The N domain of Smad7 is essential for specific inhibition of transforming growth factor-β signaling

Inhibitory Smads (I-Smads) repress signaling by cytokines of the transforming growth factor-β (TGF-β) superfamily. I-Smads have conserved carboxy-terminal Mad homology 2 (MH2) domains, whereas the amino acid sequences of their amino-terminal regions (N domains) are highly divergent from those of other Smads. Of the two different I-Smads in mammals, Smad7 inhibited signaling by both TGF-β and bone morphogenetic proteins (BMPs), whereas Smad6 was less effective in inhibiting TGF-β signaling. Analyses using deletion mutants and chimeras of Smad6 and Smad7 revealed that the MH2 domains were responsible for the inhibition of both TGF-β and BMP signaling by I-Smads, but the isolated MH2 domains of Smad6 and Smad7 were less potent than the full-length Smad7 in inhibiting TGF-β signaling. The N domains of I-Smads determined the subcellular localization of these molecules. Chimeras containing the N domain of Smad7 interacted with the TGF-β type I receptor (TβR-I) more efficiently, and were more potent in repressing TGF-β signaling, than those containing the N domain of Smad6. The isolated N domain of Smad7 physically interacted with the MH2 domain of Smad7, and enhanced the inhibitory activity of the latter through facilitating interaction with TGF-β receptors. The N domain of Smad7 thus plays an important role in the specific inhibition of TGF-β signaling

Re-Os isotope and platinum group elements of a FOcal ZOne mantle source, Louisville Seamounts Chain, Pacific ocean

The Louisville Seamount Chain (LSC) is, besides the Hawaiian-Emperor Chain, one of the longest-lived hotspot traces. We report here the first Re-Os isotope and platinum group element (PGE) data for Canopus, Rigil, and Burton Guyots along the chain, which were drilled during IODP Expedition 330. The LSC basalts possess (187Os/188Os)i = 0.1245–0.1314 that are remarkably homogeneous and do not vary with age. A Re-Os isochron age of 64.9 ± 3.2 Ma was obtained for Burton seamount (the youngest of the three seamounts drilled), consistent with 40Ar-39Ar data. Isochron-derived initial 187Os/188Os ratio of 0.1272 ± 0.0008, together with data for olivines (0.1271–0.1275), are within the estimated primitive mantle values. This (187Os/188Os)i range is similar to those of Rarotonga (0.124–0.139) and Samoan shield (0.1276–0.1313) basalts and lower than those of Cook-Austral (0.136–0.155) and Hawaiian shield (0.1283–0.1578) basalts, suggesting little or no recycled component in the LSC mantle source. The PGE data of LSC basalts are distinct from those of oceanic lower crust. Variation in PGE patterns can be largely explained by different low degrees of melting under sulfide-saturated conditions of the same relatively fertile mantle source, consistent with their primitive mantle-like Os and primordial Ne isotope signatures. The PGE patterns and the low 187Os/188Os composition of LSC basalts contrast with those of Ontong Java Plateau (OJP) tholeiites. We conclude that the Re-Os isotope and PGE composition of LSC basalts reflect a relatively pure deep-sourced common mantle sampled by some ocean island basalts but is not discernible in the composition of OJP tholeiites

Severe Aortic Stenosis in Dialysis Patients

Background: Characteristics and prognosis of hemodialysis patients with severe aortic stenosis have not yet been well defined. Methods and Results: The CURRENT AS (contemporary outcomes after surgery and medical treatment in patients with severe aortic stenosis) registry, a Japanese multicenter registry, enrolled 3815 consecutive patients with severe aortic stenosis. There were 405 hemodialysis patients (initial aortic valve replacement [AVR] group: N=135 [33.3%], and conservative group: N=270) and 3410 nonhemodialysis patients (initial AVR group: N=1062 [31.1%], and conservative group: N=2348). The median follow‐up duration after the index echocardiography was 1361 days, with 90% follow‐up rate at 2 years. The cumulative 5‐year incidence of all‐cause death was significantly higher in hemodialysis patients than in nonhemodialysis patients in both the entire cohort (71% versus 40%, P<0.001) and in the initial AVR group (63.2% versus 17.9%, P<0.001). Among hemodialysis patients, the initial AVR group as compared with the conservative group was associated with significantly lower cumulative 5‐year incidences of all‐cause death (60.6% versus 75.5%, P<0.001) and sudden death (10.2% versus 31.7%, P<0.001). Nevertheless, the rate of aortic valve procedure–related death, which predominantly occurred within 6 months of the AVR procedure, was markedly higher in the hemodialysis patients than in the nonhemodialysis patients (21.2% and 2.3%, P<0.001). Conclusions: Among hemodialysis patients with severe aortic stenosis, the initial AVR strategy as compared with the conservative strategy was associated with significantly lower long‐term mortality risk, particularly the risk for sudden death, although the effect size for the survival benefit of the initial AVR strategy was smaller than that in the nonhemodialysis patients

Bioluminescent system for dynamic imaging of cell and animal behavior

AbstractThe current utility of bioluminescence imaging is constrained by a low photon yield that limits temporal sensitivity. Here, we describe an imaging method that uses a chemiluminescent/fluorescent protein, ffLuc-cp156, which consists of a yellow variant of Aequorea GFP and firefly luciferase. We report an improvement in photon yield by over three orders of magnitude over current bioluminescent systems. We imaged cellular movement at high resolution including neuronal growth cones and microglial cell protrusions. Transgenic ffLuc-cp156 mice enabled video-rate bioluminescence imaging of freely moving animals, which may provide a reliable assay for drug distribution in behaving animals for pre-clinical studies

Percutaneous coronary intervention using new-generation drug-eluting stents versus coronary arterial bypass grafting in stable patients with multi-vessel coronary artery disease: From the CREDO-Kyoto PCI/CABG registry Cohort-3

AIMS: There is a scarcity of studies comparing percutaneous coronary intervention (PCI) using new-generation drug-eluting stents (DES) with coronary artery bypass grafting (CABG) in patients with multi-vessel coronary artery disease. METHODS AND RESULTS: The CREDO-Kyoto PCI/CABG registry Cohort-3 enrolled 14927 consecutive patients who underwent first coronary revascularization with PCI or isolated CABG between January 2011 and December 2013. The current study population consisted of 2464 patients who underwent multi-vessel coronary revascularization including revascularization of left anterior descending coronary artery (LAD) either with PCI using new-generation DES (N = 1565), or with CABG (N = 899). Patients in the PCI group were older and more often had severe frailty, but had less complex coronary anatomy, and less complete revascularization than those in the CABG group. Cumulative 5-year incidence of a composite of all-cause death, myocardial infarction or stroke was not significantly different between the 2 groups (25.0% versus 21.5%, P = 0.15). However, after adjusting confounders, the excess risk of PCI relative to CABG turned to be significant for the composite endpoint (HR 1.27, 95%CI 1.04-1.55, P = 0.02). PCI as compared with CABG was associated with comparable adjusted risk for all-cause death (HR 1.22, 95%CI 0.96-1.55, P = 0.11), and stroke (HR 1.17, 95%CI 0.79-1.73, P = 0.44), but with excess adjusted risk for myocardial infarction (HR 1.58, 95%CI 1.05-2.39, P = 0.03), and any coronary revascularization (HR 2.66, 95%CI 2.06-3.43, P<0.0001). CONCLUSIONS: In this observational study, PCI with new-generation DES as compared with CABG was associated with excess long-term risk for major cardiovascular events in patients who underwent multi-vessel coronary revascularization including LAD

IODP Expedition 330: Drilling the Louisville Seamount Trail in the SW Pacific

Deep-Earth convection can be understood by studying hotspot volcanoes that form where mantle plumes rise up and intersect the lithosphere, the Earth's rigid outer layer. Hotspots characteristically leave age-progressive trails of volcanoes and seamounts on top of oceanic lithosphere, which in turn allow us to decipher the motion of these plates relative to "fixed" deep-mantle plumes, and their (isotope) geochemistry provides insights into the long-term evolution of mantle source regions. However, it is strongly suggested that the Hawaiian mantle plume moved ~15° south between 80 and 50 million years ago. This raises a fundamental question about other hotspot systems in the Pacific, whether or not their mantle plumes experienced a similar amount and direction of motion. Integrated Ocean Drilling Program (IODP) Expedition 330 to the Louisville Seamounts showed that the Louisville hotspot in the South Pacific behaved in a different manner, as its mantle plume remained more or less fixed around 48°S latitude during that same time period. Our findings demonstrate that the Pacific hotspots move independently and that their trajectories may be controlled by differences in subduction zone geometry. Additionally, shipboard geochemistry data shows that, in contrast to Hawaiian volcanoes, the construction of the Louisville Seamounts doesn’t involve a shield-building phase dominated by tholeiitic lavas, and trace elements confirm the rather homogenous nature of the Louisville mantle source. Both observations set Louisville apart from the Hawaiian-Emperor seamount trail, whereby the latter has been erupting abundant tholeiites (characteristically up to 95% in volume) and which exhibit a large variability in (isotope) geochemistry and their mantle source components

SORL1 Is Genetically Associated with Late-Onset Alzheimer’s Disease in Japanese, Koreans and Caucasians

To discover susceptibility genes of late-onset Alzheimer’s disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values ,261025 were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P=7.3361027 in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P=1.7761029) and rs3781834 (P=1.0461028). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P=1.7161025) and rs744373 near BIN1 (P = 1.3961024). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations

Workshop report: Exploring deep oceanic crust off Hawai‘i

For more than half a century, exploring a complete sequence of the oceanic crust from the seafloor through the Mohorovičić discontinuity (Moho) and into the uppermost mantle has been one of the most challenging missions of scientific ocean drilling. Such a scientific and technological achievement would provide humankind with profound insights into the largest realm of our planet and expand our fundamental understanding of Earth's deep interior and its geodynamic behavior. The formation of new oceanic crust at mid-ocean ridges and its subsequent aging over millions of years, leading to subduction, arc volcanism, and recycling of some components into the mantle, comprise the dominant geological cycle of matter and energy on Earth. Although previous scientific ocean drilling has cored some drill holes into old (> 110 Ma) and young (< 20 Ma) ocean crust, our sampling remains relatively shallow (< 2 km into intact crust) and unrepresentative of average oceanic crust. To date, no hole penetrates more than 100 m into intact average-aged oceanic crust that records the long-term history of seawater–basalt exchange (60 to 90 Myr). In addition, the nature, extent, and evolution of the deep subseafloor biosphere within oceanic crust remains poorly unknown. To address these fundamentally significant scientific issues, an international workshop “Exploring Deep Oceanic Crust off Hawai`i” brought together 106 scientists and engineers from 16 countries that represented the entire spectrum of disciplines, including petrologists, geophysicists, geochemists, microbiologists, geodynamic modelers, and drilling/logging engineers. The aim of the workshop was to develop a full International Ocean Discovery Program (IODP) proposal to drill a 2.5 km deep hole into oceanic crust on the North Arch off Hawai`i with the drilling research vessel Chikyu. This drill hole would provide samples down to cumulate gabbros of mature (∼ 80 Ma) oceanic crust formed at a half spreading rate of ∼ 3.5 cm a−1. A Moho reflection has been observed at ∼ 5.5 km below the seafloor at this site, and the workshop concluded that the proposed 2.5 km deep scientific drilling on the North Arch off Hawai`i would provide an essential “pilot hole” to inform the design of future mantle drilling

Isotopic evidence for a link between the Lyra Basin and Ontong Java Plateau

The few geological and geophysical studies of the Lyra Basin at the western margin of 45 the Ontong Java Plateau (OJP; Pacific Ocean) revealed that it is underlain by thicker than normal 46 oceanic crust. The unusually thick oceanic crust is attributed to the emplacement of massive lava 47 flows from the OJP. Dredging was conducted to sample the inferred OJP crust on the Lyra Basin 48 but instead recovered younger extrusives that may have covered the older plateau lavas in the 49 area. The Lyra Basin extrusives are alkalic basalts with (87Sr/86Sr)t = 0.704513-0.705105, 50 (143Nd/144Nd)t = 0.512709-0.512749, εNd(t) = +3.0 to +3.8, (206Pb/204Pb)t = 18.488-18.722, 51 (207Pb/204Pb)t = 15.558-15.577, and (208Pb/204Pb)t = 38.467-38.680, values that are distinct from 52 those of the OJP tholeiites. They have age-corrected (187Os/188Os)t = 0.1263-0.1838 that overlap 53 with the range of values determined for the Kroenke-type and Kwaimbaita-type OJP basalts, but 54 their (176Hf/177Hf)t = 0.28295-0.28299 and εHf(t) = +7.9 to +9.3 values are lower. These isotopic 55 compositions do not match those of any Polynesian ocean island volcanics. Instead, the Lyra 56 Basin basalts have geochemical affinity and isotopic compositions that overlap with those of 57 some alkalic suite and alnoites in the island of Malaita, Solomon Islands. Although not directly 58 related to the main plateau volcanism at 120 Ma, the geochemical data and modeling suggest that 59 the origin of the Lyra Basin alkalic rocks may be genetically linked to the mantle preserved in 60 the OJP thick lithospheric root, with magmatic contribution from the Rarotongan hotspot