Correction of MR image distortions induced by metallic objects using a 3D cubic B-Spline basis set: Application to stereotactic surgical planning. Magn Reson Med

Metallic implants in MRI cause spin-echo (SE) images to be distorted in the slice and frequency-encoding directions. Chang and Fitzpatrick (IEEE Trans Med Imaging 1992;11:319 -329) proposed a distortion correction method (termed the CF method) based on the magnitude images from two SE acquisitions that differ only in the polarity of the frequency-encoding and sliceselection gradients. In the present study we solved some problems with the CF method, primarily by modeling the field inhomogeneities as a single 3D displacement field built by 3D cubic B-splines. The 3D displacement field was applied in the actual distortion direction in the slice/frequency-encoding plane. To account for patient head motion, a 3D rigid body motion correction was also incorporated in the model. Experiments on a phantom containing an aneurysm clip showed that the knot spacing between the B-splines is a very important factor in both the final image quality and the processing speed. Depending on the knot spacing and the image volume size, the number of unknowns range from a few thousands to over 100,000, leading to processing times ranging from minutes to days. Optimal knot spacing, a means of increasing the processing speed, and other parameters are investigated and discussed. Magn Reson Med 54:169 -181, 2005

Random noise in Diffusion Tensor Imaging, its Destructive Impact and Some Corrections

The empirical origin of random noise is described, its influence on DTI variables is illustrated by a review of numerical and in vivo studies supplemented by new simulations investigating high noise levels. A stochastic model of noise propagation is presented to structure noise impact in DTI. Finally, basics of voxelwise and spatial denoising procedures are presented. Recent denoising procedures are reviewed and consequences of the stochastic model for convenient denoising strategies are discussed

Structural determination of the complement inhibitory domain of Borrelia burgdorferi BBK32 provides insight into classical pathway complement evasion by Lyme disease spirochetes

The carboxy-terminal domain of the BBK32 protein from Borrelia burgdorferi sensu stricto, termed BBK32-C, binds and inhibits the initiating serine protease of the human classical complement pathway, C1r. In this study we investigated the function of BBK32 orthologues of the Lyme-associated Borrelia burgdorferi sensu lato complex, designated BAD16 from B. afzelii strain PGau and BGD19 from B. garinii strain IP90. Our data show that B. afzelii BAD16-C exhibits BBK32-C-like activities in all assays tested, including high-affinity binding to purified C1r protease and C1 complex, and potent inhibition of the classical complement pathway. Recombinant B. garinii BGD19-C also bound C1 and C1r with high-affinity yet exhibited significantly reduced in vitro complement inhibitory activities relative to BBK32-C or BAD16-C. Interestingly, natively produced BGD19 weakly recognized C1r relative to BBK32 and BAD16 and, unlike these proteins, BGD19 did not confer significant protection from serum killing. Site-directed mutagenesis was performed to convert BBK32-C to resemble BGD19-C at three residue positions that are identical between BBK32 and BAD16 but different in BGD19. The resulting chimeric protein was designated BXK32-C and this BBK32-C variant mimicked the properties observed for BGD19-C. To query the disparate complement inhibitory activities of BBK32 orthologues, the crystal structure of BBK32-C was solved to 1.7Ã… limiting resolution. BBK32-C adopts an anti-parallel four-helix bundle fold with a fifth alpha-helix protruding from the helical core. The structure revealed that the three residues targeted in the BXK32-C chimera are surface-exposed, further supporting their potential relevance in C1r binding and inhibition. Additional binding assays showed that BBK32-C only recognized C1r fragments containing the serine protease domain. The structure-function studies reported here improve our understanding of how BBK32 recognizes and inhibits C1r and provide new insight into complement evasion mechanisms of Lyme-associated spirochetes of the B. burgdorferi sensu lato complex

Novel Phr1 mutations and the evolution of phenol reaction variation

Summary • Red rice, a major agricultural weed, is phenotypically diverse and possesses traits that are similar to both wild and cultivated rice. The genetic resources available for rice make it possible to examine the molecular basis and evolution of traits characterizing this weed. Here, we assess the phenol reaction -a classical trait for distinguishing among cultivated rice varieties -in red rice at the phenotypic and molecular levels. • We phenotyped more than 100 US weed samples for the phenol reaction and sequenced the underlying Phr1 locus in a subset of samples. Data were analyzed in combination with previously published Phr1 data for cultivated rice. • Most weed accessions (96.3%) are positive for the phenol reaction, and samples with a negative response carry loss-of-function alleles that are rare or heretofore undocumented. One such allele may have evolved through mutational convergence of a 1-bp frameshift insertion. Haplotype sharing between red rice and US cultivars suggests occasional crop-weed hybridization. • Our discovery of previously undocumented nonfunctional phr1 alleles suggests that there are likely to be other loss-of-function mutations segregating in Oryza sativa around the world. Red rice may provide a useful study system for understanding the adaptive significance of Phr1 variation in agricultural settings

Clinical Application of Readout-Segmented؊ Echo-Planar Imaging for Diffusion-Weighted Imaging in Pediatric Brain

BACKGROUND AND PURPOSE: RS-EPI has been suggested as an alternative approach to EPI for high-resolution DWI with reduced distortions. To determine whether RS-EPI is a useful approach for routine clinical use, we implemented GRAPPA-accelerated RS-EPI DWI at our pediatric hospital and graded the images alongside standard accelerated (ASSET) EPI DWI used routinely for clinical studies

A Structural Basis for Inhibition of the Complement Initiator Protease C1r by Lyme Disease Spirochetes

Complement evasion is a hallmark of extracellular microbial pathogens such as Borreliella burgdorferi, the causative agent of Lyme disease. Lyme disease spirochetes express nearly a dozen outer surface lipoproteins that bind complement components and interfere with their native activities. Among these, BBK32 is unique in its selective inhibition of the classical pathway. BBK32 blocks activation of this pathway by selectively binding and inhibiting the C1r serine protease of the first component of complement, C1. To understand the structural basis for BBK32-mediated C1r inhibition, we performed crystallography and size exclusion chromatography-coupled small angle x-ray scattering experiments, which revealed a molecular model of BBK32-C in complex with activated human C1r. Structure-guided site-directed mutagenesis was combined with surface plasmon resonance binding experiments and assays of complement function to validate the predicted molecular interface. Analysis of the structures shows that BBK32 inhibits activated forms of C1r by occluding substrate interaction subsites (i.e., S1 and S1’) and reveals a surprising role for the C1r B loop for full inhibitory activity of BBK32. The studies reported here provide a structural basis for classical pathway-specific inhibition by a human pathogen

The Borrelia afzelii outer membrane protein BAPKO_0422 binds human Factor-H and is predicted to form a membrane-spanning beta-barrel

The deep evolutionary history of the Spirochetes places their branch point early in the evolution of the diderms, before the divergence of the present day Proteobacteria. As a Spirochete, the morphology of the Borrelia cell envelope shares characteristics of both Gram-positive and Gram-negative bacteria. A thin layer of peptidoglycan, tightly associated with the cytoplasmic membrane is surrounded by a more labile outer membrane (OM). This OM is rich in lipoproteins but with few known integral membrane proteins. The OmpA domain is an eight-stranded membrane-spanning β-barrel, highly conserved among the Proteobacteria but so far unknown in the Spirochetes. In the present work we describe the identification of four novel OmpA-like β-barrels from Borrelia afzelii, the most common cause of erythema migrans rash in Europe. Structural characterisation of one these proteins (BAPKO_0422) by small angle X-ray scattering (SAXS) and circular dichroism indicate a compact globular structure rich in β-strand consistent with a monomeric β-barrel. Ab initio molecular envelopes calculated from the scattering profile are consistent with homology models and demonstrate that BAPKO_0422 adopts a peanut shape with dimensions 25 x 45 Å. Deviations from the standard C-terminal signature sequence are apparent; in particular the C-terminal Phe residue commonly found in Proteobacterial OM proteins is replaced by Ile/Leu or Asn. BAPKO_0422 is demonstrated to bind human factor-H and therefore may contribute to immune evasion by inhibition of the complement response. Encoded by chromosomal genes, these proteins are highly conserved between Borrelia subspecies and may be of diagnostic or therapeutic value

The primary glucose-lowering effect of metformin resides in the gut, not the circulation: Results from short-term pharmacokinetic and 12-week dose-ranging studies

Delayed-release metformin (Met DR) is formulated to deliver the drug to the lower bowel to leverage the gut-based mechanisms of metformin action with lower plasma exposure. Met DR was assessed in two studies. Study 1 compared the bioavailability of single daily doses of Met DR to currently available immediaterelease metformin (Met IR) and extended-release metformin (Met XR) in otherwise healthy volunteers. Study 2 assessed glycemic control in subjects with type 2 diabetes (T2DM) over 12 weeks. Research Design and Methods Study 1 was a phase 1, randomized, four-period crossover study in 20 subjects. Study 2 was a 12-week, phase 2, multicenter, placebo-controlled, dose-ranging study in 240 subjects with T2DM randomized to receive Met DR 600, 800, or 1,000 mg administered once daily; blinded placebo; or unblindedMet XR 1,000 or 2,000 mg (reference). Results The bioavailability of 1,000mg Met DR b.i.d. was ∼50% that of Met IR and Met XR (study 1). In study 2, 600, 800, and 1,000 mg Met DR q.d. produced statistically significant, clinically relevant, and sustained reductions in fasting plasma glucose (FPG) levels over 12 weeks compared with placebo, with an ∼40% increase in potency compared with Met XR. The placebo-subtracted changes from baseline in HbA1c level at 12 weeks were consistent with changes in FPG levels. All treatments were generally well tolerated, and adverse events were consistent with Glucophage/ Glucophage XR prescribing information. Conclusions Dissociation of the glycemic effect from plasma exposure with gut-restricted Met DR provides strong evidence for a predominantly lower bowel-mediated mechanism of metformin action