Conditioning bounds for traveltime tomography in layered media

This paper revisits the problem of recovering a smooth, isotropic, layered wave speed profile from surface traveltime information. While it is classic knowledge that the diving (refracted) rays classically determine the wave speed in a weakly well-posed fashion via the Abel transform, we show in this paper that traveltimes of reflected rays do not contain enough information to recover the medium in a well-posed manner, regardless of the discretization. The counterpart of the Abel transform in the case of reflected rays is a Fredholm kernel of the first kind which is shown to have singular values that decay at least root-exponentially. Kinematically equivalent media are characterized in terms of a sequence of matching moments. This severe conditioning issue comes on top of the well-known rearrangement ambiguity due to low velocity zones. Numerical experiments in an ideal scenario show that a waveform-based model inversion code fits data accurately while converging to the wrong wave speed profile

Reciprocal regulation of PKA and rac signaling

Activated G protein-coupled receptors (GPCRs) and receptor tyrosine kinases relay extracellular signals through spatial and temporal controlled kinase and GTPase entities. These enzymes are coordinated by multifunctional scaffolding proteins for precise intracellular signal processing. The cAMP-dependent protein kinase A (PKA) is the prime example for compartmentalized signal transmission downstream of distinct GPCRs. A-kinase anchoring proteins tether PKA to specific intracellular sites to ensure precision and directionality of PKA phosphorylation events. Here, we show that the Rho-GTPase Rac contains A-kinase anchoring protein properties and forms a dynamic cellular protein complex with PKA. The formation of this transient core complex depends on binary interactions with PKA subunits, cAMP levels and cellular GTP-loading accounting for bidirectional consequences on PKA and Rac downstream signaling. We show that GTP-Rac stabilizes the inactive PKA holoenzyme. However, β-adrenergic receptor-mediated activation of GTP-Rac–bound PKA routes signals to the Raf-Mek-Erk cascade, which is critically implicated in cell proliferation. We describe a further mechanism of how cAMP enhances nuclear Erk1/2 signaling: It emanates from transphosphorylation of p21-activated kinases in their evolutionary conserved kinase-activation loop through GTP-Rac compartmentalized PKA activities. Sole transphosphorylation of p21-activated kinases is not sufficient to activate Erk1/2. It requires complex formation of both kinases with GTP-Rac1 to unleash cAMP-PKA–boosted activation of Raf-Mek-Erk. Consequently GTP-Rac functions as a dual kinase-tuning scaffold that favors the PKA holoenzyme and contributes to potentiate Erk1/2 signaling. Our findings offer additional mechanistic insights how β-adrenergic receptor-controlled PKA activities enhance GTP-Rac–mediated activation of nuclear Erk1/2 signaling

Extensive collection of femtoliter pad secretion droplets in beetle Leptinotarsa decemlineata allows nanoliter microrheology

Pads of beetles are covered with long, deformable setae, each ending in a micrometric terminal plate coated with secretory fluid. It was recently shown that the layer of the pad secretion covering the terminal plates is responsible for the generation of strong attractive forces. However, less is known about the fluid itself because it is produced in extremely small quantity. We here present a first experimental investigation of the rheological properties of the pad secretion in the Colorado potato beetle {\it Leptinotarsa decemlineata}. Because the secretion is produced in an extremely small amount at the level of the terminal plate, we first develop a procedure based on capillary effects to collect the secretion. We then manage to incorporate micrometric beads, initially in the form of a dry powder, and record their thermal motion to determine the mechanical properties of the surrounding medium. We achieve such a quantitative measurement within the collected volume, much smaller than the $1 {\rm \mu}$l sample volume usually required for this technique. Surprisingly, the beetle secretion was found to behave as a purely viscous liquid, of high viscosity. This suggests that no specific complex fluid behaviour is needed during beetle locomotion. We build a scenario for the contact formation between the spatula at the setal tip and a substrate, during the insect walk. We show that the attachment dynamics of the insect pad computed from the high measured viscosity is in good agreement with observed insect pace. We finally discuss the consequences of the secretion viscosity on the insect adhesion

lncRNA requirements for mouse acute myeloid leukemia and normal differentiation

A substantial fraction of the genome is transcribed in a cell type-specific manner, producing long non-coding RNAs (lncRNAs), rather than protein-coding transcripts. Here we systematically characterize transcriptional dynamics during hematopoiesis and in hematological malignancies. Our analysis of annotated and de novo assembled lncRNAs showed many are regulated during differentiation and mis-regulated in disease. We assessed lncRNA function via an in vivo RNAi screen in a model of acute myeloid leukemia. This identified several lncRNAs essential for leukemia maintenance, and found that a number act by promoting leukemia stem cell signatures. Leukemia blasts show a myeloid differentiation phenotype when these lncRNAs were depleted, and our data indicates that this effect is mediated via effects on the c-MYC oncogene. Bone marrow reconstitutions showed that a lncRNA expressed across all progenitors was required for the myeloid lineage, whereas the other leukemia-induced lncRNAs were dispensable in the normal setting

Bodies, technologies and action possibilities: when is an affordance?

Borrowed from ecological psychology, the concept of affordances is often said to offer the social study of technology a means of re-framing the question of what is, and what is not, ‘social’ about technological artefacts. The concept, many argue, enables us to chart a safe course between the perils of technological determinism and social constructivism. This article questions the sociological adequacy of the concept as conventionally deployed. Drawing on ethnographic work on the ways technological artefacts engage, and are engaged by, disabled bodies, we propose that the ‘affordances’ of technological objects are not reducible to their material constitution but are inextricably bound up with specific, historically situated modes of engagement and ways of life

A new Taxonomy of Continuous Global Optimization Algorithms

Surrogate-based optimization, nature-inspired metaheuristics, and hybrid combinations have become state of the art in algorithm design for solving real-world optimization problems. Still, it is difficult for practitioners to get an overview that explains their advantages in comparison to a large number of available methods in the scope of optimization. Available taxonomies lack the embedding of current approaches in the larger context of this broad field. This article presents a taxonomy of the field, which explores and matches algorithm strategies by extracting similarities and differences in their search strategies. A particular focus lies on algorithms using surrogates, nature-inspired designs, and those created by design optimization. The extracted features of components or operators allow us to create a set of classification indicators to distinguish between a small number of classes. The features allow a deeper understanding of components of the search strategies and further indicate the close connections between the different algorithm designs. We present intuitive analogies to explain the basic principles of the search algorithms, particularly useful for novices in this research field. Furthermore, this taxonomy allows recommendations for the applicability of the corresponding algorithms.Comment: 35 pages total, 28 written pages, 4 figures, 2019 Reworked Versio

The cross-entropy method for continuous multi-extremal optimization

In recent years, the cross-entropy method has been successfully applied to a wide range of discrete optimization tasks. In this paper we consider the cross-entropy method in the context of continuous optimization. We demonstrate the effectiveness of the cross-entropy method for solving difficult continuous multi-extremal optimization problems, including those with non-linear constraints

TRPM2 channel deficiency prevents delayed cytosolic Zn²⁺ accumulation and CA1 pyramidal neuronal death after transient global ischemia

Transient ischemia is a leading cause of cognitive dysfunction. Postischemic ROS generation and an increase in the cytosolic Zn²⁺ level ([Zn²⁺]c) are critical in delayed CA1 pyramidal neuronal death, but the underlying mechanisms are not fully understood. Here we investigated the role of ROS-sensitive TRPM2 (transient receptor potential melastatin-related 2) channel. Using in vivo and in vitro models of ischemia-reperfusion, we showed that genetic knockout of TRPM2 strongly prohibited the delayed increase in the [Zn²⁺]c, ROS generation, CA1 pyramidal neuronal death and postischemic memory impairment. Time-lapse imaging revealed that TRPM2 deficiency had no effect on the ischemia-induced increase in the [Zn²⁺]c but abolished the cytosolic Zn²⁺ accumulation during reperfusion as well as ROS-elicited increases in the [Zn²⁺]c. These results provide the first evidence to show a critical role for TRPM2 channel activation during reperfusion in the delayed increase in the [Zn²⁺]c and CA1 pyramidal neuronal death and identify TRPM2 as a key molecule signaling ROS generation to postischemic brain injury