Regulation Of Plasminogen Activator Activity In The Central Nervous System

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106118/1/jth01646.pd

Noninhibitory PAI-1 enhances plasmin-mediated matrix degradation both in vitro and in experimental nephritis

Plasminogen activator inhibitor-type 1 (PAI-1) is thought to be profibrotic by inhibiting plasmin generation, thereby decreasing turnover of pathological extracellular matrix (ECM). A mutant, noninhibitory PAI-1 (PAI-1R) was recently shown by us to increase glomerular plasmin generation and reduce disease in anti-thy-1 nephritis. Here, in vitro and in vivo studies were performed to determine whether enhanced plasmin-dependent ECM degradation underlies the therapeutic effect of PAI-1R. 3H-labeled ECM was produced by rat mesangial cells (MCs). The effect of wild-type PAI-1 (wt-PAI-1) and PAI-1R on ECM degradation by newly plated MCs was measured by the release of 3H into medium. In vivo, anti-thy-1 nephritis was assessed in normal, untreated diseased and PAI-1R treated rats with or without the plasmin/plasminogen inhibitor, tranexamic acid (TA). wt-PAI-1 totally inhibited plasmin generation and reduced ECM degradation by 76% when exogenous plasminogen was added. Although PAI-1R alone had no effect, PAI-1R in the presence of wt-PAI-1 reversed the wt-PAI-1 inhibition of ECM degradation in a time- and dose-dependent manner (P<0.001). Plasmin activity and zymography were consistent with ECM degradation. Plasmin inhibitors: α2-antiplasmin, aprotinin, and TA completely blocked PAI-1R's ability to normalize ECM degradation (P<0.001). Consistent with the in vitro results, TA reversed PAI-1R-induced reductions in glomerular fibrin and ECM accumulation. Other measures of disease severity were either unaltered or partially reversed. PAI-1R reduces pathological ECM accumulation, in large part through effectively competing with native PAI-1 thereby restoring plasmin generation and increasing plasmin-dependent degradation of matrix components

Multiresolution analysis of active region magnetic structure and its correlation with the Mt. Wilson classification and flaring activity

Two different multi-resolution analyses are used to decompose the structure of active region magnetic flux into concentrations of different size scales. Lines separating these opposite polarity regions of flux at each size scale are found. These lines are used as a mask on a map of the magnetic field gradient to sample the local gradient between opposite polarity regions of given scale sizes. It is shown that the maximum, average and standard deviation of the magnetic flux gradient for alpha, beta, beta-gamma and beta-gamma-delta active regions increase in the order listed, and that the order is maintained over all length-scales. This study demonstrates that, on average, the Mt. Wilson classification encodes the notion of activity over all length-scales in the active region, and not just those length-scales at which the strongest flux gradients are found. Further, it is also shown that the average gradients in the field, and the average length-scale at which they occur, also increase in the same order. Finally, there are significant differences in the gradient distribution, between flaring and non-flaring active regions, which are maintained over all length-scales. It is also shown that the average gradient content of active regions that have large flares (GOES class 'M' and above) is larger than that for active regions containing flares of all flare sizes; this difference is also maintained at all length-scales.Comment: Accepted for publication in Solar Physic

Compensation between meridional flow components of the Atlantic MOC at 26°N

From ten years of observations of the Atlantic meridional overturning circulation (MOC) at 26° N (2004–2014), we revisit the question of flow compensation between components of the circulation. Contrasting with early results from the observations, transport variations of the Florida Current (FC) and upper mid-ocean (UMO) transports (top 1000 m east of the Bahamas) are now found to compensate on sub-annual timescales. The observed compensation between the FC and UMO transports is associated with horizontal circulation and means that this part of the correlated variability does not project onto the MOC. A deep baroclinic response to wind-forcing (Ekman transport) is also found in the lower North Atlantic Deep Water (LNADW; 3000–5000 m) transport. In contrast, co-variability between Ekman and the LNADW transports does contribute to overturning. On longer timescales, the southward UMO transport has continued to strengthen, resulting in a continued decline of the MOC. Most of this interannual variability of the MOC can be traced to changes in isopycnal displacements on the western boundary, within the top 1000 m and below 2000 m. Substantial trends are observed in isopycnal displacements in the deep ocean, underscoring the importance of deep boundary measurements to capture the variability of the Atlantic MOC

WISP genes are members of the connective tissue growth factor family that are up-regulated in Wnt-1-transformed cells and aberrantly expressed in human colon tumors

Wnt family members are critical to many developmental processes, and components of the Wnt signaling pathway have been linked to tumorigenesis in familial and sporadic colon carcinomas. Here we report the identification of two genes, WISP-1 and WISP-2, that are up-regulated in the mouse mammary epithelial cell line C57MG transformed by Wnt-1, but not by Wnt-4. Together with a third related gene, WISP-3, these proteins define a subfamily of the connective tissue growth factor family. Two distinct systems demonstrated WISP induction to be associated with the expression of Wnt-1. These included (i) C57MG cells infected with a Wnt-1 retroviral vector or expressing Wnt-1 under the control of a tetracyline repressible promoter, and (ii) Wnt-1 transgenic mice. The WISP-1 gene was localized to human chromosome 8q24.1-8q24.3. WISP-1 genomic DNA was amplified in colon cancer cell lines and in human colon tumors and its RNA overexpressed (2- to >30-fold) in 84% of the tumors examined compared with patient-matched normal mucosa. WISP-3 mapped to chromosome 6q22-6q23 and also was overexpressed (4- to >40-fold) in 63% of the colon tumors analyzed. In contrast, WISP-2 mapped to human chromosome 20q12-20q13 and its DNA was amplified, but RNA expression was reduced (2- to >30-fold) in 79% of the tumors. These results suggest that the WISP genes may be downstream of Wnt-1 signaling and that aberrant levels of WISP expression in colon cancer may play a role in colon tumorigenesis

Open Cosmic Strings in Black Hole Space-Times

We construct open cosmic string solutions in Schwarzschild black hole and non-dilatonic black p-brane backgrounds. These strings can be thought to stretch between two D-branes or between a D-brane and the horizon in curved space-time. We study small fluctuations around these solutions and discuss their basic properties.Comment: 11 pages, REVTex, 5 figures, a reference adde

The frequency of transforming growth factor-TGF-B gene polymorphisms in a normal southern Iranian population

Several single nucleotide polymorphisms (SNPs) of the transforming growth factor-β1 gene (TGFB1) have been reported. Determination of TGFB1 SNPs allele frequencies in different ethnic groups is useful for both population genetic analyses and association studies with immunological diseases. In this study, five SNPs of TGFB1 were determined in 325 individuals from a normal southern Iranian population using polymerase chain reaction-restriction fragment length polymorphism method. This population was in Hardy-Weinberg equilibrium for these SNPs. Of the 12 constructed haplotypes, GTCGC and GCTGC were the most frequent in the normal southern Iranian population. Comparison of genotype and allele frequencies of TGFB SNPs between Iranian and other populations (meta-analysis) showed significant differences, and in this case the southern Iranian population seems genetically similar to Caucasoid populations. However, neighbour-joining tree using Nei's genetic distances based on TGF-β1 allele frequencies showed that southern Iranians are genetically far from people from the USA, Germany, UK, Denmark and the Czech Republic. In conclusion, this is the first report of the distribution of TGFB1 SNPs in an Iranian population and the results of this investigation may provide useful information for both population genetic and disease studies. © 2008 The Authors

Determination of the apparent and true ileal amino acid digestibility and digestible and metabolizable energy of specialty protein sources intended for nursery pig diets

Two experiments were conducted to determine the apparent and true-ileal amino acid digestibility, and to determine the digestible energy and metabolizable energy values of rice protein concentrate, salmon protein hydrolysate, whey protein concentrate, and spray-dried animal plasma. The experimental ingredients were analyzed for essential and non-essential amino acids and crude protein so diets could be formulated. In Exp.1, pigs were fed each diet, and ileal digesta was collected and analyzed. Apparent and true digestibilities were then calculated. In Exp. 2, pigs were fed each diet and feces were collected, weighed, and sampled. Lab analyses were conducted for the determination of gross energy (GE) and digestible energy (DE). Then ME values were determined by calculation from the DE and CP concentrations of experimental diets. In Exp. 1, TID lysine, methionine, and threonine values were 86.6, 69.0, and 78.9% for rice protein concentrate; 89.7, 88.7, and 80.2% for salmon protein hydrolysate; 95.7, 93.9, and 88.4% for whey protein concentrate; and 95.4, 93.5, and 92.2% for spray-dried animal plasma, respectively. In Exp. 2, DE values for rice protein concentrate, salmon protein hydrolysate, whey protein concentrate, and spray-dried animal plasma were 2143, 1893, 2245, and 2062 kcal/lb, respectively. The ME values that were determined for the protein products were 1917, 1598, 1974, and 1805 kcal/lb, respectively