Lenalidomide regulates CNS autoimmunity by promoting M2 macrophages polarization

Multiple sclerosis (MS) is a chronic and debilitating neurological disorder of the central nervous system (CNS), characterized by infiltration of leukocytes into CNS and subsequent demyelination. Emerging evidences have revealed the beneficial roles of M2 macrophages in ameliorating experimental autoimmune encephalomyelitis (EAE), a model for MS. Here, we identify that lenalidomide alone could promote macrophages M2 polarization to prevent the progression of EAE, which is associated with subsequent inhibition of proinflammatory Th1 and Th17 cells both in peripheral lymph system and CNS. Depletion of macrophages by pharmacology treatment of clodronate liposomes or transferring lenalidomide-induced BMDMs in EAE mice completely abolished the therapeutic effect of lenalidomide or prevented EAE development, respectively. The macrophages-derived IL10 was upregulated both in vivo and in vitro after lenalidomide treatment. Moreover, lenalidomide-treated IL10-dificient EAE mice had higher clinical scores and more severe CNS damage, and intravenous injection of lenalidomide-treated IL10BMDMs into mice with EAE at disease onset did not reverse disease severity, implying IL10 may be essential in lenalidomide-ameliorated EAE. Mechanistically, lenalidomide significantly increased expression and autocrine secretion of IL10, subsequently activated STAT3-mediated expression of Ym1. These studies facilitate the development of potential novel therapeutic application of lenalidomide for the treatment of MS

A muon-track reconstruction exploiting stochastic losses for large-scale Cherenkov detectors

IceCube is a cubic-kilometer Cherenkov telescope operating at the South Pole. The main goal of IceCube is the detection of astrophysical neutrinos and the identification of their sources. High-energy muon neutrinos are observed via the secondary muons produced in charge current interactions with nuclei in the ice. Currently, the best performing muon track directional reconstruction is based on a maximum likelihood method using the arrival time distribution of Cherenkov photons registered by the experiment\u27s photomultipliers. A known systematic shortcoming of the prevailing method is to assume a continuous energy loss along the muon track. However at energies >1 TeV the light yield from muons is dominated by stochastic showers. This paper discusses a generalized ansatz where the expected arrival time distribution is parametrized by a stochastic muon energy loss pattern. This more realistic parametrization of the loss profile leads to an improvement of the muon angular resolution of up to 20% for through-going tracks and up to a factor 2 for starting tracks over existing algorithms. Additionally, the procedure to estimate the directional reconstruction uncertainty has been improved to be more robust against numerical errors

Wave-induced Hydrodynamic Responses of an Immersed Rigid Body Connected with Elastic Plates in a Two-layer Fluid

AbstractA new physical model for very large floating structures (VLFSs) connected with an immersed module is investigated for a two-layer fluid, which may provide the basic knowledge to analyze multi-module floating structures in the stratified ocean. Under the hypothesis of small-amplitude wave theory, the case with the coupling effects by the wave motion, elastic deformation of the plate and the rigid body's oscillation is solved by considering a scattering problem and a radiation one. An inner product with orthogonality is used to calculate the undetermined coefficients in eigenfunction expansions. The exciting forces and the coefficients for added mass, damping, and stiffness are obtained

Geochemistry of Sinian tillites from Hunan Province, South China - A test of the Snowball Earth hypothesis

A glaciomarine succession of Neoproterozoic age (between 748–584 Ma) is widespread on the Yangtze Platform, South China. The deposition took place during an intermediate to low paleolatitude position of the Yangtze Platform. The Snowball Earth hypothesis offers an explanation for the occurrence of low-latitude tillites in general. It is basedon records obtained of deposits underlying and overlying the tillites. In contrast, we focused on the tillites themselves by using geochemistry to obtain detailed information about the conditions during the glaciation. Of particular interest are environmental conditions, which are closely related to the climate development. Additionally, stable isotope geochemistry was used for a paleoclimate interpretation. The geochemical results of the Sinian glacial succession on the Yangtze Platform are compared to the predictions made by the Snowball Earth hypothesis.Nicole Dobrzinski, Heinrich Bahlburg, Harald Straus

Zeb2 recruits HDAC-NuRD to inhibit Notch and controls Schwann cell differentiation and remyelination

The mechanisms that coordinate and balance a complex network of opposing regulators to control Schwann cell (SC) differentiation remain elusive. Here we demonstrate that zinc-finger E-box-binding homeobox 2 (Zeb2, also called Sip1) transcription factor is a critical intrinsic timer that controls the onset of SC differentiation by recruiting histone deacetylases HDAC 1 and 2 (HDAC1/2) and nucleosome remodeling and deacetylase complex (NuRD) co-repressor complexes in mice. Zeb2 deletion arrests SCs at an undifferentiated state during peripheral nerve development and inhibits remyelination after injury. Zeb2 antagonizes inhibitory effectors including Notch and Sox2. Importantly, genome-wide transcriptome analysis reveals a Zeb2 target gene encoding the Notch effector Hey2 as a potent inhibitor for Schwann cell differentiation. Strikingly, a genetic Zeb2 variant associated with Mowat-Wilson syndrome disrupts the interaction with HDAC1/2-NuRD and abolishes Zeb2 activity for SC differentiation. Therefore, Zeb2 controls SC maturation by recruiting HDAC1/2-NuRD complexes and inhibiting a Notch-Hey2 signaling axis, pointing to the critical role of HDAC1/2-NuRD activity in peripheral neuropathies caused by ZEB2 mutations