“Soil” (“pochva”) as a metaphorical name for the political and literary direction of the “Vremya” (“Time”) and “Epokha” (“Epoch”) journals was the subject of newspaper and journal polemics in many ...periodicals in the 1860s, including the satirical and humorous press. One of the implacable opponents of the Dostoevsky brothers' magazines was the weekly “Iskra“ (“Spark”) (1859–1873), whose publications are considered in this study. In the fight against opponents, the authors of “Iskra” used the possibilities offered by satirical genres: they published caricatures, cartoons, parodies, satires, pamphlets, feuilletons, jokes on literary topics, fantastic scenes and dramatic fantasies. A feature of the controversy was the sharp criticism of the political and literary program of the Dostoevsky brothers’ magazines and their direction. The periodicals' hostility was mutual. F. M. Dostoevsky called Iskra “Firebrand” on two occasions and created a negative image of an employee of the satirical magazine in the story “A Bad Joke.” In response to criticism, the Dostoevsky brothers calmly explained the “soil” ideas, notions and concepts of their journals.
Alzheimer's disease (AD) is the most common reason for elderly dementia in the world. We proposed that memory loss in AD is related to destabilization of mushroom postsynaptic spines involved in ...long-term memory storage. We demonstrated previously that stromal interaction molecule 2 (STIM2)-regulated neuronal store-operated calcium entry (nSOC) in postsynaptic spines play a key role in stability of mushroom spines by maintaining activity of synaptic Ca(2+)/calmodulin kinase II (CaMKII). Furthermore, we demonstrated previously that the STIM2-nSOC-CaMKII pathway is downregulated in presenilin 1 M146V knock-in (PS1-M146V KI) mouse model of AD, leading to loss of hippocampal mushroom spines in this model. In the present study, we demonstrate that hippocampal mushroom postsynaptic spines are also lost in amyloid precursor protein knock-in (APPKI) mouse model of AD. We demonstrated that loss of mushroom spines occurs as a result of accumulation of extracellular β-amyloid 42 in APPKI culture media. Our results indicate that extracellular Aβ42 acts by overactivating mGluR5 receptor in APPKI neurons, leading to elevated Ca(2+) levels in endoplasmic reticulum, compensatory downregulation of STIM2 expression, impaired synaptic nSOC, and reduced CaMKII activity. Pharmacological inhibition of mGluR5 or overexpression of STIM2 rescued synaptic nSOC and prevented mushroom spine loss in APPKI hippocampal neurons. Our results indicate that downregulation of synaptic STIM2-nSOC-CaMKII pathway causes loss of mushroom synaptic spines in both presenilin and APPKI mouse models of AD. We propose that modulators/activators of this pathway may have a potential therapeutic value for treatment of memory loss in AD. Significance statement: A direct connection between amyloid-induced synaptic mushroom spine loss and neuronal store-operated calcium entry pathway is shown. These results provide strong support for the calcium hypothesis of neurodegeneration and further validate the synaptic store-operated calcium entry pathway as a potential therapeutic target for Alzheimer's disease.
Cerebellar Purkinje cells (PCs) are primarily affected in many spinocerebellar ataxias (SCA). In this study we investigated functional activity of PCs in transgenic mouse model of SCA2, a ...polyglutamine neurodegenerative hereditary disorder. In our studies we used extracellular single-unit recording method to compare spontaneous activity of PCs in age-matched wild-type mice and SCA2-58Q transgenic mice. We discovered that the fraction of PCs with bursting and an irregular pattern of spontaneous activity dramatically increases in aged SCA2-58Q mice compared with wild-type littermates. Small-conductance calcium-activated potassium (SK) channels play an important role in determining firing rate of PCs. Indeed, we demonstrated that intraperitoneal (IP) injection of SK channel inhibitor NS8593 induces an irregular pattern of PC activity in wild-type mice. Furthermore, we demonstrated that IP injection of SK channel-positive modulator chlorzoxazone (CHZ) decreases spontaneous firing rate of cerebellar PCs. Finally, we have shown that IP injections with CHZ normalize firing activity of cerebellar PCs from aging SCA2-58Q mice. We propose that alterations in PC firing patterns is one of potential causes of ataxic symptoms in SCA2 and in other SCAs and that positive modulators of SK channels can be used to normalize activity of PCs and alleviate ataxic phenotype in patients with SCA.
MXenes are a family of two-dimensional (2D) composite materials based on transition metal carbides, nitrides and carbonitrides that have been attracting attention since 2011. Combination of ...electrical and mechanical properties with hydrophilicity makes them promising materials for biomedical applications. This review briefly discusses methods for the synthesis of MXenes, their potential applications in medicine, ranging from sensors and antibacterial agents to targeted drug delivery, cancer photo/chemotherapy, tissue engineering, bioimaging, and environmental applications such as sensors and adsorbents. We focus on in vitro and in vivo toxicity and possible mechanisms. We discuss the toxicity analogies of MXenes and other 2D materials such as graphene, mentioning the greater biocompatibility of MXenes. We identify existing barriers that hinder the formation of objective knowledge about the toxicity of MXenes. The most important of these barriers are the differences in the methods of synthesis of MXenes, their composition and structure, including the level of oxidation, the number of layers and flake size; functionalization, test concentrations, duration of exposure, and individual characteristics of biological test objects Finally, we discuss key areas for further research that need to involve new methods of nanotoxicology, including predictive computational methods. Such studies will bring closer the prospect of widespread industrial production and safe use of MXene-based products.
The attribution of content of Vremya (Time) and Epokha (Epoch) journals, in which many anonymous and pseudonymous articles have been published, presents many challenges for the researchers. In the ...XIX–XX centuries, a corpus of texts, which were unambiguously attributed to F. M. Dostoevsky, M. M. Dostoevsky, A. A. Grigoriev, N. N. Strakhov and other Vremya and Epokha authors, was formed on the basis of traditional documentary (letters, payroll, income and expense book, memoirs), ideological and thematic and stylistic evidence. The following types of texts were isolated within the corpus of anonymous and pseudonymous articles, author's and collective articles, editorial inserts, notes; by type of writing - authorship, co-authorship, editing and adaptation of others texts. Modern methods of statistical analysis of formal grammatical and syntactic parameters in the text can provide sufficient grounds for expanding the source attribution base. This article presents the results of a study of a number of anonymous articles in the Dostoevsky brothers' journals using three statistical methods of attribution: linguistic and statistical analysis according to the G. Kjetsaa's method, the Transformer neural network and the Random forest algorithm. These results need to be correlated; they should be taken into account as complementary to traditional attribution methods.
Mushroom dendritic spine structures are essential for memory storage and the loss of mushroom spines may explain memory defects in aging and Alzheimer's disease (AD). The stability of mushroom spines ...depends on stromal interaction molecule 2 (STIM2)-mediated neuronal-store-operated Ca
influx (nSOC) pathway, which is compromised in AD mouse models, in aging neurons, and in sporadic AD patients. Here, we demonstrate that the Transient Receptor Potential Canonical 6 (TRPC6) and Orai2 channels form a STIM2-regulated nSOC Ca
channel complex in hippocampal mushroom spines. We further demonstrate that a known TRPC6 activator, hyperforin, and a novel nSOC positive modulator, NSN21778 (NSN), can stimulate activity of nSOC pathway in the spines and rescue mushroom spine loss in both presenilin and APP knock-in mouse models of AD. We further show that NSN rescues hippocampal long-term potentiation impairment in APP knock-in mouse model. We conclude that the STIM2-regulated TRPC6/Orai2 nSOC channel complex in dendritic mushroom spines is a new therapeutic target for the treatment of memory loss in aging and AD and that NSN is a potential candidate molecule for therapeutic intervention in brain aging and AD.
Mushroom dendritic spine structures are essential for memory storage and the loss of mushroom spines may explain memory defects in Alzheimer's disease (AD). This study demonstrated that Transient Receptor Potential Canonical 6 (TRPC6) and Orai2 form stromal interaction molecule 2 (STIM2)-regulated neuronal-store-operated Ca
influx (nSOC) channel complex in hippocampal synapse and the resulting Ca
influx is critical for long-term maintenance of mushroom spines in hippocampal neurons. A novel nSOC-positive modulator, NSN21778 (NSN), rescues mushroom spine loss and synaptic plasticity impairment in AD mice models. The TRPC6/Orai2 nSOC channel complex is a new therapeutic target and NSN is a potential candidate molecule for therapeutic intervention in brain aging and AD.
Sustainable development has increasingly found its way into the context of environmental legislation. Russian environmental legislation is not effective for transitioning toward sustainable ...development. The main obstacle is ignoring traditional environmental values, which are not properly incorporated into laws and regulations. However, rich Russian traditions and culture imply a big potential to develop environmental legislation in accordance with sustainable principles. The paper explores areas where environmental regulations should be revised and implemented with adequate legal mechanisms based on traditional values. This paper contributes to the discussion of improving environmental legal norms in any domestic legislation.
Green practices are social practices that aim to harmonize the relations between people and the natural environment. They may involve minimizing the use of resources and the generation of waste and ...emissions. Detecting green practices in social media posts helps to understand which green practices are currently common and to develop recommendations on the scaling of green practices to reduce environmental problems. This paper describes GreenRu, a novel Russian social media dataset for detecting the mentions of green practices related to waste management. It has a sentence-level markup and consists of 1326 posts collected in Russian online communities. The total number of mentions of green waste practices is 3765. The paper assessed the effectiveness of the multi-label and one-versus-rest BERT-based models for detecting the mentions of green practices in social media posts and compared several data augmentation methods in terms of both classification metrics and human evaluation. To augment the dataset, a backtranslation method and generative language models, such as RuGPT, RuT5, and ChatGPT, were used in this study. The results enable researchers to monitor the green waste practices on social networks and develop environmental policies. Additionally, GreenRu can support machine learning models to analyze social media content, assess the prevalence and effectiveness of green waste practices, and identify ways to expand them.
In Huntington's disease (HD), mutant Huntingtin (mHtt) protein causes striatal neuron dysfunction, synaptic loss, and eventual neurodegeneration. To understand the mechanisms responsible for synaptic ...loss in HD, we developed a corticostriatal coculture model that features age-dependent dendritic spine loss in striatal medium spiny neurons (MSNs) from YAC128 transgenic HD mice. Age-dependent spine loss was also observed in vivo in YAC128 MSNs. To understand the causes of spine loss in YAC128 MSNs, we performed a series of mechanistic studies. We previously discovered that mHtt protein binds to type 1 inositol (1,4,5)-trisphosphate receptor (InsP3R1) and increases its sensitivity to activation by InsP3. We now report that the resulting increase in steady-state InsP3R1 activity reduces endoplasmic reticulum (ER) Ca(2+) levels. Depletion of ER Ca(2+) leads to overactivation of the neuronal store-operated Ca(2+) entry (nSOC) pathway in YAC128 MSN spines. The synaptic nSOC pathway is controlled by the ER resident protein STIM2. We discovered that STIM2 expression is elevated in aged YAC128 striatal cultures and in YAC128 mouse striatum. Knock-down of InsP3R1 expression by antisense oligonucleotides or knock-down or knock-out of STIM2 resulted in normalization of nSOC and rescue of spine loss in YAC128 MSNs. The selective nSOC inhibitor EVP4593 was identified in our previous studies. We now demonstrate that EVP4593 reduces synaptic nSOC and rescues spine loss in YAC128 MSNs. Intraventricular delivery of EVP4593 in YAC128 mice rescued age-dependent striatal spine loss in vivo. Our results suggest EVP4593 and other inhibitors of the STIM2-dependent nSOC pathway as promising leads for HD therapeutic development.
In Huntington's disease (HD) mutant Huntingtin (mHtt) causes early corticostriatal synaptic dysfunction and eventual neurodegeneration of medium spine neurons (MSNs) through poorly understood mechanisms. We report here that corticostriatal cocultures prepared from YAC128 HD mice feature age-dependent MSN spine loss, mirroring YAC128 MSN spine loss in vivo. This finding establishes a system for mechanistic studies of synaptic instability in HD. We use it to demonstrate that sensitization of type 1 inositol (1,4,5)-trisphosphate receptors by mHtt, which depletes endoplasmic reticulum calcium, contributes to synaptotoxic enhancement of STIM2-dependent store-operated calcium (SOC) entry. Treatment with EVP4593, a neuroprotective inhibitor of neuronal SOC channels, rescues YAC128 MSN spine loss both in vitro and in vivo. These results suggest that enhanced neuronal SOC causes synaptic loss in HD-afflicted MSNs.
Graphene nanoribbons are a type of graphene characterized by remarkable electrical and mechanical properties. This review considers the prospects for the application of graphene ribbons in ...biomedicine, taking into account safety aspects. According to the analysis of the recent studies, the topical areas of using graphene nanoribbons include mechanical, chemical, photo- and acoustic sensors, devices for the direct sequencing of biological macromolecules, including DNA, gene and drug delivery vehicles, and tissue engineering. There is evidence of good biocompatibility of graphene nanoribbons with human cell lines, but a number of researchers have revealed toxic effects, including cytotoxicity and genotoxicity. Moreover, the damaging effects of nanoribbons are often higher than those of chemical analogs, for instance, graphene oxide nanoplates. The possible mechanism of toxicity is the ability of graphene nanoribbons to damage the cell membrane mechanically, stimulate reactive oxidative stress (ROS) production, autophagy, and inhibition of proliferation, as well as apoptosis induction, DNA fragmentation, and the formation of chromosomal aberrations. At the same time, the biodegradability of graphene nanoribbons under the environmental factors has been proven. In general, this review allows us to conclude that graphene nanoribbons, as components of high-precision nanodevices and therapeutic agents, have significant potential for biomedical applications; however, additional studies of their safety are needed. Particular emphasis should be placed on the lack of information about the effect of graphene nanoribbons on the organism as a whole obtained from in vivo experiments, as well as about their ecological toxicity, accumulation, migration, and destruction within ecosystems.
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