Quelques remarques sur l'holisme dans la pensée grecque

Summary The conception of the world with Greek thinkers generally differs from contemporary thought in the idea of the limitation of the world whose essence manifests itself to speculative thinking. The cosmology which culminates inPlato's Timaios attributes to the whole of being the properties of finiteness, uniqueness, life and perfection.Plato's holism subsumes inanimate and living nature under the idea of cosmic life, the parts of which are constituted by life-phenomena given in experience. His world-conception, constructed from within and intuitively, which ranges phenomena in descending order, is opposed to the atomism ofDemocritos which reduces the higher structures to the one equal material of all things. This opposition manifests itself in all essential points: toDemocritos there are worlds in infinite number, only accumulations of atoms are real, uniqueness and perfection are lacking as well as the idea of Life as a central reality.Modern research foregoes the attempt to determine the whole speculatively, but holistic and atomistic ways of thinking, after having been dogmatically applied by the Greeks, continue to exist as opposed types of mental attitude. Contemporary holism may be empirical and limited in application, but it is directed by the same intuition of life articulating itself organically as wasPlato's. It would be incorrect, however, to characterize holism as synthetical, since all synthetics is based upon analysis. The bounds of synthesis are never fixed ones, nor does it ever determine essence. Holism's way of subsuming single life-phenomena under more comprehensive wholes is an intuitional one, the connections which it creates between phenomena are not external ones, but apprehended intuitively in analogy to inner experience.—In distinction to atomism, which only admits as real atoms and their mutual relations, holism poses groups of unities, classified in grades, the higher of which dominate the lower, without debasing them to elements. As metaphysics is concerned to discover a connection between Nature and human life, it must be highly interested in the empirical demonstration, such as holism offers, of connections of life, surpassing individual being.

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Zusammenfassung Die griechische Weltauffassung unterscheidet sich van der modernen durch den Gedanken der Begrenztheit des Weltalls, das sich dem spekulativen Blick seinem Wesen nach erschliesst. Die inPlaton's Timaios gipfelnde Kosmologie bestimmt das Weltall nach den Wesensgesichtspunkten der Endlichkeit, der Einzigkeit, der Lebendigkeit und der Vollkommenheit.Platon's Holismus bezieht die leblose und die lebende Natur unter die Idee des Lebens des Kosmos, dessen Teile die in der Erfahrung gegebenen Lebenserscheinungen sind. Sein von innen her und intuitiv aufgebautes Weltbild, das die Erscheinungen von oben herab hierarchisch ordnet, tritt dem AtomismusDemokrits gegenüber, der in umgekehrtem Verfahren die höheren Strukturen auf den einen Baustoff aller Dinge reduziert. Der Gegensatz zum Holismus offenbart sich in allen Bestimmungen: fürDemokrit sind der Kosmoi unbegrenzt viele, es gibt nur Ansammlungen von Atomen, es fehlen Einzigkeit und Vollkommenheit, sowie ein Begriff des Lebens als des zentralen Geschehens.Die neuzeitliche Forschung verzichtet auf die spekulativen Bestimmungen des Ganzen, aber der bei den Griechen dogmatische Gegensatz holistischer und atomistischer Betrachtungsweise lebt fort als Gegensatz geistiger Einstellung. Der neuzeitliche Holismus ist ein empirischer, beschränkter, aber bei ihm liegt dieselbe Intuition des sich organisch gestaltenden Gesamtlebens zu Grunde wei beiPlaton. Nur wäre es, unrichtig, diesen Holismus als synthetisch zu bezeichnen. Synthetisches Denken erhebt sich immer auf analytischem Boden. Jede Synthese hat eine offene Grenze. Die Art aber, wie der Holismus die vereinzelten Lebenserscheinungen auf umfassendere Ganzheiten bezieht, ist eine intuitive. Das Band der Erscheinungen wird nicht durch äusseres Beziehen gestiftet, sondern geschaut nach Analogie einer inneren Erfahrung.Im Gegensatz zum Atomismus, der als real nur die Atome und deren Verhältnisse gelten lässt, erkennt der Holismus stufenartig aufgebaute Einheitsarten an, in denen die höheren die niedrigeren beherrschen, ohne sie zu Elementen herabzudrücken. Die Metaphysik, auf der Suche nach dem Zusammenhang zwischen dem Menschenleben und der Natur ist an der empirischen Aufweisung das Einzelne übersteigender Lebensverbände wie sie der Holismus zu Tage fordert aufs Höchste interessiert.

     

The Outer Membrane TolC-like Channel HgdD Is Part of Tripartite Resistance-Nodulation-Cell Division (RND) Efflux Systems Conferring Multiple-drug Resistance in the Cyanobacterium Anabaena sp. PCC7120

The TolC-like protein HgdD of the filamentous, heterocyst-forming cyanobacterium Anabaena sp. PCC 7120 is part of multiple three-component “AB-D” systems spanning the inner and outer membranes and is involved in secretion of various compounds, including lipids, metabolites, antibiotics, and proteins. Several components of HgdD-dependent tripartite transport systems have been identified, but the diversity of inner membrane energizing systems is still unknown. Here we identified six putative resistance-nodulation-cell division (RND) type factors. Four of them are expressed during late exponential and stationary growth phase under normal growth conditions, whereas the other two are induced upon incubation with erythromycin or ethidium bromide. The constitutively expressed RND component Alr4267 has an atypical predicted topology, and a mutant strain (I-alr4267) shows a reduction in the content of monogalactosyldiacylglycerol as well as an altered filament shape. An insertion mutant of the ethidium bromide-induced all7631 did not show any significant phenotypic alteration under the conditions tested. Mutants of the constitutively expressed all3143 and alr1656 exhibited a Fox⁻ phenotype. The phenotype of the insertion mutant I-all3143 parallels that of the I-hgdD mutant with respect to antibiotic sensitivity, lipid profile, and ethidium efflux. In addition, expression of the RND genes all3143 and all3144 partially complements the capability of Escherichia coli ΔacrAB to transport ethidium. We postulate that the RND transporter All3143 and the predicted membrane fusion protein All3144, as homologs of E. coli AcrB and AcrA, respectively, are major players for antibiotic resistance in Anabaena sp. PCC 7120.     

Saikosaponin-d,a novel SERCA inhibitor,induces autophagic cell death in apoptosis-defective cells

Autophagy is an important cellular process that controls cells in a normal homeostatic state by recycling nutrients to maintain cellular energy levels for cell survival via the turnover of proteins and damaged organelles. However, persistent activation of autophagy can lead to excessive depletion of cellular organelles and essential proteins, leading to caspase-independent autophagic cell death. As such, inducing cell death through this autophagic mechanism could be an alternative approach to the treatment of cancers. Recently, we have identified a novel autophagic inducer, saikosaponin-d (Ssd), from a medicinal plant that induces autophagy in various types of cancer cells through the formation of autophagosomes as measured by GFP-LC3 puncta formation. By computational virtual docking analysis, biochemical assays and advanced live-cell imaging techniques, Ssd was shown to increase cytosolic calcium level via direct inhibition of sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase pump, leading to autophagy induction through the activation of the Ca²⁺/calmodulin-dependent kinase kinase–AMP-activated protein kinase–mammalian target of rapamycin pathway. In addition, Ssd treatment causes the disruption of calcium homeostasis, which induces endoplasmic reticulum stress as well as the unfolded protein responses pathway. Ssd also proved to be a potent cytotoxic agent in apoptosis-defective or apoptosis-resistant mouse embryonic fibroblast cells, which either lack caspases 3, 7 or 8 or had the Bax-Bak double knockout. These results provide a detailed understanding of the mechanism of action of Ssd, as a novel autophagic inducer, which has the potential of being developed into an anti-cancer agent for targeting apoptosis-resistant cancer cells.     

Identification and characterization of carbapenem binding sites within the RND-transporter AcrB

Understanding the molecular determinants for recognition, binding and transport of antibiotics by multidrug efflux systems is important for basic research and useful for the design of more effective antimicrobial compounds. Imipenem and meropenem are two carbapenems whose antibacterial activity is known to be poorly and strongly affected by MexAB-OprM, the major efflux pump transporter in Pseudomonas aeruginosa. However, not much is known regarding recognition and transport of these compounds by AcrAB-TolC, which is the MexAB-OprM homologue in Escherichia coli and by definition the paradigm model for structural studies on efflux pumps. Prompted by this motivation, we unveiled the molecular details of the interaction of imipenem and meropenem with the transporter AcrB by combining computer simulations with biophysical experiments. Regarding the interaction with the two main substrate binding regions of AcrB, the so-called access and deep binding pockets, molecular dynamics simulations revealed imipenem to be more mobile than meropenem in the former, while comparable mobilities were observed in the latter. This result is in line with isothermal titration calorimetry, differential scanning experiments, and binding free energy calculations, indicating a higher affinity for meropenem than imipenem at the deep binding pocket, while both sharing similar affinities at the access pocket. Our findings rationalize how different physico-chemical properties of compounds reflect on their interactions with AcrB. As such, they constitute precious information to be exploited for the rational design of antibiotics able to evade efflux pumps.     

A Quantitative and Dynamic Model of the Arabidopsis Flowering Time Gene Regulatory Network

Various environmental signals integrate into a network of floral regulatory genes leading to the final decision on when to flower. Although a wealth of qualitative knowledge is available on how flowering time genes regulate each other, only a few studies incorporated this knowledge into predictive models. Such models are invaluable as they enable to investigate how various types of inputs are combined to give a quantitative readout. To investigate the effect of gene expression disturbances on flowering time, we developed a dynamic model for the regulation of flowering time in Arabidopsis thaliana. Model parameters were estimated based on expression time-courses for relevant genes, and a consistent set of flowering times for plants of various genetic backgrounds. Validation was performed by predicting changes in expression level in mutant backgrounds and comparing these predictions with independent expression data, and by comparison of predicted and experimental flowering times for several double mutants. Remarkably, the model predicts that a disturbance in a particular gene has not necessarily the largest impact on directly connected genes. For example, the model predicts that SUPPRESSOR OF OVEREXPRESSION OF CONSTANS (SOC1) mutation has a larger impact on APETALA1 (AP1), which is not directly regulated by SOC1, compared to its effect on LEAFY (LFY) which is under direct control of SOC1. This was confirmed by expression data. Another model prediction involves the importance of cooperativity in the regulation of APETALA1 (AP1) by LFY, a prediction supported by experimental evidence. Concluding, our model for flowering time gene regulation enables to address how different quantitative inputs are combined into one quantitative output, flowering time.     

Functional characterization of a NapA Na(+)/H(+) antiporter from Thermus thermophilus

Na(+)/H(+) antiporters are ubiquitous membrane proteins and play an important role in cell homeostasis. We amplified a gene encoding a member of the monovalent cation:proton antiporter-2 (CPA2) family (TC 2.A.37) from the Thermus thermophilus genome and expressed it in Escherichia coli. The gene product was identified as a member of the NapA subfamily and was found to be an active Na(+)(Li(+))/H(+) antiporter as it conferred resistance to the Na(+) and Li(+) sensitive strain E. coli EP432 (DeltanhaA, DeltanhaB) upon exposure to high concentration of these salts in the growth medium. Fluorescence measurements using the pH sensitive dye 9-amino-6-chloro-2-methoxyacridine in everted membrane vesicles of complemented E. coli EP432 showed high Li(+)/H(+) exchange activity at pH 6, but marginal Na(+)/H(+) antiport activity. Towards more alkaline conditions, Na(+)/H(+) exchange activity increased to a relative maximum at pH 8, where by contrast the Li(+)/H(+) exchange activity reached its relative minimum. Substitution of conserved residues D156 and D157 (located in the putative transmembrane helix 6) with Ala resulted in the complete loss of Na(+)/H(+) activity. Mutation of K305 (putative transmembrane helix 10) to Ala resulted in a compromised phenotype characterized by an increase in apparent K(m) for Na(+) (36 vs. 7.6 mM for the wildtype) and Li(+) (17 vs. 0.22 mM), In summary, the Na(+)/H(+) antiport activity profile of the NapA type transporter of T. thermophilus resembles that of NhaA from E. coli, whereas in contrast to NhaA the T. thermophilus NapA antiporter is characterized by high Li(+)/H(+) antiport activity at acidic pH.