Knockout of LASP1 in CXCR4 expressing CML cells promotes cell persistence,proliferation and TKI resistance

Chronic myeloid leukaemia (CML) is a clonal myeloproliferative stem cell disorder characterized by the constitutively active BCR-ABL tyrosine kinase. The LIM and SH3 domain protein 1 (LASP1) has recently been identified as a novel BCR-ABL substrate and is associated with proliferation, migration, tumorigenesis and chemoresistance in several cancers. Furthermore, LASP1 was shown to bind to the chemokine receptor 4 (CXCR4), thought to be involved in mechanisms of relapse. In order to identify potential LASP1-mediated pathways and related factors that may help to further eradicate minimal residual disease (MRD), the effect of LASP1 on processes involved in progression and maintenance of CML was investigated. The present data indicate that not only overexpression of CXCR4, but also knockout of LASP1 contributes to proliferation, reduced apoptosis and migration as well as increased adhesive potential of K562 CML cells. Furthermore, LASP1 depletion in K562 CML cells leads to decreased cytokine release and reduced NK cell-mediated cytotoxicity towards CML cells. Taken together, these results indicate that in CML, reduced levels of LASP1 alone and in combination with high CXCR4 expression may contribute to TKI resistance.     

VopA inhibits ATP binding by acetylating the catalytic loop of MAPK kinases

The bacterial pathogen Vibrio parahemeolyticus manipulates host signaling pathways during infections by injecting type III effectors. One of these effectors, Vibrio outer protein A (VopA), inhibits MAPK signaling via a novel mechanism, distinct from those described for other bacterial toxins, that disrupts this signaling pathway. VopA is an acetyltransferase that potently inhibits MAPK signaling pathways not only by preventing the activation of MAPK kinases (MKKs) but also by inhibiting the activity of activated MKKs. VopA acetylates a conserved lysine found in the catalytic loop of all kinases and blocks the binding of ATP, but not ADP, on the MKKs, resulting in an inactive phosphorylated kinase. Acetylation of this conserved lysine inhibits kinase activity by a new mechanism of regulation that has not been observed previously. Identifying the target of VopA reveals a way that the reversible post-translational modification of lysine acetylation can be used to regulate the activity of an enzyme.     

Mouse biodiversity in the genomic era

Comparative genomics has developed by comparison of distantly related genomes, for which the link between the reported evolutionary changes and species development/physiology/ecology is not obvious. It is argued that the mouse (genus Mus) is an optimal model for microevolutionary genomics in vertebrates. This is because the mouse genome sequence, physical and genetic map have been completed, because mouse genetics, morpho-anatomy, pathology, behavior and ecology are well-studied, and because the Mus genus is a diverse, well- documented taxon, allowing comparative studies at the level of individual, population, subspecies, and species. The potential of the interaction between mouse genome and mouse biodiversity is illustrated by recent studies of speciation in the house mouse Mus musculus, and studies about the evolution of isochores, the peculiar pattern of GC-content variation across mammalian genomes.     

Survival for specific life intervals of smallmouth bass, Micropterus dolomieu, during parental care

We tested whether daily mortality rates (DMR) of smallmouth bass offspring were influenced by life interval, offspring density and growth, parental male attributes, and selected mortality factors during parental care in a regulated Virginia stream. Mortality averaged 9.5% per day (range 5.2–13.9%) and 94.1% total (range 80.9–99.5%) from egg deposition to the juvenile period (29–36 d) for individual broods. Offspring losses were primarily attributed to fungus (Saprolegnia parasitica) infection of eggs and to American eel, Anguilla rostrata, predation. DMR were significantly higher for the interval from swim-up of larvae to metamorphosis relative to earlier and later intervals. There was no significant autocorrelation of DMR among life intervals for individual broods, indicating that relative mortality rates were inconsistent among broods through time. DMR were also uncorrelated with the number of offspring per brood, offspring growth rates, and parental male attributes, except during egg and embryo intervals. Daily egg mortality was negatively related to male size and positively related to the number of eggs per nest, suggesting that density-dependent egg mortality may have been partially offset in nests of larger males. Larger males received more eggs, tended to maintain larger broods throughout parental care, and contributed a high proportion of the total number of juveniles reared. This revised version was published online in August 2006 with corrections to the Cover Date.     

Genetic diversity of four populations of Qualea grandiflora Mart. in fragments of the Brazilian Cerrado

We analyzed the genetic structure and diversity of Qualea grandiflora Mart., the most abundant woody species in the Brazilian Cerrado. Eight microsatellite loci were used to analyze samples from four populations subjected to different types of anthropic pressure, distributed throughout the state of São Paulo in the regions of Assis, Brotas, Itirapina and Pedregulho. Results indicated a mean number of 12 alleles per locus, but only six effective alleles. Alleles private to particular populations and rare alleles were also detected. An excess of homozygotes and moderate levels of inbreeding were observed. No clones were identified. All populations departed from Hardy–Weinberg equilibrium (p < 0.05). Spatial structure was observed in the distribution of specimens in distance classes ranging from 30 to 40 km and three genetic clusters were identified, with genotypes in the Pedregulho population differing from the others by up to 90 %. The influence of the Wahlund effect on the studied populations lies between 8.5 and 53.3 %. Estimates of effective population size were low (<10), and the minimum viable area for conservation in the short-, medium- and long-term was estimated to be between 4 and 184 ha. Gene flow was high enough to counter the effects of genetic drift. The genetic diversity and divergence between the studied populations indicated that the Pedregulho population should be considered an Evolutionary Significant Unit and a Management Unit.     

Novel TNF-α converting enzyme (TACE) inhibitors as potential treatment for inflammatory diseases

Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors has led to an acetylene containing series that demonstrates sub-nanomolar potency (K(i)) as well as excellent activity in human whole blood. These studies led to the discovery of highly potent TACE inhibitors with good DMPK profiles.     

Piperazine sulfonamide BACE1 inhibitors: Design,synthesis, and in vivo characterization

With collaboration between chemistry, X-ray crystallography, and molecular modeling, we designed and synthesized a series of novel piperazine sulfonamide BACE1 inhibitors. Iterative exploration of the non-prime side and S2′ sub-pocket of the enzyme culminated in identification of an analog that potently lowers peripheral Aβ₄₀ in transgenic mice with a single subcutaneous dose.     

<Emphasis Type="Italic">TRAF1/C5</Emphasis>polymorphism is not associated with increased mortality in rheumatoid arthritis: two large longitudinal studies

Introduction  

Recently an association between a genetic variation in TRAF1/C5 and mortality from sepsis or cancer was found in rheumatoid arthritis (RA). The most prevalent cause of death, cardiovascular disease, may have been missed in that study, since patients were enrolled at an advanced disease stage. Therefore, we used an inception cohort of RA patients to investigate the association between TRAF1/C5 and cardiovascular mortality, and replicate the findings on all-cause mortality. As TRAF1/C5 associated mortality may not be restricted to RA, we also studied a large cohort of non-RA patients.     

A newly discovered post-translational modification--the acetylation of serine and threonine residues

Recent studies on a bacterial virulence factor, YopJ of Yersinia, have led to the realization that the acetylation of serine and threonine residues could be an important form of post-translational modification in eukaryotes. Although the identification of the machinery used for the addition and removal of acetyl groups on serine or threonine residues is in its infancy, the enzymes thus-far studied provide early insight into the mechanism of this newly discovered post-translational modification, and hint at its potential importance. For example, acetylation can compete with phosphorylation targeted to the same residues and could, therefore, alter the course of signaling pathways. What are the implications for signal transduction in eukaryotes and how widespread could acetylation of serine and threonine prove to be?