Tissue acidosis associated with ischemic stroke to guide nimodipine delivery

Background: Ischemic stroke is a leading cause of death and disability worldwide. Yet, the effective therapy of focal cerebral ischemia has been an unresolved challenge. We propose here that ischemic tissue acidosis, a sensitive metabolic indicator of injury progression in cerebral ischemia, can be harnessed for the targeted delivery of neuroprotective agents. Ischemic tissue acidosis, which represents the accumulation of lactic acid in malperfused brain tissue is significantly exacerbated by the recurrence of SD events. Deepening acidosis itself activates specific ion channels to cause neurotoxic cellular Ca2+ accumulation and cytotoxic edema. These processes are thought to contribute to the loss of the ischemic penumbra. Importantly, acidosis in the ischemic penumbra may also be used to guide therapeutic intervention. Nimodipine, an L-type VGCC antagonist dilates cerebral arterioles, but its systemic administration may cause potential side effects (mainly hypotension). We have constructed chitosan nanoparticles as drug carriers, which release nimodipine in response to decreasing pH typical of cerebral ischemia. Here we have set out to evaluate this nanomedical approach to deliver nimodipine selectively to acidic ischemic brain tissue. Methods: Two sets of experiments are presented in this thesis. In Experimental Project I, nimodipine was applied in solution (100 μM), then global forebrain ischemia was induced in half of the animals by bilateral common carotid artery occlusion under isoflurane anesthesia. Functional hyperemia in the somatosensory cortex was created by mechanical stimulation of the contralateral whisker pad under α‐chloralose anesthesia. SD events were elicited subsequently by 1 M KCl. LFP and CBF in the parietal somatosensory cortex were monitored by electrophysiology and LDF. In Experimental Project II, nimodipine was associated with pH-sensitive nanoparticles in suspension. After washing the nanoparticle suspension with or without nimodipine (100 μM) on the exposed brain surface of anesthetized rats, both common carotid arteries were occluded to create forebrain ischemia. SDs were elicited by 1 M KCl to deepen the ischemic insult. LFP, CBF and tissue pH were recorded from the cerebral cortex. Microglia activation and neuronal survival were evaluated in brain sections by immunocytochemistry. Results: Nimodipine in solution attenuated evoked potentials and SD. In addition to the elevation of baseline CBF, nimodipine augmented hyperemia in response to both somatosensory stimulation and SD, the drug effect was particularly discernable under ischemia. Ischemia-induced tissue acidosis initiated nimodipine release from nanoparticles, confirmed by the significant elevation of baseline CBF. Nimodipine shortened the duration of both SD itself, and the associated tissue acidosis, moreover it enhanced the SD-related hyperemia. Chitosan nanoparticles did not activate microglia. Conclusions: The administered nanoparticles release nimodipine in acidic tissue environment, which reliably delineates sites at risk of injury. The data support the concept that tissue acidosis linked to cerebral ischemia can be employed as a trigger for targeted drug delivery. Nimodipine-mediated vasodilation and SD inhibition can be achieved by pH-responsive chitosan nanoparticles applied directly to the brain surface. Ultimately, this approach may offer a new way to treat stroke patients with the hope of more effective therapy, and better stroke outcome

Different roles of similarity and predictability in auditory stream segregation

Sound sources often emit trains of discrete sounds, such as a series of footsteps. Previously, two dif¬ferent principles have been suggested for how the human auditory system binds discrete sounds to¬gether into perceptual units. The feature similarity principle is based on linking sounds with similar characteristics over time. The predictability principle is based on linking sounds that follow each other in a predictable manner. The present study compared the effects of these two principles. Participants were presented with tone sequences and instructed to continuously indicate whether they perceived a single coherent sequence or two concurrent streams of sound. We investigated the influence of separate manipulations of similarity and predictability on these perceptual reports. Both grouping principles affected perception of the tone sequences, albeit with different characteristics. In particular, results suggest that whereas predictability is only analyzed for the currently perceived sound organization, feature similarity is also analyzed for alternative groupings of sound. Moreover, changing similarity or predictability within an ongoing sound sequence led to markedly different dynamic effects. Taken together, these results provide evidence for different roles of similarity and predictability in auditory scene analysis, suggesting that forming auditory stream representations and competition between alter¬natives rely on partly different processes

A comprehensive systems biological study of autophagy-apoptosis crosstalk during endoplasmic reticulum stress

One of the most important tasks of a living organism is to maintain its genetic integrity with respect to stress. Endoplasmic reticulum (ER) has a crucial role in sensing cellular homeostasis by controlling metabolism, proteostasis, and several signaling processes. ER stressors can induce autophagy-dependent survival; however excessive level of stress results in apoptotic cell death. Although many molecular components of these networks have already been discovered, the analysis of the dynamical features of the regulatory network of life-or-death decision is still lacking. Our goal was to incorporate both theoretical and molecular biological techniques to explore the autophagy-apoptosis crosstalk under ER stress. Using various levels of different ER stressors we confirmed that the control network always generated an evidently detectable autophagy-dependent threshold for apoptosis activation. We explored the features of this threshold by introducing both autophagy activators and inhibitors, and transient treatment with excessive level of ER stressor was also performed. Our experimental data were also supported by a stochastic approach. Our analysis suggests that even if the switch-like characteristic of apoptosis activation is hardly seen on population level the double negative feedback loop between autophagy and apoptosis inducers introduces bistability in the control network. © 2015 Marianna Holczer et al

Quantum rings with time dependent spin-orbit coupling: Rabi oscillations, spintronic Schrodinger-cat states, and conductance properties

The strength of the (Rashba-type) spin-orbit coupling in mesoscopic semiconductor rings can be tuned with external gate voltages. Here we consider the case of a periodically changing spin-orbit interaction strength as induced by sinusoidal voltages. In a closed one dimensional quantum ring with weak spin-orbit coupling, Rabi oscillations are shown to appear. We find that the time evolution of initially localized wave packets exhibits a series of collapse and revival phenomena. Partial revivals -- that are typical in nonlinear systems -- are shown to correspond to superpositions of states localized at different spatial positions along the ring. These "spintronic Schrodinger-cat sates" appear periodically, and similarly to their counterparts in other physical systems, they are found to be sensitive to environment induced disturbances. The time dependent spin transport problem, when leads are attached to the ring, is also solved. We show that the "sideband currents" induced by the oscillating spin-orbit interaction strength can become the dominant output channel, even in the presence of moderate thermal fluctuations and random scattering events.Comment: 11 pages, 9 figures, submitted to PR

Interaction of folic acid and some matrix metalloproteinase (MMP) inhibitor folate-γ-hydroxamate derivatives with Zn(II) and human serum albumin

Human serum albumin binding of folic acid and its γ-hydroxamate/ carboxylate derivatives was studied by ultrafiltration and spectrofluorimetry, and it was found that the ligands exhibit a moderate binding (KD ∼ 2-50 μM), and the folate-γ-phenylalanine represents the highest conditional binding constant towards albumin. This feature may have importance in the serum transport processes of these ligands. Interaction of folic acid and its derivatives with Zn(II) was investigated in aqueous solution to obtain the composition and stabilities of the complexes by the means of pH-potentiometry, 1H NMR and electrospray ionization mass spectrometry, together with the characterization of the proton dissociation processes and the hydro-lipophilic properties of the ligands. The formation of mono-ligand complexes was demonstrated in all cases and the contribution of the glutamyl carboxylates to the coordination was excluded. Binding of folic acid and its γ-carboxylate derivatives to Zn(II) via the pteridine moiety is suggested, while the (O,O) coordination fashion of the folate-γ-hydroxamate ligands has importance in their inhibitory activity against Zn(II)-containing matrix metalloproteinases. It was found that the enzyme inhibition of these folate-γ-hydroxamate ligands is mainly tuned by other features, such as the lipophilic character rather than the Zn(II)-chelate stability. © 2010 Elsevier Inc. All rights reserved

Stable individual characteristics in the perception of multiple embedded patterns in multistable auditory stimuli

The ability of the auditory system to parse complex scenes into component objects in order to extract information from the environment is very robust, yet the processing principles underlying this ability are still not well understood. This study was designed to investigate the proposal that the auditory system constructs multiple interpretations of the acoustic scene in parallel, based on the finding that when listening to a long repetitive sequence listeners report switching between different perceptual organizations. Using the ‘ABA-’ auditory streaming paradigm we trained listeners until they could reliably recognise all possible embedded patterns of length four which could in principle be extracted from the sequence, and in a series of test sessions investigated their spontaneous reports of those patterns. With the training allowing them to identify and mark a wider variety of possible patterns, participants spontaneously reported many more patterns than the ones traditionally assumed (Integrated vs. Segregated). Despite receiving consistent training and despite the apparent randomness of perceptual switching, we found individual switching patterns were idiosyncratic; i.e. the perceptual switching patterns of each participant were more similar to their own switching patterns in different sessions than to those of other participants. These individual differences were found to be preserved even between test sessions held a year after the initial experiment. Our results support the idea that the auditory system attempts to extract an exhaustive set of embedded patterns which can be used to generate expectations of future events and which by competing for dominance give rise to (changing) perceptual awareness, with the characteristics of pattern discovery and perceptual competition having a strong idiosyncratic component. Perceptual multistability thus provides a means for characterizing both general mechanisms and individual differences in human perception

Measurement-induced chaos and quantum state discrimination in an iterated Tavis-Cummings scheme

A cavity quantum electrodynamical scenario is proposed for implementing a Schr¨odinger microscope capable of amplifying differences between nonorthogonal atomic quantum states. The scheme involves an ensemble of identically prepared two-level atoms interacting pairwise with a single mode of the radiation field as described by the Tavis-Cummings model. By repeated measurements of the cavity field and of one atom within each pair a measurement-induced nonlinear quantum transformation of the relevant atomic states can be realized. The intricate dynamical properties of this nonlinear quantum transformation, which exhibits measurement-induced chaos, allow approximate orthogonalization of atomic states by purification after a few iterations of the protocol and thus the application of the scheme for quantum state discrimination