The intracellular bacterial pathogen Coxiella burnetii directs biogenesis of a parasitophorous vacuole (PV) that acquires host endolysosomal components. Formation of a PV that supports C. burnetii ...replication requires a Dot/Icm type 4B secretion system (T4BSS) that delivers bacterial effector proteins into the host cell cytosol. Thus, a subset of T4BSS effectors are presumed to direct PV biogenesis. Recently, the PV-localized effector protein CvpA was found to promote C. burnetii intracellular growth and PV expansion. We predict additional C. burnetii effectors localize to the PV membrane and regulate eukaryotic vesicle trafficking events that promote pathogen growth. To identify these vacuolar effector proteins, a list of predicted C. burnetii T4BSS substrates was compiled using bioinformatic criteria, such as the presence of eukaryote-like coiled-coil domains. Adenylate cyclase translocation assays revealed 13 proteins were secreted in a Dot/Icm-dependent fashion by C. burnetii during infection of human THP-1 macrophages. Four of the Dot/Icm substrates, termed Coxiella vacuolar protein B (CvpB), CvpC, CvpD, and CvpE, labeled the PV membrane and LAMP1-positive vesicles when ectopically expressed as fluorescently tagged fusion proteins. C. burnetii ΔcvpB, ΔcvpC, ΔcvpD, and ΔcvpE mutants exhibited significant defects in intracellular replication and PV formation. Genetic complementation of the ΔcvpD and ΔcvpE mutants rescued intracellular growth and PV generation, whereas the growth of C. burnetii ΔcvpB and ΔcvpC was rescued upon cohabitation with wild-type bacteria in a common PV. Collectively, these data indicate C. burnetii encodes multiple effector proteins that target the PV membrane and benefit pathogen replication in human macrophages.
Abstract Background Hepatocyte growth factor (HGF) is a pleotropic factor posited to have metabolic homeostatic properties. The purpose of this study is to examine whether level of HGF is associated ...with the development of type 2 diabetes. Methods Data from the Multi-Ethnic Study of Atherosclerosis (MESA) were used to examine the prospective association between serum level of HGF and incident diabetes. Fasting HGF was measured at Exam 1 (2000-2002) in 5395 participants free from diabetes (61.5 ± 10.2 years old) and incidence of diabetes was determined at four subsequent follow-up exams over 12 years. Hazard ratios (HR) for incident diabetes were estimated according to 1 standard deviation (SD) unit increment of HGF (1 SD = 26 μg/l), before and after adjustment for age, sex, race/ethnicity, education, study center, smoking status, alcohol consumption, body mass index, waist circumference, fasting glucose and insulin, C-reactive protein, and interleukin-6 levels. Results A 1 SD increment of baseline HGF was associated with a 46% (95% CI = 1.37, 1.56) increased risk of diabetes before adjustment. After adjustment, diabetes risk per 1 SD increment of HGF was attenuated but remained significantly increased (HR = 1.21; 95% CI = 1.12, 1.32). Men had a significantly greater HR compared to women per equivalent increase of HGF (p-value for sex interaction = 0.04). There was no evidence of effect modification by race/ethnicity. Conclusions This study advances understanding from cross-sectional studies and investigation of incident insulin resistance, demonstrating higher level of HGF is associated with incident diabetes and may reflect a unique type of impaired metabolism.
Thymic stromal lymphopoietin (TSLP) has been shown to play a central role in the initiation and persistence of allergic responses.
We evaluated whether tezepelumab, a human monoclonal anti-TSLP ...antibody, improved the efficacy of subcutaneous allergen immunotherapy (SCIT) and promoted the development of tolerance in patients with allergic rhinitis.
We conducted a double-blind parallel design trial in patients with cat allergy. A total of 121 patients were randomized to receive either intravenous tezepelumab plus subcutaneous cat SCIT, cat SCIT alone, tezepelumab alone, or placebo for 52 weeks, followed by 52 weeks of observation. Nasal allergen challenge (NAC), skin testing, and blood and nasal samples were obtained throughout the study.
At week 52, the NAC-induced total nasal symptom scores (TNSS) (calculated as area under the curve AUC0-1h and as peak score Peak0-1h during the first hour after NAC) were significantly reduced in patients receiving tezepelumab/SCIT compared to SCIT alone. At week 104, one year after stopping treatment, the primary end point TNSS AUC0-1h was not significantly different in the tezepelumab/SCIT group compared to SCIT alone, while TNSS Peak0-1h was significantly lower in those receiving combination treatment versus SCIT. Transcriptomic analysis of nasal epithelial samples demonstrated that treatment with the combination of SCIT/tezepelumab, but neither monotherapy, caused persistent downregulation of a gene network related to type 2 inflammation that was associated with improvement in NAC responses.
Inhibition of TSLP augments the efficacy of SCIT during therapy and may promote tolerance after a 1-year course of treatment. (ClinicalTrials.gov NCT02237196).
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Background Electronic health records (EHRs) are increasingly used for clinical and translational research through the creation of phenotype algorithms. Currently, phenotype algorithms are most ...commonly represented as noncomputable descriptive documents and knowledge artifacts that detail the protocols for querying diagnoses, symptoms, procedures, medications, and/or text-driven medical concepts, and are primarily meant for human comprehension. We present desiderata for developing a computable phenotype representation model (PheRM).
Methods A team of clinicians and informaticians reviewed common features for multisite phenotype algorithms published in PheKB.org and existing phenotype representation platforms. We also evaluated well-known diagnostic criteria and clinical decision-making guidelines to encompass a broader category of algorithms.
Results We propose 10 desired characteristics for a flexible, computable PheRM: (1) structure clinical data into queryable forms; (2) recommend use of a common data model, but also support customization for the variability and availability of EHR data among sites; (3) support both human-readable and computable representations of phenotype algorithms; (4) implement set operations and relational algebra for modeling phenotype algorithms; (5) represent phenotype criteria with structured rules; (6) support defining temporal relations between events; (7) use standardized terminologies and ontologies, and facilitate reuse of value sets; (8) define representations for text searching and natural language processing; (9) provide interfaces for external software algorithms; and (10) maintain backward compatibility.
Conclusion A computable PheRM is needed for true phenotype portability and reliability across different EHR products and healthcare systems. These desiderata are a guide to inform the establishment and evolution of EHR phenotype algorithm authoring platforms and languages.
Vaccines are everywhere hugely successful but are also under attack. The reason for the latter is the perception by some people that vaccines are unsafe. However that may be, vaccine safety, life any ...other scientific subject, must be constantly studied. It was from this point of view that a meeting was organized at the Wellcome Trust in London in May 2019 to assess some aspects of vaccine safety as subjects for scientific study. The objective of the meeting was to assess what is known beyond reasonable doubt and conversely what areas need additional studies. Although the meeting could not cover all aspects of vaccine safety science, many of the most important issues were addressed by a group of about 30 experts to determine what is already known and what additional studies are merited to assess the safety of the vaccines currently in use. The meeting began with reviews of the current situation in different parts of the world, followed by reviews of specific controversial areas, including the incidence of certain conditions after vaccination and the safety of certain vaccine components. Lastly, information about the human papillomavirus vaccine was considered because its safety has been particularly challenged by vaccine opponents. The following is a summary of the meeting findings. In addition to this summary, the meeting organizers will explore opportunities to perform studies that would enlarge knowledge of vaccine safety.
Hepatocyte growth factor (HGF) is positively associated with ischemic and hemorrhagic stroke risk factors. However, understanding the relation between HGF and stroke is in its infancy. Therefore, we ...sought to examine the association of circulating HGF with incident stroke using data from the MESA (Multi-Ethnic Study of Atherosclerosis). We hypothesized that circulating HGF would be positively associated with an increased risk of stroke.
Participants aged 45 to 84 years (n=6711) had HGF measured between 2000 and 2002 and were followed for incident stroke through 2013 (n=233). Cox proportional hazards regression was used to calculate hazard ratios and 95% confidence intervals for incident stroke. A secondary analysis stratified results by adjudicated stroke type (n=183 ischemic; n=39 hemorrhagic; n=11 other).
After adjustment for potential confounding variables, risk of stroke was 17% higher with each standard deviation increase in HGF (hazard ratio, 1.17; 95% confidence interval, 1.03-1.34). This association was mainly driven by ischemic stroke and did not change on exclusion of cardioembolic strokes, although the number of excluded cases was small. The few hemorrhagic and other types of stroke were not associated with HGF.
Circulating HGF was positively associated with the incidence of stroke in a diverse, population-based cohort of men and women from the United States. Our findings support the hypothesis that circulating HGF is a marker of endothelial damage and suggest that HGF may have utility as a prognostic marker of stroke risk.
Analyses of flower‐visitor interaction networks allow application of community‐level information to conservation problems, but management recommendations that ensue from such analyses are not well ...characterized. Results of modularity analyses, which detect groups of species (modules) that interact more with each other than with species outside their module, may be particularly applicable to management concerns. We conducted modularity analyses of networks surrounding a rare endemic annual plant, Eriogonum visheri, at Badlands National Park, USA, in 2010 and 2011. Plant species visited were determined by pollen on insect bodies and by flower species upon which insects were captured. Roles within modules (network hub, module hub, connector and peripheral, in decreasing order of network structural importance) were determined for each species. Relationships demonstrated by the modularity analysis, in concert with knowledge of pollen species carried by insects, allowed us to infer effects of two invasive species on E. visheri. Sharing a module increased risk of interspecific pollen transfer to E. visheri. Control of invasive Salsola tragus, which shared a module with E. visheri, is therefore a prudent management objective, but lack of control of invasive Melilotus officinalis, which occupied a different module, is unlikely to negatively affect pollination of E. visheri. Eriogonum pauciflorum may occupy a key position in this network, supporting insects from the E. visheri module when E. visheri is less abundant. Year‐to‐year variation in species' roles suggests management decisions must be based on observations over several years. Information on pollen deposition on stigmas would greatly strengthen inferences made from the modularity analysis. Synthesis and applications: Assessing the consequences of pollination, whether at the community or individual level, is inherently time‐consuming. A trade‐off exists: rather than an estimate of fitness effects, the network approach provides a broad understanding of the relationships among insect visitors and other plant species that may affect the focal rare plant. Knowledge of such relationships allows managers to detect, target and prioritize control of only the important subset of invasive species present and identify other species that may augment a rare species' population stability, such as E. pauciflorum in our study.
Indo-Pacific high island streams experience extreme hydrological variation, and are characterised by freshwater fish species with an amphidromous life history. Amphidromy is a likely adaptation for ...colonisation of island streams following stochastic events that lead to local extirpation. In the Wet Tropics of north-eastern Australia, steep coastal mountain streams share similar physical characteristics to island systems. These streams are poorly surveyed, but may provide suitable habitat for amphidromous species. However, due to their ephemeral nature, common non-diadromous freshwater species of continental Australia are unlikely to persist. Consequently, we hypothesise that coastal Wet Tropics streams are faunally more similar, to distant Pacific island communities, than to nearby faunas of large continental rivers.
Surveys of coastal Wet Tropics streams recorded 26 species, 10 of which are first records for Australia, with three species undescribed. This fish community is unique in an Australian context in that it contains mostly amphidromous species, including sicydiine gobies of the genera Sicyopterus, Sicyopus, Smilosicyopus and Stiphodon. Species presence/absence data of coastal Wet Tropics streams were compared to both Wet Tropics river networks and Pacific island faunas. ANOSIM indicated the fish fauna of north-eastern Australian coastal streams were more similar to distant Pacific islands (R = 0.76), than to nearby continental rivers (R = 0.98).
Coastal Wet Tropics streams are faunally more similar to distant Pacific islands (79% of species shared), than to nearby continental fauna due to two factors. First, coastal Wet Tropics streams lack many non-diadromous freshwater fish which are common in nearby large rivers. Second, many amphidromous species found in coastal Wet Tropics streams and Indo-Pacific islands remain absent from large rivers of the Wet Tropics. The evolutionary and conservation significance of this newly discovered Australian fauna requires clarification in the context of the wider amphidromous fish community of the Pacific.
► We compared effects of planting methods and seed mix richness on prairie restoration. ► Seed mix richness did not affect planted cover or cover of exotic species. ► The dormant broadcast method ...favored cover of perennial forbs. ► The growing-season drill method favored cover of warm-season grasses. ► The growing-season broadcast method was never optimal.
Tallgrass prairie restoration has been practiced for more than 75years, yet few studies have systematically tested restoration methods over large geographic regions with the intent of refining methodology. In this study, we used three planting methods (dormant-season broadcast, growing-season broadcast and growing-season drill) fully crossed with three levels of seed species richness (10, 20, and 34 spp). We replicated the study on nine former agricultural fields located from east-central Iowa (Neal Smith National Wildlife Refuge) to northwestern Minnesota (Litchfield, Fergus Falls and Morris Wetland Management Districts), USA, within the northern tallgrass prairie biome. Objectives were to evaluate the relative influences of planting method, seed mix richness, and their interactions, on (1) planted cover (both total and by guild) and richness, (2) exotic species cover, and (3) non-planted native species cover. Optimal techniques varied between the two study areas: the dormant broadcast method produced greater cover of planted species at the Minnesota sites and the growing-season drill method produced greater cover of planted species at Iowa sites. The dormant broadcast method strongly favored establishment of perennial forbs while the growing-season drill favored warm-season grasses. Although increasing richness of the seed mix produced greater planted species richness, this did not result in greater resistance to exotic invasion. We conclude that, if planting during the growing season, drilling seed is preferable to broadcasting, but if the choice is between broadcasting seed in the dormant or growing season, the dormant season is preferred.
Hepatocyte growth factor (HGF) has previously been associated with risk of stroke, coronary heart disease, and atherosclerosis. We hypothesized that higher circulating HGF is associated with greater ...progression of measures of atherosclerosis: coronary artery calcium (CAC) and carotid plaque.
Participants aged 45–84 years from the prospective cohort study Multi-Ethnic Study of Atherosclerosis had HGF measured at baseline (between 2000 and 2002) and were followed for progression of atherosclerosis for up to 12 years. CAC was measured at all five exams using the Agatston method. Mixed-effects models were used to examine the association of HGF and CAC progression among 6695 participants with available data. Relative risk regression was used to assess the association between HGF and new or additional carotid plaque between exams 1 and 5 in 3400 participants with available data. All point estimates were adjusted for potential confounding variables.
Each standard deviation higher HGF at baseline was associated with 2.9 Agatston units/year greater CAC progression (95% CI: 1.6–4.2, p < 0.0001), and the magnitude of this association differed by race/ethnicity (p value for interaction by race = 0.003). Each standard deviation higher HGF at baseline was associated with a 4% higher risk of new or additional carotid plaque (95% CI: 1.01–1.08, p = 0.005).
Higher levels of HGF were significantly associated with greater progression of atherosclerosis in this large and diverse population. Circulating HGF continues to show promise as a potential clinical biomarker for cardiovascular disease.
•Hepatocyte growth factor was associated with progression of atherosclerosis.•This association differed by race/ethnicity in some instances.•Hepatocyte growth factor shows promise as a biomarker for cardiovascular disease.
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