Izhak Michaelevski

Background: Pressure pain threshold (PPT) is commonly assessed using pressure algometry. Self-administered algometry could reduce examiner involvement and may facilitate repeated assessment outside specialist settings. Objective: To examine the concurrent agreement of a previously described syringe-based pneumatic algometer with a commercially available comparator during self-administered PPT measurement in healthy adults. Methods: Thirty healthy volunteers completed researcher-administered and self-administered pain threshold measurements utilizing an AMF-500 device and the syringe-based pneumatic algometer. Results: During self-administration, measurements from the two devices were strongly correlated (r = 0.82, p < 0.05); the mean paired difference was 6.01 N (95% CI, -0.58 to 12.59 N). Self-administered test values were lower than researcher-administered test values in the fixed-order comparison (p = 0.0029). Conclusion: According to our findings the proposed device is a valid tool for autoalgometry and may potentially be introduced as an element of routine self-assessment of PPT.

Repeated radial-arm maze (RAM) exposure engages spatial, motivational, motor, and reward-related processes, but how the dorsal-striatal proteome is organized across repeated training remains unclear. We profiled bulk dorsal striatum from male mice collected after RAM trials on Days 0, 1, 3, and 5, together with a habituated, food-restricted NoRAM control collected before the first trial, using ion-mobility-enhanced data-independent LC-MS/MS. Complementary exploratory factor analysis and weighted gene co-expression network analysis resolved a dominant RAM-versus-NoRAM difference and superimposed, sampling-dependent changes within the trained series. The broad RAM-associated pattern was enriched in ribosomal and translation-initiation proteins, proteasome components, and synaptic-vesicle trafficking. The Day-1-to-Day-3 contrast shifted emphasis toward actin/cytoskeletal regulation, membrane trafficking, mitochondrial respiration, and ATP-generating processes, whereas later Day-5 contrasts emphasized postsynaptic-density organization, vesicle recycling, protein-quality control, and metabolic support. Integration of the two analytical frameworks identified 65 shared central proteins linking synaptic signaling and receptor organization with proteostasis, energy production, and structural remodeling. Candidate transcription-factor and microRNA target enrichments nominated possible regulatory associations but were not directly measured. Because NoRAM controls were collected before task exposure and no activity-, reward-, or repeated-testing-matched control was included, the observed changes cannot be assigned specifically to spatial learning or a navigational strategy. Moreover, pooled bulk tissue precludes cell-type, subregional, and synapse-specific inference. The study therefore provides a biology-centered, hypothesis-generating map of overlapping dorsal-striatal protein networks associated with repeated RAM exposure and prioritizes molecular systems for direct temporal and functional validation.

Quantitative analysis of neuronal morphology in dense cultures remains technically challenging, as extensive overlap between neuritic arbors and background signal limits the applicability of traditional tracing-based approaches. Here, we applied fractal dimension (FD) and lacunarity (LAC) analysis as scale-invariant, global measures of neurite complexity and systematically compared them with classical morphometric approaches in dense primary hippocampal neuronal cultures. Neurons were treated with the Abl tyrosine kinase inhibitor imatinib to induce cytoskeletal remodeling. Fractal analysis was performed on skeletonized representations derived from standardized binarized confocal images, enabling robust quantification of neurite space-filling properties across spatial scales. Imatinib treatment induced a pronounced reduction in FD (DMSO: ~1.56 ± 0.04 vs. IMA: ~1.36 ± 0.05, p < 0.001) together with increased lacunarity, indicating reduced multiscale complexity and increased spatial heterogeneity. In contrast, classical morphometric analysis revealed a heterogeneous phenotype, with elongation of primary neurites accompanied by reduced branching. These opposing effects partially compensated for one another, obscuring overall complexity changes when assessed using individual parameters. To integrate multivariate features, we constructed a composite Neurite Complexity Index (NCI) incorporating branching, neurite length, and distribution-sensitive descriptors (R² ≈ 0.98; F(4,106) = 89.6, p < 1 × 10⁻¹⁸⁴). FD showed strong convergence with the NCI across bootstrap analyses, and clustering and discriminant analyses confirmed its high discriminatory power. Together, these findings suggest that fractal analysis may provide a sensitive and compact framework within the present experimental context for detecting treatment-associated structural changes in dense neuronal cultures.

The prefrontal, visual, and posterior parietal cortices are key to cognition, social interaction, and novelty recognition, but the impact of social hierarchy and inherent stress sensitivity on their interplay remains underexplored. Our findings reveal significant neural differences between stress‐resilient dominant (Dom) and stress‐sensitive submissive (Sub) mice, particularly in theta band power, inter‐regional coherence, and phase–amplitude coupling. Dom mice exhibited reduced theta coherence and dynamic changes in theta‐gamma phase amplitude coupling between the prefrontal and visual cortices, which were associated with better memory recall and cognitive flexibility. In addition, Dom mice showed increased left‐to‐right visual cortex connectivity during the recognition task, linked to successful novelty discrimination, while Sub mice lacked this theta‐driven causality. These results suggest that stress sensitivity associated with social rank alters neural activity and connectivity, contributing to the differing performance of Dom and Sub mice in novelty recognition tasks, providing potential diagnostic and therapeutic implications for targeting theta‐driven connectivity.

Affinity-purified antibody to S100 calcium binding protein B that has undergone gradual technological processing and was additionally modified with an electromagnetic signal is an active pharmaceutical substance of a novel drug Prospekta. Earlier studies have shown that the drug possesses a wide range of pharmacological properties, not limited to pro-cognitive and anxiolytic activity. Here, we aimed to determine the effect of Prospekta on the baseline electrical activity of the mouse brain. Extradural electrodes were surgically implanted into the skull of adult male socially submissive mice. Mice were orally administered Prospekta or purified water as a control via gavage for 5 days starting from the end of the recovery period. Brain baseline activity was recorded during 5 min after placing animals into arena. Quantitative measures of EEG delta (1–4 Hz), theta (4–8 Hz), alpha (8–13 Hz), beta (13–30 Hz), and gamma (30–100 Hz) power were assessed. It was shown that the drug led to a decrease in theta and alpha band power in the left prefrontal cortex. Furthermore, the drug exhibited a tendency to influence the coherence of electrical activity between the left prefrontal cortex and the right hippocampus, resulting in a moderate phase shift across all examined brain regions. At the same time, no prominent changes in EEG activity were observed in the right hippocampal region. We show that Prospekta modifies EEG parameters of animals and thereby confirm that the drug mechanism of action is based on its ability to affect functional (electrophysiological) brain activity.

Protein phosphorylation is a fundamental regulatory mechanism governing a broad spectrum of cellular processes. In the nervous system, it is critical for modulating neurotransmitter release, synaptic plasticity, neuronal excitability, and cell survival. Dysregulation of protein kinase activity is closely linked to the pathogenesis of various neurological and psychiatric disorders, positioning several kinases as promising therapeutic targets. Although protein kinase inhibitors (PKIs), a major class of compounds that modulate kinase activity, have shown considerable therapeutic success in oncology, their application in neurological diseases remains in the early stages of exploration. Of the 82 PKIs approved by the Food and Drug Administration (FDA), 37 are now in various preclinical and clinical trials for neurological conditions, primarily targeting signaling pathways mediated by key protein kinases implicated in these diseases. This review examines the roles of critical protein kinases and the therapeutic effects of their inhibitors in neurodegenerative, psychiatric, and selected neurological disorders, such as autism spectrum disorders (ASD) and epilepsy. We focus on Abelson kinase I (ABL1), calmodulin-dependent kinase II (CaMKII), casein kinase 1δ (CK1δ), c-Jun N-terminal kinase (JNK), cyclin-dependent kinase 5 (CDK5), dual-specificity tyrosine-phosphorylated and regulated kinase 1A (DYRK1A), leucine-rich repeat kinase 2 (LRRK2), extracellular signal-regulated kinase 1/2 (ERK1/2), glycogen synthase kinase 3β (GSK3β), mammalian target of rapamycin (mTOR), p38 mitogen-activated protein kinase, and protein kinase C (PKC) in neurodegenerative diseases. Additionally, we discuss CaMKII, CDK5, ERK1/2, PI3K/AKT/GSK3, protein kinase A (PKA), and PKC in psychiatric disorders, focusing on schizophrenia and mood disorders, and analyze GSK3β, ERK1/2, and mTOR in ASD and epilepsy. This review underscores the therapeutic potential of PKIs in neurological disorders while highlighting ongoing challenges and the need for further research to refine kinase-targeted therapies.

The association between the clinical picture of symptomatic women with silicone breast implants (SBI) and dysregulated immunity was in dispute for decades. In the current study, we describe for the first time the functional activity of purified IgG antibodies derived from symptomatic women with SBIs (suffering from subjective/autonomic-related symptoms), both in vitro and in vivo. We found that IgGs, derived from symptomatic women with SBIs, dysregulate inflammatory cytokines (TNFα, IL-6) in activated human peripheral blood mononuclear cells, compared to healthy-women-derived IgGs. Importantly, behavioral studies conducted following intracerebroventricular injection of IgGs derived from symptomatic women with SBIs (who have dysregulated circulating level of IgG autoantibodies directed against autonomic nervous system receptors) into mice brains demonstrated a specific and transient significant increment (about 60%) in the time spent at the center of the open field arena compared with mice injected with IgG from healthy women (without SBIs). This effect was accompanied with a strong trend of reduction of the locomotor activity of the SBI-IgG treated mice, indicating an overall apathic-like behavior. Our study is the first to show the potential pathogenic activity of IgG autoantibodies in symptomatic women with SBIs, emphasizing the importance of these antibodies in SBI-related illness.

Abelson non-receptor tyrosine kinases (Abl1 and Abl2) are established cellular signaling proteins, implicated in cytoskeletal reorganization essential for modulation of cell morphology and motility. During development of the central nervous system, Abl kinases play fundamental roles in neurulation and neurite outgrowth, relaying information from axon guidance cues and growth factor receptors to promote cytoskeletal rearrangements. In mature neurons, Abl kinases localize to pre- and postsynaptic compartments and are involved in regulation of synaptic stability and plasticity. Although emerging evidence indicates interchangeability of these isoforms in managing of cellular functions, in healthy adult neurons, Abl1 contribution is less elucidated, while Abl2 is required for optimal synaptic functioning. Our previous study demonstrated compartmentalization of Abl1 to the presynapse and Abl2 to the postsynapse and characterized their modulatory effect on spontaneous excitatory synaptic transmission. Here, we further delineate the role of Abl2 on regulation of the postsynaptic component of miniature excitatory postsynaptic current (mEPSC). Our findings show that both acute and prolonged activation of Abl2, in line with reduction of mEPSC amplitude, also decrease AMPA and NMDA current amplitudes. In contrast with the current-detrimental effect, prolonged Abl2 activity stabilizes spines, particularly contributing to maintenance of active synapses at distal (perhaps apical) segments of dendrites. Hence, we propose that attenuation of ion currents via ionotropic glutamatergic receptors by Abl2 kinase derives from either reduction of the receptor sensitivity for glutamate or is due to alteration of channel gating mechanisms. Graphical Abstract Abl2 and excitatory postsynapses: Abl2 expression level affects active excitatory synapse density on distal dendrites, while Abl2 activity impacts current density through AMPA and NMDA receptors.

Amyloid beta (Aβ) peptides represent one of the most studied etiological factors of Alzheimer’s disease. Nevertheless, the effects elicited by different molecular forms of amyloid beta peptides widely vary between the studies, mostly depending on experimental conditions. Despite the enormous amount of accumulated evidences concerning the pathological effects of amyloid beta peptides, the exact identity of the amyloid beta species is still controversial, and even less is clear as regards to the downstream effectors that mediate the devastating impact of these peptides on synapses in the central nervous system. Recent publications indicate that some of the neurotoxic effects of amyloid beta peptides may be mediated via the activation of proteins belonging to the Abelson non-receptor tyrosine kinase (Abl) family, that are known to regulate actin cytoskeleton structure as well as phosphorylate microtubule-associated tau protein, a hallmark of Alzheimer’s disease. By performing series of miniature excitatory postsynaptic currents (mEPSC) recordings in cultured hippocampal cells, we demonstrate that activation of Abl kinases by acute application of 42 amino acid-length monomeric amyloid beta (Aβ_1-42) peptides reduces spontaneous synaptic release, while this effect can be rescued by pharmacologic inhibition of Abl kinase activity, or by reduction of Abl expression with small interfering RNAs. Our electrophysiological data are further reinforced by a subsequent biochemical analysis, showing enhanced phosphorylation of Abl kinase substrate CT10 Regulator of Kinase-homolog-Like (Crkl) upon treatment of hippocampal neurons with Aβ peptides. Thus, we conclude that Abl kinase activation may be involved in Aβ-induced weakening of synaptic transmission.