Identification of CpG island at the 5' end of murine leukemia inhibitory factor gene

AbstractWe identified a CpG island at the 5' end of murine leukemia inhibitory factor gene (LIF). The CpG island is 0.6 kb long and covers most of the first exon and first intron. The region is non-methylated, its G+C content is 65% and relative frequency of CpG dinucleotide is 0.7. The block of 150 nucleotides, which is 72% conserved between murine, human, ovine and porcine genes, is a part of the CpG island. Two DNA fragments from this CpG island interact with nuclear proteins from NIH 3T3 cells. One fragment partially covers the block of conserved nucleotides. Human, ovine and porcine LIF genes also contain G+C- and CpG-rich sequences in the corresponding region

The challenge of predicting groundwater quality impacts in a CO2 leakage scenario: Results from field, laboratory, and modeling studies at a natural analog site in New Mexico, USA

AbstractA vital aspect to public and regulatory acceptance of carbon sequestration is assurance that groundwater resources will be protected. Theoretical and laboratory studies can, to some extent, be used to predict the consequences of leakage. However, direct observations of CO2 flowing through shallow drinking water aquifers are invaluable for informing credible risk assessments. To this end, we have sampled shallow wells in a natural analog site in New Mexico, USA, where CO2 from natural sources is upwelling from depth. We collected major ion, trace element, and isotopic (3H, 18O, and Sr) data and, coupled with laboratory experiments and reactive transport modeling, have concluded that the major control on groundwater quality at this site is not chemical reaction of CO2 with the aquifer but intrusion of saline waters upwelling with the CO2.Using reactive transport modeling based on field data, we show the difference in reactivity of the CO2 and CO2/saline water source terms, particularly with respect to carbonate mineralogy. Sr isotopes were used to investigate whether aquifer waters were affected by carbonate mineral reaction with CO2 or by saline water intrusion. Preliminary data suggest that Sr isotopes can successfully be used to discriminate between the two types of source terms at Chimayó; this technique shows promise for monitoring CCS sites.In developing predictive capabilities for future sites, it is critical to identify the solid phases and specific reactions controlling dissolved trace metal concentrations in both the presence and absence of CO2. We have conducted laboratory experiments to identify these phases and have found that some elements (e.g., U, Ca) are largely controlled by ion exchange and/or carbonate minerals. In the experiments, the concentration of some metals increases after exposure to CO2 (although concentrations remain below the U.S. EPA primary drinking water standards); we are currently extending these experiments to determine if the reactions causing the increase are reversible and, if so, on what time scales. Metal scavenging by secondary mineral precipitation, as observed at other natural analog sites, may be important at certain temporal scales.We are using the information gained from this field and laboratory study to develop predictive models for application to risk assessment at future CCS sites. The models will be particularly useful in identifying the temporal and spatial scales of water quality changes and in developing possible mitigation strategies in the case of leaks at engineered CCS sites

SCN1A variants from bench to bedside-improved clinical prediction from functional characterization

Variants in the SCN1A gene are associated with a wide range of disorders including genetic epilepsy with febrile seizures plus (GEFS+), familial hemiplegic migraine (FHM), and the severe childhood epilepsy Dravet syndrome (DS). Predicting disease outcomes based on variant type remains challenging. Despite thousands of SCN1A variants being reported, only a minority has been functionally assessed. We review the functional SCN1A work performed to date, critically appraise electrophysiological measurements, compare this to in silico predictions, and relate our findings to the clinical phenotype. Our results show, regardless of the underlying phenotype, that conventional in silico software correctly predicted benign from pathogenic variants in nearly 90%, however was unable to differentiate within the disease spectrum (DS vs. GEFS+ vs. FHM). In contrast, patch‐clamp data from mammalian expression systems revealed functional differences among missense variants allowing discrimination between disease severities. Those presenting with milder phenotypes retained a degree of channel function measured as residual whole‐cell current, whereas those without any whole‐cell current were often associated with DS (p = .024). These findings demonstrate that electrophysiological data from mammalian expression systems can serve as useful disease biomarker when evaluating SCN1A variants, particularly in view of new and emerging treatment options in DS

On the dynamics of planetesimals embedded in turbulent protoplanetary discs

(abridged) Angular momentum transport and accretion in protoplanetary discs are generally believed to be driven by MHD turbulence via the magneto-rotational instability (MRI). The dynamics of solid bodies embedded in such discs (dust grains, boulders, planetesimals and planets) may be strongly affected by the turbulence, such that the formation pathways for planetary systems are determined in part by the strength and spatial distribution of the turbulent flow. We examine the dynamics of planetesimals, with radii between 1m \^a 10 km, embedded in turbulent protoplanetary discs, using three dimensional MHD simulations. The planetesimals experience gas drag and stochastic gravitational forces due to the turbulent disc. We use, and compare the results from, local shearing box simulations and global models in this study. The main aims of this work are to examine: the growth, and possible saturation, of the velocity dispersion of embedded planetesimals as a function of their size and disc parameters; the rate of radial migration and diffusion of planetesimals; the conditions under which the results from shearing box and global simulations agree. We find good agreement between local and global simulations when shearing boxes of dimension 4H x 16H x 2H are used (H being the local scale height). The magnitude of the density fluctuations obtained is sensitive to the box size, due to the excitation and propagation of spiral density waves. This affects the stochastic forcing experienced by planetesimals. [...] Our models show that fully developed MHD turbulence in protoplanetary discs would have a destructive effect on embedded planetesimals. Relatively low levels of turbulence are required for traditional models of planetesimal accretion to operate, this being consistent with the existence of a dead zone in protoplanetary discs.Comment: 23 pages, 28 figures, 3 tables, accepted for publication in MNRA

Uranium(III) coordination chemistry and oxidation in a flexible small-cavity macrocycle

U(III) complexes of the conformationally flexible, small-cavity macrocycle trans-calix[2]benzene[2]pyrrolide (L)2–, [U(L)X] (X = O-2,6-tBu2C6H3, N(SiMe3)2), have been synthesized from [U(L)BH4] and structurally characterized. These complexes show binding of the U(III) center in the bis(arene) pocket of the macrocycle, which flexes to accommodate the increase in the steric bulk of X, resulting in long U–X bonds to the ancillary ligands. Oxidation to the cationic U(IV) complex [U(L)X][B(C6F5)4] (X = BH4) results in ligand rearrangement to bind the smaller, harder cation in the bis(pyrrolide) pocket, in a conformation that has not been previously observed for (L)2–, with X located between the two ligand arene rings

Effects of multiple occupancy and inter-particle interactions on selective transport through narrow channels: theory versus experiment

Many biological and artificial transport channels function without direct input of metabolic energy during a transport event and without structural rearrangements involving transitions from a 'closed' to an 'open' state. Nevertheless, such channels are able to maintain efficient and selective transport. It has been proposed that attractive interactions between the transported molecules and the channel can increase the transport efficiency and that the selectivity of such channels can be based on the strength of the interaction of the specifically transported molecules with the channel. Herein, we study the transport through narrow channels in a framework of a general kinetic theory, which naturally incorporates multi-particle occupancy of the channel and non-single-file transport. We study how the transport efficiency and the probability of translocation through the channel are affected by inter-particle interactions in the confined space inside the channel, and establish conditions for selective transport. We compare the predictions of the model with the available experimental data - and find good semi-quantitative agreement. Finally, we discuss applications of the theory to the design of artificial nano-molecular sieves.Comment: 27 pages, 6 figures, 1 Appendix, in press in Biophysical Journa

Different views on Digital Scholarship: separate worlds or cohesive research field?

This article presents a systematic review of the literature on Digital Scholarship, aimed at better understanding the collocation of this research area at the crossroad of several disciplines and strands of research. The authors analysed 45 articlesin order to draw a picture of research in this area. In the first phase, the articles were classified, and relevant quantitative and qualitative data were analysed. Results showed that three clear strands of research do exist: Digital Libraries, Networked Scholarship and Digital Humanities. Moreover, researchers involved in this research area tackle the problems related to technological uptake in the scholar's profession from different points of view, and define the field in different – often complementary – ways, thus generating the perception of a research area still in need of a unifying vision. In the second phase, authors searched for evidence of the disciplinary contributions and interdisciplinary cohesion of research carried out in this area through the use of bibliometric maps. Results suggest that the area of Digital Scholarship, still in its infancy, is advancing in a rather fragmented way, shaping itself around the above-mentioned strands, each with its own research agenda. However, results from the cross-citation analysis suggest that the Networked Scholarship strand is more cohesive than the others in terms of cross-citations

Early childhood epilepsies:epidemiology, classification, aetiology, and socio-economic determinants

Epilepsies of early childhood are frequently resistant to therapy and often associated with cognitive and behavioural comorbidity. Aetiology focused precision medicine, notably gene-based therapies, may prevent seizures and comorbidities. Epidemiological data utilizing modern diagnostic techniques including whole genome sequencing and neuroimaging can inform diagnostic strategies and therapeutic trials. We present a 3-year, multicentre prospective cohort study, involving all children under 3 years of age in Scotland presenting with epilepsies. We used two independent sources for case identification: clinical reporting and EEG record review. Capture-recapture methodology was then used to improve the accuracy of incidence estimates. Socio-demographic and clinical details were obtained at presentation, and 24 months later. Children were extensively investigated for aetiology. Whole genome sequencing was offered for all patients with drug-resistant epilepsy for whom no aetiology could yet be identified. Multivariate logistic regression modelling was used to determine associations between clinical features, aetiology, and outcome. Three hundred and ninety children were recruited over 3 years. The adjusted incidence of epilepsies presenting in the first 3 years of life was 239 per 100 000 live births [95% confidence interval (CI) 216–263]. There was a socio-economic gradient to incidence, with a significantly higher incidence in the most deprived quintile (301 per 100 000 live births, 95% CI 251–357) compared with the least deprived quintile (182 per 100 000 live births, 95% CI 139–233), χ2 odds ratio = 1.7 (95% CI 1.3–2.2). The relationship between deprivation and incidence was only observed in the group without identified aetiology, suggesting that populations living in higher deprivation areas have greater multifactorial risk for epilepsy. Aetiology was determined in 54% of children, and epilepsy syndrome was classified in 54%. Thirty-one per cent had an identified genetic cause for their epilepsy. We present novel data on the aetiological spectrum of the most commonly presenting epilepsies of early childhood. Twenty-four months after presentation, 36% of children had drug-resistant epilepsy (DRE), and 49% had global developmental delay (GDD). Identification of an aetiology was the strongest determinant of both DRE and GDD. Aetiology was determined in 82% of those with DRE, and 75% of those with GDD. In young children with epilepsy, genetic testing should be prioritized as it has the highest yield of any investigation and is most likely to inform precision therapy and prognosis. Epilepsies in early childhood are 30% more common than previously reported. Epilepsies of undetermined aetiology present more frequently in deprived communities. This likely reflects increased multifactorial risk within these populations

Physiology and Pharmacology Feedback via Ca 2þ -Activated Ion Channels Modulates Endothelin 1 Signaling in Retinal Arteriolar Smooth Muscle

PURPOSE. To investigate the role of feedback by Ca 2þ -sensitive plasma-membrane ion channels in endothelin 1 (Et1) signaling in vitro and in vivo. METHODS. Et1 responses were imaged from Fluo-4-loaded smooth muscle in isolated segments of rat retinal arteriole using two-dimensional (2-D) confocal laser microscopy. Vasoconstrictor responses to intravitreal injections of Et1 were recorded in the absence and presence of appropriate ion channel blockers using fluorescein angiograms imaged using a confocal scanning laser ophthalmoscope. RESULTS. Et1 (10 nM) increased both basal [Ca 2þ ] i and the amplitude and frequency of Ca 2þ -waves in retinal arterioles. The Ca 2þ -activated Cl --channel blockers DIDS and 9-anthracene carboxylic acid (9AC) blocked Et1-induced increases in wave frequency, and 9AC also inhibited the increase in amplitude. Iberiotoxin, an inhibitor of large conductance (BK) Ca 2þ -activated K þ -channels, increased wave amplitude in the presence of Et1 but had no effect on frequency

On the dynamics of planetesimals embedded in turbulent protoplanetary discs with dead zones

(abridged) Accretion in protoplanetary discs is thought to be driven by [...] turbulence via the magnetorotational instability (MRI). Recent work has shown that a planetesimal swarm embedded in a fully turbulent disc is subject to strong excitation of the velocity dispersion, leading to collisional destruction of bodies with radii R_p < 100 km. Significant diffusion of planetesimal semimajor axes also arises, leading to large-scale spreading of the planetesimal population throughout the inner regions of the protoplanetary disc, in apparent contradiction of constraints provided by the distribution of asteroids within the asteroid belt. In this paper, we examine the dynamics of planetesimals embedded in vertically stratified turbulent discs, with and without dead zones. Our main aims are to examine the turbulent excitation of the velocity dispersion, and the radial diffusion, of planetesimals in these discs. We employ three dimensional MHD simulations [...], along with an equilibrium chemistry model [...] We find that planetesimals in fully turbulent discs develop large random velocities that will lead to collisional destruction/erosion for bodies with sizes below 100 km, and undergo radial diffusion on a scale \sim 2.5 au over a 5 Myr disc life time. But planetesimals in a dead zone experience a much reduced excitation of their random velocities, and equilibrium velocity dispersions lie between the disruption thresholds for weak and strong aggregates for sizes R_p < 100 km. We also find that radial diffusion occurs over a much reduced length scale \sim 0.25 au over the disc life time, this being consistent with solar system constraints. We conclude that planetesimal growth via mutual collisions between smaller bodies cannot occur in a fully turbulent disc. By contrast, a dead zone may provide a safe haven in which km-sized planetesimals can avoid mutual destruction through collisions.Comment: 18 pages, 13 figures, 3 tables, MNRAS in press, minor corrections to match the published versio