👤 S A Ivanova

Schizophrenia is a severe mental disorder whose molecular mechanisms remain poorly understood. Investigating brain-derived neurotrophic factor (BDNF)-dependent signaling pathways and their contribution to schizophrenia pathogenesis is a promising research direction in schizophrenia research. BDNF activates multiple intracellular cascades, among which the MAPK/ERK pathway plays a central role. In this study, expression levels of key regulatory proteins of the MAPK/ERK signaling pathway (ERK1/2, STAT3, STAT5, NF-κB, IGF1R, IRS1, IR, TSC2, and CREB1) were examined in lysates of peripheral blood mononuclear cells (PBMCs) from schizophrenia patients using multiplex analysis. The study group included 58 patients diagnosed with schizophrenia (F20); the control group included 60 healthy individuals. The results revealed significantly increased expression of ERK1/2 and STAT3, along with decreased NF-κB levels, in PBMCs from schizophrenia patients compared to controls. Moreover, patients with leading positive symptoms exhibited elevated expression of CREB1 and ERK1/2. These findings suggest that dysregulation of the MAPK/ERK signaling may play a significant role in the pathogenesis schizophrenia. BDNF-dependent signaling pathways may therefore represent promising targets for diagnostics and therapy of this disorder. Show less

To identify associations of polymorphic variants of the genes of Two hundred thirty-five patients with AfD and 62 patients with AR and comorbid AlD aged 18 to 65 years were examined. The severity of AfD was assessed using the Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorder Version (SIGH-SAD) and the Clinical Global Impression (CGI), and the level of anxiety was assessed using the Hamilton Anxiety Rating Scale (HARS) at baseline and on Day 28 of psychopharmacotherapy. Polymorphic variants rs6265, rs7124442, rs11030104, and rs7103411 of the In AfD patients, rs3924999* The polymorphic variants rs3924999 of the Show less

High-density and low-density lipoproteins (HDL and LDL) are established analytical targets for diagnosis and risk stratification of numerous chronic diseases. This study investigates potential sources of bias in lipoprotein particle counting (HDL-P and LDL-P), focusing on the most atheroprotective small-HDL and most pro-atherogenic small-LDL. Plasma samples were fractionated using asymmetric-flow field-flow fractionation (AF4), coupled with hydrodynamic size measurement and comprehensive liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of each fraction. Concentration-size profiles were deconvoluted into 10 HDL and 8 LDL Gaussian subspecies. Molecular volume ratios were used to evaluate proposed particle models, providing evidence for the presence of s-HDL disk and s-LDL dimers, as sources of bias in calculated HDL-P and LDL-P when spherical particle geometry is assumed. Matching apoA1/HDL-P and apoB/LDL-P to consensus values enabled correction of mass diameters (k*d Show less

Serous endometrial cancer (SEC) is an aggressive subtype of endometrial cancer (EC) with poor prognosis and limited treatment options. Here, we developed a clinically relevant, immunocompetent serous-like mouse model incorporating oncogenic Show less

In this functional magnetic resonance imaging study, we investigated whether language production and understanding recruit similar phoneme-specific networks. We did so by comparing the brain's response to different phoneme categories in minimal pairs: Bilabial-initial words (eg "monkey") were contrasted to alveolar-initial words (eg "donkey") in 37 participants performing both language production and comprehension tasks. Individual-specific region-of-interest analyses showed that the same sensorimotor networks were activated across the language modalities. In motor regions, word production and comprehension elicited the same phoneme-specific topographical activity patterns, with stronger haemodynamic activations for alveolar-initial words in the tongue cortex and stronger activations for bilabial-initial words in the lip cortex. In the posterior and middle superior temporal cortex, production and comprehension likewise resulted in similar activity patterns, with enhanced activations to alveolar- compared to bilabial-initial words. These results disagree with the classical asymmetry between language production and understanding in neurobiological models of language, and instead advocate for a cortical organization where phonology is carried by similar topographical activations in motor cortex and distributed activations in temporal cortex across the language modalities. Show less

Background: Hypertriglyceridemia (HTG) is one of the most common forms of lipid metabolism disorders. The leading clinical manifestations are pancreatitis, atherosclerotic vascular lesions, and the formation of eruptive xanthomas. The most severe type of HTG is primary (or hereditary) hypertriglyceridemia, linked to pathogenic genetic variants in LPL, APOC2, LMF1, and APOA5 genes. Case: We present a clinical case of severe primary hypertriglyceridemia (TG level > 55 mmol/L in a 4-year-old boy) in a consanguineous family. The disease developed due to a previously undescribed homozygous deletion in the APOA5 gene (NM₀₅₂₉₆₈: c.579₅₉₂delATACGCCGAGAGCC p.Tyr194Gly*68). We also evaluate the clinical significance of a genetic variant in the LPL gene (NM₀₀₀₂₃₇.2: c.106G>A (rs1801177) p.Asp36Asn), which was previously described as a polymorphism. In one family, we also present a different clinical significance even in heterozygous carriers: from hypertriglyceridemia to normotriglyceridemia. We provide evidence that this heterogeneity has developed due to polymorphism in the LPL gene, which plays the role of an additional trigger. Conclusions: The homozygous deletion of the APOA5 gene is responsible for the severe hypertriglyceridemia, and another SNP in the LPL gene worsens the course of the disease. Show less

Resistance to oncogene-targeted therapies involves discrete drug-tolerant persister cells, originally discovered through in vitro assays. Whether a similar phenomenon limits efficacy of programmed cell death 1 (PD-1) blockade is poorly understood. Here, we performed dynamic single-cell RNA-Seq of murine organotypic tumor spheroids undergoing PD-1 blockade, identifying a discrete subpopulation of immunotherapy persister cells (IPCs) that resisted CD8+ T cell-mediated killing. These cells expressed Snai1 and stem cell antigen 1 (Sca-1) and exhibited hybrid epithelial-mesenchymal features characteristic of a stem cell-like state. IPCs were expanded by IL-6 but were vulnerable to TNF-α-induced cytotoxicity, relying on baculoviral IAP repeat-containing protein 2 (Birc2) and Birc3 as survival factors. Combining PD-1 blockade with Birc2/3 antagonism in mice reduced IPCs and enhanced tumor cell killing in vivo, resulting in durable responsiveness that matched TNF cytotoxicity thresholds in vitro. Together, these data demonstrate the power of high-resolution functional ex vivo profiling to uncover fundamental mechanisms of immune escape from durable anti-PD-1 responses, while identifying IPCs as a cancer cell subpopulation targetable by specific therapeutic combinations. Show less

Schizophrenia is associated with a lowered life expectancy due to cardiovascular disease. This is, at least in part, related to an increased vulnerability to the development of metabolic syndrome (MetS) in patients with schizophrenia. The dysregulation of apolipoproteins (Apos) may also play a role in the pathogenesis of schizophrenia via their effect on cerebral cholesterol processing. The aim of this study was to investigate serum Apos A1, C3, E, A2 and C2 concentration in schizophrenia patients with or without MetS in comparison to healthy donors. After obtaining informed consent, 53 patients with a diagnosis of paranoid schizophrenia according to ICD-10 criteria (F20) were included. Patients were divided into two groups with (N = 26) and without (N = 27) MetS according to the criteria of the International Diabetes Federation. The control group included 20 mentally and physically healthy subjects. Serum Apos A1, A2, C2, C3 and E were measured using xMAP technology (Luminex). Serum ApoA1 was significantly decreased in patients with schizophrenia compared to healthy subjects (p = 0.002); ApoA2 was lower in patients without MetS in comparison to patients with MetS (p = 0.017) and the levels of ApoC3 and ApoC2 were increased in patients with schizophrenia with MetS in comparison with the control group and also with patients without MetS. No other significant differences were established concerning the other assayed apolipoproteins. In line with literature data the results of our study suggest that while disturbances in ApoA1 level may play a role in the pathogenesis of schizophrenia, ApoA2, ApoC2, ApoC3 and ApoE may be primarily related to metabolic imbalance. Show less

Conventional natural killer (cNK) cells, members of group 1 innate lymphoid cells, are a diverse cell subpopulation based on surface receptor expression, maturation, and functional potential. cNK cells are critical for early immunity to Show less