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Background: Patient-focused approaches to capturing day-to-day variability in sleep disturbance are needed to properly evaluate the sleep benefits of new treatments. Such approaches rely on patient-reported outcome (PRO) measures validated in the target patient population. Methods: Using atopic dermatitis (AD) as an example of a disease in which sleep is commonly disturbed, we developed a strategy for measuring sleep disturbance in AD trials. In developing this strategy, we conducted a targeted literature review and held concept elicitation interviews with adolescents and adults with AD. We subsequently identified potentially suitable PRO measures and cognitively debriefed them. Finally, we evaluated their psychometric properties using data from phase 2b (NCT03100344) and phase 3 (NCT03985943 and NCT03989349) clinical trials. Results: The literature review confirmed that sleep disturbance is a key impact of AD but failed to identify validated PRO measures for assessing fluctuations in sleep disturbance. Subsequent concept elicitation interviews confirmed the multidimensional nature of sleep disturbance in AD and supported use of a single-item measure to assess overall sleep disturbance severity, complemented by a diary to capture individual components of sleep disturbance. The single-item sleep disturbance numerical rating scale (SD NRS) and multi-item Subject Sleep Diary (SSD)—an AD-adapted version of the Consensus Sleep Diary—were identified as potentially suitable PRO measures. Cognitive debriefing of the SD NRS and SSD demonstrated their content validity and their understandability to patients. Psychometric analyses based on AD trial data showed that the SD NRS is a well-defined, reliable, and fit-for-purpose measure of sleep disturbance in adults with AD. Furthermore, the SD NRS correlated with many SSD sleep parameters, suggesting that most concepts from the SSD can be covered using the SD NRS. Conclusions: Using these findings, we developed an approach for measuring sleep disturbance in AD trials. Subject to further research, the same approach could also be applied to future trials of other skin diseases where itch causes sleep disturbance. [ABSTRACT FROM AUTHOR]

Neuromyelitis optica is a paradigmatic autoimmune disease of the central nervous system, in which the water-channel protein AQP4 is the target antigen1. The immunopathology in neuromyelitis optica is largely driven by autoantibodies to AQP42. However, the T cell response that is required for the generation of these anti-AQP4 antibodies is not well understood. Here we show that B cells endogenously express AQP4 in response to activation with anti-CD40 and IL-21 and are able to present their endogenous AQP4 to T cells with an AQP4-specific T cell receptor (TCR). A population of thymic B cells emulates a CD40-stimulated B cell transcriptome, including AQP4 (in mice and humans), and efficiently purges the thymic TCR repertoire of AQP4-reactive clones. Genetic ablation of Aqp4 in B cells rescues AQP4-specific TCRs despite sufficient expression of AQP4 in medullary thymic epithelial cells, and B-cell-conditional AQP4-deficient mice are fully competent to raise AQP4-specific antibodies in productive germinal-centre responses. Thus, the negative selection of AQP4-specific thymocytes is dependent on the expression and presentation of AQP4 by thymic B cells. As AQP4 is expressed in B cells in a CD40-dependent (but not AIRE-dependent) manner, we propose that thymic B cells might tolerize against a group of germinal-centre-associated antigens, including disease-relevant autoantigens such as AQP4.The immune system is tolerized against the neuromyelitis optica autoantigen AQP4 by thymic B cells, which present their endogenous AQP4 to AQP4-reactive thymocytes. [ABSTRACT FROM AUTHOR]

The fossil vertebrate fauna of Máriahalom contains remains from a wide range of ecologies including terrestrial and aquatic mammals, crocodiles, sharks, and rays among others. All these were found mixed in mollusc-rich, shallow water, coastal deposits. The aim of the study is to trace the origin of the fossils using their rare earth element (REE) content and their respective ecology with stable oxygen isotopic compositions. In addition, marine vertebrates and calcareous marine fossils were analysed for their Sr isotope composition to provide a new age estimate for the locality. The REE content and their distribution in the fossils indicate similar early diagenetic environments and possible contemporaneous fossilization for the entire vertebrate assemblage. Reworked fossils of significantly different age can be excluded. The enamel/enameloid-derived phosphate oxygen isotope composition of selected fossil taxa fit well with previously inferred habitats that include marine, brackish, and terrestrial environments. Notably, the stem-pinniped Potamotherium valletoni is best interpreted as freshwater dweller instead of marine, consistent with the sedimentology of other occurrences. Our novel 87Sr/86Sr data suggest an Aquitanian age (21.4 ± 0.5 Ma) for the Máriahalom site that is younger than the previously proposed Late Oligocene age based on biostratigraphy (MP28–30 European Mammal Paleogene Reference Levels). An Aquitanian age raises the possibility that the index fossil taxon, the anthracothere mammal Microbunodon minimum, may have vanished earlier in Western Europe than in the Central Paratethys region. [ABSTRACT FROM AUTHOR]

The volcanic rocks of the Chon Aike Silicic Large Igneous Province (CASP) are recognized as magmas dominantly produced by crustal anatexis. Investigating the zircon of the CASP provides an opportunity to gain further insight into geochemical and isotopic differences of the potential magmatic sources (i.e., crust versus mantle), to identify crustal reservoirs that contributed to the felsic magmas during anatexis, and to quantify the contributions of the respective sources. We present a combined zircon oxygen and hafnium isotope and trace element dataset for 16 volcanic units of the two youngest volcanic phases in Patagonia, dated here with LA-ICP-MS U–Pb geochronology at ca. 148–153 Ma (El Quemado Complex, EQC) and ca. 159 Ma (western Chon Aike Formation, WCA). The EQC zircon have 18O-enriched values (δ18O from 7 to 9.5‰) with correspondingly negative initial εHf values (− 2.0 to − 8.0). The WCA zircon have δ18O values between 6 and 7‰ and εHf values ranging between − 4.0 and + 1.5. Binary δ18O-εHf mixing models require an average of 70 and 60% melt derived from partial melting of isotopically distinct metasedimentary basements for the EQC and WCA, respectively. Zircon trace element compositions are consistent with anatexis of sedimentary protoliths derived from LIL-depleted upper continental crustal sources. The overlap between a high heat flux environment (i.e., widespread extension and lithospheric thinning) during supercontinental breakup and a fertile metasedimentary crust was key in producing voluminous felsic volcanism via anatexis following the injection and emplacement of basaltic magmas into the lower crust. [ABSTRACT FROM AUTHOR]

The phenyl ring is a basic structural element in chemistry. Here, we show the design, synthesis, and validation of its new saturated bioisostere with improved physicochemical properties − 2-oxabicyclo[2.2.2]octane. The design of the structure is based on the analysis of the advantages and disadvantages of the previously used bioisosteres: bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, and cubane. The key synthesis step is the iodocyclization of cyclohexane-containing alkenyl alcohols with molecular iodine in acetonitrile. 2-Oxabicyclo[2.2.2]octane core is incorporated into the structure of Imatinib and Vorinostat (SAHA) drugs instead of the phenyl ring. In Imatinib, such replacement leads to improvement of physicochemical properties: increased water solubility, enhanced metabolic stability, and reduced lipophilicity. In Vorinostat, such replacement results in a new bioactive analog of the drug. This study enhances the repertoire of available saturated bioisosteres of (hetero)aromatic rings for the use in drug discovery projects. The phenyl ring is a basic structural element in chemistry. Here, the authors show the design, synthesis, and validation of 2-oxabicyclo[2.2.2]octane as a new saturated bioisostere with improved physicochemical properties [ABSTRACT FROM AUTHOR]

Proximity ligation approaches, which are widely used to study the spatial organization of the genome, also make it possible to reveal patterns of RNA-DNA interactions. Here, we use RedC, an RNA-DNA proximity ligation approach, to assess the distribution of major RNA types along the genomes of E. coli, B. subtilis, and thermophilic archaeon T. adornatum. We find that (i) messenger RNAs preferentially interact with their cognate genes and the genes located downstream in the same operon, which is consistent with polycistronic transcription; (ii) ribosomal RNAs preferentially interact with active protein-coding genes in both bacteria and archaea, indicating co-transcriptional translation; and (iii) 6S noncoding RNA, a negative regulator of bacterial transcription, is depleted from active genes in E. coli and B. subtilis. We conclude that the RedC data provide a rich resource for studying both transcription dynamics and the function of noncoding RNAs in microbial organisms. Mapping of RNA-DNA interactions in two bacteria and one archaeon using RedC, an RNA-DNA proximity ligation approach, uncovers major features that broadly characterize prokaryotic gene expression. [ABSTRACT FROM AUTHOR]

The results of the first direct experiments on the passage of pulses of ultra-wideband radiation of subnanosecond duration in the Earth's atmosphere at a distance of more than 10 km are presented. In contrast to the work calculated, the preservation of the amplitude–time shape of the pulses in the process of increasing the distance is shown. The establishment of this fact is of decisive importance in the practical application of ultra-wideband pulses in new technological developments. [ABSTRACT FROM AUTHOR]

The review is devoted to the patterns of evolution of α- and β-globin gene domains. A hypothesis is presented according to which segregation of the ancestral cluster of α/β-globin genes in Amniota occurred due to the performance by α-globins and β-globins of non-canonical functions not related to oxygen transport. [ABSTRACT FROM AUTHOR]

Awakening of zygotic transcription in animal embryos relies on maternal pioneer transcription factors. The interplay of global and specific functions of these proteins remains poorly understood. Here, we analyze chromatin accessibility and time-resolved transcription in single and double mutant zebrafish embryos lacking pluripotency factors Pou5f3 and Sox19b. We show that two factors modify chromatin in a largely independent manner. We distinguish four types of direct enhancers by differential requirements for Pou5f3 or Sox19b. We demonstrate that changes in chromatin accessibility of enhancers underlie the changes in zygotic expression repertoire in the double mutants. Pou5f3 or Sox19b promote chromatin accessibility of enhancers linked to the genes involved in gastrulation and ventral fate specification. The genes regulating mesendodermal and dorsal fates are primed for activation independently of Pou5f3 and Sox19b. Strikingly, simultaneous loss of Pou5f3 and Sox19b leads to premature expression of genes, involved in regulation of organogenesis and differentiation. Zygotic genome activation in zebrafish relies on pluripotency transcription factors Pou5f3 and Sox19b. Here the authors investigate how these factors interact in vivo by analyzing the changes in chromatin state and time-resolved transcription in Pou5f3 and Sox19b single and double mutant embryos. [ABSTRACT FROM AUTHOR]

The results of Monte Carlo simulation and test reflectometry experiments on the "Gorizont" neutron reflectometer (on the IN-06 pulsed neutron source at INR RAS) after its upgrade with a two-dimensional detector with a positioning system are presented. The two-dimensional detector makes it possible to use the instrument not only for neutron reflectometry, but also for small angle neutron scattering. Estimates of the instrument resolution and the spectra of the neutron beam at different collimations have been obtained using Monte Carlo simulation. Test reflectometry experiments have been performed on mirrors with known characteristics. The characteristics match the manufacturer's data with an error of 5%, obtained from the simulation. [ABSTRACT FROM AUTHOR]

Chromatin loops represent one of the major levels of hierarchical folding of the genome. Although the situation is evolving, current methods have various difficulties with the accurate mapping of loops even in mammalian Hi-C data, and most of them fail to identify chromatin loops in animal species with substantially different genome architecture. This paper presents the loop and significant contact annotation (LASCA) pipeline, which uses Weibull distribution-based modeling to effectively identify loops and enhancer–promoter interactions in Hi-C data from evolutionarily distant species: from yeast and worms to mammals. Available at: https://github.com/ArtemLuzhin/LASCA_pipeline. [ABSTRACT FROM AUTHOR]

Mammalian and Drosophila genomes are partitioned into topologically associating domains (TADs). Although this partitioning has been reported to be functionally relevant, it is unclear whether TADs represent true physical units located at the same genomic positions in each cell nucleus or emerge as an average of numerous alternative chromatin folding patterns in a cell population. Here, we use a single-nucleus Hi-C technique to construct high-resolution Hi-C maps in individual Drosophila genomes. These maps demonstrate chromatin compartmentalization at the megabase scale and partitioning of the genome into non-hierarchical TADs at the scale of 100 kb, which closely resembles the TAD profile in the bulk in situ Hi-C data. Over 40% of TAD boundaries are conserved between individual nuclei and possess a high level of active epigenetic marks. Polymer simulations demonstrate that chromatin folding is best described by the random walk model within TADs and is most suitably approximated by a crumpled globule build of Gaussian blobs at longer distances. We observe prominent cell-to-cell variability in the long-range contacts between either active genome loci or between Polycomb-bound regions, suggesting an important contribution of stochastic processes to the formation of the Drosophila 3D genome. Genomes are partitioned into topologically associating domains (TADs). Here the authors present single-nucleus Hi-C maps in Drosophila at 10 kb resolution, demonstrating the presence of chromatin compartments in individual nuclei, and partitioning of the genome into non-hierarchical TADs at the scale of 100 kb, which resembles population TAD profiles. [ABSTRACT FROM AUTHOR]

Chromatin communities stabilized by protein machinery play essential role in gene regulation and refine global polymeric folding of the chromatin fiber. However, treatment of these communities in the framework of the classical network theory (stochastic block model, SBM) does not take into account intrinsic linear connectivity of the chromatin loci. Here we propose the polymer block model, paving the way for community detection in polymer networks. On the basis of this new model we modify the non-backtracking flow operator and suggest the first protocol for annotation of compartmental domains in sparse single cell Hi-C matrices. In particular, we prove that our approach corresponds to the maximum entropy principle. The benchmark analyses demonstrates that the spectrum of the polymer non-backtracking operator resolves the true compartmental structure up to the theoretical detectability threshold, while all commonly used operators fail above it. We test various operators on real data and conclude that the sizes of the non-backtracking single cell domains are most close to the sizes of compartments from the population data. Moreover, the found domains clearly segregate in the gene density and correlate with the population compartmental mask, corroborating biological significance of our annotation of the chromatin compartmental domains in single cells Hi-C matrices. [ABSTRACT FROM AUTHOR]

The transition from a linear economy to a circular economy is a significant component of economic, environmental and social sustainability. Underground metro infrastructures such as tunnels can play a vital role in a circular economy, resulting in greater sustainability and less contribution to climate change. This paper presents numerical models of small-scale brick-lined railway tunnels to identify the critical locations, and then proposes corresponding circular approaches and solutions for the design, maintenance, life extension and end-of-service-life (EoSL) stages of underground infrastructures. The proposed numerical model is firstly verified with respect to the relevant experimental model based on tests under various loading conditions. The results demonstrate that detailed failure processes can be realistically captured by the numerical model, while the macroscopic behaviour compares well with experimental observations. Numerical modelling and subsequent prediction stand out as a practical approach and a powerful performance-based tool for analysing the reuse/recycling potential of metro tunnels and then carrying out easy repair and design for adaptability, disassembly and recoverability of underground infrastructures for a circular economy. [ABSTRACT FROM AUTHOR]

The development of new research methods significantly changed our views on the role that the 3D organization of the genome plays in its functional activity. It was found that the genome is subdivided into structural-functional units that restrict the area of enhancer action at the level of spatial organization. Spatial reconfiguration of an extended genomic fragment was identified as a potential mechanism that activates or represses various genes. Accordingly, a distorted spatial organization of the genome often causes various diseases, including cancer. All these observations contributed to the emergence of 3D genomics as a new avenue of research. The review summarizes the most important discoveries in the field of 3D genomics and discusses the directions of its further development. [ABSTRACT FROM AUTHOR]

The procedure for the numerical study of the stress-strain state and the stability of the mesh structures of polymer composite materials under intensive force and thermal effects is considered. A simplified mathematical model of the thermomechanical behavior of the mesh structure is proposed, taking into account the reversible and irreversible changes in the physicome-chanical properties of the material during heating. The design process of computational algorithms is described. [ABSTRACT FROM AUTHOR]

The Variscan orogen in southeast Europe is exposed in isolated remnants, affected by a subsequent Alpine tectono-magmatic overprint. Unlike the central European Variscides, in SE Europe the juxtaposition and correlation of the events and products are impeded by the scarcity of Variscan domains with preserved magmatic, metamorphic, sedimentological and structural characteristics. To reveal the particular evolution of the Variscan orogen in Balkan Mts, we present the results of ID-TIMS and LA-ICP-MS dating of three potassic-alkaline intrusions: Svidnya, Buhovo-Seslavtsi and Shipka. The age determinations from the plutons do not permit to establish their unequivocal ages, but they bracket the time interval of emplacements. Based on geochronological, tectonic and stratigraphic evidence the emplacement interval for plutons could be: 317-310 Ma for Svidnya, 330-310 Ma for Buhovo-Seslavtsi and 320-303 Ma for Shipka. These results show that the generation of potassic-alkaline magmas was post-Visean and is contemporaneous with the adjacent numerous calc-alkaline granitoid plutons. Thus, the Variscan orogen in the Balkan Mts is not characterized by a time-dependent geochemical evolution of magma generation. Hence, the observed differences in the rocks’ compositions can be interpreted solely by distinction between the magma sources. The available data for both potassic-alkaline and calc-alkaline rocks indicate that the major episodes of crustal stacking and shearing in the Balkan part of the Variscan edifice are pre-Visean (~330 Ma). The present study reveals that the potassic-alkaline rocks from the Balkan Mts are younger than the central European potassic granitoids (durbachites). It suggests that melting of enriched mantle source took place at different times throughout the Variscan orogen. In spite of the alkaline character of the magmas, the studied zircons show a complex nature, with inherited cores and magmatic overgrowths. The observed heterogeneities in the zircons imply the presence of much older materials in the petrogenesis of the rocks from the potassic-alkaline plutons. [ABSTRACT FROM AUTHOR]

Nuclear lamina is a protein meshwork composed of lamins and lamin-associated proteins that lines the nuclear envelope from the inside and forms repressive transcription compartment. The review presents current data on the contribution of nuclear lamina to the repression of genes located in this compartment and on the mechanisms of chromatin attachment to the nuclear envelope. [ABSTRACT FROM AUTHOR]

Vertebrates have multiple forms of hemoglobin that differ in the composition of their polypeptide chains. During ontogenesis, the composition of these subunits changes. Genes encoding different α- and β-polypeptide chains are located in two multigene clusters on different chromosomes. Each cluster contains several genes that are expressed at different stages of ontogenesis. The phenomenon of stage-specific transcription of globin genes is referred to as globin gene switching. Mechanisms of expression switching, stage-specific activation, and repression of transcription of α- and β-globin genes are of interest from both theoretical and practical points of view. Alteration of balanced expression of globin genes, which usually occurs due to damage to adult β-globin genes, leads to development of severe diseases-hemoglobinopathies. In most cases, reactivation of the fetal hemoglobin gene in patients with β-thalassemia and sickle cell disease can reduce negative consequences of irreversible alterations of expression of the β-globin genes. This review focuses on the current state of research on genetic and epigenetic mechanisms underlying stage-specific switching of β-globin genes. [ABSTRACT FROM AUTHOR]

The Morcles microgranite is located in the N-E termination of the Aiguilles Rouges massif (External Crystalline Massifs, Switzerland). It outcrops as dykes, a few meters to 150 m in thickness, intruding the Aiguilles Rouges polymetamorphic basement, and presents variation of texture from granophyric to rhyolitic. We present here for the first time, in situ U-Pb zircon dating of the Morcles microgranite/rhyolite based on laser-ablation—inductively coupled plasma—mass spectrometry (LA-ICP-MS) data. Results indicate late Variscan emplacement ages at ~303 and ~309-312 Ma, a major Caledonian inherited component age at ~445-460 Ma, and secondary inherited ages ranging from Pan-African (550-1000 Ma) to Paleoproterozoic (2.3 Ga). Geochronological and geochemical data indicate that the Morcles microgranite/rhyolite shares a common origin with the higher (or “H”) facies of the neighbouring Vallorcine granitic intrusion. This close affinity is further corroborated by the geographical alignment of both intrusive bodies on either side of the Rhone Valley. The fine-grained texture of the microgranite groundmass and the rhyolite indicates a very rapid cooling rate and emplacement close to the surface, suggesting that the Morcles microgranite/rhyolite may constitute the shallow-level counterpart of the Vallorcine granite. The mineralogical assemblages observed in the Morcles microgranite/rhyolite support the idea of high-temperature melting conditions provided by underplating of mantle-derived magmas during the Carboniferous extension of the Variscan cordillera. [ABSTRACT FROM AUTHOR]

Authigenic phosphate mineralization was first studied on the territory of Russia on the basis of the Holocene and Pleistocene deposits of Denisova Cave. The formation of phosphates in the eastern gallery is related to biodegradation of the horizons of guano of insectivorous bats, which inhabited the cave in the absence man. The results confirmed the archaeological record of the Holocene and the upper part of Pleistocene sequences of the eastern gallery. [ABSTRACT FROM AUTHOR]

The Pınarbaşı Mo-Cu prospect is hosted within the Pınarbaşı intrusion, which is exposed together with the NW-SE-trending Koyunoba, Eğrigöz, and Baklan plutons along the northeastern border of the Menderes massif. The Pınarbaşı intrusion predominantly comprises monzonite, porphyritic granite, and monzodiorite. All units of the Pınarbaşı intrusion have sharp intrusive contacts with each other. The principal mineralization style at the Pınarbaşı prospect is a porphyry-type Mo-Cu mineralization hosted predominantly by monzonite and porphyritic granite. The porphyry type Mo-Cu mineralization consists mostly of stockwork and NE- and EW-striking sub-vertical quartz veins. Stockwork-type quartz veins hosted by the upper parts of the porphyritic granite within the monzonite, are typically enriched in chalcopyrite, molybdenite, pyrite, and limonite. The late NE- and EW-striking normal faults cut the stockwork vein system and control the quartz-molybdenite-chalcopyrite-sphalerite-fahlore-galena veins, as well as molybdenite-hematite-bearing silicified zones. Lithogeochemical and whole-rock radiogenic isotope data (Sr, Nd and Pb) of the host rocks, together with Re-Os molybdenite ages (18.3 ± 0.1 Ma - 18.2 ± 0.1 Ma) reveal that the monzonitic and granitic rocks of the Pınarbaşı intrusion were derived from an enriched lithospheric mantle-lower crust during Oligo-Miocene post-collisional magmatism. The lithospheric mantle was metasomatised by fluids and subducted sediments, and the mantle-derived melts interacted with lower crust at 35-40 km depth. This mechanism explains the Mo and Cu enrichments of the Pınarbaşı intrusion during back-arc magmatism. We conclude that the melt of the Pınarbaşı intrusion could have rapidly ascended to mid-crustal levels, with only limited crustal assimilation along major trans-lithospheric faults as a result of thinning of the middle to upper crust during regional extension, and resulted in the development of porphyry-style mineralization during the early Miocene (∼18 Ma). The subsequent exhumation history of the Mo-Cu-bearing Pınarbaşı intrusion is attributed to regional-scale uplift, and further exhumation along detachment faults of the associated core complexes during the middle to late Miocene. [ABSTRACT FROM AUTHOR]

The Åkerlandet, Järvsand, and Laisvall deposits in Sweden are calcite-fluorite-sulfide vein deposits and occurrences located close to the current erosional front of the Caledonian orogen and hosted by crystalline basement rocks in the Fennoscandian Shield. At Laisvall, basement-hosted veinlets occur beneath Ediacaran to Cambrian sandstones that host a strata-bound Pb-Zn deposit. The mineralized fractures at Åkerlandet and Järvsand occur along fault systems oriented N-S to NNW-SSE. Veins or veinlets strike NNW-SSE and NW-SE at Åkerlandet, NNE-SSW at Järvsand, and NNW-SSE and NNE-SSW to NE-SW at Laisvall. At Åkerlandet and Järvsand, fractures acted as conduits for hydrothermal fluids of variable composition and formed during separate tectonic events. At Åkerlandet, the fault zone with NNW-SSE strike shows kinematic indicators consistent with ~NE-SW bulk horizontal extension. At Järvsand, the calcite-fluorite-galena veins formed along R-Riedel shears related to the host N-S to NNW-SSE fault system. The kinematic indicators are consistent with ~NW-SE bulk horizontal extension, similar to the extensional deformation during the later part of the Caledonian orogeny (Silurian to Devonian). At Åkerlandet, adularia-quartz deposition was followed by sphalerite ± galena and finally by precipitation of fluorite and calcite. Ar-Ar thermochronology of a single adularia sample did not yield a well-defined plateau age but the gas released at higher temperatures suggests an early Tonian (980 to 950 Ma) crystallization age, i.e., during the later part of the Sveconorwegian orogeny, although the data do not exclude other less likely interpretations. Previous fluid inclusion microthermometry and geochronological studies and new petrographic and geochemical results suggest that sphalerite ± galena mineralization formed from saline, relatively oxidizing, moderate-temperature, and slightly acidic hydrothermal fluids, either during the Ediacaran or the Middle Ordovician. Metals and HS were derived from local basement rocks. Based on petrographic evidence, rare earth element composition, and S, C, and O isotope data, fluorite and calcite precipitated under near neutral and relatively reducing conditions. Occurrence of solid bitumen in veins at Åkerlandet and C and O isotope data of calcite at Åkerlandet and in the Laisvall basement veinlets suggest that the precipitation of calcite and fluorite was triggered by interaction of hot and evolved hydrothermal fluids (Sr/Sr = 0.718-0.732) with organic matter. Structural, petrographic, and geochemical data at Laisvall suggest that the basement structures hosting calcite-fluorite ± pyrite veinlets were utilized in the Middle Ordovician as the plumbing system for the oxidizing, slightly acidic, metal-bearing brines that caused the economic Pb-Zn mineralization in the overlying sandstones. [ABSTRACT FROM AUTHOR]

Chromatin is reprogrammed after fertilization to produce a totipotent zygote with the potential to generate a new organism. The maternal genome inherited from the oocyte and the paternal genome provided by sperm coexist as separate haploid nuclei in the zygote. How these two epigenetically distinct genomes are spatially organized is poorly understood. Existing chromosome conformation capture-based methods are not applicable to oocytes and zygotes owing to a paucity of material. To study three-dimensional chromatin organization in rare cell types, we developed a single-nucleus Hi-C (high-resolution chromosome conformation capture) protocol that provides greater than tenfold more contacts per cell than the previous method. Here we show that chromatin architecture is uniquely reorganized during the oocyte-to-zygote transition in mice and is distinct in paternal and maternal nuclei within single-cell zygotes. Features of genomic organization including compartments, topologically associating domains (TADs) and loops are present in individual oocytes when averaged over the genome, but the presence of each feature at a locus varies between cells. At the sub-megabase level, we observed stochastic clusters of contacts that can occur across TAD boundaries but average into TADs. Notably, we found that TADs and loops, but not compartments, are present in zygotic maternal chromatin, suggesting that these are generated by different mechanisms. Our results demonstrate that the global chromatin organization of zygote nuclei is fundamentally different from that of other interphase cells. An understanding of this zygotic chromatin 'ground state' could potentially provide insights into reprogramming cells to a state of totipotency. [ABSTRACT FROM AUTHOR]

A number of recent experimental approaches demonstrated that a three-dimensional organization of the eukaryotic genome play an important role in the regulation of its activity. One of the most important results was a discovery of the genome separation into relatively independent topologically-associated domains (TADs). They restricted the action area of regulatory elements, i.e., they simultaneously were regulatory domains of the genome. In this connection, an understanding of the molecular mechanism of the TAD formation has become a very topical problem. Here, we review and discuss our recent data which demonstrated that the TAD formation was directed by simple physical laws and was based on establishing multiple internucleosomal contacts. [ABSTRACT FROM AUTHOR]

The prospects for the homodyne recording of backscattered radiation of an Er fiber laser in measuring velocity and in Doppler spectroscopy are investigated. The sensitivity and accuracy of measuring velocity are estimated. It is shown that this method can be used to control laser-induced hydrodynamic flows that form upon the laser evaporation of biotissues. [ABSTRACT FROM AUTHOR]

In vitro perforation of gelatin-based biomodels and myocardium tissue by powerful CO and YAG:Er laser pulses is considered. Features of the thermal and shock-wave effects on the walls of the laser channel are investigated. Patterns of laser channeling in gelatin by a single YAG:Er laser pulse were studied. [ABSTRACT FROM AUTHOR]

Bull sharks Carcharhinus leucas use estuarine and riverine systems as nursery habitat. The Shark Reef Marine Reserve (SRMR) on the southern coast of Viti Levu, Fiji, is well-known for its adult bull shark population. The species' seasonal departure from the SRMR is related to reproductive activity, but nursery grounds have not yet been identified on the southern coast of Viti Levu. In order to further identify and characterise bull shark habitats in Fiji, 49 teeth were collected from bull sharks encountered at the SRMR and measured for their trace element concentrations, and 22 of them for oxygen isotopic composition in the phosphate group of bioapatite. The trace element analyses yielded relatively high Na, Mg, Sr, and F and low Ba concentrations for all the teeth supporting formation in marine environment. The phosphate oxygen isotope data concur with this result and the data evidently show that these teeth developed under marine condition relating to the temperature and oxygen isotopic composition of Fiji's coastal waters. Therefore, the investigated teeth show no signs of freshwater habitat. Our results do not support the hypothesis that bull sharks enter freshwater habitats, at least not for longer time periods, during their absence from the SRMR. Additionally, the bull shark teeth had unexpectedly high zinc concentration at the very edge of the enameloid. This cannot be explained by environmental factors; therefore the high Zn content is interpreted here as a result of biological process, a reflection of enzyme (i.e., KLK4) related organic matter removal and enhanced crystallization during tooth maturation. [ABSTRACT FROM AUTHOR]

The Adula nappe belongs to the Lower Penninic domain of the Central Swiss Alps. It consists mostly of pre-Triassic basement lithologies occurring as strongly folded and sheared gneisses of various types with mafic boudins. We propose a new lithostratigraphy for the northern Adula nappe basement that is supported by detailed field investigations, U-Pb zircon geochronology, and whole-rock geochemistry. The following units have been identified: Cambrian clastic metasediments with abundant carbonate lenses and minor bimodal magmatism (Salahorn Formation); Ordovician metapelites associated with amphibolite boudins with abundant eclogite relicts representing oceanic metabasalts (Trescolmen Formation); Ordovician peraluminous metagranites of calc-alkaline affinity ascribed to subduction-related magmatism (Garenstock Augengneiss); Ordovician metamorphic volcanic-sedimentary deposits (Heinisch Stafel Formation); Early Permian post-collisional granites recording only Alpine orogenic events (Zervreila orthogneiss). All basement lithologies except the Permian granites record a Variscan + Alpine polyorogenic metamorphic history. They document a complex Paleozoic geotectonic evolution consistent with the broader picture given by the pre-Mesozoic basement framework in the Alps. The internal consistency of the Adula basement lithologies and the stratigraphic coherence of the overlying Triassic sediments suggest that most tectonic contacts within the Adula nappe are pre-Alpine in age. Consequently, mélange models for the Tertiary emplacement of the Adula nappe are not consistent and must be rejected. The present-day structural complexity of the Adula nappe is the result of the intense Alpine ductile deformation of a pre-structured entity. [ABSTRACT FROM AUTHOR]

In Beauty and Revolution in Science, James McAllister advances a rationalistic picture of science in which scientific progress is explained in terms of aesthetic evaluations of scientific theories. Here I present a new model of aesthetic evaluations by revising McAllister's core idea of the aesthetic induction. I point out that the aesthetic induction suffers from anomalies and theoretical inconsistencies and propose a model free from such problems. The new model is based, on the one hand, on McAllister's original model and on further developments by Theo Kuipers in his 'Beauty, a Road to the Truth?'. On the other hand, it is based on empirical findings about affection and emotion, and a naturalistic aesthetic theory. The new model is thus a naturalistic model with a wider explanatory range and much more internal consistency that McAllister's. [ABSTRACT FROM AUTHOR]

The eukaryotic cell genome has a multilevel regulatory system of gene expression that includes stages of preliminary activation of genes or of extended genomic regions (switching them to potentially active states) and stages of final activation of promoters and maintaining their active status in cells of a certain lineage. Current views on the regulatory systems of transcription in eukaryotes have been formed based on results of systematic studies on a limited number of model systems, in particular, on the α- and β-globin gene domains of vertebrates. Unexpectedly, these genomic domains harboring genes responsible for the synthesis of different subunits of the same protein were found to have a fundamentally different organization inside chromatin. In this review, we analyze specific features of the organization of the α- and β-globin gene domains in vertebrates, as well as principles of activities of the regulatory systems in these domains. In the final part of the review, we attempt to answer the question how the evolution of α- and β-globin genes has led to segregation of these genes into two distinct types of chromatin domains situated on different chromosomes. [ABSTRACT FROM AUTHOR]

The author discusses an analogy between narratives and mathematical proofs that tries to account in a simple manner for the ugliness of computer-assisted proofs. He mentions that the ugliness is not essentially associated to methodological or epistemic problems with the evidence. He states that nonbeautiful proof may just be an uninspiring toward where mathematicians reveal indifference.

For the first time, an albite orthogneiss has been recognised and dated within the HP-LT blueschist facies metabasites and metapelites of the Ile de Groix. It is characterised by a peraluminous composition, high LILE, Th and U contents, MORB-like HREE abundances and moderate Nb and Y values. A U-Pb age of 480.8 ± 4.8 Ma was obtained by LA-ICP-MS dating of zircon and titanite. It is interpreted as the age of the magmatic emplacement during the Early Ordovician. Morphologically different zircon grains yield late Neoproterozoic ages of 546.6-647.4 Ma. Zircon and titanite U-Pb ages indicate that the felsic magmatism from the Ile de Groix is contemporaneous with the acid, pre-orogenic magmatism widely recognised in the internal zones of the Variscan belt, related to the Cambro-Ordovician continental rifting. The magmatic protolith probably inherited a specific chemical composition from a combination of orogenic, back-arc and anorogenic signatures because of partial melting of the Cadomian basement during magma emplacement. Besides, the late Devonian U-Pb age of 366 ± 33 Ma obtained for titanite from a blueschist facies metapelite corresponds to the age of the HP-LT peak metamorphism. [ABSTRACT FROM AUTHOR]

Whole rock major and trace element abundances in aluminous garnet–spinel websterite, sapphirine-bearing Mg–Al granulite and hibonite-bearing Ca–Al granulite xenoliths from the Chyulu Hills volcanic field, Kenya, suggest that the samples represent a meta-igneous suite linked by fractionation. The incompatible major element contents increase from the websterites to the Mg–Al granulites and further to the Ca–Al granulites. High bulk rock Mg#s and very low concentrations of most incompatible trace elements indicate that the rocks are cumulates rather than crystallized melts. Elevated Ni abundances, impoverishment in Cr and HFSE and high contents of normative plagioclase and olivine in the granulites indicate that their protoliths were similar to troctolite. The textures and metamorphic reaction paths recorded in the granulites suggest igneous emplacement in the crust and cooling from igneous to ambient crustal temperatures accompanied or followed by compression. For the websterite xenoliths, there is an apparent contradiction between the results of P– T calculations that suggest high P and T of crystallization of early generation pyroxenes and elevated P– T conditions during final equilibration (1.4–2.2 GPa/740–980°C) on the one hand and the positive Eu anomaly that suggests shallow-level plagioclase accumulation on the other hand. This contradiction can be reconciled by a model of compression of a plagioclase-bearing (gabbroic) protolith to mantle depths where it recrystallized to an ultramafic assemblage, which requires foundering of dense lower crustal material into the mantle. [ABSTRACT FROM AUTHOR]