Improving Cosmological Distance Measurements by Reconstruction of the Baryon Acoustic Peak

The baryon acoustic oscillations are a promising route to the precision measure of the cosmological distance scale and hence the measurement of the time evolution of dark energy. We show that the non-linear degradation of the acoustic signature in the correlations of low-redshift galaxies is a correctable process. By suitable reconstruction of the linear density field, one can sharpen the acoustic peak in the correlation function or, equivalently, restore the higher harmonics of the oscillations in the power spectrum. With this, one can achieve better measurements of the acoustic scale for a given survey volume. Reconstruction is particularly effective at low redshift, where the non-linearities are worse but where the dark energy density is highest. At z=0.3, we find that one can reduce the sample variance error bar on the acoustic scale by at least a factor of 2 and in principle by nearly a factor of 4. We discuss the significant implications our results have for the design of galaxy surveys aimed at measuring the distance scale through the acoustic peak.Comment: 5 pages, LaTeX. Submitted to the Astrophysical Journa

The Clustering of Massive Halos

The clustering properties of dark matter halos are a firm prediction of modern theories of structure formation. We use two large volume, high-resolution N-body simulations to study how the correlation function of massive dark matter halos depends upon their mass and formation history. We find that halos with the lowest concentrations are presently more clustered than those of higher concentration, the size of the effect increasing with halo mass; this agrees with trends found in studies of lower mass halos. The clustering dependence on other characterizations of the full mass accretion history appears weaker than the effect with concentration. Using the integrated correlation function, marked correlation functions, and a power-law fit to the correlation function, we find evidence that halos which have recently undergone a major merger or a large mass gain have slightly enhanced clustering relative to a randomly chosen population with the same mass distribution.Comment: 10 pages, 8 figures; text improved, references and one figure added; accepted for publication in Ap

LIM kinase inhibitors disrupt mitotic microtubule organization and impair tumor cell proliferation

The actin and microtubule cytoskeletons are critically important for cancer cell proliferation, and drugs that target microtubules are widely-used cancer therapies. However, their utility is compromised by toxicities due to dose and exposure. To overcome these issues, we characterized how inhibition of the actin and microtubule cytoskeleton regulatory LIM kinases could be used in drug combinations to increase efficacy. A previously-described LIMK inhibitor (LIMKi) induced dose-dependent microtubule alterations that resulted in significant mitotic defects, and increased the cytotoxic potency of microtubule polymerization inhibitors. By combining LIMKi with 366 compounds from the GSK Published Kinase Inhibitor Set, effective combinations were identified with kinase inhibitors including EGFR, p38 and Raf. These findings encouraged a drug discovery effort that led to development of CRT0105446 and CRT0105950, which potently block LIMK1 and LIMK2 activity in vitro, and inhibit cofilin phosphorylation and increase αTubulin acetylation in cells. CRT0105446 and CRT0105950 were screened against 656 cancer cell lines, and rhabdomyosarcoma, neuroblastoma and kidney cancer cells were identified as significantly sensitive to both LIMK inhibitors. These large-scale screens have identified effective LIMK inhibitor drug combinations and sensitive cancer types. In addition, the LIMK inhibitory compounds CRT0105446 and CRT0105950 will enable further development of LIMK-targeted cancer therapy

Seeking the Local Convergence Depth. V. Tully-Fisher Peculiar Velocities for 52 Abell Clusters

We have obtained I band Tully-Fisher (TF) measurements for 522 late-type galaxies in the fields of 52 rich Abell clusters distributed throughout the sky between 50 and 200\h Mpc. Here we estimate corrections to the data for various forms of observational bias, most notably Malmquist and cluster population incompleteness bias. The bias-corrected data are applied to the construction of an I band TF template, resulting in a relation with a dispersion of 0.38 magnitudes and a kinematical zero-point accurate to 0.02 magnitudes. This represents the most accurate TF template relation currently available. Individual cluster TF relations are referred to the average template relation to compute cluster peculiar motions. The line-of-sight dispersion in the peculiar motions is 341+/-93 km/s, in general agreement with that found for the cluster sample of Giovanelli and coworkers.Comment: 31 pages, 14 figures, uses AAS LaTeX; to appear in the Astronomical Journa

Actin-myosin–based contraction is responsible for apoptotic nuclear disintegration

Membrane blebbing during the apoptotic execution phase results from caspase-mediated cleavage and activation of ROCK I. Here, we show that ROCK activity, myosin light chain (MLC) phosphorylation, MLC ATPase activity, and an intact actin cytoskeleton, but not microtubular cytoskeleton, are required for disruption of nuclear integrity during apoptosis. Inhibition of ROCK or MLC ATPase activity, which protect apoptotic nuclear integrity, does not affect caspase-mediated degradation of nuclear proteins such as lamins A, B1, or C. The conditional activation of ROCK I was sufficient to tear apart nuclei in lamin A/C null fibroblasts, but not in wild-type fibroblasts. Thus, apoptotic nuclear disintegration requires actin-myosin contractile force and lamin proteolysis, making apoptosis analogous to, but distinct from, mitosis where nuclear disintegration results from microtubule-based forces and from lamin phosphorylation and depolymerization

The cyclin-dependent kinase PITSLRE/CDK11 is required for successful autophagy

(Macro)autophagy is a membrane-trafficking process that serves to sequester cellular constituents in organelles termed autophagosomes, which target their degradation in the lysosome. Autophagy operates at basal levels in all cells where it serves as a homeostatic mechanism to maintain cellular integrity. The levels and cargoes of autophagy can, however, change in response to a variety of stimuli, and perturbations in autophagy are known to be involved in the aetiology of various human diseases. Autophagy must therefore be tightly controlled. We report here that the Drosophila cyclin-dependent kinase PITSLRE is a modulator of autophagy. Loss of the human PITSLRE orthologue, CDK11, initially appears to induce autophagy, but at later time points CDK11 is critically required for autophagic flux and cargo digestion. Since PITSLRE/CDK11 regulates autophagy in both Drosophila and human cells, this kinase represents a novel phylogenetically conserved component of the autophagy machinery

Optical pulse labeling studies reveal exogenous seeding slows α-synuclein clearance

The accumulation of α-synuclein (α-syn) in intracellular formations known as Lewy bodies (LBs) is associated with several neurodegenerative diseases including Parkinson's disease and Lewy Body Dementia. There is still limited understanding of how α-syn and LB formation is associated with cellular dysfunction and degeneration in these diseases. To examine the clearance and production dynamics of α-syn we transduced organotypic murine brain slice cultures (BSCs) with recombinant adeno-associated viruses (rAAVs) to express Dendra2-tagged human wild-type (WT) and mutant A53T α-syn, with and without the addition of exogenous α-syn fibrillar seeds and tracked them over several weeks in culture using optical pulse labeling. We found that neurons expressing WT or mutant A53T human α-syn show similar rates of α-syn turnover even when insoluble, phosphorylated Ser129 α-syn has accumulated. Taken together, this data reveals α-syn aggregation and overexpression, pSer129 α-syn, nor the A53T mutation affect α-syn dynamics in this system. Prion-type seeding with exogenous α-syn fibrils significantly slows α-syn turnover, in the absence of toxicity but is associated with the accumulation of anti-p62 immunoreactivity and Thiazin Red positivity. Prion-type induction of α-syn aggregation points towards a potential protein clearance deficit in the presence of fibrillar seeds and the ease of this system to explore precise mechanisms underlying these processes. This system facilitates the exploration of α-syn protein dynamics over long-term culture periods. This platform can further be exploited to provide mechanistic insight on what drives this slowing of α-syn turnover and how therapeutics, other genes or different α-syn mutations may affect α-syn protein dynamics

A long postreproductive life span is a shared trait among genetically distinct killer whale populations.

The extended female postreproductive life span found in humans and some toothed whales remains an evolutionary puzzle. Theory predicts demographic patterns resulting in increased female relatedness with age (kinship dynamics) can select for a prolonged postreproductive life span due to the combined costs of intergenerational reproductive conflict and benefits of late-life helping. Here, we test this prediction using >40 years of longitudinal demographic data from the sympatric yet genetically distinct killer whale ecotypes: resident and Bigg's killer whales. The female relatedness with age is predicted to increase in both ecotypes, but with a less steep increase in Bigg's due to their different social structure. Here, we show that there is a significant postreproductive life span in both ecotypes with >30% of adult female years being lived as postreproductive, supporting the general prediction that an increase in local relatedness with age predisposes the evolution of a postreproductive life span. Differences in the magnitude of kinship dynamics however did not influence the timing or duration of the postreproductive life span with females in both ecotypes terminating reproduction before their mid-40s followed by an expected postreproductive period of about 20 years. Our results highlight the important role of kinship dynamics in the evolution of a long postreproductive life span in long-lived mammals, while further implying that the timing of menopause may be a robust trait that is persistent despite substantial variation in demographic patterns among populations

Flavonoid intakes inversely associate with COPD in smokers

Introduction: Higher flavonoid intakes are beneficially associated with pulmonary function parameters; however, their association with chronic obstructive pulmonary disease (COPD) is unknown. This study aimed to examine associations between intakes of 1) total flavonoids, 2) flavonoid subclasses and 3) major flavonoid compounds with incident COPD in participants from the Danish Diet, Cancer and Health study. Methods: This prospective cohort included 55 413 men and women without COPD, aged 50-65 years at recruitment. Habitual flavonoid intakes at baseline were estimated from a food frequency questionnaire using Phenol-Explorer. Danish nationwide registers were used to identify incident cases of COPD. Associations were modelled using restricted cubic splines within Cox proportional hazards models. Results: During 23 years of follow-up, 5557 participants were diagnosed with COPD. Of these, 4013 were current smokers, 1062 were former smokers and 482 were never-smokers. After multivariable adjustments, participants with the highest total flavonoid intakes had a 20 % lower risk of COPD than those with the lowest intakes (quintile 5 versus quintile 1: HR 0.80, 95% CI 0.74-0.87); a 6-22 % lower risk was observed for each flavonoid subclass. The inverse association between total flavonoid intake and COPD was present in both men and women but only in current smokers (HR 0.77, 95 % CI 0.70-0.84) and former smokers (HR 0.82, 95 % CI 0.69-0.97), not never-smokers. Furthermore, higher flavonoid intakes appeared to lessen, but not negate, the higher risk of COPD associated with smoking intensity. Conclusion: Dietary flavonoids may be important for partially mitigating the risk of smoking-related COPD. However, smoking cessation should remain the highest priority

The Intermediate-Scale Clustering of Luminous Red Galaxies

We report the intermediate-scale (0.3 to 40 Mpc/h) clustering of 35,000 luminous early-type galaxies at redshifts 0.16 to 0.44 from the Sloan Digital Sky Survey. We present the redshift-space two-point correlation function \xi(s), the projected correlation function w_p(r_p), and the deprojected real-space correlation function \xi(r), for approximately volume-limited samples. As expected, the galaxies are highly clustered, with the correlation length varying from 9.8 +/- 0.2 Mpc/h to 11.2 +/- 0.2 Mpc/h, dependent on the specific luminosity range. For the -23.2 < Mg < -21.2 sample, the inferred bias relative to that of L* galaxies is 1.84 +/- 0.11 for 1 Mpc/h < r_p < 10 Mpc/h, with yet stronger clustering on smaller scales. We detect luminosity-dependent bias within the sample but see no evidence for redshift evolution between z=0.2 and z=0.4. We find a clear indication for deviations from a power-law in the real-space correlation function, with a dip at ~ 2 Mpc/h scales and an upturn on smaller scales. The precision measurements of these clustering trends offer new avenues for the study of the formation and evolution of these massive galaxies.Comment: 11 pages, 14 figures. Accepted to the Astrophysical Journa