The low binding affinity of D-serine at the ionotropic glutamate receptor GluD2 can be attributed to the hinge region

Ionotropic glutamate receptors (iGluRs) are responsible for most of the fast excitatory communication between neurons in our brain. The GluD2 receptor is a puzzling member of the iGluR family: It is involved in synaptic plasticity, plays a role in human diseases, e.g. ataxia, binds glycine and D-serine with low affinity, yet no ligand has been discovered so far that can activate its ion channel. In this study, we show that the hinge region connecting the two subdomains of the GluD2 ligand-binding domain is responsible for the low affinity of D-serine, by analysing GluD2 mutants with electrophysiology, isothermal titration calorimetry and molecular dynamics calculations. The hinge region is highly variable among iGluRs and fine-tunes gating activity, suggesting that in GluD2 this region has evolved to only respond to micromolar concentrations of D-serine

Peptide nucleic acids (PNA) derived from N-(N-methylaminoethyl)glycine. Synthesis, hybridization and structural properties

Backbone N-methylated peptide nucleic acids (PNAs) containing the four nucleobases adenine, cytosine, guanine and thymine were synthesized via solid phase peptide oligomerization. The oligomers bind to their complementary target with a thermal stability that is 1.5–4.5°C lower per "N-methyl nucleobase unit' [dependent on the number and position(s) of the N-methyl] than that of unmodified PNA. However, even fully N-methyl modified PNAs bind as efficiently to DNA or RNA targets as DNA itself. Furthermore, the hybridization efficiency per N-methyl unit in a PNA decreased with increasing N-methyl content, and the effect was more pronounced when the N-methyl backbone units are present in the Hoogsteen versus the Watson–Crick strand in (PNA)2-DNA triplexes. Interestingly, CD spectral analyses indicate that 30% (3 out of ten) substitution with N-methyl nucleobases did not alter the structure of PNA-DNA (or RNA) duplexes or (PNA)2-DNA triplexes, and likewise CD spectroscopy and X-ray crystallography showed no major structural differences between N-methylated (30%) and unmodified PNA-PNA duplexes. However, PNA-DNA duplexes as well as triplexes adopted a different conformation when formed with all-N-methyl PNAs

Autonomous space exploration using the Turtlebot mobile platform

Cilj diplomske naloge je implementacija avtonomnega raziskovanja prostora na mobilni platformi Turtlebot, ki uporablja razvojno okolje ROS. Implementirali smo raziskovalni algoritem, ki temelji na zaznavi obrobij in njihovi uporabi kot potencialnih raziskovalnih ciljev. Ker pa lahko algoritem pri izbiri raziskovalnih ciljev upošteva različne kombinacije ocen raziskovanja, smo nato preizkušali in primerjali, katera kombinacija ocen omogoča najbolj učinkovito raziskovanje prostora. Različne strategije izbire raziskovalnih ciljev smo ocenjevali in primerjali na podlagi štirih kriterijev ter referenčne strategije, ki naključno izbira raziskovalne cilje. Podatke za primerjavo smo dobili tako, da smo za vsako strategijo opravili deset uspešnih raziskovanj. Te smo nato kot skupine povprečnih vrednosti in odstopanj primerjali med seboj na podlagi referenčne strategije in kriterijev. Implementirali smo modul, ki poleg raziskanosti prostora in časa raziskovanja omogoča tudi beleženje zgodovine premikov in s tem pot raziskovanja, ki jo opravi Turtlebot.The purpose of this undergraduate thesis is to implement the autonomous exploration of space on the Turtlebot mobile platform that uses the ROS development environment. We implemented an exploration algorithm based on the detection and use of frontier regions as potential exploration goals. Since the algorithm is able to choose an exploration goal based on the combination of different assessments, we tested and compared which combination of goal assessments enables the most efficient exploration of a given space. We assessed and compared different strategies of goal setting on the basis of four criteria and a referential strategy which selects its exploration goals randomly. In order to get the data necessary for comparison, we conducted ten successful explorations per strategy and compared them on the basis of the referential strategy and criteria. We implemented our own module, which tracks the amount of space explored and the time spent for exploration, while also documenting the path traveled by the Turtlebot during exploration

Exploring thienothiadiazine dioxides as isosteric analogues of benzo-and pyridothiadiazine dioxides in the search of new AMPA and kainate receptor positive allosteric modulators

peer reviewedThe synthesis and biological evaluation on AMPA and kainate receptors of new examples of 3,4-dihydro-2H-1,2,4-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxides is described. The introduction of a cyclopropyl chain instead of an ethyl chain at the 4-position of the thiadiazine ring was found to dramatically improve the potentiator activity on AMPA receptors, with compound 32 (BPAM395) expressing in vitro activity on AMPARs (EC2x = 0.24 μM) close to that of the reference 4-cyclopropyl-substituted benzothiadiazine dioxide 10 (BPAM344). Interestingly, the 4-allyl-substituted thienothiadiazine dioxide 27 (BPAM307) emerged as the most promising compound on kainate receptors being a more effective potentiator than the 4-cyclopropyl-substituted thienothiadiazine dioxide 32 and supporting the view that the 4-allyl substitution of the thiadiazine ring could be more favorable than the 4-cyclopropyl substitution to induce marked activity on kainate receptors versus AMPA receptors. The thieno-analogue 36 (BPAM279) of the clinically tested S18986 (11) was selected for in vivo evaluation in mice as a cognitive enhancer due to a safer profile than 32 after massive per os drug administration. Compound 36 was found to increase the cognition performance in mice at low doses (1 mg/kg) per os suggesting that the compound was well absorbed after oral administration and able to reach the central nervous system. Finally, compound 32 was selected for co-crystallization with the GluA2-LBD (L504Y,N775S) and glutamate to examine the binding mode of thienothiadiazine dioxides within the allosteric binding site of the AMPA receptor. At the allosteric site, this compound established similar interactions as the previously reported BTD-type AMPA receptor modulators