Voltage-gated Na+ channels are essential for the functioning of cardiovascular, muscular, and nervous systems. The α-subunit of eukaryotic Na+ channel consists of ~ 2000 amino acid residues and encloses 24 transmembrane (TM) helices, which form five membrane domains: four voltage-sensing (VSD) and one pore domain. The structural complexity significantly impedes recombinant production and structural studies of full-sized Na+channels. Modular organization of voltage-gated channels gives an idea for studying of the isolated second VSD of human skeletal muscle Nav1.4 channel (VSD-II). Several variants of VSD-II (~ 150 a.a., four TM helices) with different N- and C-termini were produced by cell-free expression. Screening of membrane mimetics revealed low stability of VSD-II samples in media containing phospholipids (bicelles, nanodiscs) associated with the aggregation of electrically neutral domain molecules. The almost complete resonance assignment of 13C,15N-labeled VSD-II was obtained in LPPG micelles. The secondary structure of VSD-II showed similarity with the structures of bacterial Na+ channels. The fragment of S4 TM helix between the first and second conserved Arg residues probably adopts 310-helical conformation. Water accessibility of S3 helix, observed by the Mn2 + titration, pointed to the formation of water-filled crevices in the micelle embedded VSD-II. 15N relaxation data revealed characteristic pattern of μs–ms time scale motions in the VSD-II regions sharing expected interhelical contacts. VSD-II demonstrated enhanced mobility at ps–ns time scale as compared to isolated VSDs of K+ channels. These results validate structural studies of isolated VSDs of Na+channels and show possible pitfalls in application of this ‘divide and conquer’ approach.
We investigated the effect of mobile phone use on the auditory sensory memory in children. Auditory event-related potentials (ERPs), P1, N2, mismatch negativity (MMN), and P3a, were recorded from 17 children, aged 11–12 years, in the recently developed multi-feature paradigm. This paradigm allows one to determine the neural change-detection profile consisting of several different types of acoustic changes. During the recording, an ordinary GSM (Global System for Mobile Communications) mobile phone emitting 902 MHz (pulsed at 217 Hz) electromagnetic field (EMF) was placed on the ear, over the left or right temporal area (SAR1g = 1.14 W/kg, SAR10g = 0.82 W/kg, peak value = 1.21 W/kg). The EMF was either on or off in a single-blind manner. We found that a short exposure (two 6 min blocks for each side) to mobile phone EMF has no statistically significant effects on the neural change-detection profile measured with the MMN. Furthermore, the multi-feature paradigm was shown to be well suited for studies of perception accuracy and sensory memory in children. However, it should be noted that the present study only had sufficient statistical power to detect a large effect size.
Using the linear theory of waves in a compressible atmosphere located in a gravitational field, we found a family of sound speed profiles for which the wavefield can be represented by a traveling wave with no reflection. The vertical flux of wave energy on these nonreflected profiles is retained, which proves that the energy transfer may occur over long distances.
The atomic-scale diffusion of water in the presence of several lipid bilayers mimicking biomembranes is characterized via unconstrained molecular dynamics (MD) simulations. Although the overall water dynamics corresponds well to literature data – namely, the efficient braking near polar head groups of lipids - a number of interesting and biologically relevant details observed in this work have not been sufficiently discussed so far. For instance, the fact that waters “sense” the membrane unexpectedly early – before water density begins to decrease. In this “transitional zone” the velocity distributions of water and their H-bonding patterns deviate from those in the bulk solution. The boundaries of this zone are well preserved even despite the local (<1 nm size) perturbation of the lipid bilayer, thus indicating a decoupling of the surface and bulk dynamics of water. This is in excellent agreement with recent experimental data. Near the membrane surface, water movement becomes anisotropic – solvent molecules preferentially move outward the bilayer. Deep in the membrane interior, the velocities can even exceed those in the bulk solvent and undergo large-scale fluctuations. The analysis of MD trajectories of individual waters in the middle part of the acyl chain region of lipids reveals a number of interesting rare phenomena, such as the fast (c.a. 50 ps) breakthrough across the membrane or long-time (up to 750 ps) “roaming” between lipid leaflets. The analysis of these events was accomplished to delineate the mechanisms of spontaneous water permeation inside the hydrophobic membrane core. It was shown that such nontrivial dynamics of water in an “alien” environment is driven by the dynamic heterogeneities of the local bilayer structure and the formation of transient atomic-scale “defects” in it. The picture observed in lipid bilayers is drastically different from that in a primitive membrane mimic – a hydrated cyclohexane slab. The possible biological impact of such phenomena in equilibrated lipid bilayers is discussed.
The somatotopic layout of the primary somatosensory cortex is known for its fine spatial structure as delineated in single cell recordings and macroscopic EEG evoked responses. While a gross somatotopic layout has been revealed also for neuronal oscillations responding to sensorimotor stimulation of distant body parts (e.g. hand vs. foot), it is still unclear whether these oscillatory dynamics exhibit fine spatial layout comparable to those found in evoked responses. In twelve healthy subjects we applied electric stimuli to the first (D1) and fifth finger (D5) of the same hand while performing high-density electroencephalography. We used Common Spatial Pattern analysis to optimally extract components showing the strongest Event-Related Desynchronization (ERD) in neuronal alpha oscillations. In agreement with the previous studies, dipole locations of Somatosensory Evoked Potentials (SEPs) confirmed the existence of spatially distinct representations of each finger. In contrast, dipole locations of alpha-ERD patterns did not yield spatially different source locations, indicating that the stimulation of different fingers most likely resulted in oscillatory activity of overlapping neuronal populations. When both fingers were stimulated simultaneously the SEP dipole strength was found increased in comparison to a stimulation of either finger alone, in agreement with spatially distinct SEP to finger stimulation. The strength of ERD, on the other hand, was the same regardless of whether either one or both fingers were stimulated. Our findings might reflect anatomical constraints on the sequential temporal activation of fingers' skin where almost simultaneous activation of many fingers usually occurs in everyday activities, such as grasping or holding objects. Such simultaneity is unlikely to benefit from slow amplitude modulation of alpha oscillations, which would rather be beneficial for contrasting somatosensory processing of distinct body parts.
Dinornis robustus and Emeus crassus display two variants of moa locomotor adaptations, Emeus being less cursorial. The number and topography of their pelvic muscles are similar and resemble that of Tinamiformes and geographically close Apterygiformes and Casuariiformes. Nevertheless, a number of features are probably peculiar to Dinornithiformes. The strong iliotibiales and iliofemoralis externus muscles, which prevent passive adduction of the femur, far surpass the bulk recorded for these muscles in other birds. The iliofemoralis internus muscle has a unique insertion to the cranial surface of the femur distal to the femoral head, although further inspection of mummified remains is required to prove this. The less modified pelvic muscles of moa in comparison with that of Apterygiformes, Casuariiformes, Rheiformes, and Struthioniformes are related to the retention in Dinornithiformes of the wide pelvis
A series of novel fluorescent pyrimidine nucleosides containing 2,1,3-benzoxadiazole or naphtho[1,2,3-cd]indole-6 (2h)-one fragments was designed and synthesized. Introduction of fluorescent fragments into the position 5 of the uridine or cytidine heterocycle was carried out in two ways: by Sonogashira Coupling Reaction and CuI-catalyzed cycloaddition ("click" reaction). The obtained nucleoside derivatives became fluorescent due to the inserted fragments. The excitation wavelength (440-450 nm) was outside the absorption band of many biomolecules and significantly differed from the emission wavelength (560-600 nm). In addition, the intended nucleoside analogs were shown to kill cultured human tumor cells at submicromolar concentrations
The nonlinear stage of the modulational (Benjamin–Feir) instability of unidirectional deep-water surface gravity waves is simulated numerically by the fifth-order nonlinear envelope equations. The conditions of steep and breaking waves are concerned. The results are compared with the solution of the full potential Euler equations and with the lower-order envelope models (the 3-order nonlinear Schrödinger equation and the standard 4-order Dysthe equations). The generalized Dysthe model is shown to exhibit the tendency to re-stabilization of steep waves with respect to long perturbations.
Rock glaciers and large ice‐debris complexes are common in many mountain ranges and are especially prominent in semi‐arid mountains such as the Andes or the Tien Shan. These features contain a significant amount of ice but their occurrence and evolution are not well known. Here, we present an inventory of the ice‐debris complexes for the Ak‐Shiirak, Tien Shan's second largest glacierised massif, and a holistic methodology to investigate two characteristic and large ice‐debris complexes in detail based on field investigations and remote sensing analysis using Sentinel‐1 SAR data, 1964 Corona and recent high resolution stereo images. Overall, we found 74 rock glaciers and ice‐debris complexes covering an area of 11.2 km2 (3.2% of the glacier coverage) with a mean elevation of about 3950 m asl. Most of the complexes are located south‐east of the main ridge of Ak‐Shiirak. Ground penetrating radar (GPR) measurements reveal high ice content with the occurrence of massif debris‐covered dead‐ice bodies in the parts within the Little Ice Age glacier extent. These parts showed significant surface lowering, in some places exceeding 20 m between 1964 and 2015. The periglacial parts are characterised by complex rock glaciers of different ages. These rock glaciers could be remnants of debris‐covered ice located in permafrost conditions. They show stable surface elevations with no or only very low surface movement. However, the characteristics of the fronts of most rock glacier parts indicate slight activity and elevation gains at the fronts slight advances. GPR data indicated less ice content and slanting layers which coincide with the ridges and furrows and could mainly be formed by glacier advances under permafrost conditions. Overall, the ice content is decreasing from the upper to the lower part of the ice‐debris complexes. Hence, these complexes, and especially the glacier‐affected parts, should be considered when assessing the hydrological impacts of climate change.
The aim of the communication is to report and investigate the discovery of the Steppe marmot lower jaw in the layers the first centuries AD in the ancient Greek city Panticapaeum. This is the first record of the marmot remains from the easternmost part of the Crimean Peninsula (Kerch Peninsula). Although the animal could have been delivered to the city from the northern shores of Aral and Black Seas due to the valuable meat and fat, there is still a high possibility of marmot inhabiting this part of the Peninsula at the turn of our era
The bottom pressure distribution beneath large amplitude waves is studied within linear theory in time and space domain, weakly dispersive Serre–Green–Naghdi system and fully nonlinear potential equations. These approaches are used to compare pressure fields induced by solitary waves, but also by transient wave groups. It is shown that linear analysis in time domain is in good agreement with Serre– Green–Naghdi predictions for solitary waves with highest amplitude A = 0.7h, h being water depth. In the meantime, when comparing results to fully nonlinear potential equations, neither linear theory in time domain, nor in space domain, provide a good description of the pressure peak. The linear theory in time domain underestimates the peak by an amount similar to the overestimation by linear theory in space domain. For transient wave groups (up to A = 0.52h), linear analysis in time domain provides results very similar to those based on the Serre–Green–Naghdi system. In the meantime, linear theory in space domain provides a surprisingly good comparison with prediction of fully nonlinear theory. In all cases, it has to be emphasized that a discrepancy between linear theory in space domain and in time domain was always found, and presented an averaged value of 20%. Since linear theory is often used by coastal engineers to reconstruct water elevation from bottom mounted sensors, the so-called inverse problem, an important result of this work is that special caution should be given when doing so. The method might surprisingly work with strongly nonlinear waves, but is highly sensitive to the imbalance between nonlinearity and dispersion. In most cases, linear theory, in both time and space domain, will lead to important errors when solving this inverse problem.
he operative weather forecasts with lead-time 3-5 days from best forecasting hydrodynamic models as well as the archives of the models’ forecasts and of the meteorological measurements in 2800 cities of Russia, East Europe, and Central Asia are used. The output of our scheme includes the air temperature forecast for the standard observations moments with period 6 hours and extreme temperatures for lead times from 12 up 120 hours.
The results of the operative forecasting (about ~280 Russian and Belarus cities and separately 58 cities of Central Asia) are representing on the site of Hydrometeorological Center of Russia every day at 8.30 (a.m. and p.m.) of the Moscow time. Besides temperature we represent on the site amount of precipitation, wind (including gusts), and dew-point temperature with lead-time from 12 up 72 hours with period 6 hours.
The errors of the complex forecast of the temperature and of the dew-point temperature in the standard moments as well as extreme temperature with various lead-times for the period from July 2014 up to June 2017 are represented. The accuracy of these forecasts for the standard moments is much better that the forecasts’ accuracy of the original hydrodynamic models. The estimations for our forecasting extreme temperature are compared with the similar results of the forecasting scheme “weather element computation” (WEC) and with forecasts of meteorologists of regional meteorological centers.
We describe our scheme of the operative wind (and possible gusts) forecasts with lead-time up to 3 days and evaluate its success. It uses joint statistical processing of the results of several best operative forecasting hydrodynamic weather forecasting schemes. This approach allowed to reduce the error with respect to original schemes. The operative forecast and its evaluation for the period 2014 – 2016 y. realized for ~ 2800 cities of Russia, Belarus, and Central Asia. The update results are representing on the official site of Hydrometeorological Center of Russia every day at 8.30 (a.m. and p.m.) of the Moscow time.
Sensory and cognitive deficits are common in schizophrenia. They are associated with abnormal brain rhythms, including disturbances in γ frequency (30–80 Hz) oscillations (GFO) in cortex-related networks. However, the underlying anatomofunctional mechanisms remain elusive. Clinical and experimental evidence suggests that these deficits result from a hyporegulation of glutamate N-methyl-D-aspartate receptors. Here we modeled these deficits in rats with ketamine, a non-competitive N-methyl-D-aspartate receptor antagonist and a translational psychotomimetic substance at subanesthetic doses. We tested the hypothesis that ketamine-induced sensory deficits involve an impairment of the ability of the thalamocortical (TC) system to discriminate the relevant information from the baseline activity. Furthermore, we wanted to assess whether ketamine disrupts synaptic plasticity in TC systems. We conducted multisite network recordings in the rat somatosensory TC system, natural stimulation of the vibrissae and high-frequency electrical stimulation (HFS) of the thalamus. A single systemic injection of ketamine increased the amount of baseline GFO, reduced the amplitude of the sensory-evoked TC response and decreased the power of the sensory-evoked GFO. Furthermore, cortical application of ketamine elicited local and distant increases in baseline GFO. The ketamine effects were transient. Unexpectedly, HFS of the TC pathway had opposite actions. In conclusion, ketamine and thalamic HFS have opposite effects on the ability of the somatosensory TC system to discriminate the sensory-evoked response from the baseline GFO during information processing. Investigating the link between the state and function of the TC system may conceptually be a key strategy to design innovative therapies against neuropsychiatric disorders.
Motivation: Target-specific hybridization depends on oligo-probe characteristics that improve hybridization specificity and minimize genome-wide cross-hybridization. Interplay between specific hybridization and genome-wide cross-hybridization has been insufficiently studied, despite its crucial role in efficient probe design and in data analysis. Results: In this study, we defined hybridization specificity as a ratio between oligo target-specific hybridization and oligo genome-wide cross-hybridization. A microarray database, derived from the Genomic Comparison Hybridization (GCH) experiment and performed using the Affymetrix platform, contains two different types of probes. The first type of oligo-probes does not have a specific target on the genome and their hybridization signals are derived from genome-wide cross-hybridization alone. The second type includes oligonucleotides that have a specific target on the genomic DNA and their signals are derived from specific and cross-hybridization components combined to- gether in a total signal. A comparative analysis of hybridization specificity of oligo-probes, as well as their nucleotide sequences and thermodynamic features was performed on the database. The comparison has revealed that hybridization specificity was negatively affected by low stability of the fully-paired oligo-target duplex, stable probe self-folding, G-rich content, including GGG motifs, low sequence complexity and nucleotide composition symmetry. Conclusion: Filtering out the probes with defined ‘negative’ characteristics significantly increases specific hybridization and dramatically decreasing genome-wide cross-hybridization. Selected oligo-probes have two times higher hybridization specificity on average, compared to the probes that were filtered from the analysis by applying suggested cutoff thresholds to the described parameters. A new approach for efficient oligo-probe design is described in our study.
High and moderate intensity endurance exercise alters gene expression in human white blood cells (WBCs), but the understanding of how this effect occurs is limited. To increase our knowledge of the nature of this process, we investigated the effects of passing the anaerobic threshold (AnT) on the gene expression profile in WBCs of athletes. Nineteen highly trained skiers participated in a treadmill test with an incremental step protocol until exhaustion (ramp test to exhaustion, RTE). The average total time to exhaustion was 14:40 min and time after AnT was 4:50 min. Two weeks later, seven of these skiers participated in a moderate treadmill test (MT) at 80% peak O(2) uptake for 30 min, which was slightly below their AnTs. Blood samples were obtained before and immediately after both tests. RTE was associated with substantially greater leukocytosis and acidosis than MT. Gene expression in WBCs was measured using whole genome microarray expression analysis before and immediately after each test. A total of 310 upregulated genes were found after RTE, and 69 genes after MT of which 64 were identical to RTE. Both tests influenced a variety of known gene pathways related to inflammation, stress response, signal transduction and apoptosis. A large group of differentially expressed previously unknown small nucleolar RNA and small Cajal body RNA was found. In conclusion, a 15-min test to exhaustion was associated with substantially greater changes of gene expression than a 30-min test just below the AnT.
Active ionospheric experiments using high-power, high-frequency transmitters, heaters, to study plasma processes in the ionosphere and magnetosphere continue to provide new insights into understanding plasma and geophysical proceses. This review describes the heating facilities, past and present, and discusses scientific results from these facilities and associated space missions. Phenomena that have been observed with these facilities are reviewed along with theoretical explanations that have been proposed or are commonly accepted. Gaps or uncertainties in understanding of heating-initiated phenomena are discussed together with proposed science questions to be addressed in the future. Suggestions for improvements and additions to existing facilities are presented including important satellite missions which are necessary to answer the outstanding questions in this field.
A controversial issue in neuro- and psycholinguistics is whether regular past-tense forms of verbs are stored lexically or generated productively by the application of abstract combinatorial schemas, for example affixation rules. The success or failure of models in accounting for this particular issue can be used to draw more general conclusions about cognition and the degree to which abstract, symbolic representations and rules are psychologically and neurobiologically real. This debate can potentially be resolved using a neurophysiological paradigm, in which alternative predictions of the brain response patterns for lexical and syntactic processing are put to the test. We used magnetoencephalography (MEG) to record neural responses to spoken monomorphemic words ('hide'), pseudowords ('smide'), regular past-tense forms ('cried') and ungrammatical (overregularised) past-tense forms ('flied') in a passive listening oddball paradigm, in which lexically and syntactically modulated stimuli are known to elicit distinct patterns of the mismatch negativity (MMN) brain response. We observed an enhanced ('lexical') MMN to monomorphemic words relative to pseudowords, but a reversed ('syntactic') MMN to ungrammatically inflected past tenses relative to grammatical forms. This dissociation between responses to monomorphemic and bimorphemic stimuli indicates that regular past tenses are processed more similarly to syntactic sequences than to lexically stored monomorphemic words, suggesting that regular past tenses are generated productively by the application of a combinatorial scheme to their separately represented stems and affixes. We suggest discrete combinatorial neuronal assemblies, which bind classes of sequentially occurring lexical elements into morphologically complex units, as the neurobiological basis of regular past tense inflection.
tDecision-makers show an increased risk appetite when they gamble with previously wonmoney, the house money effect, and when they have a chance to make up for a prior loss,the break even effect. To explore the origins of these effects, we use functional magneticresonance imaging to record the brain activities of subjects while they make sequential riskychoices. The behavioral data from our experiment confirm the path dependence of choices,despite the short trial duration and the many task repetitions required for neuroimaging.The brain data yield evidence that the increased risk appetite after gains and losses is relatedto an increased activity of affective brain processes and a decreased activity of deliberativebrain processes.