The protective effect of small amounts of selenite in sublimate intoxication

Résumé L'injection de très petites quantités de sélénite de sodium, administrées simultanément ou 1 h après l'intoxication par le sublimé corrosif, en abaisse considérablement la toxicité: les rats blancs intoxiqués par une dose létale de sublime corrosif survivent sous l'effet du sélénite dans un % important et les lésions typiques des reins et d'autres organes n'apparaissent pas.     

SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout

Uric acid is the end product of purine metabolism in humans and great apes, which have lost hepatic uricase activity, leading to uniquely high serum uric acid concentrations (200-500 microM) compared with other mammals (3-120 microM). About 70% of daily urate disposal occurs via the kidneys, and in 5-25% of the human population, impaired renal excretion leads to hyperuricemia. About 10% of people with hyperuricemia develop gout, an inflammatory arthritis that results from deposition of monosodium urate crystals in the joint. We have identified genetic variants within a transporter gene, SLC2A9, that explain 1.7-5.3% of the variance in serum uric acid concentrations, following a genome-wide association scan in a Croatian population sample. SLC2A9 variants were also associated with low fractional excretion of uric acid and/or gout in UK, Croatian and German population samples. SLC2A9 is a known fructose transporter, and we now show that it has strong uric acid transport activity in Xenopus laevis oocytes.     

Digoxin and ouabain increase the synthesis of cholesterol in human liver cells

Digoxin and ouabain are steroid drugs that inhibit the Na⁺/K⁺-ATPase, and are widely used in the treatment of heart diseases. They may also have additional effects, such as on metabolism of steroid hormones, although until now no evidence has been provided about the effects of these cardioactive glycosides on the synthesis of cholesterol. Here we report that digoxin and ouabain increased the synthesis of cholesterol in human liver HepG2 cells, enhancing the activity and the expression of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the rate-limiting enzyme of the cholesterol synthesis. This effect was mediated by the binding of the sterol regulatory element binding protein-2 (SREBP-2) to the HMGCR promoter, and was lost in cells silenced for SREBP-2 or loaded with increasing amounts of cholesterol. Digoxin and ouabain competed with cholesterol for binding to the SREBP-cleavage-activating protein, and are critical regulators of cholesterol synthesis in human liver cells. Received 10 January 2009; received after revision 11 February 2009; accepted 6 March 2009     

皮秒Nd:YAG激光对生物金属纯Ti和Ti–13Nb–13Zr合金的表面改性

The effects of picosecond Nd:YAG laser irradiation on chemical and morphological surface characteristics of the commercially pure titanium and Ti–13Nb–13Zr alloy in air and argon atmospheres were studied under different laser output energy values. During the interaction of laser irradiation with the investigated materials, a part of the energy was absorbed on the target surface, influencing surface modifications. Laser beam interaction with the target surface resulted in various morphological alterations, resulting in crater formation and the presence of microcracks and hydrodynamic structures. Moreover, different chemical changes were induced on the target materials’ surfaces, resulting in the titanium oxide formation in the irradiation-affected area and consequently increasing the irradiation energy absorption. Given the high energy absorption at the site of interaction, the dimensions of the surface damaged area increased. Consequently, surface roughness increased. The appearance of surface oxides also led to the increased material hardness in the surface-modified area. Observed chemical and morphological changes were pronounced after laser irradiation of the Ti–13Nb–13Zr alloy surface.     

Resource competition and social conflict in experimental populations of yeast

Understanding the conditions that promote the maintenance of cooperation is a classic problem in evolutionary biology. The essence of this dilemma is captured by the 'tragedy of the commons': how can a group of individuals that exploit resources in a cooperative manner resist invasion by 'cheaters' who selfishly use common resources to maximize their individual reproduction at the expense of the group? Here, we investigate this conflict through experimental competitions between isogenic cheater and cooperator strains of yeast with alternative pathways of glucose metabolism, and by using mathematical models of microbial biochemistry. We show that both coexistence and competitive exclusion are possible outcomes of this conflict, depending on the spatial and temporal structure of the environment. Both of these outcomes are driven by trade-offs between the rate and efficiency of conversion of resources into offspring that are mediated by metabolic intermediates.     

Cataract induced by administration of a single dose of sodium selenite to suckling rats

Summary A single dose of sodium selenite to male suckling rats causes permanent or intermittent cataracts. The resistance to the lethal effect of selenite in suckling rats is significantly higher in comparison with adult animals.     

The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers

Colorectal tumours that are wild type for KRAS are often sensitive to EGFR blockade, but almost always develop resistance within several months of initiating therapy. The mechanisms underlying this acquired resistance to anti-EGFR antibodies are largely unknown. This situation is in marked contrast to that of small-molecule targeted agents, such as inhibitors of ABL, EGFR, BRAF and MEK, in which mutations in the genes encoding the protein targets render the tumours resistant to the effects of the drugs. The simplest hypothesis to account for the development of resistance to EGFR blockade is that rare cells with KRAS mutations pre-exist at low levels in tumours with ostensibly wild-type KRAS genes. Although this hypothesis would seem readily testable, there is no evidence in pre-clinical models to support it, nor is there data from patients. To test this hypothesis, we determined whether mutant KRAS DNA could be detected in the circulation of 28 patients receiving monotherapy with panitumumab, a therapeutic anti-EGFR antibody. We found that 9 out of 24 (38%) patients whose tumours were initially KRAS wild type developed detectable mutations in KRAS in their sera, three of which developed multiple different KRAS mutations. The appearance of these mutations was very consistent, generally occurring between 5 and 6 months following treatment. Mathematical modelling indicated that the mutations were present in expanded subclones before the initiation of panitumumab treatment. These results suggest that the emergence of KRAS mutations is a mediator of acquired resistance to EGFR blockade and that these mutations can be detected in a non-invasive manner. They explain why solid tumours develop resistance to targeted therapies in a highly reproducible fashion.     

High star formation rates as the origin of turbulence in early and modern disk galaxies

Observations of star formation and kinematics in early galaxies at high spatial and spectral resolution have shown that two-thirds are massive rotating disk galaxies, with the remainder being less massive non-rotating objects. The line-of-sight-averaged velocity dispersions are typically five times higher than in today's disk galaxies. This suggests that gravitationally unstable, gas-rich disks in the early Universe are fuelled by cold, dense accreting gas flowing along cosmic filaments and penetrating hot galactic gas halos. These accreting flows, however, have not been observed, and cosmic accretion cannot power the observed level of turbulence. Here we report observations of a sample of rare, high-velocity-dispersion disk galaxies in the nearby Universe where cold accretion is unlikely to drive their high star formation rates. We find that their velocity dispersions are correlated with their star formation rates, but not their masses or gas fractions, which suggests that star formation is the energetic driver of galaxy disk turbulence at all cosmic epochs.     

Temozolomide down-regulates P-glycoprotein in human blood–brain barrier cells by disrupting Wnt3 signaling

Low delivery of many anticancer drugs across the blood–brain barrier (BBB) is a limitation to the success of chemotherapy in glioblastoma. This is because of the high levels of ATP-binding cassette transporters like P-glycoprotein (Pgp/ABCB1), which effluxes drugs back to the bloodstream. Temozolomide is one of the few agents able to cross the BBB; its effects on BBB cells permeability and Pgp activity are not known. We found that temozolomide, at therapeutic concentration, increased the transport of Pgp substrates across human brain microvascular endothelial cells and decreased the expression of Pgp. By methylating the promoter of Wnt3 gene, temozolomide lowers the endogenous synthesis of Wnt3 in BBB cells, disrupts the Wnt3/glycogen synthase kinase 3/β-catenin signaling, and reduces the binding of β-catenin on the promoter of mdr1 gene, which encodes for Pgp. In co-culture models of BBB cells and human glioblastoma cells, pre-treatment with temozolomide increases the delivery, cytotoxicity, and antiproliferative effects of doxorubicin, vinblastine, and topotecan, three substrates of Pgp that are usually poorly delivered across BBB. Our work suggests that temozolomide increases the BBB permeability of drugs that are normally effluxed by Pgp back to the bloodstream. These findings may pave the way to new combinatorial chemotherapy schemes in glioblastoma.     

Understanding the limits to generalizability of experimental evolutionary models

Given the difficulty of testing evolutionary and ecological theory in situ, in vitro model systems are attractive alternatives; however, can we appraise whether an experimental result is particular to the in vitro model, and, if so, characterize the systems likely to behave differently and understand why? Here we examine these issues using the relationship between phenotypic diversity and resource input in the T7-Escherichia coli co-evolving system as a case history. We establish a mathematical model of this interaction, framed as one instance of a super-class of host-parasite co-evolutionary models, and show that it captures experimental results. By tuning this model, we then ask how diversity as a function of resource input could behave for alternative co-evolving partners (for example, E. coli with lambda bacteriophages). In contrast to populations lacking bacteriophages, variation in diversity with differences in resources is always found for co-evolving populations, supporting the geographic mosaic theory of co-evolution. The form of this variation is not, however, universal. Details of infectivity are pivotal: in T7-E. coli with a modified gene-for-gene interaction, diversity is low at high resource input, whereas, for matching-allele interactions, maximal diversity is found at high resource input. A combination of in vitro systems and appropriately configured mathematical models is an effective means to isolate results particular to the in vitro system, to characterize systems likely to behave differently and to understand the biology underpinning those alternatives.