Realistic simulation of the ion cyclotron resonance mass spectrometer using a distributed three-dimensional particle-in-cell code

AbstractThis work describes an Internet accessible three-dimensional particle-in-cell simulation code, which is capable of near first principles modeling of complete experimental sequences in Fourier transform ion cyclotron resonance mass spectrometers. The graphical user interface is a Java client that communicates via a socket stream connection over the Internet to the computational engine, a server that executes the simulation and sends real-time particle data back to the client for display. As a first demonstration, this code is applied to the problem of the cyclotron motion of two very close mass to charge ratios at high ion density. The ion populations in these simulations range from 50,000 to 350,000 coulombically interacting particles confined in a cubic trap, which are followed for 100,000 time-steps. Image charge, coherent cyclotron positions, and snapshots of the ion population are recorded at selected time-steps. At each time-step in the simulation the potential (coulomb + image + trap) is found by the direct solution of Poisson’s equation on a 64 × 64 × 64 computational grid. Cyclotron phase locking is demonstrated at high number density. Simulations at different magnetic fields confirm a B2 dependence for the minimum number density required to lock cyclotron modes

OH(1720 MHz) Masers As Signposts of Molecular Shocks

We present observations of molecular gas made with the 15-m James Clark Maxwell Telescope toward the sites of OH(1720 MHz) masers in three supernova remnants: W28, W44 and 3C391. Maps made in the 12CO J=3-2 line reveal that the OH masers are preferentially located along the edges of thin filaments or clumps of molecular gas. There is a strong correlation between the morphology of the molecular gas and the relativistic gas traced by synchrotron emission at centimeter wavelengths. Broad CO line widths (dV=30-50 km/s) are seen along these gaseous ridges, while narrow lines are seen off the ridges. The ratio of H2CO line strengths is used to determine temperatures in the broad-line gas of 80 K, and the 13CO J=3-2 column density suggests densities of 10^4-10^5 cm{-3}. These observations support the hypothesis that the OH(1720 MHz) masers originate in post-shock gas, heated by the passage of a supernova remnant shock through dense molecular gas. From the observational constraints on the density, velocity and magnetic field we examine the physical properties of the shock and discuss the shock-production of OH. These OH(1720 MHz) masers are useful ``signposts'', which point to the most promising locations to study supernova remnant/molecular cloud interactions.Comment: ApJ (in press

Expression of type I collagen mRNA in glomeruli of rats with passive Heymann nephritis

Expression of type I collagen mRNA in glomeruli of rats with passive Heymann nephritis. In passive Heymann nephritis (PHN) glomeruli exhibit marked basement membrane expansion around subepithelial immune deposits but they fail to show any change in mRNA levels of type IV collagen, laminin or fibronectin by Northern and slot-blot analysis, or in the amount or distribution of type IV collagen or laminin by immunohistology for up to 12 weeks after disease onset. On the other hand, in situ hybridization (ISH) revealed the appearance of positive cells exhibiting mRNA for the α1 chain of rat type I collagen two to three weeks after the onset of PHN in all glomeruli of all rats. Positive cells persisted for at least eight weeks. In many glomeruli, the location of the clusters of silver grains suggested that they were in visceral epithelial cells. In controls injected with normal sheep IgG, and in early PHN (<11 days after sheep anti-Fx1A), glomeruli were negative but cells in the renal capsule and adventitia of vessels showed strong ISH and served as positive controls. RNAse pre-treatment and the “sense” probe gave appropriately negative results. RNA from PHN glomeruli contained an α1 type I collagen transcript of the same size as that from rat fibroblasts. These results show that the evolution of glomerular basement membrane expansion in rat membranous nephropathy coincides with the induction of a matrix gene that is not normally expressed in glomerular cells. Further, they suggest that the intercalation of ectopically-expressed matrix molecules may contribute to the production of a disorganized basement membrane

Evolution of associative learning in chemical networks

Organisms that can learn about their environment and modify their behaviour appropriately during their lifetime are more likely to survive and reproduce than organisms that do not. While associative learning – the ability to detect correlated features of the environment – has been studied extensively in nervous systems, where the underlying mechanisms are reasonably well understood, mechanisms within single cells that could allow associative learning have received little attention. Here, using in silico evolution of chemical networks, we show that there exists a diversity of remarkably simple and plausible chemical solutions to the associative learning problem, the simplest of which uses only one core chemical reaction. We then asked to what extent a linear combination of chemical concentrations in the network could approximate the ideal Bayesian posterior of an environment given the stimulus history so far? This Bayesian analysis revealed the ’memory traces’ of the chemical network. The implication of this paper is that there is little reason to believe that a lack of suitable phenotypic variation would prevent associative learning from evolving in cell signalling, metabolic, gene regulatory, or a mixture of these networks in cells

A Comparison of Polarization Observables in Electron Scattering from the Proton and Deuteron

Recoil proton polarization observables were measured for both the p($\vec {\rm e}$,e$^\prime\vec{\rm p}\,$) and d($\vec {\rm e}$,e$^\prime\vec{\rm p}\,)$n reactions at two values of Q$^2$ using a newly commissioned proton Focal Plane Polarimeter at the M.I.T.-Bates Linear Accelerator Center. The hydrogen and deuterium spin-dependent observables $D_{\ell\ell}$ and $D_{{\ell}t}$, the induced polarization $P_n$ and the form factor ratio $G^p_E/G^p_M$ were measured under identical kinematics. The deuterium and hydrogen results are in good agreement with each other and with the plane-wave impulse approximation (PWIA).Comment: 9 pages, 1 figure; accepted by Phys. Rev. Let

Normal levels of p27Xic1 are necessary for somite segmentation and determining pronephric organ size

The Xenopus laevis cyclin dependent kinase inhibitor p27Xic1 has been shown to be involved in exit from the cell cycle and differentiation of cells into a quiescent state in the nervous system, muscle tissue, heart and retina. We show that p27Xic1 is expressed in the developing kidney in the nephrostomal regions. Using over-expression and morpholino oligonucleotide (MO) knock-down approaches we show normal levels of p27Xic1 regulate pronephros organ size by regulating cell cycle exit. Knock-down of p27Xic1 expression using a MO prevented myogenesis, as previously reported; an effect that subsequently inhibits pronephrogenesis. Furthermore, we show that normal levels of p27Xic1 are required for somite segmentation also through its cell cycle control function. Finally, we provide evidence to suggest correct paraxial mesoderm segmentation is not necessary for pronephric induction in the intermediate mesoderm. These results indicate novel developmental roles for p27Xic1, and reveal its differentiation function is not universally utilised in all developing tissues

A low frequency multibeam assessment: Spatial mapping of shallow gas by enhanced penetration and angular response anomaly

This study highlights the potential of using a low frequency multibeam echosounder for detection and visualization of shallow gas occurring several meters beneath the seafloor. The presence of shallow gas was verified in the Bornholm Basin, Baltic Sea, at 80 m water depth with standard geochemical core analysis and hydroacoustic subbottom profiling. Successively, this area was surveyed with a 95 kHz and a 12 kHz multibeam echosounder (MBES). The bathymetric measurements with 12 kHz provided depth values systematically deeper by several meters compared to 95 kHz data. This observation was attributed to enhanced penetration of the low frequency signal energy into soft sediments. Consequently, the subbottom geoacoustic properties contributed highly to the measured backscattered signals. Those appeared up to 17 dB higher inside the shallow gas area compared to reference measurements outside and could be clearly linked to the shallow gas front depth down to 5 meter below seafloor. No elevated backscatter was visible in 95 kHz MBES data, which in turn highlights the superior potential of low frequency MBES to image shallow sub-seafloor features. Small gas pockets could be resolved even on the outer swath (up to 65°). Strongly elevated backscattering from gassy areas occurred at large incidence angles and a high gas sensitivity of the MBES is further supported by an angular response analysis presented in this study. We conclude that the MBES together with subbottom profiling can be used as an efficient tool for spatial subbottom mapping in soft sediment environments

Measurement of the Induced Proton Polarization P_n in the 12C(e,e'\vec{p}) Reaction

The first measurements of the induced proton polarization, P_n, for the 12C (e,e'\vec{p}) reaction are reported. The experiment was performed at quasifree kinematics for energy and momentum transfer (\omega,q) \approx (294 MeV, 756 MeV/c) and sampled a recoil momentum range of 0-250 MeV/c. The induced polarization arises from final-state interactions and for these kinematics is dominated by the real part of the spin-orbit optical potential. The distorted-wave impulse approximation provides good agreement with data for the 1p_{3/2} shell. The data for the continuum suggest that both the 1s_{1/2} shell and underlying l > 1 configurations contribute.Comment: 5 pages LaTeX, 2 postscript figures, accepted by Physical Reveiw Letter

Novel Protein Disulfide Isomerase Inhibitor with Anticancer Activity in Multiple Myeloma

Multiple myeloma cells secrete more disulfide bond–rich proteins than any other mammalian cell. Thus, inhibition of protein disulfide isomerases (PDI) required for protein folding in the endoplasmic reticulum (ER) should increase ER stress beyond repair in this incurable cancer. Here, we report the mechanistically unbiased discovery of a novel PDI-inhibiting compound with antimyeloma activity. We screened a 30,355 small-molecule library using a multilayered multiple myeloma cell–based cytotoxicity assay that modeled disease niche, normal liver, kidney, and bone marrow. CCF642, a bone marrow–sparing compound, exhibited a submicromolar IC50 in 10 of 10 multiple myeloma cell lines. An active biotinylated analog of CCF642 defined binding to the PDI isoenzymes A1, A3, and A4 in MM cells. In vitro, CCF642 inhibited PDI reductase activity about 100-fold more potently than the structurally distinct established inhibitors PACMA 31 and LOC14. Computational modeling suggested a novel covalent binding mode in active-site CGHCK motifs. Remarkably, without any further chemistry optimization, CCF642 displayed potent efficacy in an aggressive syngeneic mouse model of multiple myeloma and prolonged the lifespan of C57BL/KaLwRij mice engrafted with 5TGM1-luc myeloma, an effect comparable to the first-line multiple myeloma therapeutic bortezomib. Consistent with PDI inhibition, CCF642 caused acute ER stress in multiple myeloma cells accompanied by apoptosis-inducing calcium release. Overall, our results provide an illustration of the utility of simple in vivo simulations as part of a drug discovery effort, along with a sound preclinical rationale to develop a new small-molecule therapeutic to treat multiple myeloma