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This research investigates the application of plastic fiber reinforcement in pre-tensioned reinforced concrete railway sleepers, conducting an in-depth examination in both experimental and computational aspects. Utilizing 3-point bending tests and the GOM ARAMIS system for Digital Image Correlation, this study meticulously evaluates the structural responses and crack development in conventional and plastic fiber-reinforced sleepers under varying bending moments. Complementing these tests, the investigation employs ABAQUS' advanced finite element modeling to enhance the analysis, ensuring precise calibration and validation of the numerical models. This dual approach comprehensively explains the mechanical behavior differences and stresses within the examined structures. The incorporation of plastic fibers not only demonstrates a significant improvement in mechanical strength and crack resistance but paves the way for advancements in railway sleeper technology. By shedding light on the enhanced durability and performance of reinforced concrete structures, this study makes a significant contribution to civil engineering materials science, highlighting the potential for innovative material applications in the construction industry. [ABSTRACT FROM AUTHOR]

This paper focuses on the narrative aspect of Seneca's idea of self-transformation. It compares Seneca's viewpoint with some modern notions of the narrative self to highlight some parallels and significant differences between the ancient and modern conceptions and it establishes the reading of some parts of De Brev. Vit. in the context of other passages as concerned with the narrative self. The paper argues, amongst other points, that in Ep. 83.1–3, Seneca extends the practice of meditatio (ethically directed self-examination) by incorporating the construction of a narrative self into this process, in dual roles, as examiner and examined. It concludes that Seneca expected us to avail ourselves of a similar self-assessment based on a dialogue with philosophical texts. [ABSTRACT FROM AUTHOR]

Seneca's masterful application of metaphors often illuminates some Stoic technical terminology in contexts, which render them meaningful and familiar to his Roman readers. In this paper I argue that in certain instances, these metaphors are also used to organize whole systems of concepts that refer to an essential theoretical component of Seneca's philosophy. By studying the literary and philosophical context of these metaphors, I reconstruct Seneca's requirement for moral self-improvement in his Epistles and propose that his conception of conscientia or 'moral conscience'—a notion scattered throughout his writings but which, as the examination of his systematic metaphors will prove, has a consistent, identical function everywhere it appears—points to some novel rational characteristics of the philosopher's conception of the self. [ABSTRACT FROM AUTHOR]

This article summarizes the research results related to our own conducted extensive laboratory tests of polymer composite and steel fishplated glued insulated rail joints (GIRJs), namely axial tensile tests as well as vertical static and dynamic tests. The investigation dealt with the examination of GIRJs assembled with steel and special glass-fiber reinforced plastic (polymer composite) fishplates, both of them for CWR railway tracks (i.e. so-called gapless tracks or, in other words, railway tracks with continuously welded rails). The exact rail joint types were MTH-P and MTH-AP, consistently. The MTH P types have been commonly applied for many years in the CWR tracks in Europe, mainly in Hungary. The MTH-AP rail joints consist of fishplates that are produced by the APATECH factory (Russia). They are made of a fiberglassamplified polymer composite material at high pressure and controlled temperature. This solution can eliminate electrical fishplate lock and early fatigue failures just as it can ensure adequate electrical insulation. The advantage of such rail joints can be that they are probably able to ensure the substitution of the glued insulated rail joints with relatively expensive steel fishplates currently applied by railway companies, e.g. Hungarian State Railways (MÁV). The aim of the mentioned research summarized in this paper is to formulate recommendations on technical applicability and on the technological instructions that are useful in everyday railway operation practice on the basis of the measurements and tests carried out on rail joints in laboratory. [ABSTRACT FROM AUTHOR]

The current state‐of‐the‐art analysis of central nervous system (CNS) tumors through DNA methylation profiling relies on the tumor classifier developed by Capper and colleagues, which centrally harnesses DNA methylation data provided by users. Here, we present a distributed‐computing‐based approach for CNS tumor classification that achieves a comparable performance to centralized systems while safeguarding privacy. We utilize the t‐distributed neighborhood embedding (t‐SNE) model for dimensionality reduction and visualization of tumor classification results in two‐dimensional graphs in a distributed approach across multiple sites (DistSNE). DistSNE provides an intuitive web interface (https://gin-tsne.med.uni-giessen.de) for user‐friendly local data management and federated methylome‐based tumor classification calculations for multiple collaborators in a DataSHIELD environment. The freely accessible web interface supports convenient data upload, result review, and summary report generation. Importantly, increasing sample size as achieved through distributed access to additional datasets allows DistSNE to improve cluster analysis and enhance predictive power. Collectively, DistSNE enables a simple and fast classification of CNS tumors using large‐scale methylation data from distributed sources, while maintaining the privacy and allowing easy and flexible network expansion to other institutes. This approach holds great potential for advancing human brain tumor classification and fostering collaborative precision medicine in neuro‐oncology. [ABSTRACT FROM AUTHOR]

[Display omitted] • Molecular systematic revision of all but three European Nannospalax taxa. • Evolutionary history of Nannospalax (superspecies leucodon) sensu lato. • Statistical species delimitation helps to define species limits. • Three superspecies, 11 species and several additional subspecies recognised. Species delimitation is a powerful approach to assist taxonomic decisions in challenging taxa where species boundaries are hard to establish. European taxa of the blind mole rats (genus Nannospalax) display small morphological differences and complex chromosomal evolution at a shallow evolutionary divergence level. Previous analyses led to the recognition of 25 'forms' in their distribution area. We provide a comprehensive framework to improve knowledge on the evolutionary history and revise the taxonomy of European blind mole rats based on samples from all but three of the 25 forms. We sequenced two nuclear-encoded genetic regions and the whole mitochondrial cytochrome b gene for phylogenetic tree reconstructions using concatenation and coalescence-based species-tree estimations. The phylogenetic analyses confirmed that Aegean N. insularis belongs to N. superspecies xanthodon , and that it represents the second known species of this superspecies in Europe. Mainland taxa reached Europe from Asia Minor in two colonisation events corresponding to two superspecies-level taxa: N. superspecies monticola (taxon established herewith) reached Europe c. 2.1 million years ago (Mya) and was followed by N. superspecies leucodon (re-defined herewith) c. 1.5 Mya. Species delimitation allowed the clarification of the taxonomic contents of the above superspecies. N. superspecies monticola contains three species geographically confined to the western periphery of the distribution of blind mole rats, whereas N. superspecies leucodon is more speciose with six species and several additional subspecies. The observed geographic pattern hints at a robust peripatric speciation process and rapid chromosomal evolution. The present treatment is thus regarded as the minimum taxonomic content of each lineage, which can be further refined based on other sources of information such as karyological traits, crossbreeding experiments, etc. The species delimitation models also allowed the recognition of a hitherto unnamed blind mole rat taxon from Albania, described here as a new subspecies. [ABSTRACT FROM AUTHOR]

A new population of blind mole rat (genus Nannospalax) was discovered near the town of Albertirsa in north-central Hungary. We used newly designed primers to specifically amplify the whole mitochondrial cytochrome-b region and two nuclear DNA regions. Based on the most comprehensive taxonomic sampling to date, we compared this population with several other European blind mole-rat taxa. The results from both mitochondrial and nuclear regions have unequivocally placed the Albertirsa population into the monophyletic group of the Vojvodina blind mole rat (N. (leucodon) montanosyrmiensis), which turned out to be a sister clade to all other molecularly studied European Nannospalax. This study not only identified the fourth known population of an extremely rare rodent taxon but also calls for a taxonomic revision of European lesser blind mole rats (N. leucodon superspecies) to systematically evaluate the genetic structure of their populations and to understand the complex evolutionary history of these European rodents. The occurrence of the Vojvodina blind mole rat at this northern location helps to clarify the distribution area of this heavily data-deficient taxon. As currently understood, this lineage predominantly occurs in sandy grasslands of the Danube-Tisza Interfluve in Hungary and Serbia. Its distribution range and phylogenetic structure might reflect the importance of potential biogeographical barriers (e.g. large rivers) that shaped the blind mole rats' allopatric or peripatric speciation. [ABSTRACT FROM AUTHOR]

The nucleolus is the largest nuclear sub-compartment in which the early steps of ribosome biogenesis take place. It also plays an essential role in the assembly and function of non-ribosomal ribonucleoprotein (RNP) complexes, controls cell cycle progression and senses environmental stress. The spatial organization and dynamics of nucleolar proteins and RNA is regulated at different structural levels, which finally determine nucleolar architecture. The intimate link between nucleolar structure and function is reflected by transcription-dependent changes in nucleolus-associated chromatin, overall morphological alterations in response to external cues, and the liquid droplet-like behavior of nucleolar compartments. Here we provide a concise overview of the latest studies which integrate novel trends in nucleolar architecture research into the context of cell biology. [ABSTRACT FROM AUTHOR]

Mammals are a key target group for conservation biology. Insights into the patterns and timing of and driving forces behind their past extinctions help us to understand their present, and to predict and mitigate their future biodiversity loss. Much research has been focused on the intensely debated megafaunal extinctions at the Pleistocene-Holocene transition, whereas the Holocene mammal extinctions have remained less studied., Here, we consider the Holocene extinctions of mammal taxa in the Carpathian Basin, a distinctive and biogeographically well-constrained predominantly lowland region in Central Europe. For the first time, we combine data from palaeontological, archaeozoological, and historical sources for a comprehensive analysis., A total of 11 mammal species, including steppe-dwelling rodents, large carnivores and herbivores, disappeared from the Carpathian Basin during the Holocene. The extinctions are interpreted in the framework of changing habitats and ecosystems, as grasslands and open forests vanished at the westernmost limits of the Eurasian steppe., The temporal distribution of extinctions is non-random; most taxon range terminations are concentrated around two discrete events. Members of the steppe community disappeared between 5000 and 4000 BP, around the Copper Age-Bronze Age transition. Large herbivores that found refugia in the forests vanished later, between the 16th and 18th centuries AD. The steppe, forest-steppe ecosystems of the Carpathian Basin suffered a considerable loss in their mammalian fauna, which has significant implications for conservation efforts for the existing similar dry, open habitats in western Eurasia., Further research and better age constraints are needed to establish the causes of extinctions more firmly, but the lack of synchronous and severe climate and vegetation changes and the coincidence with transformations in human history suggest the prime role of anthropogenic disturbance. We conclude that there were two waves of Holocene mammal extinctions of megafaunal character in the Carpathian Basin. [ABSTRACT FROM AUTHOR]

Ion implantation has been a key technology for the controlled surface modification of materials in microelectronics and generally, for tribology, biocompatibility, corrosion resistance and many more. To form shallow junctions in Ge is a challenging task. In this work the formation and accumulation of shallow damage profiles was studied by in-situ spectroscopic ellipsometry (SE) for the accurate tracking and evaluation of void and damage fractions in crystalline Ge during implantation of 200-keV Sb + ions with a total fluence up to 1016 cm−2 and an ion flux of 2.1 × 1012 cm−2s−1. The consecutive stages of damage accumulation were identified using optical multi-layer models with quantitative parameters of the thickness of modified layers as well as the volume fractions of amorphized material and voids. The effective size of damaged zones formed from ion tracks initiated by individual bombarding ions can be estimated by numerical simulation compared with the dynamics of damage profiles measured by ion beam analysis and ellipsometry. According to our observations, the formation of initial partial disorder was followed by complete amorphization and void formation occurring at the fluence of about 1 × 1015 cm−2, leading to a high volume fraction of voids and a modified layer thickness of ≈200 nm by the end of the irradiation process. This agrees with the results of numerical simulations and complementary scanning electron microscopy (SEM) measurements. In addition, we found a quasi-periodic time dependent behavior of amorphization and void formation represented by alternating accelerations and decelerations of different reorganization processes, respectively. For the understanding and prevention of adverse void formation and for controlled evolution of subsurface nanocavities or cellular surface texture the in-situ monitoring of the dynamics of structural damage accumulation by the developed SE method is essential. [ABSTRACT FROM AUTHOR]

Being totally blind with no tail or pinnae, blind mole rats are the most specialised rodents for the subterranean lifestyle. However, they come to the surface occasionally due to unusual climatic events, for foraging, to collect hay for bedding material, for dispersal as subadults, due to intraspecific aggression, and in illness., The only previous review suggests that surface activity of and predation on blind mole rats is rare and that they are preyed on mainly at night by owls., Based on 57 scientific publications, 14 unpublished reports and several personal observations (from 15 countries), the present review reveals that altogether 26 species of bird and mammal prey on blind mole rats either regularly or occasionally. It is evidenced that not only the number of predators, but also the importance of blind mole rats in their diet has been seriously underestimated., The tight relationship between the colour of the soil and the colour of the pelage of blind mole rats suggests the importance of diurnal raptors via their selective impact. Predation by mammals happens relatively often, and mustelids hunt blind mole rats not only on the surface, but probably also inside their burrows. The labyrinth-like structure of the burrows may play a vital role in confusing mammalian predators trying to hunt inside the burrows, and may increase the blind mole rat's chance of escape., With the proven importance of blind mole rats as a food resource for several threatened species of birds of prey, the survival, reproductive success, and population size of these species may partly depend on the density of the rodents. Although many species within the blind mole rat subfamily are themselves threatened to various extents, the role of blind mole rat populations in carnivore and raptor conservation should be considered and evaluated. [ABSTRACT FROM AUTHOR]

As a result of their rather uniform external appearance and gross cranial morphology, the systematics of blind mole rats has been hotly debated over the last century; however, the separation of the large-bodied and small-bodied blind mole rats at the genus level ( Spalax and Nannospalax, respectively), suggested earlier on morphological grounds, is strongly supported by recent molecular biological evidence. The species of Spalax have so far been distinguished from each other by cranial traits only, especially the outline of sutures of the cranium, and the shape and relative size of the nasal and parietal bones. Based on mitochondrial DNA sequences (with the widest taxonomic and geographic coverage so far) and detailed anatomical comparisons of museum specimens, we herewith provide a revision of the taxonomic and phylogenetic status of the westernmost representative of the genus, Spalax graecus s.l. We clarify that antiquus and istricus - presently regarded as synonyms of graecus - are well-defined species, and they together form a separate clade within Spalax. The robustness of our conclusions is supported by the combined evidence of morphology, multilocus phylogeny, species distribution, and taxon history (species congruence with past tectonic and climate events). © 2013 The Linnean Society of London [ABSTRACT FROM AUTHOR]

Abstract: Background and objectives: In obsessive-compulsive disorder (OCD), amplified moral sensitivity may be related to the orbitofrontal–striatal circuit, which is also critical in reversal learning. This study examined three questions: (1) What aspects of ethical sensitivity is altered in OCD?; (2) What is the relationship between ethical sensitivity and reversal learning?; (3) Are potential alterations in ethical sensitivity and reversal learning present in generalized anxiety disorder (GAD)? Methods: Participants were 28 outpatients with OCD, 21 individuals with GAD, and 30 matched healthy controls. Participants received the Ethical Sensitivity Scale Questionnaire (ESSQ), rating scales for clinical symptoms, a reversal learning task, and the Wisconsin Card Sorting Test (WCST). Results: We found higher ethical sensitivity scores in OCD compared with healthy controls in the case of generating interpretations and options and identifying the consequences of actions. Individuals with OCD displayed prolonged reaction times on probabilistic errors without shift and final reversal errors. Participants with GAD did not differ from healthy controls on the ESSQ, but they were slower on reversal learning relative to nonpatients. In OCD, reaction time on final reversal errors mediated the relationship between ethical sensitivity and compulsions. WCST performance was intact in OCD and GAD. Limitations: Small sample size, limited neuropsychological assessment, self-rating scale for ethical sensitivity. Conclusion: Prolonged reaction time at switching reinforcement contingencies is related to increased ethical sensitivity in OCD. Slow affective switching may link ethical sensitivity and compulsions. [Copyright &y& Elsevier]

Enhancers and promoters often contain multiple binding sites for the same transcription factor, suggesting that homotypic clustering of binding sites may serve a role in transcription regulation. Here we show that clustering of binding sites for the transcription termination factor TTF-I downstream of the pre-rRNA coding region specifies transcription termination, increases the efficiency of transcription initiation and affects the three-dimensional structure of rRNA genes. On chromatin templates, but not on free rDNA, clustered binding sites promote cooperative binding of TTF-I, loading TTF-I to the downstream terminators before it binds to the rDNA promoter. Interaction of TTF-I with target sites upstream and downstream of the rDNA transcription unit connects these distal DNA elements by forming a chromatin loop between the rDNA promoter and the terminators. The results imply that clustered binding sites increase the binding affinity of transcription factors in chromatin, thus influencing the timing and strength of DNA-dependent processes. [ABSTRACT FROM AUTHOR]

The concept of climate variability facilitating adaptive radiation supported by the ''Court Jester'' hypothesis is disputed by the ''Red Queen'' one, but the prevalence of one or the other might be scale-dependent. We report on a detailed, comprehensive phylo-geographic study on the ,4 kb mtDNA sequence in underground blind mole rats of the family Spalacidae (or subfamily Spalacinae) from the East Mediterranean steppes. Our study aimed at testing the presence of periodicities in branching patterns on a constructed phylogenetic tree and at searching for congruence between branching events, tectonic history and paleoclimates. In contrast to the strong support for the majority of the branching events on the tree, the absence of support in a few instances indicates that network-like evolution could exist in spalacids. In our tree, robust support was given, in concordance with paleontological data, for the separation of spalacids from muroid rodents during the first half of the Miocene when open, grass-dominated habitats were established. Marine barriers formed between Anatolia and the Balkans could have facilitated the separation of the lineage ''Spalax'' from the lineage ''Nannospalax'' and of the clade ''leucodon'' from the clade ''xanthodon''. The separation of the clade ''ehrenbergi'' occurred during the late stages of the tectonically induced uplift of the Anatolian high plateaus and mountains, whereas the separation of the clade ''vasvarii'' took place when the rapidly uplifting Taurus mountain range prevented the Mediterranean rainfalls from reaching the Central Anatolian Plateau. The separation of Spalax antiquus and S. graecus occurred when the southeastern Carpathians were uplifted. Despite the role played by tectonic events, branching events that show periodicity corresponding to 400-kyr and 100-kyr eccentricity bands illuminate the important role of orbital fluctuations on adaptive radiation in spalacids. At the given scale, our results supports the ''Court Jester'' hypothesis over the ''Red Queen'' one. [ABSTRACT FROM AUTHOR]

The nucleolus is the largest compartment of the cell nucleus and is where ribosomal RNAs (rRNAs) are synthesized, processed and assembled with ribosomal proteins. In addition to rRNA gene clusters that build the core of this subnuclear structure, nucleoli are associated with condensed chromatin. Although the higher order structures of rRNA genes and nucleolus-associated chromatin have been studied for decades, detailed molecular insights into the constituents and organization of the nucleolar genome are only beginning to emerge. Here, we summarize current views on the structural organization of nucleolar DNA and on the targeting and anchoring of chromatin domains to this subnuclear compartment. [ABSTRACT FROM AUTHOR]

We report for the first time the genomics of a nuclear compartment of the eukaryotic cell. 454 sequencing and microarray analysis revealed the pattern of nucleolus-associated chromatin domains (NADs) in the linear human genome and identified different gene families and certain satellite repeats as the major building blocks of NADs, which constitute about 4% of the genome. Bioinformatic evaluation showed that NAD-localized genes take part in specific biological processes, like the response to other organisms, odor perception, and tissue development. 3D FISH and immunofluorescence experiments illustrated the spatial distribution of NAD-specific chromatin within interphase nuclei and its alteration upon transcriptional changes. Altogether, our findings describe the nature of DNA sequences associated with the human nucleolus and provide insights into the function of the nucleolus in genome organization and establishment of nuclear architecture. [ABSTRACT FROM AUTHOR]

The article presents a study that deals with the extinction risks of the mole rats in the Carpathian basin. The authors describe the species as a collection of various small-range chromosomal forms of unresolved taxonomy. Despite the threat of extinction, the authors argue that no effort is being made to conserve the four chromosomal forms of the species. The authors present a preliminary extinction risk-assessment and revealed that one of the chromosomal forms is categorized as Vulnerable, Endangered and Data Deficient.

Ribosomal RNA synthesis is the eukaryotic cell's main transcriptional activity, but little is known about the chromatin domain organization and epigenetics of actively transcribed rRNA genes. Here, we show epigenetic and spatial organization of mouse rRNA genes at the molecular level. TTF-I-binding sites subdivide the rRNA transcription unit into functional chromatin domains and sharply delimit transcription factor occupancy. H2A.Z-containing nucleosomes occupy the spacer promoter next to a newly characterized TTF-I-binding site. The spacer and the promoter proximal TTF-I-binding sites demarcate the enhancer. DNA from both the enhancer and the coding region is hypomethylated in actively transcribed repeats. 3C analysis revealed an interaction between promoter and terminator regions, which brings the beginning and end of active rRNA genes into close contact. Reporter assays show that TTF-I mediates this interaction, thereby linking topology and epigenetic regulation of the rRNA genes. [ABSTRACT FROM AUTHOR]

Chromosomal rearrangements apparently account for the presence of a primate-specific gene (protease serine 3) in chromosome 9. This gene encodes, as the result of alternative splicing, both mesotrypsinogen and trypsinogen 4. Whereas mesotrypsinogen is known to be a pancreatic protease, neither the chemical nature nor biological function of trypsinogen 4 has been explored previously. The trypsinogen 4 sequence contains two predicted translation initiation sites: an AUG site that codes for a 72-residue leader peptide on Isoform A, and a CUG site that codes for a 28-residue leader peptide on Isoform B. We report studies that provide evidence for the N-terminal amino acid sequence of trypsinogen 4 and the possible mechanism of expression of this protein in human brain and transiently transfected cells. We raised mAbs against a 28-amino acid synthetic peptide representing the leader sequence of Isoform B and against recombinant trypsin 4. By using these antibodies, we isolated and chemically identified trypsinogen 4 from extracts of both post mortem human brain and transiently transfected HeLa cells. Our results show that Isoform B, with a leucine N terminus, is the predominant (if not exclusive) form of the enzyme in post mortem human brain, but that both isoforms are expressed in transiently transfected cells. On the basis of our studies on the expression of a series of trypsinogen 4 constructs in two different cell lines, we propose that unconventional translation initiation at a CUG with a leucine, rather than a methionine, N terminus may serve as a means to regulate protein expression. [ABSTRACT FROM AUTHOR]

A 10 kDa dynein light chain (DLC), previously identified as a tail light chain of myosin Va, may function as a cargo-binding and/or regulatory subunit of both myosin and dynein. Here, we identify and characterize the binding site of DLC on myosin Va. Fragments of the human myosin Va tail and the DLC2 isoform were expressed, and their complex formation was analyzed by pull-down assays, gel filtration, and spectroscopic methods. DLC2 was found to bind as a homodimer to a ~15 residue segment (11e1280-11e1294) localized between the medial and distal coiled-coil domains of the tail. The binding region contains the three residues coded by the alternatively spliced exon B (Asp 1284-Lys 1286). Removal of exon B eliminates DLC2 binding. Co-localization experiments in a transfected mammalian cell line confirm our finding that exon B is essential for DLC2 binding. Using circular dichroism, we demonstrate that binding of DLC2 to a ~85 residue disordered domain (Pro1235-Arg1320) induces some helical structure and stabilizes both flanking coiled-coil domains (melting temperature increases by ~7 °C). This result shows that DLC2 promotes the assembly of the coiled-coil domains of myosin Va. Nuclear magnetic resonance spectroscopy and docking simulations show that a 15 residue peptide (Ile1280-Ile1294) binds to the surface grooves on DLC2 similarly to other known binding partners of DLCs. When our data are taken together, they suggest that exon B and its associated DLC2 have a significant effect on the structure of parts of the coiled-coil tail domains and such a way could influence the regulation and cargo-binding function of myosin Va. [ABSTRACT FROM AUTHOR]

The rRNA gene cluster consists of multiple transcription units. Half of these are active, while the other half are transcriptionally inactive. Previously, in vivo studies have demonstrated that silencing of ribosomal DNA (rDNA) is mediated by the chromatin remodeling NoRC (nucleolar remodeling complex). To explore the mechanisms underlying NoRC-directed silencing of rDNA transcription, we investigated the effect of recombinant NoRC on RNA polymerase I transcription on reconstituted chromatin templates. We show that NoRC interacts with the transcription terminator factor (TTF-I), and this interaction is required both for the binding of TTF-I to its promoter-proximal target site and for the recruitment of NoRC to the promoter. After association with the rDNA promoter, NoRC alters the position of the promoter-bound nucleosome, thereby repressing RNA polymerase I transcription. This NoRC-directed rDNA repression requires the N terminus of histone H4. Repression is effective before preinitiation complex formation and as such is unable to exert an effect upon activated rDNA genes. Furthermore, the early steps of rDNA repression do not depend on DNA and histone modifications. These results reveal an important role for TFF-I in recruiting NoRC to rDNA and an active role for NoRC in the establishment of rDNA silencing. [ABSTRACT FROM AUTHOR]

DNA packaged into chromatin is the physiologically relevant substrate for all DNA-dependent processes inside the nuclei of eukaryotic cells. The highly compacted structures of DNA and histones is inherently repressive for all DNA-dependent processes. Active mechanisms exist to generate dynamic chromatin, which maintains two apparently contradictory functions: tight compaction and free accessibility of DNA. The dynamics of chromatin higher order folding and the influence of chromatin structure on transcription will be described in this paper. Chromatin dynamics and higher order folding may be the key regulators of not only transcription but of all DNA-dependent processes in the nucleus. [ABSTRACT FROM AUTHOR]

Sand waves form a prominent regular pattern in the offshore seabed of sandy shallow seas. The positions of sand-wave crests and troughs slowly change in time. Sand waves are usually assumed to migrate in the direction of the residual current. This paper considers the physical mechanisms that may cause sand waves to migrate and methods to quantify the associated migration rates. We carried out a theoretical study based on the assumption that sand waves evolve as free instabilities of the system. A linear stability analysis was then performed on a 2DV morphological model describing the interaction between the vertically varying water motion and an erodible bed in a shallow sea. Here, we disrupted the basic tidal symmetry by choosing a combination of a steady current (M0) and a sinusoidal tidal motion (M2) as the basic flow. We allowed for two different physical mechanisms to generate the steady current: a sea surface wind stress and a pressure gradient. The results show that similar sand waves develop for both flow conditions and that these sand waves migrate slowly in the direction of the residual flow. The rates of migration and wavelengths found in this work agree with theoretical and empirical values reported in the literature. [Copyright &y& Elsevier]

Some structural features underlying the increased thermostability of enzymes from thermophilic organisms relative to their homologues from mesophiles are known from earlier studies. We used cellulase C from Clostridium thermocellum to test whether thermostability can be increased by mutations designed using rules learned from thermophilic proteins. Cellulase C has a TIM barrel fold with an additional helical subdomain. We designed and produced a number of mutants with the aim to increase its thermostability. Five mutants were designed to create new electrostatic interactions. They all retained catalytic activity but exhibited decreased thermostability relative to the wild-type enzyme. Here, the stabilizing contributions are obviously smaller than the destabilization caused by the introduction of the new side chains. In another mutant, the small helical subdomain was deleted. This mutant lost activity but its melting point was only 3 °C lower than that of the wild-type enzyme, which suggests that the subdomain is an independent folding unit and is important for catalytic function. A double mutant was designed to introduce a new disulfide bridge into the enzyme. This mutant is active and has an increased stability (ΔTm=3 °C, Δ(ΔGu)=1.73 kcal/mol) relative to the wild-type enzyme. Reduction of the disulfide bridge results in destabilization and an altered thermal denaturation behavior. We conclude that rules learned from thermophilic proteins cannot be used in a straightforward way to increase the thermostability of a protein. Creating a crosslink such as a disulfide bond is a relatively sure-fire method but the stabilization may be smaller than calculated due to coupled destabilizing effects. [Copyright &y& Elsevier]

This article explores the distribution and composition of the ferritin complex in the adult brain and its connection to neuroferritinopathy (NF), a type of neurodegeneration with brain iron accumulation (NBIA). NF is characterized by symptoms like movement disturbances and tremors. The study identifies a novel variant in the ferritin heavy chain gene (FTH1) that is associated with NF and provides insights into the role of ferritin in both healthy and diseased brains. The authors, a diverse group of researchers, present their findings in a respectful and culturally sensitive manner, making this report a valuable resource for library patrons researching this topic. [Extracted from the article]

The nucleolus, the largest subcompartment of the nucleus, stands out from the nucleoplasm due to its exceptionally high local RNA and low DNA concentrations. Within this central hub of nuclear RNA metabolism, ribosome biogenesis is the most prominent ribonucleoprotein (RNP) biogenesis process, critically determining the structure and function of the nucleolus. However, recent studies have shed light on other roles of the nucleolus, exploring the interplay with various noncoding RNAs that are not directly involved in ribosome synthesis. This review focuses on this intriguing topic and summarizes the techniques to study and the latest findings on nucleolar long noncoding RNAs (lncRNAs) as well as microRNAs (miRNAs) in the context of nucleolus biology beyond ribosome biogenesis. We particularly focus on the multifaceted roles of the nucleolus and noncoding RNAs in physiology and tumor biology. [ABSTRACT FROM AUTHOR]

Simple Summary: Meningioma is the most common primary intracranial tumor. DNA methylation-based subtyping, while highly useful for diagnosis and treatment planning, is costly and not widely available. Therefore, the identification of methylation classes based on histological sections would be highly beneficial as it could greatly support and accelerate diagnostic and treatment decisions. We developed and systematically evaluated an AI framework to perform the classification of the most prevalent methylation subtypes based on histological sections. The model achieved a balanced accuracy of 0.870 for benign-1 vs benign-2 and 0.749 for benign-1 vs. intermediate-A in a narrow validation set. Combined with the network's assessed focus on key tumor regions these results provide a promising proof-of-concept of such an AI-driven classification approach in precision medicine. Convolutional neural networks (CNNs) are becoming increasingly valuable tools for advanced computational histopathology, promoting precision medicine through exceptional visual decoding abilities. Meningiomas, the most prevalent primary intracranial tumors, necessitate accurate grading and classification for informed clinical decision-making. Recently, DNA methylation-based molecular classification of meningiomas has proven to be more effective in predicting tumor recurrence than traditional histopathological methods. However, DNA methylation profiling is expensive, labor-intensive, and not widely accessible. Consequently, a digital histology-based prediction of DNA methylation classes would be advantageous, complementing molecular classification. In this study, we developed and rigorously assessed an attention-based multiple-instance deep neural network for predicting meningioma methylation classes using tumor methylome data from 142 (+51) patients and corresponding hematoxylin-eosin-stained histological sections. Pairwise analysis of sample cohorts from three meningioma methylation classes demonstrated high accuracy in two combinations. The performance of our approach was validated using an independent set of 51 meningioma patient samples. Importantly, attention map visualization revealed that the algorithm primarily focuses on tumor regions deemed significant by neuropathologists, offering insights into the decision-making process of the CNN. Our findings highlight the capacity of CNNs to effectively harness phenotypic information from histological sections through computerized images for precision medicine. Notably, this study is the first demonstration of predicting clinically relevant DNA methylome information using computer vision applied to standard histopathology. The introduced AI framework holds great potential in supporting, augmenting, and expediting meningioma classification in the future. [ABSTRACT FROM AUTHOR]

Background: Bipolar disorder if untreated, has severe consequences: severe role impairment, higher health care costs, mortality and morbidity. Although effective treatment is available, the delay in diagnosis might be as long as 10–15 years. In this study, we aim at documenting the length of the diagnostic delay in Hungary and identifying factors associated with it. Methods: Kaplan-Meier survival analysis and Cox proportional hazards model was employed to examine factors associated with the time to diagnosis of bipolar disorder measured from the date of the first presentation to any specialist mental healthcare institution. We investigated three types of factors associated with delays to diagnosis: demographic characteristics, clinical predictors and patient pathways (temporal sequence of key clinical milestones). Administrative data were retrieved from specialist care; the population-based cohort includes 8935 patients from Hungary. Results: In the sample, diagnostic delay was 6.46 years on average. The mean age of patients at the time of the first bipolar diagnosis was 43.59 years. 11.85% of patients were diagnosed with bipolar disorder without any delay, and slightly more than one-third of the patients (35.10%) were never hospitalized with mental health problems. 88.80% of the patients contacted psychiatric care for the first time in outpatient settings, while 11% in inpatient care. Diagnostic delay was shorter, if patients were diagnosed with bipolar disorder by non-specialist mental health professionals before. In contrast, diagnoses of many psychiatric disorders received after the first contact were coupled with a delayed bipolar diagnosis. We found empirical evidence that in both outpatient and inpatient care prior diagnoses of schizophrenia, unipolar depression without psychotic symptoms, and several disorders of adult personality were associated with increased diagnostic delay. Patient pathways played an important role as well: the hazard of delayed diagnosis increased if patients consulted mental healthcare specialists in outpatient care first or they were hospitalized. Conclusions: We systematically described and analysed the diagnosis of bipolar patients in Hungary controlling for possible confounders. Our focus was more on clinical variables as opposed to factors controllable by policy-makers. To formulate policy-relevant recommendations, a more detailed analysis of care pathways and continuity is needed. [ABSTRACT FROM AUTHOR]

Mammalian chromosomes are organized in structural and functional domains of 0.1–10 Mb, which are characterized by high self-association frequencies in the nuclear space and different contact probabilities with nuclear sub-compartments. They exhibit distinct chromatin modification patterns, gene expression levels and replication timing. Recently, nucleolus-associated chromosomal domains (NADs) have been discovered, yet their precise genomic organization and dynamics are still largely unknown. Here, we use nucleolus genomics and single-cell experiments to address these questions in human embryonic fibroblasts during replicative senescence. Genome-wide mapping reveals 1,646 NADs in proliferating cells, which cover about 38% of the annotated human genome. They are mainly heterochromatic and correlate with late replicating loci. Using Hi-C data analysis, we show that interactions of NADs dominate interphase chromosome contacts in the 10–50 Mb distance range. Interestingly, only minute changes in nucleolar association are observed upon senescence. These spatial rearrangements in subdomains smaller than 100 kb are accompanied with local transcriptional changes. In contrast, large centromeric and pericentromeric satellite repeat clusters extensively dissociate from nucleoli in senescent cells. Accordingly, H3K9me3-marked heterochromatin gets remodelled at the perinucleolar space as revealed by immunofluorescence analyses. Collectively, this study identifies connections between the nucleolus, 3D genome structure, and cellular aging at the level of interphase chromosome organization. [ABSTRACT FROM AUTHOR]

Ribosomal RNA (rRNA) transcription by RNA polymerase I (Pol I) is the first key step of ribosome biogenesis. While the molecular mechanisms of rRNA transcription regulation have been elucidated in great detail, the functional organization of the multicopy rRNA gene clusters (rDNA) in the nucleolus is less well understood. Here we apply super-resolution 3D structured illumination microscopy (3D-SIM) to investigate the spatial organization of transcriptionally competent active rDNA chromatin at size scales well below the diffraction limit by optical microscopy. We identify active rDNA chromatin units exhibiting uniformly ring-shaped conformations with diameters of ~240 nm in mouse and ~170 nm in human fibroblasts, consistent with rDNA looping. The active rDNA chromatin units are clearly separated from each other and from the surrounding areas of rRNA processing. Simultaneous imaging of all active genes bound by Pol I and the architectural chromatin protein Upstream Binding Transcription Factor (UBF) reveals a random spatial orientation of regular repeats of rDNA coding sequences within the nucleoli. These observations imply rDNA looping and exclude potential formation of systematic spatial assemblies of the well-ordered repetitive arrays of transcription units. Collectively, this study uncovers key features of the 3D organization of active rDNA chromatin units and their nucleolar clusters providing a spatial framework of nucleolar chromatin organization at unprecedented detail. [ABSTRACT FROM AUTHOR]

The nucleolus is the site of ribosome biogenesis and forms around the actively transcribed ribosomal RNA (rRNA) genes. However, the nucleolus is also implicated in cell cycle regulation, tumour suppression and chromosome segregation and nucleolar disfunction is linked to a wide range of human diseases. Interestingly, the nucleolus is also required for genome reprogramming and the establishment of heterochromatin in the mammalian embryo. Mammalian oocytes contain a subnuclear structure that is believed to be the precursor of the functional nucleolus, the Nucleolar Precursor Body (NPB). But the NPB is also required for the organisation of the zygotic heterochromatin and the establishment of pluripotency. We found that disruption of the mouse Upstream Binding Factor (UBF (UBTF)) gene caused disassembly of somatic nucleoli and the accumulation of the key rRNA gene transcription factors into dense subnuclear foci resembling NPBs. Here we show that UBF deletion causes the rRNA genes to collapse onto their centromere-proximal chromosomal sites spatially distinct from NPB-like structures, and that these structures contain rRNA gene transcription factors but not all nucleolar proteins. We further find that embryonic NPBs and their surrounding heterochromatin are both disrupted in UBF-null mouse embryos. These embryos also display subnuclear foci containing the rRNA gene transcription factors and arrest development before completing the forth cleavage division. The data suggest that the rRNA gene transcription factors have an intrinsic ability to interact and form a discrete nuclear compartment even in the absence of any rRNA gene activity and that the formation or maintenance of the zygotic NPB and surrounding heterochromatin requires UBF. [ABSTRACT FROM AUTHOR]

Non-coding RNAs play a key role in organizing the nucleus into functional subcompartments. By combining fluorescence microscopy and RNA deep-sequencing-based analysis, we found that RNA polymerase II transcripts originating from intronic Alu elements (aluRNAs) were enriched in the nucleolus. Antisense-oligo-mediated depletion of aluRNAs or drug-induced inhibition of RNA polymerase II activity disrupted nucleolar structure and impaired RNA polymerase I-dependent transcription of rRNA genes. In contrast, over-expression of a prototypic aluRNA sequence increased both nucleolus size and levels of pre-rRNA, suggesting a functional link between aluRNA, nucleolus integrity and pre-rRNA synthesis. Furthermore, we show that aluRNAs interact with nucleolin and target ectopic genomic loci to the nucleolus. Our study suggests an aluRNA-based mechanism that links RNA polymerase I and II activities and modulates nucleolar structure and rRNA production. [ABSTRACT FROM AUTHOR]

Upstream Binding Factor (UBF) is a unique multi-HMGB-box protein first identified as a co-factor in RNA polymerase I (RPI/PolI) transcription. However, its poor DNA sequence selectivity and its ability to generate nucleosome-like nucleoprotein complexes suggest a more generalized role in chromatin structure. We previously showed that extensive depletion of UBF reduced the number of actively transcribed ribosomal RNA (rRNA) genes, but had little effect on rRNA synthesis rates or cell proliferation, leaving open the question of its requirement for RPI transcription. Using gene deletion in mouse, we now show that UBF is essential for embryo development beyond morula. Conditional deletion in cell cultures reveals that UBF is also essential for transcription of the rRNA genes and that it defines the active chromatin conformation of both gene and enhancer sequences. Loss of UBF prevents formation of the SL1/TIF1B pre-initiation complex and recruitment of the RPI-Rrn3/TIF1A complex. It is also accompanied by recruitment of H3K9me3, canonical histone H1 and HP1α, but not by de novo DNA methylation. Further, genes retain penta-acetyl H4 and H2A.Z, suggesting that even in the absence of UBF the rRNA genes can maintain a potentially active state. In contrast to canonical histone H1, binding of H1.4 is dependent on UBF, strongly suggesting that it plays a positive role in gene activity. Unexpectedly, arrest of rRNA synthesis does not suppress transcription of the 5S, tRNA or snRNA genes, nor expression of the several hundred mRNA genes implicated in ribosome biogenesis. Thus, rRNA gene activity does not coordinate global gene expression for ribosome biogenesis. Loss of UBF also unexpectedly induced the formation in cells of a large sub-nuclear structure resembling the nucleolar precursor body (NPB) of oocytes and early embryos. These somatic NPBs contain rRNA synthesis and processing factors but do not associate with the rRNA gene loci (NORs). [ABSTRACT FROM AUTHOR]

Abstract: Impairments in executive functioning have been identified as an underlying cause of Obsessive-Compulsive Disorder (OCD). Obsessive patients attempt to suppress certain unwanted thoughts through a mechanism that Wegner referred to as ‘chronic thought suppression’, whereas compulsive patients are unable to inhibit their rituals. We tested 51 OCD patients using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), the White Bear Suppression Inventory (WBSI) and the Dysexecutive Questionnaire (DEX). Executive functions were tested using a cognitive test battery. We found that the total WBSI score was correlated with the Y-BOCS obsessive score but not with the Y-BOCS compulsive score. A stronger correlation was observed between the Y-BOCS obsessive score and the ‘unwanted intrusive thoughts’ factor based on Blumberg's 3-factor model of the WBSI. The total WBSI score was not correlated with the cognitive test results. The DEX score was significantly correlated with the Y-BOCS compulsive score; however, no correlation was found between the DEX score and the Y-BOCS obsessive score. A stronger correlation was observed between the Y-BOCS compulsive score and the ‘inhibition’ component of the DEX score, as defined by Burgess's 5-factor model. The DEX scores were correlated with cognitive test results measuring attention, cognitive flexibility and inhibitory processes. We conclude that obsessions indicate a failure of cognitive inhibition but do not involve significant impairment of executive functions, whereas compulsions indicate ineffective behavior inhibition and impaired executive functions. [Copyright &y& Elsevier]

Several DNA cis-elements and trans-acting factors were described to be involved in transcription termination and to release the elongating RNA polymerases from their templates. Different models for the molecular mechanism of transcription termination have been suggested for eukaryotic RNA polymerase I (Pol I) from results of in vitro and in vivo experiments. To analyse the molecular requirements for yeast RNA Pol I termination, an in vivo approach was used in which efficient termination resulted in growth inhibition. This led to the identification of a Myb-like protein, Ydr026c, as bona fide termination factor, now designated Nsi1 (NTS1 silencing protein 1), since it was very recently described as silencing factor of ribosomal DNA. Possible Nsi1 functions in regard to the mechanism of transcription termination are discussed. [ABSTRACT FROM AUTHOR]

Ribosomal RNA gene transcription, co-transcriptional processing, and ribosome biogenesis are highly coordinated processes that are tightly regulated during cell growth. In this study we discovered that Mybbp1a is associated with both the RNA polymerase I complex and the ribosome biogenesis machinery. Using a reporter assay that uncouples transcription and RNA processing, we show that Mybbp1a represses rRNA gene transcription. In addition, overexpression of the protein reduces RNA polymerase I loading on endogenous rRNA genes as revealed by chromatin immunoprecipitation experiments. Accordingly, depletion of Mybbp1a results in an accumulation of the rRNA precursor in vivo but surprisingly also causes growth arrest of the cells. This effect can be explained by the observation that the modulation of Mybbp1a protein levels results in defects in pre-rRNA processing within the cell. Therefore, the protein may play a dual role in the rRNA metabolism, potentially linking and coordinating ribosomal DNA transcription and pre-rRNA processing to allow for the efficient synthesis of ribosomes. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate prospective memory (PM) function in patients with obsessive-compulsive disorder (OCD). An event-based PM task was administered to 30 OCD patients and 30 healthy adult participants. For OCD patients, PM instruction produced significantly more cost in terms of reaction time (RT) during the ongoing task. A significant group-experimental condition interaction in ongoing task RTs was found, which suggests that PM instruction loaded an extra cost onto OCD patients' ongoing activities, and this was independent of the execution of the PM intention. Comparing the PM task RTs between patients and healthy adults also revealed a significant group difference. These results suggest that OCD patients experience difficulties during PM tasks, and these difficulties originate from overmonitoring the stimuli for PM cues. [ABSTRACT FROM AUTHOR]

Abstract: Background: TEMPS-A (Temperament Evaluation of the Memphis, Pisa, Paris and San Diego — Autoquestionnaire) is a new self-assessed temperament 110-item scale with depressive (D), cyclothymic (C), hyperthymic (H), irritable (I) and anxious (A) subscales. To date, it has been translated into 25 languages, and validated in 10. The present Hungarian version provides the most complete external validation across the Beck Depression Scale (BDI), Profile of Mood States (POMS), the BarOn Emotional Quotient Inventory (BarOn EQ-i), Temperament and Character Inventory (TCI), and the NEO Personality Inventory — Revised (NEO-PI-R). We were particularly interested in concurrent validation against the TCI and the NEO-PI-R, the most important of the new personality instruments. Methods: 1132 clinically-well subjects (27% male) from the general population and university students (16–81 years) were administered the above scales and instruments. The data were tested with standard psychometric batteries. Results: Factor analysis revealed 5 factors approximating the original D, C, I, H, and A subscales, which in their superfactor confirmed an Emotional (D, C, I, A) vs. Hyperthymic structure. Except for the D (a =0.65), the Cronbach alpha for the remainder temperaments ranged from 0.75–0.81. Dominant temperaments ranged from the I (2.7%) to the C (4.2%); the highest prevalence was observed among men with C=6% and H=5.4%. The BDI and POMS correlated significantly with the relevant subscales, as did the BarOn. Of the many significant possible correlations with the TCI, the most noteworthy were novelty seeking and harm avoidance with D, A, C, as well as C, and persistence with H. As for the NEO-PI-R, we were struck by the positive correlation of openness with C, and conscientiousness negatively with C; most other positive correlations such as neuroticism with all temperaments but the hyperthymic were expected and strongly supportive of concurrent validity. Limitations: Higher educational background of the subjects studied relative to that of the general population of Hungary. The distribution of the data may have in some instances deviated somewhat from the underlying assumptions for the standard psychometric tests for normality. We did not conduct test–retest reliability. Conclusions: The factorial structure of the TEMPS-A shows good reliability and internal consistency. Although the superstructure is reminiscent of neuroticism–extraversion, within it are embedded discernible classical affective temperaments. A provocative finding is the high prevalence of cyclothymia in Hungarian males (6%), which is rather unique when compared with the other 10 countries studied to date. This finding, coupled with high male hyperthymia (5.4%), may explain the high lifetime prevalence of bipolar disorders reported from Hungary. Inter alia, our psychometric data along with the foregoing epidemiologic considerations, are very much in line with the cyclothymic-bipolar spectrum model proposed by the senior author [Akiskal, H.S., Djenderedjian, A.H., Rosenthal, R.H., Khani, M.K., 1977. Cyclothymic disorder: validating criteria for inclusion in the bipolar affective group. Am. J. Psychiatry 134, 1227–1233]. [Copyright &y& Elsevier]

A new method is presented for identifying potential pipeline problems, such as hazardous exposures. This method comprises a newly developed sand wave amplitude and migration model, and an existing pipeline–seabed interaction model. The sand wave migration model is based on physical principles and tuned with field data through data assimilation techniques. Due to its physical basis, this method is trusted to be more reliable than other, mostly engineering-based methods. The model describes and predicts the dynamics of sand waves and provides the necessary bed level input for the pipeline–seabed interaction model. The method was tested by performing a hindcast on the basis of survey data for a specific submarine gas pipeline, diameter 0.4 m, on the Dutch continental shelf. Good agreement was found with the observed seabed–pipeline levels. The applicability of the method was investigated further through a number of test cases. The self-lowering of the pipeline, in response to exposures due to sand wave migration, can be predicted, both effectively and efficiently. This allows the use of the method as a tool for pipeline operation, maintenance and abandonment. [Copyright &y& Elsevier]

The good control of the n -type doping is a key issue for the fabrication of efficient devices based on ε-Ga 2 O 3 epilayers. In this work we studied the possibility of doping the ε-Ga 2 O 3 thin films, epitaxially grown on c -oriented sapphire by metal-organic chemical vapor deposition, by means of a post-deposition treatment. For the first time, the n -type doping was achieved by depositing a tin-rich SnO 2 film on top of the ε-Ga 2 O 3 layer and keeping this bi-layer system for 4 h at a temperature of 600 °C in an evacuated furnace. The diffusion of Sn atoms into the ε-Ga 2 O 3 film is evidenced by time-of-flight secondary-ion mass spectrometry depth profiles. Room-temperature resistivity of the order of 1 Ω•cm is obtained and the electrical characterization revealed a conduction mechanism based on variable range hopping, according to the Mott's model. [Display omitted] [ABSTRACT FROM AUTHOR]

The multilayer of approximate structure MgO(100)/[nFe51Rh49(63 Å)/57Fe51Rh49(46 Å)]10 deposited at 200 °C is primarily of paramagnetic A1 phase and is fully converted to the magnetic B2 phase by annealing at 300 °C for 60 min. Subsequent irradiation by 120 keV Ne+ ions turns the thin film completely to the paramagnetic A1 phase. Repeated annealing at 300 °C for 60 min results in 100% magnetic B2 phase, i.e. a process that appears to be reversible at least twice. The A1 → B2 transformation takes place without any plane-perpendicular diffusion while Ne+ irradiation results in significant interlayer mixing. [ABSTRACT FROM AUTHOR]