Knockdown of orexin/hypocretin 2 receptor (Orx2) in the basolateral amygdala (BLA) affects anxious and depressive behavior. We use a new behavioral paradigm, the Stress Alternatives Model (SAM), ...designed to improve translational impact. The SAM induces social stress in adult male mice by aggression from larger mice, allowing for adaptive decision-making regarding escape. In this model, mice remain (Stay) in the oval SAM arena or escape from social aggression (Escape) via routes only large enough for the smaller mouse. We hypothesized intracerebroventricular (icv) stimulation of Orx2 receptors would be anxiolytic and antidepressive in SAM-related social behavior and the Social Interaction/Preference (SIP) test. Conversely, we predicted that icv antagonism of Orx2 receptors would promote anxious and depressive behavior in these same tests. Anxious behaviors such as freezing (both cued and conflict) and startle are exhibited more often in Stay compared with Escape phenotype mice. Time spent attentive to the escape route is more frequent in Escape mice. In Stay mice, stimulation of Orx2 receptors reduces fear conditioning, conflict freezing and startle, and promotes greater attention to the escape hole. This anxiolysis was accompanied by activation of a cluster of inhibitory neurons in the amygdala. A small percentage of those Stay mice also begin escaping; whereas Escape is reversed by the Orx2 antagonist. Escape mice were also Resilient, and Stay mice Susceptible to stress (SIP), with both conditions reversed by Orx2 antagonism or stimulation respectively. Together, these results suggest that the Orx2 receptor may be a useful potential target for anxiolytic or antidepressive therapeutics.
•Stress Alternatives Model (SAM) produces resilient (Escape) and susceptible (Stay) phenotypes.•icv Orx2 agonist reduces anxious and depressive behaviors in Stay mice.•icv Orx2 antagonist increases anxious and depressive behavior plus plasma corticosterone.•Stay mice exhibit fear conditioning, reversed by an Orx2 agonist.•icv Orx2 agonist increases immediate-early gene EGR1 in BLA parvalbumin GABA interneurons.
Recognizing lines of unconstrained handwritten text is a challenging task. The difficulty of segmenting cursive or overlapping characters, combined with the need to exploit surrounding context, has ...led to low recognition rates for even the best current recognizers. Most recent progress in the field has been made either through improved preprocessing or through advances in language modeling. Relatively little work has been done on the basic recognition algorithms. Indeed, most systems rely on the same hidden Markov models that have been used for decades in speech and handwriting recognition, despite their well-known shortcomings. This paper proposes an alternative approach based on a novel type of recurrent neural network, specifically designed for sequence labeling tasks where the data is hard to segment and contains long-range bidirectional interdependencies. In experiments on two large unconstrained handwriting databases, our approach achieves word recognition accuracies of 79.7 percent on online data and 74.1 percent on offline data, significantly outperforming a state-of-the-art HMM-based system. In addition, we demonstrate the network's robustness to lexicon size, measure the individual influence of its hidden layers, and analyze its use of context. Last, we provide an in-depth discussion of the differences between the network and HMMs, suggesting reasons for the network's superior performance.
There is growing concern that estrogenic environmental compounds that act as endocrine-disrupting chemicals might potentially have adverse effects on hormone-sensitive organs such as the breast. This ...concern is further fueled by evidence indicating that natural estrogens, specifically 17β-estradiol, are important factors in the initiation and progression of breast cancer. We have developed an in vitro—in vivo model in which we have demonstrated the carcinogenicity of E2 in human breast epithelial cells MCF-10F. Hypermethylation of NRG1, STXBP6, BMP6, CSS3, SPRY1, and SNIP were found at different progression stages in this model. The use of this powerful and unique model has provided a tool for exploring whether bisphenol A and butyl benzyl phthalate have relevance in the initiation of breast cancer. These studies provide firsthand evidence that the natural estrogen 17β-estradiol and xenoestrogenic substances like bisphenol A are able to induce neoplastic transformation in human breast epithelial cells.
► Prestige oil residues have been found in Galicia beaches nine years after the accident. ► This occurrence is explained by the hydrodynamic features of the coastal area. ► Chemical markers have been ...used for identifying the source and fate of the oil after this long period. ► Specific compositional changes attributed to biodegradation have been identified. ► New criteria for assessing the diagnostic ratios for oil fingerprinting are discussed.
Yearly monitoring in one of the most affected coastal zones by the Prestige oil spill, namely Nemiña and O Rostro beaches (NW Spain), has been carried out since 2004. Topographic data of beaches revealed seasonal altimetric changes up to 4m that would prevent the on shore persistence of oil. However, surficial and subsurficial oil was detected in the intertidal area of both beaches in all campaigns. The hydrocarbon analysis confirmed that this oil corresponded to the Prestige oil, even nine years after the accident. Tar balls were highly biodegraded suggesting that the oil was accumulated on the subtidal sediments for a long time and transported to the coast by the action of waves.
The present work provides new evidence of the long term persistence of deep oil spills from wrecks in marine areas where the hydrodynamic conditions play a twofold key role, in determining the exposed coastal area to recurrent contamination and in burying and resurfacing the oil in the intertidal zone.
Non-invasive Gamma ENtrainment Using Sensory stimulation (GENUS) at 40Hz reduces Alzheimer's disease (AD) pathology such as amyloid and tau levels, prevents cerebral atrophy, and improves behavioral ...testing performance in mouse models of AD. Here, we report data from (1) a Phase 1 feasibility study (NCT04042922, ClinicalTrials.gov) in cognitively normal volunteers (n = 25), patients with mild AD dementia (n = 16), and patients with epilepsy who underwent intracranial electrode monitoring (n = 2) to assess safety and feasibility of a single brief GENUS session to induce entrainment and (2) a single-blinded, randomized, placebo-controlled Phase 2A pilot study (NCT04055376) in patients with mild probable AD dementia (n = 15) to assess safety, compliance, entrainment, and exploratory clinical outcomes after chronic daily 40Hz sensory stimulation for 3 months. Our Phase 1 study showed that 40Hz GENUS was safe and effectively induced entrainment in both cortical regions and other cortical and subcortical structures such as the hippocampus, amygdala, insula, and gyrus rectus. Our Phase 2A study demonstrated that chronic daily 40Hz light and sound GENUS was well-tolerated and that compliance was equally high in both the control and active groups, with participants equally inaccurate in guessing their group assignments prior to unblinding. Electroencephalography recordings show that our 40Hz GENUS device safely and effectively induced 40Hz entrainment in participants with mild AD dementia. After 3 months of daily stimulation, the group receiving 40Hz stimulation showed (i) lesser ventricular dilation and hippocampal atrophy, (ii) increased functional connectivity in the default mode network as well as with the medial visual network, (iii) better performance on the face-name association delayed recall test, and (iv) improved measures of daily activity rhythmicity compared to the control group. These results support further evaluation of GENUS in a pivotal clinical trial to evaluate its potential as a novel disease-modifying therapeutic for patients with AD.
•Comparison of the Infogest in vitro gastrointestinal digestion protocol with in vivo data.•Similar milk protein degradation and release of peptides in vivo vs in vitro.•Resistant regions to ...gastrointestinal digestion from milk proteins.•The in vitro protocol constitutes a good approximation to physiological digestion.
Human jejunal digests after oral ingestion of casein and whey protein were collected by a nasogastric tube and protein degradation and peptide release was compared with that found in the digests of the same substrates using a standardised protocol. No intact casein was detected in the jejunal nor in the in vitro samples taken during the intestinal phase, while β-lactoglobulin was found in one hour-jejunal samples in agreement with the in vitro digestion. In vivo and in vitro digests showed comparable peptide profiles and high number of common sequences. A selective precipitation step was used to strengthen the identification of phosphorylated peptides. Most of the sequences found in jejunum, some of them not previously described, were also identified in the simulated digests. Common resistant regions to digestion were identified, revealing that the in vitro protocol constitutes a good approximation to the physiological gastrointestinal digestion of milk proteins.
Over the past decade, numerous reports have focused on the development and applications of Cu-mediated C–H functionalization reactions; however, to date, little is known about the Cu intermediates ...involved in these transformations. This paper details the observation and characterization of CuII and CuIII intermediates in aminoquinoline-directed C(sp2)–H functionalization of a fluoroarene substrate. An initial C(sp2)–H activation at CuII occurs at room temperature to afford an isolable anionic cyclometalated CuII complex. This complex undergoes single-electron oxidation with ferrocenium or AgI salts under mild conditions (5 min at room temperature) to afford C(sp2)–C(sp2) or C(sp2)–NO2 coupling products. Spectroscopic studies implicate the formation of a transient diamagnetic CuIII-σ-aryl intermediate that undergoes either (i) a second C(sp2)–H activation at CuIII followed by C–C bond-forming reductive elimination or (ii) reaction with a NO2 – nucleophile and C(sp2)–NO2 coupling.
•This paper presents a hybrid GGA–ELM algorithm for solar radiation prediction.•The GGA performs a feature selection, whereas the ELM produces an accurate radiation prediction.•Predictive variables ...obtained from a numerical weather meso-scale model are considered.•The proposed hybrid approach has shown excellent results for real data in Toledo, Spain.
This paper presents a novel scheme for global solar radiation prediction, based on a hybrid neural-genetic algorithm. Specifically a grouping genetic algorithm (GGA) and an Extreme Learning Machine algorithm (ELM) have been merged in a single algorithm, in such a way that the GGA solves the optimal selection of features, and the ELM carries out the prediction. The proposed scheme is also novel because it uses as input of the system the output of a numerical weather meso-scale model (WRF), i.e., atmospherical variables predicted by the WRF at different nodes. We consider then different problems associated with this general algorithmic framework: first, we evaluate the capacity of the GGA–ELM for carrying out a statistical downscaling of the WRF to a given point of interest (where a measure of solar radiation is available), i.e., we only take into account predictive variables from the WRF and the objective variable at the same time tag. In a second evaluation approach, we try to predict the solar radiation at the point of interest at different time tags t+x, using predictive variables from the WRF. Finally, we tackle the complete prediction problem by including previous values of measured solar radiation in the prediction. The proposed algorithm and its efficiency for selecting the best set of features from the WRF are analyzed in this paper, and we also describe different operators and dynamics for the GGA. Finally, we evaluate the performance of the system with these different characteristics in a real problem of solar radiation prediction at Toledo’s radiometric observatory (Spain), where the proposed system has shown an excellent performance in all the subproblems considered, in terms of different error metrics.
Recently, the cities of Yerba Buena and Tucuman in Tucumán Province, Argentina, have been affected by several storm flood events, causing hundreds of people to be evacuated from their homes
. Heavy ...intensity rainfall, new housing developments covering previously permeable grounds, and old drainage systems are the main causes for this situation.
This paper presents a simple approach of urban flood hazard assessment in a region where primary data are scarce. The objectives of this study are to develop a GIS-aided urban flood hazard zoning of the two cities applying multicriteria decision analysis and to evaluate it by means of uncertainty and sensitivity analysis. The research methodology focused on the analysis of those variables that control the water routing when high peak flows exceed the drainage-system capacity. The model incorporates five parameters: distance to the drainage channels, topography (heights and slopes), ground water table depths, and urban land use. A final hazard map for each category is obtained using an algorithm that combines factors in weighted linear combinations. The urban flood hazard map shows that the southeast part of San Miguel de Tucumán has the highest flood hazard over an extended area as a consequence of the conjunction of lowlands with slopes under 0.6% and the presence of urban stream channels with poor maintenance plan. In this area, several neighbourhoods have been flooded. The model was evaluated by the error propagation method and global sensitivity analysis to assess the uncertainty and the relative importance of model input factors. Finally, the influence of criterion weights are analyzed ranging from 25% to 75% of their original values showing a robust behaviour.
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•Novel multilevel LED regimes with C5 organic carbons were developed for mixotrophic microalgae.•Adaptation phase played an important role on the algal biomass and bioproducts ...accumulation under multilevel LED regimes.•Saturated fatty acids contributed to 35.1% of total triglyceride fatty acids production at white-red regime.•The white-blue regime increased the astaxanthin content by 51.6%.
Enhanced biosynthesis and overproduction of lipid and high-value bioproducts endows microalgae as a promising feedstock for the cost-effective development of advanced bioenergy currently. In this study, multilevel heuristic LED regimes, designed with the coordination of light, nitrogen and carbons in terms of cell physiology and morphology, have been implemented to significantly induce the growth and bioproducts accumulation of Haematococcus pluvialis under mixotrophic conditions. The white-red regime with C5 organic carbon showed a good potential for enhancing microalgal biomass and lipid synthesis, especially for saturated fatty acids. The astaxanthin biosynthesis has been significantly enhanced and the highest content of 3.3% was achieved with gluconate at the white-blue regime. Additionally, white-blue regime enhanced the protein content of H. pluvialis up to 45%, increased by 40% over the white-red culture. The multilevel LED protocol can be developed synergistically with the different adaptation and tolerance of algal cell physiology and morphology for target bioproducts.
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