The solution structure of the complement deregulator FHR5 reveals a compact dimer and provides new insights into CFHR5 nephropathy

The human complement Factor H–related 5 protein (FHR5) antagonizes the main circulating complement regulator Factor H, resulting in the deregulation of complement activation. FHR5 normally contains nine short complement regulator (SCR) domains, but a FHR5 mutant has been identified with a duplicated N-terminal SCR-1/2 domain pair that causes CFHR5 nephropathy. To understand how this duplication causes disease, we characterized the solution structure of native FHR5 by analytical ultracentrifugation and small-angle X-ray scattering. Sedimentation velocity and X-ray scattering indicated that FHR5 was dimeric, with a radius of gyration (R_g) of 5.5 ± 0.2 nm and a maximum protein length of 20 nm for its 18 domains. This result indicated that FHR5 was even more compact than the main regulator Factor H, which showed an overall length of 26–29 nm for its 20 SCR domains. Atomistic modeling for FHR5 generated a library of 250,000 physically realistic trial arrangements of SCR domains for scattering curve fits. Only compact domain structures in this library fit well to the scattering data, and these structures readily accommodated the extra SCR-1/2 domain pair present in CFHR5 nephropathy. This model indicated that mutant FHR5 can form oligomers that possess additional binding sites for C3b in FHR5. We conclude that the deregulation of complement regulation by the FHR5 mutant can be rationalized by the enhanced binding of FHR5 oligomers to C3b deposited on host cell surfaces. Our FHR5 structures thus explained key features of the mechanism and pathology of CFHR5 nephropathy.     

Tissue distribution and change in potato starch phosphorylase mRNA levels in wounded tissue and sprouting tubers.

Starch phosphorylase has been cloned from a lambda gt10 cDNA library of potato tuber mRNA. Selected recombinants have been used to demonstrate that phosphorylase mRNA is most abundant in tubers but is also detectable in stolon, root, stem and leaf tissue. The level of phosphorylase mRNA was greatly reduced in wounded stem and tuber tissue. The wounding-induced decrease in phosphorylase mRNA levels is not reversed in the presence of sucrose or mannitol. Regional differences are described in the levels of phosphorylase and patatin mRNA in different parts of the tuber and in the shoot of sprouting potatoes.     

Debate: PCI or CABG for multivessel disease? Viewpoint: No clear winner in an unfair fight

The Arterial Revascularization Therapy Study (ARTS) and the Stent or Surgery (SoS) trial each randomized patients with multivessel disease to either stenting or bypass surgery. The ARTS showed no difference in mortality between the two strategies, other than in diabetic patients, who fared better with surgery. The SoS trial demonstrated increased mortality in the stent arm, a difference that was not attributable to diabetes. Both trials found that the rates of repeat revascularization were lower with surgery, although the rate with stenting was much lower than had been seen in previous trials of angioplasty. Use of antiplatelet therapy such as intravenous glycoprotein IIb/IIIa inhibitors, especially with their pronounced effects in diabetics and in those with multivessel disease, could potentially equalize the playing field or perhaps even tip the balance in favor of percutaneous intervention     

Cystic canal mutants in Caenorhabditis elegans are defective in the apical membrane domain of the renal (excretory) cell.

The excretory cell extends a tubular process, or canal, along the basolateral surface of the epidermis to form the nematode renal epithelium. This cell can undergo normal tubulogenesis in isolated cell culture. Mutations in 12 genes cause excretory canal cysts in Caenorhabditis elegans. Genetic interactions, and their similar phenotypes, suggest these genes may encode functionally related proteins. Depending upon genotype and individual canal, defects range from focal cysts, flanked by normal width segments, to regional cysts involving the entire tubule. Oftentimes the enlarged regions are convoluted or partially septated. In mutants with very large cysts, renal function is measurably impaired. Based on histology and ultrastructure, canal cysts likely result from defects of the apical membrane domain. These mutants provide a model of tubulocystic disease without hyperplasia or basement membrane abnormalities. Similar apical mechanisms could regulate tubular morphology of vertebrate nephrons.     

Further evidence for papovavirus as the probable etiology of transmissible lymphoma of Syrian hamsters

The role of hamster papovavirus as the etiology of transmissible lymphoma was investigated under strict conditions that prevented natural exposure to the lymphoma agent. In an initial experiment, 19 hamsters that were exposed naturally to transmissible lymphoma were placed in direct and indirect contact with weanling hamsters from an uninfected source. Lymphoma developed in the original infected hamsters as well as hamsters maintained in direct and indirect contact. In addition, one of the contact hamsters developed cutaneous epitheliomas, containing hamster papovavirus. Epithelioma homogenate was inoculated into primary hamster embryo cultures, in which hamster papovavirus replicated. Second and third passage tissue culture fluid containing hamster papovavirus induced lymphomas in suckling and weanling hamsters. Cell culture fluid from uninoculated embryo cultures was not oncogenic.     

Contamination of transplantable murine tumors with lymphocytic choriomeningitis virus

Lymphocytic choriomeningitis virus (LCMV) was isolated from a transplantable tumor after mice bearing the tumor began to die prematurely. Tumor lines, mice and laboratory personnel that had an association with the index laboratory were tested for LCMV infection. Testing of tumor lines from the index laboratory and four other laboratories revealed that 16 of 55 tumor samples used in vivo and one of eight tumor samples maintained in vitro were contaminated with LCMV. Laboratory personnel and uninoculated mice that were exposed to infected tumors had no LCMV antibody. The use of carefully monitored seed stocks is recommended to protect transplantable tumors that may be inadvertently contaminated by viruses.