The regulation of ion channels and transporters by glycolytically derived ATP

Glycolysis is an evolutionary conserved metabolic pathway that provides small amounts of energy in the form of ATP when compared to other pathways such as oxidative phosphorylation or fatty acid oxidation. The ATP levels inside metabolically active cells are not constant and the local ATP level will depend on the site of production as well as the respective rates of ATP production, diffusion and consumption. Membrane ion transporters (pumps, exchangers and channels) are located at sites distal to the major sources of ATP formation (the mitochondria). We review evidence that the glycolytic complex is associated with membranes; both at the plasmalemma and with membranes of the endo/sarcoplasmic reticular network. We examine the evidence for the concept that many of the ion transporters are regulated preferentially by the glycolytic process. These include the Na⁺/K⁺-ATPase, the H⁺-ATPase, various types of Ca²⁺-ATPases, the Na⁺/H⁺ exchanger, the ATP-sensitive K⁺ channel, cation channels, Na⁺ channels, Ca²⁺ channels and other channels involved in intracellular Ca²⁺ homeostasis. Regulation of these pumps, exchangers and ion channels by the glycolytic process has important consequences in a variety of physiological and pathophysiological processes, and a better understanding of this mode of regulation may have important consequences for developing future strategies in combating disease and developing novel therapeutic approaches. Received 20 July 2007; received after revision 30 July 2007; accepted 17 August 2007     

Dating the rise of atmospheric oxygen

Several lines of geological and geochemical evidence indicate that the level of atmospheric oxygen was extremely low before 2.45 billion years (Gyr) ago, and that it had reached considerable levels by 2.22 Gyr ago. Here we present evidence that the rise of atmospheric oxygen had occurred by 2.32 Gyr ago. We found that syngenetic pyrite is present in organic-rich shales of the 2.32-Gyr-old Rooihoogte and Timeball Hill formations, South Africa. The range of the isotopic composition of sulphur in this pyrite is large and shows no evidence of mass-independent fractionation, indicating that atmospheric oxygen was present at significant levels (that is, greater than 10(-5) times that of the present atmospheric level) during the deposition of these units. The presence of rounded pebbles of sideritic iron formation at the base of the Rooihoogte Formation and an extensive and thick ironstone layer consisting of haematitic pisolites and o?lites in the upper Timeball Hill Formation indicate that atmospheric oxygen rose significantly, perhaps for the first time, during the deposition of the Rooihoogte and Timeball Hill formations. These units were deposited between what are probably the second and third of the three Palaeoproterozoic glacial events.     

Research Note: Sense-Seeking Systems as Normative Model for Innovative Sociocultural Systems

A concept of innovation as beneficial change that results from change in knowledge leads to a foundational model of sociocultural systems, labeled the Sense-Seeking Systems Model, which proclaims that the essence of human striving is to seek and disclose and thereby to gain meaning or sense. Two of the most distinctive characteristics of the model are that it entertains the concept of creation or discovery of sense as the raison d'être of human systems, and that systems characterized by this model are intrinsically dynamic, with such dynamism emanating from interaction of multiple visions and reflected in the dialectical nature of such systems. A focus on sense-gaining highlights that where possible loss of sense threatens, the urge to regain sense induces aspiration for vision, and vision promises gain of sense. Emphasizing multiple visions, though, admits the necessity and sensibility of maintaining the likes of variety, inherent tension, debate, conflict, and dialectics for effecting innovation.     

Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis

Tumour growth requires accompanying expansion of the host vasculature, with tumour progression often correlated with vascular density. Vascular endothelial growth factor (VEGF) is the best-characterized inducer of tumour angiogenesis. We report that VEGF dynamically regulates tumour endothelial expression of Delta-like ligand 4 (Dll4), which was previously shown to be absolutely required for normal embryonic vascular development. To define Dll4 function in tumour angiogenesis, we manipulated this pathway in murine tumour models using several approaches. Here we show that blockade resulted in markedly increased tumour vascularity, associated with enhanced angiogenic sprouting and branching. Paradoxically, this increased vascularity was non-productive-as shown by poor perfusion and increased hypoxia, and most importantly, by decreased tumour growth-even for tumours resistant to anti-VEGF therapy. Thus, VEGF-induced Dll4 acts as a negative regulator of tumour angiogenesis; its blockade results in a striking uncoupling of tumour growth from vessel density, presenting a novel therapeutic approach even for tumours resistant to anti-VEGF therapies.