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We use a large dark matter simulation of a LambdaCDM model to investigate the clustering and environmental dependence of the number of substructures in a halo. Focusing on redshift z=1, we find that the halo occupation distribution is sensitive at the tens of percent level to the surrounding density and to a lesser extent to asymmetry of the surrounding density distribution. We compute the autocorrelation function of halos as a function of occupation, building on the finding of Wechsler et al. (2006) and Gao and White (2007) that halos (at fixed mass) with more substructure are more clustered. We compute the relative bias as a function of occupation number at fixed mass, finding a strong relationship. At fixed mass, halos in the top 5% of occupation can have an autocorrelation function ~ 1.5-2 times higher than the mean. We also compute the bias as a function of halo mass, for fixed halo occupation. We find that for group and cluster sized halos, when the number of subhalos is held fixed, there is a strong anticorrelation between bias and halo mass. Such a relationship represents an additional challenge to the halo model.

[abridged] We present a detailed comparison of fundamental dark matter halo properties retrieved by a substantial number of different halo finders. These codes span a wide range of techniques including friends-of-friends (FOF), spherical-overdensity (SO) and phase-space based algorithms. We further introduce a robust (and publicly available) suite of test scenarios that allows halo finder developers to compare the performance of their codes against those presented here. This set includes mock haloes containing various levels and distributions of substructure at a range of resolutions as well as a cosmological simulation of the large-scale structure of the universe. All the halo finding codes tested could successfully recover the spatial location of our mock haloes. They further returned lists of particles (potentially) belonging to the object that led to coinciding values for the maximum of the circular velocity profile and the radius where it is reached. All the finders based in configuration space struggled to recover substructure that was located close to the centre of the host halo and the radial dependence of the mass recovered varies from finder to finder. Those finders based in phase space could resolve central substructure although they found difficulties in accurately recovering its properties. Via a resolution study we found that most of the finders could not reliably recover substructure containing fewer than 30-40 particles. However, also here the phase space finders excelled by resolving substructure down to 10-20 particles. By comparing the halo finders using a high resolution cosmological volume we found that they agree remarkably well on fundamental properties of astrophysical significance (e.g. mass, position, velocity, and peak of the rotation curve).

In the coming decade, astronomical surveys of the sky will generate tens of terabytes of images and detect hundreds of millions of sources every night. The study of these sources will involve computation challenges such as anomaly detection and classification, and moving object tracking. Since such studies benefit from the highest quality data, methods such as image coaddition (stacking) will be a critical preprocessing step prior to scientific investigation. With a requirement that these images be analyzed on a nightly basis to identify moving sources or transient objects, these data streams present many computational challenges. Given the quantity of data involved, the computational load of these problems can only be addressed by distributing the workload over a large number of nodes. However, the high data throughput demanded by these applications may present scalability challenges for certain storage architectures. One scalable data-processing method that has emerged in recent years is MapReduce, and in this paper we focus on its popular open-source implementation called Hadoop. In the Hadoop framework, the data is partitioned among storage attached directly to worker nodes, and the processing workload is scheduled in parallel on the nodes that contain the required input data. A further motivation for using Hadoop is that it allows us to exploit cloud computing resources, e.g., Amazon's EC2. We report on our experience implementing a scalable image-processing pipeline for the SDSS imaging database using Hadoop. This multi-terabyte imaging dataset provides a good testbed for algorithm development since its scope and structure approximate future surveys. First, we describe MapReduce and how we adapted image coaddition to the MapReduce framework. Then we describe a number of optimizations to our basic approach and report experimental results comparing their performance., 31 pages, 11 figures, 2 tables

Oxidative stress is a key factor driving the aging of cells and arteries. Studies suggest that white blood cell (WBC) telomere length is an index of systemic aging. We, therefore, investigated the association between WBC telomere length and oxidized-LDL, and vascular aging, expressed by the distensibility of the carotid artery. We studied a random population sample of 216 non-smokers and 89, smokers. In all subjects, age and gender- adjusted telomere length was inversely correlated with plasma oxidized-LDL (regression coefficient = -0.656 kb/mg/dL; p=0.0006). Independent of gender, age and mean blood pressure, carotid distensibility increased with telomere length (2.33+/- 1.18 10-3/kPa/kb; p=0.05) but decreased with higher plasma levels of oxidized LDL (-10.7+/- 3.91 10-3/kPa/ mg/dL; p=0.006). Adjusted for gender and age, smokers' telomere length was shorter (6.72 vs 6.91 kb; p=0.014) and plasma oxidized-LDL level higher (0.52 vs 0.46 mg/dL; p=0.03) than in non-smokers. Higher level of oxidized-LDL, is associated with shorter WBC telomeres and increased stiffness of the carotid artery. Smoking is marked by increased oxidative stress in concert with shortened WBC telomere length. ispartof: Frontiers in Bioscience vol:2 issue:3 pages:1164-1168 ispartof: location:Singapore status: published

Age-related cognitive decline begins in mid-life and continues with advancing age. Leukocyte telomere length (LTL) shortens with age, and inflammation and oxidative stress enhance this process. Shorter LTL is associated with dementia.The relationship between cognitive function and LTL was investigated in a cross-sectional study of 382 women (mean age 50.6 years, range 19-78), not diagnosed with any form of dementia or cognitive impairment, from the TwinsUK cohort using six tests from the Cambridge neuropsychological test automated battery (CANTAB).After adjusting for age and estimated prior intellectual ability, we observed significant correlations of LTL with episodic memory and associated learning (PAL, p=0.032), recognition memory for non-verbal patterns (DMS, p=0.007), and working memory capacity (SSP, p=0.003). In pairs of twins discordant for LTL the twin with longer telomeres also had significantly better DMS (p0.05) and SSP (p0.013) scores than their co-twin with shorter telomeres. The correlations between these two scores and LTL was significant both in women over the median mean age and in those below the median age, and remained significant after statistical adjustment for potential confounders.Leukocyte telomere length correlates with a subset of measures of cognitive performance, suggesting that it might be a biomarker of cognitive aging in women before the onset of dementia.

Telomeres are engaged in a host of cellular functions, and their length is regulated by multiple genes. Telomere shortening, in the course of somatic cell replication, ultimately leads to replicative senescence. In humans, rare mutations in genes that regulate telomere length have been identified in monogenic diseases such as dyskeratosis congenita and idiopathic pulmonary fibrosis, which are associated with shortened leukocyte telomere length (LTL) and increased risk for aplastic anemia. Shortened LTL is observed in a host of aging-related complex genetic diseases and is associated with diminished survival in the elderly. We report results of a genome-wide association study of LTL in a consortium of four observational studies ( n = 3,417 participants with LTL and genome-wide genotyping). SNPs in the regions of the oligonucleotide/oligosaccharide-binding folds containing one gene ( OBFC1 ; rs4387287; P = 3.9 × 10 −9 ) and chemokine (C-X-C motif) receptor 4 gene (CXCR4 ; rs4452212; P = 2.9 × 10 −8 ) were associated with LTL at a genome-wide significance level ( P < 5 × 10 −8 ). We attempted replication of the top SNPs at these loci through de novo genotyping of 1,893 additional individuals and in silico lookup in another observational study ( n = 2,876), and we confirmed the association findings for OBFC1 but not CXCR4 . In addition, we confirmed the telomerase RNA component (TERC) as a gene associated with LTL ( P = 1.1 × 10 −5 ). The identification of OBFC1 through genome-wide association as a locus for interindividual variation in LTL in the general population advances the understanding of telomere biology in humans and may provide insights into aging-related disorders linked to altered LTL dynamics.

Objective This study examined the relationships of high-density lipoprotein cholesterol (HDL-C) with LTL and the rate of its shortening. Background Diminished levels of HDL-C are associated with an increased risk for atherosclerosis. Shortened leukocyte telomere length (LTL) also entails an increased atherosclerotic risk. Methods We studied 472 Whites and 190 African Americans (AfAs) enrolled in the Bogalusa Heart Study. Subjects were examined serially 3–13 times for HDL-C over an average period of 27.8 years from childhood through young adulthood. LTL was measured twice during adulthood at a mean age of 31.5 years (baseline exam) and 37.8 years (follow-up exam). HDL-C trajectories with age were constructed and the area under the curve (AUC) was used as a measure of cumulative HDL-C levels. Results Multivariate regression analyses showed that LTL was positively associated with HDL-C in childhood (regression coefficient (bp per mg/dL) β =3.1, p =0.024), adulthood ( β =4.4, p =0.058) and AUC from childhood to adulthood ( β =12.2, p =0.0004) in the combined sample of AfAs and Whites. The association between LTL and HDL-C AUC was stronger in females ( β =18.5, p β =2.9, p =0.590) (difference in slopes p =0.037). A slower rate of LTL shortening per year was associated with higher HDL-C AUC in the total sample ( p =0.033), adjusting for baseline LTL. Conclusions As HDL-C exerts anti-oxidant and anti-inflammatory effects and LTL registers the accruing burden of oxidative stress and inflammation, the association between HDL-C and LTL might be explained by the lifelong status of oxidative stress and inflammation.

Leukocyte telomere length (LTL) is ostensibly a biomarker of human aging. Cross-sectional analyses have found that LTL is relatively short in a host of aging-related diseases. These studies have also provided indirect estimates of age-dependent LTL shortening. In this paper, the authors report findings of the first comprehensive longitudinal study of 450 whites and 185 African Americans in Louisiana (aged 31.4 and 37.4 years at baseline (1995–1996) and follow-up (2001–2006) examinations, respectively) participating in the Bogalusa Heart Study. Rate of change in LTL was highly variable among individuals, with some displaying a paradoxical gain in LTL during the follow-up period. The most striking observation was that age-dependent LTL shortening was proportional to LTL at baseline examination. At both baseline and follow-up examinations, African Americans had longer LTLs than whites, and smokers had shorter LTLs than nonsmokers. The longer LTL in African Americans than in whites explained in part the faster rate of LTL shortening observed among African Americans. These findings underscore the complexity of leukocyte telomere dynamics in vivo and suggest that determinants in addition to the ‘‘end-replication problem’’ contribute to telomere shortening in vivo.

Leukocyte telomere length (LTL) is ostensibly a bio-indicator of human aging. Here we report that African Americans have longer LTL than whites. We studied cross-sectionally 2453 individuals from the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study (age = 30-93 years) and the Bogalusa Heart Study (age = 19-37 years), comprising 1742 whites and 711 African Americans. We measured LTL by Southern blots of the terminal restriction fragments length. In 234 participants, telomere repeats were also measured by quantitative polymerase chain reaction (qPCR). Adjusted for age and body mass index (BMI), the respective leukocyte telomere lengths (mean +/- SEM) were considerably longer in African Americans than in whites both in the Family Heart Study (7.004 +/- 0.033 kb vs. 6.735 +/- 0.024 kb, p0.0001) and the Bogalusa Heart Study (7.923 +/- 0.063 kb vs. 7.296 +/- 0.039 kb, p0.0001). We confirmed the racial effect on LTL by qPCR (3.038 +/- 0.565 T/S units for African Americans vs. 2.714 +/- 0.487 T/S units for whites, p0.001). Cross-sectionally, sex- and BMI-adjusted LTL became shorter with age (range 19-93 years) at a steeper slope in African Americans than in whites (0.029 kb year(-1) vs. 0.020 kb year(-1), respectively, p = 0.0001). We suggest that racial difference in LTL arises from a host of interacting biological factors, including replication rates of hematopoietic stem cells.

We examine whether increased oxidative stress in vivo promotes telomere shortening in CAST/Ei mice. We explored the effects of L-buthionine sulfoximine treatment (BSO) on telomere length. BSO shortened telomere length in white fat, brown fat, skin, tail, and testis in concert with diminished tissue glutathione content, increased tissue carbonyl content, and increased plasma advanced oxidized protein products. Telomerase activity was mainly detected in testis but no reduction of telomerase activity was observed in response to BSO. In conclusion, BSO-mediated increase in systemic oxidative stress shortens telomeres in several tissues of the mouse. The variable effect of BSO treatment on telomere length in different tissue may result from their different adaptive antioxidative capacity.

With a view to understanding the association between leukocyte telomere length and the human lifespan, we performed genome-wide telomere length analyses by the terminal restriction fragment length (TRFL) and single molecule telomere length analysis (STELA) of the X and Y chromosomes in leukocytes of exceptionally old (aged 90–104 yr) and younger (aged 23–74 yr) individuals. We found that the mean TRFL of 82 exceptionally old individuals was within a range projected by age-dependent TRFL attrition of 99 younger individuals. However, compared with the younger individuals, exceptionally old persons exhibited peaking of the TRFL distribution with overrepresentation of ultra-short telomeres. These findings were confirmed by the STELA. Women had longer mean TRFL than men (6.10 vs. 5.86 kb), and exceptionally old women exhibited fewer ultra-short telomeres than exceptionally old men. Our results have implications for gerontological studies of the limitation of lifespan in humans.

The telomere length of replicating somatic cells is inversely correlated with age and has been reported to be associated cross-sectionally with cardiovascular disease (CVD). Leukocyte telomere length, as expressed by mean terminal restriction fragment (TRF) length, was measured in 419 randomly selected participants from the Cardiovascular Health Study, comprising a community-dwelling cohort recruited in four US communities. The authors investigated associations between TRF length and selected measures of subclinical CVD/risk factors for CVD (data were collected at the 1992/1993 clinic visit) and incident CVD (ascertained through June 2002). In these participants (average age = 74.2 years (standard deviation, 5.2)), mean TRF length was 6.3 kilobase pairs (standard deviation, 0.62). Significant or borderline inverse associations were found between TRF length and diabetes, glucose, insulin, diastolic blood pressure, carotid intima-media thickness, and interleukin-6. Associations with body size and C-reactive protein were modified by gender and age, occurring only in men and in participants aged 73 years or younger. In younger (but not older) participants, each shortened kilobase pair of TRF corresponded with a threefold increased risk of myocardial infarction (hazard ratio = 3.08, 95% confidence interval: 1.22, 7.73) and stroke (hazard ratio = 3.22, 95% confidence interval: 1.29, 8.02). These results support the hypotheses that telomere attrition may be related to diseases of aging through mechanisms involving oxidative stress, inflammation, and progression to CVD.

BACKGROUND Aldosterone accelerates cardiovascular aging by mechanisms that generate reactive oxygen species. Telomere length in white blood cells (WBCs) may be a bioindicator that registers the accruing burden of systemic oxidative stress. The aim of the present study was, therefore, to examine the relationship between plasma aldosterone and telomere length in WBCs. METHODS We studied 75 normotensive and never-treated mildly hypertensive men whose blood was drawn for the measurements of plasma aldosterone concentration and the terminal restriction fragment (TRF) length in WBCs. RESULTS The slope of the TRF-age relationship in the entire cohort showed a decrease in telomere length of 26 +/- 5 base pairs per year (r = -0.46, p

We use numerical simulations in a ACDM cosmology to model density profiles in a set of 16 dark matter haloes with resolutions of up to seven million particles within the virial radius. These simulations allow us to follow robustly the formation and evolution of the central cusp over a large mass range of 10 11 -10 14 M○., down to approximately 0.5 per cent of the virial radius, and from redshift of 5 to the present, covering a larger range in parameter space than previous works. We confirm that the cusp of the density profile is set at redshifts of 2 or greater and remains remarkably stable to the present time, when considered in non-comoving coordinates. Motivated by the diversity and evolution of halo profile shapes, we fit our haloes to the two-parameter profile, p oc 1/((c γ r/r vir ) γ [1 + (c γ r/r vir )] 3-γ }, where the steepness of the cusp is given by the asymptotic inner slope parameter, y, and its radial extent is described by the concentration parameter, c γ (with c γ defined as the virial radius divided by the concentration radius). In our simulations, we find γ ≃ 1.4 - 0.08 log 10 (M/M*) for haloes of 0.01 M*-1000 M*, with a large scatter of Δγ ∼ ±0.3, where M* is the redshift dependent characteristic mass of collapsing haloes; and c γ ≃ 8.(M/M*) -0.15 , with a large M/M* dependent scatter roughly equal to ± cy. Our redshift zero haloes have inner slope parameters ranging approximately from r -1 (Navarro, Frank and White) to r -1.5 (Moore et al.), with a median of roughly r- 1.3 . This two-parameter profile fit works well for all types of haloes in our simulations, whether or not they show evidence of a steep asymptotic cusp. We also model a cluster in power-law cosmologies of P k n , with n = (0, -1, -2, -2.7). Here we find that the concentration radius and the inner cusp slope are both a function of n, with larger concentration radii and shallower cusps for steeper power spectra. We have completed a thorough resolution study and find that the minimum resolved radius is well described by the mean interparticle separation over a range of masses and redshifts. The trend of steeper and more concentrated cusps for smaller M/M* haloes clearly shows that dwarf-sized ACDM haloes have, on average, significantly steeper density profiles within the inner few per cent of the virial radius than inferred from recent observations. Code to reproduce this profile can be downloaded from http://www.icc.dur.ac.uk/ ∼reed/profile.html.

We analyze high-redshift structure in three hydrodynamic simulations that have identical initial conditions and cosmological parameters and differ only in the value of the baryon density parameter, Omega_b=0.02, 0.05, 0.125. Increasing Omega_b does not change the fraction of baryons in the diffuse (unshocked) phase of the intergalactic medium, but it increases cooling rates and therefore transfers some baryons from the shocked intergalactic phase to the condensed phase associated with galaxies. Predictions of Lyman-alpha forest absorption are almost unaffected by changes of Omega_b provided that the UV background intensity is adjusted so that the mean opacity of the forest matches the observed value. The required UV background intensity scales as Omega_b^1.7, and the higher photoionization rate increases the gas temperature in low density regions. Damped Lyman-alpha absorption and Lyman limit absorption both increase with increasing Omega_b, though the impact is stronger for damped absorption and is weaker at z=4 than at z=2-3. The mass of cold gas and stars in high-redshift galaxies increases faster than Omega_b but slower than Omega_b^2, and the global star formation rate scales approximately as Omega_b^1.5. In the higher Omega_b models, the fraction of baryonic material within the virial radius of dark matter halos is usually higher than the universal fraction, indicating that gas dynamics and cooling can lead to over-representation of baryons in virialized systems. On the whole, our results imply a fairly intuitive picture of the influence of Omega_b on high-redshift structure, and we provide scalings that can be used to estimate the impact of Omega_b uncertainties on the predictions of hydrodynamic simulations.

This work explores the notion that low-frequency, acquired aneuploidy may play a role in complex genetic traits such as essential hypertension. To this end, renal epithelial cells in urinary sediments and in renal cysts were examined by fluorescent in situ hybridization with DNA probes specific for the heterochromatic and centromere regions of chromosomes 16 and 1. Chromosome 16 was probed because it harbors variant genes causing monogenic hypertension. These genes have also been investigated for their role in essential hypertension. Chromosome 1 was also probed as an internal control. Higher proportions of renal epithelial cells in the urinary sediments showed monosomy of chromosome 16 than monosomy of chromosome 1 ( P P

We examine the cooling radiation from forming galaxies in hydrodynamic simulations of the LCDM model (cold dark matter with a cosmological constant), focusing on the Ly-alpha line luminosities of high-redshift systems. Primordial composition gas condenses within dark matter potential wells, forming objects with masses and sizes comparable to the luminous regions of observed galaxies. As expected, the energy radiated in this process is comparable to the gravitational binding energy of the baryons, and the total cooling luminosity of the galaxy population peaks at z ~= 2. However, in contrast to the classical picture of gas cooling from the \sim 10^6 K virial temperature of a typical dark matter halo, we find that most of the cooling radiation is emitted by gas with T < 20,000 K. As a consequence, roughly 50% of this cooling radiation emerges in the Ly-alpha line. While a galaxy's cooling luminosity is usually smaller than the ionizing continuum luminosity of its young stars, the two are comparable in the most massive systems, and the cooling radiation is produced at larger radii, where the Ly-alpha photons are less likely to be extinguished by dust. We suggest, in particular, that cooling radiation could explain the two large (\sim 100 kpc), luminous (L_{Ly-alpha} \sim 10^{44} erg s^{-1}) ``blobs'' of Ly-alpha emission found in Steidel et al.'s (1999) narrow band survey of a z = 3 proto-cluster. Our simulations predict objects of the observed luminosity at about the right space density, and radiative transfer effects can account for the observed sizes and line widths. We discuss observable tests of this hypothesis for the nature of the Ly-alpha blobs, and we present predictions for the contribution of cooling radiation to the Ly-alpha luminosity function of galaxies as a function of redshift.

Rationale: aneuploidy and telomere length are two major parameters that have been associated with cellular senescence in vitro. In order to explore the role of aneuploidy and telomere length in aging of the human vasculature, we studied these two parameters in direct preparations of endothelial cells of the human abdominal aorta. Methods: using fluorescent in situ hybridization on ‘touch prep’ slides, we evaluated aneuploidy of two autosomes (chromosomes 6 and 16) and sex chromosomes in non cultured endothelial cells of the abdominal aorta as a function of the donor's age. Results: we found that the frequency of aneuploidy of vascular endothelial cells significantly increased with age. This was expressed by age-dependent tetrasomy (rs=0.56, P=0.006 for chromosome 6; and rs=0.54, P=0.008 for chromosome 16), and age dependent loss of the Y chromosome (rs=0.85, P=0.0003). In addition, we found that telomere length was inversely correlated with age (r=−0.38, P=0.008). Data interpretation: these findings suggest that indicators of cellular senescence, earlier observed in vitro, are also expressed in the human vascular endothelium in vivo. Aneuploidy and telomere attrition might thus play a role in the aging of the human vasculature.

In the vascular endothelium of human beings, telomere length is negatively related while the frequency of aneuploidy is positively related to donor age. Both in culture and in vivo the frequency of aneuploidy increases as telomere length is shortened. In this study we explored the relation between telomere length and aneuploidy in cultured human umbilical vein endothelial cells (HUVEC) by: (a) karyotype analysis and fluorescent in situ hybridization (FISH), (b) measurement of the terminal restriction fragments (TRF), and (c) assessment of replicative senescence by the expression of beta-galactosidase. Of 8 HUVEC strains, 7 cell strains lost chromosome 13, as shown by metaphase analysis and FISH of interphase cells. Five strains gained chromosome 11. In addition, five HUVEC strains became hypotetraploid shortly after the loss of chromosome 13. The loss of chromosome 13 was observed as early as PD 20, when mean TRF length was greater than 9 kb and the percentage of cells positive for beta-galactosidase was relatively low. The almost uniform loss of chromosome 13 suggests that this unique type of aneuploidy of HUVEC is the result of a progressive expression of clones with survival advantage.

Using cosmological N-body simulations of critical and open cold dark matter (CDM) models, we have identified galaxy-sized dark matter halos originated by major binary mergers. Remnants of major merging events between redshift z = 1 and the present have typically not yet been accreted into groups and clusters, and hence they can be linked to bright early-type field galaxies. The rate of formation of binary merger remnants is 1.9 ×10-13(1 + z)3.1±0.2 and 1.6 ×10-14(1 + z)2.5±0.4 h3 Mpc-3 yr-1 for a critical tilted CDM and an open CDM model, respectively. The average age of these merger remnants is about 6 Gyr, 40% of the age of the universe. In an open universe, field early-type galaxies formed at z < 1 by major mergers would account for only ~5% of the total population of early-type galaxies. This fraction is much higher (~55%) in critical models. These results are discussed together with present observational constraints.

Stimulation of B lymphocytes leads to diverse cellular functions including secretion, proliferation, differentiation or programmed cell death (apoptosis). Inflammatory agents binding or cross-linking surface membrane receptors increase protein kinase/phosphatase activities and activate phospholipase C, generating inositol 1,4,5-trisphosphate (IP3). IP3 mobilizes Ca2+ from intracellular Ca2+ stores and produces a transient rise in cytosolic Ca2+ (Ca2+1). The emptying of Ca2+ from IP3-sensitive Ca2+ stores also results in enhanced Ca2+ influx across the plasma membrane, which is manifested as an enhancement of the Ca2+1 transient, oscillatory increases in Ca2+1, or a secondary, sustained increase in [Ca2+]i. This Ca2+ entry pathway, termed store-operated Ca2+ entry (SOCE), is responsible for refilling intracellular Ca2+ stores (Putney, 1990) and is an important regulator of Ca2+-dependent gene expression (Negulescu et al. 1994; Dolmetsch et al. 1998; for review, see Putney & Bird, 1993). In B lymphocytes, elevation of [Ca2+]i serves as a differentiation signal towards antibody-secreting cells (Clevers et al. 1985; Huang et al. 1995) and enables interleukin-2 (IL-2) synthesis (Taira et al. 1987) and cell proliferation (Ambrus et al. 1991). The inhibition of Ca2+ influx via the SOCE pathway results in marked decreases in [Ca2+]i and IL-2 (Diegel et al. 1994), supporting the hypothesis that the B cell response is related to the degree of [Ca2+]i elevation (Clark & Lane, 1991). Additional changes in Ca2+1 regulation in anti-IgM-stimulated malignant B-1 cells suggest that dysfunctional Ca2+1 signalling may increase the susceptibility for these cells to undergo apoptosis (Dang et al. 1995). Thus, the regulation of [Ca2+]i represents a key factor in the control of B lymphocyte development and function. Cortisol and synthetic glucocorticoids such as dexamethasone are important modulators of the immune system (Cupps & Fauci, 1982), and exert both inhibitory and stimulatory actions on lymphocyte development and cellular responses to inflammatory stimuli (Guyre et al. 1988; Wilckens & De Rijk, 1997). In murine precursor B cells, slight elevation of the circulating level of glucocorticoids decreased the number of cycling cells by inducing apoptosis (Garvey et al. 1993). In B cells undergoing lymphopoiesis, negative regulatory effects of glucocorticoids were countered by the presence of (T) lymphocyte-supportive stromal cells (Borghesi et al. 1997). Glucocorticoids produce variable responses in cell surface Ia (sIa) expression, the response being dependent on the duration of exposure and the state (i.e. resting or activated) of the B cell (McMillan et al. 1988). In a report examining cell activation of resting B cells, cortisol acted as an inhibitor of anti-Ig-antibody-mediated IP3 synthesis, Ca2+1 signalling and entry into the cell cycle (Dennis et al. 1987). These results suggest that, similar to T lymphocytes, cortisol effects on B cell function are dependent on the extent of glucocorticoid exposure and the context in which inflammatory mediators are presented. In light of the significant influence of Ca2+ homeostasis on B cell proliferation and differentiation, widely different effects of glucocorticoids on Ca2+1 signalling and B cell physiology could be expected at different stages of B lymphocyte development. To examine the glucocorticoid regulation of Ca2+ homeostasis in activated B lymphocytes, we studied cortisol-induced alterations of Ca2+ signalling in Epstein- Barr virus (EBV)-transformed B lymphoblasts. In vitro transformation of peripheral blood cells by EBV leads to partial differentiation and immortalization of cells of the B lymphocyte lineage, lending to their characterization as a model of activated B cells. EBV-generated lymphoblastoid cell lines (LCLs) are often used where stable, proliferating cultures of pure B cells are required. Their growth in tissue culture surmounts obstacles often associated with freshly isolated cell populations, including low cell number, deleterious effects of cell isolation chemicals or procedures, and exposure to leucocyte-derived cytokines or hormones. Several groups have suggested that LCLs exhibit signalling and membrane ion transport properties common to non-transformed cells (Schulam et al. 1990; Kuruvilla et al. 1993; Kojima et al. 1994; Siffert et al. 1995), supporting the idea that independent of viral transformation, LCLs retain membrane signalling properties representative of B lymphocytes. Thus, to study the role of cortisol on Ca2+ homeostasis in activated B cells, we examined parameters of receptor-mediated [Ca2+]i signalling, intracellular Ca2+ stores and Ca2+ influx across the plasma membrane (SOCE) in LCLs.

We calculate the number of damped Lyman-alpha absorbers expected in various popular cosmological models as a function of redshift and compare our predictions with observed abundances. The Press-Schechter formalism is used to obtain the distribution of halos with circular velocity in different cosmologies, and we calibrate the relation between circular velocity and absorption cross-section using detailed gas dynamical simulations of a ``standard'' cold dark matter (CDM) model. Because of this calibration, our approach makes more realistic assumptions about the absorption properties of collapsed objects than previous, analytic calculations of the damped Lyman-alpha abundance. CDM models with Omega_0=1, H_0=50, baryon density Omega_b=0.05, and scale-invariant primeval fluctuations reproduce the observed incidence and redshift evolution of damped Lyman-alpha absorption to within observational uncertainty, for both COBE normalization (sigma_8=1.2) and a lower normalization (sigma_8=0.7) that better matches the observed cluster abundance at z=0. A tilted (n=0.8, sigma_8=0.7) CDM model tends to underproduce absorption, especially at z=4. With COBE normalization, a CDM model with Omega_0=0.4, Omega_{Lambda}=0.6 gives an acceptable fit to the observed absorption; an open CDM model is marginally acceptable if Omega_0 is at least 0.4 and strongly inconsistent with the z=4 data if Omega_0=0.3. Mixed dark matter models tend not to produce sufficient absorption, being roughly comparable to tilted CDM models if Omega_{nu} = 0.2 and failing drastically if Omega_{nu} = 0.3., Comment: AASlatex, 13 pages w/ 2 embedded ps figures. To be published in ApJ, Sept. 1, 1997

The physiologically active form of vitamin D, 1 alpha,25-dihydroxyvitamin D3 (1,25D3), induces promyelocytic HL60 cells to differentiate towards monocyte-like cells. During this differentiation increased cytosolic calcium (Cai2+) and expression of surface receptors for chemotactic factors "prime" the cell for the activation of monocyte functions and the triggering of the respiratory burst pathway. We examined whether the Ca2+ influx mediated by store-operated channels (SOC) contributed to the increased Cai2+ following exposure of HL60 cells to 10(-7) M 1,25D3. Cells treated with 1,25D3 for 72 hr demonstrated a rapid transient rise in Cai2+ followed by a second, phasic, increase in Cai2+ in response to the purinergic agonist ATP. This second Cai2+ transient was blocked by Ni2+, SKF 96365, or withdrawal of extracellular Ca2+. In cells suspended in Ca(2+)-free medium, peak changes (delta) in [Ca2+]i elicited by ATP-induced Ca2+ mobilization occurred with similar EC50 values in differentiated and vehicle (EtOH)-treated cells; however, peak [Ca2+]i was reduced by 55% in 1,25D3-treated cells. Decreased Ca2+ mobilization was associated with a 25-35% reduction in intracellular Ca2+ stores (determined with ionomycin). 1,25D3-treated cells exposed to ATP or thapsigargin (Tg) in Ca(2+)-free medium for 3 min with subsequent addition of 1 mM Ca2+ exhibited a respective 80% or 120% stimulation in peak [Ca2+]i compared to EtOH-treated cells. Enhanced Ca2+ influx mediated by SOC was also seen in these cells as an increase in the rate of Mn2+ entry after exposure to ATP or Tg. At 96 hr after addition of 1,25D3, when differentiated phenotype was established, basal Ca2+i and Ca2+ entry mediated by SOC returned to control values, but Ca2+ store size remained reduced. Up-regulation of Ca2+ influx via the SOC pathway during 1,25D3-induced differentiation may contribute to the functional properties of the maturing monocyte, or to the resetting of molecular programs responsible for the changing phenotype.

Numerous 16-ene vitamin D analogs were investigated as potential anticancer agents. Several structural modifications have been uncovered that contribute to the improvement in the stimulation of HL-60 cells differentiation, the inhibition of HL-60 cells proliferation and the reduction of calcemic properties in vivo. They include the introduction of 16-, 22E-, 23E- and 23Z-double bonds, 23-triple bond or 22R-allene, and substitution of C26 and C27-hydrogens with fluorine or methyl groups. The biggest gains have been achieved by combination of the 16-double bond with 23-double or triple bond and 26-trifluoro or 26,27-hexafluoro substitution patterns. Separately, the combination of the 16-double bond with 22R-allene has produced a highly active analog. In respect to modifications in the ring A, the high activities in cell differentiation and inhibition of cell proliferation with significant reduction of calcemic properties were observed in the lα-fluoro, 3-desoxy, and 19-nor series. It was also shown that the lack of the lα-hydroxy group can be overcome by an optimized modification in the ring D and the side chain; 25(OH)-16,23E-diene-26,27- F6D3 is fully active in HL-60 cell differentiation assay with only mimimal effects on the cellular calcium homeostasis.

Numerous vitamin D3 analogs (VDAs) can inhibit the proliferation of cells from several types of human malignancies. The physiologically active form of vitamin D3, 1,25-dihydroxyvitamin D3(1,25D3), is formed by successive hydroxylations of cholecalciferol at the 25 and 1 alpha positions. In this study we examined the effects of the absence of the 1 alpha (OH) group, introduction of a double bond in position 16, and further modifications at the 23, 26, and 27 positions in the side chain on the potency of the VDAs. The parameters studied were the rapidity of the induction of monocytic differentiation, the cell cycle traverse, and the effects of VDAs on intracellular calcium homeostasis in HL60 cells. The results show that (1) 1,25D3 derivatives which lace the 1 alpha (OH) group have little differentiation-inducing activity, (2) hexafluorination (6F) of the terminal methyl groups in the side chain partially restores the activity of 1 alpha-desoxy compounds and potentiates the activity of 1 alpha hydroxylated compounds, and (3) 25-(OH)-16,23E-diene-26,27-hexafluoro-vitamin D2 (Ro25-9887) alone among the twelve compounds tested induces differentiation with only minimal changes in the basal levels of intracellular calcium and store-dependent calcium influx in HL60 cells. Addition of 1 alpha (OH) group to this compound increases its differentiation-inducing activity but also elevates basal calcium level. The results suggest that altered calcium homeostasis is not an obligatory component of HL60 leukemia cell differentiation, and that Ro25-9887 and related VDAs may be suitable for testing as components of anti-leukemic therapy.

Objective To investigate differences between store-dependent Ca 2+ in African American and white men. Method Thapsigargin, a potent and specific inhibitor of the sarco(endo)plasmic reticulum Ca 2+ -ATPase, was used as a probe to elicit store-dependent Ca 2+ fluxes. Treatment with this agent caused a rise in the cytosolic free Ca 2+ due to the egress of Ca 2+ from thapsigargin-sensitive Ca 2+ stores and the acceleration of external Ca 2+ influx through store-dependent Ca 2+ channels. Design Lymphocytes were obtained from 22 African Americans and 23 whites. These cells were subjected to thapsigargin treatment and changes in the cellular Ca 2+ profiles were monitored. Results Both in Ca 2+ -free and in Ca 2+ -containing media the increases in cytosolic free Ca 2+ concentrations after thapsigargin treatment were greater in lymphocytes from African Americans than they were in those from whites. The greater levels of cytosolic Ca 2+ concentration were coupled with higher rates of Ca 2+ extrusion in thapsigargin-treated lymphocytes from African Americans. Conclusions These findings suggest that store-dependent Ca 2+ fluxes are greater in lymphocytes from African Americans than they are in those from whites. This phenomenon increases the Ca 2+ turnover rate and might augment the sensitivity to agonists acting through Ca 2+ signaling systems, thereby predisposing African Americans to essential hypertension.

Lymphocyte proliferation is guided by receptor-mediated signal transduction pathways that dictate the immunological response/clonality of that cell. We have previously reported that NZB-derived malignant B-1 cells, which serve as a murine model for human chronic lymphocytic leukaemia, demonstrate altered expression of surface IgM and CD45 signalling molecules, and a failure to proliferate following membrane IgM stimulation. To examine receptor-mediated cytosolic calcium (Cai) signalling in B cell leukaemia, we studied IgM-induced Cai responses in malignant B-1 cells and B cells from non-leukaemic mice. Basal Cai was slightly lower in malignant B-1 cells than in non-leukaemic cells. Anti-IgM stimulation induced a sustained increase in Cai to levels 1.3-fold greater than basal Cai in conventional B cells. In contrast, leukaemic B-1 cells demonstrated a sharp but transient rise in Cai followed by a gradual increase to levels 2.3-fold greater than basal [Ca]i Ca influx from extracellular sources contributed to the early and late Cai signal in both sets of cells. Pre-incubation (2-30 min) with anti-CD45 had no effect on basal Cai or the anti-IgM Cai signal in B cells, but reduced the Cai transient in malignant B-1 cells. Additional experiments characterized the effects of phosphorylation/dephosphorylation events on the Cai profile following anti-IgM stimulation. Protein tyrosine kinase inhibitors decreased the anti-IgM-induced Cai transient in malignant B-1 cells by 80%, but only moderately affected (40%) of the Cai response in non-leukaemic B cells. Protein tyrosine phosphatase inhibitors and protein kinase C (PKC) activators attenuated the Cai response to the same degree in normal and leukaemic B cells. These results show that Cai signalling differs widely between non-malignant B cells and malignant B-1 cells, and that tyrosine phosphorylation and CD45 modulation of IgM signalling are involved in the altered Cai responses in malignant B-1 cells.

Regulation of cytosolic Ca2+ and cytosolic Na+ is critical for lymphocyte cation homeostasis and function. To examine the influence of cytosolic Na+ on Ca2+ regulation in human peripheral blood lymphocytes, Ca2+ entry and cytosolic Ca2+ (measured with fura-2) were monitored in cells in which cytosolic Na+ was increased and/or the Na+ gradient was decreased by reduction of external Na+ concentration. Ouabain-treated cells (0.1 mM for 30 min at 37 degrees C), suspended in Na(+)-free medium, showed a 30-65% increase in Ca2+ uptake compared to cells in 140 mM Na+ medium. Enhanced Ca2+ influx was entirely dependent on ouabain pretreatment and reversal of the Na+ gradient. Na pump inhibition or Na ionophore addition and subsequent exposure to Na(+)-free medium resulted in a sustained elevation of cytosolic Ca2+. As preincubation of cells in Ca(2+)-free medium further enhanced the ouabain-dependent increase in cytosolic Ca2+, the effects of the microsomal Ca(2+)-ATPase inhibitor thapsigargin on Ca2+ influx and cytosolic Ca2+ were studied. Thapsigargin stimulated Ca2+ entry following ouabain pretreatment and reversal of the Na+ gradient; the effects of thapsigargin were retained in the presence of LaCl3, a potent inhibitor of store-dependent calcium influx pathways. These results show lymphocytes demonstrate Na+/Ca2+ exchange activity and suggest the Na+/Ca2+ exchanger modulates cytosolic Ca2+ following intracellular Ca2+ store depletion.

The role of telomere attrition in limiting the replicative capacity of cells in culture is well established. In humans, epidemiologic evidence suggests telomere length (TL) in leukocytes is highly variable at birth and inversely related to age. Although calorie restriction (CR) significantly increases life span in most rodent models, its association with TL is unknown. Using linear regression analysis, TLs (as measured by Southern blot analysis) of skeletal muscle (a postmitotic tissue that largely represents early development TL), fat, leukocytes, and skin were tested for effects of age, sex, and diet in 48 control and 23 calorie restriction rhesus monkeys. After controlling for the individual's muscle mean TL, differences between leukocytes muscle and skin muscle were significantly associated with age (p = .002; p = .002) and sex (p = .003; p = .042), but not calorie restriction (p = .884; p = .766). Despite an age-dependent shortening of TL in leukocytes and skin, calorie restriction did not significantly affect TL dynamics in these samples.

This article is a summary of the technology issues and challenges of data-intensive science and cloud computing as discussed in the Data-Intensive Science (DIS) workshop in Seattle, September 19–20, 2010.

TELOMERE shortening has been intrinsically linked to cell division and is a key determinant of replicative senescence of cultured somatic cells (1,2). Leukocyte telomere length (LTL) and its age-dependent shortening, that is LTL dynamics, have been the focus of intense investigations. LTL has been reported to be associated with age (3,4), gender (5,6), and many age-related diseases (7–14) as well as measures of general health (15,16). Several studies have evaluated associations between LTL and mortality with conflicting results; some observing that LTL was inversely related to mortality (17,18,20–24), whereas others have not (16,19,25,26). In addition, the mechanistic connection between LTL and mortality is an enigma and a number of problems have been cited in epidemiological studies (27,28). The question remains whether LTL is an index of aging and longevity or if its dynamics, which may mirror the kinetics of the hematopoietic stem cells (29), are actively engaged in determining end-of-life or age-related pathology (27,30). The Cardiovascular Health Study (CHS) provides the opportunity to evaluate the association between survival and LTL using a large cohort of adults aged 65 years and older (31). In addition to providing a large sample size, the CHS has been well characterized in terms of health status and incident cardiovascular disease. All participants have been followed to ascertain death and classified by trained clinicians for specific cause of death (32). Over the last several years, LTL was measured in a subset of CHS participants. In this article, we have utilized mortality and other data collected in the CHS to answer the following questions: (a) Is LTL associated with total mortality in adults aged 65 years and older? (b) Do associations between LTL and mortality differ by cause of death? (c) Are associations modified by factors including age, sex, race, or other variables?

The increasing size of cosmological simulations has led to the need for new visualization techniques. We focus on Smoothed Particle Hydrodynamical (SPH) simulations run with the GADGET code and describe methods for visually accessing the entire simulation at full resolution. The simulation snapshots are rastered and processed on supercomputers into images that are ready to be accessed through a web interface (GigaPan). This allows any scientist with a web-browser to interactively explore simulation datasets in both in spatial and temporal dimensions, datasets which in their native format can be hundreds of terabytes in size or more. We present two examples, the first a static terapixel image of the MassiveBlack simulation, a P-GADGET SPH simulation with 65 billion particles, and the second an interactively zoomable animation of a different simulation with more than one thousand frames, each a gigapixel in size. Both are available for public access through the GigaPan web interface. We also make our imaging software publicly available., Comment: 9 pages, 6 figures, Link to the Gigapan image: http://gigapan.org/gigapans/76215/ Link to the TimeMachine animation: http://timemachine.gigapan.org/wiki/Evolution_of_the_Universe Link to Gaepsi: http://web.phys.cmu.edu/~yfeng1/gaepsi

We investigate the feasibility of high performance scientific computation using cloud computers as an alternative to traditional computational tools. The availability of these large, virtualized pools of compute resources raises the possibility of a new compute paradigm for scientific research with many advantages. For research groups, cloud computing provides convenient access to reliable, high performance clusters and storage, without the need to purchase and maintain sophisticated hardware. For developers, virtualization allows scientific codes to be optimized and pre-installed on machine images, facilitating control over the computational environment. Preliminary tests are presented for serial and parallelized versions of the widely used x-ray spectroscopy and electronic structure code FEFF on the Amazon Elastic Compute Cloud, including CPU and network performance.

We have investigated plasma membrane Ca2+ transport by monitoring the fluorescence of human peripheral T-lymphocytes loaded with fura 2. Thapsigargin (TG) was utilized the block the Ca(2+)-ATPase of the endoplasmic reticulum and elevate the cytosolic Ca2+ (Ca2+i). Ca2+ influx was inhibited by chelating extracellular Ca2+ with ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA). The rate of decline in the Ca2+i signal of TG-treated lymphocytes after exposure to EGTA was used to assess Ca2+ extrusion across the plasma membrane. Initial rates of Ca2+i decline were examined in cells suspended in Na(+)-containing and Na(+)-free solutions; initial rates were linearly related to the [Ca2+]i at the onset of the Ca2+i decline and were unaffected by varying the extracellular Ca2+. Extracellular Na+ increased the rate of Ca2+ extrusion and decreased the threshold [Ca2+]i for extrusion, indicating a substantial role for the Na(+)-Ca2+ exchange in Ca2+i homeostasis. Both decreased temperature and calmodulin inhibition significantly slowed the Ca2+i decline in Na(+)-free HEPES-buffered solution, suggesting Ca2+ extrusion under these conditions was mediated by the Ca2+ pump. Protein kinase C (PKC) activation or inhibition did not affect the Ca2+i decline parameters. However, Ca2+ accumulation and Mn2+ (a Ca2+ surrogate) uptake were significantly and Mn2+ (a Ca2+ surrogate) uptake were significantly inhibited by activators of PKC. Cyclic nucleotides altered neither the parameters of the Ca2+i decline nor Mn2+ uptake. Thus human T-lymphocytes exhibit Na(+)- and Ca(2+)-dependent transporters characterized as the Na(+)-Ca2+ exchanger and Ca2+ pump. The main effect of PKC in these cells is the modulation of Ca2+ entry across the lymphocyte plasma membrane.

We constrain the linear and quadratic bias parameters from the configuration dependence of the three-point correlation function (3PCF) in both redshift and projected space, utilizing measurements of spectroscopic galaxies in the Sloan Digital Sky Survey (SDSS) Main Galaxy Sample. We show that bright galaxies (M_r < -21.5) are biased tracers of mass, measured at a significance of 4.5 sigma in redshift space and 2.5 sigma in projected space by using a thorough error analysis in the quasi-linear regime (9-27 Mpc/h). Measurements on a fainter galaxy sample are consistent with an unbiased model. We demonstrate that a linear bias model appears sufficient to explain the galaxy-mass bias of our samples, although a model using both linear and quadratic terms results in a better fit. In contrast, the bias values obtained from the linear model appear in better agreement with the data by inspection of the relative bias, and yield implied values of sigma_8 that are more consistent with current constraints. We investigate the covariance of the 3PCF, which itself is a measurement of galaxy clustering. We assess the accuracy of our error estimates by comparing results from mock galaxy catalogs to jackknife re-sampling methods. We identify significant differences in the structure of the covariance. However, the impact of these discrepancies appears to be mitigated by an eigenmode analysis that can account for the noisy, unresolved modes. Our results demonstrate that using this technique is sufficient to remove potential systematics even when using less-than-ideal methods to estimate errors., 18 pages, 17 figures. Submitted to ApJ

The three-point correlation function (3PCF) provides an important view into the clustering of galaxies that is not available to its lower order cousin, the two-point correlation function (2PCF). Higher order statistics, such as the 3PCF, are necessary to probe the non-Gaussian structure and shape information expected in these distributions. We measure the clustering of spectroscopic galaxies in the Main Galaxy Sample of the Sloan Digital Sky Survey (SDSS), focusing on the shape or configuration dependence of the reduced 3PCF in both redshift and projected space. This work constitutes the largest number of galaxies ever used to investigate the reduced 3PCF, using over 220,000 galaxies in three volume-limited samples. We find significant configuration dependence of the reduced 3PCF at 3-27 Mpc/h, in agreement with LCDM predictions and in disagreement with the hierarchical ansatz. Below 6 Mpc/h, the redshift space reduced 3PCF shows a smaller amplitude and weak configuration dependence in comparison with projected measurements suggesting that redshift distortions, and not galaxy bias, can make the reduced 3PCF appear consistent with the hierarchical ansatz. The reduced 3PCF shows a weaker dependence on luminosity than the 2PCF, with no significant dependence on scales above 9 Mpc/h. On scales less than 9 Mpc/h, the reduced 3PCF appears more affected by galaxy color than luminosty. We demonstrate the extreme sensitivity of the 3PCF to systematic effects such as sky completeness and binning scheme, along with the difficulty of resolving the errors. Some comparable analyses make assumptions that do not consistently account for these effects., 27 pages, 21 figures. Updated to match accepted version. Published in ApJ