Abstract The default mode network (DMN) has been principally investigated using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) and has received mixed support in ...electroencephalographic (EEG) studies. In particular, the existing evidence is too inconsistent to allow formulation of specific hypotheses linking DMN activity to traditional EEG frequency bands. In this study, we aimed to test whether blind decomposition methods are able to identify in EEG data spatial patterns resembling the DMN as it is described in PET and fMRI studies. Further we aimed to test a degree of task-relatedness of DMN patterns identified in the traditional EEG frequency bands. To answer these questions we collected data both in a resting state and during performance of two experimental tasks: an explicit judgment of facial affect and a social game task. Individual differences in amount of self-referential thoughts during the resting state were measured by a short self-report scale. Only alpha band spatial patterns simultaneously showed a considerable overlap with the DMN and high correlations with presumptive DMN function-related outcomes both in the resting state and during the social game task. Spontaneous self-referential thoughts were associated with enhanced alpha activity in the posterior DMN hub, whereas processing of DMN function-related external stimuli disrupted this activity and simultaneously caused partial alpha phase-locking to external events. This evidence implies that synchronization of internal mental processes, as opposed to the processing of external stimuli, might be the primary function of alpha oscillations which is bound to be related to activity of the DMN.
APOBEC3s are innate single-stranded DNA cytidine-to-uridine deaminases that catalyze mutations in both pathogen and human genomes with significant roles in human disease. However, how APOBEC3s mutate ...a single-stranded DNA that is available momentarily during DNA transcription or replication in vivo remains relatively unknown. In this study, utilizing hepatitis B virus (HBV) viral mutations, we evaluated the mutational characteristics of individual APOBEC3s with reference to the HBV replication process through HBV whole single-strand (−)-DNA genome mutation analyses. We found that APOBEC3s induced C-to-T mutations from the HBV reverse transcription start site continuing through the whole (−)-DNA transcript to the termination site with variable efficiency, in an order of A3B >> A3G > A3H-II or A3C. A3B had a 3-fold higher mutation efficiency than A3H-II or A3C with up to 65% of all HBV genomic cytidines being converted into uridines in a single mutation event, consistent with the A3B localized hypermutation signature in cancer, namely, kataegis. On the other hand, A3C expression led to a 3-fold higher number of mutation-positive HBV genome clones, although each individual clone had a lower number of C-to-T mutations. Like A3B, A3C preferred both 5′-TC and 5′-CC sequences, but to a lesser degree. The APOBEC3-induced HBV mutations were predominantly detected in the HBV rcDNA but were not detectable in other intermediates including HBV cccDNA and pgRNA by primer extension of their PCR amplification products. These data demonstrate that APOBEC3-induced HBV genome mutations occur predominantly when the HBV RNA genome was reversely transcribed into (−)-DNA in the viral capsid.
SR-BI binds various lipoproteins, including HDL, LDL as well as VLDL, and mediates selective cholesteryl ester (CE) uptake. HDL derived CE accumulates in cellular lipid droplets (LDs), which also ...store triacylglycerol (TAG). We hypothesized that SR-BI could significantly facilitate LD formation, in part, by directly transporting LDL derived neutral lipids (NL) such as CE and TAG into LDs without lipolysis and de novo lipid synthesis. SR-BI overexpression greatly increased LDL uptake and LD formation in stably transfected HeLa cells (SR-BI-HeLa). LDs isolated from SR-BI-HeLa contained 4- and 7-times more CE and TAG, respectively, than mock-transfected HeLa (Mock-HeLa). In contrast, LDL receptor overexpression in HeLa (LDLr-HeLa) greatly increased LDL uptake, degradation with moderate 1.5- and 2-fold increases of CE and TAG, respectively. Utilizing CE and TAG analogs, BODIPY-TAG (BP-TAG) and BODIPY-CE (BP-CE), for tracking LDL NL, we found that after initial binding of LDL to SR-BI-HeLa, apoB remained at the cell surface, while BP-CE and BP-TAG were sorted and simultaneously transported together to LDs. Both lipids demonstrated limited internalization to lysosomes or endoplasmic reticulum in SR-BI-HeLa. In LDLr-HeLa, NLs demonstrated clear lysosomal sequestration without their sorting to LDs. An inhibition of TAG and CE de novo synthesis by 90-95% only reduced TAG and CE LD content by 45-50%, and had little effect on BP-CE and BP-TAG transport to LDs in SR-BI HeLa. Furthermore, intravenous infusion of 1-2 mg of LDL increased liver LDs in normal (WT) but not in SR-BI KO mice. Mice transgenic for human SR-BI demonstrated higher liver LD accumulation than WT mice. Finally, Electro Spray Infusion Mass Spectrometry (ESI-MS) using deuterated d-CE found that LDs accumulated up to 40% of unmodified d-CE LDL. We conclude that SR-BI mediates LDL-induced LD formation in vitro and in vivo. In addition to cytosolic NL hydrolysis and de novo lipid synthesis, this process includes selective sorting and transport of LDL NL to LDs with limited lysosomal NL sequestration and the transport of LDL CE, and TAG directly to LDs independently of de novo synthesis.
The article reveals the main points of the historical topography of the Crimean Khanate town – Or-Kapu, and most importantly, proposed a graphic reconstruction of its general plan for the third ...quarter of the 18th century, the final stage of the existence of this state. The reconstruction of the historical topography of the late medieval town is based on three main categories of sources – written, cartographic and archaeological. All basic elements of the historical topography of the late medieval town and building inside the stone fortress are recreated by the author. The plan of town’s quarters and streets was reconstructed. Three town mosques, a bath-house, eight wells that supplied people with water, one hotel – a caravanserai, rows of stalls, and a cemetery were localized. It has been possible to determine that it was the smallest settlement in the state. By the final stage of the existence of the Crimean Khanate, the urban area of Or-Kapu was about 19.3 hectares, the town cemetery was about 5.0 hectares.
It is generally assumed that different electroencephalogram (EEG) frequency bands are somehow related to different computational modes in the brain. Integration of these computational modes is ...reflected in the phenomenon of cross-frequency coupling (CFC). On slow temporal scales, CFC may reflect trait-like properties, which posits a question of its developmental trends. This is the first study that explored source-level CFC measures in a developmental perspective using both cross-sectional and longitudinal designs. CFC measures demonstrated good test-retest stability and proved to be higher in adults in cortical areas participating in sensory-motor integration, response inhibition, and attentional control. In children, greater CFC was observed in parietal regions involved in self-centered cognition. Over the period from 7 to 10 years, CFC demonstrated nonlinear growth trajectories. Introversion was associated with higher CFC in cortical areas related to emotion, attention, and social cognition, implying that the association between introversion and CFC appears early in the development.
Golden Horde State during its existence on the Crimean Peninsula origin two towns Solkhat – Krym (modern Stariy Krym) and Kirk-Yer (modern Chufut-Kale). At the time of its emergence in the mid-15th ...century, the Crimean Khanate "inherited" only these two towns on the peninsula. Coastal Genoese towns - Caffa (modern Feodosia), Soldaia (modern Sudak), Cembalo (modern Balaklava) and Vosporo (modern Kerch) were situated near as well as two towns of the Late Byzantine principality Theodoro: the capital of the principality – Theodoro (now Mangup) and the town Calamita (now Inkerman). As a result of the Ottoman conquest of 1475 the number of Ottoman Crimean towns remained the same, only their names were changed: Caffa became Kefe, Soldaia – Sudak, Cembalo – Balaklava, Vosporo – Kerch, Theodoro – Mangup, Calamita – Inkerman. The total number of the Ottoman Crimean towns remained virtually unchanged for three centuries. In contrast, in the territory of the Crimean Khanate in the last quarter of the 15th and early 16th centuries five new towns were founded. Bahchisaray, Karasubazar, Ak-Mechet, Gezlev and Or Kapu were added to two old Golden Horde cities – Solkhat and Kirk-Yer. It were new towns that got priority in development. The political and economic center of Golden Horde Solkhat in the second half of the 15th century would lose its administrative importance and economic influence. During the khan's period it would be called Eski Krym. The main conclusion of the study is that all new towns of the Crimean Khanate (Bahchisaray, Karasubazar, Ak-Mechet, Gezlew, Or Kapu) were not connected with the previous centuries-old urbanistic tradition of local Byzantine or Genoese cities, they appeared in previously unoccupied places, where at best there were Golden Horde settlements. The original urban planning foundations of these cities come from the Golden Horde (in the broad sense – the Eastern) urban planning tradition.
Recent studies suggest an anti-inflammatory protective role for class B scavenger receptor BI (SR-BI) in endotoxin-induced inflammation and sepsis. Other data, including ours, provide evidence for an ...alternative role of SR-BI, facilitating bacterial and endotoxin uptake and contributing to inflammation and bacterial infection. Enhanced endotoxin susceptibility of SR-BI-deficient mice due to their anti-inflammatory glucocorticoid deficiency complicates the understanding of SR-BI's role in endotoxemia/sepsis, calling for the use of alternative models. In this study, using human SR-BI (hSR-BI) and hSR-BII transgenic mice, we found that SR-BI and, to a lesser extent, its splicing variant SR-BII protect against LPS-induced lung damage. At 20 h after intratracheal LPS instillation, the extent of pulmonary inflammation and vascular leakage was significantly lower in hSR-BI and hSR-BII transgenic mice than in wild-type mice. Higher bronchoalveolar lavage fluid (BALF) inflammatory cell count and protein content and lung tissue neutrophil infiltration found in wild-type mice were associated with markedly (2 to 3 times) increased proinflammatory cytokine production compared to these parameters in transgenic mice following LPS administration. The markedly lower endotoxin levels detected in BALF of transgenic versus wild-type mice and the significantly increased BODIPY-LPS uptake observed in lungs of hSR-BI and hSR-BII mice 20 h after the i.t. LPS injection suggest that hSR-BI- and hSR-BII-mediated enhanced LPS clearance in the airways could represent the mechanism of their protective role against LPS-induced acute lung injury.
The insulin receptor (IR), insulin-like growth factor 1 receptor (IGF-1R), and insulin receptor-related receptor (IRR) form a mini family of predimerized receptor-like tyrosine kinases. IR and IGF-1R ...bind to their peptide agonists triggering metabolic and cell growth responses. In contrast, IRR, despite sharing with them a strong sequence homology, has no peptide-like agonist but can be activated by mildly alkaline media. The spatial structure and activation mechanisms of IRR have not been established yet. The present work represents the first account of a structural analysis of a predimerized receptor-like tyrosine kinase by high-resolution atomic force microscopy in their basal and activated forms. Our data suggest that in neutral media, inactive IRR has two conformations, where one is symmetrical and highly similar to the inactive Λ/U-shape of IR and IGF-1R ectodomains, whereas the second is drop-like and asymmetrical resembling the IRR ectodomain in solution. We did not observe complexes of IRR intracellular catalytic domains of the inactive receptor forms. At pH 9.0, we detected two presumably active IRR conformations, Γ-shaped and T-shaped. Both of conformations demonstrated formation of the complex of their intracellular catalytic domains responsible for autophosphorylation. The existence of two active IRR forms correlates well with the previously described positive cooperativity of the IRR activation. In conclusion, our data provide structural insights into the molecular mechanisms of alkali-induced IRR activation under mild native conditions that could be valuable for interpretation of results of IR and IGF-IR structural studies.
The search of a putative physiological electron acceptor for thiocyanate dehydrogenase (TcDH) newly discovered in the thiocyanate-oxidizing bacteria Thioalkalivibrio paradoxus revealed an unusually ...large, single-heme cytochrome c (CytC552), which was co-purified with TcDH from the periplasm. Recombinant CytC552, produced in Escherichia coli as a mature protein without a signal peptide, has spectral properties similar to the endogenous protein and serves as an in vitro electron acceptor in the TcDH-catalyzed reaction. The CytC552 structure determined by NMR spectroscopy reveals significant differences compared to those of the typical class I bacterial cytochromes c: a high solvent accessible surface area for the heme group and so-called “intrinsically disordered” nature of the histidine-rich N- and C-terminal regions. Comparison of the signal splitting in the heteronuclear NMR spectra of oxidized, reduced, and TcDH-bound CytC552 reveals the heme axial methionine fluxionality. The TcDH binding site on the CytC552 surface was mapped using NMR chemical shift perturbations. Putative TcDH-CytC552 complexes were reconstructed by the information-driven docking approach and used for the analysis of effective electron transfer pathways. The best pathway includes the electron hopping through His528 and Tyr164 of TcDH, and His83 of CytC552 to the heme group in accordance with pH-dependence of TcDH activity with CytC552.
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