A novel role for Hedgehog in T-cell receptor signaling: implications for development and immunity

The Hedgehog (Hh) signaling pathway is a key regulator of both embryonic development and homeostasis of adult tissues, including thymus and blood. In the thymus, Hh signals for differentiation, survival and proliferation in the early stages of T cell development, before TCR gene rearrangement. Our recent data has shown that Hh signaling also modulates T cell receptor (TCR) signal strength in more mature T lineage cells. We showed that constitutive activation of the Hh pathway in thymocytes (by transgenic expression of the transcriptional activator form of Gli2) decreased TCR signal strength with profound consequences for the thymus--allowing self-reactive T cells to escape deletion and altering T cell CD4/CD8 lineage decisions. In contrast, in the Sonic Hh deficient thymus, TCR signaling was increased, again influencing both TCR repertoire selection and CD4/8 lineage commitment. In peripheral T cells, the transcriptional changes induced by activation of the Hh signaling pathway lead to reduced T cell activation. Hh signaling also attenuated ERK phosphorylation and proliferation in mature T cells on TCR ligation. Modulation of TCR signal strength by Hh pathway activation has importance for immunity as the presence or absence of Hh in the environment in which a T cell is activated would shape the immune response

A review of High Performance Computing foundations for scientists

The increase of existing computational capabilities has made simulation emerge as a third discipline of Science, lying midway between experimental and purely theoretical branches [1, 2]. Simulation enables the evaluation of quantities which otherwise would not be accessible, helps to improve experiments and provides new insights on systems which are analysed [3-6]. Knowing the fundamentals of computation can be very useful for scientists, for it can help them to improve the performance of their theoretical models and simulations. This review includes some technical essentials that can be useful to this end, and it is devised as a complement for researchers whose education is focused on scientific issues and not on technological respects. In this document we attempt to discuss the fundamentals of High Performance Computing (HPC) [7] in a way which is easy to understand without much previous background. We sketch the way standard computers and supercomputers work, as well as discuss distributed computing and discuss essential aspects to take into account when running scientific calculations in computers.Comment: 33 page

Smoothing a program soundly and robustly

We study the foundations of smooth interpretation, a recently-proposed program approximation scheme that facilitates the use of local numerical search techniques (e.g., gradient descent) in program analysis and synthesis. While the popular techniques for local optimization works well only on relatively smooth functions, functions encoded by real-world programs are infested with discontinuities and local irregular features. Smooth interpretation attenuates such features by taking the convolution of the program with a Gaussian function, effectively replacing discontinuous switches in the program by continuous transitions. In doing so, it extends to programs the notion of Gaussian smoothing, a popular signal-processing technique used to filter noise and discontinuities from signals. Exact Gaussian smoothing of programs is undecidable, so algorithmic implementations of smooth interpretation must necessarily be approximate. In this paper, we characterize the approximations carried out by such algorithms. First, we identify three correctness properties—soundness, robustness, and β-robustness—that an approximate smooth interpreter should satisfy. In particular, a smooth interpreter is sound if it computes an abstraction of a program’s “smoothed” semantics, and robust if it has arbitrary-order derivatives in the input variables at every point in its input space. Second, we describe the design of an approximate smooth interpreter that provably satisfies these properties. The interpreter combines program abstraction using a new domain with symbolic calculation of convolution.National Science Foundation (U.S.) (Grant CCF-0953507)Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laborator

Relaxation of Surface Profiles by Evaporation Dynamics

We present simulations of the relaxation towards equilibrium of one dimensional steps and sinusoidal grooves imprinted on a surface below its roughening transition. We use a generalization of the hypercube stacking model of Forrest and Tang, that allows for temperature dependent next-nearest-neighbor interactions. For the step geometry the results at T=0 agree well with the t^(1/4) prediction of continuum theory for the spreading of the step. In the case of periodic profiles we modify the mobility for the tips of the profile and find the approximate solution of the resulting free boundary problem to be in reasonable agreement with the T=0 simulations.Comment: 6 pages, Revtex, 5 Postscript figures, to appear in PRB 15, October 199

The rheological behavior of CO2 ice: application to glacial flow on Mars

Vast amounts of solid CO2 reside in topographic basins of the south polar layered deposits (SPLD) on Mars and exhibit morphological features indicative of glacial flow. Previous experimental studies showed that coarse-grained CO2 ice is 1–2 orders of magnitude weaker than water ice under Martian polar conditions. Here we present data from a series of deformation experiments on high-purity, fine-grained CO2 ice over a broader range of temperatures than previously explored (158–213 K). The experiments confirm previous observations of highly non-linear power-law creep at larger stresses, but also show a transition to a previously-unseen linear-viscous creep regime at lower stresses. We examine the viscosity of CO2 within the SPLD and predict that the CO2-rich layers may be stronger than previously thought. We also predict that CO2 ice flows much more readily than H2O ice on steep flanks of SPLD topographic basins, allowing the CO2 to pond as observed.National Aeronautics and Space Administration (NASA) NNH16ZDA001N-SS

The rheological behavior of CO2 ice: application to glacial flow on Mars

Author Posting. © American Geophysical Union, 2020. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geophysical Research Letters 47(22), (2020): e2020GL090431, doi:10.1029/2020GL090431.Vast quantities of solid CO2 reside in topographic basins of the south polar layered deposits (SPLD) on Mars and exhibit morphological features indicative of glacial flow. Previous experimental studies showed that CO2 ice is 1–2 orders of magnitude weaker than water ice under Martian polar conditions. Here we present data from deformation experiments on pure, fine‐grained CO2 ice, over a broader range of temperatures than previously explored (158–213 K). The experiments confirm previous observations of highly nonlinear power law creep at larger stresses, but also show a transition to a previously unseen linear‐viscous creep regime at lower stresses. We examine the viscosity of CO2 within the SPLD and predict that the CO2‐rich deposits are modestly stronger than previously thought. Nevertheless, CO2 ice flows much more readily than H2O ice, particularly on the steep flanks of SPLD topographic basins, allowing the CO2 to pond as observed.This work was funded by NASA grant NNH16ZDA001N‐SSW awarded to Smith and Goldsby. Additional salary support for Cross was provided by the WHOI Investment in Science Fund.2021-04-2

The POLST program: a retrospective review of the demographics of use and outcomes in one community where advance directives are prevalent

OBJECTIVES: Determine the use and utility of the Physician Orders for Life-Sustaining Treatment (POLST) program in a community where powers of attorney for health care (POAHCs) are prevalent. METHODS: A retrospective review of medical record and death certificate data of 400 adults who died between September 1, 2007, and March 31, 2008, in the La Crosse County, Wisconsin community. Demographic and cause-of-death data were collected from death certificates. Information about POAHC, POLST forms, and medical treatments provided in the last 30 days of life were abstracted from decedents' medical records. RESULTS: Sixty-seven percent of decedents had a POLST form, whereas 22% had POAHC alone. In comparison with decedents with POAHC alone, decedents with a POLST form were significantly older (83 versus 77 years, p<0.001), more likely to die in a nursing home than in a hospital (p<0.001), and more likely to die from a terminal or chronic illnesses (97%). Decedents with POLST orders for higher levels of medical treatment received more treatment, and in only two cases was there evidence that treatment was discrepant with POLST orders. In 31% of all POLST forms, the person appointed in the POAHC consented to the POLST orders. CONCLUSIONS: POLST can be a highly effective program to ensure that patient preferences are known and honored in all settings. POAHCs are valuable because they identify appropriate surrogates when patients are incapacitated

Carrier-density effects in many-polaron systems

Many-polaron systems with finite charge-carrier density are often encountered experimentally. However, until recently, no satisfactory theoretical description of these systems was available even in the framework of simple models such as the one-dimensional spinless Holstein model considered here. In this work, previous results obtained using numerical as well as analytical approaches are reviewed from a unified perspective, focussing on spectral properties which reveal the nature of the quasiparticles in the system. In the adiabatic regime and for intermediate electron-phonon coupling, a carrier-density driven crossover from a polaronic to a rather metallic system takes place. Further insight into the effects due to changes in density is gained by calculating the phonon spectral function, and the fermion-fermion and fermion-lattice correlation functions. Finally, we provide strong evidence against the possibility of phase separation.Comment: 13 pages, 6 figures, accepted for publication in J. Phys.: Condens. Matter; final versio

Flow properties of driven-diffusive lattice gases: theory and computer simulation

We develop n-cluster mean-field theories (0 < n < 5) for calculating the flow properties of the non-equilibrium steady-states of the Katz-Lebowitz-Spohn model of the driven diffusive lattice gas, with attractive and repulsive inter-particle interactions, in both one and two dimensions for arbitrary particle densities, temperature as well as the driving field. We compare our theoretical results with the corresponding numerical data we have obtained from the computer simulations to demonstrate the level of accuracy of our theoretical predictions. We also compare our results with those for some other prototype models, notably particle-hopping models of vehicular traffic, to demonstrate the novel qualitative features we have observed in the Katz-Lebowitz-Spohn model, emphasizing, in particular, the consequences of repulsive inter-particle interactions.Comment: 12 RevTex page