Macrophage migration inhibitory factor (MIF): mechanisms of action and role in disease

Macrophage migration inhibitory factor (MIF) is a unique cytokine and critical mediator of host defenses with a role in septic shock and chronic inflammatory and autoimmune diseases. Its mechanism of action is incompletely understood. Here, we attempt to correlate current knowledge on the molecular pathways of MIF activity with its functions in immunity and disease.     

Combined association,segregation and aggregation analysis on case-control family data

Recently genetic epidemiologists have begun using case-control family study designs to investigate the role of genetic and environmental risk factors in disease etiology. The objective of these studies is to assess the association of environmental factors with the disease trait; to characterize the disease genes using segregation analysis; and to quantify the residual familial aggregation after controlling for environmental and genetic factors. Typically these objectives are achieved by conducting separate studies and analysis. This paper describes an estimating equation based approach for a combined association, segregation and aggregation analysis on data from case-control family studies. Simulations indicate that the method performs well in a variety of settings. The method is illustrated using simulated family history data made available to participants in a recent Genetic Analysis Workshop.     

Vascular endothelial growth factor induces IP-10 chemokine expression

We have previously shown that intracavernous injection of vascular endothelial growth factor (VEGF) improved the recovery of erectile function in an arteriogenic impotence rat mode. We wished to identify genes that are affected by VEGF treatment in the penis. Specifically we examined the induction of IP-10 chemokine. Male rats were subjected to pudendal arterial ligation or sham operation. They were then treated with intracavernous injection of 4 microg of VEGF in phosphate-buffered saline (PBS) or PBS alone. At 6 and 24 h after treatment, the erectile tissue was then harvested for RNA isolation. The isolated RNA was used for microarray and RT-PCR analyses. Cultured rat cavernous smooth muscle cells (CSMC) were treated with VEGF and then subjected to RT-PCR analysis. Cultured human CSMC were treated with VEGF and then subjected to ELISA analysis. Microarray analysis detected IP-10 as an abundantly induced message in 6-h VEGF-treated tissues. This was further confirmed by RT-PCR analysis. Using cultured rat CSMC, induction of IP-10 mRNA was detectable in 1 and 2 h, but not 24 h, VEGF-treated cells. Induction of IP-10 at the protein level was observed with cultured human CSMC. Secretion of IP-10 into culture medium peaked at 4 h after treatment of human CSMC with 10 ng/ml of VEGF. Optimal VEGF dosage for IP-10 induction was 50 ng/ml when assayed with cells that were treated for 8 h.     

Microglial chemotaxis, activation, and phagocytosis of amyloid beta-peptide as linked phenomena in Alzheimer's disease

Microglia are widely held to play important pathophysiologic roles in Alzheimer's disease (AD). On exposure to amyloid β peptide (Aβ) they exhibit chemotactic, phagocytic, phenotypic and secretory responses consistent with scavenger cell activity in a localized inflammatory setting. Because AD microglial chemotaxis, phagocytosis, and secretory activity have common, tightly linked soluble intermediaries (e.g., cytokines, chemokines), cell surface intermediaries (e.g., receptors, opsonins), and stimuli (e.g., highly inert Aβ deposits and exposed neurofibrilly tangles), the mechanisms for microglial clearance of Aβ are necessarily coupled to localized inflammatory mechanisms that can be cytotoxic to nearby tissue. This presents a critical dilemma for strategies to remove Aβ by enhancing micoglial activation—a dilemma that warrants substantial further investigation.     

Mutation of Arabidopsis plastid phosphoglucose isomerase affects leaf starch synthesis and floral initiation

We isolated pgi1-1, an Arabidopsis mutant with a decreased plastid phospho-glucose (Glc) isomerase activity. While pgi1-1 mutant has a deficiency in leaf starch synthesis, it accumulates starch in root cap cells. It has been shown that a plastid transporter for hexose phosphate transports cytosolic Glc-6-P into plastids and expresses restricted mainly to the heterotrophic tissues. The decreased starch content in leaves of the pgi1-1 mutant indicates that cytosolic Glc-6-P cannot be efficiently transported into chloroplasts to complement the mutant's deficiency in chloroplastic phospho-Glc isomerase activity for starch synthesis. We cloned the Arabidopsis PGI1 gene and showed that it encodes the plastid phospho-Glc isomerase. The pgi1-1 allele was found to have a single nucleotide substitution, causing a Ser to Phe transition. While the flowering times of the Arabidopsis starch-deficient mutants pgi1, pgm1, and adg1 were similar to that of the wild type under long-day conditions, it was significantly delayed under short-day conditions. The pleiotropic phenotype of late flowering conferred by these starch metabolic mutations suggests that carbohydrate metabolism plays an important role in floral initiation.     

Halorespiring bacteria-molecular characterization and detection

Recently, a rapidly increasing number of bacteria has been isolated that is able to couple the reductive dehalogenation of various halogenated aromatic and aliphatic compounds like chlorophenols and tetrachloroethene to energy conservation by electron-transport-coupled phosphorylation. The potential of these halorespiring bacteria for innovative clean-up strategies of polluted anoxic environments has greatly stimulated efforts to unravel the molecular basis of the novel respiratory chains they possess. The thorough characterization of halorespiratory key components at the physiological, biochemical and molecular genetic level has revealed both structural and functional similarity of chloroaryl- and chloroalkyl-respiratory chains from different phylogenetically distinct microorganisms. The reductive dehalogenases from halorespiring bacteria were found to comprise a novel class of corrinoid-containing Fe/S-proteins. Sensitive molecular methods for monitoring both presence and fate of halorespiring bacteria have been developed, which will be instrumental for the design and maintenance of optimised in situ bioremediation processes.     

Plant endemism in two forests in southern Bahia, Brazil

An important factor in determining species rarity is the geographic distribution of species. Estimates were made of the level of endemism of the flora of two sites in the southern Bahian wet forest zone. Estimates were made for endemism in the Atlantic forest biome and for the much more restricted area of southern Bahia and northern Espi´rito Santo and are derived from analyses of the distributions of the species known from each area. The species checklist for each area is based on identified specimens resulting from intensive collecting in a forest near Serra Grande (40km north of Ilhe´us) and the Una Biological Reserve (40km south of Ilhe´us). Slightly less than half of the species (45.2% at Una and 47.7% at Serra Grande) have widespread distributions and 7.4% at each site are disjunct between the coastal forests and Amazonia. In the Una Reserve, 44.1% of the species are endemic to the coastal forest and 28.1% endemic to southern Bahia and northern Espi´rito Santo. At Serra Grande, 41.6% of the species are endemic to the coastal forest and 26.5% endemic to southern Bahia and northern Espi´rito Santo.