Treatment with Natalizumab in Relapsing–Remitting Multiple Sclerosis Patients Induces Changes in Inflammatory Mechanism

Natalizumab is a widely accepted drug for the relapsing–remitting subtype of multiple sclerosis (RRMS). The present longitudinal exploratory study in RRMS patients analyzes the effects of natalizumab treatment on the levels of pro-inflammatory and anti-inflammatory cytokine protein levels and also the frequency and suppressor function of regulatory T cells. Flow cytometry was used to determine cytokines and regulatory T cell frequency while regulatory T cell suppressor function was assayed in vitro at different time-points after starting with natalizumab. Results showed serum levels of pro-inflammatory interferon gamma and interleukin (IL)-12p70, as well as anti-inflammatory IL-4 and IL-10, were elevated just a few hours or days after first IV infusion of natalizumab. Interestingly, other cytokines like IL-5 or IL-13 were also elevated while pro-inflammatory IL-17, IL-2, and IL-1β increased only after a long-term treatment, suggesting different immune mechanisms. In contrast, we did not observe any effect of natalizumab treatment on regulatory T cell frequency or activity. In conclusion, these results suggest natalizumab has other immunological effects beyond VLA-4 interaction and inhibition of CNS extravasation, the relevance of which is as yet unknown and warrants further investigation

Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery

The seismicity of Mars

The InSight (Interior Exploration using Seismic Investigations, Geodesy and Heat Transport) mission landed in Elysium Planitia on Mars on 26 November 2018 and fully deployed its seismometer by the end of February 2019. The mission aims to detect, characterize and locate seismic activity on Mars, and to further constrain the internal structure, composition and dynamics of the planet. Here, we present seismometer data recorded until 30 September 2019, which reveal that Mars is seismically active. We identify 174 marsquakes, comprising two distinct populations: 150 small-magnitude, high-frequency events with waves propagating at crustal depths and 24 low-frequency, subcrustal events of magnitude Mw 3–4 with waves propagating at various depths in the mantle. These marsquakes have spectral characteristics similar to the seismicity observed on the Earth and Moon. We determine that two of the largest detected marsquakes were located near the Cerberus Fossae fracture system. From the recorded seismicity, we constrain attenuation in the crust and mantle, and find indications of a potential low-S-wave-velocity layer in the upper mantle. © 2020, The Author(s), under exclusive licence to Springer Nature Limited.We acknowledge NASA, CNES and its partner agencies and institutions (UKSA, SSO, DLR, JPL, IPGP-CNRS, ETHZ, IC and MPS-MPG) and the flight operations team at JPL, SISMOC, MSDS, IRIS-DMC and PDS for providing SEIS data. The Swiss co-authors were jointly funded by (1) the Swiss National Science Foundation and French Agence Nationale de la Recherche (SNF-ANR project 157133 ‘Seismology on Mars’), (2) the Swiss National Science Foundation (SNF project 172508 ‘Mapping the internal structure of Mars’), (3) the Swiss State Secretariat for Education, Research and Innovation (SEFRI project ‘MarsQuake Service-Preparatory Phase’) and (4) ETH Research grant no. ETH-06 17-02. Additional support came from the Swiss National Supercomputing Centre (CSCS) under project ID s922. The Swiss contribution in the implementation of the SEIS electronics was made possible by funding from the federal Swiss Space Office (SSO) and contractual and technical support from the ESA-PRODEX office. The French Team acknowledge the French Space Agency CNES, which has supported and funded all SEIS-related contracts and CNES employees, as well as CNRS and the French team universities for personal and infrastructure support. Additional support was provided by ANR (ANR-14-CE36-0012-02 and ANR-19-CE31-0008-08) and, for the IPGP team, by the UnivEarthS Labex programme (ANR-10-LABX-0023), IDEX Sorbonne Paris Cité (ANR-11-IDEX-0005-0). SEIS-SP development and delivery were funded by the UK Space Agency. A portion of the work was carried out at the InSight Project at the Jet Propulsion Laboratory, California Institute of Technology, under a contract with the National Aeronautics and Space Administration. The MPS SEIS team acknowledges funding for development of the SEIS leveling system by the DLR German Space Agency. We thank gempa GmbH for software development related to the MQS tools. This paper is InSight contribution number 102.Peer reviewe

The Novel Adaptor Protein Tks4 (SH3PXD2B) Is Required for Functional Podosome Formation

Metastatic cancer cells have the ability to both degrade and migrate through the extracellular matrix (ECM). Invasiveness can be correlated with the presence of dynamic actin-rich membrane structures called podosomes or invadopodia. We showed previously that the adaptor protein tyrosine kinase substrate with five Src homology 3 domains (Tks5)/Fish is required for podosome/invadopodia formation, degradation of ECM, and cancer cell invasion in vivo and in vitro. Here, we describe Tks4, a novel protein that is closely related to Tks5. This protein contains an amino-terminal Phox homology domain, four SH3 domains, and several proline-rich motifs. In Src-transformed fibroblasts, Tks4 is tyrosine phosphorylated and predominantly localized to rosettes of podosomes. We used both short hairpin RNA knockdown and mouse embryo fibroblasts lacking Tks4 to investigate its role in podosome formation. We found that lack of Tks4 resulted in incomplete podosome formation and inhibited ECM degradation. Both phenotypes were rescued by reintroduction of Tks4, whereas only podosome formation, but not ECM degradation, was rescued by overexpression of Tks5. The tyrosine phosphorylation sites of Tks4 were required for efficient rescue. Furthermore, in the absence of Tks4, membrane type-1 matrix metalloproteinase (MT1-MMP) was not recruited to the incomplete podosomes. These findings suggest that Tks4 and Tks5 have overlapping, but not identical, functions, and implicate Tks4 in MT1-MMP recruitment and ECM degradation

The M17 leucine aminopeptidase of the malaria parasite Plasmodium falciparum:importance of active site metal ions in the binding of substrates and inhibitors

The M17 leucine aminopeptidase of the intraerythrocytic stages of the malaria parasite Plasmodium falciparum (PfLAP) plays a role in releasing amino acids from host hemoglobin that are used for parasite protein synthesis, growth, and development. This enzyme represents a target at which new antimalarials could be designed since metalloaminopeptidase inhibitors prevent the growth of the parasites in vitro and in vivo. A study on the metal ion binding characteristics of recombinant P. falciparum M17 leucine aminopeptidase (rPfLAP) shows that the active site of this exopeptidase contains two metal-binding sites, a readily exchangeable site (site 1) and a tight binding site (site 2). The enzyme retains activity when the metal ion is removed from site 1, while removal of metal ions from both sites results in an inactive apoenzyme that cannot be reactivated by the addition of divalent metal cations. The metal ion at site 1 is readily exchangeable with several divalent metal ions and displays a preference in the order of preference Zn 2+ > Mn 2+ > Co 2+ > Mg 2+. While it is likely that native PfLAP contains a Zn 2+ in site 2, the metal ion located in site 1 may be dependent on the type and concentration of metal ions in the cytosolic compartment of the parasite. Importantly, the type of metal ion present at site 1 influences not only the catalytic efficiency of the enzyme for peptide substrates but also the mode of binding by bestatin, a metal-chelating inhibitor of M17 aminopeptidases with antimalarial activity. © 2009 American Chemical Society