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Item does not contain fulltext, A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.

Globally, treeline ecotones vary from abrupt lines to extended zones of increasingly small, stunted and/or dispersed trees. These spatial patterns contain information about the processes that control treeline dynamics. Describing these patterns consistently along ecologically meaningful dimensions is needed for generalizing hypotheses and knowledge about controlling processes and expected treeline shifts globally. However, existing spatial categorizations of treelines are very loosely defined, leading to ambiguities in their use and interpretation. To help better understand treeline‐forming processes, we present a new framework for describing alpine treeline ecotones, focusing on hillside‐scale patterns, using pattern dimensions with distinct indicative values: 1) the spatial pattern in the x‐y plane: a) decline in tree cover, and b) change in the level of clustering. Variation along these dimensions results in more or less ‘discrete' or ‘diffuse' treelines with or without islands. These patterns mainly indicate demographic processes: establishment and mortality. 2) Changes in tree stature: a) decline in tree height, and b) change in tree shape. Variation along these dimensions results in more or less ‘abrupt' or ‘gradual' treelines with or without the formation of environmental krummholz. These patterns mainly indicate growth and dieback processes. Additionally, tree population structure can help distinguish alternative hypotheses about pattern formation, while analysing the functional composition of the ecotonal vegetation is essential to understand community‐level processes, controlled by species‐specific demographic processes. Our graphical representation of this framework can be used to place any treeline pattern in the proposed multi‐dimensional space to guide hypotheses on underlying processes and associated dynamics. To quantify the dimensions and facilitate comparative research, we advocate a joint effort in gathering and analysing spatial patterns from tre

Climatic change is anticipated to alter disturbance regimes for many ecosystems. Among the most important effects are changes in the frequency, size, and intensity of wildfires. Serotiny (long-term canopy storage and the heat-induced release of seeds) is a fire-resilience mechanism found in many globally important terrestrial ecosystems. Life-history traits and physiographic differences in ecosystems lead to variation in serotiny; therefore, some systems may exhibit greater resilience to shifting disturbances than others do. We present a conceptual framework to explore the consequences of changing disturbance regimes (such as mean and variance in fire severity or return intervals) to serotinous species and ecosystems and implications of altered serotinous resilience at local and regional scales. Four case studies are presented, and areas needing further research are highlighted. These studies illustrate that, despite the reputed fire resilience of serotiny, more fire does not necessarily mean more serotinous species across all systems in which they occur.

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Instead of allowing the recovery of original passwords, forgotten passwords are often reset using online mechanisms such as password verification questions (PVQ methods) and password reset links in email. These mechanisms are generally weak, exploitable, and force users to choose new passwords. Emailing the original password exposes the password to third parties. To address these issues, and to allow forgotten passwords to be securely restored, we present a scheme called Mercury. Its primary mode employs user-level public keys and a personal mobile device (PMD) such as a smart-phone, netbook, or tablet. A user generates a key pair on her PMD; the private key remains on the PMD and the public key is shared with different sites (e.g., during account setup). For password recovery, the site sends the (public key)-encrypted password to the user's pre-registered email address, or displays the encrypted password on a webpage, e.g., as a barcode. The encrypted password is then decrypted using the PMD and revealed to the user. A prototype implementation of Mercury is available as an Android application.

Contains fulltext : 70782.pdf (publisher's version ) (Closed access), The Breast Cancer Resistance Protein (BCRP/ABCG2) is a transporter restricting absorption and enhancing excretion of many compounds including anticancer drugs. This transporter is highly expressed in many tissues; however, in human kidney, only the mRNA was found in contrast to the mouse kidney, where the transporter is abundant. In bcrp/abcg2((-/-)) mice, the expression of two sterol transporter genes, abcg5 and abcg8, was strongly increased in the kidney, perhaps as a compensatory mechanism to upregulate efflux. We found using immunohistochemical analysis clear localization of BCRP/ABCG2 to the proximal tubule brush border membrane of the human kidney comparable to that of other ABC transporters such as P-glycoprotein/ABCB1, MRP2/ABCC2, and MRP4/ABCC4. Hoechst 33342 dye efflux from primary human proximal tubule cells was significantly reduced by the BCRP/ABCG2 inhibitors fumitremorgin C and nelfinavir. Our study shows that in addition to other apical ABC transporters, BCRP/ABCG2 may be important in renal drug excretion.