CO_{2}-Undersaturated Melt Inclusions From the South West Indian Ridge Record Surprisingly Uniform Redox Conditions

The behavior of Fe3+ during mantle partial melting strongly influences the oxidation state of the resulting magmas, with implications for the evolution of the atmosphere's oxidation state. Here, we challenge a prevailing view that low-degree partial melts are more oxidized due to the incompatible behavior of Fe3+. Our study is based on measurements of Fe3+/∑Fe along with major, minor, trace and volatile elements in olivine- and plagioclase-hosted melt inclusions of CO2 undersaturated mantle melts in South West Indian Ridge lava. These inclusions record minimum entrapment pressures equivalent to depths up to 10 km below the seafloor, record magma ascent rates of 0.03–0.19 m/s, and display exceptionally high CO2/Ba, CO2/Rb, and CO2/Nb ratios, indicative of a CO2-rich mantle source. Accounting for fractional crystallization, we find a uniform melt oxidation state (with an Fe3+/ΣFe at 0.140 ± 0.005 at MgO = 10 wt.%) that displays no systematic variation with major, minor, volatile or trace element contents, thus providing no evidence for a relationship between the degree of partial melting and Fe3+/ΣFe. This can be explained by efficient buffering of Fe3+/∑Fe and fO2 of mid-ocean ridge basalt melts by their surrounding mantle and/or a decrease in the bulk peridotite-melt Fe2O3 partition coefficient with increasing partial melting. We conclude that changes in the Earth's upper mantle temperature over geological time need not have affected the oxidation state of volcanic products or of the atmosphere

Exceptional eruptive CO2 emissions from intra-plate alkaline magmatism in the Canary volcanic archipelago

Alkaline mafic magmas forming intra-plate oceanic islands are believed to be strongly enriched in CO2 due to low-degree partial melting of enriched mantle sources. However, until now, such CO2 enhancement has not been verified by measuring CO2 degassing during a subaerial eruption. Here, we provide evidence of highly CO2-rich gas emissions during the 86-day 2021 Tajogaite eruption of Cumbre Vieja volcano on La Palma Island, in the Canary archipelago. Our results reveal sustained high plume CO2/SO2 ratios, which, when combined with SO2 fluxes, melt inclusion volatile contents and magma production rates at explosive and effusive vents, imply a magmatic CO2 content of 4.5 ± 1.5 wt%. The amount of CO2 released during the 2021 eruptive activity was 28 ± 14 Mt CO2. Extrapolating to the volume of alkaline mafic magmas forming La Palma alone (estimated as 4000 km3 erupted over 11 Ma), we infer a maximum CO2 emission into the ocean and atmosphere of 1016 moles of CO2, equivalent to 20% of the eruptive CO2 emissions from a large igneous province eruption, suggesting that the formation of the Canary volcanic archipelago produced a CO2 emission of similar magnitude as a large igneous province

Mutation of Archaeal Isopentenyl Phosphate Kinase Highlights Mechanism and Guides Phosphorylation of Additional Isoprenoid Monophosphates

I sopentenyl diphosphate (IPP) and its isomeric part-ner dimethylallyl diphosphate (DMAPP) are precur-sors for a diverse collection of primary and second-ary isoprenoid metabolites in all organisms. Following its formation, successive units of IPP are used together either with DMAPP, formed by the action of types I or II IPP isomerases, or with the IPP extended isoprenoid diphosphate chain, to biosynthesize C10, C15, or C20 oligoprenyl diphosphates known as geranyl diphos-phate (GPP), farnesyl diphosphate (FPP), and gera-nylgeranyl diphosphate (GGPP), respectively, as well as larger isoprenoid diphosphates. In plants and some mi-croorganisms, GPP, FPP, and GGPP also serve as start-ingmaterials for the biosynthesis of a large class of spe-cialized and often cyclic terpene hydrocarbons (1). FPP is the most ubiquitous of the three isoprenoid diphos-phate building blocks, as it resides at the juncture of bi

A Long Baseline Neutrino Oscillation Experiment Using J-PARC Neutrino Beam and Hyper-Kamiokande

Document submitted to 18th J-PARC PAC meeting in May 2014. 50 pages, 41 figuresDocument submitted to 18th J-PARC PAC meeting in May 2014. 50 pages, 41 figuresDocument submitted to 18th J-PARC PAC meeting in May 2014. 50 pages, 41 figuresHyper-Kamiokande will be a next generation underground water Cherenkov detector with a total (fiducial) mass of 0.99 (0.56) million metric tons, approximately 20 (25) times larger than that of Super-Kamiokande. One of the main goals of Hyper-Kamiokande is the study of $CP$ asymmetry in the lepton sector using accelerator neutrino and anti-neutrino beams. In this document, the physics potential of a long baseline neutrino experiment using the Hyper-Kamiokande detector and a neutrino beam from the J-PARC proton synchrotron is presented. The analysis has been updated from the previous Letter of Intent [K. Abe et al., arXiv:1109.3262 [hep-ex]], based on the experience gained from the ongoing T2K experiment. With a total exposure of 7.5 MW $\times$ 10$^7$ sec integrated proton beam power (corresponding to $1.56\times10^{22}$ protons on target with a 30 GeV proton beam) to a $2.5$-degree off-axis neutrino beam produced by the J-PARC proton synchrotron, it is expected that the $CP$ phase $\delta_{CP}$ can be determined to better than 19 degrees for all possible values of $\delta_{CP}$, and $CP$ violation can be established with a statistical significance of more than $3\,\sigma$ ($5\,\sigma$) for $76$ ($58$) of the $\delta_{CP}$ parameter space

Identification of epigenetically regulated genes that predict patient outcome in neuroblastoma

<p>Abstract</p> <p>Background</p> <p>Epigenetic mechanisms such as DNA methylation and histone modifications are important regulators of gene expression and are frequently involved in silencing tumor suppressor genes.</p> <p>Methods</p> <p>In order to identify genes that are epigenetically regulated in neuroblastoma tumors, we treated four neuroblastoma cell lines with the demethylating agent 5-Aza-2'-deoxycytidine (5-Aza-dC) either separately or in conjunction with the histone deacetylase inhibitor trichostatin A (TSA). Expression was analyzed using whole-genome expression arrays to identify genes activated by the treatment. These data were then combined with data from genome-wide DNA methylation arrays to identify candidate genes silenced in neuroblastoma due to DNA methylation.</p> <p>Results</p> <p>We present eight genes (<it>KRT19</it>, <it>PRKCDBP</it>, <it>SCNN1A</it>, <it>POU2F2</it>, <it>TGFBI</it>, <it>COL1A2</it>, <it>DHRS3 </it>and <it>DUSP23</it>) that are methylated in neuroblastoma, most of them not previously reported as such, some of which also distinguish between biological subsets of neuroblastoma tumors. Differential methylation was observed for the genes <it>SCNN1A </it>(p < 0.001), <it>PRKCDBP </it>(p < 0.001) and <it>KRT19 </it>(p < 0.01). Among these, the mRNA expression of <it>KRT19 </it>and <it>PRKCDBP </it>was significantly lower in patients that have died from the disease compared with patients with no evidence of disease (fold change -8.3, p = 0.01 for <it>KRT19 </it>and fold change -2.4, p = 0.04 for <it>PRKCDBP</it>).</p> <p>Conclusions</p> <p>In our study, a low methylation frequency of <it>SCNN1A</it>, <it>PRKCDBP </it>and <it>KRT19 </it>is significantly associated with favorable outcome in neuroblastoma. It is likely that analysis of specific DNA methylation will be one of several methods in future patient therapy stratification protocols for treatment of childhood neuroblastomas.</p

CCN3 modulates bone turnover and is a novel regulator of skeletal metastasis

The CCN family of proteins is composed of six secreted proteins (CCN1-6), which are grouped together based on their structural similarity. These matricellular proteins are involved in a large spectrum of biological processes, ranging from development to disease. In this review, we focus on CCN3, a founding member of this family, and its role in regulating cells within the bone microenvironment. CCN3 impairs normal osteoblast differentiation through multiple mechanisms, which include the neutralization of pro-osteoblastogenic stimuli such as BMP and Wnt family signals or the activation of pathways that suppress osteoblastogenesis, such as Notch. In contrast, CCN3 is known to promote chondrocyte differentiation. Given these functions, it is not surprising that CCN3 has been implicated in the progression of primary bone cancers such as osteosarcoma, Ewing’s sarcoma and chondrosarcoma. More recently, emerging evidence suggests that CCN3 may also influence the ability of metastatic cancers to colonize and grow in bone

Physics potential of a long-baseline neutrino oscillation experiment using a J-PARC neutrino beam and Hyper-Kamiokande

39 pages, 26 figures, submitted to PTE

Hyper-Kamiokande Design Report

325 pages325 pagesOn the strength of a double Nobel prize winning experiment (Super)Kamiokande and an extremely successful long baseline neutrino programme, the third generation Water Cherenkov detector, Hyper-Kamiokande, is being developed by an international collaboration as a leading worldwide experiment based in Japan. The Hyper-Kamiokande detector will be hosted in the Tochibora mine, about 295 km away from the J-PARC proton accelerator research complex in Tokai, Japan. The currently existing accelerator will be steadily upgraded to reach a MW beam by the start of the experiment. A suite of near detectors will be vital to constrain the beam for neutrino oscillation measurements. A new cavern will be excavated at the Tochibora mine to host the detector. The experiment will be the largest underground water Cherenkov detector in the world and will be instrumented with new technology photosensors, faster and with higher quantum efficiency than the ones in Super-Kamiokande. The science that will be developed will be able to shape the future theoretical framework and generations of experiments. Hyper-Kamiokande will be able to measure with the highest precision the leptonic CP violation that could explain the baryon asymmetry in the Universe. The experiment also has a demonstrated excellent capability to search for proton decay, providing a significant improvement in discovery sensitivity over current searches for the proton lifetime. The atmospheric neutrinos will allow to determine the neutrino mass ordering and, together with the beam, able to precisely test the three-flavour neutrino oscillation paradigm and search for new phenomena. A strong astrophysical programme will be carried out at the experiment that will detect supernova neutrinos and will measure precisely solar neutrino oscillation

Physics Potentials with the Second Hyper-Kamiokande Detector in Korea

We have conducted sensitivity studies on an alternative configuration of the Hyper-Kamiokande experiment by locating the 2nd Hyper-Kamiokande detector in Korea at $\sim$1100$-\$1300 km baseline. Having two detectors at different baselines improves sensitivity to leptonic CP violation, neutrino mass ordering as well as nonstandard neutrino interactions. There are several candidate sites in Korea with greater than 1 km high mountains ranged at an 1$-$3 degree off-axis angle. Thanks to larger overburden of the candidate sites in Korea, low energy physics, such as solar and supernova neutrino physics as well as dark matter search, is expected to be improved. In this paper sensitivity studies on the CP violation phase and neutrino mass ordering are performed using current T2K systematic uncertainties in most cases. We plan to improve our sensitivity studies in the near future with better estimation of our systematic uncertainties

Primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic liver disease with a slowly progressive course. Without treatment, most patients eventually develop fibrosis and cirrhosis of the liver and may need liver transplantation in the late stage of disease. PBC primarily affects women (female preponderance 9–10:1) with a prevalence of up to 1 in 1,000 women over 40 years of age. Common symptoms of the disease are fatigue and pruritus, but most patients are asymptomatic at first presentation. The diagnosis is based on sustained elevation of serum markers of cholestasis, i.e., alkaline phosphatase and gamma-glutamyl transferase, and the presence of serum antimitochondrial antibodies directed against the E2 subunit of the pyruvate dehydrogenase complex. Histologically, PBC is characterized by florid bile duct lesions with damage to biliary epithelial cells, an often dense portal inflammatory infiltrate and progressive loss of small intrahepatic bile ducts. Although the insight into pathogenetic aspects of PBC has grown enormously during the recent decade and numerous genetic, environmental, and infectious factors have been disclosed which may contribute to the development of PBC, the precise pathogenesis remains enigmatic. Ursodeoxycholic acid (UDCA) is currently the only FDA-approved medical treatment for PBC. When administered at adequate doses of 13–15 mg/kg/day, up to two out of three patients with PBC may have a normal life expectancy without additional therapeutic measures. The mode of action of UDCA is still under discussion, but stimulation of impaired hepatocellular and cholangiocellular secretion, detoxification of bile, and antiapoptotic effects may represent key mechanisms. One out of three patients does not adequately respond to UDCA therapy and may need additional medical therapy and/or liver transplantation. This review summarizes current knowledge on the clinical, diagnostic, pathogenetic, and therapeutic aspects of PBC