Diverse response of shallow lake water levels to decadal weather patterns in a heterogeneous glacial Boreal Plains landscape

To examine the relative controls of landscape and climate on spatial variability, we measured water level dynamics of shallow lakes over two decades that represent both the heterogeneity of surficial geology classifications, and thus the potential range in surface and groundwater connectivity, and the long‐term weather patterns of the Boreal Plain hydrogeoclimatic setting. Large ranges in shallow lakes water levels (between 0.25 and 2 m) were observed corresponding to extremes in precipitation relative to the long‐term mean precipitation over the study period. We found low concurrence in water level dynamics among four detailed study lakes that received the same meteorological weather signal, but were located in different surficial geology texture classifications that incorporated important landscape parameters associated with lake water balance and storage. Surficial geology classification alone did not, however, distinguish between different ranges in lake water level measured in a broader synoptic survey of 26 lakes across the region. Thus, simple surficial geology classifications cannot alone be applied to classify Boreal Plain lake water level dynamics and other controls, notably landscape position, must also be considered. We further show that inter‐annual variability in lake water levels was significantly greater than seasonal variability in this hydrogeoclimatic setting. This emphasizes the need for studies of sufficient length to capture weather extremes that include periods of wetting and drying, and demonstrates how observed magnitudes of water level variability, and lake function, can be an artefact of study length and initiation date. These findings provide a foundation to test and calibrate conceptual understanding of the wider controls of lake water levels to form holistic frameworks to mitigate ecological and societal impacts due to hydrological changes under climate and anthropogenic disturbance within and between hydrogeoclimatic settings

Airline Disruption Recovery Using Symbiotic Simulation and Multi-fidelity Modelling

The airlines industry is prone to disruption due to various causes. Whilst an airline may not be able to control the causes of disruption, it can reduce the impact of a disruptive event, such as a mechanical failure, with its response by revising the schedule. Potential actions include swapping aircraft, delaying flights and cancellations. This paper will present our research into how symbiotic simulation could potentially be used to improve the response to a disruptive event by evaluating potential revised schedules. Due to the large solution space, exhaustive searches are infeasible. Our research is investigating the use of multi-fidelity models to help guide the search of the optimisation algorithm, leading to good solutions being generated within the time constraints of disruption management

Wheat Estimated Transcript Server (WhETS): a tool to provide best estimate of hexaploid wheat transcript sequence

Wheat biologists face particular problems because of the lack of genomic sequence and the three homoeologous genomes which give rise to three very similar forms for many transcripts. However, over 1.3 million available public-domain Triticeae ESTs (of which ∼850 000 are wheat) and the full rice genomic sequence can be used to estimate likely transcript sequences present in any wheat cDNA sample to which PCR primers may then be designed. Wheat Estimated Transcript Server (WhETS) is designed to do this in a convenient form, and to provide information on the number of matching EST and high quality cDNA (hq-cDNA) sequences, tissue distribution and likely intron position inferred from rice. Triticeae EST and hq-cDNA sequences are mapped onto rice loci and stored in a database. The user selects a rice locus (directly or via Arabidopsis) and the matching Triticeae sequences are assembled according to user-defined filter and stringency settings. Assembly is achieved initially with the CAP3 program and then with a single nucleotide polymorphism (SNP)-analysis algorithm designed to separate homoeologues. Alignment of the resulting contigs and singlets against the rice template sequence is then displayed. Sequences and assembly details are available for download in fasta and ace formats, respectively. WhETS is accessible at http://www4.rothamsted.bbsrc.ac.uk/whets

The Influence of Radiographic Phenotype and Smoking Status on Peripheral Blood Biomarker Patterns in Chronic Obstructive Pulmonary Disease

Background: Chronic obstructive pulmonary disease (COPD) is characterized by both airway remodeling and parenchymal destruction. The identification of unique biomarker patterns associated with airway dominant versus parenchymal dominant patterns would support the existence of unique phenotypes representing independent biologic processes. A cross-sectional study was performed to examine the association of serum biomarkers with radiographic airway and parenchymal phenotypes of COPD. Methodology/Principal Findings: Serum from 234 subjects enrolled in a CT screening cohort was analyzed for 33 cytokines and growth factors using a multiplex protein array. The association of serum markers with forced expiratory volume in one second percent predicted (FEV1%) and quantitative CT measurements of airway thickening and emphysema was assessed with and without stratification for current smoking status. Significant associations were found with several serum inflammatory proteins and measurements of FEV1%, airway thickening, and parenchymal emphysema independent of smoking status. The association of select analytes with airway thickening and emphysema was independent of FEV1%. Furthermore, the relationship between other inflammatory markers and measurements of physiologic obstruction or airway thickening was dependent on current smoking status. Conclusions/Significance: Airway and parenchymal phenotypes of COPD are associated with unique systemic serum biomarker profiles. Serum biomarker patterns may provide a more precise classification of the COPD syndrome, provide insights into disease pathogenesis and identify targets for novel patient-specific biological therapies. © 2009 Bon et al

A parton picture of de Sitter space during slow-roll inflation

It is well-known that expectation values in de Sitter space are afflicted by infra-red divergences. Long ago, Starobinsky proposed that infra-red effects in de Sitter space could be accommodated by evolving the long-wavelength part of the field according to the classical field equations plus a stochastic source term. I argue that--when quantum-mechanical loop corrections are taken into account--the separate-universe picture of superhorizon evolution in de Sitter space is equivalent, in a certain leading-logarithm approximation, to Starobinsky's stochastic approach. In particular, the time evolution of a box of de Sitter space can be understood in exact analogy with the DGLAP evolution of partons within a hadron, which describes a slow logarithmic evolution in the distribution of the hadron's constituent partons with the energy scale at which they are probed.Comment: 36 pages; uses iopart.cls and feynmp.sty. v2: Minor typos corrected. Matches version published in JCA

Human leukocyte antigen (HLA) class II peptide flanking residues tune the immunogenicity of a human tumor-derived epitope

CD4+ T-cells recognize peptide antigens, in the context of human leukocyte antigen (HLA) class II molecules (HLA-II), which through peptide-flanking residues (PFRs) can extend beyond the limits of the HLA binding. The role of the PFRs during antigen recognition is not fully understood; however, recent studies have indicated that these regions can influence T-cell receptor (TCR) affinity and pHLA-II stability. Here, using various biochemical approaches including peptide sensitivity ELISA and ELISpot assays, peptide-binding assays and HLA-II tetramer staining, we focused on CD4+ T-cell responses against a tumor antigen, 5T4 oncofetal trophoblast glycoprotein (5T4), which have been associated with improved control of colorectal cancer. Despite their weak TCR-binding affinity, we found that anti-5T4 CD4+ T-cells are polyfunctional and that their PFRs are essential for TCR recognition of the core bound nonamer. The high-resolution (1.95 Å) crystal structure of HLA-DR1 presenting the immunodominant 20-mer peptide 5T4111–130, combined with molecular dynamic simulations, revealed how PFRs explore the HLA-proximal space to contribute to antigen reactivity. These findings advance our understanding of what constitutes an HLA-II epitope and indicate that PFRs can tune weak affinity TCR–pHLA-II interactions

Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart Disease.

RATIONALE: Therapies that inhibit CETP (cholesteryl ester transfer protein) have failed to demonstrate a reduction in risk for coronary heart disease (CHD). Human DNA sequence variants that truncate the CETP gene may provide insight into the efficacy of CETP inhibition. OBJECTIVE: To test whether protein-truncating variants (PTVs) at the CETP gene were associated with plasma lipid levels and CHD. METHODS AND RESULTS: We sequenced the exons of the CETP gene in 58 469 participants from 12 case-control studies (18 817 CHD cases, 39 652 CHD-free controls). We defined PTV as those that lead to a premature stop, disrupt canonical splice sites, or lead to insertions/deletions that shift frame. We also genotyped 1 Japanese-specific PTV in 27561 participants from 3 case-control studies (14 286 CHD cases, 13 275 CHD-free controls). We tested association of CETP PTV carrier status with both plasma lipids and CHD. Among 58 469 participants with CETP gene-sequencing data available, average age was 51.5 years and 43% were women; 1 in 975 participants carried a PTV at the CETP gene. Compared with noncarriers, carriers of PTV at CETP had higher high-density lipoprotein cholesterol (effect size, 22.6 mg/dL; 95% confidence interval, 18-27; P<1.0×10-4), lower low-density lipoprotein cholesterol (-12.2 mg/dL; 95% confidence interval, -23 to -0.98; P=0.033), and lower triglycerides (-6.3%; 95% confidence interval, -12 to -0.22; P=0.043). CETP PTV carrier status was associated with reduced risk for CHD (summary odds ratio, 0.70; 95% confidence interval, 0.54-0.90; P=5.1×10-3). CONCLUSIONS: Compared with noncarriers, carriers of PTV at CETP displayed higher high-density lipoprotein cholesterol, lower low-density lipoprotein cholesterol, lower triglycerides, and lower risk for CHD

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)