Halo abundances and counts-in-cells: The excursion set approach with correlated steps

The Excursion Set approach has been used to make predictions for a number of interesting quantities in studies of nonlinear hierarchical clustering. These include the halo mass function, halo merger rates, halo formation times and masses, halo clustering, analogous quantities for voids, and the distribution of dark matter counts in randomly placed cells. The approach assumes that all these quantities can be mapped to problems involving the first crossing distribution of a suitably chosen barrier by random walks. Most analytic expressions for these distributions ignore the fact that, although different k-modes in the initial Gaussian field are uncorrelated, this is not true in real space: the values of the density field at a given spatial position, when smoothed on different real-space scales, are correlated in a nontrivial way. As a result, the problem is to estimate first crossing distribution by random walks having correlated rather than uncorrelated steps. In 1990, Peacock & Heavens presented a simple approximation for the first crossing distribution of a single barrier of constant height by walks with correlated steps. We show that their approximation can be thought of as a correction to the distribution associated with what we call smooth completely correlated walks. We then use this insight to extend their approach to treat moving barriers, as well as walks that are constrained to pass through a certain point before crossing the barrier. For the latter, we show that a simple rescaling, inspired by bivariate Gaussian statistics, of the unconditional first crossing distribution, accurately describes the conditional distribution, independently of the choice of analytical prescription for the former. In all cases, comparison with Monte-Carlo solutions of the problem shows reasonably good agreement. (Abridged)Comment: 14 pages, 9 figures; v2 -- revised version with explicit demonstration that the original conclusions hold for LCDM, expanded discussion on stochasticity of barrier. Accepted in MNRA

Halo bias in the excursion set approach with correlated steps

In the Excursion Set approach, halo abundances and clustering are closely related. This relation is exploited in many modern methods which seek to constrain cosmological parameters on the basis of the observed spatial distribution of clusters. However, to obtain analytic expressions for these quantities, most Excursion Set based predictions ignore the fact that, although different k-modes in the initial Gaussian field are uncorrelated, this is not true in real space: the values of the density field at a given spatial position, when smoothed on different real-space scales, are correlated in a nontrivial way. We show that when the excursion set approach is extended to include such correlations, then one must be careful to account for the fact that the associated prediction for halo bias is explicitly a real-space quantity. Therefore, care must be taken when comparing the predictions of this approach with measurements in simulations, which are typically made in Fourier-space. We show how to correct for this effect, and demonstrate that ignorance of this effect in recent analyses of halo bias has led to incorrect conclusions and biased constraints.Comment: 7 pages, 3 figures; v2 -- minor clarifications, accepted in MNRA

Halo statistics in non-Gaussian cosmologies: the collapsed fraction, conditional mass function, and halo bias from the path-integral excursion set method

Characterizing the level of primordial non-Gaussianity (PNG) in the initial conditions for structure formation is one of the most promising ways to test inflation and differentiate among different scenarios. The scale-dependent imprint of PNG on the large-scale clustering of galaxies and quasars has already been used to place significant constraints on the level of PNG in our observed Universe. Such measurements depend upon an accurate and robust theory of how PNG affects the bias of galactic halos relative to the underlying matter density field. We improve upon previous work by employing a more general analytical method - the path-integral extension of the excursion set formalism - which is able to account for the non-Markovianity caused by PNG in the random-walk model used to identify halos in the initial density field. This non-Markovianity encodes information about environmental effects on halo formation which have so far not been taken into account in analytical bias calculations. We compute both scale-dependent and -independent corrections to the halo bias, along the way presenting an expression for the conditional collapsed fraction for the first time, and a new expression for the conditional halo mass function. To leading order in our perturbative calculation, we recover the halo bias results of Desjacques et. al. (2011), including the new scale-dependent correction reported there. However, we show that the non-Markovian dynamics from PNG can lead to marked differences in halo bias when next-to-leading order terms are included. We quantify these differences here. [abridged]Comment: Accepted for publication in MNRAS. Includes minor revisions recommended by referee, slightly revised notation for clarity, and corrected typo

Effects of Common Polymorphisms rs11614913 in miR-196a2 and rs2910164 in miR-146a on Cancer Susceptibility: A Meta-Analysis

BACKGROUND: MicroRNAs regulate gene expression at the post-transcriptional level and involved in diverse biological and pathological processes, including tumorigenesis. Rs11614913 in miR-196a2 and rs2910164 in miR-146a are shown to associate with increased/decreased cancer risk. We performed a meta-analysis to systematically summarize the possible association. METHODOLOGY/PRINCIPAL FINDINGS: We assessed published studies of the association between these microRNA polymorphisms and cancer risk from eleven studies with 16,771 subjects for miR-196a2 and from ten studies with 15,126 subjects for miR-146a. As for rs11614913, the contrast of homozygote (TT vs CC: OR = 0.92, 95% CI = 0.85-0.99, P(heterogeneity) = 0.45), allele (T vs C: OR = 0.96, 95% CI = 0.92-0.99, P(heterogeneity) = 0.61) and recessive model (OR = 0.90, 95% CI = 0.84-0.97, P(heterogeneity) = 0.50) produced statistically association. Subgroup analysis by ethnicity, statistically significantly decreased cancer risks were found among Asians for allele contrast (OR = 0.95, 95% CI = 0.90-0.99, P(heterogeneity) = 0.74) and the recessive genetic model (OR = 0.90, 95% CI = 0.82-0.98, P(heterogeneity) = 0.85). According to subgroup analysis by tumor types, the protective effect of C/T polymorphism was only found in breast cancer under allele contrast (T vs C: OR = 0.94, 95% CI = 0.88-0.99, P(heterogeneity) = 0.26). For rs2910164, no significant associations were found among overall analysis model with relatively large heterogeneity. Through the stratified analysis, heterogeneity decreased significantly. In the subgroup analyses by cancer types, the C allele of rs2910164 was associated with protection from digestive cancer in allele contrast (C vs G: OR = 0.86, 95% CI = 0.77-0.96, P(heterogeneity) = 0.51). CONCLUSIONS/SIGNIFICANCE: Our meta-analysis suggests that the rs11614913 most likely contributes to decreased susceptibility to cancer, especially in Asians and breast cancer. Besides, the C allele of the rs2910164 might be associated with a protection from digestive cancer

Isosteviol Has Beneficial Effects on Palmitate-Induced α-Cell Dysfunction and Gene Expression

BACKGROUND: Long-term exposure to high levels of fatty acids impairs insulin secretion and exaggerates glucagon secretion. The aim of this study was to explore if the antihyperglycemic agent, Isosteviol (ISV), is able to counteract palmitate-induced α-cell dysfunction and to influence α-cell gene expression. METHODOLOGY/PRINCIPAL FINDINGS: Long-term incubation studies with clonal α-TC1-6 cells were performed in the presence of 0.5 mM palmitate with or without ISV. We investigated effects on glucagon secretion, glucagon content, cellular triglyceride (TG) content, cell proliferation, and expression of genes involved in controlling glucagon synthesis, fatty acid metabolism, and insulin signal transduction. Furthermore, we studied effects of ISV on palmitate-induced glucagon secretion from isolated mouse islets. Culturing α-cells for 72-h with 0.5 mM palmitate in the presence of 18 mM glucose resulted in a 56% (p<0.01) increase in glucagon secretion. Concomitantly, the TG content of α-cells increased by 78% (p<0.01) and cell proliferation decreased by 19% (p<0.05). At 18 mM glucose, ISV (10(-8) and 10(-6) M) reduced palmitate-stimulated glucagon release by 27% (p<0.05) and 27% (p<0.05), respectively. ISV (10(-6) M) also counteracted the palmitate-induced hypersecretion of glucagon in mouse islets. ISV (10(-6) M) reduced α-TC1-6 cell proliferation rate by 25% (p<0.05), but ISV (10(-8) and 10(-6) M) had no effect on TG content in the presence of palmitate. Palmitate (0.5 mM) increased Pcsk2 (p<0.001), Irs2 (p<0.001), Fasn (p<0.001), Srebf2 (p<0.001), Acaca (p<0.01), Pax6 (p<0.05) and Gcg mRNA expression (p<0.05). ISV significantly (p<0.05) up-regulated Insr, Irs1, Irs2, Pik3r1 and Akt1 gene expression in the presence of palmitate. CONCLUSIONS/SIGNIFICANCE: ISV counteracts α-cell hypersecretion and apparently contributes to changes in expression of key genes resulting from long-term exposure to palmitate. ISV apparently acts as a glucagonostatic drug with potential as a new anti-diabetic drug for the treatment of type 2 diabetes

Scale-up and large-scale production of Tetraselmis sp CTP4 (Chlorophyta) for CO2 mitigation: from an agar plate to 100-m(3) industrial photobioreactors

Industrial production of novel microalgal isolates is key to improving the current portfolio of available strains that are able to grow in large-scale production systems for different biotechnological applications, including carbon mitigation. In this context, Tetraselmis sp. CTP4 was successfully scaled up from an agar plate to 35-and 100-m(3) industrial scale tubular photobioreactors (PBR). Growth was performed semi-continuously for 60 days in the autumn-winter season (17th October -14th December). Optimisation of tubular PBR operations showed that improved productivities were obtained at a culture velocity of 0.65-1.35 m s(-1) and a pH set-point for CO2 injection of 8.0. Highest volumetric (0.08 +/- 0.01 g L-1 d(-1)) and areal (20.3 +/- 3.2 g m(-2) d(-1)) biomass productivities were attained in the 100-m(3) PBR compared to those of the 35-m(3) PBR (0.05 +/- 0.02 g L-1 d(-1) and 13.5 +/- 4.3 g m(-2) d(-1), respectively). Lipid contents were similar in both PBRs (9-10% of ash free dry weight). CO2 sequestration was followed in the 100-m(3) PBR, revealing a mean CO2 mitigation efficiency of 65% and a biomass to carbon ratio of 1.80. Tetraselmis sp. CTP4 is thus a robust candidate for industrial-scale production with promising biomass productivities and photosynthetic efficiencies up to 3.5% of total solar irradiance.Portuguese national budget; Foundation for Science and Technology (FCT) [CCMAR/Multi/04326/2013]; INTERREG V-A Espana-Portugal project [0055 ALGARED + 5 E]; COST Action - European Network for Bio-products [1408]; FCT [SFRH/BD/105541/2014]; Nord Universityinfo:eu-repo/semantics/publishedVersio

Complete In Vitro Life Cycle of Trypanosoma congolense: Development of Genetic Tools

Trypanosoma congolense is a parasite responsible for severe disease of African livestock. Its life cycle is complex and divided into two phases, one in the tsetse fly vector and one in the bloodstream of the mammalian host. Molecular tools for gene function analyses in parasitic organisms are essential. Previous studies described the possibility of completing the entire T. congolense life cycle in vitro. However, the model showed major flaws including the absence of stable long-term culture of the infectious bloodstream forms, a laborious time-consuming period to perform the cycle and a lack of genetic tools. We therefore aimed to develop a standardized model convenient for genetic engineering. We succeeded in producing long-term cultures of all the developmental stages on long-term, to define all the differentiation steps and to finally complete the whole cycle in vitro. This improved model offers the opportunity to conduct phenotype analyses of genetically modified strains throughout the in vitro cycle and also during experimental infections

Low adherent cancer cell subpopulations are enriched in tumorigenic and metastatic epithelial-to-mesenchymal transition-induced cancer stem-like cells

Cancer stem cells are responsible for tumor progression, metastasis, therapy resistance and cancer recurrence, doing their identification and isolation of special relevance. Here we show that low adherent breast and colon cancer cells subpopulations have stem-like properties. Our results demonstrate that trypsin-sensitive (TS) breast and colon cancer cells subpopulations show increased ALDH activity, higher ability to exclude Hoechst 33342, enlarged proportion of cells with a cancer stem-like cell phenotype and are enriched in sphere- and colony-forming cells in vitro. Further studies in MDA-MB-231 breast cancer cells reveal that TS subpopulation expresses higher levels of SLUG, SNAIL, VIMENTIN and N-CADHERIN while show a lack of expression of E-CADHERIN and CLAUDIN, being this profile characteristic of the epithelial-to-mesenchymal transition (EMT). The TS subpopulation shows CXCL10, BMI-1 and OCT4 upregulation, differing also in the expression of several miRNAs involved in EMT and/or cell self-renewal such as miR-34a-5p, miR-34c-5p, miR-21-5p, miR-93-5p and miR-100-5p. Furthermore, in vivo studies in immunocompromised mice demonstrate that MDA-MB-231 TS cells form more and bigger xenograft tumors with shorter latency and have higher metastatic potential. In conclusion, this work presents a new, non-aggressive, easy, inexpensive and reproducible methodology to isolate prospectively cancer stem-like cells for subsequent biological and preclinical studies.Ministry of Economy and Competitiveness, Instituto de Salud Carlos III (FEDER funds) PI10/02295 PI10/02149Fundacion Progreso y Salud, Consejeria de Salud, Junta de Andalucia (Ministry of Health, Government of Andalucia) PI-0533-2014Consejeria Economia, Innovacion, Ciencia y Empleo, Junta de Andalucia (Ministry of Economy, Innovation, Science and Employment, Government of Andalucia) CTS-656

Phenotypic and Functional Characterization of Human Mammary Stem/Progenitor Cells in Long Term Culture

Background: Cancer stem cells exhibit close resemblance to normal stem cells in phenotype as well as function. Hence, studying normal stem cell behavior is important in understanding cancer pathogenesis. It has recently been shown that human breast stem cells can be enriched in suspension cultures as mammospheres. However, little is known about the behavior of these cells in long-term cultures. Since extensive self-renewal potential is the hallmark of stem cells, we undertook a detailed phenotypic and functional characterization of human mammospheres over long-term passages. Methodology: Single cell suspensions derived from human breast `organoids' were seeded in ultra low attachment plates in serum free media. Resulting primary mammospheres after a week (termed T1 mammospheres) were subjected to passaging every 7th day leading to the generation of T2, T3, and T4 mammospheres. Principal Findings: We show that primary mammospheres contain a distinct side-population (SP) that displays a CD24(low)/CD44(low) phenotype, but fails to generate mammospheres. Instead, the mammosphere-initiating potential rests within the CD44(high)/CD24(low) cells, in keeping with the phenotype of breast cancer-initiating cells. In serial sphere formation assays we find that even though primary (T1) mammospheres show telomerase activity and fourth passage T4 spheres contain label-retaining cells, they fail to initiate new mammospheres beyond T5. With increasing passages, mammospheres showed an increase in smaller sized spheres, reduction in proliferation potential and sphere forming efficiency, and increased differentiation towards the myoepithelial lineage. Significantly, staining for senescence-associated beta-galactosidase activity revealed a dramatic increase in the number of senescent cells with passage, which might in part explain the inability to continuously generate mammospheres in culture. Conclusions: Thus, the self-renewal potential of human breast stem cells is exhausted within five in vitro passages of mammospheres, suggesting the need for further improvisation in culture conditions for their long-term maintenance