Cannabinoids in the treatment of epilepsy: current status and future prospects

Cannabidiol (CBD) is one of the prominent phytocannabinoids found in Cannabis sativa, differentiating from Δ9-tetrahydrocannabinol (THC) for its non-intoxicating profile and its antianxiety/antipsychotic effects. CBD is a multi-target drug whose anti-convulsant properties are supposed to be independent of endocannabinoid receptor CB1 and might be related to several underlying mechanisms, such as antagonism on the orphan GPR55 receptor, regulation of adenosine tone, activation of 5HT1A receptors and modulation of calcium intracellular levels. CBD is a lipophilic compound with low oral bioavailability (6%) due to poor intestinal absorption and high first-pass metabolism. Its exposure parameters are greatly influenced by feeding status (ie, high fatcontaining meals). It is mainly metabolized by cytochrome P 450 (CYP) 3A4 and 2C19, which it strongly inhibits. A proprietary formulation of highly purified, plant-derived CBD has been recently licensed as an adjunctive treatment for Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS), while it is being currently investigated in tuberous sclerosis complex. The regulatory agencies’ approval was granted based on four pivotal double-blind, placebocontrolled, randomized clinical trials (RCTs) on overall 154 DS patients and 396 LGS ones, receiving CBD 10 or 20 mg/kg/day BID as active treatment. The primary endpoint (reduction in monthly seizure frequency) was met by both CBD doses. Most patients reported adverse events (AEs), generally from mild to moderate and transient, which mainly consisted of somnolence, sedation, decreased appetite, diarrhea and elevation in aminotransferase levels, the last being documented only in subjects on concomitant valproate therapy. The interaction between CBD and clobazam, likely due to CYP2C19 inhibition, might contribute to some AEs, especially somnolence, but also to CBD clinical effectiveness. Cannabidivarin (CBDV), the propyl analogue of CBD, showed anti-convulsant properties in pre-clinical studies, but a plant-derived, purified proprietary formulation of CBDV recently failed the Phase II RCT in patients with uncontrolled focal seizures

The Near-Infrared Spectrograph (NIRSpec) on the James Webb Space Telescope V. Optimal algorithms for planning multi-object spectroscopic observations

We present an overview of the capabilities and key algorithms employed in the so-called eMPT software suite developed for planning scientifically optimized, multi-object spectroscopic (MOS) observations with the Micro-Shutter Array (MSA) of the Near-Infrared Spectrograph (NIRSpec) instrument on board the James Webb Space Telescope (JWST), the first multi-object spectrograph to operate in space. NIRSpec MOS mode is enabled by a programmable MSA, a regular grid of ~250,000 individual apertures that projects to a static, semi-regular pattern of available slits on the sky and makes the planning and optimization of an MSA observation a rather complex task. As such, the eMPT package is offered to the NIRSpec user community as a supplement to the MSA Planning Tool (MPT) included in the STScI Astronomer's Proposal Tool (APT) to assist in the planning of NIRSpec MOS proposals requiring advanced functionality to meet ambitious science goals. The eMPT produces output that can readily be imported and incorporated into the user's observing program within the APT to generate a customized MPT MOS observation. Furthermore, its novel algorithms and modular approach make it highly flexible and customizable, providing users the option to finely control the workflow and even insert their own software modules to tune their MSA slit masks to the particular scientific objectives at hand

Reliability of a 2-Bout exercise test on a Wattbike cycle ergometer

Purpose: To determine the intraday and interday reliability of a 2 × 4-min performance test on a cycle ergometer (Wattbike) separated by 30 min of passive recovery (2 × 4MMP). Methods: Twelve highly trained cyclists (mean ± SD; age = 20 ± 2 y, predicted VO2max = 59.0 ± 3.6 mL · kg–1 · min–1) completed six 2 × 4MMP cycling tests on a Wattbike ergometer separated by 7 d. Mean power was measured to determine intraday (test 1 [T1] to test 2 [T2]) and interday reliability (weeks 1–6) over the repeated trials. Results: The mean intraday reliabilities of the 2 × 4MMP test, as expressed by the typical error of measurement (TEM, W) and coefficient of variation (CV, %) over the 6 wk, were 10.0 W (95% confidence limits [CL] 8.2–11.8), and 2.6% (95%CL 2.1–3.1), respectively. The mean interday reliability TEM and CV for T1 over the 6 wk were 10.4 W (95%CL 8.7–13.3) and 2.7% (95%CL 2.3–3.5), respectively, and 11.7 W (95%CL 9.8–15.1) and 3.0% (95%CL 2.5–3.9) for T2. Conclusion: The testing protocol performed on a Wattbike cycle ergometer in the current study is reproducible in highly trained cyclists. The high intraday and interday reliability make it a reliable method for monitoring cycling performance and for investigating factors that affect performance in cycling events

Predicting success in the worldwide start-up network

By drawing on large-scale online data we construct and analyze the time-varying worldwide network of professional relationships among start-ups. The nodes of this network represent companies, while the links model the flow of employees and the associated transfer of know-how across companies. We use network centrality measures to assess, at an early stage, the likelihood of the long-term positive performance of a start-up, showing that the start-up network has predictive power and provides valuable recommendations doubling the current state of the art performance of venture funds. Our network-based approach not only offers an effective alternative to the labour-intensive screening processes of venture capital firms, but can also enable entrepreneurs and policy-makers to conduct a more objective assessment of the long-term potentials of innovation ecosystems and to target interventions accordingly

A Prospective Observational Study on the Role of Immunohistochemical Expression of Orphanin in Laryngeal Squamous Cell Carcinoma Recurrence

To date, histological biomarkers expressed by laryngeal cancer are poorly known. The identification of biomarkers associated with laryngeal squamous cell carcinoma (SCC), would help explain the tumorogenesis and prevent the possible recurrence of the lesion after treatment. For this reason, the aim of this study is to investigate, for the first time, the Orphanin expression in 48 human specimens of laryngeal SCC and evaluate its possible correlation with patients prognosis. We analyzed pathological specimens from 48 patients with laryngeal SCC to detect the presence of Orphanin by using an immunohistochemistry test. We compared the findings with healthy tissue acquired from patients who underwent surgery for mesenchymal benign tumours of the larynx. The specimens were stained with anti-Orphanin monoclonal antibodies. Results were processed through a computerised image analysis system to determine a scale of staining intensity. All the tumoural specimens examined showed a significant immunoreaction for Orphanin when compared with healthy tissues (p < 0.05) but with a different immune reactivity related to clinical-pathological features. A high Orphanin expression was not significantly related to Histological Grading (HG), TNM, and stage (p > 0.05). In the multivariate analysis, the Orphanin expression was significantly related only to the malignant recurrence (p < 0.05). Our study suggests that Orphanin could have a role in tumorigenesis by increasing the recurrence of cancer; therefore, it should be further explored as a possible biomarker for laryngeal cancer

The ICON-1.2 hydrostatic atmospheric dynamical core on triangular grids – Part 1: Formulation and performance of the baseline version

Abstract. As part of a broader effort to develop next-generation models for numerical weather prediction and climate applications, a hydrostatic atmospheric dynamical core is developed as an intermediate step to evaluate a finite-difference discretization of the primitive equations on spherical icosahedral grids. Based on the need for mass-conserving discretizations for multi-resolution modelling as well as scalability and efficiency on massively parallel computing architectures, the dynamical core is built on triangular C-grids using relatively small discretization stencils. This paper presents the formulation and performance of the baseline version of the new dynamical core, focusing on properties of the numerical solutions in the setting of globally uniform resolution. Theoretical analysis reveals that the discrete divergence operator defined on a single triangular cell using the Gauss theorem is only first-order accurate, and introduces grid-scale noise to the discrete model. The noise can be suppressed by fourth-order hyper-diffusion of the horizontal wind field using a time-step and grid-size-dependent diffusion coefficient, at the expense of stronger damping than in the reference spectral model. A series of idealized tests of different complexity are performed. In the deterministic baroclinic wave test, solutions from the new dynamical core show the expected sensitivity to horizontal resolution, and converge to the reference solution at R2B6 (35 km grid spacing). In a dry climate test, the dynamical core correctly reproduces key features of the meridional heat and momentum transport by baroclinic eddies. In the aqua-planet simulations at 140 km resolution, the new model is able to reproduce the same equatorial wave propagation characteristics as in the reference spectral model, including the sensitivity of such characteristics to the meridional sea surface temperature profile. These results suggest that the triangular-C discretization provides a reasonable basis for further development. The main issues that need to be addressed are the grid-scale noise from the divergence operator which requires strong damping, and a phase error of the baroclinic wave at medium and low resolutions

Molecular basis of a novel adaptation to hypoxic-hypercapnia in a strictly fossorial mole

<p>Abstract</p> <p>Background</p> <p>Elevated blood O₂affinity enhances survival at low O₂pressures, and is perhaps the best known and most broadly accepted evolutionary adjustment of terrestrial vertebrates to environmental hypoxia. This phenotype arises by increasing the intrinsic O₂affinity of the hemoglobin (Hb) molecule, by decreasing the intracellular concentration of allosteric effectors (e.g., 2,3-diphosphoglycerate; DPG), or by suppressing the sensitivity of Hb to these physiological cofactors.</p> <p>Results</p> <p>Here we report that strictly fossorial eastern moles (<it>Scalopus aquaticus</it>) have evolved a low O₂affinity, DPG-insensitive Hb - contrary to expectations for a mammalian species that is adapted to the chronic hypoxia and hypercapnia of subterranean burrow systems. Molecular modelling indicates that this functional shift is principally attributable to a single charge altering amino acid substitution in the β-type δ-globin chain (δ136Gly→Glu) of this species that perturbs electrostatic interactions between the dimer subunits via formation of an intra-chain salt-bridge with δ82Lys. However, this replacement also abolishes key binding sites for the red blood cell effectors Cl^-, lactate and DPG (the latter of which is virtually absent from the red cells of this species) at δ82Lys, thereby markedly reducing competition for carbamate formation (CO₂binding) at the δ-chain N-termini.</p> <p>Conclusions</p> <p>We propose this Hb phenotype illustrates a novel mechanism for adaptively elevating the CO₂carrying capacity of eastern mole blood during burst tunnelling activities associated with subterranean habitation.</p

Molecular basis of a novel adaptation to hypoxic-hypercapnia in a strictly fossorial mole

Background: Elevated blood O2 affinity enhances survival at low O2 pressures, and is perhaps the best known and most broadly accepted evolutionary adjustment of terrestrial vertebrates to environmental hypoxia. This phenotype arises by increasing the intrinsic O2 affinity of the hemoglobin (Hb) molecule, by decreasing the intracellular concentration of allosteric effectors (e.g., 2,3-diphosphoglycerate; DPG), or by suppressing the sensitivity of Hb to these physiological cofactors. Results: Here we report that strictly fossorial eastern moles (Scalopus aquaticus) have evolved a low O2 affinity, DPG-insensitive Hb - contrary to expectations for a mammalian species that is adapted to the chronic hypoxia and hypercapnia of subterranean burrow systems. Molecular modelling indicates that this functional shift is principally attributable to a single charge altering amino acid substitution in the β-type δ-globin chain (δ136Gly→Glu) of this species that perturbs electrostatic interactions between the dimer subunits via formation of an intra-chain salt-bridge with δ82Lys. However, this replacement also abolishes key binding sites for the red blood cell effectors Cl-, lactate and DPG (the latter of which is virtually absent from the red cells of this species) at δ82Lys, thereby markedly reducing competition for carbamate formation (CO2 binding) at the δ-chain N-termini. Conclusions: We propose this Hb phenotype illustrates a novel mechanism for adaptively elevating the CO2 carrying capacity of eastern mole blood during burst tunnelling activities associated with subterranean habitation