Quantifying Missing Heritability at Known GWAS Loci

Recent work has shown that much of the missing heritability of complex traits can be resolved by estimates of heritability explained by all genotyped SNPs. However, it is currently unknown how much heritability is missing due to poor tagging or additional causal variants at known GWAS loci. Here, we use variance components to quantify the heritability explained by all SNPs at known GWAS loci in nine diseases from WTCCC1 and WTCCC2. After accounting for expectation, we observed all SNPs at known GWAS loci to explain more heritability than GWAS-associated SNPs on average (). For some diseases, this increase was individually significant: for Multiple Sclerosis (MS) () and for Crohn''s Disease (CD) (); all analyses of autoimmune diseases excluded the well-studied MHC region. Additionally, we found that GWAS loci from other related traits also explained significant heritability. The union of all autoimmune disease loci explained more MS heritability than known MS SNPs () and more CD heritability than known CD SNPs (), with an analogous increase for all autoimmune diseases analyzed. We also observed significant increases in an analysis of Rheumatoid Arthritis (RA) samples typed on ImmunoChip, with more heritability from all SNPs at GWAS loci () and more heritability from all autoimmune disease loci () compared to known RA SNPs (including those identified in this cohort). Our methods adjust for LD between SNPs, which can bias standard estimates of heritability from SNPs even if all causal variants are typed. By comparing adjusted estimates, we hypothesize that the genome-wide distribution of causal variants is enriched for low-frequency alleles, but that causal variants at known GWAS loci are skewed towards common alleles. These findings have important ramifications for fine-mapping study design and our understanding of complex disease architecture.     

Drought effects on resource partition and conservation among leaf ontogenetic stages in epiphytic tank bromeliads

Studying the response to drought stress of keystone epiphytes such as tank bromeliads is essential to better understand their resistance capacity to future climate change. The objective was to test whether there is any variation in the carbon, water and nutrient status among different leaf ontogenetic stages in a bromeliad rosette subjected to a gradient of drought stress. We used a semi-controlled experiment consisting in a gradient of water shortage in Aechmea aquilega and Lutheria splendens. For each bromeliad and drought treatment, three leaves were collected based on their position in the rosette and several functional traits related to water and nutrient status, and carbon metabolism were measured. We found that water status traits (relative water content, leaf succulence, osmotic and midday water potentials) and carbon metabolism traits (carbon assimilation, maximum quantum yield of photosystem II, chlorophyll and starch contents) decreased with increasing drought stress, while leaf soluble sugars and carbon, nitrogen and phosphorus contents remained unchanged. The different leaf ontogenetic stages showed only marginal variations when subjected to a gradient of drought. Resources were not reallocated between different leaf ontogenetic stages but we found a reallocation of soluble sugars from leaf starch reserves to the root system. Both species were capable of metabolic and physiological adjustments in response to drought. Overall, this study advances our understanding of the resistance of bromeliads faced with increasing drought stress and paves the way for in-depth reflection on their strategies to cope with water shortage.     

The tyrosine‐sulfated peptide receptors PSKR1 and PSY1R modify the immunity of Arabidopsis to biotrophic and necrotrophic pathogens in an antagonistic manner

The tyrosine‐sulfated peptides PSKα and PSY1 bind to specific leucine‐rich repeat surface receptor kinases and control cell proliferation in plants. In a reverse genetic screen, we identified the phytosulfokine (PSK) receptor PSKR1 as an important component of plant defense. Multiple independent loss‐of‐function mutants in PSKR1 are more resistant to biotrophic bacteria, show enhanced pathogen‐associated molecular pattern responses and less lesion formation after infection with the bacterial pathogen Pseudomonas syringae pv. tomato DC3000. By contrast, pskr1 mutants are more susceptible to necrotrophic fungal infection with Alternaria brassicicola, show more lesion formation and fungal growth which is not observed on wild‐type plants. The antagonistic effect on biotrophic and necrotrophic pathogen resistance is reflected by enhanced salicylate and reduced jasmonate responses in the mutants, suggesting that PSKR1 suppresses salicylate‐dependent defense responses. Detailed analysis of single and multiple mutations in the three paralogous genes PSKR1, ‐2 and PSY1‐receptor (PSY1R) determined that PSKR1 and PSY1R, but not PSKR2, have a partially redundant effect on plant immunity. In animals and plants, peptide sulfation is catalyzed by a tyrosylprotein sulfotransferase (TPST). Mutants lacking TPST show increased resistance to bacterial infection and increased susceptibility to fungal infection, mimicking the triple receptor mutant phenotypes. Feeding experiments with PSKα in tpst‐1 mutants partially restore the defense‐related phenotypes, indicating that perception of the PSKα peptide has a direct effect on plant defense. These results suggest that the PSKR subfamily integrates growth‐promoting and defense signals mediated by sulfated peptides and modulates cellular plasticity to allow flexible adjustment to environmental changes.     

Alirocumab,a Therapeutic Human Antibody to PCSK9, Does Not Affect CD81 Levels or Hepatitis C Virus Entry and Replication into Hepatocytes

BackgroundProprotein convertase subtilisin/kexin type 9 (PSCK9) is secreted mainly from the liver and binds to the low-density lipoprotein receptor (LDLR), reducing LDLR availability and thus resulting in an increase in LDL-cholesterol. While the LDLR has been implicated in the cell entry process of the hepatitis C virus (HCV), overexpression of an artificial non-secreted, cell membrane-bound form of PCSK9 has also been shown to reduce surface expression of CD81, a major component of the HCV entry complex, leading to concerns that pharmacological inhibition of PCSK9 may increase susceptibility to HCV infection by increasing either CD81 or LDLR availability. Here, we evaluated effects of PCSK9 and PCSK9 blockade on CD81 levels and HCV entry with a physiologically relevant model using native secreted PCSK9 and a monoclonal antibody to PCSK9, alirocumab.ConclusionThese results suggest that inhibition of PCSK9 with alirocumab has no effect on CD81 and does not result in increased susceptibility to HCV entry.     

通往风景园林行业的BIM之路——数字化竖向设计教育

随着全球建造业向数字化全面转型,建筑信息模型（BIM)的教学将是未来几年风景园林设计与实施的重要主题。介绍了风景园林专业BIM的教学方法和数字化竖向设计及其应用在BIM场地设计项目中的重要性。数字化竖向设计是实现BIM的途径。风景园林教育必须在其教学中讲解BIM建模方法和过程。     

Spatially balanced sampling and ground‐level imagery for vegetation monitoring on reclaimed well pads

Land reclamation associated with natural gas development has become increasingly important to mitigate land surface disturbance in western North America. Since well pads occur on sites with multiple land use and ownership, the progress and outcomes of these efforts are of interest to multiple stakeholders including industry, practitioners and consultants, regulatory agents, private landowners, and the scientific community. Reclamation success criteria often vary within, and among, government agencies and across land ownership type. Typically, reclamation success of a well pad is judged by comparing vegetation cover from a single transect on the pad to a single transect in an adjacent reference site and data are collected by a large number of technicians with various field monitoring skills. We utilized “SamplePoint” image analysis software and a spatially balanced sampling design, called balanced acceptance sampling, to demonstrate how spatially explicit quantitative data can be used to determine if sites are meeting various reclamation success criteria and used chi‐square tests to show how sites in vegetation percent cover differ from a statistical standpoint. This method collects field data faster than traditional methods. We demonstrate how quantitative and spatially explicit data can be utilized by multiple stakeholders, how it can improve upon current reference site selection, how it can satisfy reclamation monitoring requirements for multiple regulatory agencies, how it may help improve future seed mix selection, and discuss how it may reduce costs for operations responsible for reclamation and how it may reduce observer bias.