Imputation Server PGS: an automated approach to calculate polygenic risk scores on imputation servers.

Polygenic scores (PGS) enable the prediction of genetic predisposition for a wide range of traits and diseases by calculating the weighted sum of allele dosages for genetic variants associated with the trait or disease in question. Present approaches for calculating PGS from genotypes are often inefficient and labor-intensive, limiting transferability into clinical applications. Here, we present 'Imputation Server PGS', an extension of the Michigan Imputation Server designed to automate a standardized calculation of polygenic scores based on imputed genotypes.

The Type 2 Diabetes Knowledge Portal: An open access genetic resource dedicated to type 2 diabetes and related traits.

Associations between human genetic variation and clinical phenotypes have become a foundation of biomedical research. Most repositories of these data seek to be disease-agnostic and therefore lack disease-focused views. The Type 2 Diabetes Knowledge Portal (T2DKP) is a public resource of genetic datasets and genomic annotations dedicated to type 2 diabetes (T2D) and related traits.

FIVEx: an interactive eQTL browser across public datasets.

Summary: Expression quantitative trait loci (eQTLs) characterize the associations between genetic variation and gene expression to provide insights into tissue-specific gene regulation. Interactive visualization of tissue-specific eQTLs or splice QTLs (sQTLs) can facilitate our understanding of functional variants relevant to disease-related traits. However, combining the multi-dimensional nature of eQTLs/sQTLs into a concise and informative visualization is challenging.

A novel recognition site for polyubiquitin and ubiquitin-like signals in an unexpected region of proteasomal subunit Rpn1.

The ubiquitin (Ub)-proteasome system is the primary mechanism for maintaining protein homeostasis in eukaryotes, yet the underlying signaling events and specificities of its components are poorly understood. Proteins destined for degradation are tagged with covalently linked polymeric Ub chains and subsequently delivered to the proteasome, often with the assistance of shuttle proteins that contain Ub-like domains. This degradation pathway is riddled with apparent redundancy-in the form of numerous polyubiquitin chains of various lengths and distinct architectures, multiple shuttle proteins, and at least three proteasomal receptors.

LocusZoom.js: interactive and embeddable visualization of genetic association study results.

Summary: LocusZoom.js is a JavaScript library for creating interactive web-based visualizations of genetic association study results. It can display one or more traits in the context of relevant biological data (such as gene models and other genomic annotation), and allows interactive refinement of analysis models (by selecting linkage disequilibrium reference panels, identifying sets of likely causal variants, or comparisons to the GWAS catalog).

Polyubiquitin and ubiquitin-like signals share common recognition sites on proteasomal subunit Rpn1.

Proteasome-mediated substrate degradation is an essential process that relies on the coordinated actions of ubiquitin (Ub), shuttle proteins containing Ub-like (UBL) domains, and the proteasome. Proteinaceous substrates are tagged with polyUb and shuttle proteins, and these signals are then recognized by the proteasome, which subsequently degrades the substrate. To date, three proteasomal receptors have been identified, as well as multiple shuttle proteins and numerous types of polyUb chains that signal for degradation.

Branching via K11 and K48 Bestows Ubiquitin Chains with a Unique Interdomain Interface and Enhanced Affinity for Proteasomal Subunit Rpn1.

Post-translational substrate modification with ubiquitin is essential for eukaryotic cellular signaling. Polymeric ubiquitin chains are assembled with specific architectures, which convey distinct signaling outcomes depending on the linkages involved. Recently, branched K11/K48-linked polyubiquitins were shown to enhance proteasomal degradation during mitosis.

Genes for Good: Engaging the Public in Genetics Research via Social Media.

The Genes for Good study uses social media to engage a large, diverse participant pool in genetics research and education. Health history and daily tracking surveys are administered through a Facebook application, and participants who complete a minimum number of surveys are mailed a saliva sample kit ("spit kit") to collect DNA for genotyping. As of March 2019, we engaged >80,000 individuals, sent spit kits to >32,000 individuals who met minimum participation requirements, and collected >27,000 spit kits.

Probing the Binding Modes of a Multidomain Protein to Lipid-based Nanoparticles by Relaxation-based NMR.

The interactions of two model multidomain proteins-covalently linked diubiquitins, Ub-with lipid-based nanoparticles have been quantitatively probed by the measurements of NMR lifetime line broadening, ΔR. By combined analysis of ΔR profiles arising from interactions with liposomes of varying sizes, an approach recently developed for the characterization of interactions of monoubiquitin with liposomes, we determine how the parameters of exchange (liposome binding) and dynamics of each individual domain of Ub on the surface of liposomes change when the domains are covalently attached to one another by a flexible linker. Two different covalent linkages were used: K63-linked and K48-linked Ub.

Live-cell quantification and comparison of mammalian oocyte cytosolic lipid content between species, during development, and in relation to body composition using nonlinear vibrational microscopy.

Cytosolic lipids participate in the growth, development, and overall health of mammalian oocytes including many roles in cellular homeostasis. Significant emphasis has been placed on the study of lipids as a dynamic organelle, which in turn requires the development of tools and techniques to quantitate and compare how lipid content relates to cellular structure, function, and normalcy. Objectives of this study were to determine if nonlinear vibrational microscopy (e.

Hyperspectral imaging and characterization of live cells by broadband coherent anti-Stokes Raman scattering (CARS) microscopy with singular value decomposition (SVD) analysis.

Coherent anti-Stokes Raman scattering (CARS) microscopy can be used as a powerful imaging technique to identify chemical compositions of complex samples in biology, biophysics, medicine, and materials science. In this work we developed a CARS microscopic system capable of hyperspectral imaging. By employing an ultrafast laser source, a photonic crystal fiber, and a scanning laser microscope together with spectral detection by a highly sensitive back-illuminated cooled charge-coupled device (CCD) camera, we were able to rapidly acquire and process hyperspectral images of live cells with chemical selectivity.

Membrane orientation of Gα(i)β(1)γ(2) and Gβ(1)γ(2) determined via combined vibrational spectroscopic studies.

The manner in which the heterotrimeric G protein complexes Gβ1γ2 and Gαiβ1γ2 interact with membranes is likely related to their biological function. We combined complementary measurements from sum frequency generation (SFG) vibrational and attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy to determine the possible membrane orientations of Gβ1γ2 and the Gαiβ1γ2 heterotrimer more precisely than could be achieved using SFG alone. The most likely orientations of Gβ1γ2 and the Gαiβ1γ2 heterotrimer were both determined to fall within a similar narrow range of twist and tilt angles, suggesting that Gβ1γ2 may bind to Gαi without a significant change in orientation.

Observing a model ion channel gating action in model cell membranes in real time in situ: membrane potential change induced alamethicin orientation change.

Ion channels play crucial roles in transport and regulatory functions of living cells. Understanding the gating mechanisms of these channels is important to understanding and treating diseases that have been linked to ion channels. One potential model peptide for studying the mechanism of ion channel gating is alamethicin, which adopts a split α/3(10)-helix structure and responds to changes in electric potential.

Interfacial orientation and secondary structure change in tachyplesin I: molecular dynamics and sum frequency generation spectroscopy studies.

Recent advances in the collection and interpretation of surface-sensitive vibrational spectroscopic measurements have made it possible to study the orientation of peptides and proteins in situ in a biologically relevant environment. However, interpretation of sum frequency generation (SFG) and attenuated total reflectance Fourier transform infrared (ATR-FTIR) vibrational spectroscopy is hindered by the fact that orientation cannot be inferred without some prior knowledge of the protein structure. In this work, molecular dynamics simulations were used to study the interfacial orientation and structural deformation of the short β-sheet peptide tachyplesin I at the polystyrene/water interface.

Heterotrimeric G protein beta1gamma2 subunits change orientation upon complex formation with G protein-coupled receptor kinase 2 (GRK2) on a model membrane.

Few experimental techniques can assess the orientation of peripheral membrane proteins in their native environment. Sum Frequency Generation (SFG) vibrational spectroscopy was applied to study the formation of the complex between G protein-coupled receptor (GPCR) kinase 2 (GRK2) and heterotrimeric G protein β(1)γ(2) subunits (Gβγ) at a lipid bilayer, without any exogenous labels. The most likely membrane orientation of the GRK2-Gβγ complex differs from that predicted from the known protein crystal structure, and positions the predicted receptor docking site of GRK2 such that it would more optimally interact with GPCRs.

Surface orientation of magainin 2: molecular dynamics simulation and sum frequency generation vibrational spectroscopic studies.

We combined molecular dynamics based free energy calculations with sum frequency generation (SFG) spectroscopy to study the orientational distribution of solvated peptides near hydrophobic surfaces. Using a simplified atomistic model of the polystyrene (PS) surface, molecular dynamics simulations have been applied to compute the orientational probability of an α-helical peptide, magainin 2, with respect to the PS/water interface. Free energy calculations revealed that the preferred (horizontal) peptide orientation was driven by the favorable interactions between the hydrophobic PS surface and the hydrophobic residues on the helix, and additional simulations examined the importance of small aggregate formation.

Orientation difference of chemically immobilized and physically adsorbed biological molecules on polymers detected at the solid/liquid interfaces in situ.

A surface sensitive second order nonlinear optical technique, sum frequency generation vibrational spectroscopy, was applied to study peptide orientation on polymer surfaces, supplemented by a linear vibrational spectroscopy, attenuated total reflectance Fourier transform infrared spectroscopy. Using the antimicrobial peptide Cecropin P1 as a model system, we have quantitatively demonstrated that chemically immobilized peptides on polymers adopt a more ordered orientation than less tightly bound physically adsorbed peptides. These differences were also observed in different chemical environments, for example, air versus water.