Probabilistic Tensor Decomposition of Neural Population Spiking Activity

The firing of neural populations is coordinated across cells, in time, and across experimental conditions or repeated experimental trials, and so a full understanding of the computational significance of neural responses must be based on a separation of these different contributions to structured activity. Tensor decomposition is an approach to untangling the influence of multiple factors in data that is common in many fields. However, despite some recent interest in neuroscience, wider applicability of the approach is hampered by the lack of a full probabilistic treatment allowing principled inference of a decomposition from non-Gaussian spike-count data. Here, we extend the Polya-Gamma (PG) augmentation, previously used in sampling-based Bayesian inference, to implement scalable variational inference in non-conjugate spike-count models. Using this new approach, we develop techniques related to automatic relevance determination to infer the most appropriate tensor rank, as well as to incorporate priors based on known brain anatomy such as the segregation of cell response properties by brain area. We apply the model to neural recordings taken under conditions of visual-vestibular sensory integration, revealing how the encoding of self- and visual-motion signals is modulated by the sensory information available to the animal

Bivalirudin started during emergency transport for primary PCI.

BACKGROUND: Bivalirudin, as compared with heparin and glycoprotein IIb/IIIa inhibitors, has been shown to reduce rates of bleeding and death in patients undergoing primary percutaneous coronary intervention (PCI). Whether these benefits persist in contemporary practice characterized by prehospital initiation of treatment, optional use of glycoprotein IIb/IIIa inhibitors and novel P2Y12 inhibitors, and radial-artery PCI access use is unknown. METHODS: We randomly assigned 2218 patients with ST-segment elevation myocardial infarction (STEMI) who were being transported for primary PCI to receive either bivalirudin or unfractionated or low-molecular-weight heparin with optional glycoprotein IIb/IIIa inhibitors (control group). The primary outcome at 30 days was a composite of death or major bleeding not associated with coronary-artery bypass grafting (CABG), and the principal secondary outcome was a composite of death, reinfarction, or non-CABG major bleeding. RESULTS: Bivalirudin, as compared with the control intervention, reduced the risk of the primary outcome (5.1% vs. 8.5%; relative risk, 0.60; 95% confidence interval [CI], 0.43 to 0.82; P=0.001) and the principal secondary outcome (6.6% vs. 9.2%; relative risk, 0.72; 95% CI, 0.54 to 0.96; P=0.02). Bivalirudin also reduced the risk of major bleeding (2.6% vs. 6.0%; relative risk, 0.43; 95% CI, 0.28 to 0.66; P<0.001). The risk of acute stent thrombosis was higher with bivalirudin (1.1% vs. 0.2%; relative risk, 6.11; 95% CI, 1.37 to 27.24; P=0.007). There was no significant difference in rates of death (2.9% vs. 3.1%) or reinfarction (1.7% vs. 0.9%). Results were consistent across subgroups of patients. CONCLUSIONS: Bivalirudin, started during transport for primary PCI, improved 30-day clinical outcomes with a reduction in major bleeding but with an increase in acute stent thrombosis. (Funded by the Medicines Company; EUROMAX ClinicalTrials.gov number, NCT01087723.)

The DEAD-box helicase DDX3X is a critical component of the TANK-binding kinase 1-dependent innate immune response

TANK-binding kinase 1 (TBK1) is of central importance for the induction of type-I interferon (IFN) in response to pathogens. We identified the DEAD-box helicase DDX3X as an interaction partner of TBK1. TBK1 and DDX3X acted synergistically in their ability to stimulate the IFN promoter, whereas RNAi-mediated reduction of DDX3X expression led to an impairment of IFN production. Chromatin immunoprecipitation indicated that DDX3X is recruited to the IFN promoter upon infection with Listeria monocytogenes, suggesting a transcriptional mechanism of action. DDX3X was found to be a TBK1 substrate in vitro and in vivo. Phosphorylation-deficient mutants of DDX3X failed to synergize with TBK1 in their ability to stimulate the IFN promoter. Overall, our data imply that DDX3X is a critical effector of TBK1 that is necessary for type I IFN induction

Impaired Cellular Responses to Cytosolic DNA or Infection with Listeria monocytogenes and Vaccinia Virus in the Absence of the Murine LGP2 Protein

Innate immune signaling is crucial for detection of and the initial response to microbial pathogens. Evidence is provided indicating that LGP2, a DEXH box domain protein related to the RNA recognition receptors RIG-I and MDA5, participates in the cellular response to cytosolic double-stranded DNA (dsDNA). Analysis of embryonic fibroblasts and macrophages from mice harboring targeted disruption in the LGP2 gene reveals that LGP2 can act as a positive regulator of type I IFN and anti-microbial gene expression in response to transfected dsDNA. Results indicate that infection of LGP2-deficient mice with an intracellular bacterial pathogen, Listeria monocytogenes, leads to reduced levels of type I IFN and IL12, and allows increased bacterial growth in infected animals, resulting in greater colonization of both spleen and liver. Responses to infection with vaccinia virus, a dsDNA virus, are also suppressed in cells lacking LGP2, reinforcing the ability of LGP2 to act as a positive regulator of antiviral signaling. In vitro mechanistic studies indicate that purified LGP2 protein does not bind DNA but instead mediates these responses indirectly. Data suggest that LGP2 may be acting downstream of the intracellular RNA polymerase III pathway to activate anti-microbial signaling. Together, these findings demonstrate a regulatory role for LGP2 in the response to cytosolic DNA, an intracellular bacterial pathogen, and a DNA virus, and provide a plausible mechanistic hypothesis as the basis for this activity

GNSS transpolar earth reflectometry exploriNg system (G-TERN): Mission concept

The global navigation satellite system (GNSS) Transpolar Earth Reflectometry exploriNg system (G-TERN) was proposed in response to ESA's Earth Explorer 9 revised call by a team of 33 multi-disciplinary scientists. The primary objective of the mission is to quantify at high spatio-temporal resolution crucial characteristics, processes and interactions between sea ice, and other Earth system components in order to advance the understanding and prediction of climate change and its impacts on the environment and society. The objective is articulated through three key questions. 1) In a rapidly changing Arctic regime and under the resilient Antarctic sea ice trend, how will highly dynamic forcings and couplings between the various components of the ocean, atmosphere, and cryosphere modify or influence the processes governing the characteristics of the sea ice cover (ice production, growth, deformation, and melt)? 2) What are the impacts of extreme events and feedback mechanisms on sea ice evolution? 3) What are the effects of the cryosphere behaviors, either rapidly changing or resiliently stable, on the global oceanic and atmospheric circulation and mid-latitude extreme events? To contribute answering these questions, G-TERN will measure key parameters of the sea ice, the oceans, and the atmosphere with frequent and dense coverage over polar areas, becoming a "dynamic mapper" of the ice conditions, the ice production, and the loss in multiple time and space scales, and surrounding environment. Over polar areas, the G-TERN will measure sea ice surface elevation (&lt;10 cm precision), roughness, and polarimetry aspects at 30-km resolution and 3-days full coverage. G-TERN will implement the interferometric GNSS reflectometry concept, from a single satellite in near-polar orbit with capability for 12 simultaneous observations. Unlike currently orbiting GNSS reflectometry missions, the G-TERN uses the full GNSS available bandwidth to improve its ranging measurements. The lifetime would be 2025-2030 or optimally 2025-2035, covering key stages of the transition toward a nearly ice-free Arctic Ocean in summer. This paper describes the mission objectives, it reviews its measurement techniques, summarizes the suggested implementation, and finally, it estimates the expected performance

Requirement of cellular DDX3 for hepatitis C virus replication is unrelated to its interaction with the viral core protein

The cellular DEAD-box protein DDX3 was recently shown to be essential for hepatitis C virus (HCV) replication. Prior to that, we had reported that HCV core binds to DDX3 in yeast-two hybrid and transient transfection assays. Here, we confirm by co-immunoprecipitation that this interaction occurs in cells replicating the JFH1 virus. Consistent with this result, immunofluorescence staining of infected cells revealed a dramatic redistribution of cytoplasmic DDX3 by core protein to the virus assembly sites around lipid droplets. Given this close association of DDX3 with core and lipid droplets, and its involvement in virus replication, we investigated the importance of this host factor in the virus life cycle. Mutagenesis studies located a single amino acid in the N-terminal domain of JFH1 core that when changed to alanine significantly abrogated this interaction. Surprisingly, this mutation did not alter infectious virus production and RNA replication, indicating that the core–DDX3 interaction is dispensable in the HCV life cycle. Consistent with previous studies, siRNA-led knockdown of DDX3 lowered virus production and RNA replication levels of both WT JFH1 and the mutant virus unable to bind DDX3. Thus, our study shows for the first time that the requirement of DDX3 for HCV replication is unrelated to its interaction with the viral core protein

Hepatitis C Virus Core-Derived Peptides Inhibit Genotype 1b Viral Genome Replication via Interaction with DDX3X

The protein DDX3X is a DEAD-box RNA helicase that is essential for the hepatitis C virus (HCV) life cycle. The HCV core protein has been shown to bind to DDX3X both in vitro and in vivo. However, the specific interactions between these two proteins and the functional importance of these interactions for the HCV viral life cycle remain unclear. We show that amino acids 16–36 near the N-terminus of the HCV core protein interact specifically with DDX3X both in vitro and in vivo. Replication of HCV replicon NNeo/C-5B RNA (genotype 1b) is significantly suppressed in HuH-7-derived cells expressing green fluorescent protein (GFP) fusions to HCV core protein residues 16–36, but not by GFP fusions to core protein residues 16–35 or 16–34. Notably, the inhibition of HCV replication due to expression of the GFP fusion to HCV core protein residues 16–36 can be reversed by overexpression of DDX3X. These results suggest that the protein interface on DDX3X that binds the HCV core protein is important for replicon maintenance. However, infection of HuH-7 cells by HCV viruses of genotype 2a (JFH1) was not affected by expression of the GFP fusion protein. These results suggest that the role of DDX3X in HCV infection involves aspects of the viral life cycle that vary in importance between HCV genotypes

Requirement of NOX2 and Reactive Oxygen Species for Efficient RIG-I-Mediated Antiviral Response through Regulation of MAVS Expression

The innate immune response is essential to the host defense against viruses, through restriction of virus replication and coordination of the adaptive immune response. Induction of antiviral genes is a tightly regulated process initiated mainly through sensing of invading virus nucleic acids in the cytoplasm by RIG-I like helicases, RIG-I or Mda5, which transmit the signal through a common mitochondria-associated adaptor, MAVS. Although major breakthroughs have recently been made, much remains unknown about the mechanisms that translate virus recognition into antiviral genes expression. Beside the reputed detrimental role, reactive oxygen species (ROS) act as modulators of cellular signaling and gene regulation. NADPH oxidase (NOX) enzymes are a main source of deliberate cellular ROS production. Here, we found that NOX2 and ROS are required for the host cell to trigger an efficient RIG-I-mediated IRF-3 activation and downstream antiviral IFNβ and IFIT1 gene expression. Additionally, we provide evidence that NOX2 is critical for the expression of the central mitochondria-associated adaptor MAVS. Taken together these data reveal a new facet to the regulation of the innate host defense against viruses through the identification of an unrecognized role of NOX2 and ROS

Characterization of the Endothelial Cell Cytoskeleton following HLA Class I Ligation

Vascular endothelial cells (ECs) are a target of antibody-mediated allograft rejection. In vitro, when the HLA class I molecules on the surface of ECs are ligated by anti-HLA class I antibodies, cell proliferation and survival pathways are activated and this is thought to contribute to the development of antibody-mediated rejection. Crosslinking of HLA class I molecules by anti-HLA antibodies also triggers reorganization of the cytoskeleton, which induces the formation of F-actin stress fibers. HLA class I induced stress fiber formation is not well understood.The present study examines the protein composition of the cytoskeleton fraction of ECs treated with HLA class I antibodies and compares it to other agonists known to induce alterations of the cytoskeleton in endothelial cells. Analysis by tandem mass spectrometry revealed unique cytoskeleton proteomes for each treatment group. Using annotation tools a candidate list was created that revealed 12 proteins, which were unique to the HLA class I stimulated group. Eleven of the candidate proteins were phosphoproteins and exploration of their predicted kinases provided clues as to how these proteins may contribute to the understanding of HLA class I induced antibody-mediated rejection. Three of the candidates, eukaryotic initiation factor 4A1 (eIF4A1), Tropomyosin alpha 4-chain (TPM4) and DDX3X, were further characterized by Western blot and found to be associated with the cytoskeleton. Confocal microscopy analysis showed that class I ligation stimulated increased eIF4A1 co-localization with F-actin and paxillin.Colocalization of eIF4A1 with F-actin and paxillin following HLA class I ligation suggests that this candidate protein could be a target for understanding the mechanism(s) of class I mediated antibody-mediated rejection. This proteomic approach for analyzing the cytoskeleton of ECs can be applied to other agonists and various cells types as a method for uncovering novel regulators of cytoskeleton changes

SEASTAR: a mission to study ocean submesoscale dynamics and small-scale atmosphere-ocean processes in coastal, shelf and polar seas

High-resolution satellite images of ocean color and sea surface temperature reveal an abundance of ocean fronts, vortices and filaments at scales below 10 km but measurements of ocean surface dynamics at these scales are rare. There is increasing recognition of the role played by small scale ocean processes in ocean-atmosphere coupling, upper-ocean mixing and ocean vertical transports, with advanced numerical models and in situ observations highlighting fundamental changes in dynamics when scales reach 1 km. Numerous scientific publications highlight the global impact of small oceanic scales on marine ecosystems, operational forecasts and long-term climate projections through strong ageostrophic circulations, large vertical ocean velocities and mixed layer re-stratification. Small-scale processes particularly dominate in coastal, shelf and polar seas where they mediate important exchanges between land, ocean, atmosphere and the cryosphere, e.g., freshwater, pollutants. As numerical models continue to evolve toward finer spatial resolution and increasingly complex coupled atmosphere-wave-ice-ocean systems, modern observing capability lags behind, unable to deliver the high-resolution synoptic measurements of total currents, wind vectors and waves needed to advance understanding, develop better parameterizations and improve model validations, forecasts and projections. SEASTAR is a satellite mission concept that proposes to directly address this critical observational gap with synoptic two-dimensional imaging of total ocean surface current vectors and wind vectors at 1 km resolution and coincident directional wave spectra. Based on major recent advances in squinted along-track Synthetic Aperture Radar interferometry, SEASTAR is an innovative, mature concept with unique demonstrated capabilities, seeking to proceed toward spaceborne implementation within Europe and beyond