mtDNA data reveal disparate population structures and High Arctic colonization patterns in three intertidal invertebrates with contrasting life history traits

Introduction: Post-glacial climate variation is known to have influenced the distribution of marine species in the North Atlantic. In particular, the Atlantic side of the Arctic has experienced strong fluctuations in both atmospheric and sea surface temperature, as well as seasonal ice coverage since the last glacial maximum (LGM). Here, we aim to unveil the phylogeography and historical demography of three rocky intertidal marine invertebrates showing a trans-Atlantic distribution and presently inhabiting the Arctic: Gammarus oceanicus, Littorina saxatilis and Semibalanus balanoides. Methods: We used a large amount of mitochondrial DNA barcode data, both newly-obtained and stored in public databases. We performed phylogeographic and demographic analyses on 1119 G. oceanicus, 205 L. saxatilis, and 884 S. balanoides sequences. Results: Our results show that all three of these boreal species have expanded their effective population sizes in the high Arctic Svalbard Archipelago since the LGM. Analyses investigating the origin of all these populations point to the eastern Atlantic. Discussion: Based on our results we conclude that the expansion of these boreal species to the Arctic possibly happened during an earlier warm cycle of the Holocene era, and is probably not the result of the recent ‘Atlantification’ of the Arctic. We also discuss the effects of dispersal potential on population structure as an important aspect of comparative biogeographical studies

Ranked Reward: Enabling Self-Play Reinforcement Learning for Combinatorial Optimization

Adversarial self-play in two-player games has delivered impressive results when used with reinforcement learning algorithms that combine deep neural networks and tree search. Algorithms like AlphaZero and Expert Iteration learn tabula-rasa, producing highly informative training data on the fly. However, the self-play training strategy is not directly applicable to single-player games. Recently, several practically important combinatorial optimisation problems, such as the travelling salesman problem and the bin packing problem, have been reformulated as reinforcement learning problems, increasing the importance of enabling the benefits of self-play beyond two-player games. We present the Ranked Reward (R2) algorithm which accomplishes this by ranking the rewards obtained by a single agent over multiple games to create a relative performance metric. Results from applying the R2 algorithm to instances of a two-dimensional and three-dimensional bin packing problems show that it outperforms generic Monte Carlo tree search, heuristic algorithms and integer programming solvers. We also present an analysis of the ranked reward mechanism, in particular, the effects of problem instances with varying difficulty and different ranking thresholds

Evaluating the Suitability of Using Rat Models for Preclinical Efficacy and Side Effects with Inhaled Corticosteroids Nanosuspension Formulations

Inhaled corticosteroids (ICS) are often prescribed as first-line therapy for patients with asthma Despite their efficacy and improved safety profile compared with oral corticosteroids, the potential for systemic side effects continues to cause concern. In order to reduce the potential for systemic side effects, the pharmaceutical industry has begun efforts to generate new drugs with pulmonary-targeted topical efficacy. One of the major challenges of this approach is to differentiate both efficacy and side effects (pulmonary vs. systemic) in a preclinical animal model. In this study, fluticasone and ciclesonide were used as tool compounds to explore the possibility of demonstrating both efficacy and side effects in a rat model using pulmonary delivery via intratracheal (IT) instillation with nanosuspension formulations. The inhibition of neutrophil infiltration into bronchoalveolar lavage fluid (BALF) and cytokine (TNFα) production were utilized to assess pulmonary efficacy, while adrenal and thymus involution as well as plasma corticosterone suppression was measured to assess systemic side effects. Based on neutrophil infiltration and cytokine production data, the ED50s for ciclesonide and fluticasone were calculated to be 0.1 and 0.03 mg, respectively. At the ED50, the average adrenal involution was 7.6 ± 5.3% for ciclesonide versus 16.6 ± 5.1% for fluticasone, while the average thymus involution was 41.0 ± 4.3% for ciclesonide versus 59.5 ± 5.8% for fluticasone. However, the differentiation became less significant when the dose was pushed to the EDmax (0.3 mg for ciclesonide, 0.1 mg for fluticasone). Overall, the efficacy and side effect profiles of the two compounds exhibited differentiation at low to mid doses (0.03–0.1 mg ciclesonide, 0.01–0.03 mg fluticasone), while this differentiation diminished at the maximum efficacious dose (0.3 mg ciclesonide, 0.1 mg fluticasone), likely due to overdosing in this model. We conclude that the rat LPS model using IT administration of nanosuspensions of ICS is a useful tool to demonstrate pulmonary-targeted efficacy and to differentiate the side effects. However, it is only suitable at sub-maximum efficacious levels

Anti-Allergic Cromones Inhibit Histamine and Eicosanoid Release from Activated Human and Murine Mast Cells by Releasing Annexin A1

PMCID: PMC3601088This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Identification of New Alleles and the Determination of Alleles and Genotypes Frequencies at the CYP2D6 Gene in Emiratis

CYP2D6 belongs to the cytochrome P450 superfamily of enzymes and plays an important role in the metabolism of 20–25% of clinically used drugs including antidepressants. It displays inter-individual and inter-ethnic variability in activity ranging from complete absence to excessive activity which causes adverse drug reactions and toxicity or therapy failure even at normal drug doses. This variability is due to genetic polymorphisms which form poor, intermediate, extensive or ultrarapid metaboliser phenotypes. This study aimed to determine CYP2D6 alleles and their frequencies in the United Arab Emirates (UAE) local population. CYP2D6 alleles and genotypes were determined by direct DNA sequencing in 151 Emiratis with the majority being psychiatric patients on antidepressants. Several new alleles have been identified and in total we identified seventeen alleles and 49 genotypes. CYP2D6*1 (wild type) and CYP2D6*2 alleles (extensive metaboliser phenotype) were found with frequencies of 39.1% and 12.2%, respectively. CYP2D6*41 (intermediate metaboliser) occurred in 15.2%. Homozygous CYP2D6*4 allele (poor metaboliser) was found with a frequency of 2% while homozygous and heterozygous CYP2D6*4 occurred with a frequency of 9%. CYP2D6*2xn, caused by gene duplication (ultrarapid metaboliser) had a frequency of 4.3%. CYP2D6 gene duplication/multiduplication occurred in 16% but only 11.2% who carried more than 2 active functional alleles were considered ultrarapid metabolisers. CYP2D6 gene deletion in one copy occurred in 7.5% of the study group. In conclusion, CYP2D6 gene locus is heterogeneous in the UAE national population and no significant differences have been identified between the psychiatric patients and controls

Loss of sucrase-isomaltase function increases acetate levels and improves metabolic health in Greenlandic cohorts

Background & Aims The sucrase-isomaltase (SI) c.273_274delAG loss-of-function variant is common in Arctic populations and causes congenital sucrase-isomaltase deficiency, which is an inability to break down and absorb sucrose and isomaltose. Children with this condition experience gastrointestinal symptoms when dietary sucrose is introduced. We aimed to describe the health of adults with sucrase-isomaltase deficiency. Methods The association between c.273_274delAG and phenotypes related to metabolic health was assessed in 2 cohorts of Greenlandic adults (n = 4922 and n = 1629). A sucrase-isomaltase knockout (Sis-KO) mouse model was used to further elucidate the findings. Results Homozygous carriers of the variant had a markedly healthier metabolic profile than the remaining population, including lower body mass index (β [standard error], –2.0 [0.5] kg/m2; P = 3.1 × 10–5), body weight (–4.8 [1.4] kg; P = 5.1 × 10–4), fat percentage (–3.3% [1.0%]; P = 3.7 × 10–4), fasting triglyceride (–0.27 [0.07] mmol/L; P = 2.3 × 10–6), and remnant cholesterol (–0.11 [0.03] mmol/L; P = 4.2 × 10–5). Further analyses suggested that this was likely mediated partly by higher circulating levels of acetate observed in homozygous carriers (β [standard error], 0.056 [0.002] mmol/L; P = 2.1 × 10–26), and partly by reduced sucrose uptake, but not lower caloric intake. These findings were verified in Sis-KO mice, which, compared with wild-type mice, were leaner on a sucrose-containing diet, despite similar caloric intake, had significantly higher plasma acetate levels in response to a sucrose gavage, and had lower plasma glucose level in response to a sucrose-tolerance test. Conclusions These results suggest that sucrase-isomaltase constitutes a promising drug target for improvement of metabolic health, and that the health benefits are mediated by reduced dietary sucrose uptake and possibly also by higher levels of circulating acetate

Mesoscale Atmospheric Transport of Ragweed Pollen Allergens from Infected to Uninfected Areas

Allergenic ragweed (Ambrosia spp.) pollen grains, after being released from anthers, can be dispersed by air masses far from their source. However, the action of air temperature,humidity and solar radiation on pollen grains in the atmosphere could impact on the ability of long distance transported (LDT) pollen to maintain allergenic potency. Here, we report that the major allergen of Ambrosia artemisiifolia pollen (Amb a 1) collected in ambient air during episodes of LDT still have immunoreactive properties. The amount of Amb a 1 found in LDT ragweed pollen grains was not constant and varied between episodes. In addition to allergens in pollen sized particles, we detected reactive Amb a 1 in subpollen sized respirable particles. These findings suggest that ragweed pollen grains have the potential to cause allergic reactions, not only in the heavily infested areas but, due to LDT episodes, also in the regions unaffected by ragweed populations

Interaction of the tetracyclines with double-stranded RNAs of random base sequence: new perspectives on the target and mechanism of action

The 16S rRNA binding mechanism proposed for the antibacterial action of the tetracyclines does not explain their mechanism of action against non-bacterial pathogens. In addition, several contradictory base pairs have been proposed as their binding sites on the 16S rRNA. This study investigated the binding of minocycline and doxycycline to short double-stranded RNAs (dsRNAs) of random base sequences. These tetracyclines caused a dose-dependent decrease in the fluorescence intensities of 6-carboxyfluorescein (FAM)-labelled dsRNA and ethidium bromide (EtBr)-stained dsRNA, indicating that both drugs bind to dsRNA of random base sequence in a manner that is competitive with the binding of EtBr and other nucleic acid ligands often used as stains. This effect was observable in the presence of Mg2+. The binding of the tetracyclines to dsRNA changed features of the fluorescence emission spectra of the drugs and the CD spectra of the RNA, and inhibited RNase III cleavage of the dsRNA. These results indicate that the double-stranded structures of RNAs may have a more important role in their interaction with the tetracyclines than the specific base pairs, which had hitherto been the subject of much investigation. Given the diverse functions of cellular RNAs, the binding of the tetracyclines to their double-stranded helixes may alter the normal processing and functioning of the various biological processes they regulate. This could help to explain the wide range of action of the tetracyclines against various pathogens and disease condition

Physiological dynamics of chemosynthetic symbionts in hydrothermal vent snails

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Breusing, C., Mitchell, J., Delaney, J., Sylva, S. P., Seewald, J. S., Girguis, P. R., & Beinart, R. A. Physiological dynamics of chemosynthetic symbionts in hydrothermal vent snails. Isme Journal, (2020), doi:10.1038/s41396-020-0707-2.Symbioses between invertebrate animals and chemosynthetic bacteria form the basis of hydrothermal vent ecosystems worldwide. In the Lau Basin, deep-sea vent snails of the genus Alviniconcha associate with either Gammaproteobacteria (A. kojimai, A. strummeri) or Campylobacteria (A. boucheti) that use sulfide and/or hydrogen as energy sources. While the A. boucheti host–symbiont combination (holobiont) dominates at vents with higher concentrations of sulfide and hydrogen, the A. kojimai and A. strummeri holobionts are more abundant at sites with lower concentrations of these reductants. We posit that adaptive differences in symbiont physiology and gene regulation might influence the observed niche partitioning between host taxa. To test this hypothesis, we used high-pressure respirometers to measure symbiont metabolic rates and examine changes in gene expression among holobionts exposed to in situ concentrations of hydrogen (H2: ~25 µM) or hydrogen sulfide (H2S: ~120 µM). The campylobacterial symbiont exhibited the lowest rate of H2S oxidation but the highest rate of H2 oxidation, with fewer transcriptional changes and less carbon fixation relative to the gammaproteobacterial symbionts under each experimental condition. These data reveal potential physiological adaptations among symbiont types, which may account for the observed net differences in metabolic activity and contribute to the observed niche segregation among holobionts.We thank the Schmidt Ocean Institute, the crew of the R/V Falkor and the pilots of the ROV ROPOS for facilitating the sample collections and shipboard experiments, and the Broad Institute Microbial ‘Omics Core for preparing and sequencing the transcriptomic libraries. This material is based in part upon work supported by the National Science Foundation under Grant Numbers NSF OCE-1536653 (to PRG), OCE-1536331 (to RAB and JSS), OCE-1819530 and OCE-1736932 (to RAB)