Heterogeneity in susceptibility dictates the order of epidemiological models

The fundamental models of epidemiology describe the progression of an infectious disease through a population using compartmentalized differential equations, but do not incorporate population-level heterogeneity in infection susceptibility. We show that variation strongly influences the rate of infection, while the infection process simultaneously sculpts the susceptibility distribution. These joint dynamics influence the force of infection and are, in turn, influenced by the shape of the initial variability. Intriguingly, we find that certain susceptibility distributions (the exponential and the gamma) are unchanged through the course of the outbreak, and lead naturally to power-law behavior in the force of infection; other distributions often tend towards these "eigen-distributions" through the process of contagion. The power-law behavior fundamentally alters predictions of the long-term infection rate, and suggests that first-order epidemic models that are parameterized in the exponential-like phase may systematically and significantly over-estimate the final severity of the outbreak

A Titin mutation defines roles for circulation in endothelial morphogenesis

AbstractMorphogenesis of the developing vascular network requires coordinated regulation of an extensive array of endothelial cell behaviors. Precisely regulated signaling molecules such as vascular endothelial growth factor (VEGF) direct some of these endothelial behaviors. Newly forming blood vessels also become subjected to novel biomechanical forces upon initiation of cardiac contractions. We report here the identification of a recessive mouse mutation termed shrunken-head (shru) that disrupts function of the Titin gene. Titin was found to be required for the initiation of proper heart contractions as well as for maintaining the correct overall shape and orientation of individual cardiomyocytes. Cardiac dysfunction in shrunken-head mutant embryos provided an opportunity to study the effects of lack of blood circulation on the morphogenesis of endothelial cells. Without blood flow, differentiating endothelial cells display defects in their shapes and patterns of cell–cell contact. These endothelial cells, without exposure to blood circulation, have an abnormal distribution within vasculogenic vessels. Further effects of absent blood flow include abnormal spatial regulation of angiogenesis and elevated VEGF signaling. The shrunken-head mutation has provided an in vivo model to precisely define the roles of circulation on cellular and network aspects of vascular morphogenesis

Galactic Extinction from Colors and Counts of Field Galaxies in WFPC2 Frames: An Application to GRB 970228

We develop the ``simulated extinction method'' to measure average foreground Galactic extinction from field galaxy number-counts and colors. The method comprises simulating extinction in suitable reference fields by changing the isophotal detection limit. This procedure takes into account selection effects, in particular, the change in isophotal detection limit (and hence in isophotal magnitude completeness limit) with extinction, and the galaxy color--magnitude relation. We present a first application of the method to the HST WFPC2 images of the gamma-ray burster GRB 970228. Four different WFPC2 high-latitude fields, including the HDF, are used as reference to measure the average extinction towards the GRB in the F606W passband. From the counts, we derive an average extinction of A_V = 0.5 mag, but the dispersion of 0.4 mag between the estimates from the different reference fields is significantly larger than can be accounted by Poisson plus clustering uncertainties. Although the counts differ, the average colors of the field galaxies agree well. The extinction implied by the average color difference between the GRB field and the reference galaxies is A_V = 0.6 mag, with a dispersion in the estimated extinction from the four reference fields of only 0.1 mag. All our estimates are in good agreement with the value of 0.81\pm0.27 mag obtained by Burstein & Heiles, and with the extinction of 0.78\pm0.12 measured by Schlegel et al. from maps of dust IR emission. However, the discrepancy between the widely varying counts and the very stable colors in these high-latitude fields is worth investigating.Comment: 14 pages, 2 figures; submitted to the Astrophysical Journa

Using Perturbation Theory to Compute the Morphological Similarity of Diffusion Tensors

Computing the morphological similarity of diffusion tensors (DTs) at neighboring voxels within a DT image, or at corresponding locations across different DT images, is a fundamental and ubiquitous operation in the postprocessing of DT images. The morphological similarity of DTs typically has been computed using either the principal directions (PDs) of DTs (i.e., the direction along which water molecules diffuse preferentially) or their tensor elements. Although comparing PDs allows the similarity of one morphological feature of DTs to be visualized directly in eigenspace, this method takes into account only a single eigenvector, and it is therefore sensitive to the presence of noise in the images that can introduce error in to the estimation of that vector. Although comparing tensor elements, rather than PDs, is comparatively more robust to the effects of noise, the individual elements of a given tensor do not directly reflect the diffusion properties of water molecules. We propose a measure for computing the morphological similarity of DTs that uses both their eigenvalues and eigenvectors, and that also accounts for the noise levels present in DT images. Our measure presupposes that DTs in a homogeneous region within or across DT images are random perturbations of one another in the presence of noise. The similarity values that are computed using our method are smooth (in the sense that small changes in eigenvalues and eigenvectors cause only small changes in similarity), and they are symmetric when differences in eigenvalues and eigenvectors are also symmetric. In addition, our method does not presuppose that the corresponding eigenvectors across two DTs have been identified accurately, an assumption that is problematic in the presence of noise. Because we compute the similarity between DTs using their eigenspace components, our similarity measure relates directly to both the magnitude and the direction of the diffusion of water molecules. The favorable performance characteristics of our measure offer the prospect of substantially improving additional postprocessing operations that are commonly performed on DTI datasets, such as image segmentation, fiber tracking, noise filtering, and spatial normalization

Generation of orthotopic patient-derived xenografts from gastrointestinal stromal tumor.

BackgroundGastrointestinal stromal tumor (GIST) is the most common sarcoma and its treatment with imatinib has served as the paradigm for developing targeted anti-cancer therapies. Despite this success, imatinib-resistance has emerged as a major problem and therefore, the clinical efficacy of other drugs has been investigated. Unfortunately, most clinical trials have failed to identify efficacious drugs despite promising in vitro data and pathological responses in subcutaneous xenografts. We hypothesized that it was feasible to develop orthotopic patient-derived xenografts (PDXs) from resected GIST that could recapitulate the genetic heterogeneity and biology of the human disease.MethodsFresh tumor tissue from three patients with pathologically confirmed GISTs was obtained immediately following tumor resection. Tumor fragments (4.2-mm3) were surgically xenografted into the liver, gastric wall, renal capsule, and pancreas of immunodeficient mice. Tumor growth was serially assessed with ultrasonography (US) every 3-4 weeks. Tumors were also evaluated with positron emission tomography (PET). Animals were sacrificed when they became moribund or their tumors reached a threshold size of 2500-mm3. Tumors were subsequently passaged, as well as immunohistochemically and histologically analyzed.ResultsHerein, we describe the first model for generating orthotopic GIST PDXs. We have successfully xenografted three unique KIT-mutated tumors into a total of 25 mice with an overall success rate of 84% (21/25). We serially followed tumor growth with US to describe the natural history of PDX growth. Successful PDXs resulted in 12 primary xenografts in NOD-scid gamma or NOD-scid mice while subsequent successful passages resulted in 9 tumors. At a median of 7.9 weeks (range 2.9-33.1 weeks), tumor size averaged 473 ± 695-mm³ (median 199-mm3, range 12.6-2682.5-mm³) by US. Furthermore, tumor size on US within 14 days of death correlated with gross tumor size on necropsy. We also demonstrated that these tumors are FDG-avid on PET imaging, while immunohistochemically and histologically the PDXs resembled the primary tumors.ConclusionsWe report the first orthotopic model of human GIST using patient-derived tumor tissue. This novel, reproducible in vivo model of human GIST may enhance the study of GIST biology, biomarkers, personalized cancer treatments, and provide a preclinical platform to evaluate new therapeutic agents for GIST

Landscape-Scale Land-Cover Change and Long-Term Abundance of Scaled Quail and Northern Bobwhite in Texas

Between 1978 and 1998, scaled quail (Callipepla squamata) abundance in the Rolling Plains ecological region declined (r1 = -0.85, P \u3c 0.001), while no trend (P = 0.74) was exhibited in the South Texas Plains. Northern bobwhites (Colinus virginianus) exhibited no trend (P \u3e 0.10) in either ecological region. Changes in land-cover between 1976 and 1998 indicated a loss of Savannah and Shrubland and an increase in Parkland cover types in the Rolling Plains. In the South Texas Plains, Woodland and Brush/Shrubland decreased between 1976 and 1998, whereas Brush/Shrub Parkland and Parkland increased. We examined land-cover change as a possible component in the scaled quail decline in the Rolling Plains. Loss of the Shrubland cover type may explain the decline of scaled quail in the Rolling Plains. Our results further suggest intraspecific spatial usability boundaries. These boundaries differed by species, with scaled quail associated with dense structure near the ground, whereas northern bobwhite were less abundant in areas dominated by scattered shrubs and trees, and large expanses of short, close-canopy cover types. A method is proposed for quickly obtaining data on land-cover changes on time

FGF19 Regulates Cell Proliferation, Glucose and Bile Acid Metabolism via FGFR4-Dependent and Independent Pathways

Fibroblast growth factor 19 (FGF19) is a hormone-like protein that regulates carbohydrate, lipid and bile acid metabolism. At supra-physiological doses, FGF19 also increases hepatocyte proliferation and induces hepatocellular carcinogenesis in mice. Much of FGF19 activity is attributed to the activation of the liver enriched FGF Receptor 4 (FGFR4), although FGF19 can activate other FGFRs in vitro in the presence of the coreceptor βKlotho (KLB). In this report, we investigate the role of FGFR4 in mediating FGF19 activity by using Fgfr4 deficient mice as well as a variant of FGF19 protein (FGF19v) which is specifically impaired in activating FGFR4. Our results demonstrate that FGFR4 activation mediates the induction of hepatocyte proliferation and the suppression of bile acid biosynthesis by FGF19, but is not essential for FGF19 to improve glucose and lipid metabolism in high fat diet fed mice as well as in leptin-deficient ob/ob mice. Thus, FGF19 acts through multiple receptor pathways to elicit pleiotropic effects in regulating nutrient metabolism and cell proliferation

Loss of the retrograde motor for IFT disrupts localization of Smo to cilia and prevents the expression of both activator and repressor functions of Gli

AbstractSonic Hedgehog (Shh) signals are transduced into nuclear ratios of Gli transcriptional activator versus repressor. The initial part of this process is accomplished by Shh acting through Patched (Ptc) to regulate Smoothened (Smo) activity. The mechanisms by which Ptc regulates Smo, and Smo activity is transduced to processing of Gli proteins remain unclear. Recently, a forward genetic approach in mice identified a role for intraflagellar transport (IFT) genes in Shh signal transduction, downstream of Patched (Ptc) and Rab23. Here, we show that the retrograde motor for IFT is required in the mouse for the phenotypic expression of both Gli activator and repressor function and for effective proteolytic processing of Gli3. Furthermore, we show that the localization of Smo to primary cilia is disrupted in mutants. These data indicate that primary cilia act as specialized signal transduction organelles required for coupling Smo activity to the biochemical processing of Gli3 protein