Epoxide-Mediated CifR Repression of cif Gene Expression Utilizes Two Binding Sites in Pseudomonas aeruginosa

Pseudomonas aeruginosa secretes an epoxide hydrolase virulence factor that reduces the apical membrane expression of ABC transporters such as the cystic fibrosis transmembrane conductance regulator (CFTR). This virulence factor, named CFTR inhibitory factor (Cif), is regulated by a TetR-family, epoxide-responsive repressor known as CifR via direct binding and repression. We identified two sites of CifR binding in the intergenic space between cifR and morB, the first gene in the operon containing the cif gene. We have mapped these binding sites and found they are 27 bp in length, and they overlap the -10 and +1 sites of both the cifR and morB regulatory region and the start of transcription, respectively. In addition, we found that CifR binds to each repression site with differing affinity. Mutagenesis of these binding sites resulted in a loss of DNA binding in vitro, and mutation of one of these sites in vivo resulted in an increase in transcription of both the cif and cifR genes. We characterized cif and cifR gene expression in sputum and found that, whereas cif gene expression varied relative to an in vitro coculture control, cifR gene expression was consistently higher. Analysis of a longitudinal sample of CF isolates from nine patients revealed that Cif protein was expressed over time, although variably, and these changes could not be linked to mutations in the cifR gene or the promoters of these genes. Finally, we tested CifR responsiveness to other epoxides and showed that CifR can respond to multiple epoxides to various degrees

Adherence to the updated guidelines for the prevention of perinatal Group B streptococcal disease

In 2010, the Centers for Disease Control and Prevention updated the Guidelines for the Prevention of Perinatal Group B Streptococcal (GBS) Disease. Previous studies of adherence to GBS guidelines have focused on the treatment of carriers of GBS. Our objective was to determine whether there was any difference in adherence to the guidelines for screening and treatment of women who delivered at our institution between the beginning of 2011 and the end of 2011 as the revised guidelines were published in November 2010. Our secondary outcome was to determine whether any differences in adherence occurred between prenatal provider types (OB/Gyn, Certified Nurse Midwives, and Family Practice)

Land-use change and propagule pressure promote plant invasions in tropical rainforest remnants

Context: Intact tropical rainforests are considered robust to plant invasions. However, land-use change alters the structure and species composition of native forest, opening up tropical landscapes to invasion. Yet, the relative roles of key drivers on tropical forest invasions remain little investigated. Objectives: We examine factors affecting plant invasion of rainforest remnants in oil-palm dominated landscapes in Sabah, Malaysian Borneo. We hypothesized that invasion is greater in highly fragmented landscapes, and in disturbed forests with lower native plant diversity (cf. old-growth rainforests). Methods: Native and exotic plants were surveyed in 47 plots at 17 forest sites, spanning gradients in landscape-scale fragmentation and local forest disturbance. Using partial least squares path-modelling, we examined correlations between invasion, fragmentation, forest disturbance, propagule pressure, soil characteristics and native plant community. Results: We recorded 6999 individuals from 329 genera in total, including eight exotic species (0–51% of individuals/plot, median = 1.4%) representing shrubs, forbs, graminoids and climbers. The best model (R2 = 0.343) revealed that invasion was correlated with disturbance and propagule pressure (high prevalence of exotic species in plantation matrix), the latter being driven by greater fragmentation of the landscape. Our models revealed a significant negative correlation between invasion and native tree seedlings and sapling community diversity. Conclusions: Increasing landscape fragmentation promotes exotic plant invasion in remnant tropical forests, especially if local disturbance is high. The association between exotic species invasion and young native tree community may have impacts for regeneration given that fragmentation is predicted to increase and so plant invasion may become more prevalent

Inhibiting the mitochondrial pyruvate carrier does not ameliorate synucleinopathy in the absence of inflammation or metabolic deficits

Epidemiological studies suggest a link between type-2 diabetes and Parkinson’s disease (PD) risk. Treatment of type-2 diabetes with insulin sensitizing drugs lowers the risk of PD. We previously showed that the insulin sensitizing drug, MSDC-0160, ameliorates pathogenesis in some animal models of PD. MSDC-0160 reversibly binds the mitochondrial pyruvate carrier (MPC) protein complex, which has an anti-inflammatory effect and restores metabolic deficits. Since PD is characterized by the deposition of α-synuclein (αSyn), we hypothesized that inhibiting the MPC might directly inhibit αSyn aggregation in vivo in mammals. To answer if modulation of MPC can reduce the development of αSyn assemblies, and reduce neurodegeneration, we treated two chronic and progressive mouse models; a viral vector-based αSyn overexpressing model and a pre-formed fibril (PFF) αSyn seeding model with MSDC-0160. These two models present distinct types of αSyn pathology but lack inflammatory or autophagy deficits. Contrary to our hypothesis, we found that a modulation of MPC in these models did not reduce the accumulation of αSyn aggregates or mitigate neurotoxicity. Instead, MSDC-0160 changed the post-translational modification and aggregation features of αSyn. These results are consistent with the lack of a direct effect of MPC modulation on synuclein clearance in these models

Pregnancy per- and polyfluoroalkyl substance concentrations and postpartum health in Project Viva, a prospective cohort

CONTEXT: Per- and polyfluoroalkyl substances (PFAS) are environmental chemicals linked to weight gain and type 2 diabetes. OBJECTIVE: We examined the extent to which PFAS plasma concentrations during pregnancy were associated with postpartum anthropometry and biomarkers. DESIGN, PATIENTS, MEASURES: We studied women recruited between 1999-2002 in the Project Viva prospective cohort with pregnancy plasma concentrations of PFAS, including perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and 2-(N-ethyl-perfluorooctane sulfonamide) acetic acid (EtFOSAA). Three-year postpartum anthropometry measurements were available from 786-801 women, blood pressure from 761 women, and blood biomarkers from 450-454 women. We used multivariable regression to evaluate the association of log2-transformed PFAS with postpartum anthropometry, blood pressure, and blood biomarkers (leptin, adiponectin, sex hormone binding globulin [SHBG], hemoglobin A1c [HbA1c], interleukin-6 [IL-6], C-reactive protein [CRP]), adjusting for age, pre-pregnancy BMI, marital status, race/ethnicity, education, income, smoking, parity, and breastfeeding history. RESULTS: Pregnancy concentrations of certain PFAS were associated with greater adiposity (e.g., 0.4 cm [95%CI: -0.1, 0.9] greater waist circumference per doubling in EtFOSAA; 0.2 cm [95%CI: -0.1, 0.5] greater mid-upper arm circumference per doubling in PFOA; 1.2 mm [95%CI: 0.1, 2.2] thicker sum of subscapular and triceps skinfolds per doubling in PFOS) and higher systolic blood pressure (e.g., 1.2 mm Hg [95%CI: 0.3, 2.2] per doubling in PFOS) at three years postpartum. Higher EtFOSAA concentrations were also associated with 10.8% higher IL-6 (95%CI: 3.3, 18.9) and 6.1% lower SHBG (95%CI: 0.7, 11.2) per doubling. CONCLUSIONS: Pregnancy concentrations of EtFOSAA, PFOS, and PFOA were associated with adverse postpartum cardiometabolic markers

Trait filtering during exotic plant invasion of tropical rainforest remnants along a disturbance gradient

1. Human‐modified tropical landscapes are often invaded by exotic plant species, but relatively few species are able to colonise remnant areas of rainforest embedded within such landscapes. The functional traits of successful invaders of natural versus anthropogenic habitats are poorly known, especially in tropical regions, and identifying such traits provides insight into the mechanisms that drive invasion. Here, we examine the invasion of tropical rainforest remnants along a disturbance gradient, within a human‐modified agricultural landscape, and determine whether exotic species that invade these forests are selected according to particular traits. 2. We surveyed the occurrence of 18 exotic species along 100‐m transects in four habitats—oil palm road, forest‐oil palm edges and disturbed and intact forest within rainforest remnants—at 21 sites across Sabah, Malaysian Borneo. We collated data on four functional traits relevant to the barriers plants encounter when colonising new environments (e.g. dispersal and persistence) and tested whether trait filtering occurs during invasion of rainforest remnants. 3. Exotic species richness declined significantly from oil palm (mean 9.2 species per transect) to forest edge (7.8 species) to inside rainforest remnants (3.1 species in disturbed forest), and only one species, Clidemia hirta, invaded intact forest. Exotic communities within rainforest remnants had long‐distance (vertebrate) dispersal, were woodier and had taller maximum heights, compared to those found in oil palm. For each trait, the community‐weighted mean for the forest edge community was intermediate between oil palm and disturbed forest, suggesting trait filtering during the invasion of rainforest remnants. 4. Our study provides strong evidence that trait filtering occurs during invasion from human‐modified agricultural habitats into previously disturbed forests via the forest edge. Successful invasion of rainforest remnants requires relatively long‐distance dispersal, in particular by vertebrates, as well as traits that are more similar to those of native forest species (i.e. tall and woody), making these exotic species more able to compete and persist in that environment. Our results show that disturbed tropical rainforests with open canopies are susceptible to invasion and highlight the traits of exotic species which can invade rainforest habitats, and which may pose a threat to regenerating tropical rainforests

Iterative Near-Term Ecological Forecasting: Needs, Opportunities, And Challenges

Two foundational questions about sustainability are “How are ecosystems and the services they provide going to change in the future?” and “How do human decisions affect these trajectories?” Answering these questions requires an ability to forecast ecological processes. Unfortunately, most ecological forecasts focus on centennial-scale climate responses, therefore neither meeting the needs of near-term (daily to decadal) environmental decision-making nor allowing comparison of specific, quantitative predictions to new observational data, one of the strongest tests of scientific theory. Near-term forecasts provide the opportunity to iteratively cycle between performing analyses and updating predictions in light of new evidence. This iterative process of gaining feedback, building experience, and correcting models and methods is critical for improving forecasts. Iterative, near-term forecasting will accelerate ecological research, make it more relevant to society, and inform sustainable decision-making under high uncertainty and adaptive management. Here, we identify the immediate scientific and societal needs, opportunities, and challenges for iterative near-term ecological forecasting. Over the past decade, data volume, variety, and accessibility have greatly increased, but challenges remain in interoperability, latency, and uncertainty quantification. Similarly, ecologists have made considerable advances in applying computational, informatic, and statistical methods, but opportunities exist for improving forecast-specific theory, methods, and cyberinfrastructure. Effective forecasting will also require changes in scientific training, culture, and institutions. The need to start forecasting is now; the time for making ecology more predictive is here, and learning by doing is the fastest route to drive the science forward

RAD51 foci as a biomarker predictive of platinum chemotherapy response in ovarian cancer

PURPOSE: To determine the ability of RAD51 foci to predict platinum chemotherapy response in high-grade serous ovarian cancer (HGSOC) patient-derived samples. EXPERIMENTAL DESIGN: RAD51 and γH2AX nuclear foci were evaluated by immunofluorescence in HGSOC patient-derived cell lines (n = 5), organoids (n = 11), and formalin-fixed, paraffin-embedded tumor samples (discovery n = 31, validation n = 148). Samples were defined as RAD51-High if \u3e10% of geminin-positive cells had ≥5 RAD51 foci. Associations between RAD51 scores, platinum chemotherapy response, and survival were evaluated. RESULTS: RAD51 scores correlated with in vitro response to platinum chemotherapy in established and primary ovarian cancer cell lines (Pearson r = 0.96, P = 0.01). Organoids from platinum-nonresponsive tumors had significantly higher RAD51 scores than those from platinum-responsive tumors (P \u3c 0.001). In a discovery cohort, RAD51-Low tumors were more likely to have a pathologic complete response (RR, 5.28; P \u3c 0.001) and to be platinum-sensitive (RR, ∞; P = 0.05). The RAD51 score was predictive of chemotherapy response score [AUC, 0.90; 95% confidence interval (CI), 0.78-1.0; P \u3c 0.001). A novel automatic quantification system accurately reflected the manual assay (92%). In a validation cohort, RAD51-Low tumors were more likely to be platinum-sensitive (RR, ∞; P \u3c 0.001) than RAD51-High tumors. Moreover, RAD51-Low status predicted platinum sensitivity with 100% positive predictive value and was associated with better progression-free (HR, 0.53; 95% CI, 0.33-0.85; P \u3c 0.001) and overall survival (HR, 0.43; 95% CI, 0.25-0.75; P = 0.003) than RAD51-High status. CONCLUSIONS: RAD51 foci are a robust marker of platinum chemotherapy response and survival in ovarian cancer. The utility of RAD51 foci as a predictive biomarker for HGSOC should be tested in clinical trials

Conservation set-asides improve carbon storage and support associated plant diversity in certified sustainable oil palm plantations

Maintaining forest conservation set-asides is a key criterion of sustainability certification of many crops that drive tropical deforestation, but their value for carbon storage and associated biodiversity is unclear. We conducted vegetation measurements to examine the benefits of set-asides for aboveground carbon stocks (AGC) in certified oil palm plantations on Borneo, and whether their AGC is positively associated with plant diversity. The mean estimated AGC of live trees and palms ≥10 cm diameter in set-asides in certified oil palm plantations (52.8 Mg ha−1) was >1.5-times that of oil palm (30.3 Mg ha−1), with some plots supporting similar AGC to primary forest. For lowland Borneo, we estimate that the average AGC of oil palm plantations with 10% coverage of set-asides is up to 20% greater than the average AGC of oil palm plantations without set-asides, newly demonstrating carbon storage as a benefit of conservation set-asides. We found positive relationships between AGC and plant diversity, highlighting the carbon–biodiversity co-benefits of set-asides. However, set-asides had a lower density of tree seedlings than continuous primary forest, indicating potential suppression of future tree regeneration and AGC. Our findings support the application of zero-deforestation during agricultural development, to conserve areas of remaining forest with high AGC and high biodiversity. We recommend management practices that boost regeneration in existing set-asides (e.g. enrichment planting), which would be most effective in larger set-asides, and could substantially increase the AGC of agricultural landscapes without removing land from production, and help conserve forest-dependent biodiversity