Mucosal Vaccination with a Self-Adjuvanted Lipopeptide Is Immunogenic and Protective against Mycobacterium tuberculosis

Tuberculosis (TB) remains a staggering burden on global public health. Novel preventative tools are desperately needed to reach the targets of the WHO post-2015 End-TB Strategy. Peptide or protein-based subunit vaccines offer potential as safe and effective generators of protection, and enhancement of local pulmonary immunity may be achieved by mucosal delivery. We describe the synthesis of a novel subunit vaccine via native chemical ligation. Two immunogenic epitopes, ESAT61−20 and TB10.43−11 from Mycobacterium tuberculosis (Mtb), were covalently conjugated to the TLR2-ligand Pam2Cys to generate a self-adjuvanting lipopeptide vaccine. When administered mucosally to mice, the vaccine enhanced pulmonary immunogenicity, inducing strong Th17 responses in the lungs and multifunctional peripheral T-lymphocytes. Mucosal, but not peripheral vaccination, provided substantial protection against Mtb infection, emphasizing the importance of delivery route for optimal efficacy.NHMR

The Orbit of the Eclipsing X-ray Pulsar EXO 1722-363

With recent and archival Rossi X-Ray Timing Explorer (RXTE) X-ray measurements of the heavily obscured X-ray pulsar EXO 1722-363 (IGR J17252-3616), we carried out a pulse timing analysis to determine the orbital solution for the first time. The binary system is characterized by a_x sin(i) = 101 +/- 3 lt-s and P_orb = 9.7403 +/- 0.0004 days (90% confidence), with the precision of the orbital period being obtained by connecting datasets separated by more than 7 years (272 orbital cycles). The orbit is consistent with circular, and e < 0.19 at the 90% confidence level. The mass function is 11.7 +/- 1.2 M_sun and confirms that this source is a High Mass X-ray Binary (HMXB) system. The orbital period, along with the previously known ~414 s pulse period, places this system in the part of the Corbet diagram populated by supergiant wind accretors. Using previous eclipse time measurements by Corbet et al. and our orbital solution, combined with the assumption that the primary underfills its Roche lobe, we find i > 61 degrees at the 99% confidence level, the radius of the primary is between 21 R_sun and 37 R_sun, and its mass is less than about 22 M_sun. The acceptable range of radius and mass shows that the primary is probably a supergiant of spectral type B0I-B5I. Photometric measurements of its likely counterpart are consistent with the spectral type and luminosity if the distance to the system is between 5.3 kpc and 8.7 kpc. Spectral analysis of the pulsar as a function of orbital phase reveals an evolution of the hydrogen column density suggestive of dense filaments of gas in the downstream wake of the pulsar, with higher levels of absorption seen at orbital phases 0.5-1.0, as well as a variable Fe K_alpha line.Comment: Submitted to ApJ, 11 pages, 11 figure

Long-term Clinical and Cost-effectiveness of Early Endovenous Ablation in Venous Ulceration: A Randomized Clinical Trial

Importance One-year outcomes from the Early Venous Reflux Ablation (EVRA) randomized trial showed accelerated venous leg ulcer healing and greater ulcer-free time for participants who are treated with early endovenous ablation of lower extremity superficial reflux.Objective To evaluate the clinical and cost-effectiveness of early endovenous ablation of superficial venous reflux in patients with venous leg ulceration.Design, Setting, and Participants Between October 24, 2013, and September 27, 2016, the EVRA randomized clinical trial enrolled 450 participants (450 legs) with venous leg ulceration of less than 6 months’ duration and superficial venous reflux. Initially, 6555 patients were assessed for eligibility, and 6105 were excluded for reasons including ulcer duration greater than 6 months, healed ulcer by the time of randomization, deep venous occlusive disease, and insufficient superficial venous reflux to warrant ablation therapy, among others. A total of 426 of 450 participants (94.7%) from the vascular surgery departments of 20 hospitals in the United Kingdom were included in the analysis for ulcer recurrence. Surgeons, participants, and follow-up assessors were not blinded to the treatment group. Data were analyzed from August 11 to November 4, 2019.Interventions Patients were randomly assigned to receive compression therapy with early endovenous ablation within 2 weeks of randomization (early intervention, n = 224) or compression with deferred endovenous treatment of superficial venous reflux (deferred intervention, n = 226). Endovenous modality and strategy were left to the preference of the treating clinical team.Main Outcomes and Measures The primary outcome for the extended phase was time to first ulcer recurrence. Secondary outcomes included ulcer recurrence rate and cost-effectiveness.Results The early-intervention group consisted of 224 participants (mean [SD] age, 67.0 [15.5] years; 127 men [56.7%]; 206 White participants [92%]). The deferred-intervention group consisted of 226 participants (mean [SD] age, 68.9 [14.0] years; 120 men [53.1%]; 208 White participants [92%]). Of the 426 participants whose leg ulcer had healed, 121 (28.4%) experienced at least 1 recurrence during follow-up. There was no clear difference in time to first ulcer recurrence between the 2 groups (hazard ratio, 0.82; 95% CI, 0.57-1.17; P = .28). Ulcers recurred at a lower rate of 0.11 per person-year in the early-intervention group compared with 0.16 per person-year in the deferred-intervention group (incidence rate ratio, 0.658; 95% CI, 0.480-0.898; P = .003). Time to ulcer healing was shorter in the early-intervention group for primary ulcers (hazard ratio, 1.36; 95% CI, 1.12-1.64; P = .002). At 3 years, early intervention was 91.6% likely to be cost-effective at a willingness to pay of £20 000 ($26 283) per quality-adjusted life year and 90.8$45 995) per quality-adjusted life year.Conclusions and Relevance Early endovenous ablation of superficial venous reflux was highly likely to be cost-effective over a 3-year horizon compared with deferred intervention. Early intervention accelerated the healing of venous leg ulcers and reduced the overall incidence of ulcer recurrence

The Impact of Global Warming and Anoxia on Marine Benthic Community Dynamics: an Example from the Toarcian (Early Jurassic)

The Pliensbachian-Toarcian (Early Jurassic) fossil record is an archive of natural data of benthic community response to global warming and marine long-term hypoxia and anoxia. In the early Toarcian mean temperatures increased by the same order of magnitude as that predicted for the near future; laminated, organic-rich, black shales were deposited in many shallow water epicontinental basins; and a biotic crisis occurred in the marine realm, with the extinction of approximately 5% of families and 26% of genera. High-resolution quantitative abundance data of benthic invertebrates were collected from the Cleveland Basin (North Yorkshire, UK), and analysed with multivariate statistical methods to detect how the fauna responded to environmental changes during the early Toarcian. Twelve biofacies were identified. Their changes through time closely resemble the pattern of faunal degradation and recovery observed in modern habitats affected by anoxia. All four successional stages of community structure recorded in modern studies are recognised in the fossil data (i.e. Stage III: climax; II: transitional; I: pioneer; 0: highly disturbed). Two main faunal turnover events occurred: (i) at the onset of anoxia, with the extinction of most benthic species and the survival of a few adapted to thrive in low-oxygen conditions (Stages I to 0) and (ii) in the recovery, when newly evolved species colonized the re-oxygenated soft sediments and the path of recovery did not retrace of pattern of ecological degradation (Stages I to II). The ordination of samples coupled with sedimentological and palaeotemperature proxy data indicate that the onset of anoxia and the extinction horizon coincide with both a rise in temperature and sea level. Our study of how faunal associations co-vary with long and short term sea level and temperature changes has implications for predicting the long-term effects of “dead zones” in modern oceans

Captive reptile mortality rates in the home and implications for the wildlife trade

The trade in wildlife and keeping of exotic pets is subject to varying levels of national and international regulation and is a topic often attracting controversy. Reptiles are popular exotic pets and comprise a substantial component of the live animal trade. High mortality of traded animals raises welfare concerns, and also has implications for conservation if collection from the wild is required to meet demand. Mortality of reptiles can occur at any stage of the trade chain from collector to consumer. However, there is limited information on mortality rates of reptiles across trade chains, particularly amongst final consumers in the home. We investigated mortality rates of reptiles amongst consumers using a specialised technique for asking sensitive questions, additive Randomised Response Technique (aRRT), as well as direct questioning (DQ). Overall, 3.6% of snakes, chelonians and lizards died within one year of acquisition. Boas and pythons had the lowest reported mortality rates of 1.9% and chameleons had the highest at 28.2%. More than 97% of snakes, 87% of lizards and 69% of chelonians acquired by respondents over five years were reported to be captive bred and results suggest that mortality rates may be lowest for captive bred individuals. Estimates of mortality from aRRT and DQ did not differ significantly which is in line with our findings that respondents did not find questions about reptile mortality to be sensitive. This research suggests that captive reptile mortality in the home is rather low, and identifies those taxa where further effort could be made to reduce mortality rate

The U.K. Deep and Medium Surveys with Rosat: log N-Log S relation

We have carried out a soft X-ray survey of the sky using the ROSAT Position Sensitive Proportional Counter (PSPC) in a region of very low Galactic column density (NH = 6–9 × 1019 cm–2). The data consist of a deep > 70 ks pointing (the Deep Survey) and six pointings at lower sensitivity (13–20 ks; the Medium Survey). We detect a total of 141 sources over the 0.9 deg2 of sky area used. The faintest source detected has a flux of 3.2 × 10–15 erg cm–2 s–1 (0.5–2.0 keV). We present the source number-flux distribution, and we compare it with the distributions constructed from other ROSAT observations and from surveys carried out with X-ray instruments operating at higher energies. We estimate the contribution of the resolved sources to the soft X-ray background by direct comparison of their integrated spectrum with that of the diffuse background: 44 per cent of the extragalactic X-ray background between 0.5 and 2.0 keV is resolved directly into discrete sources whose average spectrum is steeper than that of the background. Integration of our number-flux relation to infinite flux produces a background resolved fraction of 44±565 per cent (0.5–2.0 keV). Limits on the slope of the log N–log S curve at very faint fluxes are set by the measured value of the X-ray background.KOM, ACF and RGM acknowledge the support of the Royal Society.Peer Reviewe

Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis.

Tuberculosis (TB) is responsible for enormous global morbidity and mortality, and current treatment regimens rely on the use of drugs that have been in use for more than 40 years. Owing to widespread resistance to these therapies, new drugs are desperately needed to control the TB disease burden. Herein, we describe the rapid synthesis of analogues of the sansanmycin uridylpeptide natural products that represent promising new TB drug leads. The compounds exhibit potent and selective inhibition of Mycobacterium tuberculosis, the etiological agent of TB, both in vitro and intracellularly. The natural product analogues were also shown to be nanomolar inhibitors of Mtb phospho-MurNAc-pentapeptide translocase, the enzyme responsible for the synthesis of lipid I in mycobacteria. This work lays the foundation for the development of uridylpeptide natural product analogues as new TB drug candidates that operate through the inhibition of peptidoglycan biosynthesis

Long-term annual and monthly changes in mysids and caridean decapods in a macrotidal estuarine environment in relation to climate change and pollution

© 2018 Elsevier B.V. A 26-year time series of monthly samples from the water intake of a power station has been used to analyse the trends exhibited by number of species, total abundance, and composition of the mysids and caridean decapods in the inner Bristol Channel. During this period, annual water temperatures, salinities and the North Atlantic Oscillation Index (NAOI) in winter did not change significantly, whereas annual NAOI declined. Annual mean monthly values for the number of species and total abundance both increased over the 26 years, but these changes were not correlated with any of the measured physico-chemical/climatic factors. As previous studies demonstrated that, during a similar period, metal concentrations in the Severn Estuary and Bristol Channel (into which that estuary discharges) declined and water quality increased, it is proposed that the above changes are due to an improved environment. The fauna was dominated by the mysids Mesopodopsis slabberi and Schistomysis spiritus, which collectively contributed 94% to total abundance. Both species, which were represented by juveniles, males, non-brooding females and brooding females, underwent statistically-indistinguishable patterns of change in abundance over the 26 years. When analysis was based on the abundances of the various species, the overall species composition differed significantly among years and changed serially with year. When abundances were converted to percentage compositions, this pattern of seriation broke down, demonstrating that changes in abundance and not percentage composition were responsible for the seriation. As with the number and abundance of species, changes in composition over the 26 years were not related to any of the physico-chemical/climatic factors tested. Species composition changed monthly in a pronounced cyclical manner throughout the year, due to statistically different time-staggered changes in the abundance of each species. This cyclicity was related most strongly to salinity

The scene of the crime: inventing the serial killer

This article examines the meanings of the crime scene in serial killings, and the tensions between the real and the imagined in the circulation of those meanings. Starting with the Whitechapel Murders of 1888 it argues that they, as well as forming an origin for the construction of the identity of 'the serial killer', initiate certain ideas about the relationship of subjects to spaces and the existence of the self in the modern urban landscape. It suggests that these ideas come to play an integral part in the contemporary discourse of serial killing, both in the popular imagination and in professional analysis. Examining the Whitechapel Murders, more recent cases and modern profiling techniques, it argues that popular and professional representations of crime scenes reveal more of social anxieties about the nature of the public and the private than they do about serial killers. It suggests that 'the serial killer' is not a coherent type, but an invention produced from the confusions of persons and places. Copyright 2006 SAGE Publications. All rights reserved. Not for commercial use or unauthorized distribution