Functional Rearrangements Research Articles

P02.26.B METABOLIC PLASTICITY IN GLIOBLASTOMA TUMOR-INITIATING CELL AND RESISTANCE TO LSD1-DIRECTED THERAPY

Abstract BACKGROUND Glioblastoma (GBM), the most common primary brain tumor in adults, remains incurable despite multimodal therapy. There is a pressing unmet medical need for new therapeutic strategies, especially because patients experience only short-term benefit after primary treatment and the vast majority inevitably relapse. Adaptation to harsh microenvironmental conditions, including nutrient deprivation, proteostasis perturbation, hypoxia and drug treatment, induce molecular and metabolic changes in glioblastoma that lead to the acquisition of a tolerance to stress and resistance to drug. In this context, we demonstrated that Lysine-specific histone demethylase 1 (LSD1) is a regulator of tumor-initiating cell (TICs) survival, adaptation and recovery from stress. LSD1 pharmacological inhibition with a specific and brain penetrant inhibitor (LSD1i) induces a maladaptive integrated stress response (ISR) which leads to the death of TICs exposed to ER stress or nutrient deficiency. MATERIAL AND METHODS Given the high GBM heterogeneity, we analyzed different patient-derived TICs grown in vitro as sphere and characterized for their genetic landscape and in vitro/in vivo stem cell-like features. We applied mechanistically different strategies, including biological, metabolic and pharmacological approaches, as well as transcriptomic and proteomic profiling. Zebrafish and GBM xenografts have been exploited as in vivo models. RESULTS LSD1i treatment induces physical and functional rearrangements of mitochondria, culminating into their enhanced bioenergetic activity and ATP production that predispose to cell death. Interestingly, only a subset of patient-derived TICs benefits from LSD1i therapy. These samples are largely dependent on glycolysis and, upon LSD1i administration, they are unable to further enhance it when mitochondrial energy production is inhibited. The samples resistant to LSD1i maintain their cellular behavior unaltered even upon prolonged treatment. They display reduced susceptibility to the stressful cues represented by either LSD1i and the known ER stressors Thapsigargin and Tunicamycin, by efficiently restoring energy homeostasis and properly activating the Activating Transcription Factor 4 (ATF4)-dependent ISR. Remarkably, LSD1i resistant samples display metabolic flexibility and switch between glycolytic and oxidative metabolism to ensure their survival. CONCLUSION The identification of specific metabolic vulnerabilities could offer unique opportunities for therapeutic intervention: the selective LSD1i vulnerability relies on the preferential dependence on glycolysis, while the great metabolic plasticity of LSD1i resistant TICs coordinates changes that favor their adaptation to stressful microenvironments and therapeutic insults.

Role of Neural Plasticity of Motor Cortex in Gliomas Evaluated by Brain Imaging and Mapping Techniques in Pre- and Postoperative Period: A Systematic Review.

Resection of infiltrative neuroepithelial primary brain tumors, such as low-grade gliomas (LGGs) remains a neurosurgical challenge. Usual lack of clinical deficit despite LGGs growing in eloquent brain areas may be explained by reshaping and reorganization of functional networks. The development of modern diagnostic imaging techniques could disclose better understanding of the rearrangement of the brain cortex; however, mechanisms underlying such compensation and how it occurs in the motor cortex remain unclear. This systematic review aims to analyze the neuroplasticity of motor cortex in patients with LGGs, as determined by neuroimaging and functional techniques. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, medical subject headings (MeSH) and the following terms related to neuroimaging, LGGs and neuroplasticity were used with the Boolean operators AND and OR to synonymous terms in the PubMed database. Among the 118 results, 19 studies were included in the systematic review. Motor function in patients with LGG was characterized by a compensation in the contralateral and supplementary motor areas and premotor functional networks. Furthermore, ipsilateral activation in these types of gliomas was rarely described. Moreover, some studies did not reveal statistical significance in association between functional reorganization and the postoperative period, which can be explained by the low number of patients. Our findings suggest a high pattern of reorganization per different eloquent motor areas and gliomas diagnosis. Understanding this process is useful to guide safe surgical resection and to develop protocols that assess the plasticity, even though functional network rearrangement needs to be better characterized by more studies.

Immediate Effects of Anti-Spastic Epidural Cervical Spinal Cord Stimulation on Functional Connectivity of the Central Motor System in Patients with Stroke- and Traumatic Brain Injury-Induced Spasticity: A Pilot Resting-State Functional Magnetic Resonance Imaging Study.

Spinal cord stimulation (SCS) is one approach to the potential improvement of patients with post-stroke or post-traumatic spasticity. However, little is known about whether and how such interventions alter supraspinal neural systems involved in the pathogenesis of spasticity. This pilot study investigated whether epidural spinal cord stimulation at the level of the C3-C5 cervical segments, aimed at reducing spasticity, alters the patterns of functional connectivity of the brain. Eight patients with spasticity in the right limbs as a result of left cerebral hemisphere damage (due to hemorrhagic and ischemic stroke or traumatic and anoxic brain injury) were assessed with fMRI immediately before and immediately after short-term (1 to 6 days) test cervical epidural SCS therapy. Eight demographically and clinically comparable patients with spasticity in the right extremities due to a left hemisphere ischemic stroke and brain injury who received conventional therapy were examined as a control group. All patients also had paresis of one or two limbs and hyperreflexia. After the SCS therapy, there were three main findings: (1) higher functional connectivity of the brainstem to the right premotor cortex and changes in functional connectivity between cortical motor areas, (2) increased functional connectivity between the right and left lateral nodes of the sensorimotor network, and (3) a positive correlation between decreased spasticity in the right leg and increased functional connectivity within the right hemisphere sensorimotor cortex. All these changes in functional connectivity occurred with a statistically significant decrease in spasticity, as assessed using the modified Ashworth scale. The control group showed no decrease in spasticity or increase in functional connectivity in any of the seeds of interest. On the contrary, a decrease in functional connectivity of the brainstem and right postcentral gyrus was observed in this group during the observation period. We were thus able to detect intrinsic brain connectivity rearrangements that occurred during spasticity mitigation following short epidural SCS therapy. The clinical results obtained confirmed the efficacy of short-term anti-spastic SCS therapy. The obtained data on functional rearrangements of the central motor system may shed light on the mechanism of antispastic action of this procedure.

Study of changes in the histological structure of the gills of carp and zander living in lake Balkhash

The problem of adaptation and reactivity of an organism to various environmental factors is one of the central problems in theoretical and practical biology. At present, the attention of researchers is especially attracted bythe issues of ecological adaptation. Morphological works that shed light on the corresponding structural and functional rearrangements of fish gills in connection with their ecology are still poorly understood. In particular, the issues of comparative morphological assessment of the adaptive responses of gas exchange organs have not been developed. The impact of the enterprises of the metal and mining complex is reflected in the tissues of the organs of fish. Thus, environmental factors, such as the accumulation of heavy metals in water, subject the fish body to a structural and functional rearrangement, thereby changing the normal tissue structure. In this regard, the purpose of the study was to study changes in the histological structures of the gills of carp and zander living in Lake Balkhash. Changes in the tissue structure of the gill arch of fish were in the form of emerging pathologies, the frequency of which was noted using a comparative analysis. For the implementation of this work, a histological, morphometric and statistical study of the tissues of the gills of the studied fish individuals was also carried out. The following pathological processes were observed in the structure of the gills of carp and zander: changes in the shape of secondary lamellae, hyperplasia of the gill epithelium, necrosis and edema of the respiratory epithelium, as well as foci of hemorrhages. The detected changes in the histological structures of fish gills indicate the impact of external environmental factors, one of which, in this article, is the accumulation of heavy metals in water. This study was carried out from a natural ecosystem, thus, literary sources are used to compare the data obtained.

Age - related vulnerability of the human brain connectome (P11-6.008)

<h3>Objective:</h3> To evaluate how aging affects functional connectivity of pivotal regions of the human brain connectome (i.e., hubs), which represent potential vulnerability ‘stations’ to aging, and whether such effects influence the functional and structural changes of the whole brain. <h3>Background:</h3> Multifactorial models integrating brain variables at multiple scales are warranted to investigate aging and its relationship with neurodegeneration. <h3>Design/Methods:</h3> We enrolled 128 cognitively unimpaired participants that were divided into two groups according to age: 50 young adults (≤ 35 years old) and 78 older adults (&gt; 35 years old). At study entry, both groups underwent brain MRI scan. We combined the information of the functional connectome vulnerability, studied through an innovative graph-analysis approach (stepwise functional connectivity), with brain cortical thinning in aging. <h3>Results:</h3> First, investigating the topological functional network organization in the optimal healthy condition (i.e., young adults), we observed that fronto-temporo-parietal hubs showed direct functional connectivity with themselves and among each other, while occipital hubs showed direct functional connectivity within occipital regions and sensorimotor areas. Then, modelling cortical thickness changes over lifespan, we observed that fronto-temporo-parietal hubs were among the brain regions that changed the most, whereas occipital hubs showed a quite spared cortical thickness across ages. Finally, cortical regions highly functionally linked to the fronto-temporo-parietal hubs in healthy adults were characterized by the greatest cortical thinning along the lifespan. <h3>Conclusions:</h3> Our findings reveal a significant role of hub connectome topology and geometry in shaping the accumulation of biological damage and distribution of atrophy with aging, supporting the hypothesis that hub functional connectivity rearrangements appear to govern the region-specific structural alterations of the brain regions. <b>Disclosure:</b> Federica Agosta has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Philips. Federica Agosta has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier INC. Ms. Cividini has nothing to disclose. Silvia Basaia has nothing to disclose. Dr. Spinelli has nothing to disclose. Dr. Castelnovo has nothing to disclose. Dr. Leocadi has nothing to disclose. The institution of Elisa Canu has received research support from Italian Ministry of Health . Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA).

Morphological Profiling Identifies the Motor Protein Eg5 as Cellular Target of Spirooxindoles.

Oxindoles and iso-oxindoles are natural product-derived scaffolds that provide inspiration for the design and synthesis of novel biologically relevant compound classes. Notably, the spirocyclic connection of oxindoles with iso-oxindoles has not been explored by nature but promises to provide structurally related compounds endowed with novel bioactivity. Therefore, methods for their efficient synthesis and the conclusive discovery of their cellular targets are highly desirable. We describe a selective RhIII -catalyzed scaffold-divergent synthesis of spirooxindole-isooxindoles and spirooxindole-oxindoles from differently protected diazooxindoles and N-pivaloyloxy aryl amides which includes a functional group-controlled Lossen rearrangement as key step. Unbiased morphological profiling of a corresponding compound collection in the Cell Painting assay efficiently identified the mitotic kinesin Eg5 as the cellular target of the spirooxindoles, defining a unique Eg5 inhibitor chemotype.

Molecular mechanisms of astrocyte involvement in synaptogenesis and brain synaptic plasticity

Astrocytes perform a wide range of important functions in the brain. As structural and functional components of synapses, astrocytes secrete various factors (proteins, lipids, small molecules, etc.) that bind to neuronal receptor and contribute to synaptogenesis and regulation of synaptic contacts. Astrocytic factors play a key role in the formation of neural networks undergoing short- and long-term synaptic morphological and functional rearrangements essential in the memory formation and behavior. The review summarizes the data on the molecular mechanisms mediating the involvement of astrocyte-secreted factors in synaptogenesis in the brain and provides up-to-date information on the role of astrocytes and astrocytic synaptogenic factors in the long-term plastic rearrangements of synaptic contacts.

Molecular Mechanisms of Astrocyte Involvement in Synaptogenesis and Brain Synaptic Plasticity

Astrocytes perform a wide range of important functions in the brain. As structural and functional components of synapses, astrocytes secrete various factors (proteins, lipids, small molecules, etc.) that bind to neuronal receptor and contribute to synaptogenesis and regulation of synaptic contacts. Astrocytic factors play a key role in the formation of neural networks undergoing short- and long-term synaptic morphological and functional rearrangements essential in the memory formation and behavior. The review summarizes the data on the molecular mechanisms mediating the involvement of astrocyte-secreted factors in synaptogenesis in the brain and provides up-to-date information on the role of astrocytes and astrocytic synaptogenic factors in the long-term plastic rearrangements of synaptic contacts.

Morphological and mitochondrial changes in murine choroid plexus epithelial cells during healthy aging

BackgroundChoroid plexuses (ChPs) are intraventricular structures mainly composed by specialized epithelial cells interconnected by tight junctions that establish the blood-cerebrospinal fluid (CSF) barrier. ChPs are essential to produce CSF and transport solutes from and into the brain. Deterioration of ChP function and morphology has been correlated to worsening of neurodegenerative disorders. We here map morpho-functional changes in the ChP epithelial cells during healthy aging, starting from young adult to 2-years old mice.MethodsWe used a multi-tiered approach, including transmission electron microscopy (TEM), immunohistochemistry, RT-qPCR, Western Blot and 2-photon microscopy (2-PM) at multiple timepoints ranging from young adult to 2-years old mice.ResultsWe identified distinct morpho-functional modifications in epithelial cells of ChP starting from 8 to 12 months of age, which mostly remained stable up to 2 years. These changes include flattening of the epithelium, reduction of microvilli length and an augmentation of interrupted tight junctions. We also found a decrease in mitochondria density together with elongation of mitochondria in older mice. Morphological mitochondrial rearrangements were accompanied by increased superoxide levels, decreased membrane potential and decreased mitochondrial motility in aged mice. Interestingly, most of the age-related changes were not accompanied by modification of protein and/or gene expression levels and aged mitochondria effectively responded to acute pharmacological stressful stimuli.ConclusionsOur study suggests a long-term progression of multiple morpho-functional features of the mouse choroid plexus epithelium during adulthood followed by structural remodeling during the aging process. These findings can lead to a better understanding on how functional and morphological rearrangements of ChP are correlated during aging.

Dependence of P/E tRNA hybrid formation on subunit rotation in the ribosome.

The ribosome, a massive nucleoprotein assembly that executes protein synthesis in all living cells, undergoes several large-scale functional rearrangements during the protein elongation cycle. Here we explore two such rearrangements in the ribosome bound tRNA molecules during the translocation step in bacteria, namely, P/E tRNA hybrid formation and inter-subunit rotation in the ribosome. We utilize multi-basin all-atom structure-based models and Ribosome Angle Decomposition (RAD) method to study the dependence of P/E hybrid formation on rotation of small subunit body with respect to the large subunit. Structure-based models provide simplified energetics with experimental atomic structures defined to be the potential energy minima. We employ these models to simulate spontaneous transition of the P-tRNA from P to E tRNA binding site on the large subunit for different degrees of small subunit body rotation. RAD method provides a complete coordinate system that describes any orientation of the ribosomal small subunit body and head in terms of rotation, tilt, tilt direction and translation. We identify reference E. coli structures at different degrees of body rotation but with minimal body tilt, head rotation and head tilt from the Ribosome Analysis Database based on RAD. Utilizing these methods, we explore the influence of subunit rotation on the free-energy barrier associated with P/E tRNA hybrid formation and obtain the quantitative dependence of P/E hybrid formation on subunit rotation.

Effect of preterm birth in rats on proliferation and hyperplasia of cardiomyocytes

Aim. To identify the effect of preterm birth on proliferation and hyperplasia of cardiomyocytes in the early postnatal period of ontogenesis in rats.Materials and methods. Preterm birth (on day 21 and 21.5 of gestation) in Wistar rats was induced by subcutaneous administration of mifepristone. Immunohistochemistry was used to identify and calculate the number of Ki67-positive and Mklp2-positive cardiomyocytes in the left ventricle of preterm and full-term rats on days 1, 2, 3, 4, 5, and 6 of postnatal ontogenesis. Statistical analysis of morphometric parameters was performed using the Shapiro – Wilk test and Mann – Whitney test with the Bonferroni correction.Results. We revealed an increase in the number of Ki67-positive cardiomyocytes in the left ventricle of the rats: on day 1 of postnatal ontogenesis (in the rats born on day 21 of gestation) and on days 3–5 of postnatal ontogenesis (in the rats born on day 21.5 of gestation). Preterm birth in rats did not result in a change in the number of Mklp2-positive cardiomyocytes in the left ventricular wall.Conclusion. A change in the pattern of Ki67 expression by cardiomyocytes in the rats born 12 or 24 hours before full term was demonstrated in the early postnatal period of ontogenesis. An isolated increase in Ki67 expression without a change in Mklp2 expression by cardiomyocytes in the left ventricular wall of preterm rats indicates acceleration of cardiomyocyte hypertrophy. Shorter duration of prenatal development is associated with more pronounced morphological and functional rearrangements in the rat myocardium.

Global brain c-Fos profiling reveals major functional brain networks rearrangements after alcohol reexposure

Many fundamental questions on alcohol use disorder (AUD) are frequently difficult to address by examining a single brain structure, but should be viewed from the whole brain perspective. c-Fos is a marker of neuronal activation. Global brain c-Fos profiling in rodents represents a promising platform to study brain functional networks rearrangements in AUD.We used a mouse model of alcohol drinking in IntelliCage. We trained mice to voluntarily drink alcohol, next subjected them to withdrawal and alcohol reexposure. We have developed a dedicated image computational workflow to identify c-Fos-positive cells in three-dimensional images obtained after whole-brain optical clearing and imaging in the light-sheet microscope.We provide a complete list of 169 brain structures with annotated c-Fos expression. We analyzed functional networks, brain modularity and engram index. Brain c-Fos levels in animals reexposed to alcohol were different from both control and binge drinking animals. Structures involved in reward processing, decision making and characteristic for addictive behaviors, such as precommissural nucleus, nucleus Raphe, parts of colliculus and tecta stood out particularly. Alcohol reexposure leads to a massive change of brain modularity including a formation of numerous smaller functional modules grouping structures involved in addiction development.Binge drinking can lead to substantial functional remodeling in the brain. We provide a list of structures that can be used as a target in pharmacotherapy but also point to the networks and modules that can hold therapeutic potential demonstrated by a clinical trial in patients.

Assessing the evolution of oxygenated functional groups on the graphene oxide surface upon mild thermal annealing in water.

Graphene oxide (GO) is known to be a 2D metastable nanomaterial that can be reconstructed under thermal annealing into distinct oxidized and graphitic phases. Up to now, such phase transformation, mainly related to epoxide and hydroxyl functional groups, has been usually achieved by thermally treating layers of GO in the solid state. Here, we present the mild annealing of GO dispersed in an aqueous medium, performed at two temperatures, 50 °C and 80 °C, for different intervals of time. We show experimental evidences of the epoxide instability in the presence of water by means of XPS, cyclic voltammetry and Raman spectroscopy, demonstrating the reorganization of epoxide and hydroxyl moieties initiated by water molecules. In fact, at 50 °C an increase in oxygen content is detected in all annealed samples compared to untreated GO, with a transformation of epoxide groups into vicinal diols. On the other hand, at 80 °C the oxygen content decreases towards the initial value since the vicinal diols, previously formed, transform into single hydroxyls and C[double bond, length as m-dash]C bonds. Moreover, the higher temperature annealing likely favours oxygenated functional groups rearrangements and clustering, in accordance with the literature, leading to a higher electron affinity and conductivity of the graphenic network.

ВЛИЯНИЕ НЕФТЯНЫХ УГЛЕВОДОРОДОВ НА БИОХИМИЧЕСКИЕ ПОКАЗАТЕЛИ ЧЕРНОМОРСКОЙ МИДИИ MYTILUS GALLOPROVINCIALIS

Almost all oil components are more or less toxic and have a toxic effect on aquatic organisms, and some groups of petroleum hydrocarbons (PH) can accumulate in organs and tissues and transmitted through food chains. Depending on the duration and scale of PH pollution, a wide range of responses can be observed – from physiological and biochemical, morphological, behavioral anomalies at organism level to structural and functional rearrangements in populations and communities. The study of the biochemical response in tissues of bivalve mollusks living in conditions of elevated PH concentrations in the experiment is necessary to understand the mechanisms of metabolism reorganization and adaptive reactions that occur in the body of hydrobionts when exposed to toxicants. The paper presents the results of a study of the PH effect on the parameters of the prooxidant-antioxidant system parameters (superoxide dismutase and catalase activities, level of lipid peroxidation and oxidized proteins) and amnotransferase activities (alanine aminotransferase and aspartate aminotransferase) in hepatopancreas of the Black Sea mussel Mytilus galloprovincialis in the acute toxicological experiment. The results of the experiment allowed to establish that PH at concentrations of 0.5 mg/l (10 MPC) and 1 mg/l (20 MPC) do not affect the activity of aminotransferases, but stimulate the development of oxidative stress by shifting the prooxidant-antioxidant balance towards the intensification of lipid peroxidation and protein oxidization; at the 1 mg/l concentration PH cause activation of superoxide dismutase and inhibition of catalase activity. Prooxidant-antioxidant system parameters demonstrate high sensitivity to PH and can be used along with other recommended parameters to assess the functional state of mollusks in conditions of oil environmental pollution.

Метаболическая активность иммунокомпетентных клеток в оценке индивидуальной холодовой чувствительности

The rapid switch on of the transient short-term responses involved in adjustment of homeostasis plays a key role in human adaptation to low temperatures that is essential for adjustment to low-temperature environment. The network of signaling pathways together with metabolic regulators provide sufficient plasticity of the cells of immune system, the normal function of which is extremely important for successful human adaptation. Sufficient energy supply to immunocompetent cells makes it possible to form an adequate immune response to any negative factor and to ensure adaptive functional rearrangements. The study was aimed to assess the variants of the immunocompetent cell metabolic pathways involved in acquiring individual cold sensitivity. A total of 180 people aged 25–55 (130 females, 50 males) were assessed before and after the short-term whole body cooling. Enzyme immunoassay was used to define the levels of IL10, IL6, TNFα, irisin, transferrin, sTfR, HIF-1α, Sirt3 in peripheral blood and cell lysate. The levels of glycogen (cytochemical methods) and ATP (luciferin-luciferase assay) in lymphocytes were defined. The decrease in peripheral blood lymphocyte levels after cooling was indicative of the formation of immediate adaptive response and activation of glycolysis amid less intense inflammatory response. The increase in the levels of circulating lymphocytes after the cold esposure was associated with activation of inflammatory responses. The lower ratio of HIF-1α/SIRT3 metabolic regulators was found in the surveyed volunteers who showed no changes in the levels of lymphocytes. This indicated predominance of mitochondrial activity in adaptation to low temperatures.

Military physician D.E. Tanfiliev: life and contribution to the development of military dentistry

On the memory pages among the Russian dentists and maxillofacial surgeons, it is impossible not to remember the prominent scientist and clinician, the candidate of medical sciences, associate professor, colonel of the medical service David Evseevich Tanfiliev.&#x0D; Research is to illuminate the scientific, clinical, pedagogical and social activity of the prominent military dentist and maxillofacial surgeon of the candidate of medical sciences, associate professor, colonel of the medical service David Tanfiliev.&#x0D; On the basis of the analysis of the domestic literature, and also life, professional activity and scientific labors of the candidate of medical sciences, associate professor, colonel of the medical service D.E. Tanfilyev to present his role in the development of the domestic stomatology and military medicine in Russia.&#x0D; The information about the life of the military dentist D.E. Tanfiliev, the candidate of medical sciences, associate professor, colonel of the medical service is represented. His activity during the Soviet-Finnish (winter) and the Great Patriotic War is marked. The main directions of his scientific activity in the issues of the development and improvement of the techniques of tooth extraction, treatment of difficult wisdom teeth eruption, odontogenic maxillary sinusitis, gunshot fractures and osteomyelitis of the upper jaw are examined. It is shown, that D.E. Tanfiliev has specified the function of the maxillary sinuses and physiological significance of its walls, described an age and functional rearrangement of the maxillary sinus bone tissue under the maxillary sinus floor and its significance for direct prosthesis. Received by D.E. Tanfiliev the information about age anatomy of maxillary sinuses is important for the practicing dentist, not only for facilitating diagnostics and therapy of this or that pathology, but also for knowing the genesis of old age and struggle for prolongation of active longevity. It is no coincidence that today special importance is given to dental rehabilitation of patients with severe atrophy of the alveolar processes and jaw parts using dentures on artificial supports He has improved the therapy of maxillary sinusitis in connection with the age-related features of the maxillary sinus structure and the types of bone structure of the upper jaw. He paid special attention to the clinical picture and treatment of concomitant gunshot injuries of the upper jaw.&#x0D; It is underlined that D.E. Tanfiliev was one of the pioneers of the national military stomatology.

Unravelling Contributions of Astrocytic Connexin 43 to the Functional Activity of Brain Neuron-Glial Networks under Hypoxic State In Vitro.

Brain hypoxia remains an Achilles’ heel for public health that must be urgently addressed. Hypoxic damage affects both neurons and glial cells, particularly astrocytes, which are in close dynamic bi-directional communication, and are organized in plastic and tightly regulated networks. However, astroglial networks have received limited attention regarding their influence on the adaptive functional rearrangements of neural networks to oxygen deficiency. Herein, against the background of astrocytic Cx43 gap junction blockade by the selective blocker Gap19, we evaluated the features of spontaneous calcium activity and network characteristics of cells in primary cultures of the cerebral cortex, as well as the expression levels of metabotropic glutamate receptors 2 (mGluR2) and 5 (mGluR5) in the early and late periods after simulated hypoxia in vitro. We showed that, under normoxic conditions, blockade of Cx43 leads to an increase in the expression of metabotropic glutamate receptors mGluR2 and mGluR5 and long-term modulation of spontaneous calcium activity in primary cortical cultures, primarily expressed in the restructuring of the functional architectonics of neuron–glial networks through reducing the level of correlation between cells in the network and the percentage of existing correlated connections between cells. Blocking Cx43 during hypoxic injury has a pronounced neuroprotective effect. Together with the increased expression of mGluR5 receptors, a decrease in mGluR2 expression to the physiological level was found, which suggests the triggering of alternative molecular mechanisms of cell adaptation to hypoxia. Importantly, the blockade of Cx43 in hypoxic damage contributed to the maintenance of both the main parameters of the spontaneous calcium activity of primary cortical cultures and the functional architectonics of neuron–glial networks while maintaining the profile of calcium oscillations and calcium signal communications between cells at a highly correlated level. Our results demonstrate the crucial importance of astrocytic networks in functional brain adaptation to hypoxic damage and could be a promising target for the development of rational anti-hypoxic therapy.

Two Step Selection for Bias in β Chain V-J Pairing.

The β chain rearrangement in T cells is a two-step process where first Dβ and Jβ bind, and only then Vβ is joined to the complex. We here show that the frequency of human and mouse Vβ Jβ combinations deviates from the one expected based on each gene usage frequency. This bias is observed mainly in functional (F) rearrangements, but also slightly in non-functional (NF) rearrangements. Preferred Vβ Jβ combinations in F clones are shared between donors and samples, suggesting a common structural mechanism for these biases in addition to any host-specific antigen-induced peripheral selection. The sharing holds even in clones with J β 1 that share the same Dβ 1 gene. Vβ Jβ usage is correlated with the Molecular Weight and Isoelectric Point in F clones. The pairing is also observed in the Double Positive cells in mice thymocytes, suggesting that the selection leading to such a pairing occurs before thymic selection. These results suggest an additional structural checkpoint in the beta chain development prior to thymic selection during the T cell receptor expression. Understanding this structural selection is important for the distinction between normal and aberrant T cell development, and crucial for the design of engineered TCRs.

Proteolytic control in ciliogenesis: Temporal restriction or early initiation?

Cellular processes are highly dependent on a dynamic proteome that undergoes structural and functional rearrangements to allow swift conversion between different cellular states. By inducing proteasomal degradation of inhibitory or stimulating factors, ubiquitylation is particularly well suited to trigger such transitions. One prominent example is the remodelling of the centrosome upon cell cycle exit, which is required for the formation of primary cilia - antenna-like structures on the surface of most cells that act as integrative hubs for various extracellular signals. Over the last decade, many reports on ubiquitin-related events involved in the regulation of ciliogenesis have emerged. Very often, these processes are considered to be initiated ad hoc, that is, directly before its effect on cilia biogenesis becomes evident. While such a temporal restriction may hold true for the majority of events, there is evidence that some of them are initiated earlier during the cell cycle. Here, we provide an overview of ubiquitin-dependent processes in ciliogenesis and discuss available data that indicate such an early onset of proteolytic regulation within preceding cell cycle stages.

Environmental Enrichment Enhances Cerebellar Compensation and Develops Cerebellar Reserve.

The brain is able to change its structure and function in response to environmental stimulations. Several human and animal studies have documented that enhanced stimulations provide individuals with strengthened brain structure and function that allow them to better cope with damage. In this framework, studies based on the exposure of animals to environmental enrichment (EE) have provided indications of the mechanisms involved in such a beneficial action. The cerebellum is a very plastic brain region that responds to every experience with deep structural and functional rearrangement. The present review specifically aims to collect and synthesize the evidence provided by animal models on EE exposure effects on cerebellar structure and function by considering the studies on healthy subjects and on animals exposed to EE both before and after damage involving cerebellar functionality. On the whole, the evidence supports the role of EE in enhancing cerebellar compensation and developing cerebellar reserve. However, since studies addressing this issue are still scarce, large areas of inconsistency and lack of clarity remain. Further studies are required to provide suggestions on possible mechanisms of enhancement of compensatory responses in human patients following cerebellar damage.