Hermeneutic strategies in Gerd Buchdahl’s Kantian philosophy of science

Gerd Buchdahl’s international reputation rests on his masterly writings on Kant. In them he showed how Kant transformed the philosophical problems of his predecessors and he minutely investigated the ways in which Kant related his critical philosophy to the contents and methods of natural science. Less well known, if only because in large part unpublished, are the writings in which Buchdahl elaborated his own views on the methods and status of the sciences. In this paper I examine the roles of hermeneutics in Buchdahl’s reconstruction of Kant’s philosophical system and in his own ‘transcendental methodological’ approach to the philosophy of science. The first section looks at Buchdahl’s views on the theory and practice of historical interpretation and at the Husserlian hermeneutic scheme of reduction and realisation that he used in his later accounts of the philosophies of science of Kant and himself. The second section concentrates on Buchdahl’s treatment of the grounds of science in Kant; and the third on the hermeneutic strategies Buchdahl employed in articulating and justifying his own views. The paper closes with reflections on the impact and importance of Buchdahl’s interpretation of Kant’s critical philosophy in relation to the sciences and of his own hermeneutically based philosophy of science.     

Control of DNA integrity in skeletal muscle under physiological and pathological conditions

Skeletal muscle is a highly oxygen-consuming tissue that ensures body support and movement, as well as nutrient and temperature regulation. DNA damage induced by reactive oxygen species is present in muscles and tends to accumulate with age. Here, we present a summary of data obtained on DNA damage and its implication in muscle homeostasis, myogenic differentiation and neuromuscular disorders. Controlled and transient DNA damage appears to be essential for muscular homeostasis and differentiation while uncontrolled and chronic DNA damage negatively affects muscle health.     

Targeting mitochondria by α-tocopheryl succinate overcomes hypoxia-mediated tumor cell resistance to treatment

Rapidly proliferating tumor cells easily become hypoxic. This results in acquired stability towards treatment with anticancer drugs. Here, we show that cells grown at 0.1 % oxygen are more resistant towards treatment with the conventionally used anticancer drugs doxorubicin and cisplatin. The stimulation of apoptosis, as assessed by the number of cells in the SubG1 fraction of the cell cycle, release of cytochrome c into the cytosol, activation of caspase-3, and cleavage of PARP, was markedly suppressed under low oxygen content or when hypoxia was mimicked by deferoxamine. Hypoxia or deferoxamine treatment was accompanied by stabilization of the hypoxia-inducible factor (HIF-1). The downregulation of HIF-1 using siRNA technique restored cell sensitivity to treatment under hypoxic conditions to the levels detected under normoxic conditions. In contrast to cisplatin or doxorubicin, α-tocopheryl succinate (α-TOS), a compound that targets mitochondria, stimulated cell death irrespective of the oxygen concentration. Moreover, under hypoxic condition cell death induced by α-TOS was even enhanced. Thus, α-TOS can successfully overcome resistance to treatment caused by hypoxia, which makes α-TOS an attractive candidate for antitumor therapy via mitochondrial targeting.     

'Infotaxis' as a strategy for searching without gradients

Chemotactic bacteria rely on local concentration gradients to guide them towards the source of a nutrient. Such local cues pointing towards the location of the source are not always available at macroscopic scales because mixing in a flowing medium breaks up regions of high concentration into random and disconnected patches. Thus, animals sensing odours in air or water detect them only intermittently as patches sweep by on the wind or currents. A macroscopic searcher must devise a strategy of movement based on sporadic cues and partial information. Here we propose a search algorithm, which we call 'infotaxis', designed to work under such conditions. Any search process can be thought of as acquisition of information on source location; for infotaxis, information plays a role similar to concentration in chemotaxis. The infotaxis strategy locally maximizes the expected rate of information gain. We demonstrate its efficiency using a computational model of odour plume propagation and experimental data on mixing flows. Infotactic trajectories feature 'zigzagging' and 'casting' paths similar to those observed in the flight of moths. The proposed search algorithm is relevant to the design of olfactory robots, but the general idea of infotaxis can be applied more broadly in the context of searching with sparse information.     

Effect of evaporite deposition on Early Cretaceous carbon and sulphur cycling

The global carbon and sulphur cycles are central to our understanding of the Earth's history, because changes in the partitioning between the reduced and oxidized reservoirs of these elements are the primary control on atmospheric oxygen concentrations. In modern marine sediments, the burial rates of reduced carbon and sulphur are positively coupled, but high-resolution isotope records indicate that these rates were inversely related during the Early Cretaceous period. This inverse relationship is difficult to reconcile with our understanding of the processes that control organic matter remineralization and pyrite burial. Here we show that the inverse correlation can be explained by the deposition of evaporites during the opening of the South Atlantic Ocean basin. Evaporite deposition can alter the chemical composition of sea water, which can in turn affect the ability of sulphate-reducing bacteria to remineralize organic matter and mediate pyrite burial. We use a reaction-transport model to quantify these effects, and the resulting changes in the burial rates of carbon and sulphur, during the Early Cretaceous period. Our results indicate that deposition of the South Atlantic evaporites removed enough sulphate from the ocean temporarily to reduce biologically mediated pyrite burial and organic matter remineralization by up to fifty per cent, thus explaining the inverse relationship between the burial rates of reduced carbon and sulphur during this interval. Furthermore, our findings suggest that the effect of changing seawater sulphate concentrations on the marine subsurface biosphere may be the key to understanding other large-scale perturbations of the global carbon and sulphur cycles.     

Genome sequence and analysis of the tuber crop potato

Potato (Solanum tuberosum L.) is the world's most important non-grain food crop and is central to global food security. It is clonally propagated, highly heterozygous, autotetraploid, and suffers acute inbreeding depression. Here we use a homozygous doubled-monoploid potato clone to sequence and assemble 86% of the 844-megabase genome. We predict 39,031 protein-coding genes and present evidence for at least two genome duplication events indicative of a palaeopolyploid origin. As the first genome sequence of an asterid, the potato genome reveals 2,642 genes specific to this large angiosperm clade. We also sequenced a heterozygous diploid clone and show that gene presence/absence variants and other potentially deleterious mutations occur frequently and are a likely cause of inbreeding depression. Gene family expansion, tissue-specific expression and recruitment of genes to new pathways contributed to the evolution of tuber development. The potato genome sequence provides a platform for genetic improvement of this vital crop.     

Metabolic priming by a secreted fungal effector

Maize smut caused by the fungus Ustilago maydis is a widespread disease characterized by the development of large plant tumours. U. maydis is a biotrophic pathogen that requires living plant tissue for its development and establishes an intimate interaction zone between fungal hyphae and the plant plasma membrane. U. maydis actively suppresses plant defence responses by secreted protein effectors. Its effector repertoire comprises at least 386 genes mostly encoding proteins of unknown function and expressed exclusively during the biotrophic stage. The U. maydis secretome also contains about 150 proteins with probable roles in fungal nutrition, fungal cell wall modification and host penetration as well as proteins unlikely to act in the fungal-host interface like a chorismate mutase. Chorismate mutases are key enzymes of the shikimate pathway and catalyse the conversion of chorismate to prephenate, the precursor for tyrosine and phenylalanine synthesis. Root-knot nematodes inject a secreted chorismate mutase into plant cells likely to affect development. Here we show that the chorismate mutase Cmu1 secreted by U. maydis is a virulence factor. The enzyme is taken up by plant cells, can spread to neighbouring cells and changes the metabolic status of these cells through metabolic priming. Secreted chorismate mutases are found in many plant-associated microbes and might serve as general tools for host manipulation.     

Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency

An isolated defect of respiratory chain complex I activity is a frequent biochemical abnormality in mitochondrial disorders. Despite intensive investigation in recent years, in most instances, the molecular basis underpinning complex I defects remains unknown. We report whole-exome sequencing of a single individual with severe, isolated complex I deficiency. This analysis, followed by filtering with a prioritization of mitochondrial proteins, led us to identify compound heterozygous mutations in ACAD9, which encodes a poorly understood member of the mitochondrial acyl-CoA dehydrogenase protein family. We demonstrated the pathogenic role of the ACAD9 variants by the correction of the complex I defect on expression of the wildtype ACAD9 protein in fibroblasts derived from affected individuals. ACAD9 screening of 120 additional complex I-defective index cases led us to identify two additional unrelated cases and a total of five pathogenic ACAD9 alleles.