant malaria parasites can be determined in vitro with the ring-stage survival assay (RSA). The conventional assay protocol reflects the exposure profile of dihydroartemisinin. METHODS: Taking into account that other anti-malarial peroxides, such as the synthetic ozonides OZ439 (artefenomel) and OZ609, have different pharmacokinetics, the RSA was adjusted to the concentration-time profile of these ozonides in humans and a novel, semi-automated readout was introduced. RESULTS: When tested at clinically relevant parameters, it was shown that OZ439 and OZ609 are active against the Plasmodium falciparum clinical isolate Cam3.I(R539T). CONCLUSION: If the in vitro RSA does indeed predict the potency of compounds against parasites with increased tolerance to artemisinin and its derivatives, then the herein presented data suggest that following drug-pulses of at least 48 h, OZ439 and OZ609 will be highly potent against kelch 13 mutant isolates, such as P. falciparum Cam3.I(R539T)

Tendencias en el desarrollo temporal del mal del ciprés en parcelas permanentes de una reserva forestal nacional de Austrocedrus chilensis (Patagonia, Argentina)

Longevity is a characteristic of forest trees that influences their responses to challenges by biotic and abiotic stresses and the temporal development of symptoms. Monitoring programs have been extensively used to detect the impact of climatic change, air pollution and outbreaks of pathogens on forest health, growth and dynamics. In Argentina, forests of Patagonian cypress are affected since mid twenty century by a mortality process called «mal del ciprés» (cypress mortality), but information about their temporal progression is scarce. In the present work we used a database from a program of dasometric permanent plots to analyse the temporal development of cypress mortality on plot and tree level, and determine qualitatively the spatial distribution of affected trees. Particular pulses of appearance of affected trees shared by all plots, rapid or slow progress of mortality at tree level and a homogeneous distribution of affected trees without a clear pattern of expansion from a central point were determined. The results indicate that the episodic appearance of affected trees can be related with warm and dry climatic periods and suggest that the individuals affected by cypress mortality share some special characteristics such as genetic background, developmental conditions or physiological mechanisms for drought responses.La longevidad de las especies arbóreas afecta la respuesta a estreses bióticos o abióticos y, en gran medida, determina el desarrollo temporal de los síntomas. Por tal motivo, los programas de monitoreo se han empleado para detectar el impacto del cambio climático, la polución ambiental o estallidos de patógenos en la sanidad y dinámica de los bosques. En Argentina, los bosques de Austrocedrus chilensis sufren desde 1945 una mortalidad masiva conocida como «mal del ciprés»; sin embargo, hay escasa información sobre su progresión temporal. En el presente trabajo una base de datos de un programa de parcelas permanentes se empleó para analizar el desarrollo temporal de la mortalidad a nivel de parcela e individuo y la distribución espacial de los árboles afectados. Se determinó que la aparición de síntomas sigue un patrón de pulsos compartido por todas las parcelas, con mortalidad rápida o lenta a nivel de individuo y una distribución homogénea de la mortalidad sin un patrón de expansión desde un punto central. Los resultados indican que los episodios de afectación pueden ser relacionados con períodos climáticos cálidos y secos, sugiriendo que los individuos afectados comparten características tales como background genético, condiciones de sitio o respuesta a la sequía.Facultad de Ciencias ExactasInstituto de Biotecnologia y Biologia Molecula

Tendencias en el desarrollo temporal del mal del ciprés en parcelas permanentes de una reserva forestal nacional de Austrocedrus chilensis (Patagonia, Argentina)

Longevity is a characteristic of forest trees that influences their responses to challenges by biotic and abiotic stresses and the temporal development of symptoms. Monitoring programs have been extensively used to detect the impact of climatic change, air pollution and outbreaks of pathogens on forest health, growth and dynamics. In Argentina, forests of Patagonian cypress are affected since mid twenty century by a mortality process called «mal del ciprés» (cypress mortality), but information about their temporal progression is scarce. In the present work we used a database from a program of dasometric permanent plots to analyse the temporal development of cypress mortality on plot and tree level, and determine qualitatively the spatial distribution of affected trees. Particular pulses of appearance of affected trees shared by all plots, rapid or slow progress of mortality at tree level and a homogeneous distribution of affected trees without a clear pattern of expansion from a central point were determined. The results indicate that the episodic appearance of affected trees can be related with warm and dry climatic periods and suggest that the individuals affected by cypress mortality share some special characteristics such as genetic background, developmental conditions or physiological mechanisms for drought responses.La longevidad de las especies arbóreas afecta la respuesta a estreses bióticos o abióticos y, en gran medida, determina el desarrollo temporal de los síntomas. Por tal motivo, los programas de monitoreo se han empleado para detectar el impacto del cambio climático, la polución ambiental o estallidos de patógenos en la sanidad y dinámica de los bosques. En Argentina, los bosques de Austrocedrus chilensis sufren desde 1945 una mortalidad masiva conocida como «mal del ciprés»; sin embargo, hay escasa información sobre su progresión temporal. En el presente trabajo una base de datos de un programa de parcelas permanentes se empleó para analizar el desarrollo temporal de la mortalidad a nivel de parcela e individuo y la distribución espacial de los árboles afectados. Se determinó que la aparición de síntomas sigue un patrón de pulsos compartido por todas las parcelas, con mortalidad rápida o lenta a nivel de individuo y una distribución homogénea de la mortalidad sin un patrón de expansión desde un punto central. Los resultados indican que los episodios de afectación pueden ser relacionados con períodos climáticos cálidos y secos, sugiriendo que los individuos afectados comparten características tales como background genético, condiciones de sitio o respuesta a la sequía.Facultad de Ciencias ExactasInstituto de Biotecnologia y Biologia Molecula

Tendencias en el desarrollo temporal del mal del ciprés en parcelas permanentes de una reserva forestal nacional de Austrocedrus chilensis (Patagonia, Argentina)

Longevity is a characteristic of forest trees that influences their responses to challenges by biotic and abiotic stresses and the temporal development of symptoms. Monitoring programs have been extensively used to detect the impact of climatic change, air pollution and outbreaks of pathogens on forest health, growth and dynamics. In Argentina, forests of Patagonian cypress are affected since mid twenty century by a mortality process called «mal del ciprés» (cypress mortality), but information about their temporal progression is scarce. In the present work we used a database from a program of dasometric permanent plots to analyse the temporal development of cypress mortality on plot and tree level, and determine qualitatively the spatial distribution of affected trees. Particular pulses of appearance of affected trees shared by all plots, rapid or slow progress of mortality at tree level and a homogeneous distribution of affected trees without a clear pattern of expansion from a central point were determined. The results indicate that the episodic appearance of affected trees can be related with warm and dry climatic periods and suggest that the individuals affected by cypress mortality share some special characteristics such as genetic background, developmental conditions or physiological mechanisms for drought responses.La longevidad de las especies arbóreas afecta la respuesta a estreses bióticos o abióticos y, en gran medida, determina el desarrollo temporal de los síntomas. Por tal motivo, los programas de monitoreo se han empleado para detectar el impacto del cambio climático, la polución ambiental o estallidos de patógenos en la sanidad y dinámica de los bosques. En Argentina, los bosques de Austrocedrus chilensis sufren desde 1945 una mortalidad masiva conocida como «mal del ciprés»; sin embargo, hay escasa información sobre su progresión temporal. En el presente trabajo una base de datos de un programa de parcelas permanentes se empleó para analizar el desarrollo temporal de la mortalidad a nivel de parcela e individuo y la distribución espacial de los árboles afectados. Se determinó que la aparición de síntomas sigue un patrón de pulsos compartido por todas las parcelas, con mortalidad rápida o lenta a nivel de individuo y una distribución homogénea de la mortalidad sin un patrón de expansión desde un punto central. Los resultados indican que los episodios de afectación pueden ser relacionados con períodos climáticos cálidos y secos, sugiriendo que los individuos afectados comparten características tales como background genético, condiciones de sitio o respuesta a la sequía.Facultad de Ciencias ExactasInstituto de Biotecnologia y Biologia Molecula

Calmodulin-like proteins localized to the conoid regulate motility and cell invasion by Toxoplasma gondii

Toxoplasma gondii contains an expanded number of calmodulin (CaM)-like proteins whose functions are poorly understood. Using a combination of CRISPR/Cas9-mediated gene editing and a plant-like auxin-induced degron (AID) system, we examined the roles of three apically localized CaMs. CaM1 and CaM2 were individually dispensable, but loss of both resulted in a synthetic lethal phenotype. CaM3 was refractory to deletion, suggesting it is essential. Consistent with this prediction auxin-induced degradation of CaM3 blocked growth. Phenotypic analysis revealed that all three CaMs contribute to parasite motility, invasion, and egress from host cells, and that they act downstream of microneme and rhoptry secretion. Super-resolution microscopy localized all three CaMs to the conoid where they overlap with myosin H (MyoH), a motor protein that is required for invasion. Biotinylation using BirA fusions with the CaMs labeled a number of apical proteins including MyoH and its light chain MLC7, suggesting they may interact. Consistent with this hypothesis, disruption of MyoH led to degradation of CaM3, or redistribution of CaM1 and CaM2. Collectively, our findings suggest these CaMs may interact with MyoH to control motility and cell invasion

The role of clathrin in post-golgi trafficking in toxoplasma gondii

Apicomplexan parasites are single eukaryotic cells with a highly polarised secretory system that contains unique secretory organelles (micronemes and rhoptries) that are required for host cell invasion. In contrast, the role of the endosomal system is poorly understood in these parasites. With many typical endocytic factors missing, we speculated that endocytosis depends exclusively on a clathrin-mediated mechanism. Intriguingly, in Toxoplasma gondii we were only able to observe the endogenous clathrin heavy chain 1 (CHC1) at the Golgi, but not at the parasite surface. For the functional characterisation of Toxoplasma gondii CHC1 we generated parasite mutants conditionally expressing the dominant negative clathrin Hub fragment and demonstrate that CHC1 is essential for vesicle formation at the trans-Golgi network. Consequently, the functional ablation of CHC1 results in Golgi aberrations, a block in the biogenesis of the unique secretory microneme and rhoptry organelles, and of the pellicle. However, we found no morphological evidence for clathrin mediating endocytosis in these parasites and speculate that they remodelled their vesicular trafficking system to adapt to an intracellular lifestyle

Monitoring credit risk in the social economy sector by means of a binary goal programming model

The final publication is available at Springer via http://dx.doi.org/10.1007/s11628-012-0173-7Monitoring the credit risk of firms in the social economy sector presents a considerable challenge, since it is difficult to calculate ratings with traditional methods such as logit or discriminant analysis, due to the relatively small number of firms in the sector and the low default rate among cooperatives. This paper intro- duces a goal programming model to overcome such constraints and to successfully manage credit risk using economic and financial information, as well as expert advice. After introducing the model, its application to a set of Spanish cooperative societies is described.García García, F.; Guijarro Martínez, F.; Moya Clemente, I. (2013). Monitoring credit risk in the social economy sector by means of a binary goal programming model. 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Alveolar proteins stabilize cortical microtubules in Toxoplasma gondii

Single-celled protists use elaborate cytoskeletal structures, including arrays of microtubules at the cell periphery, to maintain polarity and rigidity. The obligate intracellular parasite Toxoplasma gondii has unusually stable cortical microtubules beneath the alveoli, a network of flattened membrane vesicles that subtends the plasmalemma. However, anchoring of microtubules along alveolar membranes is not understood. Here, we show that GAPM1a, an integral membrane protein of the alveoli, plays a role in maintaining microtubule stability. Degradation of GAPM1a causes cortical microtubule disorganisation and subsequent depo-lymerisation. These changes in the cytoskeleton lead to parasites becoming shorter and rounder, which is accompanied by a decrease in cellular volume. Extended GAPM1a depletion leads to severe defects in division, reminiscent of the effect of disrupting other alveolar proteins. We suggest that GAPM proteins link the cortical microtubules to the alveoli and are required to maintain the shape and rigidity of apicomplexan zoites

The value of postmortem computed tomography as an alternative for autopsy in trauma victims: a systematic review

The aim of this study was to assess the role of postmortem computed tomography (PMCT) as an alternative for autopsy in determining the cause of death and the identification of specific injuries in trauma victims. A systematic review was performed by searching the EMBASE and MEDLINE databases. Articles were eligible if they reported both PMCT as well as autopsy findings and included more than one trauma victim. Two reviewers independently assessed the eligibility and quality of the articles. The outcomes were described in terms of the percentage agreement on causes of death and amount of injuries detected. The data extraction and analysis were performed together. Fifteen studies were included describing 244 victims. The median sample size was 13 (range 5–52). The percentage agreement on the cause of death between PMCT and autopsy varied between 46 and 100%. The overall amount of injuries detected on CT ranged from 53 to 100% compared with autopsy. Several studies suggested that PMCT was capable of identifying injuries not detected during normal autopsy. This systematic review provides inconsistent evidence as to whether PMCT is a reliable alternative for autopsy in trauma victims. PMCT has promising features in postmortem examination suggesting PMCT is a good alternative for a refused autopsy or a good adjunct to autopsy because it detects extra injuries overseen during autopsies. To examine the value of PMCT in trauma victims there is a need for well-designed and larger prospective studies