E3 Ubiquitin Ligase Synoviolin Is Involved in Liver Fibrogenesis

Chronic hepatic damage leads to liver fibrosis, which is characterized by the accumulation of collagen-rich extracellular matrix. However, the mechanism by which E3 ubiquitin ligase is involved in collagen synthesis in liver fibrosis is incompletely understood. This study aimed to explore the involvement of the E3 ubiquitin ligase synoviolin (Syno) in liver fibrosis.The expression and localization of synoviolin in the liver were analyzed in CCl(4)-induced hepatic injury models and human cirrhosis tissues. The degree of liver fibrosis and the number of activated hepatic stellate cells (HSCs) was compared between wild type (wt) and Syno(+/-) mice in the chronic hepatic injury model. We compared the ratio of apoptosis in activated HSCs between wt and Syno(+/-) mice. We also analyzed the effect of synoviolin on collagen synthesis in the cell line from HSCs (LX-2) using siRNA-synoviolin and a mutant synoviolin in which E3 ligase activity was abolished. Furthermore, we compared collagen synthesis between wt and Syno(-/-) mice embryonic fibroblasts (MEF) using quantitative RT-PCR, western blotting, and collagen assay; then, we immunohistochemically analyzed the localization of collagen in Syno(-/-) MEF cells.In the hepatic injury model as well as in cirrhosis, synoviolin was upregulated in the activated HSCs, while Syno(+/-) mice developed significantly less liver fibrosis than in wt mice. The number of activated HSCs was decreased in Syno(+/-) mice, and some of these cells showed apoptosis. Furthermore, collagen expression in LX-2 cells was upregulated by synoviolin overexpression, while synoviolin knockdown led to reduced collagen expression. Moreover, in Syno(-/-) MEF cells, the amounts of intracellular and secreted mature collagen were significantly decreased, and procollagen was abnormally accumulated in the endoplasmic reticulum.Our findings demonstrate the importance of the E3 ubiquitin ligase synoviolin in liver fibrosis

Constraints on axion-like polarization oscillations in the cosmic microwave background with POLARBEAR

Very light pseudoscalar fields, often referred to as axions, are compelling dark matter candidates and can potentially be detected through their coupling to the electromagnetic field. Recently a novel detection technique using the cosmic microwave background (CMB) was proposed, which relies on the fact that the axion field oscillates at a frequency equal to its mass in appropriate units, leading to a time-dependent birefringence. For appropriate oscillation periods this allows the axion field at the telescope to be detected via the induced sinusoidal oscillation of the CMB linear polarization. We search for this effect in two years of POLARBEAR data. We do not detect a signal, and place a median $95 \%$ upper limit of $0.65 ^\circ$ on the sinusoid amplitude for oscillation frequencies between $0.02\,\text{days}^{-1}$ and $0.45\,\text{days}^{-1}$, which corresponds to axion masses between $9.6 \times 10^{-22} \, \text{eV}$ and $2.2\times 10^{-20} \,\text{eV}$. Under the assumptions that 1) the axion constitutes all the dark matter and 2) the axion field amplitude is a Rayleigh-distributed stochastic variable, this translates to a limit on the axion-photon coupling $g_{\phi \gamma} < 2.4 \times 10^{-11} \,\text{GeV}^{-1} \times ({m_\phi}/{10^{-21} \, \text{eV}})$.Comment: 17 pages, 5 figures, 2 tables. Published in Physical Review

A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma.

Efst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinnIL-33 is a tissue-derived cytokine that induces and amplifies eosinophilic inflammation and has emerged as a promising new drug target for asthma and allergic disease. Common variants at IL33 and IL1RL1, encoding the IL-33 receptor ST2, associate with eosinophil counts and asthma. Through whole-genome sequencing and imputation into the Icelandic population, we found a rare variant in IL33 (NM_001199640:exon7:c.487-1G>C (rs146597587-C), allele frequency = 0.65%) that disrupts a canonical splice acceptor site before the last coding exon. It is also found at low frequency in European populations. rs146597587-C associates with lower eosinophil counts (β = -0.21 SD, P = 2.5×10-16, N = 103,104), and reduced risk of asthma in Europeans (OR = 0.47; 95%CI: 0.32, 0.70, P = 1.8×10-4, N cases = 6,465, N controls = 302,977). Heterozygotes have about 40% lower total IL33 mRNA expression than non-carriers and allele-specific analysis based on RNA sequencing and phased genotypes shows that only 20% of the total expression is from the mutated chromosome. In half of those transcripts the mutation causes retention of the last intron, predicted to result in a premature stop codon that leads to truncation of 66 amino acids. The truncated IL-33 has normal intracellular localization but neither binds IL-33R/ST2 nor activates ST2-expressing cells. Together these data demonstrate that rs146597587-C is a loss of function mutation and support the hypothesis that IL-33 haploinsufficiency protects against asthma.Netherlands Asthma Foundation University Medical Center Groningen Ministry of Health and Environmental Hygiene of Netherlands Netherlands Asthma Stichting Astma Bestrijding BBMRI European Respiratory Society private and public research funds AstraZeneca ALK-Abello, Denmar

CMB-S4: Forecasting Constraints on Primordial Gravitational Waves

CMB-S4---the next-generation ground-based cosmic microwave background (CMB) experiment---is set to significantly advance the sensitivity of CMB measurements and enhance our understanding of the origin and evolution of the Universe, from the highest energies at the dawn of time through the growth of structure to the present day. Among the science cases pursued with CMB-S4, the quest for detecting primordial gravitational waves is a central driver of the experimental design. This work details the development of a forecasting framework that includes a power-spectrum-based semi-analytic projection tool, targeted explicitly towards optimizing constraints on the tensor-to-scalar ratio, $r$, in the presence of Galactic foregrounds and gravitational lensing of the CMB. This framework is unique in its direct use of information from the achieved performance of current Stage 2--3 CMB experiments to robustly forecast the science reach of upcoming CMB-polarization endeavors. The methodology allows for rapid iteration over experimental configurations and offers a flexible way to optimize the design of future experiments given a desired scientific goal. To form a closed-loop process, we couple this semi-analytic tool with map-based validation studies, which allow for the injection of additional complexity and verification of our forecasts with several independent analysis methods. We document multiple rounds of forecasts for CMB-S4 using this process and the resulting establishment of the current reference design of the primordial gravitational-wave component of the Stage-4 experiment, optimized to achieve our science goals of detecting primordial gravitational waves for $r > 0.003$ at greater than $5\sigma$, or, in the absence of a detection, of reaching an upper limit of $r < 0.001$ at $95\%$ CL.Comment: 24 pages, 8 figures, 9 tables, submitted to ApJ. arXiv admin note: text overlap with arXiv:1907.0447

CMB-S4

We describe the stage 4 cosmic microwave background ground-based experiment CMB-S4

CMB-S4: Forecasting Constraints on Primordial Gravitational Waves

Abstract: CMB-S4—the next-generation ground-based cosmic microwave background (CMB) experiment—is set to significantly advance the sensitivity of CMB measurements and enhance our understanding of the origin and evolution of the universe. Among the science cases pursued with CMB-S4, the quest for detecting primordial gravitational waves is a central driver of the experimental design. This work details the development of a forecasting framework that includes a power-spectrum-based semianalytic projection tool, targeted explicitly toward optimizing constraints on the tensor-to-scalar ratio, r, in the presence of Galactic foregrounds and gravitational lensing of the CMB. This framework is unique in its direct use of information from the achieved performance of current Stage 2–3 CMB experiments to robustly forecast the science reach of upcoming CMB-polarization endeavors. The methodology allows for rapid iteration over experimental configurations and offers a flexible way to optimize the design of future experiments, given a desired scientific goal. To form a closed-loop process, we couple this semianalytic tool with map-based validation studies, which allow for the injection of additional complexity and verification of our forecasts with several independent analysis methods. We document multiple rounds of forecasts for CMB-S4 using this process and the resulting establishment of the current reference design of the primordial gravitational-wave component of the Stage-4 experiment, optimized to achieve our science goals of detecting primordial gravitational waves for r > 0.003 at greater than 5σ, or in the absence of a detection, of reaching an upper limit of r < 0.001 at 95% CL

Neuronal SNARE Ykt6: Molecular mechanisms controlling solubility, subcellular localization and SNARE complex assembly.

SNARE proteins mediate specific membrane fusion events in eukaryotic cells. Ykt6 is a conserved SNARE protein that lacks a protemaceous transmembrane domain, but is both farnesylated and palmitoylated at its C-terminus. While yeast Ykt6p is an essential protein that is suggested to function in multiple biosynthetic transport pathways including ER-Golgi, intra-Golgi, and Golgi-vacuole transports that are important to all cells, mammalian ykt6 protein is predominantly expressed in neurons and the functions do not appear to mirror those of yeast Ykt6p. Despite its C-terminal lipidation, about 60% of ykt6 is soluble in the cytosol as monomers, while the other 40% is found in a pellet fraction and forms unidentified protein complexes. Because of the lipid modifications, particulate ykt6 behaves as an integral membrane protein, thereby suggesting that the C-terminal lipids are stably inserted to the membrane. In neuronal cells, ykt6 localizes to punctate structures that do not overlap with conventional organelle markers, but partially colocalize with sedlin, the protein responsible for the X-linked genetic disease spondyloepiphyseal dysplasia tarda. The N-terminal longin domain of ykt6 not only provides targeting information and a mode of membrane association, but it also functions as an intramolecular lipid chaperone that directly binds to the lipids of its own C-terminus. While the overall tertiary structure of the longin domain is important for the specific targeting to the vesicular structures and the initial membrane association, the lipid chaperone property was encoded in the conserved surface residues. The C-terminal lipids contribute to a stable membrane anchorage of ykt6 and, under certain conditions, can provide spurious dominant mistargeting signals that drive ykt6 to the plasma membrane. Because of the direct interactions between the N-terminal longin domain and the C-terminal lipids, lipidated cytosolic ykt6 is soluble and forms a compact conformation that is recalcitrant to SNARE interactions. Likewise, the longin domain masks the otherwise dominant mistargeting information to localize to the punctate structures of unknown function. Thus, the intramolecular interactions provide a conformational switch to down-regulate the SNARE assembly activity as well as to control the solubility and the subcellular localization of neuronal ykt6.Ph.D.Biological SciencesCellular biologyMolecular biologyNeurosciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/124809/2/3163817.pd