Bacteriophage predation selects for diverse antiphage systems that frequently cluster on mobilizable defense islands in bacterial genomes. However, molecular insight into the reciprocal dynamics of ...phage-bacterial adaptations in nature is lacking, particularly in clinical contexts where there is need to inform phage therapy efforts and to understand how phages drive pathogen evolution. Using time-shift experiments, we uncovered fluctuations in
's resistance to phages in clinical samples. We mapped phage resistance determinants to SXT integrative and conjugative elements (ICEs), which notoriously also confer antibiotic resistance. We found that SXT ICEs, which are widespread in γ-proteobacteria, invariably encode phage defense systems localized to a single hotspot of genetic exchange. We identified mechanisms that allow phage to counter SXT-mediated defense in clinical samples, and document the selection of a novel phage-encoded defense inhibitor. Phage infection stimulates high-frequency SXT ICE conjugation, leading to the concurrent dissemination of phage and antibiotic resistances.
Bacteria, bacteriophages that prey upon them, and mobile genetic elements (MGEs) compete in dynamic environments, evolving strategies to sense the milieu. The first discovered environmental sensing ...by phages, lysis inhibition, has only been characterized and studied in the limited context of T-even coliphages. Here, we discover lysis inhibition in the etiological agent of the diarrheal disease cholera,
infected by ICP1, a phage ubiquitous in clinical samples. This work identifies the ICP1-encoded holin,
and antiholin,
that mediate lysis inhibition. Further, we show that an MGE, the defensive phage satellite PLE, collapses lysis inhibition. Through
ysis
nhibition
isruption a conserved PLE protein, LidI, is sufficient to limit the phage produced from infection, bottlenecking ICP1. These studies link a novel incarnation of the classic lysis inhibition phenomenon with conserved defensive function of a phage satellite in a disease context, highlighting the importance of lysis timing during infection and parasitization.
Inflammatory dilated cardiomyopathy (DCMi) is a major cause of heart failure in children and young adults. DCMi develops in up to 30% of myocarditis patients, but the mechanisms involved in disease ...progression are poorly understood. Patients with eosinophilia frequently develop cardiomyopathies. In this study, we used the experimental autoimmune myocarditis (EAM) model to determine the role of eosinophils in myocarditis and DCMi. Eosinophils were dispensable for myocarditis induction but were required for progression to DCMi. Eosinophil-deficient ΔdblGATA1 mice, in contrast to WT mice, showed no signs of heart failure by echocardiography. Induction of EAM in hypereosinophilic IL-5Tg mice resulted in eosinophilic myocarditis with severe ventricular and atrial inflammation, which progressed to severe DCMi. This was not a direct effect of IL-5, as IL-5TgΔdblGATA1 mice were protected from DCMi, whereas IL-5
mice exhibited DCMi comparable with WT mice. Eosinophils drove progression to DCMi through their production of IL-4. Our experiments showed eosinophils were the major IL-4-expressing cell type in the heart during EAM, IL-4
mice were protected from DCMi like ΔdblGATA1 mice, and eosinophil-specific IL-4 deletion resulted in improved heart function. In conclusion, eosinophils drive progression of myocarditis to DCMi, cause severe DCMi when present in large numbers, and mediate this process through IL-4.
Climate change and overfishing may lead to ecosystem instability and may benefit nonexploited organisms such as jellyfish. In the Irish Sea, an increase in jellyfish abundance was evident (r²=0.29, ...P=0.03) in a 16-year time-series (1994-2009) collected during juvenile fish surveys. Jellyfish abundance correlated positively with sea surface temperature (SST) over the preceding 18 months (r=0.65, pACF<0.001) and copepod biomass in the previous year (r=0.56, pACF=0.03) and negatively with spring (February-May) precipitation (r=−0.57, pACF=0.02). Principal components regression indicated that climatic indices explained 68% of the interannual variability in jellyfish abundance (P=0.003), where the components were based on the North Atlantic Oscillation Index, SST and precipitation. The frequency of cnidarian material present in Continuous Plankton Recorder (CPR) samples has also increased since 1970, with a period of frequent outbreaks between 1982 and 1991. Before this period, the herring stock in the northern Irish Sea declined rapidly to a low level, potentially stimulating structural change in the ecosystem. In 1985, there was a step decrease in CPR copepod biomass and in 1989, a step increase in the phytoplankton colour index, suggesting a cascading regime shift during the 1980s. Subsequent overexploitation of gadids, coupled with warm temperatures and the poor recruitment of cod, led to the rapid decline in cod biomass from 1990. While the biomass of sprat has decreased in the last decade, the herring stock has recovered partially. Reductions in demersal fishing pressure since 2000, intended to stimulate cod recovery, appear to have facilitated further rises in haddock biomass. Since the 1980s regime shift, sea temperatures have increased, the fish community has altered and jellyfish abundance has risen such that jellyfish and haddock may now play an increasingly important role in the ecosystem.
The advent of Fastloc-GPS is helping to transform marine animal tracking by allowing the collection of high-quality location data for species that surface only briefly. We show how the improved ...location accuracy of Fastloc-GPS compared to Argos tracking is expected to lead to far more accurate home range estimates, particularly for animals moving over the scale of a few km. We reach this conclusion using simulated data and home range estimates derived from empirical tracking data for green sea turtles (
Chelonia mydas
) equipped with Argos linked Fastloc-GPS tags at three different foraging areas (western Indian Ocean, Western Australia, and Caribbean). Poor-quality Argos locations (e.g., location classes A, B) produced home range estimates ranging from 10 to 100 times larger than those derived from Fastloc-GPS data, whereas high-quality Argos locations (location classes 1–3) produced home range estimates that were generally comparable to those derived from Fastloc-GPS data. However, the limited number of Argos class 1–3 locations obtained for all three turtles—an average of 14.6 times more Fastloc-GPS locations were obtained compared to Argos class 1–3 locations—resulted in blurred patterns of space use. In contrast, the high volume of Fastloc-GPS locations revealed fine-scale movements in striking detail (i.e., use of discrete patches separated by just a few 100 m). We recommend careful consideration of the effects of location accuracy and data volume when developing sampling regimes for marine tracking studies and make recommendations regarding how sampling can be standardized to facilitate meaningful spatial and temporal comparisons of space use.
The recently commissioned Linac Coherent Light Source is an X-ray free-electron laser at the SLAC National Accelerator Laboratory. It produces coherent soft and hard X-rays with peak brightness ...nearly ten orders of magnitude beyond conventional synchrotron sources and a range of pulse durations from 500 to <10 fs (10-15 s). With these beam characteristics this light source is capable of imaging the structure and dynamics of matter at atomic size and timescales. The facility is now operating at X-ray wavelengths from 22 to 1.2 A and is presently delivering this high-brilliance beam to a growing array of scientific researchers. We describe the operation and performance of this new 'fourth-generation light source'.
Background PCSK9 (proprotein convertase subtilisin/kexin type 9) is well recognized for its important role in cholesterol metabolism. Elevated levels are associated with increased cardiovascular risk ...and inhibition with PCSK9 antibodies (PCSK9i) lowers cardiovascular events in patients with coronary artery disease. PCSK9 levels are also elevated in people living with HIV (PLWH) and those with dyslipidemia. Because increased PCSK9 in PLWH is associated with impaired coronary endothelial function, a barometer of coronary vascular health, we tested the hypothesis that PCSK9i improves impaired coronary endothelial function in dyslipidemia without coronary artery disease and in PLWH with nearly optimal/above goal low-density lipoprotein cholesterol levels. Methods and Results We performed a single-center study in 19 PLWH and 11 with dyslipidemia to evaluate the effects of the PCSK9i evolocumab on coronary endothelial function using cine 3T MRI to noninvasively measure coronary endothelial function, assessed as the changes in coronary cross-sectional area and coronary blood flow from rest to that during isometric handgrip exercise, a known endothelial-dependent vasodilator. Before evolocumab, there was a decrease or no coronary vasodilation and no increase in coronary blood flow (the normal responses) to isometric handgrip exercise in either group. Following 6 weeks of evolocumab, 480 mg q4 weeks, the % cross-sectional area changes from rest to isometric handgrip exercise were +5.6±5.5% and +4.5±3.1% in the PLWH and dyslipidemia groups, respectively, both
<0.01 versus baseline. Improved cross-sectional area was paralleled by a significant coronary blood flow improvement in both groups. Conclusions To our knowledge, these data represent the first evidence that PCSK9 inhibition improves coronary artery health in PLWH and people with dyslipidemia. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03500302.
Telemetry is a key, widely used tool to understand marine megafauna distribution, habitat use, behavior, and physiology; however, a critical question remains: “How many animals should be tracked to ...acquire meaningful data sets?” This question has wide-ranging implications including considerations of statistical power, animal ethics, logistics, and cost. While power analyses can inform sample sizes needed for statistical significance, they require some initial data inputs that are often unavailable. To inform the planning of telemetry and biologging studies of marine megafauna where few or no data are available or where resources are limited, we reviewed the types of information that have been obtained in previously published studies using different sample sizes. We considered sample sizes from one to >100 individuals and synthesized empirical findings, detailing the information that can be gathered with increasing sample sizes. We complement this review with simulations, using real data, to show the impact of sample size when trying to address various research questions in movement ecology of marine megafauna. We also highlight the value of collaborative, synthetic studies to enhance sample sizes and broaden the range, scale, and scope of questions that can be answered.
Our understanding of global seagrass ecosystems comes largely from regions characterized by human impacts with limited data from habitats defined as notionally pristine. Seagrass assessments also ...largely focus on shallow-water coastal habitats with comparatively few studies on offshore deep-water seagrasses. We satellite tracked green turtles (Chelonia mydas), which are known to forage on seagrasses, to a remote, pristine deep-water environment in the Western Indian Ocean, the Great Chagos Bank, which lies in the heart of one of the world's largest marine protected areas (MPAs). Subsequently we used in-situ SCUBA and baited video surveys to survey the day-time sites occupied by turtles and discovered extensive monospecific seagrass meadows of Thalassodendron ciliatum. At three sites that extended over 128 km, mean seagrass cover was 74% (mean range 67–88% across the 3 sites at depths to 29 m. The mean species richness of fish in seagrass meadows was 11 species per site (mean range 8–14 across the 3 sites). High fish abundance (e.g. Siganus sutor: mean MaxN.site−1 = 38.0, SD = 53.7, n = 5) and large predatory shark (Carcharhinus amblyrhynchos) (mean MaxN.site−1 = 1.5, SD = 0.4, n = 5) were recorded at all sites. Such observations of seagrass meadows with large top predators, are limited in the literature. Given that the Great Chagos Bank extends over approximately 12,500 km2 and many other large deep submerged banks exist across the world's oceans, our results suggest that deep-water seagrass may be far more abundant than previously suspected.