5 S,15 S-Dihydroperoxyeicosatetraenoic Acid (5,15-diHpETE) as a Lipoxin Intermediate: Reactivity and Kinetics with Human Leukocyte 5-Lipoxygenase, Platelet 12-Lipoxygenase, and Reticulocyte 15-Lipoxygenase-1.

The reaction of 5 S,15 S-dihydroperoxyeicosatetraenoic acid (5,15-diHpETE) with human 5-lipoxygenase (LOX), human platelet 12-LOX, and human reticulocyte 15-LOX-1 was investigated to determine the reactivity and relative rates of producing lipoxins (LXs). 5-LOX does not react with 5,15-diHpETE, although it can produce LXA4 when 15-HpETE is the substrate. In contrast, both 12-LOX and 15-LOX-1 react with 5,15-diHpETE, forming specifically LXB4. For 12-LOX and 5,15-diHpETE, the kinetic parameters are kcat = 0.17 s-1 and kcat/ KM = 0.011 μM-1 s-1 [106- and 1600-fold lower than those for 12-LOX oxygenation of arachidonic acid (AA), respectively]. On the other hand, for 15-LOX-1 the equivalent parameters are kcat = 4.6 s-1 and kcat/ KM = 0.21 μM-1 s-1 (3-fold higher and similar to those for 12-HpETE formation by 15-LOX-1 from AA, respectively). This contrasts with the complete lack of reaction of 15-LOX-2 with 5,15-diHpETE [Green, A. R., et al. (2016) Biochemistry 55, 2832-2840]. Our data indicate that 12-LOX is markedly inferior to 15-LOX-1 in catalyzing the production of LXB4 from 5,15-diHpETE. Platelet aggregation was inhibited by the addition of 5,15-diHpETE, with an IC50 of 1.3 μM; however, LXB4 did not significantly inhibit collagen-mediated platelet activation up to 10 μM. In summary, LXB4 is the primary product of 12-LOX and 15-LOX-1 catalysis, if 5,15-diHpETE is the substrate, with 15-LOX-1 being 20-fold more efficient than 12-LOX. LXA4 is the primary product with 5-LOX but only if 15-HpETE is the substrate. Approximately equal proportions of LXA4 and LXB4 are produced by 12-LOX but only if LTA4 is the substrate, as described previously [Sheppard, K. A., et al. (1992) Biochim. Biophys. Acta 1133, 223-234]

Interventions at the Supreme Court of Canada: Accuracy, Affiliation, and Acceptance

Interveners make submissions in about half of the cases heard by the Supreme Court of Canada, but the motivations for and consequences of the practice are not clearly understood. Considered broadly, there are at least three functions that the practice of intervention might perform. The first possibility is that hearing from interveners might provide objectively useful information to the Court (i.e., interveners might promote the accuracy of the Court\u27s decision making). A second possibility is that the practice of intervention allows interveners to provide the best argument for certain partisan interests that judges might want to affiliate with. A third possibility is that interventions are allowed mainly (if not only) so that intervening parties feel they have had their voices heard by the Court and the greater public, including Parliament, regardless of the effect on the outcome of the appeal (i.e., the Court might be promoting the acceptability of its decisions by allowing for an outlet for expression). We examine empirically the role of interveners in all the cases decided by the Supreme Court of Canada from January 2000 to July 2009 and find statistical evidence that interveners matter

Classifying Single Stars and Spectroscopic Binaries Using Optical Stellar Templates

Stellar spectral classification is a fundamental tool of modern astronomy, providing insight into physical characteristics such as effective temperature, surface gravity, and metallicity. Accurate and fast spectral typing is an integral need for large all-sky spectroscopic surveys like the SDSS and LAMOST. Here, we present the next version of PyHammer, stellar spectral classification software that uses optical spectral templates and spectral line index measurements. PyHammer v2.0 extends the classification power to include carbon (C) stars, DA white dwarf (WD) stars, and also double-lined spectroscopic binaries (SB2). This release also includes a new empirical library of luminosity-normalized spectra that can be used to flux calibrate observed spectra, or to create synthetic SB2 spectra. We have generated physically reasonable SB2 combinations as templates, adding to PyHammer the ability to spectrally type SB2s. We test classification success rates on SB2 spectra, generated from the SDSS, across a wide range of spectral types and signal-to-noise ratios. Within the defined range of pairings described, more than $95\%$ of SB2s are correctly classified.Comment: 16 pages, 7 figures, 4 tables; accepted to ApJ

Pathognomonic and epistatic genetic alterations in B-cell non-Hodgkin lymphoma [preprint]

B-cell non-Hodgkin lymphoma (B-NHL) encompasses multiple clinically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common subtypes of B-NHL such as diffuse large B-cell lymphoma (DLBCL) have been comprehensively interrogated at the genomic level, but other less common subtypes such as mantle cell lymphoma (MCL) remain sparsely characterized. Furthermore, multiple B-NHL subtypes have thus far not been comprehensively compared to identify conserved or subtype-specific patterns of genomic alterations. Here, we employed a large targeted hybrid-capture sequencing approach encompassing 380 genes to interrogate the genomic landscapes of 755 B-NHL tumors at high depth; primarily including DLBCL, MCL, follicular lymphoma (FL), and Burkitt lymphoma (BL). We identified conserved hallmarks of B-NHL that were deregulated across major subtypes, such as the frequent genetic deregulation of the ubiquitin proteasome system (UPS). In addition, we identified subtype-specific patterns of genetic alterations, including clusters of co-occurring mutations that are pathognomonic. The cumulative burden of mutations within a single cluster were more significantly discriminatory of B-NHL subtypes than individual mutations, implicating likely patterns of genetic epistasis that contribute to disease etiology. We therefore provide a framework of co-occurring mutations that deregulate genetic hallmarks and likely cooperate in lymphomagenesis of B-NHL subtypes

The Poincare' coset models ISO(d-1,1)/R^n and T-duality

We generalize a family of Lagrangians with values in the Poincar\'e group ISO(d-1,1), which contain the description of spinning strings in flat (d-1)+1 dimensions, by including symmetric terms in the world-sheet coordinates. Then, by promoting a subgroup H=R^n, n less than or equal to d, which acts invariantly from the left on the element of ISO(d-1,1), to a gauge symmetry of the action, we obtain a family of sigma-models. They describe bosonic strings moving in (generally) curved, and in some cases degenerate, space-times with an axion field. Further, the space-times of the effective theory admit in general T-dual geometries. We give explicit results for two non degenerate cases.Comment: LaTeX, 24 pages, no figure

Self-renewal of single mouse hematopoietic stem cells is reduced by JAK2V617F without compromising progenitor cell expansion

Recent descriptions of significant heterogeneity in normal stem cells and cancers have altered our understanding of tumorigenesis, emphasizing the need to understand how single stem cells are subverted to cause tumors. Human myeloproliferative neoplasms (MPNs) are thought to reflect transformation of a hematopoietic stem cell (HSC) and the majority harbor an acquired V617F mutation in the JAK2 tyrosine kinase, making them a paradigm for studying the early stages of tumor establishment and progression. The consequences of activating tyrosine kinase mutations for stem and progenitor cell behavior are unclear. In this article, we identify a distinct cellular mechanism operative in stem cells. By using conditional knock-in mice, we show that the HSC defect resulting from expression of heterozygous human JAK2V617F is both quantitative (reduced HSC numbers) and qualitative (lineage biases and reduced self-renewal per HSC). The defect is intrinsic to individual HSCs and their progeny are skewed toward proliferation and differentiation as evidenced by single cell and transplantation assays. Aged JAK2V617F show a more pronounced defect as assessed by transplantation, but mice that transform reacquire competitive self-renewal ability. Quantitative analysis of HSC-derived clones was used to model the fate choices of normal and JAK2-mutant HSCs and indicates that JAK2V617F reduces self-renewal of individual HSCs but leaves progenitor expansion intact. This conclusion is supported by paired daughter cell analyses, which indicate that JAK2-mutant HSCs more often give rise to two differentiated daughter cells. Together these data suggest that acquisition of JAK2V617F alone is insufficient for clonal expansion and disease progression and causes eventual HSC exhaustion. Moreover, our results show that clonal expansion of progenitor cells provides a window in which collaborating mutations can accumulate to drive disease progression. Characterizing the mechanism(s) of JAK2V617F subclinical clonal expansions and the transition to overt MPNs will illuminate the earliest stages of tumor establishment and subclone competition, fundamentally shifting the way we treat and manage cancers

MicroRNA Molecular Profiling from Matched Tumor and Bio-Fluids in Bladder Cancer

MicroRNAs have been identified as potential cancer biomarkers due to their presence and stability in many body fluids including urine and plasma, but the relationship of the pattern of expression of these messengers across various biological media has not been addressed and could provide important information in order to translate these biomarkers for epidemiologic or clinical use. We analyzed microRNA of matched FFPE-tumor tissue, plasma, urine exosomes (n = 16) and WBCs (n = 11) from patients with bladder cancer, using Nanostring miRNA assays and droplet digital PCR for validation. Pearson correlations were used to compare expression between media

A Chandra Study: Are Dwarf Carbon Stars Spun Up and Rejuvenated by Mass Transfer?

Carbon stars (with C/O> 1) were long assumed to all be giants, because only AGB stars dredge up significant carbon into their atmospheres. The case is nearly iron-clad now that the formerly mysterious dwarf carbon (dC) stars are actually far more common than C giants, and have accreted carbon-rich material from a former AGB companion, yielding a white dwarf and a dC star that has gained both significant mass and angular momentum. Some such dC systems have undergone a planetary nebula phase, and some may evolve to become CH, CEMP, or Ba giants. Recent studies indicate that most dCs are likely from older, metal-poor kinematic populations. Given the well-known anti-correlation of age and activity, dCs would not be expected to show significant X-ray emission related to coronal activity. However, accretion spin-up might be expected to rejuvenate magnetic dynamos in these post mass-transfer binary systems. We describe our Chandra pilot study of six dCs selected from the SDSS for Halpha emission and/or a hot white dwarf companion, to test whether their X-ray emission strength and spectral properties are consistent with a rejuvenated dynamo. We detect all 6 dCs in the sample, which have X-ray luminosities ranging from logLx= 28.5 - 29.7, preliminary evidence that dCs may be active at a level consistent with stars that have short rotation periods of several days or less. More definitive results require a sample of typical dCs with deeper X-ray observations to better constrain their plasma temperatures.Comment: 13 pages, 5 figures. Revised and resubmitted June 20, accepted June 21, 2019 to Ap

An integrable shallow water equation with peaked solitons

We derive a new completely integrable dispersive shallow water equation that is biHamiltonian and thus possesses an infinite number of conservation laws in involution. The equation is obtained by using an asymptotic expansion directly in the Hamiltonian for Euler's equations in the shallow water regime. The soliton solution for this equation has a limiting form that has a discontinuity in the first derivative at its peak.Comment: LaTeX file. Figure available from authors upon reques

Celiac disease and risk of myasthenia gravis – nationwide population-based study

Background Case reports suggest there may be an association between celiac disease (CD) and myasthenia gravis (MG). Methods We identified 29,086 individuals with CD in Sweden from 1969 to 2008. We compared these individuals with 144,480 matched controls. Hazard ratios (HRs) for future MG (identified through ICD codes) were estimated using Cox regression. Results During 326,376 person-years of follow-up in CD patients, there were 7 MG cases (21/million person-years) compared to 22 MG cases in controls during 1,642,273 years of follow-up (14/million person-years) corresponding to a HR of 1.48 (95% CI = 0.64–3.41). HRs did not differ when stratifying for age, sex or calendar period. HRs were highest in the first year after follow-up, though insignificant. Individuals with CD were at no increased risk of MG more than 5 years after CD diagnosis (HR = 0.70; 95% CI = 0.16–3.09). Conclusion This study found no increased risk of MG in patients with CD