Performance of rodent spermatozoa over time is enhanced by increased ATP concentrations: The role of sperm competition

© 2015 by the Society for the Study of Reproduction, Inc. Sperm viability, acrosome integrity, motility, and swimming velocity are determinants of male fertility and exhibit an extreme degree of variation among closely related species. Many of these sperm parameters are associated with sperm ATP content, which has led to predictions of trade-offs between ATP content and sperm motility and velocity. Selective pressures imposed by sperm competition have been proposed as evolutionary causes of this pattern of diversity in sperm traits. Here, we examine variation in sperm viability, acrosome integrity, motility, swimming velocity, and ATP content over time, among 18 species of closely related muroid rodents, to address the following questions: (a) Do sperm from closely related species vary in ATP content after a period of incubation? (b) Are these differences in ATP levels related to differences in other sperm traits? (c) Are differences in ATP content and sperm performance over time explained by the levels of sperm competition in these species? Our results revealed a high degree of interspecific variability in changes in sperm ATP content, acrosome integrity, sperm motility and swimming velocity over time. Additionally, species with high sperm competition levels were able to maintain higher levels of sperm motility and faster sperm swimming velocity when they were incubated under conditions that support sperm survival. Furthermore, we show that the maintenance of such levels of sperm performance is correlated with the ability of sperm to sustain high concentrations of intracellular ATP over time. Thus, sperm competition may have an important role maximizing sperm metabolism and performance and, ultimately, the fertilizing capacity of spermatozoa.Peer Reviewe

Reseñas

Allouch, Jean. Marguerite ou l'Aimée de lacan (Margarita o la amada de lacan) E.P.E.L., parís. 1990. / Gay Peter. Freud: una vida de nuestro tiempo. Ed. Paidós. Barcelona, 1989. / Moreno Duran, Rafael H. Taberna in fabula: la experiencia leída Monteavila editores, Caracas, 1992. / Safoun, Moustapha. El inconsciente y su escriba. Ed. Paidós, Argentina, 1985. Wiesel, Eli. El crepúsculo a lo lejos Ed. Norma, Col. La otra orilla, Bogotá, 1991

Reseñas

Allouch, Jean. Marguerite ou l'Aimée de lacan (Margarita o la amada de lacan) E.P.E.L., parís. 1990. / Gay Peter. Freud: una vida de nuestro tiempo. Ed. Paidós. Barcelona, 1989. / Moreno Duran, Rafael H. Taberna in fabula: la experiencia leída Monteavila editores, Caracas, 1992. / Safoun, Moustapha. El inconsciente y su escriba. Ed. Paidós, Argentina, 1985. Wiesel, Eli. El crepúsculo a lo lejos Ed. Norma, Col. La otra orilla, Bogotá, 1991

Effect of set up protocols on the accuracy of alchemical free energy calculation over a set of ACK1 inhibitors

Hit-to-lead virtual screening frequently relies on a cascade of computational methods that starts with rapid calculations applied to a large number of compounds and ends with more expensive computations restricted to a subset of compounds that passed initial filters. This work focuses on set up protocols for alchemical free energy (AFE) scoring in the context of a Docking–MM/PBSA–AFE cascade. A dataset of 15 congeneric inhibitors of the ACK1 protein was used to evaluate the performance of AFE set up protocols that varied in the steps taken to prepare input files (using previously docked and best scored poses, manual selection of poses, manual placement of binding site water molecules). The main finding is that use of knowledge derived from X-ray structures to model binding modes, together with the manual placement of a bridging water molecule, improves the R2 from 0.45 ± 0.06 to 0.76 ± 0.02 and decreases the mean unsigned error from 2.11 ± 0.08 to 1.24 ± 0.04 kcal mol-1. By contrast a brute force automated protocol that increased the sampling time ten-fold lead to little improvements in accuracy. Besides, it is shown that for the present dataset hysteresis can be used to flag poses that need further attention even without prior knowledge of experimental binding affinitiesPeer ReviewedPostprint (published version

Nuevos fármacos antiepilépticos en Pediatría

Se estima que unos 70 millones de personas padecen epilepsia a nivel mundial de los cuales más de la mitad son niños, en los que la prevalencia estimada se sitúa en torno al 0,5-0,8%. Aunque existen diversas terapias, el tratamiento de la epilepsia se basa mayoritariamente en fármacos, que en función de su año de comercialización se clasifican como de primera, segunda o tercera generación. En el presente artículo se revisan las principales características de los fármacos antiepilépticos de última generación (lacosamida, acetato de eslicarbazepina, brivaracetam, perampanel, retigabina, everolimus y cannabidiol) que, con excepción de la retigabina (ya no está comercializada), se consideran seguros y efectivos en población pediátrica. El everolimus y el cannabidiol tienen indicaciones muy concretas (esclerosis tuberosa, síndrome de Dravet y síndrome de Lennox Gastaut) mientras que el resto están indicados en el manejo de crisis de origen focal en niños a partir de 4 años. Estas nuevas moléculas han sido desarrolladas para aportar un perfil farmacocinético y de tolerancia superior a los fármacos previamente disponibles y es previsible que a medida que aumente su uso, se vaya perfilando y ampliando su verdadero potencial. Además, por primera vez en epileptología pediátrica, se ha utilizado la extrapolación de datos de efectividad en adultos (junto con estudios de seguridad y farmacocinética específicos en población pediátrica), para acelerar la aprobación de uso en población infantil.It is estimated that about 70 million people all over the world suffer from epilepsy, half of which are children, in whom the prevalence is around 0.5 to 0.8%. Although there are several therapies, the treatment of epilepsy is based mainly on drugs, which, depending on the year of coming onto the market are classified as first, second, or third generation. In this article, a description is presented on the main characteristics of the latest generation of antiepileptic drugs (lacosamide, eslicarbazepine acetate, brivaracetam, perampanel, retigabine, everolimus and cannabidiol). These, with the exception of retigabine (is not yet on the market), are considered safe and effective in the paediatric population. Everolimus and cannabidiol have very specific indications (tuberous sclerosis, Dravet syndrome, and Lennox Gastaut syndrome), while the rest are indicated in the management of seizures of focal origin in children from 4 years-old. These new molecules have been developed in order to provide a pharmaceutical profile and tolerance superior to the previously available drugs, and it is forecast that as their use increases, their true potential and profile will widen. Furthermore, for the first time in Paediatric Epileptology,the extrapolation ofthe efficacy data in adults have been used (together with specific safety and pharmacokinetic studies in the paediatric population), in order to speed up their approval for use in the child population

Delta-24-RGD combined with radiotherapy exerts a potent antitumor effect in diffuse intrinsic pontine glioma and pediatric high grade glioma models

Pediatric high grade gliomas (pHGG), including diffuse intrinsic pontine gliomas (DIPGs), are aggressive tumors with a dismal outcome. Radiotherapy (RT) is part of the standard of care of these tumors; however, radiotherapy only leads to a transient clinical improvement. Delta-24-RGD is a genetically engineered tumor-selective adenovirus that has shown safety and clinical efficacy in adults with recurrent gliomas. In this work, we evaluated the feasibility, safety and therapeutic efficacy of Delta-24-RGD in combination with radiotherapy in pHGGs and DIPGs models. Our results showed that the combination of Delta-24-RGD with radiotherapy was feasible and resulted in a synergistic anti-glioma effect in vitro and in vivo in pHGG and DIPG models. Interestingly, Delta-24-RGD treatment led to the downregulation of relevant DNA damage repair proteins, further sensitizing tumors cells to the effect of radiotherapy. Additionally, Delta-24-RGD/radiotherapy treatment significantly increased the trafficking of immune cells (CD3, CD4+ and CD8+) to the tumor niche compared with single treatments. In summary, administration of the Delta-24-RGD/radiotherapy combination to pHGG and DIPG models is safe and significantly increases the overall survival of mice bearing these tumors. Our data offer a rationale for the combination Delta-24-RGD/radiotherapy as a therapeutic option for children with these tumors. SIGNIFICANCE: Delta-24-RGD/radiotherapy administration is safe and significantly increases the survival of treated mice. These positive data underscore the urge to translate this approach to the clinical treatment of children with pHGG and DIPGs

Revelando la geometría en profundidad de las fallas activas que limitan el valle del Guadalentín mediante sísmica de reflexión de alta resolución: resultados preliminares

[EN]: To produce seismic hazard assessments to the current state-of-the-art, it is essential to characterize the active faults in terms of geometry, interrelation and seismotectonic status. The Guadalentin Depression is the main basin within the Eastern Betic Shear Zone, which corresponds to a NE-SW tectonic corridor bounded by the Carrascoy, Alhama de Murcia and Palomares faults, from north to south. Although a number of active tectonics and paleoseismological studies have been carried out in these faults, almost nothing is known about their geometry at depth. To unveil the deep structure, geometry and upper Neogene deformation history of these faults we have carried out a high-resolution seismic reflection survey. The acquired seismic profiles will allow to improve our understanding of the deep geometry of the known active faults (up to 2 km depth), as well as to identify potential buried branches and will help to reduce the uncertainties in seismic hazard assessment.[ES]: Para producir evaluaciones del peligro sísmico actualizadas al estado del arte actual, es esencial caracterizar las fallas activas de una región en términos de geometría, interrelación y estado sismotectónico. La depresión del Guadalentín es la principal cuenca cuaternaria dentro de la Zona de Cizalla de las Béticas Orientales, la cual corresponde a un corredor tectónico con dirección NE-SW delimitado por las fallas de Carrascoy, Alhama de Murcia y Palomares, de norte a sur. Aunque varios estudios de tectónica activa y paleosismología se han centrado en estas fallas, su geometría en profundidad es bastante incierta. Para revelar la estructura profunda, la geometría y el historial de deformación desde el Neógeno superior de estas fallas, hemos llevado a cabo un estudio de sísmica de reflexión de alta resolución. Los perfiles sísmicos adquiridos permitirán mejorar nuestra comprensión de la geometría profunda de las fallas activas conocidas (hasta 2 km de profundidad), así como identificar posibles ramas ciegas, y ayudarán a reducir las incertidumbres en los cálculos de peligrosidad sísmicaHector Perea es un investigador postdoctoral del programa "Atracción de Talento" en la Universidad Complutense de Madrid financiado por la Comunidad de Madrid (2018-T1/AMB-11039). Paula Herrero y Júlia Molins han estado contratadas por el proyecto UNrIDDLE (2018-T1/AMB-11039). Juan Alcalde ha recibido financiación de las ayudas IJC2018-036074-I financiadas por MCIN/AEI/10.13039/501100011033.Peer reviewe

A clinically compatible drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis

We report a medium‐throughput drug‐screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to the unmet clinical need of brain metastasis, we identified several vulnerabilities. Among them, a blood–brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to metastases treated with the chaperone inhibitor uncovered a novel molecular program in brain metastasis, which includes biomarkers of poor prognosis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug‐screening and unbiased omic approaches that is compatible with human samples. Thus, this clinically relevant strategy is aimed to personalize the management of metastatic disease in the brain and elsewhere

Assessing positive mental health in people with chronic physical health problems: correlations with socio-demographic variables and physical health status

Background: A holistic perspective on health implies giving careful consideration to the relationship between physical and mental health. In this regard the present study sought to determine the level of Positive Mental Health (PMH) among people with chronic physical health problems, and to examine the relationship between the observed levels of PMH and both physical health status and socio-demographic variables. Methods: The study was based on the Multifactor Model of Positive Mental Health (Lluch, 1999), which comprises six factors: Personal Satisfaction (F1), Prosocial Attitude (F2), Self-control (F3), Autonomy (F4), Problem-solving and Self-actualization (F5), and Interpersonal Relationship Skills (F6). The sample comprised 259 adults with chronic physical health problems who were recruited through a primary care center in the province of Barcelona (Spain). Positive mental health was assessed by means of the Positive Mental Health Questionnaire (Lluch, 1999). Results: Levels of PMH differed, either on the global scale or on specific factors, in relation to the following variables: age: global PMH scores decreased with age (r=-0.129; p=0.038); b) gender: men scored higher on F1 (t=2.203; p=0.028) and F4 (t=3.182; p=0.002), while women scored higher on F2 (t -3.086; p=0.002) and F6 (t=-2.744; p=0.007); c) number of health conditions: the fewer the number of health problems the higher the PMH score on F5 (r=-0.146; p=0.019); d) daily medication: polymedication patients had lower PMH scores, both globally and on various factors; e) use of analgesics: occasional use of painkillers was associated with higher PMH scores on F1 (t=-2.811; p=0.006). There were no significant differences in global PMH scores according to the type of chronic health condition. The only significant difference in the analysis by factors was that patients with hypertension obtained lower PMH scores on the factor Autonomy (t=2.165; p=0.032). Conclusions: Most people with chronic physical health problems have medium or high levels of PMH. The variables that adversely affect PMH are old age, polypharmacy and frequent consumption of analgesics. The type of health problem does not influence the levels of PMH. Much more extensive studies with samples without chronic pathology are now required in order to be able to draw more robust conclusions