Sphingolipid subtypes differentially control proinsulin processing and systemic glucose homeostasis

Impaired proinsulin-to-insulin processing in pancreatic β-cells is a key defective step in both type 1 diabetes and type 2 diabetes (T2D) (refs. $^{1}$$^{,}$$^{2}$), but the mechanisms involved remain to be defined. Altered metabolism of sphingolipids (SLs) has been linked to development of obesity, type 1 diabetes and T2D (refs. $^{3-8}$); nonetheless, the role of specific SL species in β-cell function and demise is unclear. Here we define the lipid signature of T2D-associated β-cell failure, including an imbalance of specific very-long-chain SLs and long-chain SLs. β-cell-specific ablation of CerS2, the enzyme necessary for generation of very-long-chain SLs, selectively reduces insulin content, impairs insulin secretion and disturbs systemic glucose tolerance in multiple complementary models. In contrast, ablation of long-chain-SL-synthesizing enzymes has no effect on insulin content. By quantitatively defining the SL-protein interactome, we reveal that CerS2 ablation affects SL binding to several endoplasmic reticulum-Golgi transport proteins, including Tmed2, which we define as an endogenous regulator of the essential proinsulin processing enzyme Pcsk1. Our study uncovers roles for specific SL subtypes and SL-binding proteins in β-cell function and T2D-associated β-cell failure

Multiple expressions of plume-ridge interaction in the Galapagos : volcanic lineaments and ridge jumps

Author Posting. © American Geophysical Union, 2012. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry Geophysics Geosystems 13 (2012): Q05018, doi:10.1029/2012GC004093.Anomalous volcanism and tectonics between near-ridge mantle plumes and mid-ocean ridges provide important insights into the mechanics of plume-lithosphere interaction. We present new observations and analysis of multibeam, side scan sonar, sub-bottom chirp, and total magnetic field data collected during the R/V Melville FLAMINGO cruise (MV1007; May–June, 2010) to the Northern Galápagos Volcanic Province (NGVP), the region between the Galápagos Archipelago and the Galápagos Spreading Center (GSC) on the Nazca Plate, and to the region east of the Galápagos Transform Fault (GTF) on the Cocos Plate. The NGVP exhibits pervasive off-axis volcanism related to the nearby Galápagos hot spot, which has dominated the tectonic evolution of the region. Observations indicate that ~94% of the excess volcanism in our survey area occurs on the Nazca Plate in three volcanic lineaments. Identified faults in the NGVP are consistent with normal ridge spreading except for those within a ~60 km wide swath of transform-oblique faults centered on the GTF. These transform-oblique faults are sub-parallel to the elongation direction of larger lineament volcanoes, suggesting that lineament formation is influenced by the lithospheric stress field. We evaluate current models for lineament formation using existing and new observations as well as numerical models of mantle upwelling and melting. The data support a model where the lithospheric stress field controls the location of volcanism along the lineaments while several processes likely supply melt to these eruptions. Synthetic magnetic models and an inversion for crustal magnetization are used to determine the tectonic history of the study area. Results are consistent with creation of the GTF by two southward ridge jumps, part of a series of jumps that have maintained a plume-ridge separation distance of 145 km to 215 km since ~5 Ma.This work was supported by NSF grant OCE-0926637 and OCE-1030904 to DF and KH. DG’s work was supported by NSF grants EAR- 0838461 and EAR-1145271. Additional support was provided to E.M. by the Deep Ocean Exploration Institute at the Woods Hole Oceanographic Institution.2012-11-3

The Arabidopsis cytochrome P450 CYP86A1 encodes a fatty acid ω-hydroxylase involved in suberin monomer biosynthesis

The lipophilic biopolyester suberin forms important boundaries to protect the plant from its surrounding environment or to separate different tissues within the plant. In roots, suberin can be found in the cell walls of the endodermis and the hypodermis or periderm. Apoplastic barriers composed of suberin accomplish the challenge to restrict water and nutrient loss and prevent the invasion of pathogens. Despite the physiological importance of suberin and the knowledge of the suberin composition of many plants, very little is known about its biosynthesis and the genes involved. Here, a detailed analysis of the Arabidopsis aliphatic suberin in roots at different developmental stages is presented. This study demonstrates some variability in suberin amount and composition along the root axis and indicates the importance of ω-hydroxylation for suberin biosynthesis. Using reverse genetics, the cytochrome P450 fatty acid ω-hydroxylase CYP86A1 (At5g58860) has been identified as a key enzyme for aliphatic root suberin biosynthesis in Arabidopsis. The corresponding horst mutants show a substantial reduction in ω-hydroxyacids with a chain length <C20, demonstrating that CYP86A1 functions as a hydroxylase of root suberized tissue. Detailed expression studies revealed a strong root specificity and a localized expression in the root endodermis. Transgenic expression of CYP86A1 fused to GFP distributed CYP86A1 to the endoplasmic reticulum, indicating that suberin monomer biosynthesis takes place in this sub-cellular compartment before intermediates are exported in the apoplast

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

The influence of balanced and imbalanced resource supply on biodiversity – functioning relationship across ecosystems

Numerous studies show that increasing species richness leads to higher ecosystem productivity. This effect is often attributed to more efficient portioning of multiple resources in communities with higher numbers of competing species, indicating the role of resource supply and stoichiometry for biodiversity-ecosystem functioning relationships. Here, we merged theory on ecological stoichiometry with a framework of biodiversity-ecosystem functioning to understand how resource use transfers into primary production. We applied a structural equation model to define patterns of diversity-productivity relationships with respect to available resources. Meta-analysis was used to summarize the findings across ecosystem types ranging from aquatic ecosystems to grasslands and forests. As hypothesized, resource supply increased realized productivity and richness, but we found significant differences between ecosystems and study types. Increased richness was associated with increased productivity, although this effect was not seen in experiments. More even communities had lower productivity, indicating that biomass production is often maintained by a few dominant species, and reduced dominance generally reduced ecosystem productivity. This synthesis, which integrates observational and experimental studies in a variety of ecosystems and geographical regions, exposes common patterns and differences in biodiversity-functioning relationships, and increases the mechanistic understanding of changes in ecosystems productivity

Experiment for cryogenic large-aperture intensity mapping: instrument design

The experiment for cryogenic large-aperture intensity mapping (EXCLAIM) is a balloon-borne telescope designed to survey star formation in windows from the present to z  =  3.5. During this time, the rate of star formation dropped dramatically, while dark matter continued to cluster. EXCLAIM maps the redshifted emission of singly ionized carbon lines and carbon monoxide using intensity mapping, which permits a blind and complete survey of emitting gas through statistics of cumulative brightness fluctuations. EXCLAIM achieves high sensitivity using a cryogenic telescope coupled to six integrated spectrometers employing kinetic inductance detectors covering 420 to 540 GHz with spectral resolving power R  =  512 and angular resolution ≈4  arc min. The spectral resolving power and cryogenic telescope allow the survey to access dark windows in the spectrum of emission from the upper atmosphere. EXCLAIM will survey 305  deg2 in the Sloan Digital Sky Survey Stripe 82 field from a conventional balloon flight in 2023. EXCLAIM will also map several galactic fields to study carbon monoxide and neutral carbon emission as tracers of molecular gas. We summarize the design phase of the mission

Temporally resolved GC-MS-based metabolic profiling of herbicide treated plants treated reveals that changes in polar primary metabolites alone can distinguish herbicides of differing mode of action

We conducted a comprehensive metabolic phenotyping of primary metabolism of photosynthetic tissue of Arabidopsis thaliana following spray treatment with a number of commercially used herbicides using a well established gas-chromatography mass-spectrometry profiling method. Applying this technique we were able to identify and quantify in excess of 80 polar metabolites and based on a combination of co-elution with standards and prediction from the mass spectra a similar number of lipophillic components within two chromatographic runs. The herbicides selected were glufosinate, sulcotrione, AE944 [N2-(1-ethyl-3-phenylpropyl)-6-(1-fluoro-1-methylethyl)-1,3,5-triazine-2,4-diamine], foramsulfuron, benfuresate and glyphosate. We determined causal changes in the metabolite profiles by following their time-dependent changes using a serial sampling strategy. The resultant profiles were compared both by looking at the largest changes in a metabolite by metabolite manner and by performance of statistical analyses. These data revealed that analysis of the polar metabolites allows clear separation of the compounds under test. This finding is discussed in the context of current strategies for agrochemical discovery

Competition among bird species at the University of Michigan Biological Station.

We investigated the degree of competition among nine bird species at UMBS. Competition among species often depends on niche overlap. Since members of the same species are most likely to have completely overlapping niches, one hypothesis is that intraspecific competition will be greater than interspecific competition. Another hypothesis is that species with greater niche overlaps will engage in higher levels of interspecific competition than those species with less niche overlap. Our data indicate that interspecific competition is more frequent and more intense among birds while feeding at a feeder than intraspecific competition. No correlation exists between the degree of resource overlap of two species and the frequency and intensity of competition.http://deepblue.lib.umich.edu/bitstream/2027.42/54518/1/2957.pdfDescription of 2957.pdf : Access restricted to on-site users at the U-M Biological Station