Jay Wohlgemuth

Replication of centromere II of Schizosaccharomyces pombe.

The centromeric DNAs of Schizosaccharomyces pombe chromosomes resemble those of higher eukaryotes in being large and composed predominantly of repeated sequences. To begin a detailed analysis of the mode of replication of a complex centromere, we examined whether any sequences within S. pombe centromere II (cen2) have the ability to mediate autonomous replication. We found a high density of segments with such activity, including at least eight different regions comprising most of the repeated and unique centromeric DNA elements. A physical mapping analysis using two-dimensional gels showed that autonomous replication initiated within the S. pombe sequences in each plasmid. A two-dimensional gel analysis of replication on the chromosomes revealed that the K and L repeat elements, which occur in multiple copies at all three centromeres and comprise approximately 70% of total centromeric DNA mass in S. pombe, are both sites of replication initiation. In contrast, the unique cen2 central core, which contains multiple segments that can support autonomous replication, appears to be repressed for initiation on the chromosome. We discuss the implications of these findings for our understanding of DNA replication and centromere function.

Genomic Assessment of Cardiac Transplant Rejection

Publisher Summary Heart failure (HF) is a leading cause of morbidity and mortality in the United States. The disease accounts for being the major cause of hospitalization for individuals aged 65 or greater. Despite major advances in the treatment of this disease over the past decade, a sizable number of patients with terminal or progressive myocardial dysfunction are fated to die or to be severely limited by symptoms. In these patients, biological replacement of the heart with human organs has become standard therapy and is widely accepted as a modality for prolonging life and improving its quality in carefully selected patients. Heart transplantation is the definitive therapy for end-stage HF, but is complicated by recipient immune responses to the transplanted heart, often resulting in cardiac allograft rejection. Different forms of rejection are recognized, including hyperacute rejection, acute cellular rejection, acute antibody-mediated rejection, mixed rejection, and chronic rejection. Most patients with acute rejection are asymptomatic and have no clinical findings of cardiac allograft dysfunction. The signs and symptoms of rejection are nonspecific and only manifest in the late stages of rejection. Thus, close surveillance of heart transplant recipients for acute rejection is critical. Protocols for the timing of rejection surveillance are variable among transplant programs, but are generally chosen to match the observed frequency of rejection episodes.

Molecular Biology of Vascular Remodeling

The earliest form of vascular remodeling occurs during embryonic development, during vascular formation. In this process endothelial cells arise and form a dense plexus throughout the mesoderm. This plexus then remodels to form a recognizable branching vascular pattern. This remodeling has been considered to be primarily an endothelial cell event. It is now increasingly clear that this earliest form of remodeling actually represents a complex coordinated development process involving endothelial cells and smooth muscle cells. Recent gene-targeting experiments have begun to dissect the signaling pathways that mediate various aspects of this complex process, which appears to be regulated by secreted factors and physical forces. Subsequently, there is extensive remodeling as the primitive vascular pattern reorganizes to reflect the definitive circulation found in higher vertebrates. And finally, there is continuous remodeling in embryogenesis and during postnatal development as the organism increases in size.