Calcitriol increases frataxin levels and restores mitochondrial function in cell models of Friedreich Ataxia.

Friedreich ataxia (FA) is a neurodegenerative disease caused by the deficiency of frataxin, a mitochondrial protein. In primary cultures of dorsal root ganglia neurons, we showed that frataxin depletion resulted in decreased levels of the mitochondrial calcium exchanger NCLX, neurite degeneration and apoptotic cell death. Here, we describe that frataxin-deficient dorsal root ganglia neurons display low levels of ferredoxin 1 (FDX1), a mitochondrial Fe/S cluster-containing protein that interacts with frataxin and, interestingly, is essential for the synthesis of calcitriol, the active form of vitamin D. We provide data that calcitriol supplementation, used at nanomolar concentrations, is able to reverse the molecular and cellular markers altered in DRG neurons. Calcitriol is able to recover both FDX1 and NCLX levels and restores mitochondrial membrane potential indicating an overall mitochondrial function improvement. Accordingly, reduction in apoptotic markers and neurite degeneration was observed and, as a result, cell survival was also recovered. All these beneficial effects would be explained by the finding that calcitriol is able to increase the mature frataxin levels in both, frataxin-deficient DRG neurons and cardiomyocytes; remarkably, this increase also occurs in lymphoblastoid cell lines derived from FA patients. In conclusion, these results provide molecular bases to consider calcitriol for an easy and affordable therapeutic approach for FA patients.

Brain structural changes in schizoaffective disorder compared to schizophrenia and bipolar disorder.

OBJECTIVE: Brain structural changes in schizoaffective disorder, and how far they resemble those seen in schizophrenia and bipolar disorder, have only been studied to a limited extent. METHOD: Forty-five patients meeting DSM-IV and RDC criteria for schizoaffective disorder, groups of patients with 45 matched schizophrenia and bipolar disorder, and 45 matched healthy controls were examined using voxel-based morphometry (VBM). RESULTS: Analyses comparing each patient group with the healthy control subjects found that the patients with schizoaffective disorder and the patients with schizophrenia showed widespread and overlapping areas of significant volume reduction, but the patients with bipolar disorder did not. A subsequent analysis compared the combined group of patients with the controls followed by extraction of clusters. In regions where the patients differed significantly from the controls, no significant differences in mean volume between patients with schizoaffective disorder and patients with schizophrenia in any of five regions of volume reduction were found, but mean volumes in the patients with bipolar disorder were significantly smaller in three of five. CONCLUSION: The findings provide evidence that, in terms of structural gray matter brain abnormality, schizoaffective disorder resembles schizophrenia more than bipolar disorder.

Selective estrogen receptor modulators differentially alter the immune response of gilthead seabream juveniles.

17α-ethynylestradiol (EE2), a synthetic estrogen used in oral contraceptives and hormone replacement therapy, tamoxifen (Tmx), a selective estrogen-receptor modulator used in hormone replacement therapy, and G1, a G protein-coupled estrogen receptor (GPER) selective agonist, differentially increased the hepatic vitellogenin (vtg) gene expression and altered the immune response in adult gilthead seabream (Sparus aurata L.) males. However, no information exists on the effects of these compounds on the immune response of juveniles. This study aims, for the first time, to investigate the effects of the dietary intake of EE2, Tmx or G1 on the immune response of gilthead seabream juveniles and the capacity of the immune system of the specimens to recover its functionality after ceasing exposures (recovery period). The specimens were immunized with hemocyanin in the presence of aluminium adjuvant 1 (group A) or 120 (group B) days after the treatments ceased (dpt). The results indicate that EE2 and Tmx, but not G1, differentially promoted a transient alteration in hepatic vtg gene expression. Although all three compounds did not affect the production of reactive oxygen intermediates, they inhibited the induction of interleukin-1ß (il1b) gene expression after priming. Interestingly, although Tmx increased the percentage of IgM-positive cells in both head kidney and spleen during the recovery period, the antibody response of vaccinated fish varied depending on the compound used and when the immunization was administered. Taken together, our results suggest that these compounds differentially alter the capacity of fish to respond to infection during ontogeny and, more interestingly, that the adaptive immune response remained altered to an extent that depends on the compound.

Particle trapping and structuring on the surface of LiNbO3:Fe optical waveguides using photovoltaic fields.

We report on the successful trapping and patterning of micro- and nanometric particles on the surface of LiNbO3 optical waveguides via photovoltaic tweezers. A waveguide configuration is used for the first time combined with this recently proposed technique. The electric field pattern is generated by light propagating in the waveguide, allowing us to separate the light channel with the region in which particles are deposited. Results on micro- and nanoparticle trapping, by two different deposition methods on two types of planar waveguides (by soft proton exchanged and by swift heavy ion irradiation), and using single-beam and two-beam interferometric configuration, are presented and discussed.

Prevalence of clozapine-induced sialorrhea and its effect on quality of life.

RATIONALE: Clozapine has proven to be superior to other antipsychotic drugs in the treatment of schizophrenia but is under-prescribed due to its potentially severe side effects. Clozapine-induced sialorrhea (CIS) is a frequent and extremely uncomfortable side effect, which remains understudied. OBJECTIVES: To examine the prevalence of diurnal and nocturnal CIS in a sample of patients treated with clozapine, and to evaluate its impact on quality of life. METHODS: We conducted a cross-sectional, observational study of 130 patients with schizophrenia spectrum disorders treated with clozapine. The prevalence of CIS was evaluated via specific sialorrhea scales. None of the patients included in the study was receiving a specific treatment for hypersalivation during the study period. Possible associations between sialorrhea and clinical and quality of life variables were analyzed. RESULTS: Of 130 subjects, 120 (92.3%) suffered from CIS. Eighty-one (62.31%) suffered from diurnal CIS, 115 (88.56%) from nocturnal CIS, and 85 (65.38%) suffered from both. Significant positive associations between quality of life and diurnal CIS (B = 0.417; p = 2.1e - 6, R2 = 0.156) and nocturnal CIS (B = 0.411; p = 7.7e - 6, R2 = 0.139) were detected. Thirty per cent of the subjects reported a moderate to severe negative impact of sialorrhea on their quality of life. CONCLUSIONS: The present study suggests that CIS is highly prevalent in patients with schizophrenia and has an important impact on quality of life in one-third of our sample. Therefore, the inclusion of a systematic evaluation and treatment of CIS in standard clinical practice is highly recommended. TRIAL REGISTRATION: Clinical Trials ( https://clinicaltrials.gov ) under reference NCT04197037.

Metabolic adjustments of Dentex dentex to prolonged starvation and refeeding.

The particular metabolic strategies of the common dentex (Dentex dentex) to face a period of prolonged starvation and subsequent refeeding were assessed. Plasma metabolites, endogenous reserves, and the activity of key enzymes of intermediary metabolism in liver, white muscle, and heart were evaluated. Plasma glucose, total lipid, triglycerides, total-, HDL- and LDL-cholesterol, and protein levels, liver, and white muscle glycogen, and perivisceral, and muscle fat were significantly reduced by starvation, whereas liver lipid content was surprisingly increased. Those enzymes involved in phosphorylation and oxidation of glucose and lipid synthesis, as well as alanine aminotransferase activity, were significantly depressed in liver of starved fish. The increase in ß-hydroxyacyl-CoA dehydrogenase (HOAD) indicated an enhanced fatty acid oxidation during starvation. Part of the acetyl-CoA generated by ß-oxidation was oxidized in the hepatic Krebs cycle, as reflected the increased citrate synthase (CS) activity. The oxaloacetate required for the reaction catalized by CS activity would be supplied by aspartate aminotransferase (ASAT) activity whose activity was also enhanced. Glutamate dehydrogenase also increased to deaminate the glutamate produced by transaminases, especially by the increased ASAT activity. Liver gluconeogenesis of starved fish was maintained at the same rate that in controls, with glycerol playing an important role as glucogenic substrate. The increased hepatic ß-hydroxybutyrate dehydrogenase (ß-OHBDH) activity indicates that part of the acetyl-CoA arriving from ß-oxidation was being diverted for ketone bodies production with dentex liver playing an important role in providing ketone bodies as fuels for other tissues under such circumstances. Most enzyme activities in white muscle of starved dentex were significantly depressed. In heart, starvation induced an important inhibition of those enzymes involved in glucose and protein metabolism, whereas CS, HOAD, and ß-OHBDH activities were maintained at control levels. Although several biomarkers assayed returned to control values after refeeding, many others did not, which indicate that after 3 weeks of refeeding, pre-starved dentex is still experiencing a transient period of metabolic adjustments directed toward the restoration of body mass.

Augmentation of EMDR with multifocal transcranial current stimulation (MtCS) in the treatment of fibromyalgia: study protocol of a double-blind randomized controlled exploratory and pragmatic trial.

BACKGROUND: Fibromyalgia (FM) is a generalized, widespread chronic pain disorder affecting 2.7% of the general population. In recent years, different studies have observed a strong association between FM and psychological trauma. Therefore, a trauma-focused psychotherapy, such as eye movement desensitization and reprocessing (EMDR), combined with a non-invasive brain stimulation technique, such as multifocal transcranial current stimulation (MtCS), could be an innovative adjunctive treatment option. This double-blind randomized controlled trial (RCT) analyzes if EMDR therapy is effective in the reduction of pain symptoms in FM patients and if its potential is boosted with the addition of MtCS. METHODS: Forty-five patients with FM and a history of traumatic events will be randomly allocated to Waiting List, EMDR + active-MtCS, or EMDR + sham-MtCS. Therapists and patients will be kept blind to MtCS conditions, and raters will be kept blind to both EMDR and MtCS. All patients will be evaluated at baseline, post-treatment, and follow-up at 6 months after post-treatment. Evaluations will assess the following variables: sociodemographic data, pain, psychological trauma, sleep disturbance, anxiety and affective symptoms, and wellbeing. DISCUSSION: This study will provide evidence of whether EMDR therapy is effective in reducing pain symptoms in FM patients, and whether the effect of EMDR can be enhanced by MtCS. TRIAL REGISTRATION: ClinicalTrials.gov NCT04084795 . Registered on 2 August 2019.

Analysis of photorefractive optical damage in lithium niobate: application to planar waveguides.

Photorefractive optical damage of single beams in LiNbO(3) crystals is analyzed within a framework of two photoactive centres (Fe(2+)/Fe(3+) and Nb(Li) (4+)/Nb(Li) (5+)). It compares model simulations and significant experimental measurements in LiNbO(3) waveguides. A good agreement is found in the performed comparisons: photovoltaic currents, refractive index changes and, especially relevant, in degraded beam-profiles. The progress of the degraded wavefront has been simulated by implementing a finite-difference beam-propagating method which includes the model equations. These results, together with previous ones on grating recording, provide a comprehensive, satisfactory explanation of most important questions on photorefractive optical damage.

Bloat control operators and diversity in genetic programming: a comparative study.

This paper reports a comparison of several bloat control methods and also evaluates a recent proposal for limiting the size of the individuals: a genetic operator called prune and plant. The aim of this work is to test the adequacy of this method. Since a preliminary study of the method has already shown promising results, we have performed a thorough study in a set of benchmark problems aiming at demonstrating the utility of the new approach. Prune and plant has obtained results that maintain the quality of the final solutions in terms of fitness while achieving a substantial reduction of the mean tree size in all four problem domains considered. In addition, in one of these problem domains, prune and plant has demonstrated to be better in terms of fitness, size reduction, and time consumption than any of the other bloat control techniques under comparison. The experimental part of the study presents a comparison of performance in terms of phenotypic and genotypic diversity. This comparison study can provide the practitioner with some relevant clues as to which bloat control method is better suited to a particular problem and whether the advantage of a method does or does not derive from its influence on the genetic pool diversity.

A role for matrix metalloproteinases in granulocyte infiltration and testicular remodelation in a seasonal breeding teleost.

The testicular cystic structure and the abrupt morphological changes that the fish testis undergoes during the reproductive cycle (RC) make it an interesting model for studying the regulation of spermatogenesis, in particular the role of matrix metalloproteinases (Mmps). The gilthead seabream is a seasonal breeding teleost whose testis undergoes drastic remodeling events, especially during the post-spawning stage when a massive infiltration of a immune cell type, the acidophilic granulocytes, occurred. Bearing this in mind, we studied the gilthead seabream testis gelatinolytic activities involved in migration and tissue remodeling and its regulation by endocrine, immune and tissue stimuli. Thus, we demonstrated that the germinal epithelium of the testis showed gelatinolytic activity during spermatogenesis and post-spawning but not during resting, when only scarce interstitial cells were stained. Moreover, the precursor and mature forms of two gelatinases, Mmp2- and Mmp9-like, were active in the gonad, whose activities were up-regulated by 17beta-estradiol (E(2)) but not by lipopolysaccharide (LPS)/bacterial DNA (VaDNA) in testicular cell suspensions. E(2) and LPS/VaDNA also up-regulated a variety of cytokines and chemokines. We also cloned mmp9, mmp13, tissue inhibitors of Mmps (timp)-2a and timp2b genes and found that all of them were expressed in the gonad in a RC stage-dependent manner. Interestingly, mmps and timps were highly expressed by the testicular acidophilic granulocytes. Moreover, in these cells, the gelatinolytic activity seemed to correspond to the precursor and mature forms of putative Mmp2 and Mmp9 gelatinases, while the main gelatinolytic activity seemed to correspond to the mature form of Mmp2 in head-kidney acidophilic granulocytes. Finally, although none of the stimuli used were able to induce the gelatinolytic activity of Mmp9-like in head-kidney acidophilic granulocytes, the expression of mmp9, timp2a and timp2b were all up-regulated by LPS/VaDNA in these cells, while only mmp9 and timp2a expression increased upon stimulation with gelatin.

Differentiation of certified brands of origins of Spanish white wines by HS-SPME-GC and chemometrics.

A headspace solid-phase microextraction gas-chromatographic (HS-SPME-GC) procedure was used to determine the composition of the volatile fraction of white wine samples from several Spanish certified brands of origin (CBO). The compounds present were previously identified by gas chromatography-mass spectrometry (GC-MS) and quantitative determinations were carried out by GC-FID. Four CBO, Rueda, Ribeiro, Penedés, and Condado de Huelva, were studied. Rueda wines present the highest concentrations of ethyl acetate (55.86-125.27 microg mL(-1)), isoamyl acetate (0.91-6.72 microg mL(-1)), hexyl acetate (0.09-0.81 microg g mL(-1)), and 2-phenethyl acetate (0.14-0.66 microg mL(-1)). Compounds such as ethyl hexanoate (0.88-2.15 microg mL(-1)) and ethyl decanoate (0.29-0.96 microg mL(-1)) appeared in higher concentration in Ribeiro, Rueda, and Penedés samples. According to the results obtained and by applying pattern-recognition procedures differentiation of the considered CBO was attained. Principal-component analysis (PCA), linear discriminant analysis (LDA), and multilayer perceptrons neural networks (MLP-NN) were used as chemometric tools for pattern-recognition studies.

Los niños preguntan, los niños quieren saber. 100 preguntas que hacen los niños sobre el cerebro / Children ask, children want to know. 100 questions that children ask about the brain

Introducción: La neurociencia desempeña un papel crucial en el desarrollo educativo, abarcando desde la etapa preescolar hasta la universitaria, al proporcionar conocimientos que enriquecen la cultura y los valores humanos. Objetivo: El grupo GME-CZH desarrolló un proyecto de proyección social centrado en la niñez y adolescencia y la enseñanza de neurociencias. El objetivo principal fue estimular el desarrollo cognitivo de niños y adolescentes a través de métodos innovadores, como juegos, charlas, Rally cerebral, etc., con el fin de reactivar sus mentes y enseñarles sobre el funcionamiento del cerebro. Materiales y Métodos: El proyecto se dividió en dos fases. La primera, "Semana del Cerebro 2018", se enfocó en niños y adolescentes de educación primaria y preuniversitaria, implementando actividades para estimular su interés en temas cerebrales. La segunda fase consistió en la colaboración de 150 niños y adolescentes (7-17 años) y expertos en neurociencias para la creación del libro "100 Preguntas que hacen los niños sobre el Cerebro". Resultados: La colaboración entre niños y expertos culminó en la creación exitosa del libro, abordando las inquietudes y preguntas planteadas por los niños sobre el cerebro y su funcionamiento. Conclusión: El proyecto demostró que la integración de métodos lúdicos y educativos puede ser efectiva para estimular el interés y desarrollo cognitivo en niños y adolescentes, destacando la importancia de la enseñanza de neurociencias en estas etapas educativas. Este proyecto innovador no solo contribuye al avance educativo, sino que también promueve el entendimiento del cerebro desde edades tempranas, fomentando el desarrollo integral de los estudiantes.

Introduction: Neuroscience plays a crucial role in educational development, spanning from preschool to university, providing knowledge that enriches culture and human values. Objective: The GME-CZH group developed a social outreach project focused on childhood and adolescence, specifically in the teaching of neuroscience. The main objective was to stimulate the cognitive development of children and adolescents through innovative methods such as games, talks, Brain Rally, etc., aiming to reinvigorate their minds and educate them about the functioning of the brain. Materials and Methods: The project was divided into two phases. The first, "Brain Week 2018," focused on primary and pre-university children and adolescents, implementing activities to stimulate their interest in brain-related topics. The second phase involved the collaboration of 150 children and adolescents (7-17 years old) and neuroscience experts for the creation of the book "100 Questions Children Ask About the Brain." Results: The collaboration between children and experts culminated in the successful creation of the book, addressing the concerns and questions posed by children about the brain and its functioning. Conclusion: The project demonstrated that the integration of playful and educational methods can be effective in stimulating interest and cognitive development in children and adolescents, emphasizing the importance of teaching neuroscience in these educational stages. This innovative project not only contributes to educational advancement but also promotes understanding of the brain from an early age, fostering the comprehensive development of students.

Detection of anti-heat shock protein 90 beta (Hsp90beta) antibodies in cerebrospinal fluid.

Antibodies against heat shock protein 90 beta (Hsp90beta) recognize the antigen on the cell surface of the oligodendrocyte precursor cells and cause a decrease of oligodendrocyte population in cell cultures. These antibodies have been found in patients with multiple sclerosis (MS). This report describes an original and sensitive method to detect anti-Hsp90beta antibodies in cerebrospinal fluid (CSF) using a western blot procedure. We have developed the method for autoantibody detection using Hsp90beta from cell membrane fraction instead of commercial Hsp90beta as antigen. The presence of anti-Hsp90beta antibodies in CSF of MS patients may play a pathogenic role in MS, and a large-scale study is needed to establish a possible diagnostic value of these antibodies in MS patients.

Anti-heat shock protein 90beta antibodies are detected in patients with multiple sclerosis during remission.

Antibodies against heat shock protein 90beta (Hsp90beta) recognize the antigen on the surface of oligodendrocyte precursor cells and induce a decrease in the oligodendrocyte population of cell cultures. This study investigated the presence of anti-Hsp90beta antibodies in patients with multiple sclerosis (MS) during remission. Anti-Hsp90beta antibodies were detected in the cerebrospinal fluid (CSF) of patients with a specific and sensitive western blot procedure using Hsp90beta from cell membrane fraction. The number of patients with anti-Hsp90beta antibodies detected in the CSF was significantly greater in MS patients than in control patients with other neurological diseases, which included patients with other inflammatory neurological diseases. CSF anti-Hsp90beta antibody levels were significantly higher in MS patients than in control patients. The presence of anti-Hsp90beta antibodies in the CSF of MS patients during remission could suggest a potential pathogenic role for these autoantibodies in MS.

Differentiation of green, white, black, Oolong, and Pu-erh teas according to their free amino acids content.

In this paper, the differentiation of green, black, Oolong, white, and Pu-erh teas has been carried out according to their free amino acid contents. Alanine, arginine, asparagine, aspartic acid, glutamic acid, isoleucine, histidine, leucine, phenylalanine, serine, theanine, threonine, and tyrosine have been determined by liquid chromatography with derivatization with o-phthalaldehyde and fluorescence detection. The chromatographic separation was achieved with a Hypersil ODS column and gradient elution. The amino acid contents were used as chemometric descriptors for classification purposes of different tea varieties. Principal component analysis, k-nearest neighbors, linear discriminant analysis, and artificial neural networks were applied to differentiate tea varieties. Using back-propagation multilayer perceptron artificial neural networks, 100% success in the classification was obtained. The most differentiating amino acids were glutamic acid, asparagine, serine, alanine, leucine, and isoleucine.

Some practical considerations for linearity assessment of calibration curves as function of concentration levels according to the fitness-for-purpose approach.

Since linear calibration is mostly preferred for analytical determinations, linearity in the calibration range is an important performance characteristic of any instrumental analytical method. Linearity can be proved by applying several graphical and numerical approaches. The principal graphical criteria are visual inspection of the calibration plot, the residuals plot, and the response factors plot, also called sensitivity or linearity plot. All of them must include confidence limits in order to visualize linearity deviations. In this work, the graphical representation of percent relative errors of back-calculated concentrations against the concentration of the calibration standards is proposed as linearity criterion. This graph considers a confidence interval based on the expected recovery related to the concentration level according to AOAC approach. To illustrate it, four calibration examples covering different analytical techniques and calibration situations have been studied. The proposed %RE graph was useful in all examples, helping to highlight problems related to non-linear behavior such as points with high leverage and deviations from linearity at the extremes of the calibration range. By this way, a numerical decision limit which takes into account the concentration of calibration standards can be easily included as linearity criterion in the form of %RETh=2·C-0.11. Accordingly, this %RE parameter is accurate for the decision-making related to linearity assessment according to the fitness-for-purpose approach.