Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia

Acetyl coenzyme A (AcCoA) is the central biosynthetic precursor for fatty-acid synthesis and protein acetylation. In the conventional view of mammalian cell metabolism, AcCoA is primarily generated from glucose-derived pyruvate through the citrate shuttle and ATP citrate lyase in the cytosol. However, proliferating cells that exhibit aerobic glycolysis and those exposed to hypoxia convert glucose to lactate at near-stoichiometric levels, directing glucose carbon away from the tricarboxylic acid cycle and fatty-acid synthesis. Although glutamine is consumed at levels exceeding that required for nitrogen biosynthesis, the regulation and use of glutamine metabolism in hypoxic cells is not well understood. Here we show that human cells use reductive metabolism of α-ketoglutarate to synthesize AcCoA for lipid synthesis. This isocitrate dehydrogenase-1 (IDH1)-dependent pathway is active in most cell lines under normal culture conditions, but cells grown under hypoxia rely almost exclusively on the reductive carboxylation of glutamine-derived α-ketoglutarate for de novo lipogenesis. Furthermore, renal cell lines deficient in the von Hippel-Lindau tumour suppressor protein preferentially use reductive glutamine metabolism for lipid biosynthesis even at normal oxygen levels. These results identify a critical role for oxygen in regulating carbon use to produce AcCoA and support lipid synthesis in mammalian cells.     

Effect of salinity and planting density on physiological responses of Allenrolfea occidentalis

Physiological responses of Allenrolfea occidentalis to salinity and seedling density were investigated. Effects of salinity (0, 200, 400, 600, 800, and 1000 mM NaCl) and 3 planting densities (2000, 4000, 6000 plants m -2 ) on the growth, survival, and ecophysiology of A. occidentalis , a stem succulent inland halophyte, were studied under controlled greenhouse conditions. Plants were grown in a sand culture using subirrigation. Dry mass of roots was highest at 600 mM NaCl at low density (2000 plants m -2 ), but declined as salinity increased. Tissue water content was highest at the 200 mM NaCl treatment and decreased with increased salinity. Water potential of the plants became more negative with increasing salinity due to the accumulation of NaCl in the leaves. Inorganic ions, especially Na + and Cl - , contributed substantially to dry mass. Na + and Cl - concentration in shoots and roots increased when NaCl level was increased while K + , Ca ++ , Mg ++ , SO 4 -- , and NO 3 - contents decreased. Net photosynthesis increased at low salinity (200 mM), but photosynthesis at other salinities was not significantly different from the control. While A. occidentalis is very salt tolerant and photosynthesis functioned reasonably well at high salinities, extremely high salinity did decrease dry mass of roots and shoots.     

Thallium isotopic evidence for ferromanganese sediments in the mantle source of Hawaiian basalts

Ocean island basalts are generally thought to be the surface expression of mantle plumes, but the nature of the components in the source regions of such mantle plumes is a subject of long-standing debate. The lavas erupted at Hawaii have attracted particular attention, as it has been proposed that coupled 186Os and 187Os anomalies reflect interaction with the Earth's metallic core. It has recently been suggested, however, that such variations could also result from addition of oceanic ferromanganese sediments to the mantle source of these lavas. Here we show that Hawaiian picrites with osmium isotope anomalies also exhibit pronounced thallium isotope variations, which are coupled with caesium/thallium ratios that extend to values much lower than commonly observed for mantle-derived rocks. This correlation cannot be created by admixing of core material, and is best explained by the addition of ferromanganese sediments into the Hawaii mantle source region. However, the lack of correlation between thallium and osmium isotopes and the high thallium/osmium ratios of ferromanganese sediments preclude a sedimentary origin for the osmium isotope anomalies, and leaves core-mantle interaction as a viable explanation for the osmium isotope variations of the Hawaiian picrites.     

Direct observation of ligand recognition by T cells

The activation of T cells through interaction of their T-cell receptors with antigenic peptide bound to major histocompatibility complex (MHC) on the surface of antigen presenting cells (APCs) is a crucial step in adaptive immunity. Here we use three-dimensional fluorescence microscopy to visualize individual peptide-I-E(k) class II MHC complexes labelled with the phycobiliprotein phycoerythrin in an effort to characterize T-cell sensitivity and the requirements for forming an immunological synapse in single cells. We show that T cells expressing the CD4 antigen respond with transient calcium signalling to even a single agonist peptide-MHC ligand, and that the organization of molecules in the contact zone of the T cell and APC takes on the characteristics of an immunological synapse when only about ten agonists are present. This sensitivity is highly dependent on CD4, because blocking this molecule with antibodies renders T cells unable to detect less than about 30 ligands.     

The genome of Cryptosporidium hominis

Cryptosporidium species cause acute gastroenteritis and diarrhoea worldwide. They are members of the Apicomplexa--protozoan pathogens that invade host cells by using a specialized apical complex and are usually transmitted by an invertebrate vector or intermediate host. In contrast to other Apicomplexans, Cryptosporidium is transmitted by ingestion of oocysts and completes its life cycle in a single host. No therapy is available, and control focuses on eliminating oocysts in water supplies. Two species, C. hominis and C. parvum, which differ in host range, genotype and pathogenicity, are most relevant to humans. C. hominis is restricted to humans, whereas C. parvum also infects other mammals. Here we describe the eight-chromosome approximately 9.2-million-base genome of C. hominis. The complement of C. hominis protein-coding genes shows a striking concordance with the requirements imposed by the environmental niches the parasite inhabits. Energy metabolism is largely from glycolysis. Both aerobic and anaerobic metabolisms are available, the former requiring an alternative electron transport system in a simplified mitochondrion. Biosynthesis capabilities are limited, explaining an extensive array of transporters. Evidence of an apicoplast is absent, but genes associated with apical complex organelles are present. C. hominis and C. parvum exhibit very similar gene complements, and phenotypic differences between these parasites must be due to subtle sequence divergence.     

Scientific progress without increasing verisimilitude: In response to Niiniluoto

First, I argue that scientific progress is possible in the absence of increasing verisimilitude in science's theories. Second, I argue that increasing theoretical verisimilitude is not the central, or primary, dimension of scientific progress. Third, I defend my previous argument that unjustified changes in scientific belief may be progressive. Fourth, I illustrate how false beliefs can promote scientific progress in ways that cannot be explicated by appeal to verisimilitude.     

Kuhn vs. Popper on criticism and dogmatism in science: a resolution at the group level

Popper repeatedly emphasised the significance of a critical attitude, and a related critical method, for scientists. Kuhn, however, thought that unquestioning adherence to the theories of the day is proper; at least for ‘normal scientists’. In short, the former thought that dominant theories should be attacked, whereas the latter thought that they should be developed and defended (for the vast majority of the time).Both seem to have missed a trick, however, due to their apparent insistence that each individual scientist should fulfil similar functions (at any given point in time). The trick is to consider science at the group level; and doing so shows how puzzle solving and ‘offensive’ critical activity can simultaneously have a legitimate place in science. This analysis shifts the focus of the debate. The crucial question becomes ‘How should the balance between functions be struck?’     

Intersubjective corroboration

How are we to understand the use of probability in corroboration functions? Popper says logically, but does not show we could have access to, or even calculate, probability values in a logical sense. This makes the logical interpretation untenable, as Ramsey and van Fraassen have argued.If corroboration functions only make sense when the probabilities employed therein are subjective, however, then what counts as impressive evidence for a theory might be a matter of convention, or even whim. So isn’t so-called ‘corroboration’ just a matter of psychology?In this paper, I argue that we can go some way towards addressing this objection by adopting an intersubjective interpretation, of the form advocated by Gillies, with respect to corroboration. I show why intersubjective probabilities are preferable to subjective ones when it comes to decision making in science: why group decisions are liable to be superior to individual ones, given a number of plausible conditions. I then argue that intersubjective corroboration is preferable to intersubjective confirmation of a Bayesian variety, because there is greater opportunity for principled agreement concerning the factors involved in the former.