Impact of Genetic Background on Allele Selection in a Highly Mutable Candida albicans Gene, PNG2

In many microbes rapid mutation of highly mutable contingency genes continually replenishes a pool of variant alleles from which the most suitable are selected, assisting in rapid adaptation and evasion of the immune response. In some contingency genes mutability is achieved through DNA repeats within the coding region. The fungal human pathogen Candida albicans has 2600 repeat-containing ORFs. For those investigated (ALS genes, HYR1, HYR2, CEK1, RLM1) many protein variants with differing amino acid repeat regions exist, as expected for contingency genes. However, specific alleles dominate in different clades, which is unexpected if allele variation is used for short-term adaptation. Generation of new alleles of repeat-containing C. albicans ORFs has never been observed directly. Here we present evidence for restrictions on the emergence of new alleles in a highly mutable C. albicans repeat-containing ORF, PNG2, encoding a putative secreted or cell surface glycoamidase. In laboratory cultures new PNG2 alleles arose at a rate of 2.8×10−5 (confidence interval 3.3×10−6−9. 9×10−5) per cell per division, comparable to rates measured for contingency genes. Among 80 clinical isolates 17 alleles of different length and 23 allele combinations were distinguishable; sequence differences between repeat regions of identical size suggest the existence of 36 protein variants. Specific allele combinations predominated in different genetic backgrounds, as defined by DNA fingerprinting and multilocus sequence typing. Given the PNG2 mutation rate, this is unexpected, unless in different genetic backgrounds selection favors different alleles. Specific alleles or allele combinations were not preferentially associated with C. albicans isolates from particular body sites or geographical regions. Our results suggest that the mutability of PNG2 is not used for short-term adaptation or evasion of the immune system. Nevertheless the large number of alleles observed indicates that mutability of PNG2 may assist C. albicans strains from different genetic backgrounds optimize their interaction with the host in the long term

Increasing Resiliency to Natural Hazards—A Strategic Plan for the Multi-Hazards Demonstration Project in Southern California

The U.S. Geological Survey (USGS) is initiating a new project designed to improve resiliency to natural hazards in southern California through the application of science to community decision making and emergency response. The Multi-Hazards Demonstration Project will assist the region’s communities to reduce their risk from natural hazards by directing new and existing research towards the community’s needs, improving monitoring technology, producing innovative products, and improving dissemination of the results. The natural hazards to be investigated in this project include coastal erosion, earthquakes, floods, landslides, tsunamis, and wildfires. Americans are more at risk from natural hazards now than at any other time in our Nation’s history. Southern California, in particular, has one of the Nation’s highest potentials for extreme catastrophic losses due to natural hazards, with estimates of expected losses exceeding $3 billion per year. These losses can only be reduced through the decisions of the southern California community itself. To be effective, these decisions must be guided by the best information about hazards, risk, and the cost-effectiveness of mitigation technologies. The USGS will work with collaborators to set the direction of the research and to create multi-hazard risk frameworks where communities can apply the results of scientific research to their decision-making processes. Partners include state, county, city, and public-lands government agencies, public and private utilities, companies with a significant impact and presence in southern California, academic researchers, the Federal Emergency Management Agency (FEMA), National Oceanic and Atmospheric Administration (NOAA), and local emergency response agencies. Prior to the writing of this strategic plan document, three strategic planning workshops were held in February and March 2006 at the USGS office in Pasadena to explore potential relationships. The goal of these planning sessions was to determine the external organizations’ needs for mitigation efforts before potential natural hazard events, and response efforts during and after the event. On the basis of input from workshop participants, four priority areas were identified for future research to address. They are (1) helping decision makers design planning scenarios, (2) improving upon the mapping of multiple hazards in urban areas, (3) providing real-time information from monitoring networks, and (4) integrating information in a risk and decision-making analysis. Towards this end, short-term and out-year goals have been outlined with the priorities in mind. First-year goals are (1) to engage the user community to establish the structures and processes for communications and interactions, (2) to develop a program to create scenarios of anticipated disasters, beginning in the first year with a scenario of a southern San Andreas earthquake that triggers secondary hazards, (3) to compile existing datasets of geospatial data, and (4) to target research efforts to support more complete and robust products in future years. Both the first-year and out-year goals have been formulated around a working-group structure that builds on existing research strengths within the USGS. The project is intended to demonstrate how developments in methodology and products can lead to improvement in our management of natural hazards in an urban environment for application across the Nation

Bioavailability of Microplastics to Marine Zooplankton: Effect of Shape and Infochemicals

The underlying mechanisms that influence microplastic ingestion in marine zooplankton remain poorly understood. Here, we investigate how microplastics of a variety of shapes (bead, fiber, and fragment), in combination with the algal-derived infochemicals dimethyl sulfide (DMS) and dimethylsulfoniopropionate (DMSP), affect the ingestion rate of microplastics in three species of zooplankton, the copepods Calanus helgolandicus and Acartia tonsa and larvae of the European lobster Homarus gammarus. We show that shape affects microplastic bioavailability to different species of zooplankton, with each species ingesting significantly more of a certain shape: C. helgolandicus—fragments (P < 0.05); A. tonsa—fibers (P < 0.01); H. gammarus larvae—beads (P < 0.05). Thus, different feeding strategies between species may affect shape selectivity. Our results also showed significantly increased ingestion rates by C. helgolandicus on all microplastics that were infused with DMS (P < 0.01) and by H. gammarus larvae and A. tonsa on DMS-infused fibers and fragments (P < 0.05). By using a range of more environmentally relevant microplastics, our findings highlight how the feeding strategies of different zooplankton species may influence their susceptibility to microplastic ingestion. Furthermore, our novel study suggests that species reliant on chemosensory cues to locate their prey may be at an increased risk of ingesting aged microplastics in the marine environment

The Influence of Body Mass Index on Clinical Interpretation of Established and Novel Biomarkers in Acute Heart Failure

Background: Body mass index (BMI) is a known confounder for natriuretic peptides, but its influence on other biomarkers is less well described. We investigated whether BMI interacts with biomarkers’ association with prognosis in patients with acute heart failure (AHF).Methods and Results: B-type natriuretic peptide (BNP), high-sensitivity cardiac troponin I (hs-cTnI), galectin-3, serum neutrophil gelatinase-associated lipocalin (sNGAL), and urine NGAL were measured serially in patients with AHF during hospitalization in the AKINESIS (Acute Kidney Injury Neutrophil gelatinase-associated lipocalin Evaluation of Symptomatic Heart Failure) study. Cox regression analysis was used to determine the association of biomarkers and their interaction with BMI for 30-day, 90-day and 1-year composite outcomes of death or HF readmission. Among 866 patients, 21.2%, 29.7% and 46.8% had normal (18.5–24.9 kg/m2), overweight (25–29.9 kg/m2) or obese (≥ 30 kg/m2) BMIs on admission, respectively. Admission values of BNP and hs-cTnI were negatively associated with BMI, whereas galectin-3 and sNGAL were positively associated with BMI. Admission BNP and hs-cTnI levels were associated with the composite outcome within 30 days, 90 days and 1 year. Only BNP had a significant interaction with BMI. When BNP was analyzed by BMI category, its association with the composite outcome attenuated at higher BMIs and was no longer significant in obese individuals. Findings were similar when evaluated by the last-measured biomarkers and BMIs.Conclusions: In patients with AHF, only BNP had a significant interaction with BMI for the outcomes, with its association attenuating as BMI increased; hs-cTnI was prognostic, regardless of BMI.</p

Genetic regulatory signatures underlying islet gene expression and type 2 diabetes

The majority of genetic variants associated with type 2 diabetes (T2D) are located outside of genes in noncoding regions that may regulate gene expression in disease-relevant tissues, like pancreatic islets. Here, we present the largest integrated analysis to date of high-resolution, high-throughput human islet molecular profiling data to characterize the genome (DNA), epigenome (DNA packaging), and transcriptome (gene expression). We find that T2D genetic variants are enriched in regions of the genome where transcription Regulatory Factor X (RFX) is predicted to bind in an islet-specific manner. Genetic variants that increase T2D risk are predicted to disrupt RFX binding, providing a molecular mechanism to explain how the genome can influence the epigenome, modulating gene expression and ultimately T2D risk

Short-term prognostic implications of serum and urine neutrophil gelatinase-associated lipocalin in acute heart failure:findings from the AKINESIS study

AIMS: Kidney impairment has been associated with worse outcomes in acute heart failure (AHF), although recent studies challenge this association. Neutrophil gelatinase-associated lipocalin (NGAL) is a novel biomarker of kidney tubular injury. Its prognostic role in AHF has not been evaluated in large cohorts. The present study aimed to determine if serum NGAL (sNGAL) or urine NGAL (uNGAL) is superior to creatinine for predicting short-term outcomes in AHF. METHODS AND RESULTS: The study was conducted in an international, multicentre, prospective cohort consisting of 927 patients with AHF. Admission and peak values of sNGAL, uNGAL and uNGAL/urine creatinine (uCr) ratio were compared to admission and peak serum creatinine (sCr). The composite endpoints were death, initiation of renal replacement therapy, heart failure (HF) readmission and any emergent HF-related outpatient visit within 30 and 60 days, respectively. The mean age of the cohort was 69 years and 62% were male. The median length of stay was 6 days. The composite endpoint occurred in 106 patients and 154 patients within 30 and 60 days, respectively. Serum NGAL was more predictive than uNGAL and the uNGAL/uCr ratio but was not superior to sCr (area under the curve [AUC]; admission sNGAL 0.61 [95% confidence interval (CI) 0.55-0.67] and 0.59 [95% CI 0.54-0.65], peak sNGAL 0.60 [95% CI 0.54-0.66] and 0.57 [95% CI 0.52-0.63], admission sCr 0.60 [95% CI 0.54-0.64] and 0.59 [95% CI 0.53-0.64] [area under the curve: admission sNGAL 0.61, 95% confidence interval (CI) 0.55-0.67, and 0.59, 95% CI 0.54-0.65; peak sNGAL: 0.60, 95% CI 0.54-0.66, and 0.57, 95% CI 0.52-0.63; admission sCr: 0.60, 95% CI 0.54-0.64, and 0.59, 95% CI 0.53-0.64, at 30 and 60 days, respectively], peak sCr 0.61 [95% CI 0.55-0.67] and 0.59 [95% CI 0.54-0.64] at 30 and 60 days, respectively). NGAL was not predictive of the composite endpoint in multivariate analysis. CONCLUSIONS: Serum NGAL outperformed uNGAL but neither was superior to admission or peak sCr for predicting adverse events

Potential Utility of Cardiorenal Biomarkers for Prediction and Prognostication of Worsening Renal Function in Acute Heart Failure

Background: Multiple different pathophysiologic processes can contribute to worsening renal function (WRF) in acute heart failure. Methods and Results: We retrospectively analyzed 787 patients with acute heart failure for the relationship between changes in serum creatinine and biomarkers including brain natriuretic peptide, high sensitivity cardiac troponin I, galectin 3, serum neutrophil gelatinase-associated lipocalin, and urine neutrophil gelatinase-associated lipocalin. WRF was defined as an increase of greater than or equal to 0.3 mg/dL or 50% in creatinine within first 5 days of hospitalization. WRF was observed in 25% of patients. Changes in biomarkers and creatinine were poorly correlated (r < 0.21) and no biomarker predicted WRF better than creatinine. In the multivariable Cox analysis, brain natriuretic peptide and high sensitivity cardiac troponin I, but not WRF, were significantly associated with the 1-year composite of death or heart failure hospitali-zation. WRF with an increasing urine neutrophil gelatinase-associated lipocalin predicted an increased risk of heart failure hospitalization. Conclusions: Biomarkers were not able to predict WRF better than creatinine. The 1-year outcomes were associated with biomarkers of cardiac stress and injury but not with WRF, whereas a kidney injury bio-marker may prognosticate WRF for heart failure hospitalization