Systematic pathway analysis using high-resolution fitness profiling of combinatorial gene deletions

Systematic genetic interaction studies have illuminated many cellular processes. Here we quantitatively examine genetic interactions among 26 Saccharomyces cerevisiae genes conferring resistance to the DNA-damaging agent methyl methanesulfonate (MMS), as determined by chemogenomic fitness profiling of pooled deletion strains. We constructed 650 double-deletion strains, corresponding to all pairings of these 26 deletions. The fitness of single- and double-deletion strains were measured in the presence and absence of MMS. Genetic interactions were defined by combining principles from both statistical and classical genetics. The resulting network predicts that the Mph1 helicase has a role in resolving homologous recombination-derived DNA intermediates that is similar to (but distinct from) that of the Sgs1 helicase. Our results emphasize the utility of small molecules and multifactorial deletion mutants in uncovering functional relationships and pathway order.     

The silence of the norms: The missing historiography of The Structure of Scientific Revolutions

History has been disparaged since the late 19th century for not conforming to norms of scientific explanation. Nonetheless, as a matter of fact a work of history upends the regnant philosophical conception of science in the second part of the 20th century. Yet despite its impact, Kuhn’s Structure has failed to motivate philosophers to ponder why works of history should be capable of exerting rational influence on an understanding of philosophy of science. But all this constitutes a great irony and a mystery. The mystery consists of the persistence of a complete lack of interest in efforts to theorize historical explanation. Fundamental questions regarding why an historical account could have any rational influence remain not merely unanswered, but unasked. The irony arises from the fact that analytic philosophy of history went into an eclipse where it remains until this day just around the time that the influence of Kuhn’s great work began to make itself felt. This paper highlights puzzles long ignored regarding the challenges a work of history managed to pose to the epistemic authority of science, and what this might imply generally for the place of philosophy of history vis-à-vis the problems of philosophy.     

Chemotherapy and immunotherapy of malignant glioma: molecular mechanisms and clinical perspectives

Despite the considerable progress in modern tumor therapy, the prognosis for patients with glioblastoma, the most frequent malignant brain tumor, has not been substantially improved. Although cytoreductive surgery and radiotherapy are the mainstays of treatment for malignant glioma at present, novel cytotoxic drugs and immunotherapeutic approaches hold great promise as effective weapons against these malignancies. Thus, great efforts are being made to enhance antitumoral efficacy by combining various cytotoxic agents, by novel routes of drug administration, or by combining anticancer drugs and immune modulators. Immunotherapeutic approaches include cytotoxic cytokines, targeted antibodies, and vaccination strategies. However, the success of most of these experimental therapies is prevented by the marked molecular resistance of glioma cells to diverse cytotoxic agents or by glioma-associated immunosuppression. One promising experimental strategy to target glioma is the employment of death ligands such as CD95 (Fas/Apo1) ligand or Apo2 ligand (TRAIL). Specific proapoptotic approaches may overcome many of the obvious obstacles to a satisfactory management of malignant brain tumors. Received 8 March 1999; received after revision 27 May 1999; accepted 14 June 1999     

Light and electron microscopic demonstration ofd-mannose andd-glucose like sites at the cell surface by means of the lectin from theLens culinaris

Zusammenfassung Es wird über die Verwendung des Lektins vonLens culinaris zum immunologisch-spezifischen licht- und elektronenmikroskopischen Nachweis vond-Mannose- undd-Glukose-artigen Orten der Zelloberfläche berichtet.     

Thymine dimer repair in fibroblasts of patients with dysplastic naevus syndrome (DNS)

Dysplastic naevus syndrome (DNS) is frequently observed in association with familial melanoma and xeroderma pigmentosum (XP), but the role of UV-light in the development of DNS has not been elucidated. Previous work has shown that UV-induced unscheduled DNA synthesis is associated with the early loss of antigenicity observed in immunoassays using a monoclonal antibody specific for thymine-thymine dimers. We now show that the rate of loss of antigenicity, which reflects the relative amount of bound antibody, observed during the first 60 min following 10 Jm-2 UVC irradiation is significantly reduced (p = 0.02) in cultures of fibroblasts from 7 out of 8 DNS patients compared with the results from cells of a group of 30 healthy volunteers. This observation suggests an early event in excision repair is altered in the majority of DNS patients.     

The consequences of the discovery by W. C. Röntgen for present-day medical physics and radiation protection

When the German physicist W. C. Röntgen discovered X-rays, which were named after him, he introduced a new development in medicine and biology: together with the discoveries of A. H. Becquerel and M. Curie, radiology with its diagnostic and therapeutic methods was made possible. The medical physicist has an important task to fulfill in modern radiotherapy, nuclear medicine and radiodiagnostics. The longtime interdisciplinary collaboration has won the international recognition of medical physics as a scientific discipline, a health care profession and a university subject. Several incidents, including contemporary ones, show that the efforts made towards radiation protection must remain an important domain of the specialist.