Nonlinear competition between asters and stripes in filament-motor-systems

A model for polar filaments interacting via molecular motor complexes is investigated which exhibits bifurcations to spatial patterns. It is shown that the homogeneous distribution of filaments, such as actin or microtubules, may become either unstable with respect to an orientational instability of a finite wave number or with respect to modulations of the filament density, where long wavelength modes are amplified as well. Above threshold nonlinear interactions select either stripe patterns or periodic asters. The existence and stability ranges of each pattern close to threshold are predicted in terms of a weakly nonlinear perturbation analysis, which is confirmed by numerical simulations of the basic model equations. The two relevant parameters determining the bifurcation scenario of the model can be related to the concentrations of the active molecular motors and of the filaments respectively, which both could be easily regulated by the cell.Comment: 13 pages, 7 figure

Abundance ratios in the hot ISM of elliptical galaxies

To constrain the recipes put forth to solve the theoretical Fe discrepancy in the hot interstellar medium of elliptical galaxies and at the same time explain the [alpha/Fe] ratios. In order to do so we use the latest theoretical nucleosynthetic yields, we incorporate the dust, we explore differing SNIa progenitor scenarios by means of a self-consistent chemical evolution model which reproduces the properties of the stellar populations in elliptical galaxies. Models with Fe-only dust and/or a lower effective SNIa rate achieve a better agreement with the observed Fe abundance. However, a suitable modification to the SNIa yield with respect to the standard W7 model is needed to fully match the abundance ratio pattern. The 2D explosion model C-DDT by Maeda et al. (2010) is a promising candidate for reproducing the [Fe/H] and the [alpha/Fe] ratios. (A&A format)Comment: 11 pages, 4 figures, to appear on A&

Large-Scale Atomistic Simulations of Environmental Effects on the Formation and Properties of Molecular Junctions

Using an updated simulation tool, we examine molecular junctions comprised of benzene-1,4-dithiolate bonded between gold nanotips, focusing on the importance of environmental factors and inter-electrode distance on the formation and structure of bridged molecules. We investigate the complex relationship between monolayer density and tip separation, finding that the formation of multi-molecule junctions is favored at low monolayer density, while single-molecule junctions are favored at high density. We demonstrate that tip geometry and monolayer interactions, two factors that are often neglected in simulation, affect the bonding geometry and tilt angle of bridged molecules. We further show that the structures of bridged molecules at 298 and 77 K are similar.Comment: To appear in ACS Nano, 30 pages, 5 figure

Ultraluminous X-ray sources out to z~0.3 in the COSMOS field

Using Chandra observations we have identified a sample of seven off-nuclear X-ray sources, in the redshift range z=0.072-0.283, located within optically bright galaxies in the COSMOS Survey. Using the multi-wavelength coverage available in the COSMOS field, we study the properties of the host galaxies of these ULXs. In detail, we derived their star formation rate from H_alpha measurements and their stellar masses using SED fitting techniques with the aim to compute the probability to have an off-nuclear source based on the host galaxy properties. We divide the host galaxies in different morphological classes using the available ACS/HST imaging. We find that our ULXs candidates are located in regions of the SFR versus M$_star$ plane where one or more off-nuclear detectable sources are expected. From a morphological analysis of the ACS imaging and the use of rest-frame colours, we find that our ULXs are hosted both in late and early type galaxies. Finally, we find that the fraction of galaxies hosting a ULX ranges from ~0.5% to ~0.2% going from L[0.5-2 keV]=3 x 10^39 erg s^-1 to L[0.5-2 keV]= 2 x 10^40 erg s^-1.Comment: 10 pages, 9 figures, accepted for publication in Astronomy & Astrophysic

The radio properties of a complete, X-ray selected sample of nearby, massive elliptical galaxies

We investigate the radio properties of a complete sample of nearby, massive, X-ray bright elliptical and S0 galaxies. Our sample contains 18 galaxies with ROSAT All-Sky Survey X-ray fluxes Fx_(0.1-2.4 keV) > 3 x 10^(-12) erg/s/cm^2, within a distance of 100 Mpc. For these galaxies, we have complete (18/18) VLA radio and Chandra X-ray coverage. Nuclear radio emission is detected from 17/18 of the galaxies. Ten of the galaxies exhibit extended radio emission; of these ten, all but one also exhibit clear evidence of interaction of the radio source with the surrounding, X-ray emitting gas. Among the seven galaxies with unresolved radio sources, one has clear, and one has small, cavity-like features in the Chandra X-ray images; a third has a disturbed X-ray morphology. Using a radio luminosity limit equivalent to L_(1.4 Ghz) > 10^(23) W/Hz to calculate the radio-loud fraction, we find that this misses the majority of the radio detected galaxies in the sample. We determine integrated radio-to-X-ray flux ratios for the galaxies, GRx, which are shown to span a large range (factor of 100). We calculate the mass-weighted cooling times within 1 kpc, and find hints for an anticorrelation with the radio luminosity. We also calculate limits on k/f, where k is the ratio of the total particle energy to that of relativistic electrons radiating in the range 10 MHz-10 GHz and f is the volume filling factor of the plasma in the cavity. The k/f distribution is also broad, reflecting previous results for larger galaxy clusters. Lowering the X-ray flux limit, at the expense of less complete VLA and Chandra coverage, increases the size of our sample to 42 galaxies. Nuclear radio activity is detected in at least 34/42 of this extended sample.Comment: Accepted for publication in MNRAS, 19 pages, 11 Figures and 7 Table

Immersed boundary-finite element model of fluid-structure interaction in the aortic root

It has long been recognized that aortic root elasticity helps to ensure efficient aortic valve closure, but our understanding of the functional importance of the elasticity and geometry of the aortic root continues to evolve as increasingly detailed in vivo imaging data become available. Herein, we describe fluid-structure interaction models of the aortic root, including the aortic valve leaflets, the sinuses of Valsalva, the aortic annulus, and the sinotubular junction, that employ a version of Peskin's immersed boundary (IB) method with a finite element (FE) description of the structural elasticity. We develop both an idealized model of the root with three-fold symmetry of the aortic sinuses and valve leaflets, and a more realistic model that accounts for the differences in the sizes of the left, right, and noncoronary sinuses and corresponding valve cusps. As in earlier work, we use fiber-based models of the valve leaflets, but this study extends earlier IB models of the aortic root by employing incompressible hyperelastic models of the mechanics of the sinuses and ascending aorta using a constitutive law fit to experimental data from human aortic root tissue. In vivo pressure loading is accounted for by a backwards displacement method that determines the unloaded configurations of the root models. Our models yield realistic cardiac output at physiological pressures, with low transvalvular pressure differences during forward flow, minimal regurgitation during valve closure, and realistic pressure loads when the valve is closed during diastole. Further, results from high-resolution computations demonstrate that IB models of the aortic valve are able to produce essentially grid-converged dynamics at practical grid spacings for the high-Reynolds number flows of the aortic root

The impact of early discontinuation/dose modification of venetoclax on outcomes in patients with relapsed/refractory chronic lymphocytic leukemia: <i>post-hoc</i> analyses from the phase III MURANO study

Fixed-duration venetoclax plus rituximab (VenR) has a manageable safety profile and improves survival in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). We present data from the phase III MURANO study on the impact of venetoclax modification or premature discontinuation on outcomes in patients with R/R CLL. Timedependent Cox proportional hazards regression models, stratified by 17p deletion and risk status, evaluated the impact of venetoclax discontinuation/ modification on investigator-assessed progression-free survival (PFS) and overall survival (OS). Analyses were performed retrospectively (without type-1 error control) in intention-to-treat patients from the VenR arm of MURANO. Overall, 140 of 194 (72%) patients in the VenR arm completed 2 years of therapy; 54 of 194 (28%) patients prematurely discontinued treatment. Inferior PFS was observed in patients prematurely discontinuing venetoclax for any reason (disease progression excluded; P<0.0001) and specifically in patients discontinuing due to adverse event (AE) (P<0.0001), versus those who did not discontinue early. Risk of a PFS/OS event was significantly reduced by each extra month (exposure cycle) of venetoclax therapy (P=0.0263 for PFS; P<0.0001 for OS). Treatment interruption for AE occurred in 134 of 194 (69%) patients, most commonly due to neutropenia (84 of 194; 43%), per protocol requirements. Treatment interruption had no impact on PFS or OS, regardless of duration. Dose reductions were required by 45 of 194 (23%) patients, but had no significant impact on outcomes. In MURANO, premature discontinuation was associated with suboptimal outcomes; venetoclax treatment modification was not. These data highlight the importance of effective toxicity control to realize the full benefit of venetoclax treatment (clinicaltrials gov. Identifier: NCT02005471)

A Longitudinal 6-Year Study of the Molecular Epidemiology of Clinical Campylobacter Isolates in Oxfordshire, United Kingdom

Temporal and seasonal trends in Campylobacter genotypes causing human gastroenteritis were investigated in a 6-year study of 3,300 recent isolates from Oxfordshire, United Kingdom. Genotypes (sequence types [ST]) were defined using multilocus sequence typing and assigned to a clonal complex (a cluster of related strains that share four or more identical alleles with a previously defined central genotype). A previously undescribed clonal complex (ST-464) was identified which, together with ST-42, ST-45, and ST-52 complexes, showed increasing incidence. Concurrently, the incidence of ST-574, ST-607, and ST-658 complexes declined. The relative frequencies of three clonal complexes (ST-45, ST-283, and ST-42) peaked during summer and those of two (ST-353 and ST-403) peaked during winter. Nine clonal complexes (ST-22, ST-45, ST-48, ST-61, ST-257, ST-283, ST-403, ST-658, and ST-677) were significantly associated with ciprofloxacin sensitivity (P < 0.05). Seven clonal complexes (ST-49, ST-206, ST-354, ST-446, ST-460, ST-464, and ST-607) were associated with ciprofloxacin resistance (P < 0.05). Clonal complexes exhibited changing incidence and differences in seasonality and antibiotic resistance phenotype. These data also demonstrated that detailed surveillance at a single site captures information which reflects that observed nationally

Protein misfolding is the molecular mechanism underlying MCADD identified in newborn screening

Newborn screening (NBS) for medium-chain acyl-CoA dehydrogenase deficiency (MCADD) revealed a higher birth prevalence and genotypic variability than previously estimated, including numerous novel missense mutations in the ACADM gene. On average, these mutations are associated with milder biochemical phenotypes raising the question about their pathogenic relevance. In this study, we analyzed the impact of 10 ACADM mutations identified in NBS (A27V, Y42H, Y133H, R181C, R223G, D241G, K304E, R309K, I331T and R388S) on conformation, stability and enzyme kinetics of the corresponding proteins. Partial to total rescue of aggregation by co-overexpression of GroESL indicated protein misfolding. This was confirmed by accelerated thermal unfolding in all variants, as well as decreased proteolytic stability and accelerated thermal inactivation in most variants. Catalytic function varied from high residual activity to markedly decreased activity or substrate affinity. Mutations mapping to the β-domain of the protein predisposed to severe destabilization. In silico structural analyses of the affected amino acid residues revealed involvement in functionally relevant networks. Taken together, our results substantiate the hypothesis of protein misfolding with loss-of-function being the common molecular basis in MCADD. Moreover, considerable structural alterations in all analyzed variants do not support the view that novel mutations found in NBS bear a lower risk of metabolic decompensation than that associated with mutations detected in clinically ascertained patients. Finally, the detailed insight into how ACADM missense mutations induce loss of MCAD function may provide guidance for risk assessment and counseling of patients, and in future may assist delineation of novel pharmacological strategies