Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance.

We describe noncovalent, reversible asparagine ethylenediamine (AsnEDA) inhibitors of the Plasmodium falciparum proteasome (Pf20S) ß5 subunit that spare all active subunits of human constitutive and immuno-proteasomes. The compounds are active against erythrocytic, sexual, and liver-stage parasites, against parasites resistant to current antimalarials, and against P. falciparum strains from patients in Africa. The ß5 inhibitors synergize with a ß2 inhibitor in vitro and in mice and with artemisinin. P. falciparum selected for resistance to an AsnEDA ß5 inhibitor surprisingly harbored a point mutation in the noncatalytic ß6 subunit. The ß6 mutant was resistant to the species-selective Pf20S ß5 inhibitor but remained sensitive to the species-nonselective ß5 inhibitors bortezomib and carfilzomib. Moreover, resistance to the Pf20S ß5 inhibitor was accompanied by increased sensitivity to a Pf20S ß2 inhibitor. Finally, the ß5 inhibitor-resistant mutant had a fitness cost that was exacerbated by irradiation. Thus, used in combination, multistage-active inhibitors of the Pf20S ß5 and ß2 subunits afford synergistic antimalarial activity with a potential to delay the emergence of resistance to artemisinins and each other.

Inseguridad subjetiva y representaciones sociales de la delincuencia / Subjective Insecurity and Social Representations of Delinquency

Resumen El presente trabajo analiza las dinámicas de las representaciones sociales de la delincuencia en jóvenes universitarios de Venezuela (n = 305) y el País Vasco (n = 237) y la centralidad de la inseguridad subjetiva en sus principios organizadores. Siguiendo la metodología de Doise, Clèmence y Lorenzi-Cioldi (1993), se estudian los significados compartidos y diferenciales de la delincuencia, así como su anclaje en la percepción subjetiva del riesgo, experiencia de victimización y pertenencia a dos realidades nacionales. Los resultados muestran una representación más estereotipada de la delincuencia en los universitarios vascos asociando ciertos delitos a grupos y contextos criminógenos. Sin embargo, los venezolanos enfatizan las causas y consecuencias destructivas para la vida social y un estado de miedo e inseguridad, debido a una experiencia más cercana al delito. La percepción subjetiva del riesgo y la experiencia de victimización quedan asociadas a dichas representaciones, lo que permite la propuesta de nuevas prioridades y desafíos en los métodos utilizados para estudiar y combatir el miedo e inseguridad subjetiva.

Abstract This work analyses the dynamics of social representations with a sample of university students in Spain (n = 237) and Venezuela (n = 305) along with the centrality of subjective insecurity on their organizational principles. Following the methodology proposed by Doise, Clèmence, and Lorenzi-Cioldi (1993), the shared and differential meanings of delinquency are studied, as well as their anchoring in the subjective perception of risk, victimization experience and belonging to two national realities. Results show that Basque students represent delinquency stereotypically, associating some crime types to certain groups and criminogenic contexts related to young people, drugs, and immigration. Nevertheless Venezuelan students emphasise the causes of crime and its destructive consequences for social life, and a state of fear and insecurity due to a closer experience of crime. The subjective perception of risk and the victimization experiences are associated with these representations, allowing us to propose new priorities and challenges in the methods used for studying and facing fear and subjective insecurity.

Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose-Efficacy Modeling.

BACKGROUND: Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. METHOD AND FINDINGS: The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3-4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11-16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23-39). The compound's preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as survival) in relation to area under the concentration versus time curve (AUC), maximum observed plasma concentration (Cmax), and time above a threshold concentration. The determination of the dose-efficacy relationship of ACT-451840 under curative conditions in rodent malaria models allowed prediction of the human efficacious exposure. CONCLUSION: The dual activity of ACT-451840 against asexual and sexual stages of P. falciparum and the activity on P. vivax have the potential to meet the specific profile of a target compound that could replace the fast-acting artemisinin component and harbor additional gametocytocidal activity and, thereby, transmission-blocking properties. The fast parasite reduction ratio (PRR) and gametocytocidal effect of ACT-451840 were recently also confirmed in a clinical proof-of-concept (POC) study.

Self-reported health status in primary health care: the influence of immigration and other associated factors.

OBJECTIVE: The aims of this study are to compare self-reported health status between Spanish-born and Latin American-born Spanish residents, adjusted by length of residence in the host country; and additionally, to analyse sociodemographic and psychosocial variables associated with a better health status. DESIGN: This is a cross-sectional population based study of Latin American-born (n = 691) and Spanish-born (n = 903) in 15 urban primary health care centres in Madrid (Spain), carried out between 2007 and 2009. The participants provided information, through an interview, about self-reported health status, socioeconomic characteristics, psychosocial factors and migration conditions. Descriptive and multiple logistic regression analyses were conducted. RESULTS: The Spanish-born participants reported a better health status than the Latin America-born participants (79.8% versus 69.3%, p<0.001). Different patterns of self-reported health status were observed depending on the length of residence in the host country. The proportion of immigrants with a better health status is greater in those who have been in Spain for less than five years compared to those who have stayed longer. Better health status is significantly associated with being men, under 34 years old, being Spanish-born, having a monthly incomes of over 1000 euros, and having considerable social support and low stress. CONCLUSIONS: Better self-reported health status is associated with being Spanish-born, men, under 34 years old, having an uppermiddle-socioeconomic status, adequate social support, and low stress. Additionally, length of residence in the host country is seen as a related factor in the self-reported health status of immigrants.

The relationship between social support and self-reported health status in immigrants: an adjusted analysis in the Madrid Cross Sectional Study.

BACKGROUND: Social support is an important factor in the adaptation process of immigrants, helping for their integration in a new environment. The lack of social support may influence on well-being and health status. The aim of this study is to describe the social support of immigrant and native population and study the possible association between immigration and lack social support after adjusting for sociodemographic factors, income, stress and self-reported health status. METHODS: Cross-sectional population based study of immigrants and national patients without mental disorders of 15 urban primary health centers in the north-eastern area of Madrid. Participants provided information on social support, stress level, perceived health status and socio-economic characteristics. Descriptive and multiple logistic regression were conducted. RESULTS: The proportion of the global perception of social support among immigrants and natives was 79.2% and 94.2%, respectively. The lack of global social support adjusted prevalence ratio (PR) of immigrant was 2.72 (95% Confidence Interval=1.81-4.09), showing a significant association with being male (PR=2.26), having monthly income below 500 euros (PR=3.81) and suffering stress (PR=1.94). For the dimensions of lack of social support the higher association was being an immigrant and suffering stress. CONCLUSIONS: We conclude that with regardless of the level of monthly income, stress level, self-reported health status, and gender, immigrant status is directly associated with lack social support. The variable most strongly associated with lack social support has been monthly income below 500 euros.

Engineering human cells for in vivo secretion of antibody and non-antibody therapeutic proteins.

Purified proteins such as antibodies are widely used as therapeutic agents in clinical medicine. However, clinical-grade proteins for therapeutic use require sophisticated technologies and are extremely expensive to produce. In vivo secretion of therapeutic proteins by genetically engineered human cells may advantageously replace injection of highly purified proteins. The use of gene transfer methods circumvents problems related to large-scale production and purification and offers additional benefits by achieving sustained concentrations of therapeutic protein with a syngenic glycosylation pattern that make the protein potentially less immunogenic. The feasibility of the in vivo production of therapeutic proteins by diverse cells/tissues has now been demonstrated using different techniques, such as ex vivo genetically modified cells and in vivo gene transfer mediated by viral vectors.