Cannabidiol regulation of learned fear: implications for treating anxiety-related disorders

Anxiety and trauma-related disorders are psychiatric diseases with a lifetime prevalence of up to 25%. Phobias and post-traumatic stress disorder (PTSD) are characterized by abnormal and persistent memories of fear-related contexts and cues. The effects of psychological treatments such as exposure therapy are often only temporary and medications can be ineffective and have adverse side effects. Growing evidence from human and animal studies indicates that cannabidiol, the main non-psychotomimetic phytocannabinoid present in Cannabis sativa, alleviates anxiety in paradigms assessing innate fear. More recently, the effects of cannabidiol on learned fear have been investigated in preclinical studies with translational relevance for phobias and PTSD. Here we review the findings from these studies, with an emphasis on cannabidiol regulation of contextual fear. The evidence indicates that cannabidiol reduces learned fear in different ways: (1) cannabidiol decreases fear expression acutely, (2) cannabidiol disrupts memory reconsolidation, leading to sustained fear attenuation upon memory retrieval, and (3) cannabidiol enhances extinction, the psychological process by which exposure therapy inhibits learned fear. We also present novel data on cannabidiol regulation of learned fear related to explicit cues, which indicates that auditory fear expression is also reduced acutely by cannabidiol. We conclude by outlining future directions for research to elucidate the neural circuit, psychological, cellular, and molecular mechanisms underlying the regulation of fear memory processing by cannabidiol. This line of investigation may lead to the development of cannabidiol as a novel therapeutic approach for treating anxiety and trauma-related disorders such as phobias and PTSD in the future

Synchrotron Radiation X-Ray Microfluorescence Reveals Polarized Distribution of Atomic Elements during Differentiation of Pluripotent Stem Cells

The mechanisms underlying pluripotency and differentiation in embryonic and reprogrammed stem cells are unclear. In this work, we characterized the pluripotent state towards neural differentiated state through analysis of trace elements distribution using the Synchrotron Radiation X-ray Fluorescence Spectroscopy. Naive and neural-stimulated embryoid bodies (EB) derived from embryonic and induced pluripotent stem (ES and iPS) cells were irradiated with a spatial resolution of 20 µm to make elemental maps and qualitative chemical analyses. Results show that these embryo-like aggregates exhibit self-organization at the atomic level. Metallic elements content rises and consistent elemental polarization pattern of P and S in both mouse and human pluripotent stem cells were observed, indicating that neural differentiation and elemental polarization are strongly correlated

Mini Review: An Unexplored Role for Peroxiredoxin in Exercise-induced Redox Signalling?

Peroxiredoxin (PRDX) is a ubiquitous oxoreductase protein with a conserved ionised thiol that permits catalysis of hydrogen peroxide (H2O2) up to a million times faster than any thiol-containing signalling protein. The increased production of H2O2 within active tissues during exercise is thought to oxidise conserved cysteine thiols, which may in turn facilitate a wide variety of physiological adaptations. The precise mechanisms linking H2O2 with the oxidation of signalling thiol proteins (phosphates, kinases and transcription factors) are unclear due to these proteins’ low reactivity with H2O2 relative to abundant thiol peroxidases such as PRDX. Recent work has shown that following exposure to H2O2 in vitro, the sulfenic acid of the PRDX cysteine can form mixed disulphides with transcription factors associated with cell survival. This implicates PRDX as an ‘active’ redox relay in transmitting the oxidising equivalent of H2O2 to downstream proteins. Furthermore, under oxidative stress, PRDX can form high molecular weight structures that can be secreted into the extracellular space, potentially acting as an extracellular ‘stress’ signal. There is extensive literature assessing non-specific markers of oxidative stress in response to exercise, however the PRDX catalytic cycle may offer a more robust approach for measuring changes in redox balance following exercise. This review discusses studies assessing PRDX-mediated cellular signalling and integrates the recent advances in redox biology with investigations that have examined the role of PRDX during exercise in humans and animals. Future studies should explore the role of PRDX as a key regulator of peroxide mediated-signal transduction during exercise in humans

Cellular and Mitochondrial Effects of Alcohol Consumption

Alcohol dependence is correlated with a wide spectrum of medical, psychological, behavioral, and social problems. Acute alcohol abuse causes damage to and functional impairment of several organs affecting protein, carbohydrate, and fat metabolism. Mitochondria participate with the conversion of acetaldehyde into acetate and the generation of increased amounts of NADH. Prenatal exposure to ethanol during fetal development induces a wide spectrum of adverse effects in offspring, such as neurologic abnormalities and pre- and post-natal growth retardation. Antioxidant effects have been described due to that alcoholic beverages contain different compounds, such as polyphenols as well as resveratrol. This review analyzes diverse topics on the alcohol consumption effects in several human organs and demonstrates the direct participation of mitochondria as potential target of compounds that can be used to prevent therapies for alcohol abusers

Bullying escolar: um fenômeno multifacetado

School bullying can involve children in different ways, making them play different roles, among them, victims, bullies and bully-victims. The aim of this study was to describe how bullying occurs in high social vulnerability schools of Florianópolis metropolitan area and the roles played by students in this phenomenon. Overall, 409 children and adolescents from the 3rd to 5th grades and of two public elementary schools aged 8-16 years (X = 11.14) participated in this study. As a tool, the Olweus Questionnaire adapted to the Brazilian population was used. For data analysis, descriptive statistics and inferential statistics were applied by the Mann Whitney and Kruskal Wallis tests. As for results, 29.8% of boys and 40.5% of girls reported being victims; 32.3% of boys and 24.6% of girls reported being bullies. Victims were the most willing to help a colleague who is suffering from bullying (X = 1.54; p> 0.001), even if they do not know the victims (X = 1.57; p> 0.004). Bullies are differentiated from the group that does not participate (X = 1.73) and the group of victims (X = 2.34), being those who felt less alone (x = 1.47; p> 0.001). It was concluded that the information obtained in this study is indispensable in the search for alternatives to reduce school bullying. The strengthening of relations between school and students and a better preparation of teachers and school staff are extremely necessary to try to minimize the effects of risk factors to which these children are exposed and consequently violence at school.O bullying escolar pode envolver crianças de diferentes maneiras, fazendo com que essas assumam papéis diferenciados. Dentre estes, têm-se vítimas, agressores e vítimas-agressoras. O objetivo deste estudo foi descrever como ocorre o bullying em escolas de alta vulnerabilidade social da Grande Florianópolis e os papéis assumidos pelos alunos nesse fenômeno. Quanto ao método, participaram 409 crianças e adolescentes do terceiro ao quinto ano e da quarta à sexta série do ensino fundamental, de duas escolas públicas municipais, com idades entre 8 e 16 anos (X=11,14). Como instrumento, utilizou-se o Questionário de Olweus adaptado à população brasileira. Para a análise dos dados, empregaram-se a estatística descritiva e estatística inferencial por meio dos testes Mann Whitney e Kruskal Wallis. Quanto aos resultados, 29,8% dos meninos e 40,5% das meninas relataram terem sido vítimas; já 32,3% dos meninos e 24,6% das meninas relataram terem sido agressores. As vítimas foram as que se mostraram mais dispostas a ajudar como podem um colega que esteja sofrendo agressão (X=1,54; p>0,001), mesmo que não o conheçam (X=1,57; p>0,004). Em contrapartida, os agressores se diferenciaram do grupo que não participa (X=1,73) e do grupo das vítimas (X=2,34), sendo aqueles que menos se sentiram sozinhos (X=1,47; p>0,001). Concluiu-se que as informações obtidas neste estudo são indispensáveis na busca de alternativas para redução do bullying escolar. O fortalecimento das relações entre escola e alunos, e um maior preparo dos professores e funcionários são extremamente necessários para tentar minimizar os efeitos dos fatores de risco a que essas crianças estão expostas e consequentemente a violência na escola.CAPES - Proc. nº 0815/14-4CIEC - Centro de Investigação em Estudos da Criança, IE, UMinho (UI 317 da FCT)Projeto Estratégico da FCT: UID/CED/00317/201

Antimicrobial Resistance in Escherichia coli

Multidrug resistance in Escherichia coli has become a worrying issue that is increasingly observed in human but also in veterinary medicine worldwide. E. coli is intrinsically susceptible to almost all clinically relevant antimicrobial agents, but this bacterial species has a great capacity to accumulate resistance genes, mostly through horizontal gene transfer. The most problematic mechanisms in E. coli correspond to the acquisition of genes coding for extended-spectrum β-lactamases (conferring resistance to broad-spectrum cephalosporins), carbapenemases (conferring resistance to carbapenems), 16S rRNA methylases (conferring pan-resistance to aminoglycosides), plasmid-mediated quinolone resistance (PMQR) genes (conferring resistance to [fluoro]quinolones), and mcr genes (conferring resistance to polymyxins). Although the spread of carbapenemase genes has been mainly recognized in the human sector but poorly recognized in animals, colistin resistance in E. coli seems rather to be related to the use of colistin in veterinary medicine on a global scale. For the other resistance traits, their cross-transfer between the human and animal sectors still remains controversial even though genomic investigations indicate that extended- spectrum β-lactamase producers encountered in animals are distinct from those affecting humans. In addition, E. coli of animal origin often also show resistances to other—mostly older—antimicrobial agents, including tetracyclines, phenicols, sulfonamides, trimethoprim, and fosfomycin. Plasmids, especially multiresistance plasmids, but also other mobile genetic elements, such as transposons and gene cassettes in class 1 and class 2 integrons, seem to play a major role in the dissemination of resistance genes. Of note, coselection and persistence of resistances to critically important antimicrobial agents in human medicine also occurs through the massive use of antimicrobial agents in veterinary medicine, such as tetracyclines or sulfonamides, as long as all those determinants are located on the same genetic elements

Impact of cross-section uncertainties on supernova neutrino spectral parameter fitting in the Deep Underground Neutrino Experiment

A primary goal of the upcoming Deep Underground Neutrino Experiment (DUNE) is to measure the $\mathcal{O}(10)$ MeV neutrinos produced by a Galactic core-collapse supernova if one should occur during the lifetime of the experiment. The liquid-argon-based detectors planned for DUNE are expected to be uniquely sensitive to the $\nu_e$ component of the supernova flux, enabling a wide variety of physics and astrophysics measurements. A key requirement for a correct interpretation of these measurements is a good understanding of the energy-dependent total cross section $\sigma(E_\nu)$ for charged-current $\nu_e$ absorption on argon. In the context of a simulated extraction of supernova $\nu_e$ spectral parameters from a toy analysis, we investigate the impact of $\sigma(E_\nu)$ modeling uncertainties on DUNE's supernova neutrino physics sensitivity for the first time. We find that the currently large theoretical uncertainties on $\sigma(E_\nu)$ must be substantially reduced before the $\nu_e$ flux parameters can be extracted reliably: in the absence of external constraints, a measurement of the integrated neutrino luminosity with less than 10\% bias with DUNE requires $\sigma(E_\nu)$ to be known to about 5%. The neutrino spectral shape parameters can be known to better than 10% for a 20% uncertainty on the cross-section scale, although they will be sensitive to uncertainties on the shape of $\sigma(E_\nu)$. A direct measurement of low-energy $\nu_e$-argon scattering would be invaluable for improving the theoretical precision to the needed level.Comment: 25 pages, 21 figure

Redox homeostasis and age-related deficits in neuromuscular integrity and function

Skeletal muscle is a major site of metabolic activity and is the most abundant tissue in the human body. Age-related muscleatrophy (sarcopenia) and weakness, characterized by progressive loss of lean muscle mass and function, is a major contributorto morbidity and has a profound effect on the quality of life of older people. With a continuously growing older population(estimated 2 billion of people aged >60 by 2050), demand for medical and social care due to functional deficits, associatedwith neuromuscular ageing, will inevitably increase. Desp ite the importance of this ‘epidemic’ problem, the primarybiochemical and molecular mechanisms underlying age-related deficits in neuromuscular integrity and function have not beenfully determined. Skeleta l muscle generates reactive oxygen and nitrogen species (RONS) from a variety of subcellular sources,and age-associated oxidative damage has been suggested to be a major fac tor contributing to the initiation and progression ofmuscle atrophy inherent with ageing. RONS can modulate a variety of intracellular signal transduction processes, anddisruption of these events over time due to altered redox control has been proposed as an underlying mechanis m of ageing.The role of oxidants in ageing has been extensively examined in different model organisms that have undergone geneticmanipulations with inconsistent findings. Transgenic and knockout rodent studies have provided insight into the function ofRONS regulatory systems in neuromuscular ageing. This review summarizes almost 30 years of research in the field of redoxhomeostasis and muscle ageing, providing a detailed discussion of the experimental approaches that have been undertaken inmurine models to examine the role of redox regulation in age-related muscle atrophy and weakness

Highly-parallelized simulation of a pixelated LArTPC on a GPU

The rapid development of general-purpose computing on graphics processing units (GPGPU) is allowing the implementation of highly-parallelized Monte Carlo simulation chains for particle physics experiments. This technique is particularly suitable for the simulation of a pixelated charge readout for time projection chambers, given the large number of channels that this technology employs. Here we present the first implementation of a full microphysical simulator of a liquid argon time projection chamber (LArTPC) equipped with light readout and pixelated charge readout, developed for the DUNE Near Detector. The software is implemented with an end-to-end set of GPU-optimized algorithms. The algorithms have been written in Python and translated into CUDA kernels using Numba, a just-in-time compiler for a subset of Python and NumPy instructions. The GPU implementation achieves a speed up of four orders of magnitude compared with the equivalent CPU version. The simulation of the current induced on 10^3 pixels takes around 1 ms on the GPU, compared with approximately 10 s on the CPU. The results of the simulation are compared against data from a pixel-readout LArTPC prototype