In memoriam : docteur Jean-Paul Cagnard Muller, J.-Y.
Transfusion clinique et biologique : journal de la Société française de transfusion sanguine,
20/May , Letnik:
25, Številka:
2
Journal Article
Spaceborne Synthetic Aperture Radar (SAR) sensors obtain regular and frequent radar images from which ground motion can be precisely detected using a variety of different techniques. The ability to ...measure slope displacements remotely over large regions can have many uses, although the limitations of the most commonplace technique, differential InSAR (D-InSAR), must be considered prior to interpreting the final results. One such limitation is the assumption that different rates of movement over a given distance cannot exceed a threshold value, dependent upon the pixel spacing of the SAR images and the radar wavelength. Characteristic features of landslides (i.e. the sharp boundary between stable/active ground and the range of temporally-variable velocities) can exhibit high spatial displacement gradients, breaking a fundamental assumption for reliable D-InSAR analysis. Areas of low coherence are also known to hinder the exploitation of InSAR data. This study assesses the capability of TerraSAR-X Spotlight, TerraSAR-X Stripmap and Envisat Stripmap images for monitoring the slow-moving Shuping landslide in the densely vegetated Three Gorges region, China. In this case study, the episodic nature of movement is shown to exceed the measurable limit for regular D-InSAR analysis even for the highest resolution 11-day TSX Spotlight interferograms. A Sub-Pixel Offset Time-series technique applied to corner reflectors (SPOT-CR) using only the SAR amplitude information is applied as a robust method of resolving time-varying displacements, with verifiable offset measurements presented from TSX Spotlight and TSX Stripmap imagery. Care should be exercised when measuring potentially episodic landslide movements in densely vegetated areas such as the Three Gorges region and corner reflectors are shown to be highly useful for SPOT techniques even when the assumptions for valid D-InSAR analysis are broken. Finally the capability to derive two-dimensional movements from sub-pixel offsets (in range and along-track directions) can be used to derive estimates of the vertical and northwards movements to help infer the landslide failure mechanism.
•InSAR and sub-pixel offset results from 3 different SAR datasets are compared.•SAR sub-pixel offsets successfully measured fast, episodic landslide movements.•Corner reflectors generated verifiable offsets in densely vegetated terrain.•Time-series offsets show landslide movement related to reservoir lowering.•A rotational component of the Shuping landslide is inferred for the first time.
We review three common methods to estimate predicted probabilities following confounder-adjusted logistic regression: marginal standardization (predicted probabilities summed to a weighted average ...reflecting the confounder distribution in the target population); prediction at the modes (conditional predicted probabilities calculated by setting each confounder to its modal value); and prediction at the means (predicted probabilities calculated by setting each confounder to its mean value). That each method corresponds to a different target population is underappreciated in practice. Specifically, prediction at the means is often incorrectly interpreted as estimating average probabilities for the overall study population, and furthermore yields nonsensical estimates in the presence of dichotomous confounders. Default commands in popular statistical software packages often lead to inadvertent misapplication of prediction at the means.
Using an applied example, we demonstrate discrepancies in predicted probabilities across these methods, discuss implications for interpretation and provide syntax for SAS and Stata.
Marginal standardization allows inference to the total population from which data are drawn. Prediction at the modes or means allows inference only to the relevant stratum of observations. With dichotomous confounders, prediction at the means corresponds to a stratum that does not include any real-life observations.
Marginal standardization is the appropriate method when making inference to the overall population. Other methods should be used with caution, and prediction at the means should not be used with binary confounders. Stata, but not SAS, incorporates simple methods for marginal standardization.
Pyroptosis is a lytic type of cell death that is initiated by inflammatory caspases. These caspases are activated within multi‐protein inflammasome complexes that assemble in response to pathogens ...and endogenous danger signals. Pyroptotic cell death has been proposed to proceed via the formation of a plasma membrane pore, but the underlying molecular mechanism has remained unclear. Recently, gasdermin D (GSDMD), a member of the ill‐characterized gasdermin protein family, was identified as a caspase substrate and an essential mediator of pyroptosis. GSDMD is thus a candidate for pyroptotic pore formation. Here, we characterize GSDMD function in live cells and in vitro. We show that the N‐terminal fragment of caspase‐1‐cleaved GSDMD rapidly targets the membrane fraction of macrophages and that it induces the formation of a plasma membrane pore. In vitro, the N‐terminal fragment of caspase‐1‐cleaved recombinant GSDMD tightly binds liposomes and forms large permeability pores. Visualization of liposome‐inserted GSDMD at nanometer resolution by cryo‐electron and atomic force microscopy shows circular pores with variable ring diameters around 20 nm. Overall, these data demonstrate that GSDMD is the direct and final executor of pyroptotic cell death.
Synopsis
Inflammatory caspases induce a lytic type of cell death known as pyroptosis by cleaving the protein gasdermin D. New findings show that cleaved gasdermin D targets the plasma membrane, where it forms a large permeability pore.
Pyroptosis induction involves the cleavage of gasdermin D by inflammatory caspases.
The N‐terminal fragment of gasdermin D targets cellular membranes and leads to plasma membrane permeabilization.
Gasdermin D targets and permeabilizes liposome membranes after in vitro cleavage by caspase‐1.
A caspase‐1‐processed fragment of gasdermin D inserts into plasma membranes to form large permeable pores, demonstrating the direct role of gasdermin D in pyroptotic cell death.
Discovery of IDO1 Inhibitors: From Bench to Bedside Prendergast, George C; Malachowski, William P; DuHadaway, James B ...
Cancer research (Chicago, Ill.),
12/2017, Letnik:
77, Številka:
24
Journal Article
Recenzirano
Odprti dostop
Small-molecule inhibitors of indoleamine 2,3-dioxygenase-1 (IDO1) are emerging at the vanguard of experimental agents in oncology. Here, pioneers of this new drug class provide a bench-to-bedside ...review on preclinical validation of IDO1 as a cancer therapeutic target and on the discovery and development of a set of mechanistically distinct compounds, indoximod, epacadostat, and navoximod, that were first to be evaluated as IDO inhibitors in clinical trials. As immunometabolic adjuvants to widen therapeutic windows, IDO inhibitors may leverage not only immuno-oncology modalities but also chemotherapy and radiotherapy as standards of care in the oncology clinic.
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This handbook aims to provide a complete overview of modern floating-point arithmetic, including a detailed treatment of the newly revised (IEEE 754-2008) standard for floating-point arithmetic. ...Presented throughout are algorithms for implementing floating-point arithmetic as well as algorithms that use floating-point arithmetic. So that the techniques presented can be put directly into practice in actual coding or design, they are illustrated, whenever possible, by a corresponding program. Key topics and features include a presentation of the history and basic concepts of floating-point arithmetic, a development of smart and nontrivial algorithms, and algorithmic possibilities induced by the availability of a fused multiply-add (fma) instruction, implementation of floating-point arithmetic either in software-on an integer processor-or hardware, and a discussion of issues related to compilers and languages, coverage of several recent advances related to elementary functions, and extensions of floating-point arithmetic such as certification, verification, and precision. Handbook of Floating-Point Arithmetic is designed for programmers of numerical applications, compiler designers, programmers of floating-point algorithms, designers of arithmetic operators, and more generally, students and researchers in numerical analysis who wish to better understand a tool used in their daily work and research. TOC:List of Figures.- List of Tables.- Preface.- Part I. Introduction, Basic Definitions, and Standards. Introduction.- Definitions and Basic Notions.- Floating-Point Formats and Environment.- Part II. Cleverly Using Floating-Point Arithmetic. Basic Properties and Algorithms.- The Fused Multiply-Add Instructions.- Enhanced Floating-Point Sums, Dot Products, and Polynomial Values.- Languages and Compilers.- Part III. Implementing Floating-Point Operators. Algorithms for the Five Basic Operations.- Hardware Implementation of Floating-Point Arithmetic.- Software Implementation of Floating-Point Arithmetic.- Part IV. Elementary Functions. Evaluating Floating-Point Elementary Functions.- Solving the Table Maker`s Dilemma.- Part V. Extensions. Formalisms for Certifying Floating-Point Algorithms.- Extending the Precision.- Part VI. Perspectives and Appendix. Conclusion and Perspectives.- Appendix: Number Theory Tools for Floating-Point Arithmetic.- Bibliography.- Index.
In about half of all human cancers, the tumor suppressor p53 protein is either lost or mutated, frequently resulting in the expression of a transcriptionally inactive mutant p53 protein. Loss of p53 ...function is well known to influence cell cycle checkpoint controls and apoptosis. But it is now clear that p53 regulates other key stages of metastatic progression, such as cell migration and invasion. Moreover, recent data suggests that expression of mutant p53 is not the equivalent of p53 loss, and that mutant p53s can acquire new functions to drive cell migration, invasion, and metastasis, in part by interfering with p63 function.
Abstract
In models of radiative–convective equilibrium it is known that convection can spontaneously aggregate into one single localized moist region if the domain is large enough. The large changes ...in the mean climate state and radiative fluxes accompanying this self-aggregation raise questions as to what simulations at lower resolutions with parameterized convection, in similar homogeneous geometries, should be expected to produce to be considered successful in mimicking a cloud-resolving model.
The authors investigate this self-aggregation in a nonrotating, three-dimensional cloud-resolving model on a square domain without large-scale forcing. It is found that self-aggregation is sensitive not only to the domain size, but also to the horizontal resolution. With horizontally homogeneous initial conditions, convective aggregation only occurs on domains larger than about 200km and with resolutions coarser than about 2km in the model examined. The system exhibits hysteresis, so that with aggregated initial conditions, convection remains aggregated even at our finest resolution, 500m, as long as the domain is greater than 200–300km.
The sensitivity of self-aggregation to resolution and domain size in this model is due to the sensitivity of the distribution of low clouds to these two parameters. Indeed, the mechanism responsible for the aggregation of convection is the dynamical response to the longwave radiative cooling from low clouds. Strong longwave cooling near cloud top in dry regions forces downward motion, which by continuity generates inflow near cloud top and near-surface outflow from dry regions. This circulation results in the net export of moist static energy from regions with low moist static energy, yielding a positive feedback.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Nirsevimab is a monoclonal antibody to the RSV fusion protein that has an extended half-life. In this clinical trial, a single dose of nirsevimab resulted in a significantly lower incidence of ...medically attended RSV-associated lower respiratory tract infection than that with placebo.
With immunotherapy enjoying a rapid resurgence based on the achievement of durable remissions in some patients with agents that derepress immune function, commonly referred to as “checkpoint ...inhibitors,” enormous attention developed around the IDO1 enzyme as a metabolic mediator of immune escape in cancer. In particular, outcomes of multiple phase 1/2 trials encouraged the idea that small molecule inhibitors of IDO1 may improve patient responses to anti-PD1 immune checkpoint therapy. However, recent results from ECHO-301, the first large phase 3 trial to evaluate an IDO1-selective enzyme inhibitor (epacadostat) in combination with an anti-PD1 antibody (pembrolizumab) in advanced melanoma, showed no indication that epacadostat provided an increased benefit. Here we discuss several caveats associated with this failed trial. First is the uncertainty as to whether the target was adequately inhibited. In particular, there remains a lack of direct evidence regarding the degree of IDO1 inhibition within the tumor, and previous trial data suggest that sufficient drug exposure may not have been achieved at the dose tested in ECHO-301. Second, while there is a mechanistic rationale for the combination tested, the preclinical data were not particularly compelling. More efficacious combinations have been demonstrated with DNA damaging modalities which may therefore be a more attractive alternative. Third, as a highly selective IDO1 inhibitor, epacadostat was advanced aggressively despite preclinical genetic evidence of tumors bypassing IDO1 blockade. Indeed, a well-grounded literature starting in 2011 points to targeting strategies that account for both IDO and tryptophan 2,3-dioxygenase as more appealing directions to pursue, including dual inhibitors and inhibitors of nodal downstream effector pathways such as aryl hydrocarbon receptor blockade. Overall, the clinical readout from a single trial with significant limitations is by no means a definitive test for the field. While biomarker information yet to be gleaned from ECHO-301 may yet reveal useful information regarding IDO1 pathway drugs, better rationalized compounds and better rationalized trial designs will be important in the future to accurately gauge medical impact.
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