The N-end rule pathway is a sensor of heme

The conjugation of arginine, by arginyl-transferase, to N-terminal aspartate, glutamate or oxidized cysteine is a part of the N-end rule pathway of protein degradation. We report that arginyl-transferase of either the mouse or the yeast Saccharomyces cerevisiae is inhibited by hemin (Fe3+-heme). Furthermore, we show that hemin inhibits arginyl-transferase through a redox mechanism that involves the formation of disulfide between the enzyme's Cys-71 and Cys-72 residues. Remarkably, hemin also induces the proteasome-dependent degradation of arginyl-transferase in vivo, thus acting as both a "stoichiometric" and "catalytic" down-regulator of the N-end rule pathway. In addition, hemin was found to interact with the yeast and mouse E3 ubiquitin ligases of the N-end rule pathway. One of substrate-binding sites of the yeast N-end rule's ubiquitin ligase UBR1 targets CUP9, a transcriptional repressor. This site of UBR1 is autoinhibited but can be allosterically activated by peptides that bear destabilizing N-terminal residues and interact with two other substrate-binding sites of UBR1. We show that hemin does not directly occlude the substrate-binding sites of UBR1 but blocks the activation of its CUP9-binding site by dipeptides. The N-end rule pathway, a known sensor of short peptides, nitric oxide, and oxygen, is now a sensor of heme as well. One function of the N-end rule pathway may be to coordinate the activities of small effectors, both reacting to and controlling the redox dynamics of heme, oxygen, nitric oxide, thiols, and other compounds, in part through conditional degradation of specific transcription factors and G protein regulators

Extreme oceanographic events recorded in the Southern Benguela during the 1999-2000 summer season

Two unusual oceanographic events occurred during the 1999-2000 summer season off the west coast of South Africa. The first was a strong and sustained warming that occurred in mid-December and lasted for two weeks. The second was an enhanced cooling that lasted from mid to late summer. These two events were the result of fluctuations in wind-induced upwelling. The spatial as well as the temporal extent of these conditions are analysed and the corresponding atmospheric setting is described. Using climatological data, the 1999-2000 summer season is placed in the long-term context of the climatic variability in the region. The influence of those two events on phytoplankton and anchovy recruitment may have contributed to a record high level of anchovy recruitment in 2000

The reversible polydisperse Parking Lot Model

We use a new version of the reversible Parking Lot Model to study the compaction of vibrated polydisperse media. The particle sizes are distributed according to a truncated power law. We introduce a self-consistent desorption mechanism with a hierarchical initialization of the system. In this way, we approach densities close to unity. The final density depends on the polydispersity of the system as well as on the initialization and will reach a maximum value for a certain exponent in the power law.Comment: 7 pages, Latex, 12 figure

Reactions at polymer interfaces: A Monte Carlo Simulation

Reactions at a strongly segregated interface of a symmetric binary polymer blend are investigated via Monte Carlo simulations. End functionalized homopolymers of different species interact at the interface instantaneously and irreversibly to form diblock copolymers. The simulations, in the framework of the bond fluctuation model, determine the time dependence of the copolymer production in the initial and intermediate time regime for small reactant concentration $\rho_0 R_g^3=0.163 ... 0.0406$. The results are compared to recent theories and simulation data of a simple reaction diffusion model. For the reactant concentration accessible in the simulation, no linear growth of the copolymer density is found in the initial regime, and a $\sqrt{t}$-law is observed in the intermediate stage.Comment: to appear in Macromolecule

Low self-esteem and the formation of global self-performance estimates in emerging adulthood

High self-esteem, an overall positive evaluation of self-worth, is a cornerstone of mental health. Previously we showed that people with low self-esteem differentially construct beliefs about momentary self-worth derived from social feedback. However, it remains unknown whether these anomalies extend to constructing beliefs about self-performance in a non-social context, in the absence of external feedback. Here, we examined this question using a novel behavioral paradigm probing subjects’ self-performance estimates with or without external feedback. We analyzed data from young adults (N = 57) who were selected from a larger community sample (N = 2402) on the basis of occupying the bottom or top 10% of a reported self-esteem distribution. Participants performed a series of short blocks involving two perceptual decision-making tasks with varying degrees of difficulty, with or without feedback. At the end of each block, they had to decide on which task they thought they performed best, and gave subjective task ratings, providing two measures of self-performance estimates. We found no robust evidence of differences in objective performance between high and low self-esteem participants. Nevertheless, low self-esteem participants consistently underestimated their performance as expressed in lower subjective task ratings relative to high self-esteem participants. These results provide an initial window onto how cognitive processes underpinning the construction of self-performance estimates across different contexts map on to global dispositions relevant to mental health such as self-esteem

fMRI Reveals Mitigation of Cerebrovascular Dysfunction by Bradykinin Receptors 1 and 2 Inhibitor Noscapine in a Mouse Model of Cerebral Amyloidosis

Functional magnetic resonance imaging (fMRI) techniques can be used to assess cerebrovascular dysfunction in Alzheimer's disease, an important and early contributor to pathology. We hypothesized that bradykinin receptor inhibition alleviates the vascular dysfunction in a transgenic arcA\u3b2 mouse model of cerebral amyloidosis and that fMRI techniques can be used to monitor the treatment response. Transgenic arcA\u3b2 mice, and non-transgenic littermates of 14 months-of-age were either treated with the bradykinin receptors 1 and 2 blocker noscapine or received normal drinking water as control over 3 months (n = 8-11/group) and all mice were assessed using fMRI at the end of the treatment period. Perfusion MRI using an arterial spin labeling technique showed regional hypoperfusion in arcA\u3b2 compared to non-transgenic controls, which was alleviated by noscapine treatment. Similarly, measuring cerebral blood volume changes upon pharmacological stimulation using vessel dilator acetazolamide revealed recovery of regional impairment of cerebral vascular reactivity in arcA\u3b2 mice upon noscapine treatment. In addition, we assessed with immunohistochemistry beta-amyloid (A\u3b2) and inflammation levels in brain sections. Immunohistological stainings for A\u3b2 deposition (6E10) and related microgliosis (Iba1) in the cortex and hippocampus were found comparable between noscapine-treated and untreated arcA\u3b2 mice. In addition, levels of soluble and insoluble A\u3b238, A\u3b240, A\u3b242 were found to be similar in brain tissue homogenates of noscapine-treated and untreated arcA\u3b2 mice using electro-chemiluminescent based immunoassay. In summary, bradykinin receptors blockade recovered cerebral vascular dysfunction in a mouse model of cerebral amyloidosis. fMRI methods revealed the functional deficit in disease condition and were useful tools to monitor the treatment response

Monitoring the oceanic flow between Africa and Antarctica: Report of the first GoodHope cruise

The southern ocean plays a major role in the global oceanic circulation role in the global oceanic circulation, as a component of the Meridional Overturning Circulation, and it is postulated that it has a great influence on present-day climate. However, our understanding of its complex three-dimensional dynamics and of the impact of its variability on the climate system is rudimentary. The newly constituted, international GoodHope research venture aims to address this knowledge gap by establishing a programme of regular observations across the Southern Ocean between the African and Antarctic continents. The objectives of this programme are fivefold: (1) to improve understanding of Indo-Atlantic inter-ocean exchanges and their impact on the global thermohaline circulation and thus on global climate change; (2) to understand in more detail the influence these exchanges have on the climate variability of the southern African subcontinent; (3) to monitor the variability of the main Southern Ocean frontal systems associated with the Antarctic Circumpolar Current; (4) to study air–sea exchanges and their role on the global heat budget, with particular emphasis on the intense exchanges occurring within the Agulhas Retroflection region south of South Africa, and (5) to examine the role of major frontal systems as areas of elevated biological activity and as biogeographical barriers to the distribution of plankton. We present here preliminary results on the physical and biological structure of the frontal systems using the first GoodHope transect that was completed during February–March 2004

Monitoring the oceanic flow between Africa and Antarctica: report of the first Good Hope cruise

The Southern Ocean plays a major role in the global oceanic circulation, as a component of the Meridional Overturning Circulation, and it is postulated that it has a great influence on present-day climate. However, our understanding of its complex three-dimensional dynamics and of the impact of its variability on the climate system is rudimentary. The newly constituted, international GoodHope research venture aims to address this knowledge gap by establishing a programme of regular observations across the Southern Ocean between the African and Antarctic continents. The objectives of this programme are fivefold: (1) to improve understanding of Indo-Atlantic inter-ocean exchanges and their impact on the global thermohaline circulation and thus on global climate change; (2) to understand in more detail the influence these exchanges have on the climate variability of the southern African subcontinent; (3) to monitor the variability of the main Southern Ocean frontal systems associated with the Antarctic Circumpolar Current; (4) to study air-sea exchanges and their role on the global heat budget, with particular emphasis on the intense exchanges occurring within the Agulhas Retroflection region south of South Africa, and (5) to examine the role of major frontal systems as areas of elevated biological activity and as biogeographical barriers to the distribution of plankton. We present here preliminary results on the physical and biological structure of the frontal systems using the first GoodHope transect that was completed during February-March 2004

Acute Loss of Iron-Sulfur Clusters Results in Metabolic Reprogramming and Generation of Lipid Droplets in Mammalian Cells

Iron–sulfur (Fe-S) clusters are ancient cofactors in cells and participate in diverse biochemical functions, including electron transfer and enzymatic catalysis. Although cell lines derived from individuals carrying mutations in the Fe-S cluster biogenesis pathway or siRNA-mediated knockdown of the Fe-S assembly components provide excellent models for investigating Fe-S cluster formation in mammalian cells, these experimental strategies focus on the consequences of prolonged impairment of Fe-S assembly. Here, we constructed and expressed dominant–negative variants of the primary Fe-S biogenesis scaffold protein iron–sulfur cluster assembly enzyme 2 (ISCU2) in human HEK293 cells. This approach enabled us to study the early metabolic reprogramming associated with loss of Fe-S–containing proteins in several major cellular compartments. Using multiple metabolomics platforms, we observed a ∼12-fold increase in intracellular citrate content in Fe-S–deficient cells, a surge that was due to loss of aconitase activity. The excess citrate was generated from glucose-derived acetyl-CoA, and global analysis of cellular lipids revealed that fatty acid biosynthesis increased markedly relative to cellular proliferation rates in Fe-S–deficient cells. We also observed intracellular lipid droplet accumulation in both acutely Fe-S–deficient cells and iron-starved cells. We conclude that deficient Fe-S biogenesis and acute iron deficiency rapidly increase cellular citrate concentrations, leading to fatty acid synthesis and cytosolic lipid droplet formation. Our findings uncover a potential cause of cellular steatosis in nonadipose tissues