Associations between polygenic risk scores for four psychiatric illnesses and brain structure using multivariate pattern recognition

Psychiatric illnesses are complex and polygenic. They are associated with widespread alterations in the brain, which are partly influenced by genetic factors. There have been some attempts to relate polygenic risk scores (PRS) - a measure of the overall genetic risk an individual carries for a disorder - to brain structure using univariate methods. However, PRS are likely associated with distributed and covarying effects across the brain. We therefore used multivariate machine learning in this proof-of-principle study to investigate associations between brain structure and PRS for four psychiatric disorders; attention deficit-hyperactivity disorder (ADHD), autism, bipolar disorder and schizophrenia. The sample included 213 individuals comprising patients with depression (69), bipolar disorder (33), and healthy controls (111). The five psychiatric PRSs were calculated based on summary data from the Psychiatric Genomics Consortium. T1-weighted magnetic resonance images were obtained and voxel-based morphometry was implemented in SPM12. Multivariate relevance vector regression was implemented in the Pattern Recognition for Neuroimaging Toolbox (PRoNTo). Across the whole sample, a multivariate pattern of grey matter significantly predicted the PRS for autism (r = 0.20, pFDR = 0.03; MSE = 4.20 × 10-5, pFDR = 0.02). For the schizophrenia PRS, the MSE was significant (MSE = 1.30 × 10-5, pFDR = 0.02) although the correlation was not (r = 0.15, pFDR = 0.06). These results lend support to the hypothesis that polygenic liability for autism and schizophrenia is associated with widespread changes in grey matter concentrations. These associations were seen in individuals not affected by these disorders, indicating that this is not driven by the expression of the disease, but by the genetic risk captured by the PRSs

Grape seed extracts modify the outcome of oxaliplatin in colon cancer cells by interfering with cellular mechanisms of drug cytotoxicity

Grape seed extracts are commonly utilized as dietary supplements for their antioxidant properties, even from cancer patients. However, whether these natural extracts interfere with chemotherapeutics utilized in colon cancer treatment is still poorly investigated. The cytotoxicity of extracts from Italia and Palieri cultivars either alone or in combination with oxaliplatin was evaluated in colon cancer cells. Grape seed extracts displayed anti-proliferative activity depending on the concentration utilized through apoptosis induction. In combination, they affected the activation of Erk1/2 and counteracted the intrinsic and the extrinsic pathway of apoptosis, the DNA damage and the generation of ROS induced by oxaliplatin. Noteworthy grape seed extracts strongly enhanced the uptake of oxaliplatin into all cells, by affecting the cell transport system of platinum. The addition of these natural extracts to oxaliplatin strongly reduced the cellular response to oxaliplatin and allowed a huge accumulation of platinum into cells. Here, we shed light on the chemical biology underlying the combination of grape seed extracts and oxaliplatin, demonstrating that they might be detrimental to oxaliplatin effectiveness in colon cancer therap

Numerical Modeling of physical-biological interactions in the Alboran Sea with a submesoscale-resolving model

Ageostrophic motion, such those associated to internal hydraulic jumps, propagating nonlinear internal waves, and submesoscale vortices, are recognized to efficiently supply nutrients to the euphotic zone and thereby fuel biological productivity. These processes are ubiquitous in the Strait of Gibraltar and the adjacent Alboran Sea, and therefore are expected to play an important role in the overall biomass budget of the basin. This has been investigated with a three-dimensional, tidally-forced, high-resolution model [O(1km)] ocean model embedded with an ecosystem NPZD module. We found that tidal mixing in the Strait of Gibraltar enhances remarkably local primary production and drive a net flow of biomass to the Alboran Sea. Additionally, tides also cause an inflow of nutrients confined to the photic layer, which increase further the Alboran Sea biomass through the enhancement of local primary productivity. Subinertial accelerations of the Atlantic flow are also found to temporary enhance biological productivity through the advection of shear vorticity (and submesoscale eddies) from the Strait to the Alboran Sea.JRC.H.1-Water Resource

Monte Carlo Simulation of Bony Heterogeneity Effects on Dose Profile for Small Irradiation Field in Radiotherapy

In the radiotherapy treatment planning of a lesion located in the head region with small field radiation beams, the heterogeneity corrections play an important role. In this work, we investigated the influence of a bony heterogeneity on dose profile inside a soft tissue phantom containing a bony material. PDD curves were obtained by simulation using the Monte Carlo code EGSnrc and employing Eclipse® treatment planning system algorithms (Batho, Modified Batho, Equivalent TAR and Anisotropic Analytic Algorithm) for a 15 MV photon beam and field sizes of 2×2 and 10×10 cm2. The Equivalent TAR method exhibited better agreement with Monte Carlo simulations for the 2×2 cm2 field size. The magnitude of the effect on PDD due to the bony heterogeneity for 1×1, 2×2 and 10×10 cm2 field sizes increases to 10, 5 and 3%, respectively

Antiviral Potential of Naphthoquinones Derivatives Encapsulated within Liposomes

HSV infections, both type 1 and type 2, are among the most widespread viral diseases affecting people of all ages. Their symptoms could be mild, with cold sores up to 10 days of infection, blindness and encephalitis caused by HSV-1 affecting immunocompetent and immunosuppressed individuals. The severe effects derive from co-evolution with the host, resulting in immune evasion mechanisms, including latency and growing resistance to acyclovir and derivatives. An efficient alternative to controlling the spreading of HSV mutations is the exploitation of new drugs, and the possibility of enhancing their delivery through the encapsulation of drugs into nanoparticles, such as liposomes. In this work, liposomes were loaded with a series of 2-aminomethyl- 3-hydroxy-1,4-naphthoquinones derivatives with n-butyl (compound 1), benzyl (compound 2) and nitrobenzene (compound 3) substituents in the primary amine of naphthoquinone. They were previously identified to have significant inhibitory activity against HSV-1. All of the aminomethylnaphthoquinones derivatives encapsulated in the phosphatidylcholine liposomes were able to control the early and late phases of HSV-1 replication, especially those substituted with the benzyl (compound 2) and nitrobenzene (compound 3), which yields selective index values that are almost nine times more efficient than acyclovir. The growing interest of the industry in topical administration against HSV supports our choice of liposome as a drug carrier of aminomethylnaphthoquinones derivatives for formulations of in vivo pre-clinical assays

In Vitro

Jaboticaba is a fruit from a native tree to Brazil, Plinia peruviana. Jaboticaba peels are an important source of antioxidant molecules such as phenolic compounds. This study aimed to evaluate in vitro the activity of a hydroalcoholic extract of jaboticaba fruit peels (HEJFP) in wound healing processes and antioxidant activity in murine fibroblasts (L929 cell line). HEJFP concentrations (0.5, 1, 5, 10, 25, 50, 100, and 200 µg/mL) were tested in MTT assay and cell proliferation was verified at 100 µg/mL after 24 h and at 25, 50, and 100 µg/mL after 48 h of extract exposure. Evaluation of antioxidant activity was performed at 0.5, 5, 25, 50, and 100 µg/mL HEJFP concentrations. Cell treatment with HEJFP at 25, 50, and 100 µg/mL for 24 h followed by H2O2 exposure for 3 h showed a strong cytoprotective effect. In vitro scratch wound healing assay indicated that none of tested HEJFP concentrations (0.5, 5, 25, 50, and 100 µg/mL) were capable of increasing migration rate after 12 h of incubation. These results demonstrate a positive effect of HEJFP on the wound healing process on L929 fibroblasts cell line, probably due to the antioxidant activity exhibited by phytochemicals in the extract

Search for spontaneous muon emission from lead nuclei

We describe a possible search for muonic radioactivity from lead nuclei using the base elements ("bricks" composed by lead and nuclear emulsion sheets) of the long-baseline OPERA neutrino experiment. We present the results of a Monte Carlo simulation concerning the expected event topologies and estimates of the background events. Using few bricks, we could reach a good sensitivity level.Comment: 12 pages, 4 figure

Modeling Gamma-ray burst Afterglow observations with an Off-axis Jet emission

Gamma-ray bursts (GRBs) are fascinating extragalactic objects. They represent a fantastic opportunity to investigate unique properties not exhibited in other sources. Multi-wavelength afterglow observations from some short- and long-duration GRBs reveal an atypical long-lasting emission that evolves differently from the canonical afterglow light curves favoring the off-axis emission. We present an analytical synchrotron afterglow scenario, and the hydrodynamical evolution of an off-axis top-hat jet decelerated in a stratified surrounding environment. The analytical synchrotron afterglow model is shown during the coasting, deceleration (off- and on-axis emission), and the post-jet-break decay phases, and the hydrodynamical evolution is computed by numerical simulations showing the time evolution of the Doppler factor, the half-opening angle, the bulk Lorentz factor, and the deceleration radius. We show that numerical simulations are in good agreement with those derived with our analytical approach. We apply the current synchrotron model and describe successfully the delayed non-thermal emission observed in a sample of long and short GRBs with evidence of off-axis emission. Furthermore, we provide constraints on the possible afterglow emission by requiring the multi-wavelength upper limits derived for the closest Swift-detected GRBs and promising gravitational-wave events.Comment: 36 pages, 16 figures, accepted for publication in Ap

Prospect for Charge Current Neutrino Interactions Measurements at the CERN-PS

Tensions in several phenomenological models grew with experimental results on neutrino/antineutrino oscillations at Short-Baseline (SBL) and with the recent, carefully recomputed, antineutrino fluxes from nuclear reactors. At a refurbished SBL CERN-PS facility an experiment aimed to address the open issues has been proposed [1], based on the technology of imaging in ultra-pure cryogenic Liquid Argon (LAr). Motivated by this scenario a detailed study of the physics case was performed. We tackled specific physics models and we optimized the neutrino beam through a full simulation. Experimental aspects not fully covered by the LAr detection, i.e. the measurements of the lepton charge on event-by-event basis and their energy over a wide range, were also investigated. Indeed the muon leptons from Charged Current (CC) (anti-)neutrino interactions play an important role in disentangling different phenomenological scenarios provided their charge state is determined. Also, the study of muon appearance/disappearance can benefit of the large statistics of CC muon events from the primary neutrino beam. Results of our study are reported in detail in this proposal. We aim to design, construct and install two Spectrometers at "NEAR" and "FAR" sites of the SBL CERN-PS, compatible with the already proposed LAr detectors. Profiting of the large mass of the two Spectrometers their stand-alone performances have also been exploited.Comment: 70 pages, 38 figures. Proposal submitted to SPS-C, CER