Analytic philosophy for biomedical research: the imperative of applying yesterday's timeless messages to today's impasses

The mantra that "the best way to predict the future is to invent it" (attributed to the computer scientist Alan Kay) exemplifies some of the expectations from the technical and innovative sides of biomedical research at present. However, for technical advancements to make real impacts both on patient health and genuine scientific understanding, quite a number of lingering challenges facing the entire spectrum from protein biology all the way to randomized controlled trials should start to be overcome. The proposal in this chapter is that philosophy is essential in this process. By reviewing select examples from the history of science and philosophy, disciplines which were indistinguishable until the mid-nineteenth century, I argue that progress toward the many impasses in biomedicine can be achieved by emphasizing theoretical work (in the true sense of the word 'theory') as a vital foundation for experimental biology. Furthermore, a philosophical biology program that could provide a framework for theoretical investigations is outlined

Altered Hematopoiesis in Mice Lacking DNA Polymerase μ Is Due to Inefficient Double-Strand Break Repair

Polymerase mu (Polμ) is an error-prone, DNA-directed DNA polymerase that participates in non-homologous end-joining (NHEJ) repair. In vivo, Polμ deficiency results in impaired Vκ-Jκ recombination and altered somatic hypermutation and centroblast development. In Polμ−/− mice, hematopoietic development was defective in several peripheral and bone marrow (BM) cell populations, with about a 40% decrease in BM cell number that affected several hematopoietic lineages. Hematopoietic progenitors were reduced both in number and in expansion potential. The observed phenotype correlates with a reduced efficiency in DNA double-strand break (DSB) repair in hematopoietic tissue. Whole-body γ-irradiation revealed that Polμ also plays a role in DSB repair in non-hematopoietic tissues. Our results show that Polμ function is required for physiological hematopoietic development with an important role in maintaining early progenitor cell homeostasis and genetic stability in hematopoietic and non-hematopoietic tissues

Numt-Mediated Double-Strand Break Repair Mitigates Deletions during Primate Genome Evolution

Non-homologous end joining (NHEJ) is the major mechanism of double-strand break repair (DSBR) in mammalian cells. NHEJ has traditionally been inferred from experimental systems involving induced double strand breaks (DSBs). Whether or not the spectrum of repair events observed in experimental NHEJ reflects the repair of natural breaks by NHEJ during chromosomal evolution is an unresolved issue. In primate phylogeny, nuclear DNA sequences of mitochondrial origin, numts, are inserted into naturally occurring chromosomal breaks via NHEJ. Thus, numt integration sites harbor evidence for the mechanisms that act on the genome over evolutionary timescales. We have identified 35 and 55 lineage-specific numts in the human and chimpanzee genomes, respectively, using the rhesus monkey genome as an outgroup. One hundred and fifty two numt-chromosome fusion points were classified based on their repair patterns. Repair involving microhomology and repair leading to nucleotide additions were detected. These repair patterns are within the experimentally determined spectrum of classical NHEJ, suggesting that information from experimental systems is representative of broader genetic loci and end configurations. However, in incompatible DSBR events, small deletions always occur, whereas in 54% of numt integration events examined, no deletions were detected. Numts show a statistically significant reduction in deletion frequency, even in comparison to DSBR involving filler DNA. Therefore, numts show a unique mechanism of integration via NHEJ. Since the deletion frequency during numt insertion is low, native overhangs of chromosome breaks are preserved, allowing us to determine that 24% of the analyzed breaks are cohesive with overhangs of up to 11 bases. These data represent, to the best of our knowledge, the most comprehensive description of the structure of naturally occurring DSBs. We suggest a model in which the sealing of DSBs by numts, and probably by other filler DNA, prevents nuclear processing of DSBs that could result in deleterious repair

The effect of nitrogen and oxygen on the mechanical properties of molybdenum

An investigation has been made of the effects of nitrogen and oxygen in solid solution on the mechanical properties of molybdenum single crystals. This is believed to be the first investigation of its type, involving the controlled addition of interstitfal solutes to a Group Vla metal. The establishment of a standard route for the preparation of molybdenum single crystals of well characterised purity has been undertaken as a necessary preliminary to the investigation of interstitially doped material. High purity molybdenum with a resistance ratio >5,000 and a total interstitial content < 10 at~ppm has been prepared by the successive zone-melting,decarburisation and high vacuum annealin;_" of commercial purity material. Resistance ratio measurements and chemical analysis have been used to define the purification mechanisms which operate durine; these treatments. A high speed quenching technique has been developed for doping molybdenum mechanical test specimens with nitrogen and oxygen., Compression specimens may be prepared with only small concentrations of interstitials in solid solution 0 at.ppm) but comparatively large concentrations (>100 at.ppm) may be quenched into solution in wire tension specimens., The nitrogen doped molybdenum is more thoroughly characterised than the oxygen doped molybdenum. [Abstract continued in thesis]</p

Comparison of debris extruded apically and working time used by ProTaper Universal rotary and ProTaper retreatment system during gutta-percha removal

OBJECTIVE: The aim of this study was to evaluate the in vitro action of ProTaper retreatment files and ProTaper Universal in the retreatment of mandibular premolars. MATERIAL AND METHODS: The amount of debris extruded apically was measured and the time to reach the working length and to complete the removal of gutta-percha was observed. Thirty teeth had their canals prepared using ProTaper Universal files and were obturated by the single cone technique. The teeth were then stored at 37ºC in a humid environment for 7 days. During the use of the rotary instruments for root canal filling removal, the apical portions of the teeth were attached to the open end of a resin tube to collect the apically extruded debris. RESULTS: ProTaper Universal files were significantly faster (p=0.0011) than the ProTaper retreatment files to perform gutta-percha removal, but no significant difference was found between the files regarding the time to reach the working length or the amount of apical extrusion. CONCLUSIONS: ProTaper Universal rotary had better results for endodontic retreatment, and both techniques promote similar apical extrusion of debris