Absorption-Line Probes of Gas and Dust in Galactic Superwinds

We discuss moderate resolution spectra of the NaD absorption-line in a sample of 32 far-IR-bright starburst galaxies. In 18 cases, the line is produced primarily by interstellar gas, and in 12 of these it is blueshifted by over 100 km/s relative to the galaxy systemic velocity. The absorption-line profiles in these outflow sources span the range from near the galaxy systemic velocity to a maximum blueshift of 400 to 600 km/s. The outflows occur in galaxies systematically viewed more nearly face-on than the others. We therefore argue that the absorbing material consists of ambient interstellar gas accelerated along the minor axis of the galaxy by a hot starburst-driven superwind. The NaD lines are optically-thick, but indirect arguments imply total Hydrogen column densities of N_H = few X 10^{21} cm^{-2}. This implies that the superwind is expelling matter at a rate comparable to the star-formation rate. This outflowing material is very dusty: we find a strong correlation between the depth of the NaD profile and the line-of-sight reddening (E(B-V) = 0.3 to 1 over regions several-to-ten kpc in size). The estimated terminal velocities of superwinds inferred from these data and extant X-ray data are typically 400 to 800 km/s, are independent of the galaxy rotation speed, and are comparable to (substantially exceed) the escape velocities for $L_*$ (dwarf) galaxies. The resulting loss of metals can establish the mass-metallicity relation in spheroids, produce the observed metallicity in the ICM, and enrich a general IGM to 10$^{-1}$ solar metallicity. If the outflowing dust grains survive their journey into the IGM, their effect on observations of cosmologically-distant objects is significant.Comment: 65 pages, including 16 figures. ApJ, in pres

The pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis

Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. Raw data have been deposited in the Gene Expression Omnibus (GEO) (http://www.ncbi.nlm.nih.gov/geo/) under accession number GSE54810. Funding: This work was supported in part by grants to EMB from the MRC (G0501164) and BBSRC (BB/G009619/1), to EMB and NDR from the Wellcome Trust (WT093596MA), to MB from Imperial College London (Division of Investigative Sciences PhD Studentship), to HH from the ERA-NET PathoGenoMics project TRANSPAT, Austrian Science Foundation (FWF I282-B09), to SGF from the National Institutes of Health, USA (R01AI073829). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Does presence of a mid-ocean ridge enhance biomass and biodiversity?

In contrast to generally sparse biological communities in open-ocean settings, seamounts and ridges are perceived as areas of elevated productivity and biodiversity capable of supporting commercial fisheries. We investigated the origin of this apparent biological enhancement over a segment of the North Mid-Atlantic Ridge (MAR) using sonar, corers, trawls, traps, and a remotely operated vehicle to survey habitat, biomass, and biodiversity. Satellite remote sensing provided information on flow patterns, thermal fronts, and primary production, while sediment traps measured export flux during 2007-2010. The MAR, 3,704,404 km 2 in area, accounts for 44.7% lower bathyal habitat (800-3500 m depth) in the North Atlantic and is dominated by fine soft sediment substrate (95% of area) on a series of flat terraces with intervening slopes either side of the ridge axis contributing to habitat heterogeneity. The MAR fauna comprises mainly species known from continental margins with no evidence of greater biodiversity. Primary production and export flux over the MAR were not enhanced compared with a nearby reference station over the Porcupine Abyssal Plain. Biomasses of benthic macrofauna and megafauna were similar to global averages at the same depths totalling an estimated 258.9 kt C over the entire lower bathyal north MAR. A hypothetical flat plain at 3500 m depth in place of the MAR would contain 85.6 kt C, implying an increase of 173.3 kt C attributable to the presence of the Ridge. This is approximately equal to 167 kt C of estimated pelagic biomass displaced by the volume of the MAR. There is no enhancement of biological productivity over the MAR; oceanic bathypelagic species are replaced by benthic fauna otherwise unable to survive in the mid ocean. We propose that globally sea floor elevation has no effect on deep sea biomass; pelagic plus benthic biomass is constant within a given surface productivity regime.Peer reviewe

Acquisition of pneumococci specific effector and regulatory Cd4+ T cells localising within human upper respiratory-tract mucosal lymphoid tissue

The upper respiratory tract mucosa is the location for commensal Streptococcus (S.) pneumoniae colonization and therefore represents a major site of contact between host and bacteria. The CD4(+) T cell response to pneumococcus is increasingly recognised as an important mediator of immunity that protects against invasive disease, with data suggesting a critical role for Th17 cells in mucosal clearance. By assessing CD4 T cell proliferative responses we demonstrate age-related sequestration of Th1 and Th17 CD4(+) T cells reactive to pneumococcal protein antigens within mucosal lymphoid tissue. CD25(hi) T cell depletion and utilisation of pneumococcal specific MHCII tetramers revealed the presence of antigen specific Tregs that utilised CTLA-4 and PDL-1 surface molecules to suppress these responses. The balance between mucosal effector and regulatory CD4(+) T cell immunity is likely to be critical to pneumococcal commensalism and the prevention of unwanted pathology associated with carriage. However, if dysregulated, such responses may render the host more susceptible to invasive pneumococcal infection and adversely affect the successful implementation of both polysaccharide-conjugate and novel protein-based pneumococcal vaccines

Monocytes regulate the mechanism of T-cell death by inducing Fas-mediated apoptosis during bacterial infection.

Monocytes and T-cells are critical to the host response to acute bacterial infection but monocytes are primarily viewed as amplifying the inflammatory signal. The mechanisms of cell death regulating T-cell numbers at sites of infection are incompletely characterized. T-cell death in cultures of peripheral blood mononuclear cells (PBMC) showed 'classic' features of apoptosis following exposure to pneumococci. Conversely, purified CD3(+) T-cells cultured with pneumococci demonstrated necrosis with membrane permeabilization. The death of purified CD3(+) T-cells was not inhibited by necrostatin, but required the bacterial toxin pneumolysin. Apoptosis of CD3(+) T-cells in PBMC cultures required 'classical' CD14(+) monocytes, which enhanced T-cell activation. CD3(+) T-cell death was enhanced in HIV-seropositive individuals. Monocyte-mediated CD3(+) T-cell apoptotic death was Fas-dependent both in vitro and in vivo. In the early stages of the T-cell dependent host response to pneumococci reduced Fas ligand mediated T-cell apoptosis was associated with decreased bacterial clearance in the lung and increased bacteremia. In summary monocytes converted pathogen-associated necrosis into Fas-dependent apoptosis and regulated levels of activated T-cells at sites of acute bacterial infection. These changes were associated with enhanced bacterial clearance in the lung and reduced levels of invasive pneumococcal disease

Conformation and dynamics of human urotensin II and urotensin related peptide in aqueous solution

Conformation and dynamics of the vasoconstrictive peptides human urotensin II (UII) and urotensin related peptide (URP) have been investigated by both unrestrained and enhanced-sampling molecular-dynamics (MD) simulations and NMR spectroscopy. These peptides are natural ligands of the G-protein coupled urotensin II receptor (UTR) and have been linked to mammalian pathophysiology. UII and URP cannot be characterized by a single structure but exist as an equilibrium of two main classes of ring conformations, <i>open</i> and <i>folded</i>, with rapidly interchanging subtypes. The <i>open</i> states are characterized by turns of various types centered at K⁸Y⁹ or F⁶W⁷ predominantly with no or only sparsely populated transannular hydrogen bonds. The <i>folded</i> conformations show multiple turns stabilized by highly populated transannular hydrogen bonds comprising centers F⁶W⁷K⁸ or W⁷K⁸Y⁹. Some of these conformations have not been characterized previously. The equilibrium populations that are experimentally difficult to access were estimated by replica-exchange MD simulations and validated by comparison of experimental NMR data with chemical shifts calculated with density-functional theory. UII exhibits approximately 72% <i>open</i>:28% <i>folded</i> conformations in aqueous solution. URP shows very similar ring conformations as UII but differs in an <i>open:folded</i> equilibrium shifted further toward <i>open</i> conformations (86:14) possibly arising from the absence of folded N-terminal tail-ring interaction. The results suggest that the different biological effects of UII and URP are not caused by differences in ring conformations but rather by different interactions with UTR

Chlamydia suis undergoes interclade recombination promoting Tet-island exchange

Background The obligate intracellular bacterial family Chlamydiaceae comprises a number of different species that cause disease in various vertebrate hosts including humans. Chlamydia suis, primarily found in the gastrointestinal tract of pigs, is the only species of the Chlamydiaceae family to have naturally gained tetracycline resistance (TetR), through a genomic island (Tet-island), integrated into the middle of chromosomal invasin-like gene inv. Previous studies have hypothesised that the uptake of the Tet-island from a host outside the Chlamydiaceae family was a unique event, followed by spread among C. suis through homologous recombination. In vitro recombination studies have shown that Tet-island exchange between C. suis strains is possible. Our aim in this study was to gain a deeper understanding of the interclade recombination of the Tet-island, among currently circulating C. suis field strains compared to in vitro-generated recombinants, using published whole genome sequences of C. suis field strains (n = 35) and in vitro-generated recombinants (n = 63). Results We found that the phylogeny of inv better reflected the phylogeny of the Tet-island than that of the whole genome, supporting recombination rather than site-specific insertion as the means of transfer. There were considerable differences between the distribution of recombinations within in vitro-generated strains compared to that within the field strains. These differences are likely because in vitro-generated recombinants were selected for a tetracycline and rifamycin/rifampicin resistant background, leading to the largest peak of recombination across the Tet-island. Finally, we found that interclade recombinations across the Tet-island were more variable in length downstream of the Tet-island than upstream. Conclusions Our study supports the hypothesis that the occurrence of TetR strains in both clades of C. suis came about through interclade recombination after a single ancestral horizontal gene transfer event

Multiple and Multidimensional life transitions in the context of life-limiting health conditions:Longitudinal study focussing on perspectives of Young Adults, Families and Professionals

Background: There is a dearth of literature that investigates life transitions of young adults (YAs) with life-limiting conditions, families and professionals. The scant literature that is available has methodological limitations, including not listening to the voice of YAs, collecting data retrospectively, at one time point, from one group’s perspective and single case studies. The aim of this study was to address the gaps found in our literature review and provide a clearer understanding of the multiple and multi-dimensional life transitions experienced by YAs and significant others, over a period of time. Methods: This qualitative study used a longitudinal design and data were collected using semi-structured interviews over a 6-month period at 3 time points. Participants included 12 YAs with life-limiting conditions and their nominated significant others (10 family members and 11 professionals). Data were analysed using a thematic analysis approach. Results: Life transitions of YA and significant others are complex; they experience multiple and multi-dimensional transitions across several domains. The findings challenge the notion that all life transitions are triggered by health transitions of YAs, and has highlighted environmental factors (attitudinal and systemic) that can be changed to facilitate smoother transitions in various aspects of their lives. Conclusions: This study makes a unique and significant contribution to literature. It provides evidence and rich narratives for policy makers and service providers to change policies and practices that are in line with the needs of YAs with life-limiting conditions as they transition to adulthood. Families and professionals have specific training needs that have not yet been met fully

Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis

Visceral leishmaniasis causes considerable mortality and morbidity in many parts of the world. There is an urgent need for the development of new, effective treatments for this disease. Here we describe the development of an anti-leishmanial drug-like chemical series based on a pyrazolopyrimidine scaffold. The leading compound from this series (7, DDD853651/GSK3186899) is efficacious in a mouse model of visceral leishmaniasis, has suitable physicochemical, pharmacokinetic and toxicological properties for further development, and has been declared a preclinical candidate. Detailed mode-of-action studies indicate that compounds from this series act principally by inhibiting the parasite cdc-2-related kinase 12 (CRK12), thus defining a druggable target for visceral leishmaniasis