A common cardiac sodium channel variant associated with sudden infant death in African Americans, SCN5A S1103Y.

Thousands die each year from sudden infant death syndrome (SIDS). Neither the cause nor basis for varied prevalence in different populations is understood. While 2 cases have been associated with mutations in type Valpha, cardiac voltage-gated sodium channels (SCN5A), the "Back to Sleep" campaign has decreased SIDS prevalence, consistent with a role for environmental influences in disease pathogenesis. Here we studied SCN5A in African Americans. Three of 133 SIDS cases were homozygous for the variant S1103Y. Among controls, 120 of 1,056 were carriers of the heterozygous genotype, which was previously associated with increased risk for arrhythmia in adults. This suggests that infants with 2 copies of S1103Y have a 24-fold increased risk for SIDS. Variant Y1103 channels were found to operate normally under baseline conditions in vitro. As risk factors for SIDS include apnea and respiratory acidosis, Y1103 and wild-type channels were subjected to lowered intracellular pH. Only Y1103 channels gained abnormal function, demonstrating late reopenings suppressible by the drug mexiletine. The variant appeared to confer susceptibility to acidosis-induced arrhythmia, a gene-environment interaction. Overall, homozygous and rare heterozygous SCN5A missense variants were found in approximately 5% of cases. If our findings are replicated, prospective genetic testing of SIDS cases and screening with counseling for at-risk families warrant consideration

Runx1 binds as a dimeric complex to overlapping Runx1 sites within a palindromic element in the human GM-CSF enhancer

Runx1 is a developmentally regulated transcription factor that is essential for haemopoiesis. Runx1 can bind as a monomer to the core consensus sequence TGTGG, but binds more efficiently as a hetero-dimer together with the non-DNA binding protein CBFβ as a complex termed core binding factor (CBF). Here, we demonstrated that CBF can also assemble as a dimeric complex on two overlapping Runx1 sites within the palindromic sequence TGTGGCTGCCCACA in the human granulocyte macrophage colony-stimulating factor enhancer. Furthermore, we demonstrated that binding of Runx1 to the enhancer is rigidly controlled at the level of chromatin accessibility, and is dependent upon prior induction of NFAT and AP-1, which disrupt a positioned nucleosome in this region. We employed in vivo footprinting to demonstrate that, upon activation of the enhancer, both sites are efficiently occupied. In vitro binding assays confirmed that two CBF complexes can bind this site simultaneously, and transfection assays demonstrated that both sites contribute significantly to enhancer function. Computer modelling based on the Runx1/CBFβ/DNA crystal structure further revealed that two molecules of CBF could potentially bind to this class of palindromic sequence as a dimeric complex in a conformation whereby both Runx1 and CBFβ within the two CBF complexes are closely aligned

Simulations of electromagnetic effects in high frequency capacitively coupled discharges using the Darwin approximation

The Darwin approximation is investigated for its possible use in simulation of electromagnetic effects in large size, high frequency capacitively coupled discharges. The approximation is utilized within the framework of two different fluid models which are applied to typical cases showing pronounced standing wave and skin effects. With the first model it is demonstrated that Darwin approximation is valid for treatment of such effects in the range of parameters under consideration. The second approach, a reduced nonlinear Darwin approximation-based model, shows that the electromagnetic phenomena persist in a more realistic setting. The Darwin approximation offers a simple and efficient way of carrying out electromagnetic simulations as it removes the Courant condition plaguing explicit electromagnetic algorithms and can be implemented as a straightforward modification of electrostatic algorithms. The algorithm described here avoids iterative schemes needed for the divergence cleaning and represents a fast and efficient solver, which can be used in fluid and kinetic models for self-consistent description of technical plasmas exhibiting certain electromagnetic activity

Signature of Electron Capture in Iron-Rich Ejecta of SN 2003du

Late-time near-infrared and optical spectra are presented for the normal-bright SN2003du. At about 300 days after the explosion, the emission profiles of well isolated [FeII] lines (in particular that of the strong 1.644mu feature) trace out the global kinematic distribution of radioactive material in the expanding. In SN2003du, the 1.644 mu [FeII] line shows a flat-topped, profile, indicative of a thick but hollow-centered expanding shell, rather than a strongly-peaked profile that would be expected from a ``center-filled'' distribution.Based on detailed models for exploding Chandrasekhar mass white dwarfs, we show that the feature is consistent with spherical explosion models.Our model predicts central region of non-radioactive electron-capture elements up to 2500--3000km/s as a consequence of burning under high density, and an extended region of 56Ni up to 9,000--10,000km/s. Furthermore our analysis indicates that the 1.644mu [FeII] profile is not consistent with strong mixing between the regions of electron- capture isotopes and the 56Ni layers as is predicted by detailed 3D models for nuclear deflagration fronts. We discuss the possibility that the flat-topped profile could be produced as a result of an infrared catastrophe and conclude that such an explanation is unlikely. We put our results in context to other SNeIa and briefly discuss the implications of our result for the use of SNe Ia as cosmological standard candles.Comment: 12 pages + 8 figures, ApJ (in press, Dec. 20, 2004) For high resolution figures send E-mail to [email protected]

Reconceiving Reproductive Health

While reproduction is fairly often touched upon in theological and Christian ethical discussions, reproductive health is not. However, reproductive health is a matter of theological and ethical concern. Discussion pertaining to reproductive health includes a number of debates about, for instance, abortion and the termination of pregnancy, reproductive loss, childlessness, infertility, stillbirth, miscarriage and adoption. Additionally, new reproductive possibilities made available by the development of reproductive technology have necessitated theological and ethical reflection on, for example, surrogacy, post-menopausal pregnancies, litter births, single mothers or fathers by choice, in vitro fertilisation and the so-called saviour siblings. These new developments compel us to reconceive our notions of what reproductive health is or should be. Many of these topics are receiving increasing attention in a variety of theological publications. The focus of this volume is unique, however, and to the best of our knowledge, this is the first volume dealing not only with reproductive issues, but also reflecting theologically and ethically on reproductive health. It makes a contribution by providing a variety of perspectives from different theological fields on this theme, and in many chapters, focussing especially on the South African context. These discussions are also part of urgent debates within churches, which require developing life-giving theological language and imaginative theological alternatives that may speak to experiences of matters relating to reproductive health. The popular books, TV series and films that touch upon these discussions – including The Handmaid’s Tale and Mother! – strengthen the perception that a more in-depth theological and ethical discussion on the theme may be necessary, particularly towards exploring stories and confessions from our faith tradition that may provide us with a timely opportunity to do the important work of theological ‘reconceiving’

Infrared Spectra of the Subluminous Type Ia Supernova 1999by

Near-infrared spectra of the subluminous Type Ia SN1999by are presented which cover the time evolution from about 4 days before to 2 weeks after maximum. Analysis of these data was accomplished through the construction of an extended set of delayed detonation (DD) models. The explosion, light curves and spectra including their evolution with time are calculated consistently leaving the initial WD and the description of the nuclear burning front the free parameters. We cover the entire range of normal to subluminous SNeIa. From this model set, one was selected for SN99by by matching properties of the synthetic & observed optical light curves. We find DD models require a certain amount of burning during the deflagration phase setting a lower limit for the absolute brightness. For SN1999by, a model close to the minimum 56Ni production is required. Without tuning,good agreement has been found between synthetic and observed IR spectra. In contrast to 'normal' SNeIa and prior to maximum, the NIR spectra of SN1999by are dominated by products of explosive carbon burning. Spectra taken after maximum are dominated by products of incomplete Si burning. Pure deflagration scenarios or mergers are unlikely. However,problems for DD models still remain, as the data seem to be at odds with recent predictions from 3-D models which find significant mixing of the inner layers. Possible solutions include the effects of rapid rotation on the propagation of nuclear flames, or extensive burning of carbon just prior to the runaway.Comment: 42 pages including 14 figures, ApJ, accepte

Improving the hyperpolarization of (31)p nuclei by synthetic design

Traditional (31)P NMR or MRI measurements suffer from low sensitivity relative to (1)H detection and consequently require longer scan times. We show here that hyperpolarization of (31)P nuclei through reversible interactions with parahydrogen can deliver substantial signal enhancements in a range of regioisomeric phosphonate esters containing a heteroaromatic motif which were synthesized in order to identify the optimum molecular scaffold for polarization transfer. A 3588-fold (31)P signal enhancement (2.34% polarization) was returned for a partially deuterated pyridyl substituted phosphonate ester. This hyperpolarization level is sufficient to allow single scan (31)P MR images of a phantom to be recorded at a 9.4 T observation field in seconds that have signal-to-noise ratios of up to 94.4 when the analyte concentration is 10 mM. In contrast, a 12 h 2048 scan measurement under standard conditions yields a signal-to-noise ratio of just 11.4. (31)P-hyperpolarized images are also reported from a 7 T preclinical scanner

Comparative Microbial Modules Resource: Generation and Visualization of Multi-species Biclusters

The increasing abundance of large-scale, high-throughput datasets for many closely related organisms provides opportunities for comparative analysis via the simultaneous biclustering of datasets from multiple species. These analyses require a reformulation of how to organize multi-species datasets and visualize comparative genomics data analyses results. Recently, we developed a method, multi-species cMonkey, which integrates heterogeneous high-throughput datatypes from multiple species to identify conserved regulatory modules. Here we present an integrated data visualization system, built upon the Gaggle, enabling exploration of our method's results (available at http://meatwad.bio.nyu.edu/cmmr.html). The system can also be used to explore other comparative genomics datasets and outputs from other data analysis procedures – results from other multiple-species clustering programs or from independent clustering of different single-species datasets. We provide an example use of our system for two bacteria, Escherichia coli and Salmonella Typhimurium. We illustrate the use of our system by exploring conserved biclusters involved in nitrogen metabolism, uncovering a putative function for yjjI, a currently uncharacterized gene that we predict to be involved in nitrogen assimilation