Knowledge-Based Design of Long-Chain Arylpiperazine Derivatives Targeting Multiple Serotonin Receptors as Potential Candidates for Treatment of Autism Spectrum Disorder.

Autism spectrum disorder (ASD) includes a group of neurodevelopmental disorders characterized by core symptoms such as impaired social interaction and communication, repetitive and stereotyped behaviors, and restricted interests. To date, there are no effective treatments for these core symptoms. Several studies have shown that the brain serotonin (5-HT) neurotransmission system is altered in both ASD patients and animal models of the disease. Multiple pieces of evidence suggest that targeting 5-HT receptors may treat the core symptoms of ASD and associated intellectual disabilities. In fact, stimulation of the 5-HT1A receptor reduces repetitive and restricted behaviors; blockade of the 5-HT2A receptor reduces both learning deficits and repetitive behavior, and activation of the 5-HT7 receptor improves cognitive performances and reduces repetitive behavior. On such a basis, we have designed novel arylpiperazine derivatives pursuing unprecedently reported activity profiles: dual 5-HT7/5-HT1A receptor agonist properties and mixed 5-HT7 agonist/5-HT1A agonist/5-HT2A antagonist properties. Seventeen new compounds were synthesized and tested in radioligand binding assay at the target receptors. We have identified the dual 5-HT1AR/5-HT7R agonists 8c and 29 and the mixed 5-HT1AR agonist/5-HT7R agonist/5-HT2AR antagonist 20b. These compounds are metabolically stable in vitro and have suitable central nervous system druglike properties

Supporting Earth-Observation Calibration and Validation: A new generation of tools for crowdsourcing and citizen science

Citizens are providing vast amounts of georeferenced data in the form of in situ data collections as well as interpretations and digitization of Earth-observation (EO) data sets. These new data streams have considerable potential for supporting the calibration and validation of current and future products derived from EO. We provide a general introduction to this growing area of interest and review existing crowdsourcing and citizen science (CS) initiatives of relevance to EO. We then draw upon our own experiences to provide case studies that highlight different types of data collection and citizen engagement and discuss the various barriers to adoption. Finally, we highlight opportunities for how citizens can become part of an integrated EO monitoring system in the framework of the European Union (EU) space program, including Copernicus and other monitoring initiatives

mTORC1 activity is supported by spatial association with focal adhesions

The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogenic and stress signals to control growth and metabolism. Activation of mTORC1 by amino acids and growth factors involves recruitment of the complex to the lysosomal membrane and is further supported by lysosome distribution to the cell periphery. Here, we show that translocation of lysosomes toward the cell periphery brings mTORC1 into proximity with focal adhesions (FAs). We demonstrate that FAs constitute discrete plasma membrane hubs mediating growth factor signaling and amino acid input into the cell. FAs, as well as the translocation of lysosome-bound mTORC1 to their vicinity, contribute to both peripheral and intracellular mTORC1 activity. Conversely, lysosomal distribution to the cell periphery is dispensable for the activation of mTORC1 constitutively targeted to FAs. This study advances our understanding of spatial mTORC1 regulation by demonstrating that the localization of mTORC1 to FAs is both necessary and sufficient for its activation by growth-promoting stimuli

Spermidine protects from age-related synaptic alterations at hippocampal mossy fiber-CA3 synapses

Aging is associated with functional alterations of synapses thought to contribute to age-dependent memory impairment (AMI). While therapeutic avenues to protect from AMI are largely elusive, supplementation of spermidine, a polyamine normally declining with age, has been shown to restore defective proteostasis and to protect from AMI in Drosophila. Here we demonstrate that dietary spermidine protects from age-related synaptic alterations at hippocampal mossy fiber (MF)-CA3 synapses and prevents the aging-induced loss of neuronal mitochondria. Dietary spermidine rescued age-dependent decreases in synaptic vesicle density and largely restored defective presynaptic MF-CA3 long-term potentiation (LTP) at MF-CA3 synapses (MF-CA3) in aged animals. In contrast, spermidine failed to protect CA3-CA1 hippocampal synapses characterized by postsynaptic LTP from age-related changes in function and morphology. Our data demonstrate that dietary spermidine attenuates age-associated deterioration of MF-CA3 synaptic transmission and plasticity. These findings provide a physiological and molecular basis for the future therapeutic usage of spermidine

Coupling early warning services, crowdsourcing, and modelling for improved decision support and wildfire emergency management

The threat of a forest fire disaster increases around the globe as the human footprint continues to encroach on natural areas and climate change effects increase the potential of extreme weather. It is essential that the tools to educate, prepare, monitor, react, and fight natural fire disasters are available to emergency managers and responders and reduce the overall disaster effects. In the context of the I-REACT project, such a big crisis data system is being developed and is based on the integration of information from different sources, automated data processing chains and decision support systems. This paper presents the wildfire monitoring for emergency management system for those involved and affected by wildfire disasters developed for European forest fire disasters

Ratiometric high-resolution imaging of JC-1 fluorescence reveals the subcellular heterogeneity of astrocytic mitochondria

Using the mitochondrial potential (ΔΨm) marker JC-1 (5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide) and high-resolution imaging, we functionally analyzed mitochondria in cultured rat hippocampal astrocytes. Ratiometric detection of JC-1 fluorescence identified mitochondria with high and low ΔΨm. Mitochondrial density was highest in the perinuclear region, whereas ΔΨm tended to be higher in peripheral mitochondria. Spontaneous ΔΨm fluctuations, representing episodes of increased energization, appeared in individual mitochondria or synchronized in mitochondrial clusters. They continued upon withdrawal of extracellular Ca2+, but were antagonized by dantrolene or 2-aminoethoxydiphenylborate (2-APB). Fluo-3 imaging revealed local cytosolic Ca2+ transients with similar kinetics that also were depressed by dantrolene and 2-APB. Massive cellular Ca2+ load or metabolic impairment abolished ΔΨm fluctuations, occasionally evoking heterogeneous mitochondrial depolarizations. The detected diversity and ΔΨm heterogeneity of mitochondria confirms that even in less structurally polarized cells, such as astrocytes, specialized mitochondrial subpopulations coexist. We conclude that ΔΨm fluctuations are an indication of mitochondrial viability and are triggered by local Ca2+ release from the endoplasmic reticulum. This spatially confined organelle crosstalk contributes to the functional heterogeneity of mitochondria and may serve to adapt the metabolism of glial cells to the activity and metabolic demand of complex neuronal networks. The established ratiometric JC-1 imaging—especially combined with two-photon microscopy—enables quantitative functional analyses of individual mitochondria as well as the comparison of mitochondrial heterogeneity in different preparations and/or treatment conditions

Макрофагальная активность в коже больных псориазом при NB-UVB (311 нм) терапии

Досліджено 55 пацієнтів хворих на псоріаз. Пацієнти були розділені на 2 групи. Група 1 – 27 пацієнтів, які отримували тільки стандартне лікування і група 2 – 28 пацієнтів, які отримували стандартну і NB-UVB терапію. NB-UVB призначалась 3 рази в тиждень, при цьому використовували стартову дозу 0,1-0,3 J/cm2 , середня кумулятивна доза від 30 до 60 J/cm2 . Рівень макрофагальної активності в біоптатах шкіри досліджували за допомогою імуногістохімічного методу на 1 і 21 добу. NB-UVB терапія призовдить до зниження рівня експресії CD68 – маркера макрофагів, більшою часткою якої є функціонально-активні клітини, що свідчить про адекватність імуної відповіді і зниження запальної реакції.There were researched 55 psoriasis patients. Patients were divided in two groups. Group 1 – 27 patients who received only standard therapy and Group 2 – 28 patients who received standard and NB-UVB therapy. NB-UVB treatment was applied three times weekly. Starting UVB dose 0.1-0.3 J/cm2 , the mean cumulative UVB dose was 42.0 J/cm2 . The level of macrophage activity in skin biopsy was investigated by an immunohistochemical method on 1 and 21 days. NB-UVB therapy is linked to decline of level of CD68 expression with predominant of functionally active cells which testifies to adequacy of immune reactions and decline of inflammatory reaction

Low exposure long-baseline neutrino oscillation sensitivity of the DUNE experiment

The Deep Underground Neutrino Experiment (DUNE) will produce world-leading neutrino oscillation measurements over the lifetime of the experiment. In this work, we explore DUNE's sensitivity to observe charge-parity violation (CPV) in the neutrino sector, and to resolve the mass ordering, for exposures of up to 100 kiloton-megawatt-years (kt-MW-yr). The analysis includes detailed uncertainties on the flux prediction, the neutrino interaction model, and detector effects. We demonstrate that DUNE will be able to unambiguously resolve the neutrino mass ordering at a 3$\sigma$ (5$\sigma$) level, with a 66 (100) kt-MW-yr far detector exposure, and has the ability to make strong statements at significantly shorter exposures depending on the true value of other oscillation parameters. We also show that DUNE has the potential to make a robust measurement of CPV at a 3$\sigma$ level with a 100 kt-MW-yr exposure for the maximally CP-violating values \delta_{\rm CP}} = \pm\pi/2. Additionally, the dependence of DUNE's sensitivity on the exposure taken in neutrino-enhanced and antineutrino-enhanced running is discussed. An equal fraction of exposure taken in each beam mode is found to be close to optimal when considered over the entire space of interest

Snowmass Neutrino Frontier: DUNE Physics Summary

The Deep Underground Neutrino Experiment (DUNE) is a next-generation long-baseline neutrino oscillation experiment with a primary physics goal of observing neutrino and antineutrino oscillation patterns to precisely measure the parameters governing long-baseline neutrino oscillation in a single experiment, and to test the three-flavor paradigm. DUNE's design has been developed by a large, international collaboration of scientists and engineers to have unique capability to measure neutrino oscillation as a function of energy in a broadband beam, to resolve degeneracy among oscillation parameters, and to control systematic uncertainty using the exquisite imaging capability of massive LArTPC far detector modules and an argon-based near detector. DUNE's neutrino oscillation measurements will unambiguously resolve the neutrino mass ordering and provide the sensitivity to discover CP violation in neutrinos for a wide range of possible values of δCP. DUNE is also uniquely sensitive to electron neutrinos from a galactic supernova burst, and to a broad range of physics beyond the Standard Model (BSM), including nucleon decays. DUNE is anticipated to begin collecting physics data with Phase I, an initial experiment configuration consisting of two far detector modules and a minimal suite of near detector components, with a 1.2 MW proton beam. To realize its extensive, world-leading physics potential requires the full scope of DUNE be completed in Phase II. The three Phase II upgrades are all necessary to achieve DUNE's physics goals: (1) addition of far detector modules three and four for a total FD fiducial mass of at least 40 kt, (2) upgrade of the proton beam power from 1.2 MW to 2.4 MW, and (3) replacement of the near detector's temporary muon spectrometer with a magnetized, high-pressure gaseous argon TPC and calorimeter