Nanoscale FasL Organization on DNA Origami to Decipher Apoptosis Signal Activation in Cells

Cell signaling is initiated by characteristic protein patterns in the plasma membrane, but tools to decipher their molecular organization and activation are hitherto lacking. Among the well-known signaling pattern is the death inducing signaling complex with a predicted hexagonal receptor architecture. To probe this architecture, DNA origami-based nanoagents with nanometer precise arrangements of the death receptor ligand FasL are introduced and presented to cells. Mimicking different receptor geometries, these nanoagents act as signaling platforms inducing fastest time-to-death kinetics for hexagonal FasL arrangements with 10 nm inter-molecular spacing. Compared to naturally occurring soluble FasL, this trigger is faster and 100x more efficient. Nanoagents with different spacing, lower FasL number or higher coupling flexibility impede signaling. The results present DNA origami as versatile signaling scaffolds exhibiting unprecedented control over molecular number and geometry. They define molecular benchmarks in apoptosis signal initiation and constitute a new strategy to drive particular cell responses

Quiescent Radio Emission from Southern Late-type M Dwarfs and a Spectacular Radio Flare from the M8 Dwarf DENIS 1048-3956

We report the results of a radio monitoring program conducted at the Australia Telescope Compact Array to search for quiescent and flaring emission from seven nearby Southern late-type M and L dwarfs. Two late-type M dwarfs, the M7 V LHS 3003 and the M8 V DENIS 1048-3956, were detected in quiescent emission at 4.80 GHz. The observed emission is consistent with optically thin gyrosynchrotron emission from mildly relativistic (~1-10 keV) electrons with source densities n_e ~ 10 G magnetic fields. DENIS 1048-3956 was also detected in two spectacular, short-lived flares, one at 4.80 GHz (peak f_nu = 6.0+/-0.8 mJy) and one at 8.64 GHz (peak f_nu = 29.6+/-1.0 mJy) approximately 10 minutes later. The high brightness temperature (T_B >~ 10^13 K), short emission period (~4-5 minutes), high circular polarization (~100%), and apparently narrow spectral bandwidth of these events imply a coherent emission process in a region of high electron density (n_e ~ 10^11-10^12 cm^-3) and magnetic field strength (B ~ 1 kG). If the two flare events are related, the apparent frequency drift in the emission suggests that the emitting source either moved into regions of higher electron or magnetic flux density; or was compressed, e.g., by twisting field lines or gas motions. The quiescent fluxes from the radio-emitting M dwarfs violate the Gudel-Benz empirical radio/X-ray relations, confirming a trend previously noted by Berger et al. (abridged)Comment: 28 pages, 8 figures, accepted for publication in Ap

Blockade of T-cell activation by dithiocarbamates involves novel mechanisms of inhibition of nuclear factor of activated T cells.

Dithiocarbamates (DTCs) have recently been reported as powerful inhibitors of NF-kappaB activation in a number of cell types. Given the role of this transcription factor in the regulation of gene expression in the inflammatory response, NF-kappaB inhibitors have been suggested as potential therapeutic drugs for inflammatory diseases. We show here that DTCs inhibited both interleukin 2 (IL-2) synthesis and membrane expression of antigens which are induced during T-cell activation. This inhibition, which occurred with a parallel activation of c-Jun transactivating functions and expression, was reflected by transfection experiments at the IL-2 promoter level, and involved not only the inhibition of NF-kappaB-driven reporter activation but also that of nuclear factor of activated T cells (NFAT). Accordingly, electrophoretic mobility shift assays (EMSAs) indicated that pyrrolidine DTC (PDTC) prevented NF-kappaB, and NFAT DNA-binding activity in T cells stimulated with either phorbol myristate acetate plus ionophore or antibodies against the CD3-T-cell receptor complex and simultaneously activated the binding of AP-1. Furthermore, PDTC differentially targeted both NFATp and NFATc family members, inhibiting the transactivation functions of NFATp and mRNA induction of NFATc. Strikingly, Western blotting and immunocytochemical experiments indicated that PDTC promoted a transient and rapid shuttling of NFATp and NFATc, leading to their accelerated export from the nucleus of activated T cells. We propose that the activation of an NFAT kinase by PDTC could be responsible for the rapid shuttling of the NFAT, therefore transiently converting the sustained transactivation of this transcription factor that occurs during lymphocyte activation, and show that c-Jun NH2-terminal kinase (JNK) can act by directly phosphorylating NFATp. In addition, the combined inhibitory effects on NFAT and NF-KB support a potential use of DTCs as immunosuppressants

Overcoming the Back Reaction on Turbulent Motions in the Presence of Magnetic Fields

Standard magnetohydrodynamic theories, such as the mean field dynamo theory, have been criticized when the back reaction of the magnetic field on turbulent motions is neglected. For the dynamo, this back reaction has been argued to suppress the turbulent motions required for optimal mean field production. Here it is suggested that if the magnetic field is spatially intermittent, for example residing in flux tubes, the back reaction on turbulent flows may be significantly reduced.Comment: Accepted to Physical Review Letters, 15 pages, plain Te

Lipid-Based Passivation in Nanofluidics

Stretching DNA in nanochannels is a useful tool for direct, visual studies of genomic DNA at the single molecule level. To facilitate the study of the interaction of linear DNA with proteins in nanochannels, we have implemented a highly effective passivation scheme based on lipid bilayers. We demonstrate virtually complete long-term passivation of nanochannel surfaces to a range of relevant reagents, including streptavidin-coated quantum dots, RecA proteins, and RecA-DNA complexes. We show that the performance of the lipid bilayer is significantly better than that of standard bovine serum albumin-based passivation. Finally, we show how the passivated devices allow us to monitor single DNA cleavage events during enzymatic degradation by DNase I. We expect that our approach will open up for detailed, systematic studies of a wide range of protein-DNA interactions with high spatial and temporal resolution

On the rotational evolution of solar- and late-type stars, its magnetic origins, and the possibility of stellar gyrochronology

We propose a simple interpretation of the rotation period data for solar- and late-type stars. The open cluster and Mt. Wilson star observations suggest that rotating stars lie primarily on two sequences, initially called I and C. Some stars lie in the intervening gap. These sequences, and the fractional numbers of stars on each sequence evolve systematically with cluster age, enabling us to construct crude rotational isochrones allowing `stellar gyrochronology', a procedure, upon improvement, likely to yield ages for individual field stars. The age and color dependences of the sequences allow the identification of the underlying mechanism, which appears to be primarily magnetic. The majority of solar- and late-type stars possess a dominant Sun-like, or Interface magnetic field, which connects the convective envelope both to the radiative interior of the star and to the exterior where winds can drain off angular momentum. These stars spin down Skumanich-style. An age-decreasing fraction of young G, K, and M stars, which are rapid rotators, possess only a Convective field which is not only inefficient in depleting angular momentum, but also incapable of coupling the surface convection zone to the inner radiative zone, so that only the outer zone is spun down, and on an exponential timescale. These stars do not yet possess large-scale dynamos. The large-scale magnetic field associated with the dynamo, apparently created by the shear between the decoupled radiative and convective zones, (re)couples the convective and radiative zones and drives a star from the Convective to the Interface sequence through the gap on a timescale that increases as stellar mass decreases. (Abstract is truncated here.)Comment: 32 pages, 6 figures (4 in color), accepted by Ap

The case for a distributed solar dynamo shaped by near-surface shear

Arguments for and against the widely accepted picture of a solar dynamo being seated in the tachocline are reviewed and alternative ideas concerning dynamos operating in the bulk of the convection zone, or perhaps even in the near-surface shear layer, are discussed. Based on the angular velocities of magnetic tracers it is argued that the observations are compatible with a distributed dynamo that may be strongly shaped by the near-surface shear layer. Direct simulations of dynamo action in a slab with turbulence and shear are presented to discuss filling factor and tilt angles of bipolar regions in such a model.Comment: 10 pages, 6 figures, Astrophys. J. 625 (scheduled for the 1 June 2005 issue

Promoting Functional Health in Midlife and Old Age: Long-Term Protective Effects of Control Beliefs, Social Support, and Physical Exercise

Previous studies have examined physical risk factors in relation to functional health, but less work has focused on the protective role of psychological and social factors. We examined the individual and joint protective contribution of control beliefs, social support and physical exercise to changes in functional health, beyond the influence of health status and physical risk factors in middle-aged and older adults. Given that functional health typically declines throughout adulthood, it is important to identify modifiable factors that can be implemented to maintain functioning, improve quality of life, and reduce disability.We conducted a national longitudinal study, Midlife in the United States (MIDUS), with assessments in 1995-1996 and 2004-2006, and 3,626 community-residing adults, aged 32 to 84, were included in the analyses. Functional health (Physical Functioning subscale of the SF-36) and protective factors were measured at both occasions. While controlling for socio-demographic, health status, and physical risk factors (large waist circumference, smoking, and alcohol or drug problems), a composite of the three protective variables (control beliefs, social support, and physical exercise) at Time 1 was significantly related to functional health change. The more of these factors at Time 1, the better the health maintenance over 10 years. Among middle-aged and older adults, declines in health were significantly reduced with an increased number of protective factors.Age-related declines in health were reduced among those with more protective factors up to a decade earlier in life. Modifiable psychological, social, and physical protective factors, individually and in the aggregate, are associated with maintenance of functional health, beyond the damaging effects of physical risk factors. The results are encouraging for the prospect of developing interventions to promote functional health and for reducing public health expenditures for physical disability in later life