Sequential Wnt Agonist then Antagonist Treatment Accelerates Tissue Repair and Minimizes Fibrosis

Tissue fibrosis compromises organ function and occurs as a potential long-term outcome in response to acute tissue injuries. Currently, lack of mechanistic understanding prevents effective prevention and treatment of the progression from acute injury to fibrosis. Here, we combined quantitative experimental studies with a mouse kidney injury model and a computational approach to determine how the physiological consequences are determined by the severity of ischemia injury, and to identify how to manipulate Wnt signaling to accelerate repair of ischemic tissue damage while minimizing fibrosis. The study reveals that Wnt-mediated memory of prior injury contributes to fibrosis progression, and ischemic preconditioning reduces the risk of death but increases the risk of fibrosis. Furthermore, we validated the prediction that sequential combination therapy of initial treatment with a Wnt agonist followed by treatment with a Wnt antagonist can reduce both the risk of death and fibrosis in response to acute injuries

Boosted Schwarzschild Metrics from a Kerr-Schild Perspective

The Kerr-Schild version of the Schwarzschild metric contains a Minkowski background which provides a definition of a boosted black hole. There are two Kerr-Schild versions corresponding to ingoing or outgoing principle null directions. We show that the two corresponding Minkowski backgrounds and their associated boosts have an unexpected difference. We analyze this difference and discuss the implications in the nonlinear regime for the gravitational memory effect resulting from the ejection of massive particles from an isolated system. We show that the nonlinear effect agrees with the linearized result based upon the retarded Green function only if the velocity of the ejected particle corresponds to a boost symmetry of the ingoing Minkowski background. A boost with respect to the outgoing Minkowski background is inconsistent with the absence of ingoing radiation from past null infinity.Comment: 13 pages, matches published versio

Corporate influence and the academic computer science discipline. [4: CMU]

Prosopographical work on the four major centers for computer research in the United States has now been conducted, resulting in big questions about the independence of, so called, computer science

The Aemulus Project II: Emulating the Halo Mass Function

Existing models for the dependence of the halo mass function on cosmological parameters will become a limiting source of systematic uncertainty for cluster cosmology in the near future. We present a halo mass function emulator and demonstrate improved accuracy relative to state-of-the-art analytic models. In this work, mass is defined using an overdensity criteria of 200 relative to the mean background density. Our emulator is constructed from the AEMULUS simulations, a suite of 40 N-body simulations with snapshots from z=3 to z=0. These simulations cover the flat wCDM parameter space allowed by recent Cosmic Microwave Background, Baryon Acoustic Oscillation and Type Ia Supernovae results, varying the parameters w, Omega_m, Omega_b, sigma_8, N_{eff}, n_s, and H_0. We validate our emulator using five realizations of seven different cosmologies, for a total of 35 test simulations. These test simulations were not used in constructing the emulator, and were run with fully independent initial conditions. We use our test simulations to characterize the modeling uncertainty of the emulator, and introduce a novel way of marginalizing over the associated systematic uncertainty. We confirm non-universality in our halo mass function emulator as a function of both cosmological parameters and redshift. Our emulator achieves better than 1% precision over much of the relevant parameter space, and we demonstrate that the systematic uncertainty in our emulator will remain a negligible source of error for cluster abundance studies through at least the LSST Year 1 data set.Comment: https://aemulusproject.github.io

Energy-based trajectory tracking and vibration control for multilink highly flexible manipulators

In this paper, a discrete model is adopted, as proposed by Hencky for elastica based on rigid bars and lumped rotational springs, to design the control of a lightweight planar manipulator with multiple highly flexible links. This model is particularly suited to deal with nonlinear equations of motion as those associated with multilink robot arms, because it does not include any simplification due to linearization, as in the assumed modes method. The aim of the control is to track a trajectory of the end effector of the robot arm, without the onset of vibrations. To this end, an energy-based method is proposed. Numerical simulations show the effectiveness of the presented approach

Novel roles for mucin 1 in the kidney

Purpose of review Recent studies in the kidney have revealed that the well characterized tumor antigen mucin 1 (MUC1/Muc1) also has numerous functions in the normal and injured kidney. Recent findings Mucin 1 is a transmembrane mucin with a robust glycan-dependent apical targeting signal and efficient recycling from endosomes. It was recently reported that the TRPV5 calcium channel is stabilized on the cell surface by galectin-dependent cross-linking to mucin 1, providing a novel mechanism for regulation of ion channels and normal electrolyte balance. Our recent studies in mice show that Muc 1 is induced after ischemia, stabilizing hypoxia-inducible factor 1 (HIF-1)α and β-catenin levels, and transactivating the HIF-1 and β-catenin protective pathways. However, prolonged induction of either pathway in the injured kidney can proceed from apparent full recovery to chronic kidney disease. A very recent report indicates that aberrant activation of mucin 1 signaling after ischemic injury in mice and humans is associated with development of chronic kidney disease and fibrosis. A frameshift mutation in MUC1 was recently identified as the genetic lesion causing medullary cystic kidney disease type 1, now appropriately renamed MUC1 Kidney Disease. Summary Studies of mucin 1 in the kidney now reveal significant functions for the extracellular mucin-like domain and signaling through the cytoplasmic tail

Association of Coding Variants in Hydroxysteroid 17-beta Dehydrogenase 14 (HSD17B14) with Reduced Progression to End Stage Kidney Disease in Type 1 Diabetes

Background Rare variants ingenecodingregions likely have agreater impactondisease-relatedphenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of ESKD in individuals with type 1 diabetes at advanced kidney disease stage. Methods Gene-basedexome array analyses of15,449genes infivelarge incidence cohortsof individualswith type 1diabetes andproteinuriawere analyzedfor survival time toESKD, testing the top gene in a sixth cohort (n52372/1115 events all cohorts) and replicating in two retrospective case-control studies (n51072 cases, 752 controls). Deep resequencing of the top associated gene in five cohorts confirmed the findings. We performed immunohistochemistry and gene expression experiments in human control and diseased cells, and in mouse ischemia reperfusion and aristolochic acid nephropathy models. Results Protein coding variants in the hydroxysteroid 17- b dehydrogenase 14 gene (HSD17B14), predicted to affect protein structure, had a net protective effect against development of ESKD at exome-wide significance (n54196; P value53.331027). The HSD17B14 gene and encoded enzyme were robustly expressed in healthy human kidney, maximally in proximal tubular cells. Paradoxically, gene and protein expression were attenuated in human diabetic proximal tubules and in mouse kidney injury models. Expressed HSD17B14 gene and protein levels remained low without recovery after 21 days in a murine ischemic reperfusion injury model. Decreased gene expression was found in other CKD-associated renal pathologies. Conclusions HSD17B14 gene ismechanistically involved in diabetic kidney disease. The encoded sex steroid enzyme is a druggable target, potentially opening a new avenue for therapeutic development.Peer reviewe