N-Cadherin cleavage during activated hepatic stellate cell apoptosis is inhibited by tissue inhibitor of metalloproteinase-1. [In supplement: 11th International Symposium on the Cells of the Hepatic Sinusoid and their Relation to Other Cells]

Apoptosis of hepatic stellate cells (HSC) has previously been shown to occur during spontaneous resolution of experimental liver fibrosis. TIMP-1 has also been shown to have a key role because of its ability to inhibit apoptosis of HSC via matrix metalloproteinase (MMP) inhibition. This has led to further study of novel substrates for MMPs that might impact on HSC survival. N-Cadherin is known to mediate cell-cell contacts in fibroblasts. In this study we demonstrate that N-Cadherin is expressed by activated rat HSC. Furthermore, during apoptosis of HSC, the N-Cadherin is cleaved into smaller fragments. Apoptosis of HSC may be inhibited by TIMP-1. This is associated with reduced fragmentation of N-Cadherin. N-Cadherin may have an important role in supporting HSC survival while N-Cadherin cleavage may play a part in promoting HSC apoptosis in recovery from liver fibrosis

Parallel software tools at Langley Research Center

This document gives a brief overview of parallel software tools available on the Intel iPSC/860 parallel computer at Langley Research Center. It is intended to provide a source of information that is somewhat more concise than vendor-supplied material on the purpose and use of various tools. Each of the chapters on tools is organized in a similar manner covering an overview of the functionality, access information, how to effectively use the tool, observations about the tool and how it compares to similar software, known problems or shortfalls with the software, and reference documentation. It is primarily intended for users of the iPSC/860 at Langley Research Center and is appropriate for both the experienced and novice user

The Ucsd/Keck Damped Lya Abundance Database: A Decade of High Resolution Spectroscopy

We publish the Keck/HIRES and Keck/ESI spectra that we have obtained during the first 10 years of Keck observatory operations. Our full sample includes 42 HIRES spectra and 39 ESI spectra along 65 unique sightlines providing abundance measurements on ~85 damped Lya systems. The normalized data can be downloaded from the journal or from our supporting website: http://www.ucolick.org/~xavier/DLA/. The database includes all of the sightlines that have been included in our papers on the chemical abundances, kinematics, and metallicities of the damped Lya systems. This data has also been used to argue for variations in the fine-structure constant. We present new chemical abundance measurements for 10 damped Lya systems and a summary table of high-resolution metallicity measurements (including values from the literature) for 153 damped Lya systems at z>1.6. We caution, however, that this metallicity sample (and all previous ones) is biased to higher N(HI) values than a random sample.Comment: 55 pages, 11 figures. Accepted to ApJS. See http://www.ucolick.org/~xavier/DLA/ for the dat

Comparison of terbium (III) luminescence enhancement in mutants of EF hand calcium binding proteins.

The luminescent isomorphous Ca2+ analogue, Tb3+, can be bound in the 12-amino acid metal binding sites of proteins of the EF hand family, and its luminescence can be enhanced by energy transfer from a nearby aromatic amino acid. Tb3+ can be used as a sensitive luminescent probe of the structure and function of these proteins. The effect of changing the molecular environment around Tb3+ on its luminescence was studied using native Cod III parvalbumin and site-directed mutants of both oncomodulin and calmodulin. Titrations of these proteins showed stoichiometries of fill corresponding to the number of Ca2+ binding loops present. Tryptophan in binding loop position 7 best enhanced Tb3+ luminescence in the oncomodulin mutant Y57W, as well as VU-9 (F99W) and VU-32 (T26W) calmodulin. Excitation spectra of Y57F, F102W, Y65W oncomodulin, and Cod III parvalbumin revealed that the principal Tb3+ luminescence donor residues were phenylalanine or tyrosine located in position 7 of a loop, despite the presence of other nearby donors, including tryptophan. Spectra also revealed conformational differences between the Ca2+- and Tb(3+)-bound forms. An alternate binding loop, based on Tb3+ binding to model peptides, was inserted into the CD loop of oncomodulin by cassette mutagenesis. The order of fill of Tb3+ in this protein reversed, with the mutated loop binding Tb3+ first. This indicates a much higher affinity for the consensus-based mutant loop. The mutant loop inserted into oncomodulin had 32 times more Tb3+ luminescence than the identical synthetic peptide, despite having the same donor tryptophan and metal binding ligands. In this paper, a ranking of sensitivity of luminescence of bound Tb3+ is made among this subset of calcium binding proteins. This ranking is interpreted in light of the structural differences affecting Tb3+ luminescence enhancement intensity. The mechanism of energy transfer from an aromatic amino acid to Tb3+ is consistent with a short-range process involving the donor triplet state as described by Dexter (Dexter, D. L. (1953) J. Chem. Phys. 21, 836). This cautions against the use of the Forster equation in approximating distances in these systems

Role of atmospheric horizontal resolution in simulating tropical and subtropical South American precipitation in HadGEM3-GC31

We assess the effect of increasing horizontal resolution on simulated precipitation over South America in a climate model. We use atmosphere-only simulations, performed with HadGEM3-GC31 at three horizontal resolutions: N96 (∼130 km; 1.88∘×1.25∘), N216 (∼60 km; 0.83∘×0.56∘), and N512 (∼25 km; 0.35∘×0.23∘). We show that all simulations have systematic biases in annual mean and seasonal mean precipitation over South America (e.g. too wet over the Amazon and too dry in the northeast). Increasing horizontal resolution improves simulated precipitation over the Andes and northeast Brazil. Over the Andes, improvements from horizontal resolution continue to ∼25 km, while over northeast Brazil, there are no improvements beyond ∼60 km resolution. These changes are primarily related to changes in atmospheric dynamics and moisture flux convergence. Over the Amazon Basin, precipitation variability increases at higher resolution. We show that some spatial and temporal features of daily South American precipitation are improved at high resolution, including the intensity spectra of rainfall. Spatial scales of daily precipitation features are also better simulated, suggesting that higher resolution may improve the representation of South American mesoscale convective systems

Terbium luminescence in synthetic peptide loops from calcium-binding proteins with different energy donors.

Fourteen 14-mer peptides corresponding to a consensus sequence of metal-binding loops from proteins of the calmodulin family were synthesized. The effect of varying both the position in the binding loop, and the type of aromatic side chains as energy donors for enhancement of terbium luminescence, was studied. It was concluded that tryptophan in loop position 7 gave optimal luminescence enhancement, and that the additional inclusion of a tyrosine in the loop at positions 2 or 4 could further boost emission from the bound terbium. In all further cases energy transfer from aromatic residues at positions other than 7 was markedly less efficient. These results suggest that the peptides assume a configuration which allows a hexadentate ligand structure around the bound terbium ion. This is consistent with a Dexter-type electron exchange model of energy transfer

Positive Health and Health Assets: Re-analysis of Longitudinal Datasets

Most approaches to health over the centuries have focused on the absence of illness. In contrast, we are investigating Positive Health —well-being beyond the mere absence of disease. In this article, we describe our theoretical framework and empirical work to date on Positive Health. Positive Health empirically identifies health assets by determining factors that predict health and illness over and above conventional risk factors. Biological health assets might include, for example, high heart rate variability, high levels of HDL, and cardiorespiratory fitness. Subjective health assets might include positive emotions, life satisfaction, hope, optimism, and a sense of meaning and purpose. Functional health assets might include close friends and family members; a stable marriage; meaningful work; participation in a social community; and the ability to carry out work, family, and social roles

Increased high-density lipoprotein cholesterol levels in mice with XX versus XY sex chromosomes

Objective— The molecular mechanisms underlying sex differences in dyslipidemia are poorly understood. We aimed to distinguish genetic and hormonal regulators of sex differences in plasma lipid levels. Approach and Results— We assessed the role of gonadal hormones and sex chromosome complement on lipid levels using the four core genotypes mouse model (XX females, XX males, XY females, and XY males). In gonadally intact mice fed a chow diet, lipid levels were influenced by both male–female gonadal sex and XX–XY chromosome complement. Gonadectomy of adult mice revealed that the male–female differences are dependent on acute effects of gonadal hormones. In both intact and gonadectomized animals, XX mice had higher HDL cholesterol (HDL-C) levels than XY mice, regardless of male–female sex. Feeding a cholesterol-enriched diet produced distinct patterns of sex differences in lipid levels compared with a chow diet, revealing the interaction of gonadal and chromosomal sex with diet. Notably, under all dietary and gonadal conditions, HDL-C levels were higher in mice with 2 X chromosomes compared with mice with an X and Y chromosome. By generating mice with XX, XY, and XXY chromosome complements, we determined that the presence of 2 X chromosomes, and not the absence of the Y chromosome, influences HDL-C concentration. Conclusions— We demonstrate that having 2 X chromosomes versus an X and Y chromosome complement drives sex differences in HDL-C. It is conceivable that increased expression of genes escaping X-inactivation in XX mice regulates downstream processes to establish sexual dimorphism in plasma lipid levels