Long-Term Safety of Repeated Blood-Brain Barrier Opening via Focused Ultrasound with Microbubbles in Non-Human Primates Performing a Cognitive Task

Focused Ultrasound (FUS) coupled with intravenous administration of microbubbles (MB) is a non-invasive technique that has been shown to reliably open (increase the permeability of) the blood-brain barrier (BBB) in multiple in vivo models including non-human primates (NHP). This procedure has shown promise for clinical and basic science applications, yet the safety and potential neurological effects of long term application in NHP requires further investigation under parameters shown to be efficacious in that species (500kHz, 200–400 kPa, 4–5μm MB, 2 minute sonication). In this study, we repeatedly opened the BBB in the caudate and putamen regions of the basal ganglia of 4 NHP using FUS with systemically-administered MB over 4–20 months. We assessed the safety of the FUS with MB procedure using MRI to detect edema or hemorrhaging in the brain. Contrast enhanced T1-weighted MRI sequences showed a 98% success rate for openings in the targeted regions. T2-weighted and SWI sequences indicated a lack edema in the majority of the cases. We investigated potential neurological effects of the FUS with MB procedure through quantitative cognitive testing of’ visual, cognitive, motivational, and motor function using a random dot motion task with reward magnitude bias presented on a touchpanel display. Reaction times during the task significantly increased on the day of the FUS with MB procedure. This increase returned to baseline within 4–5 days after the procedure. Visual motion discrimination thresholds were unaffected. Our results indicate FUS with MB can be a safe method for repeated opening of the BBB at the basal ganglia in NHP for up to 20 months without any long-term negative physiological or neurological effects with the parameters used.     

Mathematical model of honeycomb construction

We developed a mathematical model and an algorithm for numerical treatment of a model of honeycomb construction in a beehive. The model contains essential features of the bee-bee and bee-wax interactions, and in a qualitative way captures the dynamics of parallel comb construction. The construction is represented by a set of dynamical coupled partial differential equations for the density of bees situated on the hive ceiling, and the quantity of wax distributed by the bees. A spectral algorithm is invented for treatment of these equations, based on a modified thin-sheet gain scheme and a fast Fourier transform technique.Work at City College supported in part by the Army Research Office and the Department of Energy     

Informationstheoretisches lernmodell

Summary The formation of the interconnection stimulus-response in a learning system is analysed. The system, a technical or a biological one establishes this correspondence by processing the information fed back from the medium during the learning process. This information has two aspects: a quantitative one related to the probability of the events, and a qualitative one related to the utility of the events in view of a goal. Both aspects are taken into consideration; by successive experiences the system eliminates the double uncertainty concerning the probabilistic dependence: stimulu — sresponse — outcome and its utility. Learning implies then a system for evaluating the utilities of different outcomes in view of a goal, a memory to record them and a decision system for selecting the corresponding responses upon a given criterion.

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Der Beitrag stellt einen Teil der Untersuchungen dar, die zur Ausarbeitung der Doktor-Dissertation am Polytechnischen Institut Gheorghe Gheorghiu-Dej in Bukarest unternommen wurden.     

Isolation and characterization of a new class of acidic glycans implicated in sea urchin embryonal cell adhesion

Three major glycan fractions of 580 kDa (g580), 150 kDa (g150), and 2 kDa (g2) were isolated and purified from Lytechinus pictus sea urchin embryos at the mesenchyme blastula stage by gel filtration and high pressure liquid chromatography. Chemical analysis, by gas chromatography, revealed that g580 is highly sulfated and rich in N-acetylglucosamine, N-acetylgalactosamine, glucuronic acid, and fucose. The g150 fraction is less acidic than g580 and contains high amounts of amino sugars, xylose, and mannose. The g2 fraction is neutral, rich in N-acetylglucosamine, mannose, and galactose. The g580 and g150 fractions are resistant to glycosaminoglycan-degrading enzymes, indicating that they are distinct from the glycosaminoglycans. The g580 fraction resembles, with respect to chemical composition, a previously characterized 200 kDa sponge adhesion glycan (g200). The binding of the monoclonal antibody Block 2, which recognizes a repetitive epitope on g200, as well as of the anti-g580 polyclonal antibodies to both g580 and g200 indicated that these two glycans share similar antigenic determinants. The Fab fragments of the Block 2 antibody, which previously have been shown to inhibit cell adhesion in sponges, also blocked the reaggregation of dissociated sea urchin mesenchyme blastula cells. These results indicate that g580 carries a carbohydrate epitope, similar to the sponge adhesion epitope of g200, which is involved in sea urchin embryonal cell adhesion.     

Inhibition of TRAP-induced angiogenesis by the tripeptide Phe-Pro-Arg, a thrombin-receptor-derived peptide analogue

Summary We have recently shown that thrombin promotes angiogenesis by a mechanism independent of fibrin formation. In the present paper, we investigated the effect of the thrombin-receptor-activating tetradecapeptide (TRAP_1–14, S₄₂FLLRNPNDKYEPF₅₅) for its effects on angiogenesis in the chick chorioallantoic membrane (CAM) system of angiogenesis. A dose-dependent promotion of angiogenesis is evident with TRAP. In contrast, a thrombin-receptor-derived tripeptide analogue H-Phe-Pro-Arg-OH (FPR), which was designed based on the S₄₂FLLR₄₆ sequence, caused an inhibition of angiogenesis in the CAM, and when it was combined with TRAP it caused a complete reversal of the angiogenesis-promoting effect of TRAP. These results indicate that the proteolytic exposure of the receptor N-terminal tetradecapeptide by thrombin can activate the post-thrombotic events related to angiogenesis. These events can be modulated by constrained peptide analogues such as FPR.     

Involvement of the cell wall ofNocardia restricta on the bioconversions of steroid sapogenins

The bioconversion of tigogenin, (25R)-5-spirostan-3-ol byNocardia restricta to (25R)-4-spirosten-3-one and (25R)-1,4-spirostadien-3-one was strongly increased using protoplasts instead of intact cells. The same effect could be achieved by adding-cyclodextrin to the medium. Since 5-steroid sapogenins pass through the cell wall without hindrance, it can be concluded that the cell wall ofNocardia restricta is a rate-limiting factor only for 5-isomers.     

The distribution of Dishevelled in convergently extending mesoderm

Convergent extension (CE) is a conserved morphogenetic movement that drives axial lengthening of the primary body axis and depends on the planar cell polarity (PCP) pathway. In Drosophila epithelia, a polarised subcellular accumulation of PCP core components, such as Dishevelled (Dvl) protein, is associated with PCP function. Dvl has long been thought to accumulate in the mediolateral protrusions in Xenopus chordamesoderm cells undergoing CE. Here we present a quantitative analysis of Dvl intracellular localisation in Xenopus chordamesoderm cells. We find that, surprisingly, accumulations previously observed at mediolateral protrusions of chordamesodermal cells are not protrusion-specific but reflect yolk-free cytoplasm and are quantitatively matched by the distribution of the cytoplasm-filling lineage marker dextran. However, separating cell cortex-associated from bulk Dvl signal reveals a statistical enrichment of Dvl in notochord–somite boundary-(NSB)-directed protrusions, which is dependent upon NSB proximity. Dvl puncta were also observed, but only upon elevated overexpression. These puncta showed no statistically significant spatial bias, in contrast to the strongly posteriorly-enriched GFP-Dvl puncta previously reported in zebrafish. We propose that Dvl distribution is more subtle and dynamic than previously appreciated and that in vertebrate mesoderm it reflects processes other than protrusion as such.     

First documentation of the otoliths of the species of Gouania (Teleostei: Gobiesocidae) in the Mediterranean Sea

Otolith morphology is a widely accepted tool for species identification in teleost fish, but whether this holds true for very small species remains to be explored. Here, the saccular otoliths of the cryptobenthic Mediterranean clingfish Gouania (Gobiesocidae) are described for the first time. The new data, although preliminary, indicate that otolith morphology and morphometry support the recognition of the recently differentiated five species of Gouania in the Mediterranean Sea. Furthermore, otoliths of phylogenetically closely related Gouania species resemble each other more than do those of the more distantly related species.