Enhanced IL-2 in early life limits the development of TFH and protective antiviral immunity

T follicular helper cell (TFH)-dependent antibody responses are critical for long-term immunity. Antibody responses are diminished in early life, limiting long-term protective immunity and allowing prolonged or recurrent infection, which may be important for viral lung infections that are highly prevalent in infancy. In a murine model using respiratory syncytial virus (RSV), we show that TFH and the high-affinity antibody production they promote are vital for preventing disease on RSV reinfection. Following a secondary RSV infection, TFH-deficient mice had significantly exacerbated disease characterized by delayed viral clearance, increased weight loss, and immunopathology. TFH generation in early life was compromised by heightened IL-2 and STAT5 signaling in differentiating naive T cells. Neutralization of IL-2 during early-life RSV infection resulted in a TFH-dependent increase in antibody-mediated immunity and was sufficient to limit disease severity upon reinfection. These data demonstrate the importance of TFH in protection against recurrent RSV infection and highlight a mechanism by which this is suppressed in early life

Luminescent 1,8-Naphthalimide-Derived ReI Complexes: syntheses, spectroscopy, X-ray structure and preliminary bioimaging in fission yeast cells

A series of picolyl-functionalised, fluorescent 1,8-naphthalimide ligands (L) have been synthesised and coordi-nated to ReI to form luminescent cationic complexes of the general form fac-[Re(phen)(CO)3(L)]BF4. The complexes were characterised by using a range of spectroscopic and analytical techniques. One example of a complex was also characterised in the solid-state by using single-crystal X-ray diffraction, reveal-ing a distorted octahedral coordination sphere at ReI and Re– C/Re–N bond lengths within the expected ranges. All ligands were shown to be fluorescent, with the 4-amino derivatives showing intramolecular charge transfer in the visible region (511–534 nm). The complexes generally showed a mixture of ligand-centred and/or 3MLCT emission depending upon the na-ture of the coordinated 1,8-naphthalimide ligand. For selected complexes, confocal fluorescence microscopy was undertaken by using fission yeast cells (Schizosaccharomyces pombe) and showed that the structure of the 1,8-naphthalimide ligand influ-ences the uptake and localisation of the rhenium complex

Functional imaging of a model unicell: Spironucleus vortens as an anaerobic but aerotolerant flagellated protist

Advances in optical microscopy are continually narrowing the chasm in our appreciation of biological organization between the molecular and cellular levels, but many practical problems are still limiting. Observation is always limited by the rapid dynamics of ultrastructural modifications of intracellular components, and often by cell motility: imaging of the unicellular protist parasite of ornamental fish, Spironucleus vortens, has proved challenging. Autofluorescence of nicotinamide nucleotides and flavins in the 400–580 nm region of the visible spectrum, is the most useful indicator of cellular redox state and hence vitality. Fluorophores emitting in the red or near-infrared (i.e., phosphors) are less damaging and more penetrative than many routinely employed fluors. Mountants containing free radical scavengers minimize fluorophore photobleaching. Two-photon excitation provides a small focal spot, increased penetration, minimizes photon scattering and enables extended observations. Use of quantum dots clarifies the competition between endosomal uptake and exosomal extrusion. Rapid motility (161 μm/s) of the organism makes high resolution of ultrastructure difficult even at high scan speeds. Use of voltage-sensitive dyes determining transmembrane potentials of plasma membrane and hydrogenosomes (modified mitochondria) is also hindered by intracellular motion and controlled anesthesia perturbs membrane organization. Specificity of luminophore binding is always questionable; e.g. cationic lipophilic species widely used to measure membrane potentials also enter membrane-bounded neutral lipid droplet-filled organelles. This appears to be the case in S. vortens, where Coherent Anti-Stokes Raman Scattering (CARS) micro-spectroscopy unequivocally images the latter and simultaneous provides spectral identification at 2840 cm−1. Secondary Harmonic Generation highlights the highly ordered structure of the flagella

Fluorescent functionalised naphthalimides and their Au(i)–NHC complexes for potential use in cellular bioimaging

A series of cationic, dihydroimidazolinium-functionalized 1,8-naphthalimide fluorophores have been isolated as their hexafluorophosphate salts, [HL]PF6. These pro-ligands react with [AuCl(tht)] in the presence of base to form N-heterocyclic carbene (NHC) complexes, [AuCl(L)]. Two X-ray structures represent a pro-ligand and complex pairing: the latter reveals the two-coordinate linear geometry of the NHC–Au(I) species, as well as intermolecular interactions supported by both ligand π–π stacking and a weak aurophilic interaction of 3.3205(6) Å. The luminescence properties of the pro-ligands and complexes are dominated by the ICT character of the substituted fluorophore at ca. 500 nm, which is further modulated via functionalization at the 4-position of the naphthalimide. Cytotoxicity assessments were performed for all [HL]PF6 and [AuCl(L)] species against LOVO, MCF-7, A549 and PC3 cell lines; added lipophilicity seems to correlate with increased cytotoxicity. Confocal fluorescence microscopy was undertaken on a selected [HL]PF6 and [AuCl(L)] species and showed that the intracellular distribution is dependent upon the specific ligand structure. More detailed co-localisation studies show that selected examples present a predominant lysosomal staining pattern. FLIM studies exemplified the applicability of these probes, and secondly suggest that fluorescence lifetime could be used to provide information on the integrity of the complex and thus liberation of gold in a biological environment

Sediment routing and basin evolution in Proterozoic to Mesozoic east Gondwana: A case study from southern Australia

Sedimentary rocks along the southern margin of Australia host an important record of the break-up history of east Gondwana, as well as fragments of a deeper geological history, which collectively help inform the geological evolution of a vast and largely underexplored region. New drilling through Cenozoic cover has allowed examination of the Cretaceous rift-related Madura Shelf sequence (Bight Basin), and identification of two new stratigraphic units beneath the shelf; the possibly Proterozoic Shanes Dam Conglomerate and the interpreted Palaeozoic southern Officer Basin unit, the Decoration Sandstone. Recognition of these new units indicates an earlier basinal history than previously known. Lithostratigraphy of the new drillcore has been integrated with that published from onshore and offshore cores to present isopach maps of sedimentary cover on the Madura Shelf. New palynological data demonstrate progression from more localised freshwater-brackish fluvio-lacustrine clastics in the early Cretaceous (Foraminisporis wonthaggiensis – Valanginian to Barremian) to widespread topography-blanketing, fully marine, glauconitic mudrocks in the mid Cretaceous (Endoceratium ludbrookiae – Albian). Geochronology and Hf-isotope geochemistry show detrital zircon populations from the Madura Shelf are comparable to those from the southern Officer Basin, as well as Cenozoic shoreline and palaeovalley sediments in the region. The detrital zircon population from the Shanes Dam Conglomerate is defined by a unimodal ~1400 Ma peak, which correlates with directly underlying crystalline basement of the Madura Province. Peak ages of ~1150 Ma and ~1650 Ma dominate the age spectra of all other samples, indicating a stable sediment reservoir through much of the Phanerozoic, with sediments largely sourced from the Albany-Fraser Orogen and Musgrave Province (directly and via multiple recycling events). The Madura Shelf detrital zircon population differs from published data for the Upper CretaceousCeduna Delta to the east, indicating significant differences in sediment provenance and routing between the Ceduna Sub-basin and central Bight Basin

The SAMI Galaxy Survey: Data Release One with emission-line physics value-added products

We present the first major release of data from the SAMI Galaxy Survey. This data release focuses on the emission-line physics of galaxies. Data Release One includes data for 772 galaxies, about 20 per cent of the full survey. Galaxies included have the redshift range 0.004 < z < 0.092, a large mass range (7.6 < logM*/M⊙ < 11.6), and star formation rates of ~10-4 to ~101M⊙ yr-1. For each galaxy, we include two spectral cubes and a set of spatially resolved 2D maps: single- and multi-component emission-line fits (with dust-extinction corrections for strong lines), local dust extinction, and star formation rate. Calibration of the fibre throughputs, fluxes, and differential atmospheric refraction has been improved over the Early Data Release. The data have average spatial resolution of 2.16 arcsec (full width at half-maximum) over the 15 arcsec diameter field of view and spectral (kinematic) resolution of R = 4263 (σ = 30 km s-1) around Ha. The relative flux calibration is better than 5 per cent, and absolute flux calibration has an rms of 10 per cent. The data are presented online through the Australian Astronomical Observatory's Data Central.The SAMI Galaxy Survey is funded by the Australian Research Council Centre of Excellence for All-sky Astrophysics (CAASTRO), through project number CE110001020, and other participating institutions. JTA acknowledges the award of a SIEF John Stocker Fellowship. MSO acknowledges the funding support from the Australian Research Council through a Future Fellowship (FT140100255). BG is the recipient of an Australian Research Council Future Fellowship (FT140101202). NS acknowledges support of a University of Sydney Postdoctoral Research Fellowship. SB acknowledges the funding support from the Australian Research Council through a Future Fellowship (FT140101166). JvdS is funded under Bland-Hawthorn’s ARC Laureate Fellowship (FL140100278). SMC acknowledges the support of an Australian Research Council Future Fellowship (FT100100457). Support for AMM is provided by NASA through Hubble Fellowship grant #HST-HF2-51377 awarded by the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc., for NASA, under contract NAS5-26555. CF gratefully acknowledges funding provided by the Australian Research Council’s Discovery Projects (grants DP150104329 and DP170100603). BC is the recipient of an Australian Research Council Future Fellowship (FT120100660)

Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic non-inferiority randomised controlled trial

Background: Bullous pemphigoid (BP) is a blistering skin disorder with increased mortality. We tested whether a strategy of starting treatment with doxycycline conveys acceptable short-term blister control whilst conferring long-term safety advantages over starting treatment with oral corticosteroids. Methods: Pragmatic multi-centre parallel-group randomised controlled trial of adults with BP (≥3 blisters ≥2 sites and linear basement membrane IgG/C3) plus economic evaluation. Participants were randomised to doxycycline (200 mg/day) or prednisolone (0·5 mg/kg/day). Localised adjuvant potent topical corticosteroids (<30 g/week) was permitted weeks 1-3. The non-inferiority primary effectiveness outcome was the proportion of participants with ≤3 blisters at 6 weeks. We assumed that doxycycline would be 25% less effective than corticosteroids with a 37% acceptable margin of noninferiority. The primary safety outcome was the proportion with severe, life-threatening or fatal treatment-related adverse events by 52 weeks. Analysis used a regression model adjusting for baseline disease severity, age and Karnofsky score, with missing data imputed. Results: 132 patients were randomised to doxycycline and 121 to prednisolone from 54 UK and 7 German dermatology centres. Mean age was 77·7 years and 68.4% had moderate to severe baseline disease. For those starting doxycycline, 83/112 (74·1%) had ≤3 blisters at 6 weeks compared with 92/101 (91·1%) for prednisolone, a difference of 18·6% favouring prednisolone (upper limit of 90% CI, 26·1%, within the predefined 37% margin). Related severe, life-threatening and fatal events at 52 weeks were 18·5% for those starting doxycycline and 36·6% for prednisolone (mITT analysis), an adjusted difference of 19·0% (95% CI, 7·9%, 30·1%, p=0·001). Conclusions: A strategy of starting BP patients on doxycycline is non-inferior to standard treatment with oral prednisolone for short-term blister control and significantly safer long-term

Impact of solitary pulmonary nodule size on qualitative and quantitative assessment using 18F-fluorodeoxyglucose PET/CT: the SPUTNIK trial

Purpose: To compare qualitative and semi-quantitative PET/CT criteria, and the impact of nodule size on the diagnosis of solitary pulmonary nodules in a prospective multicentre trial. / Methods: Patients with an SPN on CT ≥ 8 and ≤ 30 mm were recruited to the SPUTNIK trial at 16 sites accredited by the UK PET Core Lab. Qualitative assessment used a five-point ordinal PET-grade compared to the mediastinal blood pool, and a combined PET/CT grade using the CT features. Semi-quantitative measures included SUVmax of the nodule, and as an uptake ratio to the mediastinal blood pool (SURBLOOD) or liver (SURLIVER). The endpoints were diagnosis of lung cancer via biopsy/histology or completion of 2-year follow-up. Impact of nodule size was analysed by comparison between nodule size tertiles. / Results: Three hundred fifty-five participants completed PET/CT and 2-year follow-up, with 59% (209/355) malignant nodules. The AUCs of the three techniques were SUVmax 0.87 (95% CI 0.83;0.91); SURBLOOD 0.87 (95% CI 0.83; 0.91, p = 0.30 versus SUVmax); and SURLIVER 0.87 (95% CI 0.83; 0.91, p = 0.09 vs. SUVmax). The AUCs for all techniques remained stable across size tertiles (p > 0.1 for difference), although the optimal diagnostic threshold varied by size. For nodules  16 mm, an SUVmax ≥ 3.6 or visual PET uptake greater than the mediastinum was the most accurate. / Conclusion: In this multicentre trial, SUVmax was the most accurate technique for the diagnosis of solitary pulmonary nodules. Diagnostic thresholds should be altered according to nodule size. / Trial registration: ISRCTN - ISRCTN30784948. ClinicalTrials.gov - NCT0201306

Systematic Conservation Planning in the Face of Climate Change: Bet-Hedging on the Columbia Plateau

Systematic conservation planning efforts typically focus on protecting current patterns of biodiversity. Climate change is poised to shift species distributions, reshuffle communities, and alter ecosystem functioning. In such a dynamic environment, lands selected to protect today's biodiversity may fail to do so in the future. One proposed approach to designing reserve networks that are robust to climate change involves protecting the diversity of abiotic conditions that in part determine species distributions and ecological processes. A set of abiotically diverse areas will likely support a diversity of ecological systems both today and into the future, although those two sets of systems might be dramatically different. Here, we demonstrate a conservation planning approach based on representing unique combinations of abiotic factors. We prioritize sites that represent the diversity of soils, topographies, and current climates of the Columbia Plateau. We then compare these sites to sites prioritized to protect current biodiversity. This comparison highlights places that are important for protecting both today's biodiversity and the diversity of abiotic factors that will likely determine biodiversity patterns in the future. It also highlights places where a reserve network designed solely to protect today's biodiversity would fail to capture the diversity of abiotic conditions and where such a network could be augmented to be more robust to climate-change impacts