Magnetic resonance imaging of pH in vivo using hyperpolarized 13C-labelled bicarbonate

As alterations in tissue pH underlie many pathological processes, the capability to image tissue pH in the clinic could offer new ways of detecting disease and response to treatment. Dynamic nuclear polarization is an emerging technique for substantially increasing the sensitivity of magnetic resonance imaging experiments. Here we show that tissue pH can be imaged in vivo from the ratio of the signal intensities of hyperpolarized bicarbonate (H(13)CO(3)(-)) and (13)CO(2) following intravenous injection of hyperpolarized H(13)CO(3)(-). The technique was demonstrated in a mouse tumour model, which showed that the average tumour interstitial pH was significantly lower than the surrounding tissue. Given that bicarbonate is an endogenous molecule that can be infused in relatively high concentrations into patients, we propose that this technique could be used clinically to image pathological processes that are associated with alterations in tissue pH, such as cancer, ischaemia and inflammation.     

A conformationally isoformic thermophilic protein with high kinetic unfolding barriers

The basis for the stability of thermophilic proteins is of fundamental interest for extremophile biology. We investigated the folding and unfolding processes of the homotetrameric Thermoanaerobacter brockii alcohol dehydrogenase (TBADH). TBADH subunits were 4.8 kcal/mol less stable towards guanidinium chloride (GdmCl) unfolding compared to urea, indicating ionic modulation of TBADH stability. Strongly denaturing conditions promoted mono-exponential unfolding kinetics with linear dependence on denaturant concentration. Here TBADH unfolded >40-fold slower when extrapolated from urea as compared to GdmCl unfolding. A marked unfolding hysteresis was shown when comparing refolding and unfolding in urea. An unusual biphasic unfolding trajectory with an exceptionally slow phase at intermediate concentrations of GdmCl and urea was also observed. We advocate that TBADH forms two distinctly different tetrameric isoforms, and likely an ensemble of native states. This unusual supramolecular folding behavior has been shown responsible for formation of amyloidotic yeast prion strains and can have functional importance for TBADH. Received 9 November 2007; received after revision 19 December 2007; accepted 8 January 2008     

Duplication of FGF3, FGF4, FGF19 and ORAOV1 causes hair ridge and predisposition to dermoid sinus in Ridgeback dogs

The dorsal hair ridge in Rhodesian and Thai Ridgeback dogs is caused by a dominant mutation that also predisposes to the congenital developmental disorder dermoid sinus. Here we show that the causative mutation is a 133-kb duplication involving three fibroblast growth factor (FGF) genes. FGFs play a crucial role in development, suggesting that the ridge and dermoid sinus are caused by dysregulation of one or more of the three FGF genes during development.     

A novel class II MHC molecule with unusual tissue distribution.

The repertoire of mature class II-restricted T cells is generated through a complex process of selection whereby early T cells confront class II molecules in the thymus, especially on epithelial cells. Expression of class II molecules on such cells is prominent both in the cortex and in the medulla. We have identified a novel class II molecule, H-20, which is expressed only in epithelial cells of the thymic medulla and in B cells. The unusual tissue distribution and the nonpolymorphic nature of H-20 suggest that its function is different from that of classical class II molecules.     

A major difference between transdetermination and homeosis

IN Drosophila, the adult structures arise from nests of larval cells called imaginal disks, whose state of determination with respect to disk type is usually fixed. However, two processes are known which can change determination from one disk type to another; one occurs in situ and is due to homeotic mutations, and the other is seen after culture of disk material and is called transdetermination. Similarities between the two, notably the lack of intermediate states, have led to the idea that they are different aspects of the same phenomenon(1,2). The existence of homeotic mutations argues that determination in normal development is underlain by a genetic switching mechanism(3,4); transdetermination could result from epigenetic changes in this system. If this is so then the two phenomena should have characteristics in common. Studies of homeotic mutants have shown that a structure in one disk is always transformed into a specific structure from the other disk(5,6); for example clones of bithorax in an anterior dorsal position in the haltere show anterior dorsal wing structures(5). This is used as a criterion of homology, and also indicates that all disks use the same positional information(7). Differences between disks must be due to different interpretation of this information, mediated in some way by the wild-type alleles of the homeotic genes. It is not yet known whether transdetermination also shows position-specific transformation; if the two phenomena are closely related then this should be the case. It is often assumed to be so, because there have been reports of transdetermination between leg and antenna in which structures such as claw and arista, thought from homeotic mutants to be homologous, are found adjacent to one another in implants(1). However, these findings could also be explained by non-homologous transdetermination followed by either movement together of homologous structures due to preferential cell affinities, or intercalary regeneration between the non-homologous structures. Also, regeneration before transdetermination can give misleading results. One cannot simply ask to what structures a given disk fragment will transdetermine as the fragment might regenerate the rest of the disk first, and non-regenerating (that is duplicating) fragments do not appear to transdetermine (unpublished observations, and ref. 8). One solution to these problems is to find a disk in which transdetermination occurs only in one part, and this is the case in the foreleg disk. The experiments reported here were designed to find whether this part transdetermines to a homologous part of the wing disk.     

Temporal evolution of the electric field accelerating electrons away from the auroral ionosphere.

The bright night-time aurorae that are visible to the unaided eye are caused by electrons accelerated towards Earth by an upward-pointing electric field. On adjacent geomagnetic field lines the reverse process occurs: a downward-pointing electric field accelerates electrons away from Earth. Such magnetic-field-aligned electric fields in the collisionless plasma above the auroral ionosphere have been predicted, but how they could be maintained is still a matter for debate. The spatial and temporal behaviour of the electric fields-a knowledge of which is crucial to an understanding of their nature-cannot be resolved uniquely by single satellite measurements. Here we report on the first observations by a formation of identically instrumented satellites crossing a beam of upward-accelerated electrons. The structure of the electric potential accelerating the beam grew in magnitude and width for about 200 s, accompanied by a widening of the downward-current sheet, with the total current remaining constant. The 200-s timescale suggests that the evacuation of the electrons from the ionosphere contributes to the formation of the downward-pointing magnetic-field-aligned electric fields. This evolution implies a growing load in the downward leg of the current circuit, which may affect the visible discrete aurorae.     

Bonding and reactivity at oxide mineral surfaces from model aqueous complexes

The kinetic stability of oxide surfaces affects a broad range of physical phenomena, including mineral dissolution and sorption reactions, stable-isotope fractionation, and catalyst support degradation. Our knowledge of the rates of these processes derives mostly from the rates of net mass transfer between the bulk solid and fluid phases. But from such data it is difficult to determine rates of elementary steps that are needed to test theoretical models. Here we determine the rates of oxygen exchange between an aqueous fluid and specific sites on the 'Al13' polyoxocation--AlO4Al12(OH)24(H2O)12(7+)--the structure of which closely resembles the surfaces of some Al-(hydr)oxide minerals in soils and catalyst supports. Extrapolation of these data to 298 K (and near pH 5.3) yields half-lives for oxygen on the complex that range from approximately 0.6 milliseconds for bound water to 41 seconds and 13 hours for the two distinct, but structurally similar, bridging hydroxyls. This surprisingly large range of labilities (approximately 10(7)) indicates that reactivity is very sensitive to molecular structure. Moreover, these results indicate that well chosen aqueous complexes provide important information to relate bonding to reactivity at mineral surfaces.