A Hybrid N-body--Coagulation Code for Planet Formation

We describe a hybrid algorithm to calculate the formation of planets from an initial ensemble of planetesimals. The algorithm uses a coagulation code to treat the growth of planetesimals into oligarchs and explicit N-body calculations to follow the evolution of oligarchs into planets. To validate the N-body portion of the algorithm, we use a battery of tests in planetary dynamics. Several complete calculations of terrestrial planet formation with the hybrid code yield good agreement with previously published calculations. These results demonstrate that the hybrid code provides an accurate treatment of the evolution of planetesimals into planets.Comment: Astronomical Journal, accepted; 33 pages + 11 figure

Let-7 Expression Defines Two Differentiation Stages of Cancer

The early phases of carcinogenesis resemble embryonic development, often involving the reexpression of embryonic mesenchymal genes. The NCI60 panel of human tumor cell lines can genetically be subdivided into two superclusters (SCs) that correspond to CD95 Type I and II cells. SC1 cells are characterized by a mesenchymal and SC2 cells by an epithelial gene signature, suggesting that SC1 cells represent less differentiated, advanced stages of cancer. miRNAs are small 20- to 22-nucleotide-long noncoding RNAs that inhibit gene expression at the posttranscriptional level. By performing miRNA expression analysis on 10 Type I and 10 Type II cells, we have determined that SC1 cells express low and SC2 cells high levels of the miRNA let-7, respectively, suggesting that let-7 is a marker for less advanced cancers. Expression of the let-7 target high-mobility group A2 (HMGA2), an early embryonic gene, but not of classical epithelial or mesenchymal markers such as E-cadherin or vimentin, inversely correlated with let-7 expression in SC1 and SC2 cells. Using ovarian cancer as a model, we demonstrate that expression of let-7 and HMGA2 is a better predictor of prognosis than classical markers such as E-cadherin, vimentin, and Snail. These data identify loss of let-7 expression as a marker for less differentiated cancer

Tumor site immune markers associated with risk for subsequent basal cell carcinomas.

BackgroundBasal cell carcinoma (BCC) tumors are the most common skin cancer and are highly immunogenic.ObjectiveThe goal of this study was to assess how immune-cell related gene expression in an initial BCC tumor biopsy was related to the appearance of subsequent BCC tumors.Materials and methodsLevels of mRNA for CD3ε (a T-cell receptor marker), CD25 (the alpha chain of the interleukin (IL)-2 receptor expressed on activated T-cells and B-cells), CD68 (a marker for monocytes/macrophages), the cell surface glycoprotein intercellular adhesion molecule-1 (ICAM-1), the cytokine interferon-γ (IFN-γ) and the anti-inflammatory cytokine IL-10 were measured in BCC tumor biopsies from 138 patients using real-time PCR.ResultsThe median follow-up was 26.6 months, and 61% of subjects were free of new BCCs two years post-initial biopsy. Patients with low CD3ε CD25, CD68, and ICAM-1 mRNA levels had significantly shorter times before new tumors were detected (p = 0.03, p = 0.02, p = 0.003, and p = 0.08, respectively). Furthermore, older age diminished the association of mRNA levels with the appearance of subsequent tumors.ConclusionsOur results show that levels of CD3ε, CD25, CD68, and ICAM-1 mRNA in BCC biopsies may predict risk for new BCC tumors

Inference for Constrained Estimation of Tumor Size Distributions

In order to develop better treatment and screening programs for cancer prevention programs, it is important to be able to understand the natural history of the disease and what factors affect its progression. We focus on a particular framework first outlined by Kimmel and Flehinger (1991, Biometrics , 47, 987–1004) and in particular one of their limiting scenarios for analysis. Using an equivalence with a binary regression model, we characterize the nonparametric maximum likelihood estimation procedure for estimation of the tumor size distribution function and give associated asymptotic results. Extensions to semiparametric models and missing data are also described. Application to data from two cancer studies is used to illustrate the finite-sample behavior of the procedure.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65536/1/j.1541-0420.2008.01001.x.pd

Cluster-Randomized Test-Negative Design Trials: A Novel and Efficient Method to Assess the Efficacy of Community-Level Dengue Interventions.

Cluster-randomized controlled trials are the gold standard for assessing efficacy of community-level interventions, such as vector-control strategies against dengue. We describe a novel cluster-randomized trial methodology with a test-negative design (CR-TND), which offers advantages over traditional approaches. This method uses outcome-based sampling of patients presenting with a syndrome consistent with the disease of interest, who are subsequently classified as test-positive cases or test-negative controls on the basis of diagnostic testing. We used simulations of a cluster trial to demonstrate validity of efficacy estimates under the test-negative approach. We demonstrated that, provided study arms are balanced for both test-negative and test-positive illness at baseline and that other test-negative design assumptions are met, the efficacy estimates closely match true efficacy. Analytical considerations for an odds ratio-based effect estimate arising from clustered data and potential approaches to analysis are also discussed briefly. We concluded that application of the test-negative design to certain cluster-randomized trials could increase their efficiency and ease of implementation

The distribution of ammonia on Jupiter from a preliminary inversion of Juno Microwave Radiometer data

The Juno microwave radiometer measured the thermal emission from Jupiter's atmosphere from the cloud tops at about 1 bar to as deep as a hundred bars of pressure during its first flyby over Jupiter (PJ1). The nadir brightness temperatures show that the Equatorial Zone is likely to be an ideal adiabat, which allows a determination of the deep ammonia abundance in the range 362^(+33)_(-33) ppm. The combination of Markov chain Monte Carlo method and Tikhonov regularization is studied to invert Jupiter's global ammonia distribution assuming a prescribed temperature profile. The result shows (1) that ammonia is depleted globally down to 50–60 bars except within a few degrees of the equator, (2) the North Equatorial Belt is more depleted in ammonia than elsewhere, and (3) the ammonia concentration shows a slight inversion starting from about 7 bars to 2 bars. These results are robust regardless of the choice of water abundance

Negative regulation of syntaxin4/SNAP-23/VAMP2-mediated membrane fusion by Munc18c <i>In Vitro</i>

Background: Translocation of the facilitative glucose transporter GLUT4 from an intracellular store to the plasma membrane is responsible for the increased rate of glucose transport into fat and muscle cells in response to insulin. This represents a specialised form of regulated membrane trafficking. Intracellular membrane traffic is subject to multiple levels of regulation by conserved families of proteins in all eukaryotic cells. Notably, all intracellular fusion events require SNARE proteins and Sec1p/Munc18 family members. Fusion of GLUT4-containing vesicles with the plasma membrane of insulin-sensitive cells involves the SM protein Munc18c, and is regulated by the formation of syntaxin 4/SNAP23/VAMP2 SNARE complexes. Methodology/Principal Findings Here we have used biochemical approaches to characterise the interaction(s) of Munc18c with its cognate SNARE proteins and to examine the role of Munc18c in regulating liposome fusion catalysed by syntaxin 4/SNAP23/VAMP2 SNARE complex formation. We demonstrate that Munc18c makes contacts with both t- and v-SNARE proteins of this complex, and directly inhibits bilayer fusion mediated by the syntaxin 4/SNAP23/VAMP2 SNARE complex. Conclusion/Significance Our reductionist approach has enabled us to ascertain a direct inhibitory role for Munc18c in regulating membrane fusion mediated by syntaxin 4/SNAP23/VAMP2 SNARE complex formation. It is important to note that two different SM proteins have recently been shown to stimulate liposome fusion mediated by their cognate SNARE complexes. Given the structural similarities between SM proteins, it seems unlikely that different members of this family perform opposing regulatory functions. Hence, our findings indicate that Munc18c requires a further level of regulation in order to stimulate SNARE-mediated membrane fusion