Determining the origin of synchronous multifocal bladder cancer by exome sequencing

Background: Synchronous multifocal tumours are commonly observed in urothelial carcinomas of the bladder. The origin of these physically independent tumours has been proposed to occur by either intraluminal migration (clonal) or spontaneous transformation of multiple cells by carcinogens (field effect). It is unclear which model is correct, with several studies supporting both hypotheses. A potential cause of this uncertainty may be the small number of genetic mutations previously used to quantify the relationship between these tumours. Methods: To better understand the genetic lineage of these tumours we conducted exome sequencing of synchronous multifocal pTa urothelial bladder cancers at a high depth, using multiple samples from three patients. Results: Phylogenetic analysis of high confidence single nucleotide variants (SNV) demonstrated that the sequenced multifocal bladder cancers arose from a clonal origin in all three patients (bootstrap value 100 %). Interestingly, in two patients the most common type of tumour-associated SNVs were cytosine mutations of TpC*dinucleotides (Fisher's exact test p < 10-41), likely caused by APOBEC-mediated deamination. Incorporating these results into our clonal model, we found that TpC*type mutations occurred 2-5× more often among SNVs on the ancestral branches than in the more recent private branches (p < 10-4) suggesting that TpC*mutations largely occurred early in the development of the tumour. Conclusions: These results demonstrate that synchronous multifocal bladder cancers frequently arise from a clonal origin. Our data also suggests that APOBEC-mediated mutations occur early in the development of the tumour and may be a driver of tumourigenesis in non-muscle invasive urothelial bladder cancer. © 2015 Acar et al

Atmospheric emissions from the deepwater Horizon spill constrain air-water partitioning, hydrocarbon fate, and leak rate

The fate of deepwater releases of gas and oil mixtures is initially determined by solubility and volatility of individual hydrocarbon species; these attributes determine partitioning between air and water. Quantifying this partitioning is necessary to constrain simulations of gas and oil transport, to predict marine bioavailability of different fractions of the gas-oil mixture, and to develop a comprehensive picture of the fate of leaked hydrocarbons in the marine environment. Analysis of airborne atmospheric data shows massive amounts (∼258,000 kg/day) of hydrocarbons evaporating promptly from the Deepwater Horizon spill; these data collected during two research flights constrain air-water partitioning, thus bioavailability and fate, of the leaked fluid. This analysis quantifies the fraction of surfacing hydrocarbons that dissolves in the water column (∼33% by mass), the fraction that does not dissolve, and the fraction that evaporates promptly after surfacing (∼14% by mass). We do not quantify the leaked fraction lacking a surface expression; therefore, calculation of atmospheric mass fluxes provides a lower limit to the total hydrocarbon leak rate of 32,600 to 47,700 barrels of fluid per day, depending on reservoir fluid composition information. This study demonstrates a new approach for rapid-response airborne assessment of future oil spills. Copyright 2011 by the American Geophysical Union

Egg investment in response to helper presence in cooperatively breeding Tibetan ground tits

Life-history theory predicts a trade-off between current and future reproduction to maximize lifetime fitness. In cooperatively breeding species, where offspring care is shared between breeders and helpers, helper presence may influence the female breeders' egg investment, and consequently, survival and future reproductive success. For example, female breeders may reduce egg investment in response to helper presence if this reduction is compensated by helpers during provisioning. Alternatively, female breeders may increase egg investment in response to helper presence if helpers allow the breeders to raise more or higher quality offspring successfully. In the facultatively cooperative-breeding Tibetan ground tit Pseudopodoces humilis, previous studies found that helpers improve total nestling provisioning rates and fledgling recruitment, but have no apparent effects on the number and body mass of fledglings produced, while breeders with helpers show reduced provisioning rates and higher survival. Here, we investigated whether some of these effects may be explained by female breeders reducing their investment in eggs in response to helper presence. In addition, we investigated whether egg investment is associated with the female breeder's future fitness. Our results showed that helper presence had no effect on the female breeders' egg investment, and that egg investment was not associated with breeder survival and reproductive success. Our findings suggest that the responses of breeders to helping should be investigated throughout the breeding cycle, because the conclusions regarding the breeders' adjustment of reproductive investment in response to being helped may depend on which stage of the breeding cycle is considered

Randomized Trial of Introduction of Allergenic Foods in Breast-Fed Infants.

BACKGROUND: The age at which allergenic foods should be introduced into the diet of breast-fed infants is uncertain. We evaluated whether the early introduction of allergenic foods in the diet of breast-fed infants would protect against the development of food allergy. METHODS: We recruited, from the general population, 1303 exclusively breast-fed infants who were 3 months of age and randomly assigned them to the early introduction of six allergenic foods (peanut, cooked egg, cow's milk, sesame, whitefish, and wheat; early-introduction group) or to the current practice recommended in the United Kingdom of exclusive breast-feeding to approximately 6 months of age (standard-introduction group). The primary outcome was food allergy to one or more of the six foods between 1 year and 3 years of age. RESULTS: In the intention-to-treat analysis, food allergy to one or more of the six intervention foods developed in 7.1% of the participants in the standard-introduction group (42 of 595 participants) and in 5.6% of those in the early-introduction group (32 of 567) (P=0.32). In the per-protocol analysis, the prevalence of any food allergy was significantly lower in the early-introduction group than in the standard-introduction group (2.4% vs. 7.3%, P=0.01), as was the prevalence of peanut allergy (0% vs. 2.5%, P=0.003) and egg allergy (1.4% vs. 5.5%, P=0.009); there were no significant effects with respect to milk, sesame, fish, or wheat. The consumption of 2 g per week of peanut or egg-white protein was associated with a significantly lower prevalence of these respective allergies than was less consumption. The early introduction of all six foods was not easily achieved but was safe. CONCLUSIONS: The trial did not show the efficacy of early introduction of allergenic foods in an intention-to-treat analysis. Further analysis raised the question of whether the prevention of food allergy by means of early introduction of multiple allergenic foods was dose-dependent. (Funded by the Food Standards Agency and others; EAT Current Controlled Trials number, ISRCTN14254740.)

Sea buckthorn berries <i>Hippophae rhamnoides</i> L. predict size and composition of a great tit population <i>Parus major</i> L.

In seasonal environments variation in food abundance in the non-breeding season is thought to affect songbird population dynamics. In a unique tit-sea buckthorn berry system we can estimate the berry abundance and both the tit consumption and population dynamics. Six hundred nest boxes were available to great and blue tits Cyanistes caeruleus for breeding in spring and roosting in winter. We followed the dynamics including the recapture histories of individually marked great tits from 2008 to 2014. In each year we estimated 1) the winter sea buckthorn berry availability, 2) an index of berry consumption in December based on the colour of the faeces of roosting birds, 3) the number of breeding great and blue tits, 4) both recapture probability and the return rate of the great tits and 5) immigration rates. December berry abundance positively predicted the number of breeding pairs of both species in the subsequent season and great tit return rates in the second half of the winter. There was support for a sex specific berry effect on the adult return rate in the great tit: female return rate was associated less strongly to berry abundance than male return rate. This skewed the sex ratio of the local breeders in the following breeding season. Intriguingly, annual berry consumption in December was not related to berry abundance, and individuals consuming more berries tended to have slightly lower return rates. Reproductive rate was not related to berry abundance. There was hardly support for a relation between immigration rates of first year breeders and berry abundance. Taken together these results imply that berry stock not only affected population size but also the population composition through sex specific exchange with the surroundings. Since population density covaried with berry abundance, density dependent effects provide an alternative explanation for the patterns observed

IgG4 inhibits peanut-induced basophil and mast cell activation in peanut-tolerant children sensitized to peanut major allergens

BackgroundMost children with detectable peanut-specific IgE (P-sIgE) are not allergic to peanut. We addressed 2 non–mutually exclusive hypotheses for the discrepancy between allergy and sensitization: (1) differences in P-sIgE levels between children with peanut allergy (PA) and peanut-sensitized but tolerant (PS) children and (2) the presence of an IgE inhibitor, such as peanut-specific IgG4 (P-sIgG4), in PS patients.MethodsTwo hundred twenty-eight children (108 patients with PA, 77 PS patients, and 43 nonsensitized nonallergic subjects) were studied. Levels of specific IgE and IgG4 to peanut and its components were determined. IgE-stripped basophils or a mast cell line were used in passive sensitization activation and inhibition assays. Plasma of PS subjects and patients submitted to peanut oral immunotherapy (POIT) were depleted of IgG4 and retested in inhibition assays.ResultsBasophils and mast cells sensitized with plasma from patients with PA but not PS patients showed dose-dependent activation in response to peanut. Levels of sIgE to peanut and its components could only partially explain differences in clinical reactivity between patients with PA and PS patients. P-sIgG4 levels (P = .023) and P-sIgG4/P-sIgE (P < .001), Ara h 1–sIgG4/Ara h 1–sIgE (P = .050), Ara h 2–sIgG4/Ara h 2–sIgE (P = .004), and Ara h 3–sIgG4/Ara h 3–sIgE (P = .016) ratios were greater in PS children compared with those in children with PA. Peanut-induced activation was inhibited in the presence of plasma from PS children with detectable P-sIgG4 levels and POIT but not from nonsensitized nonallergic children. Depletion of IgG4 from plasma of children with PS (and POIT) sensitized to Ara h 1 to Ara h 3 partially restored peanut-induced mast cell activation (P = .007).ConclusionsDifferences in sIgE levels and allergen specificity could not justify the clinical phenotype in all children with PA and PS children. Blocking IgG4 antibodies provide an additional explanation for the absence of clinical reactivity in PS patients sensitized to major peanut allergens

Understanding the small object argument

The small object argument is a transfinite construction which, starting from a set of maps in a category, generates a weak factorisation system on that category. As useful as it is, the small object argument has some problematic aspects: it possesses no universal property; it does not converge; and it does not seem to be related to other transfinite constructions occurring in categorical algebra. In this paper, we give an "algebraic" refinement of the small object argument, cast in terms of Grandis and Tholen's natural weak factorisation systems, which rectifies each of these three deficiencies.Comment: 42 pages; supersedes the earlier arXiv preprint math/0702290; v2: final journal version, minor corrections onl

A case of carotid body paraganglioma and haemangioblastoma of the spinal cord in a patient with the N131K missense mutation in the VHL gene

The article describes paraganglioma case in woman with von Hippel–Lindau disease. She was found to be a carrier of a rare germline mutation in the VHL gene (393C>A; N131K). The patient developed large, untypical for von Hippel–Lindau disease, carotid body paraganglioma at the common carotid artery bifurcation. The carotid body paraganglioma coexisted with the haemangioblastoma situated intramedullary in region C5/C6. The haemangioblastoma reached the right-sided dorsal part of the spinal cord in section C5/C6. It produced radicular symptoms within C5/C6, followed by the later paresis of the right limbs. The haemangioblastoma was resected completely. Twelve months after the operation, the spinal symptoms receded and the carotid body paraganglioma still was asymptomatic. The current case of carotid body paraganglioma in patient with the 393C>A (N131K) missense mutation in the VHL gene, supports association of this specific mutation and VHL disease type 2, and suggests its correlation with susceptibility to paragangliomas

Piperidinols that show anti-tubercular activity as inhibitors of arylamine N-acetyltransferase: an essential enzyme for mycobacterial survival inside macrophages

Latent M. tuberculosis infection presents one of the major obstacles in the global eradication of tuberculosis (TB). Cholesterol plays a critical role in the persistence of M. tuberculosis within the macrophage during latent infection. Catabolism of cholesterol contributes to the pool of propionyl-CoA, a precursor that is incorporated into cell-wall lipids. Arylamine N-acetyltransferase (NAT) is encoded within a gene cluster that is involved in the cholesterol sterol-ring degradation and is essential for intracellular survival. The ability of the NAT from M. tuberculosis (TBNAT) to utilise propionyl-CoA links it to the cholesterol-catabolism pathway. Deleting the nat gene or inhibiting the NAT enzyme prevents intracellular survival and results in depletion of cell-wall lipids. TBNAT has been investigated as a potential target for TB therapies. From a previous high-throughput screen, 3-benzoyl-4-phenyl-1-methylpiperidinol was identified as a selective inhibitor of prokaryotic NAT that exhibited antimycobacterial activity. The compound resulted in time-dependent irreversible inhibition of the NAT activity when tested against NAT from M. marinum (MMNAT). To further evaluate the antimycobacterial activity and the NAT inhibition of this compound, four piperidinol analogues were tested. All five compounds exert potent antimycobacterial activity against M. tuberculosis with MIC values of 2.3-16.9 µM. Treatment of the MMNAT enzyme with this set of inhibitors resulted in an irreversible time-dependent inhibition of NAT activity. Here we investigate the mechanism of NAT inhibition by studying protein-ligand interactions using mass spectrometry in combination with enzyme analysis and structure determination. We propose a covalent mechanism of NAT inhibition that involves the formation of a reactive intermediate and selective cysteine residue modification. These piperidinols present a unique class of antimycobacterial compounds that have a novel mode of action different from known anti-tubercular drugs