Arginine-rich peptides destabilize the plasma membrane, consistent with a pore formation translocation mechanism of cell penetrating peptides

Recent molecular dynamics simulations (Herce and Garcia, PNAS, 104: 20805 (2007)) have suggested that the arginine-rich HIV Tat peptides might be able to translocate by destabilizing and inducing transient pores in phospholipid bilayers. In this pathway for peptide translocation, arginine residues play a fundamental role not only in the binding of the peptide to the surface of the membrane but also in the destabilization and nucleation of transient pores across the bilayer, despite being charged and highly hydrophilic. Here we present a molecular dynamics simulation of a peptide composed of nine arginines (Arg-9) that shows that this peptide follows the same translocation pathway previously found for the Tat peptide. We test this hypothesis experimentally by measuring ionic currents across phospholipid bilayers and cell membranes through the pores induced by Arg-9 peptides. We find that Arg-9 peptides, in the presence of an electrostatic potential gradient, induce ionic currents across planar phospholipid bilayers, as well as in cultured osteosarcoma cells and human smooth muscle cells freshly isolated from the umbilical artery. Our results suggest that the mechanism of action of Arg-9 peptide involves the creation of transient pores in lipid bilayers and cell membranes.Comment: This is an extended version of the published manuscript, which had to be shortened before publication to fit within the number of pages required by the journa

VDAC Modulation of Cancer Metabolism: Advances and Therapeutic Challenges

Most anionic metabolites including respiratory substrates, glycolytic adenosine triphosphate (ATP), and small cations that enter mitochondria, and mitochondrial ATP moving to the cytosol, cross the outer mitochondrial membrane (OMM) through voltage dependent anion channels (VDAC). The closed states of VDAC block the passage of anionic metabolites, and increase the flux of small cations, including calcium. Consequently, physiological or pharmacological regulation of VDAC opening, by conditioning the magnitude of both anion and cation fluxes, is a major contributor to mitochondrial metabolism. Tumor cells display a pro-proliferative Warburg phenotype characterized by enhanced aerobic glycolysis in the presence of partial suppression of mitochondrial metabolism. The heterogeneous and flexible metabolic traits of most human tumors render cells able to adapt to the constantly changing energetic and biosynthetic demands by switching between predominantly glycolytic or oxidative phenotypes. Here, we describe the biological consequences of changes in the conformational state of VDAC for cancer metabolism, the mechanisms by which VDAC-openers promote cancer cell death, and the advantages of VDAC opening as a valuable pharmacological target. Particular emphasis is given to the endogenous regulation of VDAC by free tubulin and the effects of VDAC-tubulin antagonists in cancer cells. Because of its function and location, VDAC operates as a switch to turn-off mitochondrial metabolism (closed state) and increase aerobic glycolysis (pro-Warburg), or to turn-on mitochondrial metabolism (open state) and decrease glycolysis (anti-Warburg). A better understanding of the role of VDAC regulation in tumor progression is relevant both for cancer biology and for developing novel cancer chemotherapies.Fil: Heslop, Kareem A.. University of North Carolina; Estados UnidosFil: Milesi, Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; ArgentinaFil: Maldonado, Eduardo N.. University of North Carolina; Estados Unido

Binge eating attitudes in community adolescent sample and relationships with interview-assessed attachment representations in girls: a multi-center study from North Italy

Purpose: To compare community girls at risk and not at risk for binge eating (BE) in attachment representations through a narrative interview and to test the predictive role of attachment pattern(s) on the risk of binge eating among community girls. Methods: From 772 community adolescents of both sexes (33% boys) screened through the Binge Eating Scale (BES), 112 girls between 14 and 18 years, 56 placed in a group at risk for binge eating (BEG), and 56 matched peers, not at risk (NBEG), were assessed in attachment representations through the Friends and Family Interview (FFI). Results: (1) Compared to NBEG, girls in the BEG showed more insecure-preoccupied classifications and scores, together with lower narrative coherence, mother\u2019s representation as a secure base/safe haven, reflective functioning, adaptive response, and more anger toward mother. (2) Both insecure-dismissing and preoccupied patterns predicted 15% more binge-eating symptoms in the whole sample of community girls. Conclusions: Insecure attachment representations are confirmed risk factors for more binge eating, affecting emotional regulation and leading to \u201cemotional eating\u201d, thus a dimensional assessment of attachment could be helpful for prevention and intervention. Implications and limits are discussed. Level of evidence: III. Evidence obtained from cohort or case\u2013control analytic studie

The niche concept in Applied Ecology : there’s many a slip twixt the reality and the niche

Nuestro objetivo principal es analizar la utilidad del concepto de nicho en el marco de la Ecología aplicada. En primer lugar, resaltamos los problemas para definir e interpretar qué es el nicho repasando rápidamente las ideas y propiedades con las que fue asociado. La diversidad de análisis, conceptos y opiniones hacen confusos los intentos de implementar el nicho en una herramienta, ya que las propiedades o teoría asociadas a “un nicho” no se pueden extrapolar directamente a “otros nichos” solo porque todos lo hayan llamado igual. En segundo lugar, señalamos los problemas de tomar datos de la realidad para describir un nicho que nos resulte útil a objetivos aplicados. Ya sea porque las condiciones actuales han desarmado la correlación esperada entre el nicho y la distribución o el uso de recursos, o porque ya se conoce por qué esa relación no es evidencia confiable de las potencialidades ante un cambio, el hecho es que no se puede seguir suponiendo que el nicho “medido” tenga un significado concreto y aplicable. Por último, resaltamos algunos de los problemas para construir modelos predictivos razonablemente realistas, muchos de ellos derivados de que el concepto de nicho arrastra una serie de criterios obsoletos frente al entendimiento actual de la realidad y de los problemas que plantea cuando se intenta modificarla o predecirla en escalas compatibles con los problemas de manejo. Proveemos algunos ejemplos de invasiones biológicas, uno de los ámbitos donde se intentan aplicar modelos basados en el concepto de nicho, que ilustran estos problemas. Concluimos que todos los factores revisados convierten al concepto de nicho, tal como se nos presenta o se usa actualmente, en inadecuado para la gran mayoría de los aspectos aplicados a los que se pretende dar solución, y poco apto para contribuir a una “tecnología ecológica”.Our objective is to analyse the use of the niche concept into what we generally call Applied Ecology. In the first place, we emphasize the problems in defining and understanding what is the niche. We go quickly through the ideas and properties that had been associated with it since its origins. The diversity of analyses, concepts and opinions make the attempts of making a tool out of the niche concept very confusing. This is mainly because the properties or theory of one “niche” cannot be extrapolated to other “niches” just because they have all used the same name for it. Secondly, we highlight the problems when trying to obtain data from reality to describe or build a niche that is useful for applied goals. We cannot assume that a “measured” niche has a consistent and applicable meaning. This can be either because the present conditions have disrupted the expected correlation between the niche and the distribution or the use of resources, or because it is already known why that association is not evidence of the potential to respond to changes. Lastly, we show some of the problems to build realistic predictive models. Many of them are connected with the fact that the niche concept carries with it a series of obsolete criteria in view of the present understanding of reality and the problems involved when trying to modify it or predict it at the usual scales of management problems. We use some examples of biological invasions, one of the subjects where the models based on the niche concept are focussed, to illustrate these problems. We conclude that all of the revised factors turn the niche concept, as used nowadays, to be inadequate for the bulk of applied aspects that pretend to be solved. It also results hardly suitable to contribute to any “ecological technology”

Formative Assessment and Professional Training: Reflections from a Mathematics course in Bioengineering

Bioengineering is currently considered an interdisciplinary professional field which provides solutions to different problems arising in the area of health care. Its strategic importance is widely acknowledged since its developments and proposals could help diminish the level of technological dependence in the sector. The fast pace of innovation in the area of biomedical technology gives rise to permanent reflection on the learning goals and teaching strategies proposed by educators in the different training stages of a bioengineer. In this context, learning assessment appears as a controversial issue which needs to be debated and rethought. This paper describes the reflections of teachers of a Mathematics course within a Bioengineering program around the question, What approach to assessment favors the student's participation, autonomy and training as a future bioengineer? The investigation was carried out in the framework of a Participatory Research Action project and helped us to redesign assessment activities from a different perspective.Fil: Carrere, C.. Universidad Nacional de Entre Ríos. Facultad de Ingeniería; ArgentinaFil: Milesi, S.. Universidad Nacional de Entre Ríos. Facultad de Ingeniería; ArgentinaFil: Lapyckyj, I.. Universidad Nacional de Entre Ríos. Facultad de Ingeniería; ArgentinaFil: Ravera, Emiliano Pablo. Universidad Nacional de Entre Ríos. Facultad de Ingeniería; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Escher, L.. Universidad Nacional de Entre Ríos. Facultad de Ingeniería; ArgentinaFil: Miyara, A.. Universidad Nacional de Rosario; Argentina. Universidad Nacional de Entre Ríos. Facultad de Ingeniería; ArgentinaFil: Pita, G.. Universidad Nacional de Entre Ríos. Facultad de Ingeniería; ArgentinaFil: Añino, M.. Universidad Nacional de Entre Ríos. Facultad de Ingeniería; Argentin

Decadal variations in NDVI and food production in India

In this study we use long-term satellite, climate, and crop observations to document the spatial distribution of the recent stagnation in food grain production affecting the water-limited tropics (WLT), a region where 1.5 billion people live and depend on local agriculture that is constrained by chronic water shortages. Overall, our analysis shows that the recent stagnation in food production is corroborated by satellite data. The growth rate in annually integrated vegetation greenness, a measure of crop growth, has declined significantly (p < 0.10) in 23 of the WLT cropland area during the last decade, while statistically significant increases in the growth rates account for less than 2. Inmost countries, the decade-long declines appear to be primarily due to unsustainable crop management practices rather than climate alone. One quarter of the statistically significant declines are observed in India, which with the world's largest population of food-insecure people and largest WLT croplands, is a leading example of the observed declines. Here we show geographically matching patterns of enhanced crop production and irrigation expansion with groundwater that have leveled off in the past decade. We estimate that, in the absence of irrigation, the enhancement in dry-season food grain production in India, during 1982-2002, would have required an increase in annual rainfall of at least 30 over almost half of the cropland area. This suggests that the past expansion of use of irrigation has not been sustainable. We expect that improved surface and groundwater management practices will be required to reverse the recent food grain production declines. © 2010 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland

Arginine-rich peptides destabilize the plasma membrane, consistent with a pore formation translocation mechanism of cell-penetrating peptides

Recent molecular-dynamics simulations have suggested that the arginine-rich HIV Tat peptides translocate by destabilizing and inducing transient pores in phospholipid bilayers. In this pathway for peptide translocation, Arg residues play a fundamental role not only in the binding of the peptide to the surface of the membrane, but also in the destabilization and nucleation of transient pores across the bilayer. Here we present a molecular-dynamics simulation of a peptide composed of nine Args (Arg-9) that shows that this peptide follows the same translocation pathway previously found for the Tat peptide. We test experimentally the hypothesis that transient pores open by measuring ionic currents across phospholipid bilayers and cell membranes through the pores induced by Arg-9 peptides. We find that Arg-9 peptides, in the presence of an electrostatic potential gradient, induce ionic currents across planar phospholipid bilayers, as well as in cultured osteosarcoma cells and human smooth muscle cells. Our results suggest that the mechanism of action of Arg-9 peptides involves the creation of transient pores in lipid bilayers and cell membranes.Facultad de Ciencias Exacta

Comparison of Protein- or Amino Acid-Based Supplements in the Rehabilitation of Men with Severe Obesity: A Randomized Controlled Pilot Study

Background: Weight loss is associated with a reduction in all body compartments, including muscle mass (MM), and this effect produces a decrease in function and muscle strength. Our objective was to assess the impact of protein or amino acid supplements on MM loss in middle-aged men (age 35 kg/m2) during weight loss. Materials and Methods: We conducted a single-site randomized controlled trial (Clinicaltrials.gov NCT05143398) with 40 in-patient male subjects with severe obesity. Participants underwent an intervention program consisting of a low-calorie balanced diet and structured physical activity. They were randomly assigned to 4-week treatment groups: (1) control (CTR, N = 10), (2) protein (P, N = 10), (3) branched-chain amino acid (BCAA, N = 10), and (4) essential amino acid mixture with tricarboxylic acid cycle intermediates (PD-E07, N = 10) supplementation. Results: Following 4 weeks of intervention, all groups showed similar reductions in body weight compared to baseline. When examining the delta values, a notable increase in muscle mass (MM) was observed in the PD-E07 intervention group [MM (kg): 2.84 ± 3.57; MM (%): 3.63 ± 3.14], in contrast to the CTR group [MM (kg): −2.46 ± 3.04; MM (%): −0.47 ± 2.28], with a statistical significance of p = 0.045 and p = 0.023, respectively. However, the MM values for the P group [MM (kg): −2.75 ± 5.98, p = 0.734; MM (%): −0.44 ± 4.02, p = 0.990] and the BCAA group [MM (kg): −1 ± 3.3, p = 0.734; MM (%): 0.34 ± 2.85, p = 0.956] did not exhibit a statistically significant difference when compared to the CTR group. Conclusions: Amino acid-based supplements may effectively mitigate the loss of MM typically observed during weight reduction. Further validation through large-scale studies is necessary

VDAC Modulation of Cancer Metabolism: Advances and Therapeutic Challenges

Most anionic metabolites including respiratory substrates, glycolytic adenosine triphosphate (ATP), and small cations that enter mitochondria, and mitochondrial ATP moving to the cytosol, cross the outer mitochondrial membrane (OMM) through voltage dependent anion channels (VDAC). The closed states of VDAC block the passage of anionic metabolites, and increase the flux of small cations, including calcium. Consequently, physiological or pharmacological regulation of VDAC opening, by conditioning the magnitude of both anion and cation fluxes, is a major contributor to mitochondrial metabolism. Tumor cells display a pro-proliferative Warburg phenotype characterized by enhanced aerobic glycolysis in the presence of partial suppression of mitochondrial metabolism. The heterogeneous and flexible metabolic traits of most human tumors render cells able to adapt to the constantly changing energetic and biosynthetic demands by switching between predominantly glycolytic or oxidative phenotypes. Here, we describe the biological consequences of changes in the conformational state of VDAC for cancer metabolism, the mechanisms by which VDAC-openers promote cancer cell death, and the advantages of VDAC opening as a valuable pharmacological target. Particular emphasis is given to the endogenous regulation of VDAC by free tubulin and the effects of VDAC-tubulin antagonists in cancer cells. Because of its function and location, VDAC operates as a switch to turn-off mitochondrial metabolism (closed state) and increase aerobic glycolysis (pro-Warburg), or to turn-on mitochondrial metabolism (open state) and decrease glycolysis (anti-Warburg). A better understanding of the role of VDAC regulation in tumor progression is relevant both for cancer biology and for developing novel cancer chemotherapies.Instituto de Estudios Inmunológicos y Fisiopatológico