Rapid simultaneous estimation of relaxation rates using multi-echo, multi-contrast MRI.

Purpose: Multi-echo, multi-contrast methods are increasingly used in dynamic imaging studies to simultaneously quantify R and R. To overcome the computational challenges associated with nonlinear least squares (NLSQ) fitting, we propose a generalized linear least squares (LLSQ) solution to rapidly fit R and R.

Methods: Spin- and gradient-echo (SAGE) data were simulated across T and T values at high (200) and low (20) SNR.

CryoFold: determining protein structures and data-guided ensembles from cryo-EM density maps.

Cryo-electron microscopy (EM) requires molecular modeling to refine structural details from data. Ensemble models arrive at low free-energy molecular structures, but are computationally expensive and limited to resolving only small proteins that cannot be resolved by cryo-EM. Here, we introduce CryoFold - a pipeline of molecular dynamics simulations that determines ensembles of protein structures directly from sequence by integrating density data of varying sparsity at 3-5 Å resolution with coarse-grained topological knowledge of the protein folds.

Rapid parameter estimation for selective inversion recovery myelin imaging using an open-source Julia toolkit.

Background: Magnetic resonance imaging (MRI) is used extensively to quantify myelin content, however computational bottlenecks remain challenging for advanced imaging techniques in clinical settings. We present a fast, open-source toolkit for processing quantitative magnetization transfer derived from selective inversion recovery (SIR) acquisitions that allows parameter map estimation, including the myelin-sensitive macromolecular pool size ratio (). Significant progress has been made in reducing SIR acquisition times to improve clinically feasibility.

Sex Differences in Alzheimer's Disease Revealed by Free-Water Diffusion Tensor Imaging and Voxel-Based Morphometry.

Background: Imaging biomarkers are increasingly used in Alzheimer's disease (AD), and the identification of sex differences using neuroimaging may provide insight into disease heterogeneity, progression, and therapeutic targets.

Objective: The purpose of this study was to investigate differences in grey matter (GM) volume and white matter (WM) microstructural disorganization between males and females with AD using voxel-based morphometry (VBM) and free-water-corrected diffusion tensor imaging (FW-DTI).

Methods: Data were downloaded from the OASIS-3 database, including 158 healthy control (HC; 86 females) and 46 mild AD subjects (24 females).

Investigating the relationship between multi-scale perfusion and white matter microstructural integrity in patients with relapsing-remitting MS.

Background: Multiple sclerosis is characterized by the formation of central nervous system demyelinating lesions with microvasculature inflammation.

Objective: Evaluate how lesion cerebral perfusion relates to white matter microstructural integrity in patients with RRMS using perfusion MRI and myelin-related T-weighted to T-weighted (Tw/Tw) ratios.

Methods: Forty-eight patients with RRMS were imaged with dynamic susceptibility contrast imaging using SAGE (spin- and gradient-echo) to calculate global and capillary-sized perfusion parameters, including cerebral blood flow (CBF), volume (CBV), and mean transit time (MTT).

Evidence that the TRPV1 S1-S4 membrane domain contributes to thermosensing.

Sensing and responding to temperature is crucial in biology. The TRPV1 ion channel is a well-studied heat-sensing receptor that is also activated by vanilloid compounds, including capsaicin. Despite significant interest, the molecular underpinnings of thermosensing have remained elusive.

PIRT the TRP Channel Regulating Protein Binds Calmodulin and Cholesterol-Like Ligands.

Transient receptor potential (TRP) ion channels are polymodal receptors that have been implicated in a variety of pathophysiologies, including pain, obesity, and cancer. The capsaicin and heat sensor TRPV1, and the menthol and cold sensor TRPM8, have been shown to be modulated by the membrane protein PIRT (Phosphoinositide-interacting regulator of TRP). The emerging mechanism of PIRT-dependent TRPM8 regulation involves a competitive interaction between PIRT and TRPM8 for the activating phosphatidylinositol 4,5-bisphosphate (PIP) lipid.

Competitive Interactions between PIRT, the Cold Sensing Ion Channel TRPM8, and PIP Suggest a Mechanism for Regulation.

TRPM8 is a member of the transient receptor potential ion channel family where it functions as a cold and pain sensor in humans and other higher organisms. Previous studies show that TRPM8 requires the signaling phosphoinositide lipid PIP to function. TRPM8 function is further regulated by other diverse mechanisms, including the small modulatory membrane protein PIRT (phosphoinositide regulator of TRP).

Phosphoinositide-interacting regulator of TRP (PIRT) has opposing effects on human and mouse TRPM8 ion channels.

Transient receptor potential melastatin 8 (TRPM8) is a cold-sensitive ion channel with diverse physiological roles. TRPM8 activity is modulated by many mechanisms, including an interaction with the small membrane protein phosphoinositide-interacting regulator of TRP (PIRT). Here, using comparative electrophysiology experiments, we identified species-dependent differences between the human and mouse TRPM8-PIRT complexes.

Structural basis for KCNE3 modulation of potassium recycling in epithelia.

The single-span membrane protein KCNE3 modulates a variety of voltage-gated ion channels in diverse biological contexts. In epithelial cells, KCNE3 regulates the function of the KCNQ1 potassium ion (K(+)) channel to enable K(+) recycling coupled to transepithelial chloride ion (Cl(-)) secretion, a physiologically critical cellular transport process in various organs and whose malfunction causes diseases, such as cystic fibrosis (CF), cholera, and pulmonary edema. Structural, computational, biochemical, and electrophysiological studies lead to an atomically explicit integrative structural model of the KCNE3-KCNQ1 complex that explains how KCNE3 induces the constitutive activation of KCNQ1 channel activity, a crucial component in K(+) recycling.

Structural Insights into Conformation Differences between DNA/TNA and RNA/TNA Chimeric Duplexes.

Threose nucleic acid (TNA) is an artificial genetic polymer capable of heredity and evolution, and is studied in the context of RNA chemical etiology. It has a four-carbon threose backbone in place of the five-carbon ribose of natural nucleic acids, yet forms stable antiparallel complementary Watson-Crick homoduplexes and heteroduplexes with DNA and RNA. TNA base-pairs more favorably with RNA than with DNA but the reason is unknown.

Implications of Human Transient Receptor Potential Melastatin 8 (TRPM8) Channel Gating from Menthol Binding Studies of the Sensing Domain.

The transient receptor potential melastatin 8 (TRPM8) ion channel is the primary cold sensor in humans. TRPM8 is gated by physiologically relevant cold temperatures and chemical ligands that induce cold sensations, such as the analgesic compound menthol. Characterization of TRPM8 ligand-gated channel activation will lead to a better understanding of the fundamental mechanisms that underlie TRPM8 function.

Statistical removal of background signals from high-throughput (1)H NMR line-broadening ligand-affinity screens.

NMR ligand-affinity screens are vital to drug discovery, are routinely used to screen fragment-based libraries, and used to verify chemical leads from high-throughput assays and virtual screens. NMR ligand-affinity screens are also a highly informative first step towards identifying functional epitopes of unknown proteins, as well as elucidating the biochemical functions of protein-ligand interaction at their binding interfaces. While simple one-dimensional (1)H NMR experiments are capable of indicating binding through a change in ligand line shape, they are plagued by broad, ill-defined background signals from protein (1)H resonances.

NMR Structure of Francisella tularensis Virulence Determinant Reveals Structural Homology to Bet v1 Allergen Proteins.

Tularemia is a potentially fatal bacterial infection caused by Francisella tularensis, and is endemic to North America and many parts of northern Europe and Asia. The outer membrane lipoprotein, Flpp3, has been identified as a virulence determinant as well as a potential subunit template for vaccine development. Here we present the first structure for the soluble domain of Flpp3 from the highly infectious Type A SCHU S4 strain, derived through high-resolution solution nuclear magnetic resonance (NMR) spectroscopy; the first structure of a lipoprotein from the genus Francisella.