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Scientific promise in the therapeutic potential of early embryonic stem cell research to treat presently intractable diseases is still meeting ethical, regulatory and patent challenges. Nigel Williams reports on recent moves in Europe and the US.
Sliding clamps tether DNA polymerases to DNA to increase the processivity of synthesis. The Escherichia coli gamma complex loads the beta sliding clamp onto DNA in an ATP-dependent reaction in which ATP binding and hydrolysis modulate the affinity of the gamma complex for beta and DNA. This is the second of two reports (Williams, C. R., Snyder, A. K., Kuzmic, P., O'Donnell, M., and Bloom, L. B. (2004) J. Biol. Chem. 279, 4376-4385) addressing the question of how ATP binding and hydrolysis regulate specific interactions with DNA and beta. Mutations were made to an Arg residue in a conserved SRC motif in the delta' and gamma subunits that interacts with the ATP site of the neighboring gamma subunit. Mutation of the delta' subunit reduced the ATP-dependent beta binding activity, whereas mutation of the gamma subunits reduced the DNA binding activity of the gamma complex. The gamma complex containing the delta' mutation gave a pre-steady-state burst of ATP hydrolysis, but at a reduced rate and amplitude relative to the wild-type gamma complex. A pre-steady-state burst of ATP hydrolysis was not observed for the complex containing the gamma mutations, consistent with the reduced DNA binding activity of this complex. The differential effects of these mutations suggest that ATP binding at the gamma1 site may be coupled to conformational changes that largely modulate interactions with beta, whereas ATP binding at the gamma2 and/or gamma3 site may be coupled to conformational changes that have a major role in interactions with DNA. Additionally, these results show that the "arginine fingers" play a structural role in facilitating the formation of a conformation that has high affinity for beta and DNA.
This paper is a further study of ion binding to protein surfaces and builds on the studies of the binding of [Cr(CN)6]3- and [Fe(edta)(H2O)]- previously reported [Williams et al. (1982) FEBS Lett. 15, 293-299; Eley et al. (1982) Eur. J. Biochem. 124, 295-303]. In the present paper the binding of polyaminocarboxylate complexes of gadolinium have been studied. Eight ion-binding sites have been identified on the surface of cytochrome c. These exhibit different binding specificities which, in some cases, are not full understood. However it is clear that simple outer-sphere interactions are not the sole determining factor for the association of metal ion complexes with proteins. The NMR paramagnetic difference spectrum method has been shown to be good at locating binding sites and revealing qualitative differences in their relative affinities for a range of complex types. However the use of relaxation probes is not a good method for the quantitative determination of binding constants; for this, isostructural shift probes must be sought.
We have repeated classic dorsoventral somite rotation experiments (Aoyama and Asamoto, 1988, Development 104, 15-28) and included dorsal and ventral gene expression markers for the somitogenic tissue types, myotome and sclerotome, respectively. While the histological results are consistent with those previously published, gene expression analysis indicates that cells previously thought to be 'sclerotome' no longer express Pax1 mRNA, a sclerotome marker. These results, together with recent quail-chick transplantation experiments indicating that even very late sclerotome tissue fragments are multipotential (Dockter and Ordahl, 1998, Development 125, 2113-2124), lead to the conclusion that sclerotome tissue remains phenotypically and morphogenetically plastic during early embryonic somitogenesis. Myotome precursor cells, by contrast, appear to be determined within hours after somite epithelization; a finding consistent with recent reports (Williams and Ordahl, 1997, Development 124, 4983-4997). Therefore, while these findings support a central conclusion of Aoyama and Asamoto, that axis determination begins to occur within hours after somite epithelialization, the identity of the responding tissues, myotome versus sclerotome, differs. A simple model proposed to reconcile these observations supports the general hypothesis that determinative aspects of early paraxial mesoderm growth and morphogenesis occur in early and late phases that are governed principally by the myotome and sclerotome, respectively.
Relating to the Williams' report suggesting twofold higher incidence of diabetes mellitus in patients with the cancer of the colon, the study aiming at comparing an incidence of diabetes mellitus in patients with stomach, lung, and colon malignancies were carried out. Coexistence of the above listed neoplasms with diabetes mellitus type II was assessed in patients hospitalized at the Department of Gastroenterology and Metabolic Diseases, Institute of the Internal Diseases, Medical Academy in Warsaw within 1978-1986. Moreover, glycaemia and insulinemia curves were plotted following oral glucose load (75 g) in 16 patients with the cancer of the colon and 15 patients without malignancy. Only patients with body weight not exceeding 10% of the normal body weight, without history of diabetes mellitus and not treated with corticosteroids were classified for the study. Mean glycaemia and insulinemia values did not differ statistically in the investigated groups except statistically significantly higher serum insulin level in patients with cancer of the lung in the thirties minute of the test. Differences statistically significant were also not observed in retrospective analysis. However, an incidence of diabetes mellitus in patients with the cancer of the colon was 10.5% being higher than mean incidence of diabetes mellitus in this age group. Moreover, glucose load test has shown tolerance abnormalities in 4 patients with cancer of the colon, 1 patient with cancer of the lung, and 1 patient without malignancy. The obtained results indicate tendency to higher incidence of carbohydrate metabolism disorders in patients with cancer of the colon.
Williams-Beuren syndrome is a genetic disorder caused by a heterozygous deletion at 7q11.23. The present report describes a female patient with Williams-Beuren syndrome combined with caudal regression syndrome and two forms of coagulopathy. Besides the typical developmental abnormalities such as mental and growth retardation, a distinctive facial appearance, and cardiovascular anomalies, our patient showed fusion of fourth and fifth lumbar vertebra and a sacrococcygeal agenesis. Blood coagulation tests revealed a deficiency of coagulation factor XI and XII. Magnetic resonance imaging angiography showed multiple vascular stenoses mainly in the abdominal aorta and its major branches as a consequence of the insufficient elastin gene. Previous reports identified a deletion of HLXB9 as a possible genetic cause of the caudal regression syndrome, which could not be identified in the present case. This unusual combination of the above-mentioned genetic disorders has not been published so far.
The authors present a case of a twenty-nine-year-old woman with Williams syndrome and non-Hodgkin's lymphoma. The patient had been told that she had had an atrial septal defect from the time of her birth.
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The William Guy Forbeck Foundation was established in 1984 in memory of William Guy Forbeck, an 11-year-old boy who died of neuroblastoma. The objectives of the Forbeck Foundation are to promote advances and shorten the research timetable in the field of oncology, particularly pediatric oncology. The Foundation's centerpiece activity is an annual scientific forum held at Hilton Head Island, South Carolina, where 12 to 15 leading scientists from a variety of disciplines associated with a specific topic are invited to participate in a private "think tank" environment, where they can freely exchange ideas in the hope of building on each other's knowledge and experience. Additionally, the Foundation sponsors grants for Focus Meetings, which are designed to give other researchers an opportunity to conduct their own meetings along the lines of the Foundation's annual forum. The idea for this Focus Meeting was born during the 2000 Annual Forbeck Forum in South Carolina, which considered the current status of allogeneic hematopoietic stem cell transplantation (HSCT). Participants considered various obstacles to conducting clinical trials in this area and decided to bring together experts from academia, industry, and government to discuss ways in which these obstacles might be overcome. Topics included efficient clinical trial designs, issues of monitoring and reporting adverse events, and appropriate definitions and grading systems for transplantation-specific outcomes. This article summarizes the issue of adverse event reporting in HSCT.
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