Obesity-related perivascular adipose tissue damage is reversed by sustained weight loss in the rat

Objective – Perivascular adipose tissue (PVAT) exerts an anticontractile effect in response to various vasoconstrictor agonists and this is lost in obesity. A recent study reported that bariatric surgery reverses the damaging effects of obesity on PVAT function. However, PVAT function has not been characterised following weight loss induced by caloric restriction, which is often the first line treatment for obesity. Approach and Results – Contractility studies were performed using wire myography on small mesenteric arteries with and without PVAT from control, diet-induced obese, calorie restricted and sustained weight loss rats. Changes in the PVAT environment were assessed using immunohistochemistry. PVAT from healthy animals elicited an anticontractile effect in response to norepinephrine. This was abolished in diet-induced obesity through a mechanism involving increased local TNFα and reduced nitric oxide bioavailability within PVAT. Sustained weight loss led to improvement in PVAT function associated with restoration of adipocyte size, reduced TNFα and increased nitric oxide synthase function. This was associated with reversal of obesity-induced hypertension and normalisation of plasma adipokine levels, including leptin and insulin. Conclusions – We have shown that diet-induced weight loss reverses obesity-induced PVAT damage through a mechanism involving reduced inflammation and increased nitric oxide synthase activity within PVAT. These data reveal inflammation and nitric oxide synthase, particularly eNOS, as potential targets for the treatment of PVAT dysfunction associated with obesity and the metabolic syndrome

Impact of shortened crop rotation of oilseed rape on soil and rhizosphere microbial diversity in relation to yield decline

Oilseed rape (OSR) grown in monoculture shows a decline in yield relative to virgin OSR of up to 25%, but the mechanisms responsible are unknown. A long term field experiment of OSR grown in a range of rotations with wheat was used to determine whether shifts in fungal and bacterial populations of the rhizosphere and bulk soil were associated with the development of OSR yield decline. The communities of fungi and bacteria in the rhizosphere and bulk soil from the field experiment were profiled using terminal restriction fragment length polymorphism (TRFLP) and sequencing of cloned internal transcribed spacer regions and 16S rRNA genes, respectively. OSR cropping frequency had no effect on rhizosphere bacterial communities. However, the rhizosphere fungal communities from continuously grown OSR were significantly different to those from other rotations. This was due primarily to an increase in abundance of two fungi which showed 100% and 95% DNA identity to the plant pathogens Olpidium brassicae and Pyrenochaeta lycopersici, respectively. Real-time PCR confirmed that there was significantly more of these fungi in the continuously grown OSR than the other rotations. These two fungi were isolated from the field and used to inoculate OSR and Brassica oleracea grown under controlled conditions in a glasshouse to determine their effect on yield. At high doses, Olpidium brassicae reduced top growth and root biomass in seedlings and reduced branching and subsequent pod and seed production. Pyrenochaeta sp. formed lesions on the roots of seedlings, and at high doses delayed flowering and had a negative impact on seed quantity and quality

Sequential simulation-based inference for gravitational wave signals

The current and upcoming generations of gravitational wave experiments represent an exciting step forward in terms of detector sensitivity and performance. For example, key upgrades at the LIGO, Virgo and KAGRA facilities will see the next observing run (O4) probe a spatial volume around four times larger than the previous run (O3), and design implementations for, e.g., the Einstein Telescope, Cosmic Explorer, and LISA experiments are taking shape to explore a wider frequency range and probe cosmic distances. In this context, however, a number of very real data analysis problems face the gravitational wave community. For example, it will be critical to develop tools and strategies to analyze (among other scenarios) signals that arrive coincidentally in detectors, longer signals that are in the presence of nonstationary noise or other shorter transients, as well as noisy, potentially correlated, coherent stochastic backgrounds. With these challenges in mind, we develop peregrine, a new sequential simulation-based inference approach designed to study broad classes of gravitational wave signal. In this work, we describe the method and implementation, before demonstrating its accuracy and robustness through direct comparison with established likelihood-based methods. Specifically, we show that we are able to fully reconstruct the posterior distributions for every parameter of a spinning, precessing compact binary coalescence using one of the most physically detailed and computationally expensive waveform approximants (SEOBNRv4PHM). Crucially, we are able to do this using only 2% of the waveform evaluations that are required in, e.g., nested sampling approaches. Finally, we provide some outlook as to how this level of simulation efficiency and flexibility in the statistical analysis could allow peregrine to tackle these current and future gravitational wave data analysis problems

Repurposing a photosynthetic antenna protein as a super-resolution microscopy label

Techniques such as Stochastic Optical Reconstruction Microscopy (STORM) and Structured Illumination Microscopy (SIM) have increased the achievable resolution of optical imaging, but few fluorescent proteins are suitable for super-resolution microscopy, particularly in the far-red and near-infrared emission range. Here we demonstrate the applicability of CpcA, a subunit of the photosynthetic antenna complex in cyanobacteria, for STORM and SIM imaging. The periodicity and width of fabricated nanoarrays of CpcA, with a covalently attached phycoerythrobilin (PEB) or phycocyanobilin (PCB) chromophore, matched the lines in reconstructed STORM images. SIM and STORM reconstructions of Escherichia coli cells harbouring CpcA-labelled cytochrome bd 1 ubiquinol oxidase in the cytoplasmic membrane show that CpcA-PEB and CpcA-PCB are suitable for super-resolution imaging in vivo. The stability, ease of production, small size and brightness of CpcA-PEB and CpcA-PCB demonstrate the potential of this largely unexplored protein family as novel probes for super-resolution microscopy

Trends in Abortion Incidence and Service Availability in North Carolina, 1980-2013

Objectives: Abortion incidence has declined nationally during the last decade. In recent years, many states, including North Carolina, have passed legislation related to the provision of abortion services. Despite the changing political environment, there is no comprehensive analysis on past and current trends related to unintended pregnancy and abortion in North Carolina. Methods: This study is a secondary analysis of vital registration data made publicly available by the North Carolina State Center for Health Statistics. Birth and induced abortion records were obtained for the years 1980 to 2013. We describe abortion incidence and demographic characteristics of women obtaining abortions over time. Results: The number of North Carolina abortions declined 36% between 1980 and 2013. The abortion ratio declined from 26/100 pregnancies (live births and abortions) in 1980 to just 14/100 in 2013. These ratios, however, vary across demographic subgroups. In 2013, the abortion ratio was more than 2 times greater for non-Hispanic black women than non-Hispanic white women (22 and 9, respectively). Among non-Hispanic black and Hispanic women, the abortion ratio is greater among women with a previous pregnancy as compared with women in their first pregnancy. For non-Hispanic white women, the abortion ratios are similar for first and higher-order pregnancies. Conclusions: Trends in North Carolina are similar to national trends; however, detailed analyses by race/ethnicity, age, and parity demonstrate important distinctions among abortion patients over time in the state. We discuss these trends in relation to policy changes and increased access to effective contraceptive

Schools out : Adam Smith and pre-disciplinary international political economy

In this article, I argue that invocations of Adam Smith in international political economy (IPE) often reveal the influence therein of a disciplinary ontological disaggregation of economic and non-economic rationality, which I claim is obscured by the tendency to map its complex intellectual contours in terms of competing schools. I trace the origins of the disciplinary characterisation of Smith as the founder of IPE's liberal tradition to invocations of his thought by centrally important figures in the perceived Austrian, Chicago and German historical schools of economics, and reflect upon the significance to IPE of the reiteration of this portrayal by apparent members of its so-called American and British schools. I additionally contrast these interpretations to those put forward by scholars who seek to interpret IPE and Smith's contribution to it in pre-disciplinary terms, which I claim reflects a distinct ontology to that attributed to the British school of IPE with which their work is often associated. I therefore contend that reflection upon invocations of Smith's thought in IPE problematises the longstanding tendency to map its intellectual terrain in terms of competing schools, reveals that the disciplinary ontological consensus that informs this tendency impacts upon articulations of its core concerns and suggests that a pre-disciplinary approach offers an alternative lens through which such concerns might be more effectively framed

Influence of mild and moderate hepatic impairment on axitinib pharmacokinetics

Objective: To evaluate the effects of hepatic impairment on the pharmacokinetics and safety of a single, oral axitinib dose in subjects with mild or moderate hepatic impairment. Methods: In this phase I, open-label, parallel-group study, a total of 24 subjects with either normal hepatic function (n = 8) or with mild (n = 8) or moderate (n = 8) hepatic impairment were administered a single, oral dose of axitinib (5 mg). Blood samples were collected at intervals up to 144 h following dosing, and plasma pharmacokinetics and safety were assessed. Changes in axitinib plasma exposures in subjects with mild or moderate hepatic impairment were predicted using computer simulations and used to guide initial dosing in the clinical study. Results: Axitinib exposure was similar in subjects with normal hepatic function and those with mild hepatic impairment, but approximately twofold higher in subjects with moderate hepatic impairment. Axitinib exposure weakly correlated with measures of hepatic function but was not affected by smoking status. Axitinib protein binding was similar in the three treatment groups. No significant treatment-related adverse events were reported. Conclusions: Compared with subjects with normal hepatic function, moderate hepatic impairment increased axitinib exposure, suggesting that the oral clearance of axitinib is altered in these subjects. In addition, these data indicate a possible need for a dose reduction in subjects who develop moderate or worse hepatic impairment during axitinib treatment. A single 5-mg dose of axitinib was well tolerated in subjects with mild or moderate hepatic impairment

Genomic analysis reveals key aspects of prokaryotic symbiosis in the phototrophic consortium "<em>Chlorochromatium aggregatum</em>"

BACKGROUND: ‘Chlorochromatium aggregatum’ is a phototrophic consortium, a symbiosis that may represent the highest degree of mutual interdependence between two unrelated bacteria not associated with a eukaryotic host. ‘Chlorochromatium aggregatum’ is a motile, barrel-shaped aggregate formed from a single cell of ‘Candidatus Symbiobacter mobilis”, a polarly flagellated, non-pigmented, heterotrophic bacterium, which is surrounded by approximately 15 epibiont cells of Chlorobium chlorochromatii, a non-motile photolithoautotrophic green sulfur bacterium. RESULTS: We analyzed the complete genome sequences of both organisms to understand the basis for this symbiosis. Chl. chlorochromatii has acquired relatively few symbiosis-specific genes; most acquired genes are predicted to modify the cell wall or function in cell-cell adhesion. In striking contrast, ‘Ca. S. mobilis’ appears to have undergone massive gene loss, is probably no longer capable of independent growth, and thus may only reproduce when consortia divide. A detailed model for the energetic and metabolic bases of the dependency of ‘Ca. S. mobilis’ on Chl. chlorochromatii is described. CONCLUSIONS: Genomic analyses suggest that three types of interactions lead to a highly sophisticated relationship between these two organisms. Firstly, extensive metabolic exchange, involving carbon, nitrogen, and sulfur sources as well as vitamins, occurs from the epibiont to the central bacterium. Secondly, ‘Ca. S. mobilis’ can sense and move towards light and sulfide, resources that only directly benefit the epibiont. Thirdly, electron cycling mechanisms, particularly those mediated by quinones and potentially involving shared protonmotive force, could provide an important basis for energy exchange in this and other symbiotic relationships

Genomic analysis of the 2017 Aotearoa New Zealand outbreak of Mycoplasma bovis and its position within the global population structure

In 2017 an outbreak of Mycoplasma bovis (M. bovis), an infectious agent of cattle, was identified in Aotearoa New Zealand. This study characterizes the genomic population structure of the outbreak in New Zealand and compares it with the known global population structure using multilocus sequence typing (MLST) and genomic analysis. The New Zealand outbreak strain was MLST genotyped as ST21. A comprehensive collection of 840 genomes from the New Zealand outbreak showed a pattern of clonal expansion when characterized by MLST, core genome MLST (cgMLST) and whole genome MLST (wgMLST). A lineage of genomes was found with no in silico identifiable pta2 locus, a housekeeping gene used in the MLST scheme. We compared a sample set of 40 New Zealand genomes to 47 genomes from other countries. This group had 79 ST21 genomes and eight genomes that were single nucleotide polymorphism (SNP) variants within the MLST loci of ST21. Two of the 47 international genomes showed signs of extensive unique recombination. Unique alleles in six genes were identified as present only in the New Zealand genomes. These novel variants were in the genes; haeIIIM encoding for cytosine-specific methyltransferase, cysC encoding for cysteinyl tRNA synthetase, era encoding for GTPase Era, metK encoding for S-adenosylmethionine synthase, parE encoding for DNA topoisomerase, and hisS encoding for histidine-tRNA ligase. This finding could be due to a population bottleneck, genetic drift, or positive selection. The same sample set of 40 New Zealand genomes were compared using MLST to 404 genomes from 15 other countries and 11 genomes without a known country. A FastBAPS analysis of 455 genomes showed a global population structure with 11 clusters. Some countries, such as Canada, Denmark and Australia contained both internally closely related genomes and some genomes that were more closely related to genomes found in other countries. Our results support the need for Whole Genome Sequencing (WGS) as well as MLST genotyping in M. bovis outbreaks. They also support the importance of understanding the national and international movement patterns of cattle and their genetic material, as possible routes of transmission, when managing the spread of M. bovis

Genomic diversity of bacteriophages infecting Microbacterium spp

The bacteriophage population is vast, dynamic, old, and genetically diverse. The genomics of phages that infect bacterial hosts in the phylum Actinobacteria show them to not only be diverse but also pervasively mosaic, and replete with genes of unknown function. To further explore this broad group of bacteriophages, we describe here the isolation and genomic characterization of 116 phages that infect Microbacterium spp. Most of the phages are lytic, and can be grouped into twelve clusters according to their overall relatedness; seven of the phages are singletons with no close relatives. Genome sizes vary from 17.3 kbp to 97.7 kbp, and their G+C% content ranges from 51.4% to 71.4%, compared to ~67% for their Microbacterium hosts. The phages were isolated on five different Microbacterium species, but typically do not efficiently infect strains beyond the one on which they were isolated. These Microbacterium phages contain many novel features, including very large viral genes (13.5 kbp) and unusual fusions of structural proteins, including a fusion of VIP2 toxin and a MuF-like protein into a single gene. These phages and their genetic components such as integration systems, recombineering tools, and phage-mediated delivery systems, will be useful resources for advancing Microbacterium genetics