Rate-induced tipping and saddle-node bifurcation for quadratic differential equations with nonautonomous asymptotic dynamics

An in-depth analysis of nonautonomous bifurcations of saddle-node type for scalar differential equations $x'=-x^2+q(t)\,x+p(t)$, where $q\colon\R\to\R$ and $p\colon\R\to\R$ are bounded and uniformly continuous, is fundamental to explain the absence or occurrence of rate-induced tipping for the differential equation $y' =(y-(2/\pi)\arctan(ct))^2+p(t)$ as the rate $c$ varies on $[0,\infty)$. A classical attractor-repeller pair, whose existence for $c=0$ is assumed, may persist for any $c>0$, or disappear for a certain critical rate $c=c_0$, giving rise to rate-induced tipping. A suitable example demonstrates that this tipping phenomenon may be reversible.Marie Skłodowska-Curie grant agreement No 643073Ministerio de Ciencia, Innovación y Universidades, RTI2018-096523-B-I00Marie Skłodowska-Curie grant agreement No 75446

The structural basis for seryl-adenylate and Ap4A synthesis by seryl-tRNA synthetase

AbstractBackground: Seryl-tRNA synthetase is a homodimeric class II aminoacyl-tRNA synthetase that specifically charges cognate tRNAs with serine. In the first step of this two-step reaction, Mg·ATP and serine react to form the activated intermediate, seryl-adenylate. The serine is subsequently transferred to the 3′-end of the tRNA. In common with most other aminoacyl-tRNA synthetases, seryl-tRNA synthetase is capable of synthesizing diadenosine tetraphosphate (Ap4A) from the enzyme-bound adenylate intermediate and a second molecule of ATP. Understanding the structural basis for the substrate specificity and the catalytic mechanism of aminoacyl-tRNA synthetases is of considerable general interest because of the fundamental importance of these enzymes to protein biosynthesis in all living cells.Results Crystal structures of three complexes of seryl-tRNA synthetase from Thermus thermophilus are described. The first complex is of the enzyme with ATP and Mn2+. The ATP is found in an unusual bent conformation, stabilized by interactions with conserved arginines and three manganese ions. The second complex contains seryl-adenylate in the active site, enzymatically produced in the crystal after soaking with ATP, serine and Mn2+. The third complex is between the enzyme, Ap4A and Mn2+. All three structures exhibit a common Mn2+ site in which the cation is coordinated by two active-site residues in addition to the α-phosphate group from the bound ligands.Conclusion Superposition of these structures allows a common reaction mechanism for seryl-adenylate and Ap4A formation to be proposed. The bent conformation of the ATP and the position of the serine are consistent with nucleophilic attack of the serine carboxyl group on the α-phosphate by an in-line displacement mechanism leading to the release of the inorganic pyrophosphate. A second ATP molecule can bind with its γ-phosphate group in the same position as the β-phosphate of the original ATP. This can attack the seryl-adenylate with the formation of Ap4A by an identical in-line mechanism in the reverse direction. The divalent cation is essential for both reactions and may be directly involved in stabilizing the transition state

The application of a social cognition model in explaining fruit intake in Austrian, Norwegian and Spanish schoolchildren using structural equation modelling

<p>Abstract</p> <p>Background</p> <p>The aim of this paper was to test the goodness of fit of the Attitude – Social influence – self-Efficacy (ASE) model in explaining schoolchildren's intentions to eat fruit and their actual fruit intake in Austria, Norway and Spain; to assess how well the model could explain the observed variance in intention to eat fruit and in reported fruit intake and to investigate whether the same model would fit data from all three countries.</p> <p>Methods</p> <p>Samples consisted of schoolchildren from three of the countries participating in the cross-sectional part of the Pro Children project. Sample size varied from 991 in Austria to 1297 in Spain. Mean age ranged from 11.3 to 11.4 years. The initial model was designed using items and constructs from the Pro Children study. Factor analysis was conducted to test the structure of the measures in the model. The Norwegian sample was used to test the latent variable structure, to make a preliminary assessment of model fit, and to modify the model to increase goodness of fit with the data. The original and modified models were then applied to the Austrian and Spanish samples. All model analyses were carried out using structural equation modelling techniques.</p> <p>Results</p> <p>The ASE-model fitted the Norwegian and Spanish data well. For Austria, a slightly more complex model was needed. For this reason multi-sample analysis to test equality in factor structure and loadings across countries could not be used. The models explained between 51% and 69% of the variance in intention to eat fruit, and 27% to 38% of the variance in reported fruit intake.</p> <p>Conclusion</p> <p>Structural equation modelling showed that a rather parsimonious model was useful in explaining the variation in fruit intake of 11-year-old schoolchildren in Norway and Spain. For Austria, more modifications were needed to fit the data.</p

Plan de negocios de helados saludables: “Viking Healthy Ice Cream”

Nuestro proyecto de investigación es de Helados Artesanales con contenido proteico con la marca “Viking Healthy Ice Cream” elaborado artesanalmente con productos naturales, proteína en polvo y sin azúcares añadidos, que aporta y tiene un balance nutricional para las personas que cuidan de su cuerpo, hacen ejercicios y buscan un postre saludable. Para ello usamos la metodología de investigación exploratoria y descriptiva, ya que buscamos conocer el mercado y describir el comportamiento del consumidor de comida saludable de lima metropolitana. Realizamos entrevistas de profundidad y creamos una landing page para validar nuestra hipótesis Luego de verificar nuestro público objetivo y ver la oportunidad de mercado, realizamos un plan de marketing en donde vimos el mercado objetivo y los planes comerciales, diseñamos el producto, verificamos el precio y la distribución, creamos el plan comunicacional y que medios digitales usaríamos, luego cuando realizamos el plan de operaciones verificamos la calidad y la distribución de nuestros productos, decidimos que nuestras operaciones se realizaran bajo el modelo de negocio de dark kitchen, esta novedosa idea nos ayuda a tener mayor rentabilidad y mejor servicio a través del delivery que nos ofrecen, avanzamos nuestro proyecto verificando los procesos empresariales, asimismo hicimos todo nuestro plan de RRHH y organigrama para contar con los colaboradores adecuados y el método de contratación, finalmente realizamos el proceso financiero lo cual nos valida la rentabilidad de nuestro proyecto.Our research project is Artisan Ice Creams with protein content with the brand name "Viking Healthy Ice Cream" made by hand with natural products, protein powder and no added sugars, which provides and has a nutritional balance for people who take care of their body, they exercise and look for a healthy dessert. For this we use the exploratory and descriptive research methodology, since we seek to know the market and describe the behavior of the consumer of healthy food from metropolitan lime. We conduct in-depth interviews and create a landing page to validate our hypothesis After verifying our target audience and seeing the market opportunity, we made a marketing plan where we saw the target market and business plans, we designed the product, we verified the price and distribution, we created the communication plan and what digital media we would use, Then when we carry out the operations plan we verify the quality and distribution of our products, we decide that our operations will be carried out under the dark kitchen business model, this novel idea helps us to have greater profitability and better service through the delivery that we offer, we advance our project by verifying the business processes, we also made our entire HR plan and organization chart to have the appropriate collaborators and the hiring method, finally we carry out the financial process which validates the profitability of our project.Trabajo de investigació

Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors

Delta-9-tetrahydrocannabinol (THC), the main psychoactive compound of marijuana, induces numerous undesirable effects, including memory impairments, anxiety, and dependence. Conversely, THC also has potentially therapeutic effects, including analgesia, muscle relaxation, and neuroprotection. However, the mechanisms that dissociate these responses are still not known. Using mice lacking the serotonin receptor 5-HT2A, we revealed that the analgesic and amnesic effects of THC are independent of each other: while amnesia induced by THC disappears in the mutant mice, THC can still promote analgesia in these animals. In subsequent molecular studies, we showed that in specific brain regions involved in memory formation, the receptors for THC and the 5-HT2A receptors work together by physically interacting with each other. Experimentally interfering with this interaction prevented the memory deficits induced by THC, but not its analgesic properties. Our results highlight a novel mechanism by which the beneficial analgesic properties of THC can be dissociated from its cognitive side effects

Evolution of the global inequality in greenhouse gases emissions using multidimensional generalized entropy measures.

Given the cumulative consequences of climate change, global concentration of greenhouse gases (GHGs) must be reduced; being inequality in per-capita emissions levels a problem to achieve a commitment by all countries. Thus, the evolution of carbon dioxide (CO2) emissions inequality has received special attention because CO2 is the most abundant GHG in the atmosphere. However, it is necessary to consider other gases to provide a real illustration of our starting point to achieve a multilateral agreement. In this paper, we study the evolution of global inequality in GHGs emissions during the period 1990–2011, considering the four main gases: CO2, methane (CH4), nitrous oxide (N2O) and fluorinated gases (F-gases). The data used in this analysis is taken from the World Resources Institute (2014) and the groups of countries are constructed according to the quantity of emissions that each country released into the atmosphere in the first year of study. For this purpose we use the multidimensional generalized entropy measures proposed by Maasoumi (1986) that can be decomposable into the between- and within-group inequality components. The biggest fall in inequality is observed when we attach more weight to the emissions transfers between the most polluting countries and assume a low substitution degree among pollutants. Finally, some economic policy implications are commented.The authors thank the Ministerio de Economía y Competitividad (Project ECO2013- 48326-C2-2-P) and the Ministerio de Educación, Cultura y Deporte (FPU13/02155) for the partial support of this work

Analytical and toxicological aspects of nanomaterials in different product groups: Challenges and opportunities

The widespread integration of engineered nanomaterials into consumer and industrial products creates new challenges and requires innovative approaches in terms of design, testing, reliability, and safety of nanotechnology. The aim of this review article is to give an overview of different product groups in which nanomaterials are present and outline their safety aspects for consumers. Here, release of nanomaterials and related analytical challenges and solutions as well as toxicological considerations, such as dose-metrics, are discussed. Additionally, the utilization of engineered nanomaterials as pharmaceuticals or nutraceuticals to deliver and release cargo molecules is covered. Furthermore, critical pathways for human exposure to nanomaterials, namely inhalation and ingestion, are discussed in the context of risk assessment. Analysis of NMs in food, innovative medicine or food contact materials is discussed. Specific focus is on the presence and release of nanomaterials, including whether nanomaterials can migrate from polymer nanocomposites used in food contact materials. With regard to the toxicology and toxicokinetics of nanomaterials, aspects of dose metrics of inhalation toxicity as well as ingestion toxicology and comparison between in vitro and in vivo conclusions are considered. The definition of dose descriptors to be applied in toxicological testing is emphasized. In relation to potential exposure from different products, opportunities arising from the use of advanced analytical techniques in more unique scenarios such as release of nanomaterials from medical devices such as orthopedic implants are addressed. Alongside higher product performance and complexity, further challenges regarding material characterization and safety, as well as acceptance by the general public are expected

Vasomotion and Neurovascular Coupling in the Visual Thalamus In Vivo

Spontaneous contraction and relaxation of arteries (and in some instances venules) has been termed vasomotion and has been observed in an extensive variety of tissues and species. However, its functions and underlying mechanisms are still under discussion. We demonstrate that in vivo spectrophotometry, measured simultaneously with extracellular recordings at the same locations in the visual thalamus of the cat, reveals vasomotion, measured as an oscillation (0.14hz) in the recorded oxyhemoglobin (OxyHb) signal, which appears spontaneously in the microcirculation and can last for periods of hours. During some non-oscillatory periods, maintained sensory stimulation evokes vasomotion lasting ∼30s, resembling an adaptive vascular phenomenon. This oscillation in the oxyhaemoblobin signal is sensitive to pharmacological manipulation: it is inducible by chloralose anaesthesia and it can be temporarily blocked by systemic administration of adrenaline or acetylcholine (ACh). During these oscillatory periods, neurovascular coupling (i.e. the relationship between local neural activity and the rate of blood supply to that location) appears significantly altered. This raises important questions with regard to the interpretation of results from studies currently dependent upon a linear relationship between neural activity and blood flow, such as neuroimaging

A phase I randomized therapeutic MVA-B vaccination improves the magnitude and quality of the T cell immune responses in HIV-1-infected subjects on HAART

Trial Design Previous studies suggested that poxvirus-based vaccines might be instrumental in the therapeutic HIV field. A phase I clinical trial was conducted in HIV-1-infected patients on highly active antiretroviral therapy (HAART), with CD4 T cell counts above 450 cells/mm3 and undetectable viremia. Thirty participants were randomized (2:1) to receive either 3 intramuscular injections of MVA-B vaccine (coding for clade B HIV-1 Env, Gag, Pol and Nef antigens) or placebo, followed by interruption of HAART. Methods The magnitude, breadth, quality and phenotype of the HIV-1-specific T cell response were assayed by intracellular cytokine staining (ICS) in 22 volunteers pre- and post-vaccination. Results MVA-B vaccine induced newly detected HIV-1-specific CD4 T cell responses and expanded pre-existing responses (mostly against Gag, Pol and Nef antigens) that were high in magnitude, broadly directed and showed an enhanced polyfunctionality with a T effector memory (TEM) phenotype, while maintaining the magnitude and quality of the pre-existing HIV-1- specific CD8 T cell responses. In addition, vaccination also triggered preferential CD8+ T cell polyfunctional responses to the MVA vector antigens that increase in magnitude after two and three booster doses

Propylthiouracil Is Teratogenic in Murine Embryos

Background: Hyperthyroidism during pregnancy is treated with the antithyroid drugs (ATD) propylthiouracil (PTU) and methimazole (MMI). PTU currently is recommended as the drug of choice during early pregnancy. Yet, despite widespread ATD use in pregnancy, formal studies of ATD teratogenic effects have not been performed. Methods: We examined the teratogenic effects of PTU and MMI during embryogenesis in mice. To span different periods of embryogenesis, dams were treated with compounds or vehicle daily from embryonic day (E) 7.5 to 9.5 or from E3.5 to E7.5. Embryos were examined for gross malformations at E10.5 or E18.5 followed by histological and micro-CT analysis. Influences of PTU on gene expression levels were examined by RNA microarray analysis. Results: When dams were treated from E7.5 to E9.5 with PTU, neural tube and cardiac abnormalities were observed at E10.5. Cranial neural tube defects were significantly more common among the PTU-exposed embryos than those exposed to MMI or vehicle. Blood in the pericardial sac, which is a feature indicative of abnormal cardiac function and/or abnormal vasculature, was observed more frequently in PTU-treated than MMI-treated or vehicle-treated embryos. Following PTU treatment, a total of 134 differentially expressed genes were identified. Disrupted genetic pathways were those associated with cytoskeleton remodeling and keratin filaments. At E 18.5, no gross malformations were evident in either ATD group, but the number of viable PTU embryos per dam at E18.5 was significantly lower from those at E10.5, indicating loss o