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Quantum mechanics (QM) is derived based on a universe composed solely of events, for example, outcomes of observables. Such an event universe is represented by a dendrogram (a finite tree) and in the limit of infinitely many events by the p-adic tree. The trees are endowed with an ultrametric expressing hierarchical relationships between events. All events are coupled through the tree structure. Such a holistic picture of event-processes was formalized within the Dendrographic Hologram Theory (DHT). The present paper is devoted to the emergence of QM from DHT. We used the generalization of the QM-emergence scheme developed by Smolin. Following this scheme, we did not quantize events but rather the differences between them and through analytic derivation arrived at Bohmian mechanics. We remark that, although Bohmian mechanics is not the main stream approach to quantum physics, it describes adequately all quantum experiments. Previously, we were able to embed the basic elements of general relativity (GR) into DHT, and now after Smolin-like quantization of DHT, we can take a step toward quantization of GR. Finally, we remark that DHT is nonlocal in the treelike geometry, but this nonlocality refers to relational nonlocality in the space of events and not Einstein's spatial nonlocality. By shifting from spatial nonlocality to relational we make Bohmian mechanics less exotic., (© 2023. Springer Nature Limited.)

We developed the novel mathematical model for event-universe by representing events as branches of dendrograms (finite trees) expressing the hierarchic relation between events. At the ontic level we operate with infinite trees. Algebraically such mathematical structures are represented as p -adic numbers. We call this kind of event mechanics Dendrogramic Holographic theory (DHT). It can be considered as a fundamental theory generating both GR and QM. In this paper we endower DHT with Rao-Cramer's information geometry. Following Smolin's derivation of QM from the event-universe, we introduce views from one event to others and by using their probability distributions we invent stochastic geometry. The important mathematical result is that all such views' distributions can be parametrized by four real parameters that are a part of the shape complexity measure introduced by Barbour in his particle shape dynamics theory - adapted to DHT. Hence, within DHT all possible event-universes can be embedded in four-dimensional real space. Asin GR, we introduce proper time . This "proper time" depends only on the change between one distribution of an observer to the other. The linkage of time to change is highlighted in the ideology of Rovelli and Barbour's shape dynamics., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier Ltd.)

Toll-like receptor 3 (TLR3), plays an important role in the development of epilepsy after brain insults. Previously, TLR3 deficiency in a pilocarpine model of temporal lobe epilepsy (TLE) was shown to reduce mortality, spontaneous recurrent seizures (SRS) and neuroinflammation. We hypothesized that pharmacological inhibition of TLR3 would reduce epileptogenesis following status epilepticus. We show that Resveratrol and FC99, two TLR3 blockers, demonstrate anti-epileptogenic effects in a pilocarpine model of TLE. While both Resveratrol and FC99 were previously shown to benefit in other pathologies, neither of these blockers had been proposed for the treatment of epilepsy. Our results provide substantial evidence to the importance of TLR3 inhibition in the prevention of epilepsy and specifically highlighting FC99 as a promising novel anti-epileptic drug. We anticipate our data to be a starting point for further studies assessing the anti-epileptogenic potential of FC99 and other TLR3 blockers, paving the way for pharmacological interventions that prevent epileptogenesis., Competing Interests: FB is a consultant for NeuroHelp. None of these companies had any input into the design, execution, analyses or writing of this manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shor, Rabinowitz, Hersh, Vanichkin and Benninger.)

The diagnosis of psychiatric disorders is currently based on a clinical and psychiatric examination (intake). Ancillary tests are used minimally or only to exclude other disorders. Here, we demonstrate a novel mathematical approach based on the field of p-adic numbers and using electroencephalograms (EEGs) to identify and differentiate patients with schizophrenia and depression from healthy controls. This novel approach examines spatio-temporal relations of single EEG electrode signals and characterizes the topological structure of these relations in the individual patient. Our results indicate that the relational topological structures, characterized by either the personal universal dendrographic hologram (DH) signature (PUDHS) or personal block DH signature (PBDHS), form a unique range for each group of patients, with impressive correspondence to the clinical condition. This newly developed approach results in an individual patient signature calculated from the spatio-temporal relations of EEG electrodes signals and might help the clinician with a new objective tool for the diagnosis of a multitude of psychiatric disorders., (© 2023. The Author(s).)

Temporal lobe epilepsy (TLE), the most common focal seizure disorder in adults, can be instigated in experimental animals by convulsant-induced status epilepticus (SE). Principal hippocampal neurons from SE-experienced epileptic male rats (post-SE neurons) display markedly augmented spike output compared with neurons from nonepileptic animals (non-SE neurons). This enhanced firing results from a cAMP-dependent protein kinase A-mediated inhibition of K Ca 3.1, a subclass of Ca 2+ -gated K + channels generating the slow afterhyperpolarizing Ca 2+ -gated K + current ( I sAHP ). The inhibition of K Ca 3.1 in post-SE neurons leads to a marked reduction in amplitude of the I sAHP that evolves during repetitive firing, as well as in amplitude of the associated Ca 2+ -dependent component of the slow afterhyperpolarization potential (K Ca -sAHP). Here we show that K Ca 3.1 inhibition in post-SE neurons is induced by corticotropin releasing factor (CRF) through its Type 1 receptor (CRF 1 R). Acute application of CRF 1 R antagonists restores K Ca 3.1 activity in post-SE neurons, normalizing K Ca -sAHP/ I sAHP amplitudes and neuronal spike output, without affecting these variables in non-SE neurons. Moreover, pharmacological antagonism of CRF 1 Rs in vivo reduces the frequency of spontaneous recurrent seizures in post-SE chronically epileptic rats. These findings may provide a new vista for treating TLE. SIGNIFICANCE STATEMENT Epilepsy, a common neurologic disorder, often develops following a brain insult. Identifying key cellular mechanisms underlying acquired epilepsy is critical for developing effective antiepileptic therapies. In an experimental model of acquired epilepsy, principal hippocampal neurons manifest hyperexcitability because of downregulation of K Ca 3.1, a subtype of Ca 2+ -gated K + ion channels. We show that K Ca 3.1 downregulation is mediated by corticotropin releasing factor (CRF) acting through its Type 1 receptor (CRF 1 R). Congruently, acute application of selective CRF 1 R antagonists restores K Ca 3.1 channel activity, leading to normalization of neuronal excitability. In the same model, injection of a CRF 1 R antagonist to epileptic animals markedly decreases the frequency of electrographic seizures. Therefore, targeting CRF 1 Rs may provide a new strategy in the treatment of acquired epilepsy., (Copyright © 2022 the authors.)

The CRISPR-Cas system has transformed the field of gene-editing and created opportunities for novel genome engineering therapeutics. The field has significantly progressed, and recently, CRISPR-Cas9 was utilized in clinical trials to target disease-causing mutations. Existing tools aim to predict the on-target efficacy and potential genome-wide off-targets by scoring a particular gRNA according to an array of gRNA design principles or machine learning algorithms based on empirical results of large numbers of gRNAs. However, such tools are unable to predict the editing outcome by variant Cas enzymes and can only assess potential off-targets related to reference genomes. Here, we employ normal mode analysis (NMA) to investigate the structure of the Cas9 protein complexed with its gRNA and target DNA and explore the function of the protein. Our results demonstrate the feasibility and validity of NMA to predict the activity and specificity of SpyCas9 in the presence of mismatches by comparison to empirical data. Furthermore, despite the absence of their exact structures, this method accurately predicts the enzymatic activity of known high-fidelity engineered Cas9 variants., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Following Smolin, we proceed to unification of general relativity and quantum theory by operating solely with events, i.e., without appealing to physical systems and space-time. The universe is modelled as a dendrogram (finite tree) expressing the hierarchic relations between events. This is the observational (epistemic) model; the ontic model is based on p-adic numbers (infinite trees). Hence, we use novel mathematics: not only space-time but even real numbers are not in use. Here, the p-adic space (which is zero-dimensional) serves as the base for the holographic image of the universe. In this way our theory is connected with p-adic physics; in particular, p-adic string theory and complex disordered systems (p-adic representation of the Parisi matrix for spin glasses). Our Dendrogramic-Holographic (DH) theory matches perfectly with the Mach's principle and Brans-Dicke theory. We found a surprising informational interrelation between the fundamental constants, h , c , G , and their DH analogues, h ( D ), c ( D ), G ( D ). DH theory is part of Wheeler's project on the information restructuring of physics. It is also a step towards the Unified Field theory. The universal potential V is nonlocal, but this is relational DH nonlocality. V can be coupled to the Bohm quantum potential by moving to the real representation. This coupling enhances the role of the Bohm potential.

TUBB4A-associated disorder is a rare condition affecting the central nervous system. It displays a wide phenotypic spectrum, ranging from isolated late-onset torsion dystonia to a severe early-onset disease with developmental delay, neurological deficits, and atrophy of the basal ganglia and cerebellum, therefore complicating variant interpretation and phenotype prediction in patients carrying TUBB4A variants. We applied entropy-based normal mode analysis (NMA) to investigate genotype-phenotype correlations in TUBB4A-releated disease and to develop an in-silico approach to assist in variant interpretation and phenotype prediction in this disorder. Variants included in our analysis were those reported prior to the conclusion of data collection for this study in October 2019. All TUBB4A pathogenic missense variants reported in ClinVar and Pubmed, for which associated clinical information was available, and all benign/likely benign TUBB4A missense variants reported in ClinVar, were included in the analysis. Pathogenic variants were divided into five phenotypic subgroups. In-silico point mutagenesis in the wild-type modeled protein structure was performed for each variant. Wild-type and mutated structures were analyzed by coarse-grained NMA to quantify protein stability as entropy difference value (ΔG) for each variant. Pairwise ΔG differences between all variant pairs in each structural cluster were calculated and clustered into dendrograms. Our search yielded 41 TUBB4A pathogenic variants in 126 patients, divided into 11 partially overlapping structural clusters across the TUBB4A protein. ΔG-based cluster analysis of the NMA results revealed a continuum of genotype-phenotype correlation across each structural cluster, as well as in transition areas of partially overlapping structural clusters. Benign/likely benign variants were integrated into the genotype-phenotype continuum as expected and were clearly separated from pathogenic variants. We conclude that our results support the incorporation of the NMA-based approach used in this study in the interpretation of variant pathogenicity and phenotype prediction in TUBB4A-related disease. Moreover, our results suggest that NMA may be of value in variant interpretation in additional monogenic conditions., (© 2022. The Author(s).)

Objective: Management of a patient presenting with a first seizure depends on the risk of additional seizures. In clinical practice, the recurrence risk is estimated by the treating physician using the neurological examination, brain imaging, a thorough history for risk factors, and routine scalp electroencephalogram (EEG) to detect abnormal epileptiform activity. The decision to use antiseizure medication can be challenging when objective findings are missing. There is a need for new biomarkers to better diagnose epilepsy following a first seizure. Recently, an EEG-based novel analytical method was reported to detect paroxysmal slowing in the cortical network of patients with epilepsy. The aim of our study is to test this method's sensitivity and specificity to predict epilepsy following a first seizure., Methods: We analyzed interictal EEGs of 70 patients admitted to the emergency department of a tertiary referral center after a first seizure. Clinical data from a follow-up period of at least 18 months were available. EEGs of 30 healthy controls were also analyzed and included. For each EEG, we applied an automated algorithm to detect paroxysmal slow wave events (PSWEs)., Results: Of patients presenting with a first seizure, 40% had at least one additional recurring seizure and were diagnosed with epilepsy. Sixty percent did not report additional seizures. A significantly higher occurrence of PSWEs was detected in the first interictal EEG test of those patients who were eventually diagnosed with epilepsy. Conducting the EEG test within 72 h after the first seizure significantly increased the likelihood of detecting PSWEs and the predictive value for epilepsy up to 82%., Significance: The quantification of PSWEs by an automated algorithm can predict epilepsy and help the neurologist in evaluating a patient with a first seizure., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

No diagnostic or predictive instruments to help with early diagnosis and timely therapeutic intervention are available as yet for most neuro-psychiatric disorders. A quantum potential mean and variability score (qpmvs), to identify neuropsychiatric and neurocognitive disorders with high accuracy, based on routine EEG recordings, was developed. Information processing in the brain is assumed to involve integration of neuronal activity in various areas of the brain. Thus, the presumed quantum-like structure allows quantification of connectivity as a function of space and time (locality) as well as of instantaneous quantum-like effects in information space (non-locality). EEG signals reflect the holistic (nonseparable) function of the brain, including the highly ordered hierarchy of the brain, expressed by the quantum potential according to Bohmian mechanics, combined with dendrogram representation of data and p-adic numbers. Participants consisted of 230 participants including 28 with major depression, 42 with schizophrenia, 65 with cognitive impairment, and 95 controls. Routine EEG recordings were used for the calculation of qpmvs based on ultrametric analyses, closely coupled with p-adic numbers and quantum theory. Based on area under the curve, high accuracy was obtained in separating healthy controls from those diagnosed with schizophrenia (p<0.0001), depression (p<0.0001), Alzheimer's disease (AD; p<0.0001), and mild cognitive impairment (MCI; p<0.0001) as well as in differentiating participants with schizophrenia from those with depression (p<0.0001), AD (p<0.0001) or MCI (p<0.0001) and in differentiating people with depression from those with AD (p<0.0001) or MCI (p<0.0001). The novel EEG analytic algorithm (qpmvs) seems to be a useful and sufficiently accurate tool for diagnosis of neuropsychiatric and neurocognitive diseases and may be able to predict disease course and response to treatment., Competing Interests: The authors have declared that no competing interests exist.

This paper is devoted to the foundational problems of dendrogramic holographic theory (DH theory). We used the ontic-epistemic (implicate-explicate order) methodology. The epistemic counterpart is based on the representation of data by dendrograms constructed with hierarchic clustering algorithms. The ontic universe is described as a p-adic tree; it is zero-dimensional, totally disconnected, disordered, and bounded (in p-adic ultrametric spaces). Classical-quantum interrelations lose their sharpness; generally, simple dendrograms are "more quantum" than complex ones. We used the CHSH inequality as a measure of quantum-likeness. We demonstrate that it can be violated by classical experimental data represented by dendrograms. The seed of this violation is neither nonlocality nor a rejection of realism, but the nonergodicity of dendrogramic time series. Generally, the violation of ergodicity is one of the basic features of DH theory. The dendrogramic representation leads to the local realistic model that violates the CHSH inequality. We also considered DH theory for Minkowski geometry and monitored the dependence of CHSH violation and nonergodicity on geometry, as well as a Lorentz transformation of data.

A proposal for a fundamental theory is described in which classical and quantum physics as a representation of the universe as a gigantic dendrogram are unified. The latter is the explicate order structure corresponding to the purely number-theoretical implicate order structure given by p-adic numbers. This number field was zero-dimensional, totally disconnected, and disordered. Physical systems (such as electrons, photons) are sub-dendrograms of the universal dendrogram. Measurement process is described as interactions among dendrograms; in particular, quantum measurement problems can be resolved using this process. The theory is realistic, but realism is expressed via the the Leibniz principle of the Identity of Indiscernibles . The classical-quantum interplay is based on the degree of indistinguishability between dendrograms (in which the ergodicity assumption is removed). Depending on this degree, some physical quantities behave more or less in a quantum manner (versus classic manner). Conceptually, our theory is very close to Smolin's dynamics of difference and Rovelli's relational quantum mechanics. The presence of classical behavior in nature implies a finiteness of the Universe-dendrogram. (Infinite Universe is considered to be purely quantum.) Reconstruction of events in a four-dimensional space type is based on the holographic principle. Our model reproduces Bell-type correlations in the dendrogramic framework. By adjusting dendrogram complexity, violation of the Bell inequality can be made larger or smaller.

Objective: To describe the WFS1 c.1672C>T; p.R558C missense variant, found in 1.34% of Ashkenazi Jews, that has a relatively mild phenotype and to use computational normal mode analysis (NMA) to explain the genotype-phenotype relationship., Methods: The clinical, laboratory, and genetic features of 8 homozygotes were collected. A model of the wolframin protein was constructed, and NMA was used to simulate the effect of the variant on protein thermodynamics., Results: Mean age at Wolfram syndrome (WS) diagnosis among homozygotes was 30 years; diabetes (7/8) was diagnosed at mean age 19 years (15-21 years), and bilateral optic atrophy (with MRI evidence of optic/chiasm atrophy) (6/8) at mean age 29 years (15-48 years). The oldest patient (62 years) also had gait difficulties, memory problems, parietal and cerebellar atrophy, and white matter hyperintense lesions. All retained functional vision with independent ambulation and self-care; none had diabetes insipidus or hearing loss. The p.R558C variant caused less impairment of protein entropy than WFS1 variants associated with a more severe phenotype., Conclusions: The p.R558C variant causes a milder, late-onset phenotype of WS. We report a structural model of wolframin protein based on empirical functional studies and use NMA modeling to show a genotype-phenotype correlation across all homozygotes. Clinicians should be alert to this condition in patients with juvenile diabetes and patients of any age with a combination of diabetes and optic atrophy. Computational NMA has potential benefit for prediction of the genotype-phenotype relationship., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background The cardiac ryanodine receptor type 2 (RyR2) is a large homotetramer, located in the sarcoplasmic reticulum (SR), which releases Ca 2+ from the SR during systole. The molecular mechanism underlying Ca 2+ sensing and gating of the RyR2 channel in health and disease is only partially elucidated. Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT1) is the most prevalent syndrome caused by RyR2 mutations. Methods and Results This study involves investigation of a family with 4 cases of ventricular fibrillation and sudden death and physiological tests in HEK 293 cells and normal mode analysis (NMA) computation. We found 4 clinically affected members who were homozygous for a novel RyR2 mutation, G3118R, whereas their heterozygous relatives are asymptomatic. G3118R is located in the periphery of the protein, far from the mutation hotspot regions. HEK293 cells harboring G3118R mutation inhibited Ca 2+ release in response to increasing doses of caffeine, but decreased the termination threshold for store-overload-induced Ca 2+ release, thus increasing the fractional Ca 2+ release in response to increasing extracellular Ca 2+ . NMA showed that G3118 affects RyR2 tetramer in a dose-dependent manner, whereas in the model of homozygous mutant RyR2, the highest entropic values are assigned to the pore and the central regions of the protein. Conclusions RyR2 G3118R is related to ventricular fibrillation and sudden death in recessive mode of inheritance and has an effect of gain of function on the protein. Despite a peripheral location, it has an allosteric effect on the stability of central and pore regions in a dose-effect manner.

The developmental and epileptic encephalopathies (DEEs) are heterogeneous disorders with a strong genetic contribution, but the underlying genetic etiology remains unknown in a significant proportion of individuals. To explore whether statistical support for genetic etiologies can be generated on the basis of phenotypic features, we analyzed whole-exome sequencing data and phenotypic similarities by using Human Phenotype Ontology (HPO) in 314 individuals with DEEs. We identified a de novo c.508C>T (p.Arg170Trp) variant in AP2M1 in two individuals with a phenotypic similarity that was higher than expected by chance (p = 0.003) and a phenotype related to epilepsy with myoclonic-atonic seizures. We subsequently found the same de novo variant in two individuals with neurodevelopmental disorders and generalized epilepsy in a cohort of 2,310 individuals who underwent diagnostic whole-exome sequencing. AP2M1 encodes the μ-subunit of the adaptor protein complex 2 (AP-2), which is involved in clathrin-mediated endocytosis (CME) and synaptic vesicle recycling. Modeling of protein dynamics indicated that the p.Arg170Trp variant impairs the conformational activation and thermodynamic entropy of the AP-2 complex. Functional complementation of both the μ-subunit carrying the p.Arg170Trp variant in human cells and astrocytes derived from AP-2μ conditional knockout mice revealed a significant impairment of CME of transferrin. In contrast, stability, expression levels, membrane recruitment, and localization were not impaired, suggesting a functional alteration of the AP-2 complex as the underlying disease mechanism. We establish a recurrent pathogenic variant in AP2M1 as a cause of DEEs with distinct phenotypic features, and we implicate dysfunction of the early steps of endocytosis as a disease mechanism in epilepsy., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

The phasic release of dopamine in the hippocampal formation has been shown to facilitate the encoding of novel information. There is evidence that the subiculum operates as a detector and distributor of sensory information, which incorporates the novelty and relevance of signals received from CA1. The subiculum acts as the final hippocampal relay station for outgoing information. Subicular pyramidal cells have been classified as regular- and burst-spiking neurons. The goal of the present study was to study the effect of dopamine D1/D5 receptor activation on synaptic transmission and plasticity in the subicular regular-spiking neurons of 4-6 week old Wistar rats. We demonstrate that prior activation of D1/D5 receptors reduces the threshold for the induction of long-term potentiation (LTP) in subicular regular-spiking neurons. Our results indicate that D1/D5 receptor activation facilitates a postsynaptic form of LTP in subicular regular-spiking cells that is NMDA receptor-dependent, relies on postsynaptic Ca(2+) signaling, and requires the activation of protein kinase A. The enhanced propensity of subicular regular-spiking cells to express postsynaptic LTP after activation of D1/D5 receptors provides an intriguing mechanism for the encoding of hippocampal output information.

Encoding of novel information has been proposed to rely on the time-locked release of dopamine in the hippocampal formation during novelty detection. However, the site of novelty detection in the hippocampus remains a matter of debate. According to current models, the CA1 and the subiculum act as detectors and distributors of novel sensory information. Although most CA1 pyramidal neurons exhibit regular-spiking behavior, the majority of subicular pyramidal neurons fire high-frequency bursts of action potentials. The present study investigates the efficacy of dopamine D1/D5 receptor activation to facilitate the induction of activity-dependent long-term potentiation (LTP) in rat CA1 regular-spiking and subicular burst-spiking pyramidal cells. Using a weak stimulation protocol, set at a level subthreshold for the induction of LTP, we show that activation of D1/D5 receptors for 5-10 min facilitates LTP in subicular burst-spiking neurons but not in CA1 neurons. The results demonstrate that D1/D5 receptor-facilitated LTP is NMDA receptor-dependent, and requires the activation of protein kinase A. In addition, the D1/D5 receptor-facilitated LTP is shown to be presynaptically expressed and relies on presynaptic Ca(2+) signaling. The phenomenon of dopamine-induced facilitation of presynaptic NMDA receptor-dependent LTP in subicular burst-spiking pyramidal cells is in accordance with observations of the time-locked release of dopamine during novelty detection in this brain region, and reveals an intriguing mechanism for the encoding of hippocampal output information.

In the animal world, the regulation of ion channels by phosphoinositides (PIs) has been investigated extensively, demonstrating a wide range of channels controlled by phosphatidylinositol (4,5)bisphosphate (PtdInsP2). To understand PI regulation of plant ion channels, we examined the in planta effect of PtdInsP2 on the K+-efflux channel of tobacco (Nicotiana tabacum), NtORK (outward-rectifying K channel). We applied a patch clamp in the whole-cell configuration (with fixed "cytosolic" Ca2+ concentration and pH) to protoplasts isolated from cultured tobacco cells with genetically manipulated plasma membrane levels of PtdInsP2 and cellular inositol (1,4,5)trisphosphate: "Low PIs" had depressed levels of these PIs, and "High PIs" had elevated levels relative to controls. In all of these cells, K channel activity, reflected in the net, steady-state outward K+ currents (IK), was inversely related to the plasma membrane PtdInsP2 level. Consistent with this, short-term manipulations decreasing PtdInsP2 levels in the High PIs, such as pretreatment with the phytohormone abscisic acid (25 microM) or neutralizing the bath solution from pH 5.6 to pH 7, increased IK (i.e. NtORK activity). Moreover, increasing PtdInsP2 levels in controls or in abscisic acid-treated high-PI cells, using the specific PI-phospholipase C inhibitor U73122 (2.5-4 microM), decreased NtORK activity. In all cases, IK decreases stemmed largely from decreased maximum attainable NtORK channel conductance and partly from shifted voltage dependence of channel gating to more positive potentials, making it more difficult to activate the channels. These results are consistent with NtORK inhibition by the negatively charged PtdInsP2 in the internal plasma membrane leaflet. Such effects are likely to underlie PI signaling in intact plant cells.

It is commonly accepted that the hippocampus is critically involved in the explicit memory formation of mammals. The subiculum is the principal target of CA1 pyramidal cells and thus serves as the major relay station for the outgoing hippocampal information. Pyramidal cells in the subiculum can be classified according to their firing properties into burst-spiking and regular-spiking cells. In the present study we demonstrate that burst-spiking and regular-spiking cells show fundamentally different forms of low frequency-induced synaptic plasticity in rats. In burst-spiking cells, low-frequency stimulation (at 0.5-5 Hz) induces frequency-dependent long-term depression (LTD) with a maximum at 1 Hz. This LTD is dependent on the activation of NMDAR and masks an mGluR-dependent long-term potentiation (LTP). In contrast, in regular-spiking cells low-frequency stimulation induces an mGluR-dependent LTP that masks an NMDAR-dependent LTD. Both processes depend on postsynaptic Ca(2+)-signaling as BAPTA prevents the induction of synaptic plasticity in both cell types. Thus, mGluR-dependent LTP and NMDAR-dependent LTD occur simultaneously at CA1-subiculum synapses and the predominant direction of synaptic plasticity relies on the cell type investigated. Our data indicate a novel mechanism for the sliding-threshold model of synaptic plasticity, in which induction of LTP and LTD seems to be driven by the relative activation state of NMDAR and mGluR. Our observation that the direction of synaptic plasticity correlates with the discharge properties of the postsynaptic cell reveals a novel and intriguing mechanism of target specificity that may serve in tuning the significance of neuronal information by trafficking hippocampal output onto either subicular burst-spiking or regular-spiking cells.

The authors compare basic body plethysmography and peak flowmetry parameters, quality of life in 37 patients suffering from moderate or severe bronchial asthma. They received for 8 months low-dose glucocorticosteroids (group 1), high-dose glucocorticosteroids (group 2) and combination of low-dose glucocorticosteroids with long-acting theophyllin drugs (group 3). All the parameters assessed, quality of life was better in groups 2 and 3 (p < 0.05). Patients from these groups had also less frequent exacerbations of the disease which appeared less severe. From group 3 patients those who suffered longer and had marked emphysema showed a greater response.

The trial included 34 patients with moderate non-atopic asthma in exacerbation. After arrest of the acute attack the patients inhaled berodual via nebulizer (a single dose of 0.5 ml -125 micrograms ipratropium bromide and 250 micrograms phenoterol) or aerosol (40 micrograms ipratropium and 100 micrograms phenoterol). As shown by body plethysmography and peak-flowmetry, nebulizer therapy was characterized by earlier onset of broncholytic effect which stood longer, more pronounced effect at the level of small and middle bronchi, absence of side effects. The authors believe that berodual inhalations through nebulizer are an effective modality in the treatment of bronchial asthma in severe exacerbation.