Macrophage Responses To CF Pathogens: JNKMAP Kinase Signaling By Burkholderia Cepacia Complex Lipopolysaccharide

Chronic bacterial colonization of the airways with opportunistic pathogens is the primary cause of morbidity and mortality in cystic fibrosis (CF) patients. Burkholderia cepacia complex (Bcc) organisms pose a particular challenge in CF lung disease, due in part to their ability to trigger a fulminant pneumonia. This study compares the U937 macrophage response to two Bcc species, B. cenocepacia and Burkholderia multivorans, against Pseudomonas aeruginosa and Staphylococcus aureus. The two Bcc strains demonstrated higher levels of U937 macrophage internalization compared with both P. aeruginosa and S. aureus. Both the Bcc strains also stimulated significantly greater levels of tumor necrosis factor-a and interleukin-1b from macrophages when compared with P. aeruginosa. Further examination of the macrophage response to B. multivorans demonstrated that the lipopolysaccharide component of these bacteria was a potent inducer of proinflammatory cytokines and was shown to signal predominantly through the c-Jun N-terminal kinase mitogen-activated protein kinase pathway. These studies further characterize the host response to Bcc and in particular B. multivorans, now the predominant Bcc species in many CF populations

Housekeeping Mutualisms: Do More Symbionts Facilitate Host Performance?

Mutualisms often involve one host supporting multiple symbionts, whose identity, density and intraguild interactions can influence the nature of the mutualism and performance of the host. However, the implications of multiple co-occurring symbionts on services to a host have rarely been quantified. In this study, we quantified effects of decapod symbionts on removal of sediment from their coral host. Our field survey showed that all common symbionts typically occur as pairs and never at greater abundances. Two species, the crab Trapezia serenei and the shrimp Alpheus lottini, were most common and co-occurred more often than expected by chance. We conducted a mesocosm experiment to test for effects of decapod identity and density on sediment removal. Alone, corals removed 10% of sediment, but removal increased to 30% and 48% with the presence of two and four symbionts, respectively. Per-capita effects of symbionts were independent of density and identity. Our results suggest that symbiont density is restricted by intraspecific competition. Thus, increased sediment removal from a coral host can only be achieved by increasing the number of species of symbionts on that coral, even though these species are functionally equivalent. Symbiont diversity plays a key role, not through added functionality but by overcoming density limitation likely imposed by intraspecific mating systems

Acanthaster planci Outbreak: Decline in Coral Health, Coral Size Structure Modification and Consequences for Obligate Decapod Assemblages

Although benthic motile invertebrate communities encompass the vast majority of coral reef diversity, their response to habitat modification has been poorly studied. A variety of benthic species, particularly decapods, provide benefits to their coral host enabling them to cope with environmental stressors, and as a result benefit the overall diversity of coral-associated species. However, little is known about how invertebrate assemblages associated with corals will be affected by global perturbations, (either directly or indirectly via their coral host) or their consequences for ecosystem resilience. Analysis of a ten year dataset reveals that the greatest perturbation at Moorea over this time was an outbreak of the corallivorous sea star Acanthaster planci from 2006 to 2009 impacting habitat health, availability and size structure of Pocillopora spp. populations and highlights a positive relationship between coral head size and survival. We then present the results of a mensurative study in 2009 conducted at the end of the perturbation (A. planci outbreak) describing how coral-decapod communities change with percent coral mortality for a selected coral species, Pocillopora eydouxi. The loss of coral tissue as a consequence of A. planci consumption led to an increase in rarefied total species diversity, but caused drastic modifications in community composition driven by a shift from coral obligate to non-obligate decapod species. Our study highlights that larger corals left with live tissue in 2009, formed a restricted habitat where coral obligate decapods, including mutualists, could subsist. We conclude that the size structure of Pocillopora populations at the time of an A. planci outbreak may greatly condition the magnitude of coral mortality as well as the persistence of local populations of obligate decapods

Transit timings variations in the three-planet system : TOI-270

We present ground- and space-based photometric observations of TOI-270 (L231-32), a system of three transiting planets consisting of one super-Earth and two sub-Neptunes discovered by TESS around a bright (K-mag = 8.25) M3V dwarf. The planets orbit near low-order mean-motion resonances (5:3 and 2:1) and are thus expected to exhibit large transit timing variations (TTVs). Following an extensive observing campaign using eight different observatories between 2018 and 2020, we now report a clear detection of TTVs for planets c and d, with amplitudes of ∼10 min and a super-period of ∼3 yr, as well as significantly refined estimates of the radii and mean orbital periods of all three planets. Dynamical modelling of the TTVs alone puts strong constraints on the mass ratio of planets c and d and on their eccentricities. When incorporating recently published constraints from radial velocity observations, we obtain masses of Mb=1.48±0.18M⊕⁠, Mc=6.20±0.31M⊕⁠, and Md=4.20±0.16M⊕ for planets b, c, and d, respectively. We also detect small but significant eccentricities for all three planets : eb = 0.0167 ± 0.0084, ec = 0.0044 ± 0.0006, and ed = 0.0066 ± 0.0020. Our findings imply an Earth-like rocky composition for the inner planet, and Earth-like cores with an additional He/H2O atmosphere for the outer two. TOI-270 is now one of the best constrained systems of small transiting planets, and it remains an excellent target for atmospheric characterization

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Pyridyl-based pentadentate ligands: base-catalyzed hydrolysis of asym -[Co(dmptacn)Cl] 2+

The [Co(dmptacn)Cl]2+ (dmptacn = 1,4-bis(pyridylmethyl)-1,4,7- triazacyclononane) complex has been shown to be the asym isomer through 1D and 2D NMR studies, its optical resolution, and the single-crystal X-ray structure of its perchlorate salt. The kinetics of base-catalyzed hydrolysis establishes the usual [OH-] dependence (KOH = 0.040 M-1 s-1, 25 °C, / = 1.0 M, NaCl), but D-exchange experiments reveal that substantial if not complete reaction proceeds via the new pseudoaminate mechanism, i.e., via deprotonation at an α-CH2 center rather than the NH. The significant kinetic isotope effect (kH/kD = 2.1) is interpreted in terms of rate-limiting deprotonation followed by reprotonation of the conjugate base at a rate competitive with loss of Cl -. NMR and polarimetric studies establish geometric and optical retention for the hydrolysis reaction and exclude even the transient formation of a sym isomer intermediate

Synthesis, structure, and kinetics and stereochemistry of base-catalyzed hydrolysis of meso - and rac -[Co 2 (tmpdtne)Cl 2 ] 4+ , bis(pentaamine) complexes devoid of deprotonatable NH centers

The bis(pentadentate) ligand tmpdtne binds two Co(II) centers, and the entity is readily oxidized to the dicobalt(III) derivative [Co 2(tmpdtne)Cl2]4+ which has been separated into two isomeric forms. NMR studies establish these as meso and rac isomers arising from the different or same absolute configurations for the asym configuration about each Co(III) center. Each dinuclear ion base hydrolyses to the dihydroxo derivative [Co2(tmpdtne)(OH)2]4+ with retained asym configurations about each metal ion and also retained rac or meso configurations. The kinetics for the stepwise loss of the two Cl- ligands is uniphasic, and data are presented to show that the loss of the first chloride is rate determining and is followed by very rapid intramolecular and loss of the second Cl- via a hydroxobridged species to yield the observed dihydroxo derivative. Meso and rac forms of the latter have been crystallized. The X-ray crystal structure of the rac-dihydroxo complex is reported, and it establishes the configurations of all the complexes reported. The 1H NMR spectra for the hydroxo ions show very high field Co-OH resonances (ca. δ -0.5 ppm) not observed previously for such ions, and this result is discussed in the context of published 1H NMR data for bridged Co-OH-Co species. The base hydrolysis kinetics for the dichloro ions are first order in [OH-], and deprotonation at an α-CH2 center (α to a pyridyl) is identified as the source of the catalysis, since there is no NH center available for deprotonation on the ligand. These data further support the new pseudoaminate base hydrolysis mechanism first reported in 2003. The values of kOH for the second-order base-catalyzed reaction are ca. 4.0 M-1 s-1 for both the rac and meso isomers, and these results are discussed in terms of the increased acidities of these 4+ cations compared to their 2+ ion counterparts

Assessment of the Microbial Constituents of the Home Environment of Individuals with Cystic Fibrosis (CF) and Their Association with Lower Airways Infections.

INTRODUCTION:Cystic fibrosis (CF) airways are colonized by a polymicrobial community of organisms, termed the CF microbiota. We sought to define the microbial constituents of the home environment of individuals with CF and determine if it may serve as a latent reservoir for infection. METHODS:Six patients with newly identified CF pathogens were included. An investigator collected repeat sputum and multiple environmental samples from their homes. Bacteria were cultured under both aerobic and anaerobic conditions. Morphologically distinct colonies were selected, purified and identified to the genus and species level through 16S rRNA gene sequencing. When concordant organisms were identified in sputum and environment, pulsed-field gel electrophoresis (PFGE) was performed to determine relatedness. Culture-independent bacterial profiling of each sample was carried out by Illumina sequencing of the V3 region of the 16s RNA gene. RESULTS:New respiratory pathogens prompting investigation included: Mycobacterium abscessus(2), Stenotrophomonas maltophilia(3), Pseudomonas aeruginosa(3), Pseudomonas fluorescens(1), Nocardia spp.(1), and Achromobacter xylosoxidans(1). A median 25 organisms/patient were cultured from sputum. A median 125 organisms/home were cultured from environmental sites. Several organisms commonly found in the CF lung microbiome were identified within the home environments of these patients. Concordant species included members of the following genera: Brevibacterium(1), Microbacterium(1), Staphylococcus(3), Stenotrophomonas(2), Streptococcus(2), Sphingomonas(1), and Pseudomonas(4). PFGE confirmed related strains (one episode each of Sphinogomonas and P. aeruginosa) from the environment and airways were identified in two patients. Culture-independent assessment confirmed that many organisms were not identified using culture-dependent techniques. CONCLUSIONS:Members of the CF microbiota can be found as constituents of the home environment in individuals with CF. While the majority of isolates from the home environment were not genetically related to those isolated from the lower airways of individuals with CF suggesting alternate sources of infection were more common, a few genetically related isolates were indeed identified. As such, the home environment may rarely serve as either the source of infection or a persistent reservoir for re-infection after clearance

Culture and molecular-based profiles show shifts in bacterial communities of the upper respiratory tract that occur with age

The upper respiratory tract (URT) is a crucial site for host defense, as it is home to bacterial communities that both modulate host immune defense and serve as a reservoir of potential pathogens. Young children are at high risk of respiratory illness, yet the composition of their URT microbiota is not well understood. Microbial profiling of the respiratory tract has traditionally focused on culturing common respiratory pathogens, whereas recent culture-independent microbiome profiling can only report the relative abundance of bacterial populations. In the current study, we used both molecular profiling of the bacterial 16S rRNA gene and laboratory culture to examine the bacterial diversity from the oropharynx and nasopharynx of 51 healthy children with a median age of 1.1 years (range 1–4.5 years) along with 19 accompanying parents. The resulting profiles suggest that in young children the nasopharyngeal microbiota, much like the gastrointestinal tract microbiome, changes from an immature state, where it is colonized by a few dominant taxa, to a more diverse state as it matures to resemble the adult microbiota. Importantly, this difference in bacterial diversity between adults and children accompanies a change in bacterial load of three orders of magnitude. This indicates that the bacterial communities in the nasopharynx of young children have a fundamentally different structure from those in adults and suggests that maturation of this community occurs sometime during the first few years of life, a period that includes ages at which children are at the highest risk for respiratory disease

The K2 Bright Star Survey. I. Methodology and Data Release

While the Kepler mission was designed to look at tens of thousands of faint stars (V gsim 12), brighter stars that saturated the detector are important because they can be and have been observed very accurately by other instruments. By analyzing the unsaturated scattered-light "halo" around these stars, we retrieved precise light curves of most of the brightest stars in K2 fields from Campaign 4 onward. The halo method does not depend on the detailed cause and form of systematics, and we show that it is effective at extracting light curves from both normal and saturated stars. The key methodology is to optimize the weights of a linear combination of pixel time series with respect to an objective function. We test a range of such objective functions, finding that lagged Total Variation, a generalization of Total Variation, performs well on both saturated and unsaturated K2 targets. Applying this to the bright stars across the K2 Campaigns reveals stellar variability ubiquitously, including effects of stellar pulsation, rotation, and binarity. We describe our pipeline and present a catalog of the 161 bright stars, with classifications of their variability, asteroseismic parameters for red giants with well-measured solar-like oscillations, and remarks on interesting objects. These light curves are publicly available as a High Level Science Product from the Mikulski Archive for Space Telescopes (footnote 17)