Organizer Regions Research Articles

Tetraploid Ancestry Provided Atlantic Salmon With Two Paralogue Functional T Cell Receptor Beta Regions Whereof One Is Completely Novel.

Protective cellular immune responses have been difficult to study in fish, due to lack of basic understanding of their T cell populations, and tools to study them. Cellular immunity is thus mostly ignored in vaccination and infection studies compared to humoral responses. High throughput sequencing, as well as access to well assembled genomes, now advances studies of cellular responses. Here we have used such resources to describe organization of T cell receptor beta genes in Atlantic salmon. Salmonids experienced a unique whole genome duplication approximately 94 million years ago, which provided these species with many functional duplicate genes, where some duplicates have evolved new functions or sub-functions of the original gene copy. This is also the case for T cell receptor beta, where Atlantic salmon has retained two paralogue T cell receptor beta regions on chromosomes 01 and 09. Compared to catfish and zebrafish, the genomic organization in both regions is unique, each chromosomal region organized with dual variable- diversity- joining- constant genes in a head to head orientation. Sequence identity of the chromosomal constant sequences between TRB01 and TRB09 is suggestive of rapid diversification, with only 67 percent as opposed to the average 82-90 percent for other duplicated genes. Using virus challenged samples we find both regions expressing bona fide functional T cell receptor beta molecules. Adding the 292 variable T cell receptor alpha genes to the 100 variable TRB genes from 14 subgroups, Atlantic salmon has one of the most diverse T cell receptor alpha beta repertoire of any vertebrate studied so far. Perhaps salmonid cellular immunity is more advanced than we have imagined.

Sulci 3D mapping from human cranial endocasts: A powerful tool to study hominin brain evolution.

Key questions in paleoneurology concern the timing and emergence of derived cerebral features within the human lineage. Endocasts are replicas of the internal table of the bony braincase that are widely used in paleoneurology as a proxy for reconstructing a timeline for hominin brain evolution in the fossil record. The accurate identification of cerebral sulci imprints in endocasts is critical for assessing the topographic extension and structural organisation of cortical regions in fossil hominins. High‐resolution imaging techniques combined with established methods based on population‐specific brain atlases offer new opportunities for tracking detailed endocranial characteristics. This study provides the first documentation of sulcal pattern imprints from the superolateral surface of the cerebrum using a population‐based atlas technique on extant human endocasts. Human crania from the Pretoria Bone Collection (South Africa) were scanned using micro‐CT. Endocasts were virtually extracted, and sulci were automatically detected and manually labelled. A density map method was applied to project all the labels onto an averaged endocast to visualise the mean distribution of each identified sulcal imprint. This method allowed for the visualisation of inter‐individual variation of sulcal imprints, for example, frontal lobe sulci, correlating with previous brain‐MRI studies and for the first time the extensive overlapping of imprints in historically debated areas of the endocast (e.g. occipital lobe). In providing an innovative, non‐invasive, observer‐independent method to investigate human endocranial structural organisation, our analytical protocol introduces a promising perspective for future research in paleoneurology and for discussing critical hypotheses on the evolution of cognitive abilities among hominins.

The influence of socio-demographic and external factors on the change of urban parameters of the Luhansk region

The scale and nature of changes in the urban planning parameters of the Luhansk region under the influence of socio-demographic and external factors are studied. The actual development trends of the Lysychansk-Rubizhne-Sievierodonetsk agglomeration, the evolution of the regional settlement system, the state and problems of the urban development of the region are determined. To conduct the study, methods of system analysis, analytical comparisons, statistical analysis, urban planning analysis were used. The information base consists of literary and archival sources, cartographic materials. Quantitative and qualitative changes in the main territorial and urban planning parameters of the Luhansk region have been studied. A methodology for assessing and making urban planning decisions is proposed. The urban planning tasks and directions of transformation of the residential environment of the Luhansk region, controlled by Ukraine, are analyzed. Lugansk region in modern conditions is an outsider of socio-economic development. The occupied territories of the Lugansk region of the so-called ORLO (separate districts of the Luhansk region) are in a state of crisis. Industrial, ecological, social degradation is intensifying. This trend can lead to the devastation of settlement systems. The tasks of rational transformation of the territorial-planning organization of the Lugansk region remain relevant. From the intermediate conclusions, it is advisable to single out: the region has significantly changed its functions. The border and the line of demarcation of the JFO will still indefinitely be the determining factor influencing the state and development of the region. The task of the territorial development should be considered at the level of the Lysychansk-Rubizhne-Sievierodonetsk agglomeration and the structure of the region as a whole to ensure the growth of its potential. It is expedient to implement priority tasks according to unconditionally effective options that give a quick and demonstrable result. It can be education, transport infrastructure, anything that raises social standards. It is necessary to achieve a consensus of different groups of the population in the implementation of urban planning tasks and projects.

Trajectory of rich club properties in structural brain networks.

Many organizational principles of structural brain networks are established before birth and undergo considerable developmental changes afterwards. These include the topologically central hub regions and a densely connected rich club. While several studies have mapped developmental trajectories of brain connectivity and brain network organization across childhood and adolescence, comparatively little is known about subsequent development over the course of the lifespan. Here, we present a cross‐sectional analysis of structural brain network development in N = 8066 participants aged 5–80 years. Across all brain regions, structural connectivity strength followed an “inverted‐U”‐shaped trajectory with vertex in the early 30s. Connectivity strength of hub regions showed a similar trajectory and the identity of hub regions remained stable across all age groups. While connectivity strength declined with advancing age, the organization of hub regions into a rich club did not only remain intact but became more pronounced, presumingly through a selected sparing of relevant connections from age‐related connectivity loss. The stability of rich club organization in the face of overall age‐related decline is consistent with a “first come, last served” model of neurodevelopment, where the first principles to develop are the last to decline with age. Rich club organization has been shown to be highly beneficial for communicability and higher cognition. A resilient rich club might thus be protective of a functional loss in late adulthood and represent a neural reserve to sustain cognitive functioning in the aging brain.

Acute axon damage and demyelination are mitigated by 4-aminopyridine (4-AP) therapy after experimental traumatic brain injury

Damage to long axons in white matter tracts is a major pathology in closed head traumatic brain injury (TBI). Acute TBI treatments are needed that protect against axon damage and promote recovery of axon function to prevent long term symptoms and neurodegeneration. Our prior characterization of axon damage and demyelination after TBI led us to examine repurposing of 4-aminopyridine (4-AP), an FDA-approved inhibitor of voltage-gated potassium (Kv) channels. 4-AP is currently indicated to provide symptomatic relief for patients with chronic stage multiple sclerosis, which involves axon damage and demyelination. We tested clinically relevant dosage of 4-AP as an acute treatment for experimental TBI and found multiple benefits in corpus callosum axons. This randomized, controlled pre-clinical study focused on the first week after TBI, when axons are particularly vulnerable. 4-AP treatment initiated one day post-injury dramatically reduced axon damage detected by intra-axonal fluorescence accumulations in Thy1-YFP mice of both sexes. Detailed electron microscopy in C57BL/6 mice showed that 4-AP reduced pathological features of mitochondrial swelling, cytoskeletal disruption, and demyelination at 7 days post-injury. Furthermore, 4-AP improved the molecular organization of axon nodal regions by restoring disrupted paranode domains and reducing Kv1.2 channel dispersion. 4-AP treatment did not resolve deficits in action potential conduction across the corpus callosum, based on ex vivo electrophysiological recordings at 7 days post-TBI. Thus, this first study of 4-AP effects on axon damage in the acute period demonstrates a significant decrease in multiple pathological hallmarks of axon damage after experimental TBI.

Annotation of a Newly Sequenced Genomic Region in Drosophila ananassae

Understanding evolutionary changes across Drosophila species can lead to a better understanding of how genomes have changed over time. Drosophila species have existed for millions of years, allowing the opportunity to study and identify the functions of genes orthologous to human genes. The etiology of numerous diseases can be better elucidated through the utilization of bioinformatic tools and genomic annotation. The Genome Education Partnership (GEP) is a nationwide community that provides undergraduate students the opportunity to gain experience in annotating eukaryotic genomes. Through the use of bioinformatics tools such as UCSC Genome Browser, NCBI Blast, and Flybase, students participate in the F‐element and Pathways projects. The F‐element project involves the annotation of protein‐coding genes located on chromosome four, commonly known as the Muller F element. Over time, the F element in some species of Drosophila, including Drosophila ananassae, has been expanding. Comparative genome annotation analyzing changes in the organization of this genomic region may lead to a better understanding of the complexity of these genomes. The Pathways project involves annotating specific genes involved in the Insulin Signaling Pathway. These genes play a critical role in the regulation of expression and metabolism in many eukaryotes. In this study, the annotation of a genomic region in Drosophila ananassae is discussed.A 25,000 base pair region of chromosome 3L in D. ananassae (Muller D element) was annotated for comparison to the F element. In this region, known as Contig 21, five protein‐coding genes were identified: CG10222, CG10713, CG32121, CG33263, and flr. These genes had high protein alignment (70% to 90% amino acid identity) compared to Drosophila melanogaster, however, the flr gene possessed some interesting characteristics. Upon the annotation of the flr gene in Drosophila ananassae, it was predicted that one of the isoforms was no longer expressed and/or functional. The gene flr encodes the Drosophila Actin Interacting Protein 1, which interacts with the gene product of trs (cofillin) to promote F‐actin disassembly. In Drosophila melanogaster, the flr gene encodes two isoforms, however in Drosophila ananassae, only the flr‐PA isoform appears to be expressed and/or functional. A deletion/insertion of a nucleotide within exon 1 in the flr gene leads to a frameshift resulting in a non‐functional protein due to a change in the original stop codon of isoform B in D. ananassae. The gene flr plays an important role in the development of the organism, therefore molecular analysis was utilized to confirm the annotation model above. RNA was extracted from Drosophila ananassae, and reverse transcription PCR (RT‐PCR) was utilized to amplify this region of the genome. Dideoxy sequencing was performed to analyze the expression of different isoforms of this gene. The sequencing data was compared to the Drosophila ananassae and Drosophila melanogaster genomes using BLAST and the UCSC Genome Browser. This data supported the expression of only one isoform of the flr gene in D. ananassae. This data also suggests that one of the flr gene isoforms is highly conserved in this species. Additional analysis of newly sequenced genomic data such as this will provide additional understanding on how genomes such as these have changed over time.

Somatotopic Organization of Hyperdirect Pathway Projections From the Primary Motor Cortex in the Human Brain.

BackgroundThe subthalamic nucleus (STN) is an effective neurosurgical target to improve motor symptoms in Parkinson's Disease (PD) patients. MR-guided Focused Ultrasound (MRgFUS) subthalamotomy is being explored as a therapeutic alternative to Deep Brain Stimulation (DBS) of the STN. The hyperdirect pathway provides a direct connection between the cortex and the STN and is likely to play a key role in the therapeutic effects of MRgFUS intervention in PD patients.ObjectiveThis study aims to investigate the topography and somatotopy of hyperdirect pathway projections from the primary motor cortex (M1).MethodsWe used advanced multi-fiber tractography and high-resolution diffusion MRI data acquired on five subjects of the Human Connectome Project (HCP) to reconstruct hyperdirect pathway projections from M1. Two neuroanatomy experts reviewed the anatomical accuracy of the tracts. We extracted the fascicles arising from the trunk, arm, hand, face and tongue area from the reconstructed pathways. We assessed the variability among subjects based on the fractional anisotropy (FA) and mean diffusivity (MD) of the fibers. We evaluated the spatial arrangement of the different fascicles using the Dice Similarity Coefficient (DSC) of spatial overlap and the centroids of the bundles.ResultsWe successfully reconstructed hyperdirect pathway projections from M1 in all five subjects. The tracts were in agreement with the expected anatomy. We identified hyperdirect pathway fascicles projecting from the trunk, arm, hand, face and tongue area in all subjects. Tract-derived measurements showed low variability among subjects, and similar distributions of FA and MD values among the fascicles projecting from different M1 areas. We found an anterolateral somatotopic arrangement of the fascicles in the corona radiata, and an average overlap of 0.63 in the internal capsule and 0.65 in the zona incerta.ConclusionMulti-fiber tractography combined with high-resolution diffusion MRI data enables the identification of the somatotopic organization of the hyperdirect pathway. Our preliminary results suggest that the subdivisions of the hyperdirect pathway projecting from the trunk, arm, hand, face, and tongue motor area are intermixed at the level of the zona incerta and posterior limb of the internal capsule, with a predominantly overlapping topographical organization in both regions. Subject-specific knowledge of the hyperdirect pathway somatotopy could help optimize target definition in MRgFUS intervention.

Diversity and Evolution of Pigment Types in Marine Synechococcus Cyanobacteria.

Synechococcus cyanobacteria are ubiquitous and abundant in the marine environment and contribute to an estimated 16% of the ocean net primary productivity. Their light-harvesting complexes, called phycobilisomes (PBS), are composed of a conserved allophycocyanin core, from which radiates six to eight rods with variable phycobiliprotein and chromophore content. This variability allows Synechococcus cells to optimally exploit the wide variety of spectral niches existing in marine ecosystems. Seven distinct pigment types or subtypes have been identified so far in this taxon based on the phycobiliprotein composition and/or the proportion of the different chromophores in PBS rods. Most genes involved in their biosynthesis and regulation are located in a dedicated genomic region called the PBS rod region. Here, we examine the variability of gene content and organization of this genomic region in a large set of sequenced isolates and natural populations of Synechococcus representative of all known pigment types. All regions start with a tRNA-PheGAA and some possess mobile elements for DNA integration and site-specific recombination, suggesting that their genomic variability relies in part on a “tycheposon”-like mechanism. Comparison of the phylogenies obtained for PBS and core genes revealed that the evolutionary history of PBS rod genes differs from the core genome and is characterized by the co-existence of different alleles and frequent allelic exchange. We propose a scenario for the evolution of the different pigment types and highlight the importance of incomplete lineage sorting in maintaining a wide diversity of pigment types in different Synechococcus lineages despite multiple speciation events.

Enhanced Resting-State Functional Connectivity With Decreased Amplitude of Low-Frequency Fluctuations of the Salience Network in Mindfulness Novices.

Mindfulness and accordant interventions are often used as complementary treatments to psychological or psychosomatic problems. This has also been gradually integrated into daily lives for the promotion of psychological well-being in non-clinical populations. The experience of mindful acceptance in a non-judgmental way brought about the state, which was less interfered by a negative effect. Mindfulness practice often begins with focused attention (FA) meditation restricted to an inner experience. We postulate that the brain areas related to an interoceptive function would demonstrate an intrinsic functional change after mindfulness training for the mindful novices along with paying more attention to internal processes. To further explore the influence of mindfulness on the organization of the brain regions, both functional connectivity (FC) in the voxel and the region of interest (ROI) level were calculated. In the current study, 32 healthy volunteers, without any meditation experiences, were enrolled and randomly assigned to a mindfulness-based stress reduction group (MBSR) or control group (CON). Participants in the MBSR group completed 8 weeks of mindfulness-based stress reduction (MBSR) and rated their mindfulness skills before and after MBSR. All subjects were evaluated via resting-state functional MRI (rs-fMRI) in both baselines and after 8 weeks. They also completed a self-report measure of their state and trait anxiety as well as a positive and negative affect. Pre- and post-MBSR assessments revealed a decreased amplitude of low-frequency fluctuations (ALFF) in the right anterior cingulate gyrus (ACC.R), left anterior and posterior insula (aIC.L, pIC.L), as well as left superior medial frontal gyrus (SFGmed.L) in MBSR practitioners. Strengthened FC between right anterior cingulate cortex (ACC.R) and aIC.R was observed. The mean ALFF values of those regions were inversely and positively linked to newly acquired mindful abilities. Along with a decreased negative affect score, our results suggest that the brain regions related to attention and interoceptive function were involved at the beginning of mindfulness. This study provides new clues in elucidating the time of evaluating the brain mechanisms of mindfulness novices.

Morphology and receptive field organization of a temporal processing region in Apteronotus albifrons

The timing system of weakly electric fishes is vital for many behavioral processes, but the system has been relatively unexplored in Apteronotus albifrons. This paper describes the receptive fields of phase-locked neurons in the midbrain of A. albifrons, in combination with neuroanatomy and electron microscopy (EM) to delineate a phase-locked area in this fish, the magnocellular mesencephalic nucleus (MMN). The MMN was isolated electrophysiologically through the detection of phase-locked field potentials of high amplitude. Single-cell recordings were made with a sharp electrode while a phase-locked modulated stimulus was provided to the fish. Receptive field centers of phase-locked neurons in MMN were consistent with tuberous electroreceptor density maps from previous studies, but no receptive field centers were found in the posterior 50% of the body. Intracellular and extracellular labeling of MMN revealed three cell populations: giant cells with large somata (19-24µm) and their axonal arborizations which span across the entire extent of MMN, axon terminals from spherical cells of the electrosensory lateral line lobe (ELL), and small cell somata (3-7µm) along with their projections which extend outside the nucleus. EM revealed multiple gap junction and chemical synapses within MMN. Our results indicate that MMN is a dedicated temporal processing center in A. albifrons.

Local information fusion network for 3D shape classification and retrieval

Due to the wide applications of 3D shapes, exploring effective 3D shape recognition algorithms has attracted much research attention. Various approaches have been proposed in recent years, within which the multi-view based methods show their promising performances. Previous multi-view based methods mainly extract global features of views by employing the well-established CNN and then explore the correlations between the view-level descriptors for 3D shape representation. However, these approaches ignore the local characteristics extraction of view images. Besides, they also lack the consideration for the relationships between image regions and feature map channels, which could provide more detailed and descriptive information to improve the discrimination of shape descriptors. To address these issues, we propose a novel Local Information Fusion Network (LIFN) for local characteristics extraction and relationships exploration based on the feature maps during the convolution process. Concretely, the Region Organization Module (ROM) is introduced for feature map reorganization and region-wise feature extraction. Besides, the Region-wise Attention (RWA) and Channel-wise Attention (CWA) are designed for region-wise and channel-wise interaction exploration, respectively. Extensive experiments on the ModelNet40 database demonstrate the superiority of our proposed network against the state-of-the-art approaches.

Situation of insecticide resistance in malaria vectors in the World Health Organization of Eastern Mediterranean region 1990-2020.

Malaria is the most important mosquito-borne disease, which is transmitted by Anopheles species. According to the recent report of World Health Organization, there were an estimated 229 million malaria cases in 2019 in 87 malaria endemic countries. There are several vector control method specially using pesticides. The aim of this study was to collect all the data about insecticide resistant of malaria vectors in the Eastern Mediterranean region countries. In this study, all the published papers related to insecticide resistance of malaria vectors in the region were collected and resistant status of vectors in the countries was mapped. Resistance to different insecticide classes such as pyrethroids, organophosphate, organochlorine and carbamates were evaluated using World Health Organization guidelines. Results showed a wide variety of susceptibility/resistance status to these chemicals according to the location, historical context of pesticide used, genetic background of vectors, age and abdominal conditions of adults may play a role in the susceptibility status of these species to different insecticides. The results of this study is providing a guideline for countries to manage their vector control activities against insecticide resistance of malaria vectors and provide novel approaches such as male sterility, using Wolbachia, using new insecticide with new mode of action.

Comparative genomic analysis of dwarf Vibrio myoviruses defines a conserved gene cluster for successful phage infection.

Tailed bacteriophages have been at the center of attention, not only for their ability to infect and kill pathogenic bacteria but also due to their peculiar and intriguing complex contractile tail structure. Tailed bacteriophages with contractile tails are known to have a Myoviridae morphotype and are members of the order Caudovirales. Large bacteriophages with a genome larger than 150 kbp have been studied for their ability to use multiple infection and lysis strategies to replicate more efficiently. On the other hand, smaller bacteriophages with fewer genes are represented in the GenBank database in greater numbers, and have several genes with unknown function. Isolation and molecular characterization of a newly reported bacteriophage named Athena1 revealed that it is a strongly lytic bacteriophage with a genome size of 39,826 bp. This prompted us to perform a comparative genomic analysis of Vibrio myoviruses with a genome size of no more than 50 kbp. The results revealed a pattern of genomic organization that includes sets of genes responsible for virion morphogenesis, replication/recombination of DNA, and lysis/lysogeny switching. By studying phylogenetic gene markers, we were able to draw conclusions about evolutionary events that shaped the genomic mosaicism of these phages, pinpointing the importance of a conserved organization of the genomic region encoding the baseplate protein for successful infection of Gram-negative bacteria. In addition, we propose the creation of new genera for dwarf Vibrio myoviruses. Comparative genomics of phages infecting aquatic bacteria could provide information that is useful for combating fish pathogens in aquaculture, using novel strategies.

Recreational use and spatial organization of rural regions in terms of new sociological and economic factors

Important issues regarding the exploration of aesthetically attractive and recreationally important objects within the boundaries of traditional rural regions are discussed. The usage of the proposed methodological approach to the evaluation of aesthetical and consumer parameters regarding the regional settlement system is demonstrated in the example of rural regions located in Valuysky Municipal District, Belgorod Oblast. Specific features of recreational activities, their unique forms, and coherence between different types of environmental management are determined. Environmental representation coefficients, recreational radiuses, the local residents’ group with the appropriate frequency of recreational activity, and the recreational load are calculated. The necessity and promise of using such studies result in making social, economic, and geoscientific decisions related to the development of the land use planning documents, including recreational complex organization are shown.

Организация некодирующих элементов в геномах птиц

The review focuses on non-coding elements in bird genomes. Like most living organisms, birdscarry a significant number of non-coding sequences in their genome. Technically, these sequences cannot beclassified as genes. They include DNA regions with structural functions and high level of conservatismas well as a considerable number of sequences, including repetitive fractions, whose functions are not yetknown. Apart from a general overview of tandem repeats in avian genomes, the paper provides a special focuson differences in copy number of individual repeats. Interestingly, this number directly correlates witha reduction in genome size in birds. Besides, the review provides a detailed description of how repetitivesequences are involved in structural and functional organisation of centromeric and telomeric regions witha special emphasis given to the organisation of pericentromeric and subtelomeric heterochromatin. It alsodescribes what makes these regions different from centromeric and telomeric sequences per se. The data onthe distribution of repeats in bird genomes and their specific organisation are compared with the level of theirconservatism and their role in maintaining structural and functional organisation of the genome.

Анализ системы фармацевтической помощи населению Новосибирской области

Introduction. Uneven placement of pharmacy organizations on the territory of the Novosibirsk region, want of pharmaceutical staff, especially in remote areas, falling living standards, an increase in general morbidity of the population, limited material and financial health care resources in the Novosibirsk region necessitated an assessment of the pharmaceutical care system in order to develop measures to improve it, preserve constitutional rights and guarantees for residents. Aim. Development and testing of a methodology for analyzing the system of pharmaceutical care for the population of the Novosibirsk region. Materials and methods. SWOT analysis was used for the assessment. Based on the content analysis of scientific medical and pharmaceutical literature, regulatory documents of the Government of the Russian Federation, the Ministries of Health of the Russian Federation and the Novosibirsk region, a questionnaire was compiled in which various aspects of the pharmaceutical care to the population of the Novosibirsk region were characterized. A group of experts (heads of pharmacy chains, heads of pharmacies, chiefs or deputies, specialists of the Department of Drug Provision of the Population of the Ministry of Health of the Novosibirsk region – a total of 35 people) were asked to evaluate (rank) the proposed characteristics in a SWOT matrix. Results. It has been established that the strengths of pharmaceutical care to the population of the Novosibirsk region (the top among them are the developed infrastructure for providing the population with pharmaceutical care; the approval and implementation of federal programs on the strategy of drug provision to the population and the development of healthcare in the Russian Federation and the Novosibirsk region) exceed by 1.26 times the weaknesses of the system (insufficient financing of drug provision to the population of the region; insufficient provision of the population with pharmacy organizations and medical and obstetric stations in rural settlements of the Novosibirsk region, etc.). Possibilities of the pharmaceutical care system in the Novosibirsk region (organization of dispensing medicines by medical staff through out-patient clinics in rural settlements of the Novosibirsk region, in which there are no pharmacy organizations; an increase in the proportion of municipal and urban districts provided with medicines dispensing outlets in relation to all municipal and urban entities of the Novosibirsk region to 100%, etc.) by 1.13 times prevails over threats (an increasing staff shortage in the pharmaceutical industry, a pandemic of a new coronavirus infection, etc.). Conclusion. Pharmaceutical care for the population of the Novosibirsk region is characterized by the predominance of strengths over weaknesses, while potential opportunities exceed threats. This imples the necessity to further improve pharmaceutical care, use its resource capabilities and enhance its strengths.

Spatial heterogeneity and organization of tumor mutation burden with immune infiltrates within tumors based on whole slide images correlated with patient survival in bladder cancer

BackgroundHigh tumor mutation burden (TMB-H) could result in an increased number of neoepitopes from somatic mutations expressed by a patient’s own tumor cell which can be recognized and targeted by neighboring tumor-infiltrating lymphocytes (TILs). Deeper understanding of spatial heterogeneity and organization of tumor cells and their neighboring immune infiltrates within tumors could provide new insights into tumor progression and treatment response. MethodsHere we first developed computational approaches using whole slide images (WSIs) to predict bladder cancer patients’ TMB status and TILs across tumor regions, and then investigate spatial heterogeneity and organization of regions harboring TMB-H tumor cells and TILs within tumors, as well as their prognostic utility. Results: In experiments using WSIs from The Cancer Genome Atlas (TCGA) bladder cancer (BLCA), our findings show that computational pathology can reliably predict patient-level TMB status and delineate spatial TMB heterogeneity and co-organization with TILs. TMB-H patients with low spatial heterogeneity enriched with high TILs show improved overall survival. ConclusionsComputational approaches using WSIs have the potential to provide rapid and cost-effective TMB testing and TILs detection. Survival analysis illuminates potential clinical utility of spatial heterogeneity and co-organization of TMB and TILs as a prognostic biomarker in BLCA which warrants further validation in future studies.

The autonomous status and the local government system of the Åland Islands

The autonomous status of the Åland Islands and the system of its self-government against Finland’s territorial and administrative structure constitute a fascinating research area in the field of constitutional law and political systems. Such research makes it possible to determine which principles of the system of the division into territorial units possessing autonomous status within the territorial structure of the state and its self-government should be introduced at the legal, constitutional and statutory level in order to ensure the population inhabiting it with a sufficient level of separateness and independence, protection of fundamental rights and freedoms, and at the same time guarantee the territorial integrity of the state. The study also makes it possible to determine which legal mechanisms and instruments of the organization and functioning of autonomous regions, distinguished by some specific feature, need to be applied in order for the system of such a unit to be effective in the performance of public tasks of their own and those commissioned by state authorities by self-government bodies of this region and to enable the self-government of the region serving its citizens at its best. In the case of Finland, it is of great importance for the protection of fundamental human and civil rights and freedoms, especially for ethnically and culturally separate social groups. The aim of this study is the legal analysis of the autonomous status and the local government system of the Åland Islands, applied and currently functioning in Finland, and its subject is an exegesis of the norms concerning the subject matter under the study, contained in the Fundamental Law of 1999 being in force in Finland and the relevant statutory regulations, as well as practices of the functioning of this region within the state from the perspective of its division into other basic units and the system of local government.

Development and testing of a model of distance education

This paper aims to present a universal model applicable at all levels of distance learning, in a region and particular educational organization. The authors applied a systematic approach to consider the introduction of distance education as an activity, which result depends on the current sociocultural conditions in the region, including the specifics of the population, the labor market, the socioeconomic and political situation, and the quality of teaching in educational organizations. The scientific novelty of the research includes the theoretical and methodological substantiation of a universal model for implementing distance education. It involves mandatory monitoring and support measures at all levels of administration: the micro- (an educational organization), meso- (regional and municipal administration), and macroadministration (the State). Exploring the research problem, the authors revealed that distance learning effectiveness is directly connected with the quality of the regional analysis of sociocultural factors at the planning and forecasting stage.

DNA Environment of Centromeres and Non-Homologous Chromosomes Interactions in Mouse.

Although the pericentromeric regions of chromosomes that are enriched in tandemly repeated satellite DNA represent a significant part of eukaryotic genomes, they remain understudied, which is mainly due to interdisciplinary knowledge gaps. Recent studies suggest their important role in genome regulation, karyotype stability, and evolution. Thus, the idea of satellite DNA as a junk part of the genome has been refuted. The integration of data regarding molecular composition, chromosome behaviour, and the details of the in situ organization of pericentromeric regions is of great interest. The objective of this work was a cytogenetic analysis of the interactions between pericentromeric regions from non-homologous chromosomes in mouse spermatocytes using immuno-FISH. We analysed two events: the associations between centromeric regions of the X chromosome and autosomes and the associations between the centromeric regions of the autosomal bivalents that form chromocenters. We concluded that the X chromosome forms temporary synaptic associations with different autosomes in early meiotic prophase I, which can normally be found until the pachytene–diplotene, without signs of pachytene arrest. These associations are formed between the satellite-DNA-rich centromeric regions of the X chromosome and different autosomes but do not involve the satellite-DNA-poor centromeric region of the Y chromosome. We suggest the hypothetical model of X chromosome competitive replacement from such associations during synaptic correction. We showed that the centromeric region of the X chromosome in association remains free of γH2Ax-dependent chromatin inactivation, while the Y chromosome is completely inactivated. This finding highlights the predominant role of associations between satellite DNA-rich regions of different chromosomes, including the X chromosome. We suppose that X-autosomal transient associations are a manifestation of an additional synaptic disorder checkpoint. These associations are normally corrected before the late diplotene stage. We revealed that the intense spreading conditions that were applied to the spermatocyte I nuclei did not lead to the destruction of stretched chromatin fibers of elongated chromocenters enriched in satellite DNA. The tight associations that we revealed between the pericentromeric regions of different autosomal bivalents and the X chromosome may represent the basis for a mechanism for maintaining the repeats stability in the autosomes and in the X chromosome. The consequences of our findings are discussed.