Rapid Changes in D1 and D2 Dopamine Receptor Binding in Striatal Subregions after a Single Dose of Phencyclidine

Objective In humans, a single exposure to hencyclidine (PCP) can induce a schizophrenia-like psychosis which can persist for up to two weeks. In rats, an acute dose of PCP increases dopaminergic activity and causes changes in dopamine related behaviours some of which are sexually dimorphic. To better understand the effects of PCP on dopamine receptor adaptations in the short term we examined dopamine D1-like receptors (D1R) and D2-like receptors (D2R) in the mesolimbic and nigrostriatal dopamine pathways, 4 hours after exposure to PCP in female rats. Methods Animals received a single dose of 40 mg/kg PCP and were sacrificed 4 hours later. In vitro autoradiography was carried out using [3H] SCH 23390 and [3H] raclopride that target D1R and D2R respectively, in cryostat brain sections. Results Two way analysis of variance (ANOVA), revealed an overall effect of PCP treatment (F [1,63]=9.065; p=0.004) on D1R binding with an 18% decrease (p<0.01) in binding in the medial caudate putamen. PCP treatment also had an overall effect on D2R binding (F [1,47]=5.450; p=0.024) and a trend for an increase in D2R binding across all the brain regions examined. Conclusion These results suggest opposing D1R and D2R adaptations in striatal subregions of female rats following acute exposure to PCP that may occur through indirect mechanisms. © 2011, Korean College of NeuropsychopharmacologyThis is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Attached copy is from: http://www.cpn.or.kr/about/sub03.htm

Από τα συμβάντα του λόγου στην εγκύκλιο γνώση

Εθνικό Μετσόβιο Πολυτεχνείο. Μεταπτυχιακή Εργασία. Διεπιστημονικό - Διατμηματικό Πρόγραμμα Μεταπτυχιακών Σπουδών (Δ.Π.Μ.Σ.) " Αρχιτεκτονική - Σχεδιασμός του Χώρου : Σχεδιασμός - Χώρος - Πολιτισμός (Κατ. Α)

Modelling, optimisation and model predictive control of insulin delivery systems in Type 1 Diabetes Mellitus

Type 1 Diabetes Mellitus is a metabolic disease requiring lifelong treatment with exogenous insulin which significantly affects patient’s lifestyle. Therefore, it is of paramount importance to develop novel drug delivery techniques that achieve therapeutic efficacy and ensure patient safety with a minimum impact on their quality of life. Motivated by the challenge to improve the living standard of a diabetic patient, the idea of an artificial pancreas that mimics the endocrine function of a healthy pancreas has been developed in the scientific society. Towards this direction, model predictive control has been established as a very promising control strategy for blood glucose regulation in a system that is dominated by high intra- and inter-patient variability, long time delays, and presence of unknown disturbances such as diet, physical activity and stress levels. This thesis presents a framework for blood glucose regulation with optimal insulin infusion which consists of the following steps: 1. Development of a novel physiologically based compartmental model analysed up to organ level that describes glucose-insulin interactions in type 1 diabetes, 2. Derivation of an approximate model suitable for control applications, 3. Design of an appropriate control strategy and 4. In-silico validation of the closed loop control performance. The developed model’s accuracy and prediction ability is evaluated with data obtained from the literature and the UVa/Padova Simulator model, the model parameters are individually estimated and their effect on the model’s measured output, the blood glucose concentration, is identified. The model is then linearised and reduced to derive low-order linear approximations of the underlying system suitable for control applications. The proposed control design aims towards an individualised optimal insulin delivery that consists of a patient-specific model predictive controller, a state estimator, a personalised scheduling level and an open loop optimisation problem subjected to patient specific process model and constraints. This control design is modifiable to address the case of limited patient data availability resulting in an “approximation” control strategy. Both designs are validated in-silico in the presence of predefined, measured and unknown meal disturbances using both the proposed model and the UVa/Padova Simulator model as a virtual patient. The robustness of the control performance is evaluated in several conditions such as skipped meals, variability in the meal content, time and metabolic uncertainty. The simulation results of the closed loop validation studies indicate that the proposed control strategies can achieve promising glycaemic control as demonstrated by the study data. However, further prospective validation of the closed loop control strategy with real patient data is required.Open Acces

Testicular translocator protein expression is differentially altered by synthetic cannabinoid HU210 in adult and adolescent Rats

Objective: The translocator protein (TSPO) has been implicated in numerous functions including steroid production and regulation of stress and anxiety. Cannabinoids have been shown to reduce plasma testosterone levels and alter anxiety levels. The aim of the present study was to determine whether the synthetic cannabinoid HU210 is able to regulate TSPO expression in several peripheral organs. Methods: HU210 (100 μg/kg) was administered intraperitoneally to both adult and adolescent male ratsfor 14 days. TSPO receptor expression in several organs, including the liver, spleen, kidneys and testes, was quantified by membrane receptor binding using the selective radiolig and, PK11195. In cases where receptor binding data indicated significant cannabinoid-induced differences, further RT-qPCR was carried out to determine the transcriptional regulation of the TSPO gene. Additionally, film-autography was used to identify potential changes in the spatial distribution of the TSPO tissue binding sites. Results: Results indicate that HU210 induces significant reductions in testicular TSPO expression in adult but not adolescent rats. No changes were found in other organs examined. These results are consistent with the previously observed effects of cannabinoids on testosterone production and a presumed role for TSPO in steroidogenesis. Conclusions: Overall, these results suggest that cannabinoids may alter testosterone production by altering the expression of testicular TSPO and that the alteration of TSPO occurs in an age-dependent manner.© 2014 Chan RHY, et al

Automating Free Energy Perturbation Calculations For Drug Design

Η διαδικασία σχεδιασμού φαρμάκων έχει βελτιστοποιηθεί με τη βοήθεια των ηλεκτρονικών υπολογιστών, έχοντας γίνει πιο αποδοτική από πλευράς κόστους και χρόνου. Σήμερα, χρησιμοποιώντας την τρισδιάστατη δομή του θεραπευτικού στόχου ο ορθολογιστικός σχεδιασμός φαρμάκων μπορεί να ποσοτικοποιήσει τις μοριακές αλληλεπιδράσεις που εμπλέκονται στη δέσμευση προσδέτη-πρωτεΐνης. Η ακριβής αυτή ποσοτικοποίηση βοηθά στην βελτιστοποίηση αλληλεπιδράσεων εκτός στόχου, οι οποίες παίζουν σημαντικό ρόλο στην ανίχνευση των βέλτιστων προσδετών. Ένα από τα πιο σημαντικά καθήκοντα στον σχεδιασμό φαρμάκων είναι να προβλέψουμε μεταξύ μιας σειράς υποψήφιων ποιά από αυτά θα δεσμευτούν καλύτερα στον θεραπευτικό στόχο. Σε αυτή την κατεύθυνση έχουν αναπτυχθεί μεθοδολογίες σχετικής δέσμευσης της ελεύθερης ενέργειας, οι οποίες βασίζονται σε μοριακές προσομοιώσεις, στη φυσική και στην αυστηρή στατιστική μηχανική για τον υπολογισμό των διαφορών στην ελεύθερη ενέργεια σύνδεσης μεταξύ ενός γονικού υποψήφιου φαρμάκου και αναλόγων του. Για παράδειγμα, οι υπολογισμοί της Ελεύθερης Ενεργειακής Διαταραχής (FEP) σε συνδυασμό με τις προσομοιώσεις Μοριακής Δυναμικής (MD) υπολογίζουν την ελεύθερη διαφορά ενέργειας μεταξύ ενός αρχικού και ενός τελικού μορίου. Αυτές οι μεθοδολογίες έχουν σημαντικές δυνατότητες, ωστόσο έχουν περιοριστεί από τεχνικές προκλήσεις όπως η χειροκίνητη δημιουργία μεγάλου αριθμού αρχείων εισόδου για την εγκατάσταση / εκτέλεση / ανάλυση ελεύθερων προσομοιώσεων ενέργειας. Η αυτοματοποίηση των υπολογισμών της διαταραχής της ελεύθερης ενέργειας απλοποιεί τη χρήση των υπολογισμών FEP και παρέχει υπολογισμούς υψηλής απόδοσης για ακριβείς προβλέψεις πριν από την σύνθεση μιας ένωσης και συνεπώς εξοικονομεί τεράστιο χρόνο και κόστος. Σε αυτή τη διατριβή περιγράφεται ένας αλγόριθμος, ονομαζόμενος FEPrepare, ο οποίος αυτοματοποιεί τη διαδικασία στησίματος για σχετικές δεσμευτικές προσομοιώσεις ελεύθερης ενέργειας μέσω ενός ιστόποπου. Αυτοματοποιείται τη διαδικασία του στησίματος για υπολογισμούς FEP στο πλαίσιο του NAMD, ενός από τους σημαντικότερους μηχανισμούς MD. Ο χρήστης ανεβάζει τα αρχεία δομής πρωτεΐνης και των προσδεμάτων, ο αλγόριθμος ο οποίος είναι γραμμένος σε Python χρησιμοποιεί τα αρχεία αυτά για να μετονομάσει τα άτομα, να αναδιανείμει τα φορτία των ατόμων και να δημιουργήσει τα απαραίτητα αρχεία για το VMD, ένα πρόγραμμα μοριακής προβολής που μπορεί να χρησιμοποιηθεί για τη δημιουργία προσομοίωσης του NAMD και να βοηθήσει στην ανάλυση των δεδομένων που παράγει το NAMD, για να παράξει τα αρχεία που χρειάζονται, να κάνει την υδρόλυση και τον ιονισμό. Αφού ο αλγόριθμος επιβεβαιώσει οτι όλα τα αρχεία είναι συμβατά με το NAMD τα παρέχει στον χρήστη. Οι υπολογισμοί σχετικής ελεύθερης ενέργειας στον σχεδιασμό φαρμάκων έχουν αποδειχθεί πολύ χρήσιμοι καθώς κάνουν την διαδικασία της βελτιστοποίησης πολύ πιο γρήγορη και φθηνή. Σε αυτή τη διπλωματική παρουσιάζεται η αυτοματοποιήση υπολογισμών ελεύθερης ενέργειας πρόσδεσης, για τη διαδικασία της βελτιστοποίησης.The advent of technological advances of computer-aided drug design has streamlined the drug design process, rendering it more cost- and time-efficient. Nowadays, rational structure-based drug design may quantify underlying molecular interactions involved in ligand-protein binding by utilizing the 3D structure of the therapeutic target in the process. Accurate quantification of these interactions can aid the optimization of binding affinity,selectivity, and other off -target interactions, which are a critical part of hit-to-lead and lead optimization efforts in drug discovery. One of the most important tasks in the lead optimization phase of the drug design process is to predict, among a series of lead candidates, which ones will bind more strongly to the therapeutic target. In this direction, relative binding free energy methodologies have been developed, which rely on physics-based molecular simulations and rigorous statistical mechanics to calculate the differences in the free energy of binding between a parent candidate drug and analogues. For example, Free Energy Perturbation (FEP) calculations coupled with Molecular Dynamics (MD) simulations calculate the free energy difference between an initial (reference) and an analog (target) molecule to an average of a function of their energy difference evaluated by sampling for the initial state. Such methodologies have shown significant potential in the lead optimization process, however, they have been limited by technical challenges such as manual creation of large numbers of input files to setup/run/analyze free energy simulations. Automating free energy perturbation calculations would streamline the use of FEP calculations and would be a step forward to delivering high throughput calculations for accurate predictions of relative binding affinities before a compound is synthesized, and consequently save enormous experimental and human resources. In this thesis, an algorithm called FEPrepare, which automates the set up procedure for relative binding free energy simulations has been designed and implemented as the first web-based server. The web server automates the set-up procedure for FEP calculations within the context of NAMD, one of the major MD engines. The user has to upload the structure files to the web-server. The algorithm is written in Python, utilizes the structure files uploaded by the user in order to perform atom renaming, and partial charge redistribution and create the necessary input files for VMD, a molecular viewer program, that can be used to help set up NAMD simulations and to help analyse and visualize NAMD output, to generate all needed files for the calculations. After the algorithm confirms compatibility of the required files with NAMD, it provides the user with everything needed to run a simulation. Relative binding free energy calculations in drug design have proven very effective in facilitating the lead optimization process both time and cost efficient. The automation of Free Energy Perturbation calculations to provide access to large-scale simulations for lead optimization has been presented in this thesis

The group of experts on action against violence against women and domestic violence (GREVIO) and the monitoring system of the Istanbul convention

Σε αυτή τη μελέτη σχετικά με τη Σύμβαση της Κωνσταντινούπολης για την πρόληψη και την καταπολέμηση της βίας κατά των γυναικών και της ενδοοικογενειακής βίας, επικεντρώνομαι στις διαδικασίες εποπτείας που διεξάγονται από την Ομάδα Ειδικών (GREVIO), οι οποίες είναι η αξιολόγηση ανά χώρα και η ειδική διαδικασία διερεύνησης. Επίσης εξετάζω την πιθανή δημιουργία μιας διαδικασίας που να δίνει τη δυνατότητα υποβολής αναφορών, τόσο διακρατικών όσο και ατομικών. Τέλος, αναφέρομαι στα διαρκή εμπόδια που εντοπίζονται στη Σύμβαση και είναι απαγορευτικά για την πλήρη εξάλειψη της έμφυλης βίας. Το βασικό ερώτημα που διερευνάται είναι ο βαθμός της αποτελεσματικότητας του συστήματος εποπτείας της Σύμβασης, κρίνοντας την αποτελεσματικότητα από τις αλλαγές στους νόμους, στις πολιτικές και στις πρακτικές των κρατών, ως αποτέλεσμα του μηχανισμού εποπτείας. Παρατηρείται ότι οι διαδικασίες εποπτείας της Σύμβασης, καθώς επίσης και οι επιπρόσθετοι μηχανισμοί για την ενίσχυση της εφαρμογής της, έχουν οδηγήσει σε σημαντική πρόοδο των κρατών όσον αφορά την προστασία των γυναικών από την έμφυλη βία, αν και απαιτείται ακόμη πολλή μεγάλη προσπάθεια για την πλήρη εξάλειψη της έμφυλης βίας και την επίτευξη της ισότητας μεταξύ των φύλων. Κατά τη γνώμη μου, προς αυτήν την κατεύθυνση θα μπορούσαν να συνεισφέρουν: 1)Εργαλεία (όπως καμπάνιες και φυλλάδια) που γνωστοποιούν και εξηγούν τους σκοπούς της Σύμβασης 2)Η εγκαθίδρυση διαδικασίας υποβολής αναφορών, τόσο διακρατικών όσο και ατομικών, οι οποίες θα θέσουν τα κράτη υπό διαρκή έλεγχο και επίσης θα παρέχουν ad hoc ερμηνεία των διατάξεων της Σύμβασης.In this study on the Istanbul Convention on preventing and combating violence against women and domestic violence, I focuss on the monitoring procedures carried out by GREVIO, which are the Country-by-Country evaluation and the Special Inquiry Procedure. I also examine the possible establishment of an interstate and an individual complaint procedure, as well as other mechanisms that foster the implementation of the Convention. Finally, I refer to the persisting obstacles that do not permit the complete elimination of gender-based violence. The basic question that is explored is the extent to which the monitoring system of the Convention is effective, interpreting effectiveness as the changes registered in states’ laws, policies and practices, as a result of the monitoring mechanism. Ιt is observed that the monitoring procedures of the Convention, as well as the additional mechanisms for the enhancement of its implementation, have induced states to make important progress in the field of protection of women from gender-based violence, even though there is still a long way to go until the complete elimination of violence against women and the achievement of equality between genders. In my opinion, to this end could contribute: 1)Tools (such as campaigns and brochures) that dispel misconceptions and raise awareness about the Convention 2)The establishment of an individual and an interstate complaint procedure, which will keep states under constant control of their action and it will also offer ad hoc interpretation of the provisions of the Convention

Comparison of Cannabinoid CB1 Receptor Binding in Adolescent and Adult Rats: A Positron Emission Tomography Study Using [18F]MK-9470

Despite the important role of cannabinoid CB1 receptors (CB1R) in brain development, little is known about their status during adolescence, a critical period for both the development of psychosis and for initiation to substance abuse. In the present study, we assessed the ontogeny of CB1R in adolescent and adult rats in vivo using positron emission tomography with [18F]MK-9470. Analysis of covariance (ANCOVA) to control for body weight that would potentially influence [18F]MK-9470 values between the two groups revealed a main effect of age (F(1,109)=5.0, P = 0.02) on [18F]MK-9470 absolute binding (calculated as percentage of injected dose) with adult estimated marginal means being higher compared to adolescents amongst 11 brain regions. This finding was confirmed using in vitro autoradiography with [3H]CP55,940 (F(10,99)=140.1, P < 0.0001). This ontogenetic pattern, suggesting increase of CB1R during the transition from adolescence to adulthood, is the opposite of most other neuroreceptor systems undergoing pruning during this period

The Importance of Brain Banks for Molecular Neuropathological Research: The New South Wales Tissue Resource Centre Experience

New developments in molecular neuropathology have evoked increased demands for postmortem human brain tissue. The New South Wales Tissue Resource Centre (TRC) at The University of Sydney has grown from a small tissue collection into one of the leading international brain banking facilities, which operates with best practice and quality control protocols. The focus of this tissue collection is on schizophrenia and allied disorders, alcohol use disorders and controls. This review highlights changes in TRC operational procedures dictated by modern neuroscience, and provides examples of applications of modern molecular techniques to study the neuropathogenesis of many different brain disorders

Adult Aedes albopictus in winter: implications for mosquito surveillance in southern Europe

Comment in The Lancet Planetary HealthWe acknowledge funding from the following projects: A systematic surveillance of vector mosquitoes for the control of mosquito-borne diseases in the Region of Attica, financed by the Region of Attica; E4Warning, financed by the EU's Horizon Europe research and innovation programme under grant agreement 101086640; and IDAlert, financed by the EU's Horizon Europe research and innovation programme under grant agreement 101057554. The funders had no role in study design, data collection and analysis, the decision to publish, or the preparation of this Comment. The code used to make the figure can be found at https://earth.bsc.es/gitlab/ghr/aedes-albopictus-winter.Peer ReviewedPostprint (author's final draft