Evolution of digital organisms at high mutation rates leads to survival of the flattest.

Darwinian evolution favours genotypes with high replication rates, a process called 'survival of the fittest'. However, knowing the replication rate of each individual genotype may not suffice to predict the eventual survivor, even in an asexual population. According to quasi-species theory, selection favours the cloud of genotypes, interconnected by mutation, whose average replication rate is highest.

Interaction between directional epistasis and average mutational effects.

We investigate the relationship between the average fitness decay due to single mutations and the strength of epistatic interactions in genetic sequences. We observe that epistatic interactions between mutations are correlated to the average fitness decay, both in RNA secondary structure prediction as well as in digital organisms replicating in silico. This correlation implies that, during adaptation, epistasis and average mutational effect cannot be optimized independently.

Experimental evidence for a torus breakdown in a glow discharge plasma.

A global bifurcation scenario for a two-frequency torus breakdown depicted by Baptista and Caldas [Physica D 132, 325 (1999)] is observed on a glow-discharge experiment. The torus is broken through a crisis with an unstable periodic orbit. The torus section before the bifurcation is a sided polygon that has a number of edges equal to the period of the unstable orbit.

Internally driven spatiotemporal irregularity in a dc glow discharge.

Spatiotemporal dynamics of an undriven dc glow discharge at intermediate pressures (p(0)r(0)=6.2 Torr cm, i<50 mA) is investigated experimentally. Spatiotemporal irregularity and windows of regular nonlinear waves occur and are found to depend on the discharge current.

GM-CSF regulates bleomycin-induced pulmonary fibrosis via a prostaglandin-dependent mechanism.

To characterize the role of GM-CSF in pulmonary fibrosis, we have studied bleomycin-induced fibrosis in wild-type mice vs mice with a targeted deletion of the GM-CSF gene (GM-CSF-/- mice). Without GM-CSF, pulmonary fibrosis was worse both histologically and quantitatively. These changes were not related to enhanced recruitment of inflammatory cells because wild-type and GM-CSF-/- mice recruited equivalent numbers of cells to the lung following bleomycin.

A kinetic analysis of hybridoma growth and metabolism in batch and continuous suspension culture: effect of nutrient concentration, dilution rate, and pH. Reprinted from Biotechnology and Bioengineering, Vol. 32, Pp 947-965 (1988).

Hybridomas are finding increased use for the production of a wide variety of monoclonal antibodies. Understanding the roles of physiological and environmental factors on the growth and metabolism of mammalian cells is a prerequisite for the development of rational scale-up procedures. An SP2/0-derived mouse hybridoma has been employed in the present work as a model system for hybridoma suspension culture.

Neovascularization during venous thrombosis organization: a preliminary study.

Purpose: Thrombus organization after venous thromboembolism leading to recanalization occurs at a variable rate. The angiogenic chemokine interleukin-8 (IL-8) has been found in thrombus months after thrombus initiation. We hypothesize that thrombus organization involves neovascularization and leukocyte influx and that IL-8 administered at thrombus induction will promote thrombus organization.

Importance of surgical resection in the successful management of soft tissue sarcoma.

Hypothesis: A systemic disease-free state necessitates a local disease-free state. This cannot be accomplished without a properly performed resection by an experienced surgical team. Successful local management of soft tissue sarcoma (STS) may lead to improved disease-free survival.

Distinct CXC chemokines mediate tumorigenicity of prostate cancer cells.

Prostate cancer is the second leading cause of malignancy-related mortality in males in the United States. As a solid tumor, clinically significant tumor growth and metastasis are dependent on nutrients and oxygen supplied by tumor-associated neovasculature. As such, there is a selective tumorigenic advantage for those neoplasms that can produce angiogenic mediators.

Low-dose low-molecular-weight heparin is anti-inflammatory during venous thrombosis.

Purpose: Venous thrombosis results in a vein wall inflammatory response initiated by thrombus. Although anticoagulation with standard heparin (SH) and low-molecular-weight heparin (LMWH) is known to limit further thrombosis, their anti-inflammatory properties are poorly defined. The anti-inflammatory properties of these heparins were studied.

The murine Fhit gene is highly similar to its human orthologue and maps to a common fragile site region.

The human FHIT gene is a putative tumor suppressor gene that maps to human chromosome band 3p14.2 in a region that is frequently deleted in cancers. It exhibits both genomic deletions and aberrant transcripts in a variety of tumors and spans the common fragile site FRA3B.

IL-10 regulates thrombus-induced vein wall inflammation and thrombosis.

Vein wall inflammation associated with venous thrombosis is mediated by an imbalance in proinflammatory as compared with antiinflammatory molecules. We hypothesize that IL-10 is an important antiinflammatory cytokine that influences vein wall inflammation and thrombus propagation during venous thrombosis. To test this hypothesis a model of inferior vena caval thrombosis was used.

Frequent deletions of FHIT and FRA3B in Barrett's metaplasia and esophageal adenocarcinomas.

The FHIT gene, which spans the common fragile site FRA3B, has been shown to produce aberrant transcripts in a variety of tumor types. Homozygous deletions within the FHIT locus have been detected only in tumor-derived cell lines and LOH has been described in numerous primary tumors. Based on these findings and its location on 3p, FHIT has been proposed as a tumor suppressor gene.

Exclusion of BMP6 as a candidate gene for cleidocranial dysplasia.

Cleidocranial dysplasia (CCD) is an autosomal dominant, generalized skeletal dysplasia in humans that has been mapped to the short arm of chromosome 6. We report linkage of a CCD mutation to 6p21 in a large family and exclude the bone morphogenetic protein 6 gene (BMP6) as a candidate for the disease by cytogenetic localization and genetic recombination. CCD was linked with a maximal two-point LOD score of 7.

The CXC chemokines, IL-8 and IP-10, regulate angiogenic activity in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic and often fatal disorder. Fibroplasia and deposition of extracellular matrix are dependent, in part, on angiogenesis. We postulated that an imbalance exists in the expression of angiogenic (IL-8) vs angiostatic (IFN-gamma-inducible protein (IP-10)) CXC chemokines, which favors net angiogenesis in IPF.

Aphidicolin-induced FRA3B breakpoints cluster in two distinct regions.

The common fragile site at chromosomal band 3p14.2 (FRA3B) is the most sensitive single site in the human genome to induced chromosomal lesions. This fragile site may predispose chromosome 3p to breakage that is commonly observed in lung, renal, and many other cancers.

Anti-P-selectin antibody decreases inflammation and thrombus formation in venous thrombosis.

Purpose: Venous thrombosis and inflammation are interrelated. P-selectin contributes to activation of leukocyte-mediated inflammation. Therefore, we hypothesized that the neutralization of P-selectin would decrease vein wall inflammation and thrombosis.

Bronchoalveolar lavage neutrophilia is associated with obliterative bronchiolitis after lung transplantation: role of IL-8.

Obliterative bronchiolitis (OB) is a devastating complication in lung transplantation. We postulated that the pathogenesis of OB is mediated, in part, by neutrophils. We serially collected bronchoalveolar lavage (BAL) fluid from lung transplant recipients.

Frequent breakpoints in the 3p14.2 fragile site, FRA3B, in pancreatic tumors.

FRA3B, at chromosomal band 3p14.2, is the most active common fragile site in the human genome. Homozygous deletions in the region of FRA3B have been observed in many types of solid tumors.

Neutrophils are the initial cell type identified in deep venous thrombosis induced vein wall inflammation.

Venous thrombosis and inflammation are interrelated. The authors hypothesized that inferior vena cava thrombosis results in a predictable vein wall inflammatory response, characterized by early neutrophil infiltration. Thrombosis was induced in rats by placement of an inferior vena cava ligature with branch ligation.

P-selectin and TNF inhibition reduce venous thrombosis inflammation.

Venous thrombosis induces a detrimental inflammatory response in the vein wall. The cytokine tumor necrosis factor-alpha (TNF) and the adhesion molecules, selectins, have been found to be important in mediating inflammatory cell stimulation and leukocyte-endothelial cell adhesion, respectively. This study assesses the role of TNF and P-selectin in the inflammatory events associated with venous thrombosis.

A 350-kb cosmid contig in 3p14.2 that crosses the t(3;8) hereditary renal cell carcinoma translocation breakpoint and 17 aphidicolin-induced FRA3B breakpoints.

The constitutive fragile site at human chromosomal band 3p14.2, FRA3B, has been described as the most active common fragile site in the human genome. FRA3B is cytologically indistinguishable from the chromosome 3 breakpoint observed in the hereditary renal cell carcinoma (hRCC) translocation t(3;8) (p14.

The role of cytokine networks in the local liver injury following hepatic ischemia/reperfusion in the rat.

The liver is highly susceptible to a number of pathological insults, including ischemia/reperfusion injury. We have previously employed an animal model of hepatic ischemia/reperfusion injury, and have shown that this injury induces the production and release of hepatic-derived tumor necrosis factor alpha (TNF-alpha), which mediates, in part, local liver injury following hepatic reperfusion. In the present study, we have extended these previous observations to assess whether an interrelationship exists between TNF-alpha and the neutrophil chemoattractant/activating factor, epithelial neutrophil activating protein, that may account for some of the pathology of neutrophil-mediated ischemia/reperfusion-induced liver injury.

FRA3B extends over a broad region and contains a spontaneous HPV16 integration site: direct evidence for the coincidence of viral integration sites and fragile sites.

The common fragile site at 3p14.2 (FRA3B) is the most sensitive site on normal human chromosomes for the formation of gaps and breaks when DNA replication is perturbed by aphidicolin or folate stress. Although rare fragile sites are known to arise through the expansion of CCG repeats, the mechanism responsible for common fragile sites is unknown.