13 research outputs found

    The Sharpin interactome reveals a role for Sharpin in lamellipodium formation via the Arp2/3 complex

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    Sharpin, a multifunctional adaptor protein, regulates several signalling pathways. For example, Sharpin enhances signal-induced NF-κB signalling as part of the linear ubiquitin assembly complex (LUBAC) and inhibits integrins, the T cell receptor, caspase1 and PTEN. However, despite recent insights into Sharpin and LUBAC function, a systematic approach to identify signalling pathways regulated by Sharpin has not been reported. Here, we present the first ‘Sharpin interactome’, which identifies a large amount of novel potential Sharpin interactors in addition to several known ones. These data suggest that Sharpin and LUBAC might regulate a larger number of biological processes than previously identified, such as endosomal trafficking, RNA processing, metabolism and cytoskeleton regulation. Importantly, using the Sharpin interactome we have identified a novel role for Sharpin in lamellipodium formation. We demonstrate that Sharpin interacts with Arp2/3, a protein complex that catalyses actin filament branching. We identified the Arp2/3-binding site in Sharpin and demonstrate using a specific Arp2/3-binding deficient mutant that the Sharpin-Arp2/3 interaction promotes lamellipodium formation in a LUBAC-independent fashion.</p

    Navigated repetitive transcranial magnetic stimulation to correct eating behavior in obesity (clinical cases)

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    Obesity is a pathological condition caused by overweight and requiring medical intervention. The clinical and scientific experience gained over the past decades has allowed researchers to consider this problem as an independent disease with its own pathophysiological features, prevalence, incidence, approaches to therapy and prevention. One of the most important factors in the pathogenesis of obesity is disordered eating behavior, the central regulation of which is carried out with the active participation of the prefrontal cortex. Impact on this area (for example, using non-invasive brain stimulation) may be one of the promising ways to modulate eating behavior. The article describes clinical cases of treatment of morbid obesity using navigated rhythmic transcranial magnetic stimulation (rTMS). Different patterns of dorsolateral prefrontal cortex (DLPFC) activation before and after rTMS are demonstrated. Possible mechanisms of the influence of DLPFC on the formation of eating behavior are also considered. These data underline the important role of DLPFC dysregulation in obesity, as well as show potentially effective neuromodulation techniques

    Survival, cognitive functions, and brain MRI in patients with cSVD: 5-year observation

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    Introduction. Contributing to high disability and mortality, cerebral small vessel disease (cSVD) is a common condition in senior and elderly individuals. Objective: to assess the 5-year survival as well as cognitive and MRI changes in patients with cSVD and cognitive impairment (CI). Materials and methods. A prospective 5-year study included 54 patients (of them 37 women; mean age: 60.51 6.76 years) with cSVD, CIs, and white matter hyperintensities (WMHs; Fazekas 23). Twenty-two subjects were followed up to assess cognitive functions and a type of CI, cSVD MRI features, WMH, white and grey matter, and cerebrospinal fluid (CSF) volume as well as microstructural brain changes and correlate cognitive and MRI parameters at 5 years timepoint after the baseline. Results. Dementia developed in 14% of the subjects and 14% of the subjects died over a 5-year period. The subjects assessed twice had controlled hypertension (HTN). CIs worsened in the domain of executive functions and memory with mixed-type CI worsening. The follow-up showed that the WMH and CSF volume increased while the white matter volume decreased and axial diffusivity increased in the corpus callosum. The CSF volume correlated with the Stroop Test results and delayed memory (r = 0.803 and r = 0.701, respectively) and with white matter atrophy (r = 0.256) while the latter correlated with the axial diffusivity increased in the corpus callosum (r = 0.560). Conclusion. cSVD with advanced WMHs is associated with high mortality and dementia progression. General cognition assessment and MRI scan are not enough sensitive to assess disorder progression over a 5-year period. Stroop Test and Delayed 10-Word Recall Test results and transition to mixed-type CI indicate CI worsening and, therefore, can be used for the follow-up assessment. Cognitive decline in extensive cSVD is mediated by the brain matter atrophy and altered CSF circulation

    SHANK3 conformation regulates direct actin binding and crosstalk with Rap1 signaling

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    Actin-rich cellular protrusions direct versatile biological processes from cancer cell invasion to dendritic spine development. The stability, morphology, and specific biological functions of these protrusions are regulated by crosstalk between three main signaling axes: integrins, actin regulators, and small guanosine triphosphatases (GTPases). SHANK3 is a multifunctional scaffold protein, interacting with several actin-binding proteins and a well-established autism risk gene. Recently, SHANK3 was demonstrated to sequester integrin-activating small GTPases Rap1 and R-Ras to inhibit integrin activity via its Shank/ProSAP N-terminal (SPN) domain. Here, we demonstrate that, in addition to scaffolding actin regulators and actin-binding proteins, SHANK3 interacts directly with actin through its SPN domain. Molecular simulations and targeted mutagenesis of the SPN-ankyrin repeat region (ARR) interface reveal that actin binding is inhibited by an intramolecular closed conformation of SHANK3, where the adjacent ARR domain covers the actin-binding interface of the SPN domain. Actin and Rap1 compete with each other for binding to SHANK3, and mutation of SHANK3, resulting in reduced actin binding, augments inhibition of Rap1-mediated integrin activity. This dynamic crosstalk has functional implications for cell morphology and integrin activity in cancer cells. In addition, SHANK3-actin interaction regulates dendritic spine morphology in neurons and autism-linked phenotypes in vivo

    Feasibility of Non-Gaussian Diffusion Metrics in Chronic Disorders of Consciousness

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    Diagnostic accuracy of different chronic disorders of consciousness (DOC) can be affected by the false negative errors in up to 40% cases. In the present study, we aimed to investigate the feasibility of a non-Gaussian diffusion approach in chronic DOC and to estimate a sensitivity of diffusion kurtosis imaging (DKI) metrics for the differentiation of vegetative state/unresponsive wakefulness syndrome (VS/UWS) and minimally conscious state (MCS) from a healthy brain state. We acquired diffusion MRI data from 18 patients in chronic DOC (11 VS/UWS, 7 MCS) and 14 healthy controls. A quantitative comparison of the diffusion metrics for grey (GM) and white (WM) matter between the controls and patient group showed a significant (p &lt; 0.05) difference in supratentorial WM and GM for all evaluated diffusion metrics, as well as for brainstem, corpus callosum, and thalamus. An intra-subject VS/UWS and MCS group comparison showed only kurtosis metrics and fractional anisotropy differences using tract-based spatial statistics, owing mainly to macrostructural differences on most severely lesioned hemispheres. As a result, we demonstrated an ability of DKI metrics to localise and detect changes in both WM and GM and showed their capability in order to distinguish patients with a different level of consciousness

    Expanded Brain CT Dataset for the Development of AI Systems for Intracranial Hemorrhage Detection and Classification

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    Intracranial hemorrhage (ICH) is a dangerous life-threatening condition leading to disability. Timely and high-quality diagnosis plays a huge role in the course and outcome of this disease. The gold standard in determining ICH is computed tomography. This method requires a prompt involvement of highly qualified personnel, which is not always possible, for example, in case of a staff shortage or increased workload. In such a situation, every minute counts, and time can be lost. The solution to this problem seems to be a set of diagnostic decisions, including the use of artificial intelligence, which will help to identify patients with ICH in a timely manner and provide prompt and quality medical care. However, the main obstacle to the development of artificial intelligence is a lack of high-quality datasets for training and testing. In this paper, we present a dataset including 800 brain CT scans consisting of multiple series of DICOM images with and without signs of ICH, enriched with clinical and technical parameters, as well as the methodology of its generation utilizing natural language processing tools. The dataset is publicly available, which contributes to increased competition in the development of artificial intelligence systems and their advancement and quality improvement

    Tissue Plasminogen Activator and MRI Signs of Cerebral Small Vessel Disease

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    Cerebral small vessel disease (SVD) is one of the leading causes of cognitive impairment and stroke. The importance of endothelial dysfunction and high blood&ndash;brain barrier (BBB) permeability in pathogenesis, together with ischemia, is under discussion. The aim of this study was to clarify the relationship between tissue plasminogen activator (t-PA), plasminogen activator inhibitor (PAI-1), and magnetic resonance imaging (MRI) signs of SVD. We examined 71 patients (23 men and 48 women; mean age: 60.5 &plusmn; 6.9 years) with clinical and MRI signs of SVD, and 21 healthy volunteers with normal MRIs. All subjects underwent 3T MRI and measurements of t-PA and PAI-1 levels. An increase in t-PA level is correlated with the volume of white matter hyperintensities (WMH) (R = 0.289, p = 0.034), severity on the Fazekas scale (p = 0.000), and with the size of subcortical (p = 0.002) and semiovale (p = 0.008) perivascular spaces. The PAI-1 level is not correlated with the t-PA level or MRI signs of SVD. The correlation between t-PA and the degree of WMH and perivascular spaces&rsquo; enlargement, without a correlation with PAI-1 and lacunes, is consistent with the importance of t-PA in BBB disruption and its role in causing brain damage in SVD

    MRI Types of Cerebral Small Vessel Disease and Circulating Markers of Vascular Wall Damage

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    The evaluation of the clustering of magnetic resonance imaging (MRI) signs into MRI types and their relationship with circulating markers of vascular wall damage were performed in 96 patients with cerebral small vessel disease (cSVD) (31 men and 65 women; mean age, 60.91 &plusmn; 6.57 years). The serum concentrations of the tumor necrosis factor-&alpha; (TNF-&alpha;), transforming growth factor-&beta;1 (TGF-&beta;1), vascular endothelial growth factor-A (VEGF-A), and hypoxia-inducible factor 1-&alpha; (HIF-1&alpha;) were investigated in 70 patients with Fazekas stages 2 and 3 of white matter hyperintensities (WMH) and 21 age- and sex-matched volunteers with normal brain MRI using ELISA. The cluster analysis excluded two patients from the further analysis due to restrictions in their scanning protocol. MRI signs of 94 patients were distributed into two clusters. In the first group there were 18 patients with Fazekas 3 stage WMH. The second group consisted of 76 patients with WMH of different stages. The uneven distribution of patients between clusters limited the subsequent steps of statistical analysis; therefore, a cluster comparison was performed in patients with Fazekas stage 3 WMH, designated as MRI type 1 and type 2 of Fazekas 3 stage. There were no differences in age, sex, degree of hypertension, or other risk factors. MRI type 1 had significantly more widespread WMH, lacunes in many areas, microbleeds, atrophy, severe cognitive and gait impairments, and was associated with downregulation of VEGF-A compared with MRI type 2. MRI type 2 had more severe deep WMH, lacunes in the white matter, no microbleeds or atrophy, and less severe clinical manifestations and was associated with upregulation of TNF-&alpha; compared with MRI type 1. The established differences reflect the pathogenetic heterogeneity of cSVD and explain the variations in the clinical manifestations observed in Fazekas stage 3 of this disease

    Modern concepts of the pathogenesis of obesity and new approaches to its correction

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    The present review considers modern concepts of the physiological mechanisms of the formation of food behavior in a norm at several levels, beginning with the cellular level and ending with the level of functional systems. Neuroimaging methods used for both the study of the pathophysiological foundations of eating disorders and for determining the target for neurostimulation techniques are described. Methods of non-invasive brain stimulation such as transcranial magnetic stimulation and transcranial electrical stimulation, the mechanisms of their influence and aspects of safety of application are reviewed, the latest data on the results of studies on the use of the above methods in the therapy of obesity are summarized
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