Influence of large local and non-local bispectra on primordial black hole abundance

Primordial black holes represent a unique probe to constrain the early universe on small scales - providing the only constraints on the primordial power spectrum on the majority of scales. However, these constraints are strongly dependent on even small amounts of non-Gaussianity, which is unconstrained on scales significantly smaller than those visible in the CMB. This paper goes beyond previous considerations to consider the effects of a bispectrum of the equilateral, orthogonal and local shapes with arbitrary magnitude upon the abundance of primordial black holes. Non-Gaussian density maps of the early universe are generated from a given bispectrum and used to place constraints on the small scale power spectrum. When small, we show that the skewness provides an accurate estimate for how the constraint depends on non-Gaussianity, independently of the shape of the bispectrum. We show that the orthogonal template of non-Gaussianity has an order of magnitude weaker effect on the constraints than the local and equilateral templates.Comment: 11 pages, 4 figures, updated to match published version in JCAP02(2016)029, Journal of Cosmology and Astroparticle Physics, Volume 2016, February 201

Infrared effects in inflationary correlation functions

In this article, I briefly review the status of infrared effects which occur when using inflationary models to calculate initial conditions for a subsequent hot, dense plasma phase. Three types of divergence have been identified in the literature: secular, "time-dependent" logarithms, which grow with time spent outside the horizon; "box-cutoff" logarithms, which encode a dependence on the infrared cutoff when calculating in a finite-sized box; and "quantum" logarithms, which depend on the ratio of a scale characterizing new physics to the scale of whatever process is under consideration, and whose interpretation is the same as conventional field theory. I review the calculations in which these divergences appear, and discuss the methods which have been developed to deal with them.Comment: Invited review for focus section of Classical & Quantum Gravity on nonlinear and nongaussian perturbation theory. Some improvements compared to version which will appear in CQG, especially in Sec. 2.3. 30 pages + references

Studying the accretion geometry of EXO 2030+375 at luminosities close to the propeller regime

The Be X-ray binary EXO2030+375 was in an extended low-luminosity state during most of 2016. We observed this state with NuSTAR and Swift, supported by INTEGRAL observations and optical spectroscopy with the Nordic Optical Telescope (NOT). We present a comprehensive spectral and timing analysis of these data here to study the accretion geometry and investigate a possible onset of the propeller effect. The H alpha data show that the circumstellar disk of the Be-star is still present. We measure equivalent widths similar to values found during more active phases in the past, indicating that the low-luminosity state is not simply triggered by a smaller Be disk. The NuSTAR data, taken at a 3-78 keV luminosity of similar to 6.8 x 10(35) erg s(-1) (for a distance of 7.1 kpc), are nicely described by standard accreting pulsar models such as an absorbed power law with a high-energy cutoff. We find that pulsations are still clearly visible at these luminosities, indicating that accretion is continuing despite the very low mass transfer rate. In phase-resolved spectroscopy we find a peculiar variation of the photon index from similar to 1.5 to similar to 2.5 over only about 3% of the rotational period. This variation is similar to that observed with XMM-Newton at much higher luminosities. It may be connected to the accretion column passing through our line of sight. With Swift/XRT we observe luminosities as low as 10(34) erg s(-1) where the data quality did not allow us to search for pulsations, but the spectrum is much softer and well described by either a blackbody or soft power-law continuum. This softer spectrum might be due to the accretion being stopped by the propeller effect and we only observe the neutron star surface cooling

The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel

<p>Abstract</p> <p>Background</p> <p>Drinking water contaminated with inorganic arsenic is associated with increased risk for different types of cancer. Paradoxically, arsenic trioxide can also be used to induce remission in patients with acute promyelocytic leukemia (APL) with a success rate of approximately 80%. A comprehensive study examining the mechanisms and potential signaling pathways contributing to the anti-tumor properties of arsenic trioxide has not been carried out.</p> <p>Methods</p> <p>Here we applied a systems biology approach to identify gene biomarkers that underlie tumor cell responses to arsenic-induced cytotoxicity. The baseline gene expression levels of 14,500 well characterized human genes were associated with the GI₅₀ data of the NCI-60 tumor cell line panel from the developmental therapeutics program (DTP) database. Selected biomarkers were tested <it>in vitro</it> for the ability to influence tumor susceptibility to arsenic trioxide.</p> <p>Results</p> <p>A significant association was found between the baseline expression levels of 209 human genes and the sensitivity of the tumor cell line panel upon exposure to arsenic trioxide. These genes were overlayed onto protein-protein network maps to identify transcriptional networks that modulate tumor cell responses to arsenic trioxide. The analysis revealed a significant enrichment for the oxidative stress response pathway mediated by nuclear factor erythroid 2-related factor 2 (NRF2) with high expression in arsenic resistant tumor cell lines. The role of the NRF2 pathway in protecting cells against arsenic-induced cell killing was validated in tumor cells using shRNA-mediated knock-down.</p> <p>Conclusions</p> <p>In this study, we show that the expression level of genes in the NRF2 pathway serve as potential gene biomarkers of tumor cell responses to arsenic trioxide. Importantly, we demonstrate that tumor cells that are deficient for NRF2 display increased sensitivity to arsenic trioxide. The results of our study will be useful in understanding the mechanism of arsenic-induced cytotoxicity in cells, as well as the increased applicability of arsenic trioxide as a chemotherapeutic agent in cancer treatment.</p

NOMA: A Preventable “Scourge” of African Children

Noma is a serious orofacial gangrene originating intraorally in the gingival-oral mucosa complex before spreading extraorally to produce a visibly destructive ulcer. Although cases of noma are now rarely reported in the developed countries, it is still prevalent among children in third world countries, notably in sub-Sahara Africa, where poverty, ignorance, malnutrition, and preventable childhood infections are still common. This review summarizes historical, epidemiological, management, and research updates on noma with suggestions for its prevention and ultimate global eradication. The global annual incidence remains high at about 140,000 cases, with a mortality rate exceeding 90% for untreated diseases. Where the patients survive, noma defects result in unsightly facial disfigurement, intense scarring, trismus, oral incompetence, and social alienation. Although the etiology has long been held to be infectious, a definitive causal role between microorganisms cited, and noma has been difficult to establish. The management of noma with active disease requires antibiotics followed by reconstructive surgery. Current research efforts are focused towards a comprehensive understanding of the epidemiology, and further elucidation of the microbiology and pathogenesis of noma

A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined similar to 18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p <5 x 10(-8)) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p <5 x 10(-8)). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling MSRA, EBF2).Peer reviewe

Multiple Loci Are Associated with White Blood Cell Phenotypes

White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count—6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count—17q21; basophil count- 3p21 near RPN1 and C3orf27; lymphocyte count—6p21, 19p13 at EPS15L1; monocyte count—2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds

Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in approximate to 131 K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P <1.0 x 10(-5)). In Stage 2, these SNVs were tested for independent external replication in individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10(-8)). For African ancestry samples, we detected 18 potentially novel BP loci (P< 5.0 x 10(-8)) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2 have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension

New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P <5 x 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.Peer reviewe