Dilation of subglacial sediment governs incipient surge motion in glaciers with deformable beds.

Glacier surges are quasi-periodic episodes of rapid ice flow that arise from increases in slip rate at the ice-bed interface. The mechanisms that trigger and sustain surges are not well understood. Here, we develop a new model of incipient surge motion for glaciers underlain by sediments to explore how surges may arise from slip instabilities within a thin layer of saturated, deforming subglacial till. Our model represents the evolution of internal friction, porosity and pore water pressure within the till as functions of the rate and history of shear deformation, and couples the till mechanics to a simple ice-flow model. Changes in pore water pressure govern incipient surge motion, with less permeable till facilitating surging because dilation-driven reductions in pore water pressure slow the rate at which till tends towards a new steady state, thereby allowing time for the glacier to thin dynamically. The reduction of overburden (and thus effective) pressure at the bed caused by dynamic thinning of the glacier sustains surge acceleration in our model. The need for changes in both the hydromechanical properties of the till and the thickness of the glacier creates restrictive conditions for surge motion that are consistent with the rarity of surge-type glaciers and their geographical clustering.

The Reference Image Database to Evaluate Response to therapy in lung cancer (RIDER) project: a resource for the development of change-analysis software.

Critical to the clinical evaluation of effective novel therapies for lung cancer is the early and accurate determination of tumor response, which requires an understanding of the sources of uncertainty in tumor measurement and subsequent attempts to minimize their effects on the assessment of the therapeutic agent. The Reference Image Database to Evaluate Response (RIDER) project seeks to develop a consensus approach to the optimization and benchmarking of software tools for the assessment of tumor response to therapy and to provide a publicly available database of serial images acquired during lung cancer drug and radiation therapy trials. Images of phantoms and patient images acquired under situations in which tumor size or biology is known to be unchanged also will be provided. The RIDER project will create standardized methods for benchmarking software tools to reduce sources of uncertainty in vital clinical assessments such as whether a specific tumor is responding to therapy.

Comparing pairwise and simultaneous joint registrations of decorrelating interval exams using entropic graphs.

The interest in registering a set of images has quickly risen in the field of medical image analysis. Mutual information (MI) based methods are well-established for pairwise registration but their extension to higher dimensions (multiple images) has encountered practical implementation difficulties. We extend the use of alpha mutual information (alphaMI) as the similarity measure to simultaneously register multiple images. alphaMI of a set of images can be directly estimated using entropic graphs spanning feature vectors extracted from the images, which is demonstrated to be practically feasible for joint registration. In this paper we are specifically interested in monitoring malignant tumor changes using simultaneous registration of multiple interval MR or CT scans. Tumor scans are typically a decorrelating sequence due to the cycles of heterogeneous cell death and growth. The accuracy of joint and pairwise registration using entropic graph methods is evaluated by registering several sets of interval exams. We show that for the parameters we investigated simultaneous joint registration method yields lower average registration errors compared to pairwise. Different degrees of decorrelation in the serial scans are studied and registration performance suggests that an appropriate scanning interval can be determined for efficiently monitoring lesion changes. Different levels of observation noise are added to the image sequences and the experimental results show that entropic graph based methods are robust and can be used reliably for multiple image registration.

Automated generation of a four-dimensional model of the liver using warping and mutual information.

The use of mutual information (MI) based alignment to map changes in liver shape and position from exhale to inhale was investigated. Inhale and exhale CT scans were obtained with intravenous contrast for six patients. MI based alignment using thin-plate spine (TPS) warping was performed between each inhale and exhale image set. An expert radiation oncologist identified corresponding vessel bifurcations on the exhale and inhale CT image and the transformation for identified points was determined. This transformation was then used to determine the accuracy of the MI based alignment. The reproducibility of the vessel bifurcation identification was measured through repeat blinded vessel bifurcation identification. Reproducibility [standard deviation (SD)] in the L/R, A/P, and I/S directions was 0.11, 0.09, and 0.14 cm, respectively. The average absolute difference between the transformation obtained using MI based alignment and the vessel bifurcation in the L/R, A/P, and I/S directions was 0.13 cm (SD=0.10 cm), 0.15 cm (SD=0.12 cm), and 0.15 cm (SD-0.14 cm), respectively. These values are comparable to the reproducibility of bifurcation identification, indicating that MI based alignment using TPS warping is accurate to within measurement error and is a reliable tool to aid in describing deformation that the liver undergoes from the exhale to inhale state.

Effects of locally-delivered human macrophage products and estrogen on murine inflammatory bone resorption.

The objective of this study was to use an in vivo model of periodontitis (mouse calvaria) to quantify the effects of local release of secreted human macrophage products, 17beta-estradiol (E2), and proinflammatory lipopolysaccharide (LPS) on histologic bone resorption. Human THP-1 monocytes (106) were converted to macrophage phenotype by 500 ng/ml phorbol 12-myristate- 13-acetate (PMA) and treated as follows: no stimulation or Escherichia coli LPS (10 microg/ml) alone or in combination with a physiologic dose of E2 (100 pg/ml) for 24 h in RPMI/10% FBS, washed extensively, then incubated for 24 h in serum-free media. Supernatant products were concentrated and incorporated into a 4% (w/v) methylcellulose gel. Separate gels were incorporated with the following: LPS (500 microg/animal) alone, high dose of E2 (10 ng/animal) alone, a combination of LPS + E2, or gel only (controls). Loaded or control gels were placed into a polylactic acid occlusive dome, inserted subcutaneously over the calvaria of mature ovariectomized ICR Swiss mice (8 mice x 7 groups x 2 times [5/14 days] = 112 animals), then calvaria were evaluated histologically. Macrophage stimulation with LPS alone, but not LPS in combination with E2, produced supernatants which upregulated osteoclast numbers in the suture area compared to gel controls at 5 days (p = 0.009). The addition of LPS directly to the local delivery gels significantly upregulated osteoclasts in endosteal surfaces compared to gel controls at 5 days (p = 0.024) and at 14 days (p = 0.025). The addition of E2 to LPS down-regulated resorption to a level not different from gel controls at 14 days. This in vivo model appears effective in studying inflammatory bone resorption, which may be inhibited by E2 directly or through its influence on secreted macrophage products.

Identification of functionally important amino-terminal arginines of Agrobacterium tumefaciens ADP-glucose pyrophosphorylase by alanine scanning mutagenesis.

Treatment of the Agrobacterium tumefaciens ADP-glucose pyrophosphorylase with the arginyl reagent phenylglyoxal resulted in complete desensitization to fructose 6-phosphate (F6P) activation, and partial desensitization to pyruvate activation. The enzyme was protected from desensitization by ATP, F6P, pyruvate, and phosphate. Alignment studies revealed that this enzyme contains arginine residues in the amino-terminal region that are relatively conserved in similarly regulated ADP-glucose pyrophosphorylases. To functionally evaluate the role(s) of these arginines, alanine scanning mutagenesis was performed to generate the following enzymes: R5A, R11A, R22A, R25A, R32A, R33A, R45A, and R60A. All of the enzymes, except R60A, were successfully expressed and purified to near homogeneity. Both the R5A and R11A enzymes displayed desensitization to pyruvate, partial activation by F6P, and increased sensitivity to phosphate inhibition. Both the R22A and R25A enzymes exhibited reduced V(max) values in the absence of activators, lower apparent affinities for ATP and F6P, and reduced sensitivities to phosphate. The presence of F6P restored R22A enzyme activity, while the R25A enzyme exhibited only approximately 1.5% of the wild-type activity. The R32A enzyme displayed an approximately 11.5-fold reduced affinity for F6P while exhibiting behavior identical to that of the wild type with respect to pyruvate activation. Both the R33A and R45A enzymes demonstrated a higher activity than the wild-type enzyme in the absence of activators, no response to F6P, partial activation by pyruvate, and desensitization to phosphate inhibition. These altered enzymes were also insensitive to phenylglyoxal. The data demonstrate unique functional roles for these arginines and the presence of separate subsites for the activators.

Regional mu opioid receptor regulation of sensory and affective dimensions of pain.

The endogenous opioid system is involved in stress responses, in the regulation of the experience of pain, and in the action of analgesic opiate drugs. We examined the function of the opioid system and mu-opioid receptors in the brains of healthy human subjects undergoing sustained pain. Sustained pain induced the regional release of endogenous opioids interacting with mu-opioid receptors in a number of cortical and subcortical brain regions. The activation of the mu-opioid receptor system was associated with reductions in the sensory and affective ratings of the pain experience, with distinct neuroanatomical involvements. These data demonstrate the central role of the mu-opioid receptors and their endogenous ligands in the regulation of sensory and affective components of the pain experience.

Cloning and sequencing of glycogen metabolism genes from Rhodobacter sphaeroides 2.4.1. Expression and characterization of recombinant ADP-glucose pyrophosphorylase.

A 6-kb DNA fragment of the Rhodobacter sphaeroides 2.4.1 glg operon was cloned from a genomic library using a polymerase chain reaction probe coding for part of the ADP-glucose pyrophosphorylase (glgC) gene. The DNA fragment was sequenced and found to harbor complete open reading frames for the glgC and glgA (glycogen synthase) genes and partial sequences corresponding to glgP (glycogen phosphorylase) and glgX (glucan hydrolase/transferase) genes. The genomic fragment also contained an apparent truncated sequence corresponding to the C-terminus of the glgB gene (branching enzyme). The presence of active branching enzyme activity in crude sonicates of Rb. sphaeroides cells indicates that the genome contains a full-length glgB at another location. The structure of this operon in relation to other glg operons is further discussed. The deduced sequence of the ADP-glucose pyrophosphorylase enzyme is compared to other known ADP-glucose pyrophosphorylase sequences and discussed in relation to the allosteric regulation of this enzyme family. The glgC gene was subcloned in the vector pSE420 (Invitrogen) for high-level expression in E. coli. The successful overexpression of the recombinant enzyme allowed for the purification of over 35 mg of protein from 10 g of cells, representing a dramatic improvement over enzyme isolation from the native strain. The recombinant enzyme was purified to near homogeneity and found to be physically, immunologically, and kinetically identical to the native enzyme, verifying the fidelity of the cloning step.

3D spatial compounding of ultrasound images using image-based nonrigid registration.

Medical ultrasound images are often distorted enough to significantly limit resolution during compounding (i.e., summation of images from multiple views). A new, volumetric image registration technique has been used successfully to enable high spatial resolution in three-dimensional (3D) spatial compounding of ultrasound images. Volumetric ultrasound data were acquired by scanning a linear matrix array probe in the elevational direction in a focal lesion phantom and in a breast in vivo. To obtain partly uncorrelated views, the volume of interest was scanned at five different transducer tilt angles separated by 4 degrees to 6 degrees. Pairs of separate views were registered by an automatic procedure based on a mutual information metric, using global full affine and thin-plate spline warping transformations. Registration accuracy was analyzed automatically in the phantom data, and manually in vivo, yielding average registration errors of 0.31 mm and 0.65 mm, respectively. In the vicinity of the warping control points, registrations obtained with warping transformations were significantly more accurate than full affine registrations. Compounded images displayed the expected reduction in speckle noise and increase in contrast-to-noise ratio (CNR), as well as better delineation of connective tissues and reduced shadowing. Compounding also revealed some apparent low contrast lobulations that were not visible in the single-sweep images. Given expected algorithmic and hardware enhancements, nonrigid, image-based registration shows great promise for reducing tissue motion and refraction artifacts in 3D spatial compounding.